A Scoping Review of Codeine Use, Misuse and

A Scoping
Review of
Codeine Use,
Misuse and
Dependence
Marie Claire van Hout
Michael Bergin
Michelle Foley
Eileen Rich
Anna Izabela Rapca
Richard Harris
Ian Norman
1
Address for correspondence:
Dr Marie Claire van Hout
School of Health Sciences
Waterford Institute of Technology
Cork Road
Waterford
Ireland
Email: mcvanhout@wit.ie
This report should be referenced as follows:
Van Hout, MC. Bergin, M. Foley, M. Rich, E. Rapca, AI. Harris, R. Norman I.
(2014) A Scoping Review of Codeine Use, Misuse and Dependence, final
report. CODEMISUSED Project European Commission 7th Framework
Programme, EU. Brussels.
Copyright information:
This report may be freely reproduced for the purposes of private research and
study. Extracts may be included in professional journals provided that suitable
acknowledgement is made and that the reproduction is not associated with
any form of advertising. Application for commercial reproduction should be
made to the CODEMISUSED Project, European Commission, 7th Framework,
EU. Brussels.
Disclaimer:
This report presents an independent review commissioned by the EU. The
views and opinions expressed by the authors in this publication are those of
the authors and do not necessarily reflect those of the European Commission,
7th Framework, EU Brussels.
Funding Acknowledgement The research leading to these results has
received funding from the European Community's Seventh Framework
Programme FP7/2007-2013 under grant agreement no 611736.
List of authors:
Marie Claire van Hout, School of Health Sciences, Waterford Institute of
Technology, Waterford, Ireland
Michael Bergin, School of Health Sciences, Waterford Institute of Technology,
Waterford, Ireland
Michelle Foley, School of Health Sciences, Waterford Institute of Technology,
Waterford, Ireland
Eileen Rich, Alcohol, Tobacco and Other Drug Research Unit, South African.
Medical Research Council, Pretoria, South Africa
Anna Izabela Rapca, H.I. Weldrick Ltd, Doncaster, United Kingdom
Richard Harris, H.I. Weldrick Ltd, Doncaster, United Kingdom
Ian Norman, Kings College London, Florence Nightingale School of Nursing &
Midwifery, London, United Kingdom
2
Table of Contents
LIST OF FIGURES ................................................................................................................................ 6
LIST OF TABLES .................................................................................................................................. 6
GLOSSARY OF SIGNIFICANT TERMS AND ABBREVIATIONS ............................................... 7
EXECUTIVE SUMMARY .................................................................................................................... 9
BACKGROUND ...................................................................................................................................... 9
AIM AND OBJECTIVES: ....................................................................................................................... 11
METHODS ........................................................................................................................................... 11
RESULTS ............................................................................................................................................. 12
(1) Production, manufacture, consumption and regulation of codeine ................. 12
(2) Prevalence of codeine use, misuse and dependence and associated risk
factors ......................................................................................................................................... 12
(3) Use and efficacy of codeine within healthcare practice ....................................... 13
(4) Consequences of codeine use, misuse and dependence ................................... 14
(5) Prevention of codeine misuse and dependence .................................................... 15
(6) Interventions and treatment for codeine misuse ................................................... 15
(7) Conclusions and implications for practice, policy and research ...................... 15
RAISING AWARENESS ......................................................................................................................... 15
DETECTING AND MANAGING RISK ..................................................................................................... 17
DISPENSING PRACTICES...................................................................................................................... 18
MONITORING AND SURVEILLANCE OF CODEINE ................................................................................. 19
RECOMMENDATIONS FOR FUTURE RESEARCH .................................................................................... 19
PATTERNS OF USE, MISUSE AND DEPENDENCE .................................................................................. 20
PREVALENCE ...................................................................................................................................... 20
TREATMENT/INTERVENTIONS ............................................................................................................. 21
RISK ................................................................................................................................................... 22
EPIDEMIOLOGY................................................................................................................................... 23
POLICY ............................................................................................................................................... 23
CHAPTER 1 ......................................................................................................................................... 24
INTRODUCTION ................................................................................................................................ 24
1.1 CODEINE ....................................................................................................................................... 25
1.1.1 Available Formulations........................................................................................................ 25
1.1.2 Pharmacodynamics and Pharmacokinetics ......................................................................... 29
1.2 USE OF CODEINE WITHIN NORMAL MEDICAL PRACTICE............................................................... 31
1.2 1 Use in Adults ........................................................................................................................ 31
1.2.2 Use in Children .................................................................................................................... 31
1.2.3 Use in Pregnancy and Lactation .......................................................................................... 33
1.2.4 Use in Older People ............................................................................................................. 34
1.2.5 Use in the treatment of opiate dependence .......................................................................... 34
1.3 DIVERSIONARY USE OF CODEINE OUTSIDE OF NORMAL MEDICAL PRACTICE............................... 35
1.3.1 Non Medicinal and Recreational use of Codeine ................................................................. 35
1.3.2 Tampering with codeine containing pharmaceuticals ......................................................... 35
1.3.3 Home produced drugs made from codeine .......................................................................... 36
1.4 COMMON SIDE EFFECTS OF CODEINE ............................................................................................. 38
1.4.1 Opioid Side Effects ............................................................................................................... 38
1.4.2 Tolerance and Dependence .................................................................................................. 39
1.4.3 Non-Opioid Side Effects ....................................................................................................... 40
1.5 THE PROBLEM OF CODEINE MISUSE ............................................................................................... 41
1.6 MISUSE, ABUSE AND DEPENDENCE .............................................................................................. 42
1.6.1 Terminology ......................................................................................................................... 42
1.6.2 Characteristics of codeine misusers ..................................................................................... 45
1.6.3 Factors leading to misuse of codeine ................................................................................... 47
1.6.5 Behavioural indicators of codeine misuse ........................................................................... 48
1.7 CONCLUSION ................................................................................................................................ 48
3
CHAPTER 2 ......................................................................................................................................... 49
METHODS............................................................................................................................................ 49
2.1 INTRODUCTION ............................................................................................................................. 49
2.2 APPROACH .................................................................................................................................... 49
2.3 METHODS ..................................................................................................................................... 49
2.4 RESULTS OF THE SEARCH .............................................................................................................. 52
2.5 CONCLUSION ................................................................................................................................ 53
CHAPTER 3 ......................................................................................................................................... 54
PRODUCTION, MANUFACTURE, CONSUMPTION AND REGULATION OF CODEINE ... 54
3.1 INTRODUCTION ............................................................................................................................. 54
3.1.1 Definition of terms ............................................................................................................... 54
3.2 GLOBAL STOCKS AND REQUIREMENTS .......................................................................................... 54
3.3 GLOBAL CONSUMPTION ................................................................................................................ 56
3.4 GLOBAL MANUFACTURE, EXPORTS AND IMPORTS ......................................................................... 57
3.5 CODEINE UTILISATION .................................................................................................................. 59
3.5.1 Utilisation, exports, imports and stocks of codeine in Ireland, South Africa and UK ......... 60
3.6 OVER-THE- COUNTER CONSUMPTION OF CODEINE PREPARATIONS ............................................... 63
3.7 REGULATION OF CODEINE ............................................................................................................ 64
CHAPTER 4 ......................................................................................................................................... 71
PREVALENCE RATES OF CODEINE USE, MISUSE AND DEPENDENCE AND
ASSOCIATED RISK FACTORS ....................................................................................................... 71
4.1 INTRODUCTION ............................................................................................................................. 71
4.2 PREVALENCE OF CODEINE USE ...................................................................................................... 71
4.2.1 Codeine related deaths......................................................................................................... 74
4.2.2 Misuse of Codeine Cough Syrups ........................................................................................ 75
4.2.3 Codeine use in pregnancy .................................................................................................... 77
4.2.4 Pain ...................................................................................................................................... 77
4.2.5 Recreational Use .................................................................................................................. 78
4.2.5 Illicit drug use ...................................................................................................................... 79
4.3 CONCLUSION ................................................................................................................................ 80
CHAPTER 5 ......................................................................................................................................... 81
USE AND EFFICACY OF CODEINE WITHIN HEALTHCARE PRACTICE ........................... 81
5.1 INTRODUCTION ............................................................................................................................. 81
5.2 POST-OPERATIVE TREATMENT ...................................................................................................... 82
5.3 CHRONIC PAIN .............................................................................................................................. 83
5.4 OPIATE REPLACEMENT TREATMENT.............................................................................................. 83
5.5 CHILDREN AND BREASTFEEDING .................................................................................................. 84
5.6 FREQUENCY OF CODEINE PRESCRIBING VERSUS OTHER ANALGESICS ............................................ 85
5.7 MOTIVES FOR MISUSE OF CODEINE ............................................................................................... 86
5.8 CONCLUSION ................................................................................................................................ 86
CHAPTER 6 ......................................................................................................................................... 88
CONSEQUENCES OF CODEINE USE, MISUSE AND DEPENDENCE ..................................... 88
6.1 INTRODUCTION ............................................................................................................................. 88
6.2 IMPAIRMENT ................................................................................................................................. 88
6.3 INJURY .......................................................................................................................................... 89
6.4 ADVERSE HEALTH EFFECTS........................................................................................................... 90
6.5 DEPENDENCE ................................................................................................................................ 93
6.6 CONCLUSION ................................................................................................................................ 95
CHAPTER 7 ......................................................................................................................................... 96
PREVENTION OF CODEINE MISUSE, ABUSE AND DEPENDENCE ...................................... 96
7.1 INTRODUCTION ............................................................................................................................. 96
4
7.2 MEDICAL PRACTICE AND PHARMACOVIGILANCE ......................................................................... 96
7.2.1 Co-prescribing and effects on health ................................................................................... 97
7.2.2 Pain ...................................................................................................................................... 97
7.2.3 Prescription drug monitoring .............................................................................................. 97
7.2.4 Screening ............................................................................................................................. 98
7.2.5 Clinical presentations of injecting use of home produced drug solutions ........................... 99
7.3 PHARMACY PRACTICE AND PREVENTATIVE STRATEGIES ........................................................... 100
7.3.1 Pharmacy Preventative Strategies ..................................................................................... 101
7.4 CONCLUSION .............................................................................................................................. 103
CHAPTER 8 ....................................................................................................................................... 104
INTERVENTIONS/TREATMENT AND CODEINE DEPENDENCE ........................................ 104
8.1 INTRODUCTION ........................................................................................................................... 104
8.2 EXTRACTABILITY RATING SYSTEM (ERS) .................................................................................. 104
8.3 HARM-MINIMISATION INTERVENTION MODEL ........................................................................... 104
8.4 ASSESSMENT AND MANAGEMENT OF CODEINE DEPENDENCE .................................................... 106
8.5 BARRIERS TO TREATMENT COMPLETION .................................................................................... 108
8.6 CONCLUSION .............................................................................................................................. 109
CHAPTER 9 ....................................................................................................................................... 110
CONCLUSIONS AND IMPLICATIONS FOR PRACTICE, POLICY AND RESEARCH ....... 110
9.1 INTRODUCTION ........................................................................................................................... 110
9.2 IMPROVED UNDERSTANDING AND PHARMACOVIGILANCE .......................................................... 110
9.3 KEY RECOMMENDATIONS: .......................................................................................................... 111
9.3.1 Raising Awareness ............................................................................................................. 111
9.3.2 Detecting and Managing Risk ............................................................................................ 112
9.3.3 Dispensing Practices.......................................................................................................... 113
9.3.4 Monitoring and Surveillance of Codeine ........................................................................... 114
9.4 RECOMMENDATIONS FOR FUTURE RESEARCH ............................................................................ 115
9.4 1 Patterns of Use, Misuse and Dependence .......................................................................... 115
9.4.2 Prevalence.......................................................................................................................... 116
9.4.3 Treatment/Interventions ..................................................................................................... 116
9.4.4 Risk..................................................................................................................................... 118
9.4.5 Epidemiology ..................................................................................................................... 118
9.4.6 Policy ................................................................................................................................. 118
9.5 LIMITATIONS OF THE REVIEW ..................................................................................................... 119
REFERENCES ................................................................................................................................... 120
APPENDIX 1CHARACTERISTICS OF THE RESEARCH STUDIES INCLUDED IN THE
REVIEW ............................................................................................................................................. 149
5
List of Figures
Figure 1.1 Chemical Structure of Codeine Base
Figure 2.1
Framework utilised in the scoping review (Arskey & O’Malley
2005)
Figure 2.2
Flow diagram of articles included and excluded in the scoping
review
Figure 3.1
Major stockists (countries) of codeine 2010-2011
Figure 3.2
Global consumption of codeine 2007-2011
Figure 3.3
Global manufacture of codeine in 2011 (tonnes)
Figure 3.4
Codeine Exports
Figure 3.5
Codeine Imports
Figure 3.6
Utilisation
of
codeine
preparations
for
manufacture
of
preparations
Figure 3.7
Quantity utilized for manufacture of preparation 2008-2012
Figure 3.8
Quantity utilized for the manufacture of other drug (UK 20082012)
Figure 3.9
Imports of Codeine 2008-2012
Figure 3.10 Exports of codeine 2008 - 2012
Figure 3.11 Codeine Stocks 2008-2012
List of Tables
Table 1.1
Codeine preparations listed in the British National Formulary No
66 September 2013
Table 1.2
Examples of Codeine Containing Medicines available Over-theCounter in the UK
Table 1.3
CYP2D6 phenotypes by ethnicity {Iedema, 2011 #143;Madadi,
2008 #345;Actavis, 2014 #520}(Actavis, 2014; Iedema, 2011; Madadi &
Koren, 2008)
Table 2.1
Broad categories used to organise literature included in the
review
Table 3.1
Codeine and dihydocodeine estimated requirements in grams
2013
Table 3.2
The sales of over the counter codeine preparations
Table 3.3
Regulation of codeine, over the counter and prescribed
6
Glossary of Significant Terms and
Abbreviations
Abuse:
‘A pattern of maladaptive substance use that is
associated with recurrent and significant adverse
consequences.’ (DSM-IV, 2000)
Codeine:
The name codeine is derived from the Greek word kodeia
(κώδεια) for ‘poppy head’ and is found naturally in the
poppy plant ‘Papaver somniferum var. album’. Codeine is
a phenanthrene derivative extracted from opium or
produced synthetically by the methylation of morphine.
Codeine or 3-methylmorphine is the most commonly
consumed opiate worldwide and is used for its analgesic,
antitussive and anti-diarrheal properties.
Consumption:
Act of supplying a narcotic drug to any person or
enterprise for retail distribution, medical use or scientific
research.
Dependence:
Substance dependence occurs following prolonged and
sustained exposure to a drug and is defined as: ‘A
compulsive pattern of substance use characterized by a
loss of control over substance use and continued use
despite the significant substance-related problems.’
(DSM-IV, 2000)
Drug:
Substances included in Schedules I or II of the Single
Convention on Narcotic Drugs, 1961 (United Nations),
whether natural or synthetic.
Manufacture:
All processes, other than production (see the definition
below), by which drugs may be obtained and includes
refining as well as the transformation of drugs into other
drugs. Preparation - any mixture, solid or liquid, subject to
international control owing to the fact that it contains a
drug under international control. Preparations listed in
Schedule III of the 1961 Convention are exempted from
some control measures (when compounded with one or
more other ingredients and containing not more than 100
milligrams of the drug per dosage unit and with a
concentration of not more than 2.5 per cent in undivided
preparations).
Misuse:
‘The problematic consumption of a drug where risks and
adverse consequences outweigh the benefits, and which
includes use of codeine with or without prescription,
outside of acceptable medical practice or guidelines, for
7
recreational reasons, when self-medicating, with higher
doses and for longer than advisable’. (Casati, Sedefov, &
Pfeiffer-Gerschel, 2012)
Production:
Refers to the separation of opium, coca leaves, cannabis
and cannabis resin from the plants from which they are
obtained.
Stocks:
Amounts of drugs held in a country or territory for
domestic consumption, manufacture of other drugs or
export
APA
American Psychiatric Association
CDSCO
Central Drug Standards Control Organisation (India)
DSM
Diagnostic Statistical Manual
EC
European Community
EMA
European Medicines Agency
EMCDDA
European Monitoring Centre for Drugs and Drug Abuse
FDA
The Federal Drugs Agency USA
NHS
National Health Service UK
ICD-10
International Classification of Diseases
INCB:
International Narcotics Control Board
LGBT
Lesbian, Gay, Bisexual and Transgender
NICE
National Institute for Health and Clinical Excellence
PRAC
Pharmacovigilance Risk Assessment Committee
UNODC
United Nations Office on Drugs and Crime
UK
United Kingdom
US
United States of America
WHO
World Health Organisation
8
Executive Summary
Background
Little is known about the extent of misuse of opioid analgesic medications in
both the European Community (EC) and global context (Casati et al., 2012;
UNODC 2011). Prescribed opioid analgesics are dispensed legally to patients
for treatment of symptoms such as pain, cough and diarrhoea, and are also
widely available and accessible to the public in over the counter preparations.
Increased purchases of over-the-counter analgesics without medical
consultation have resulted in increased use of potentially habit-forming
substances (Peterson, 2005).
Misuse of prescribed and over the counter opioid analgesic medication 1, is
driven by a host of factors which include pharmaceutical marketing tactics,
inappropriate and increased prescribing, access to licit and illicit drug
sourcing, government drug policies, public misconceptions around safety,
social influences, self-medication of emotional and physical pain and
recreational popularity (Alexander, Mohajir, & Meltzer, 2005; Daniulaityte,
Carlson, & Kenne, 2006; Maxwell, 2011; Ling, Mooney, & Hillhouse, 2011;
Nosyk, Marshall, Fischer, Montaner, Wood, & Kerr, 2012; UNODC, 2011;
UNODC, 2013). The patients and pharmacy customers misusing these
medications are frequently not identified and their reasons for non-compliant
medicinal use, overuse and intentional misuse for euphoric and other effects
are not well understood, despite development of tolerance, misuse, excessive
use, poly use of other medications and illicit drugs, and resultant adverse
health consequences (Benyamin et al., 2008; Manchikanti & Singh; 2008,
Nielsen, Cameron, & Pahoki, 2010). However, behavioural indicators of
misuse of over the counter opioid analgesics include requesting certain drugs,
hoarding of medications, use of multiple doctors and pharmacies, forging
prescriptions, selling prescription opioids, stealing prescription opioids from
other patients, injecting formulations, sourcing on the street, concurrent abuse
of other licit and illicit drugs, multiple unsanctioned dose escalations, and
repeated lost or stolen prescriptions (UNODC, 2011).
One such opioid analgesic medication which is of public health concern is the
common weak opioid, codeine or 3-methylmorphine which is widely and
frequently consumed worldwide for its analgesic, antitussive and antidiarrhoeal properties. It is a listed narcotic drug under international control and
is regulated by the medicine regulatory authority in individual countries. Pure
codeine is listed under Schedule II, of the Single Convention on Narcotic
Drugs, 1961. However, most codeine preparations are classified under
Schedule III and are pharmacy controlled with a medical prescription required.
Under Schedule III there is no requirement to keep controlled registers.
1
Drugs available from pharmaceutical sources, i.e. manufactured by the pharmaceutical industry or made up by a
pharmacist. Caffeine, antihistamines, codeine (an opiate) and alcohol are the most common psychoactive
constituents of over-the-counter drugs.
9
Globally, the demand for codeine remains high and has risen by
approximately 27% over the last decade. Recent reported figures estimate
that global purchasing reached an all-time high at 269 tonnes in 2011
compared to 164 tonnes in 1992 (INCB 2012). Codeine products can be
purchased on prescription from a medical or dental health professional and
over the counter in pharmacies (Moore, Collins, Carroll, McQuay, & Edwards,
1998). In some countries codeine preparations are available without
prescription in combination preparations (paracetamol, ibuprofen or aspirin)
from licensed pharmacies and in retail outlets. Over the counter sales of
products containing codeine generally must be supervised by the pharmacist.
However, the regulation and control of codeine dispensing varies between
countries with some restricting the visual display and advertisement of over
the counter codeine preparations to the consumer. The amount of over the
counter sales of codeine containing medications is not easy to determine due
to trade exemptions and because disclosure of information might prejudice
the commercial interests of any person or public authority, but there is little
doubt that it forms a substantial proportion of pharmacy sales.
Contemporary research has underscored the need for ‘increased pharmacovigilance’ around codeine prescribing and over the counter dispensing.
Deregulation of codeine has contributed to increased patient or customer
consumerism, self-medication, as well as pharmacist empowerment around
codeine supply over the counter (Albsoul-Younes, Wazaify, Yousef, &
Tahaineh, 2010; Francis, Barnett, & Denha, 2005). As a result, efforts to
quantify levels of misuse in the public and the impact of associated adverse
health consequences remain problematic. Its opioid analgesic effect and
potential risk of development of tolerance within a short timeframe of regular
or excessive use contributes to potential misuse and dependence (Sproule,
Busto, Somer, Romach, & Sellers, 1999). Of note is that individuals vary in
their metabolism of codeine, estimation of safe dosages, reasons for use
(misuse) of codeine and dependence potential.
Inappropriate use, misuse and abuse of codeine take a variety of forms. It can
include individuals: using codeine and exceeding recommended doses and
treatment duration; becoming dependent on codeine for medical reasons;
using codeine to stave off opioid withdrawals; using codeine for its euphoric
effects; or extracting from codeine based pharmaceuticals to manufacture
homemade opiates such as desomorphine.
Codeine consumption and the appropriate use of codeine is a matter of public
health concern, but little is known about codeine use, misuse and
dependence as situated within medical, pharmacy and addiction treatment
practice. Thus the need for this scoping review which examines the evidence
in relation to the use, misuse and dependence of over the counter and
prescribed codeine products. The evidence in relation to codeine regulation,
prevalence rates, associated risk factors, consequences of use and misuse,
prevention strategies and treatment options are explored. Recommendations
for practice and policy and areas for further research are offered.
10
Aim and Objectives:
The aim of this scoping review is to report what is known about the regulation,
production, distribution, prevalence, consequences and prevention in relation
to the use, misuse and dependence of codeine in the partner countries
(Ireland, UK, South Africa), across the EU and internationally and to identify
gaps in the evidence base.
Specific objectives are:
 To map the existing literature examining codeine use, misuse and
dependence.
 To identify gaps in the evidence base and make recommendations for
future research.
 To make recommendations for practice and policy to promote improved
understanding and awareness of codeine misuse and dependence.
 To provide an overview of the healthcare system, prescribing of
codeine and addiction treatment in the three partner countries 2 and
presented as supplementary appendix to this report.
Methods
The scoping review was guided by Arksey & O’Malley’s (2005) six stage
framework and was conducted by a team of researchers from academic and
pharmacy practice backgrounds that were recruited to the CODEMISUSED
project. A broad search was conducted in order to achieve a comprehensive
scope of the field (Daudt, van Mossel, & Scott. 2013). Databases searched
included PubMed, EBSCO Host, Science Direct, EMBASE, PsycINFO,
Cochrane library and Medline from 1994 to 2014. Follow up search strategies
included hand searching of pharmaceutical, health, medical and drug related
websites, and contacting key organisations such as the World Health
Organisation (WHO), International Narcotics Control Board (INCB), European
Medicines Agency (EMA), European Monitoring Centre for Drugs and Drug
Abuse (EMCDDA), authorised medicine boards in each of the European
membered states, The Federal Drugs Agency (FDA) USA, the Canadian
Pharmacy Authority, and the National Health Service (NHS) in the UK.
A spreadsheet was created to chart relevant data (data collection categories
included author, setting, study aim and design/intervention, sample size, and
results/outcomes), to enable the identification of commonalities, themes, and
gaps in the literature. No restrictions were placed on inclusion so long as the
article reported the results of research (collecting empirical data) or other
systematic enquiry into the use or misuse of codeine. Inclusion criteria were
established prior to the search and are reported in Chapter 2. Two reviewers
independently screened titles and abstracts to determine inclusion status. A
second screen of the full-text of each article, again by two independent
reviewers, ensured that the studies were relevant to the focus of the review
and, through a charting exercise (as per Levac, Colquhoun, & O’Brien, 2010),
2
This objective is addressed in: 2Foley et al. (2014) Codeine consumption through prescribing in the Republic of
Ireland, the Republic of South Africa and the United Kingdom, Supplement to the CODEMISUSED Scoping Review,
CODEMISUSED Project, Funded by the European Commission 7th Framework Programme
11
identified the specific areas of the review to which they could contribute and
extracted article data manually into a database. Disagreements were resolved
through discussion.
A stakeholder consultation stage from addiction, nursing, psychiatry,
psychology, health, pharmacy, drug control and pharmacovigilant
backgrounds (Arksey & O’ Malley, 2005; Daudt et al., 2013; Levac et al. 2010)
with CODEMISUSED partners and the CODEMISUSED Expert Panel was
undertaken and contributed to extraction of multifaceted perspectives from the
extant literature on codeine throughout the review process.
Results
The findings are presented under seven headings: (1) Production,
manufacture consumption and regulation of codeine; (2) Prevalence of
codeine use, misuse and dependence and associated risk factors; (3) Use
and efficacy of codeine within healthcare; (4) Consequences of codeine use,
misuse and dependence; (5) Prevention of codeine misuse, abuse and
dependence; (6) Interventions/treatment and codeine dependence and (7)
Conclusions and implications for practice, policy and research.
(1) Production, manufacture, consumption and regulation of
codeine
Globally, the demand for codeine remains high and has risen by
approximately 27% over the last decade (INCB, 2012). Recent INCB figures
demonstrate that global consumption reached an all-time high in 2011 at 269
tonnes. Both exports and manufacture of codeine have also seen a rising
trend. In 2011, figures show that the UK was the highest codeine
manufacturer globally representing 22%, followed by France (21%), US (17%)
and Australia (8%).
Over the counter sales of codeine containing medications is not easy to
determine. Sales of over the counter medicines information is protected
because it is commercially sensitive and qualifies exemptions where
information is a trade secret and where disclosure would likely prejudice the
commercial interests of any person or public authority holding it. Over the
counter sales of products containing codeine generally must be supervised by
a pharmacist (European Medicines Agency, 2013). See table 3.1 on page 62
for details of the scheduling of codeine across the EU, Australia, Canada,
United States of America, Asia and South Africa.
(2) Prevalence of codeine use, misuse and dependence and
associated risk factors
EU prevalence data on the topic of codeine use, misuse and dependence is at
present confined to French and Norwegian studies, but presumably
widespread across other European countries (Casati et al. 2012; Fredheim,
Skurtveit, Moroz, Breivik, & Borchgrevink, 2009). Trend in sales of opioid
analgesic drugs like codeine in nine European countries recorded highest
consumption of codeine in the UK in the period 2001-2003 (De Conno,
Ripamonti, & Brunelle, 2005). The prevalence of the non-medical use of
12
prescription opioids in the USA (2008-2009) found that a substantial number
of individuals reported using combination products containing codeine with
paracetamol (Wang, Becker, & Fiellin, 2013).
The literature highlights a number of issues in relation to the prevalence of
codeine use, misuse and dependence. These include paediatric use of
codeine, codeine prescribed for pain, misuse of over the counter forms of
codeine (i.e. Codeine Cough Syrups); codeine use in pregnancy, codeine
products used to manufacture home-made drug solutions such as
desomorphine and recreational use of codeine. Psychotic disorders,
especially paranoid psychosis are a frequent psychiatric diagnosis associated
with codeine cough mixture abuse, and along with symptoms of anxiety and
depression, are associated with long term use (Dobbin & Tobin, 2008;
Romach, Sproule, Sellers, Somer, & Busto, 1999). Codeine may also be an
iatrogenic cause of psychiatric disturbances (Manchia, Alda, & Clakin, 2013).
A withdrawal based medication overuse headache is associated with
sustained long-term codeine use (Bendtsen et al. 2012; Katsarava & Jensen,
2007). Other health consequences relate to misuse of combination products
containing ibuprofen and paracetamol, and include gastrointestinal
haemorrhage, nephro-toxicity and hypokalaemia (Chetty et al., 2003; Ernest
Chia, & Corallo, 2010; Frei, Nielsen, Dobbin, & Tobin, 2010).
There is a gap in the evidence base in relation to the extent of misuse and
dependent use of over the counter analgesics containing codeine. For
example, studies relating to codeine are often combined with general
prescription opioid studies and therefore are not specific to codeine alone. We
recommend more education of codeine users about variations in metabolism,
and risks of long term use, risks associated with polypharmacy intake to
challenge the widely held but misinformed perception that codeine based
products are low risk in terms of their potential for dependence. Greater
concentration of policy and practice focus on prevention, referral and support
strategies for those who are at risk of or are currently problematic opioid users
is required.
(3) Use and efficacy of codeine within healthcare practice
Codeine is widely used in healthcare. The main therapeutic indications for
codeine are the relief of mild to moderate pain and cough suppression. It is
also used to a lesser degree as an anti-diarrhoeal agent. Like all drugs,
codeine, is not free of problems (Tremlett, Anderson, & Wolf, 2010). It is
however generally viewed as a safe and effective analgesic, despite calls to
withdraw it from the market (MacDonald & MacLeod, 2010; Tremlett et al.,
2010).
The effectiveness and role of codeine in treatment of minor and moderate
pain is debatable. The World Health Organisation has placed codeine on ‘step
2’ of its pain ladder, and it is commonly used in the management of mild to
moderate pain in adults (often dental or post-partum) and under strict
monitoring in children (Campbell, 2006; Cartabuke, Kelly & Madadi, 2012;
European Medicines Agency (EMA), 2013; Tobias, Taghon, & Rice, 2013).
Some authorities have suggested omitting ‘step 2’ due to the potential
13
dependent properties and side effects of codeine (and tramadol), and
guidelines generally do not recommend codeine for management of pain, due
to limited evidence of its effectiveness, variations in metabolism and
availability of more predictable opioids.
A meta-analysis of six studies by Derry, Karlin, & Moore (2013), demonstrated
combined ibuprofen (400mg) and codeine (25.6 to 60mg) has good analgesic
efficiency, but underscored the lack of data relating to low dose
codeine(<10mg), with limited data available on medium dose (10-20mg), and
most relating to high dose (>20mg, 25.6 to 60mg). In general, codeine is
thought to be effective in the treatment of non-cancer pain over a short period
of time (less than 6 months). Long-term treatment with codeine cannot be
supported as the evidence for its effectiveness is variable and the risk of
misuse and abuse is significantly increased (Trescot et al., 2008).
Codeine is available in over the counter combination preparations with
caffeine, paracetamol or ibuprofen. However, one of the main reasons for
selling over the counter products as combined preparations is to decrease
their addictive and abuse potential. However, misuse of combination products
particularly ibuprofen is associated with gastrointestinal haemorrhage,
nephro-toxicity, hypokalaemia and acute haemorrhagic necrotising
pancreatitis. (Barreto, Tiong, & Williams, 2011; Chetty et al., 2003; Dobbin &
Tobin, 2008; Dutch, 2008; Dyer, Martin, Mitchell, Sauven, & Gazzard, 2004;
Ernest et al., 2010; Evans & Gearry, 2010; Ford & Good, 2007; Frei et al.,
2010; Hastier et al., 2000; Hou et al., 2011; Lambert & Close, 2005; McAvoy,
Dobbin, & Tobin, 2011; Ng et al., 2011; Tormey, 2013).
Codeine appears more clinically useful when combined with paracetamol
(Derry, Moore, & McQuay, 2010; Derry et al.; 2013; Iedema, 2011).
Franceschi et al. (2013), suggest that codeine-paracetamol combined
preparations should be the treatment of choice for mild to moderate pain (for
example headache, post-operative, osteoarticular and post traumatic) rather
than non-steroidal anti-inflammatory drugs. Baratta, Gandhi, & Viscusi (2013),
reported limited evidence for single dose oral ibuprofen plus codeine being
more effective for postoperative pain than either drug in isolation. A metaanalysis of opioids for osteoarthritis of the knee or hip reported that modest
benefits of codeine were outweighed by adverse consequences (Nuesch,
Rutjes, Husni, Welch, & Juni. 2009). Equally given the low dose codeine used
in non-prescription medicines, it may be the case that non opioid analgesics
perform better (Murnion, 2010). Moreover, ibuprofen (400mg) was shown to
be statistically superior to dihydrocodeine (30mg, or 60mg) for relief of pain
(Moore, 2011).
(4) Consequences of codeine use, misuse and dependence
The potential for overuse and misuse of codeine containing medications is not
only detrimental to a person’s health but has economic and social implications
(Feinberg, 2006). The adverse consequences of codeine use and misuse are
considered under four categories (1) impairment, (2) injury, (3) adverse health
effects and (4) dependence.
14
(5) Prevention of codeine misuse and dependence
The misuse, abuse and dependence on codeine products are a public health
challenge throughout the world. Notwithstanding prescription misuse, codeine
is present in a range of over the counter medicines that are dispensed to the
public without prescription (Cooper, 2013a; Robinson, Robinson, McCarthy, &
Cameron, 2010). Increased pharmacovigilance, for example prescription drug
monitoring and screening in relation to codeine use within primary care and
community pharmacies, is warranted (Jones, Mogali, & Comer, 2012; Kahan,
Srivastava, Wilson, Gourlay, & Midmer, 2006). Recent innovative approaches
for raising public awareness, identifying misuse, managing misuse and
treating dependence are considered. Strategies to empower pharmacy staff
as custodians of medicine are warranted alongside brief interventions to raise
public awareness and support individuals experiencing tolerance and
withdrawal.
(6) Interventions and treatment for codeine misuse
The majority of codeine dependent individuals do not view themselves as
needing help and do not identify themselves as ‘drug addicts’. Hidden
populations of codeine misusers include those with ‘iatrogenic’ dependence
following medical use of codeine for pain, anxiety or insomnia, recreational
drug users and problematic opiate dependents (Nielsen et al., 2010). The
literature in relation to interventions for the treatment and management of
codeine misuse is limited, lacks specificity to codeine protocols and requires
further development despite potential for extrapolation from extant policy and
practice protocols for the misuse of prescribed opioids and treatment of opiate
dependence. Despite the use of criteria to establish codeine dependency,
recent research has commented on the lack of evidence to guide
development of specific treatment and referral pathways for codeine
dependence. Further research is needed to guide the development of specific
referral and treatment modalities for over the counter codeine misuse and
dependence.
(7) Conclusions and implications for practice, policy and research
There is a societal need for improved understanding in relation to the risks
and consequences of codeine use, misuse and dependence. A global
emergence of ‘respectable addiction’ has occurred alongside a heightened
awareness by the general public and health professionals with regard to this
addiction issue (Cooper 2013a, 2011; EMCDDA 2011). Increasing public selfmedication with over the counter available medications containing codeine,
whilst beneficial to society, also warrants the continued surveillance of certain
populations and products (Hughes, 2003).
Recommendations for practice and policy are addressed under the following
headings: (1) raising awareness; (2) detecting and managing risk; (3)
dispensing practices and (4) monitoring and surveillance of codeine.
Raising Awareness
A significant number of people who consume medications cannot identify the
active ingredients in their chosen medications (Roumie & Griffin, 2004). A
15
minority of customers appear willing to accept risks associated with increased
access to over the counter medications containing codeine and other active
ingredients (Alexander et al. 2005). This is despite high public awareness of
the abuse potential of over the counter medicine (Wazaify, Shields, Hughes, &
McElnay, 2005; 2005a) and pharmacists’ concerns in relation to safety and
codeine misuse and dependence. Pharmacists are trusted by the public as a
source of information about over the counter medications (Wawruch et al.
2013). Dobbin & Tobin (2008), have described particular characteristics of
individuals misusing codeine containing pharmaceuticals, whereby they may
not identify as an addict, the medication prescribed infers safety and
sanctioning by the prescriber, and with the products purchased having
different legal consequences in comparison to illicit drug users. It is important
to recognise variance in groups of codeine misusers and target patient and
customer awareness initiatives appropriately.
Recommendations for raising public and professionals’ awareness of
prescribed and over the counter codeine use, misuse and dependence:
Professional education and public awareness campaigns should seek to:
 Promote recognition and early detection by healthcare professionals of
signs of dependence and withdrawals in relation to codeine based
products.

Promote drug monitoring systems, drug workers and clinicians should
be aware of potential presentations for emerging and harmful forms of
home produced drug abuse, particularly in the case of injecting drug
use.

Develop and disseminate key health related messages about the risks
of exceeding therapeutic dosages of codeine based products.

Promote improved awareness by professionals in relation to coprescribing and effects on health.

Heighten public awareness about the risks surrounding the use of
codeine based products whilst driving.

Increase awareness and access to psychological treatments, for
example, cognitive-behavioural therapy, biofeedback, and relaxation
techniques for the treatment of chronic headache. (Eng &
Lachenmeyer, 1996).
In addition we recommend the further development of:

Brief interventions at point of sale to raise customer awareness of
potential risk of tolerance and dependence over time.

Parenting classes to highlight the potential side effects of codeine such
as respiratory depression when prescribed for children. The evidence
suggests that codeine should not be used for children with
16
neuromuscular disorders, severe cardiac or respiratory conditions,
upper respiratory or lung infections, multiple trauma or extensive
surgical procedures and be contraindicated in breastfeeding women.
Moreover, calculations of dose should be based on ideal body weight
and not actual body weight.
Detecting and Managing Risk
Evidence on the extent of use, non-compliant use and misuse of
pharmaceuticals containing codeine is limited. We recommend more
education for codeine misusers about the risks associated with poly use of
medication and intake of alcohol and illicit drugs to challenge misinformed
perceptions that codeine based products are low risk in terms of their potential
for dependence.
Recommendations for detecting and managing risk are as follows:

Develop community pharmacy practice strategies that promote safety
strengthen warnings, or remove potential products of abuse from point
of sale or sight.

Develop and improve referral mechanisms to primary care teams for
people suspected to be misusing codeine or to be dependent.

Identify of patients who are in need of psychological services to assist
in pain management.

Develop strategies to detect deception especially in pain related cases
thereby minimising risk for failing to improve or overdose.

Increase availability of disposable containers for unused prescriptions.

Incorporate routine enquiries about maternal medication use, including
codeine-containing cough preparations, when evaluating new-born
infants with evidence of cerebral infarction into assessment protocols.

Assess opioid addiction with the misuse of ibuprofen-codeine
combinations when assessing patients presenting with severe
hypokalaemia, pancreatitis and medication overuse headache.

Develop strategies to manage access and reduce treatment barriers in
relation to codeine misuse and dependence. For example, the
reluctance of problem opiate users to access treatment is an
immediate concern.

Develop clearer guidelines for interpretation of DSM V criteria for
abuse and dependence in chronic pain patients, especially in cases of
‘maladaptive or aberrant behaviour’.
17

In cases where substance misuse psychiatric disorders are suspected,
a high index of suspicion for cough mixtures misuse/abuse is
warranted.

Develop appropriate harm reduction tactics (needle exchange, bleach
distribution, hygiene, provision of filters, foil packs to encourage route
reversals, and safer injection facilities), screening, treatment (opiate
substitution therapy, antiretroviral therapy), therapy and prevention
programmes which target injecting drug users who inject home drug
solutions made from codeine.
Dispensing Practices
Safety is central to pharmacists’ decision making with regard to medication
dispensing (Hanna & Hughes, 2010). Pharmacy practice strategies that
promote safety in relation to codeine dispensing practices are detailed in
chapter 3, table 1.
Recommendations for dispensing practices:
We recommend that dispensing practices

Continue to expand the clinical and public health role of the community
pharmacist with ongoing inter-disciplinary training for counter
assistants, pharmacists and other health professionals.

Adopt a ‘universal precautions’ systematic approach for each codeine
sale, rather than a selective approach based on customer appearance.

Introduce short term restricted dispensing practices of codeine based
products.

Provide clearer product labelling of the active ingredients in over the
counter and prescribed products.

Remove potential products of abuse from sight in community
pharmacies.

Refuse sales of codeine to users who are problematic misusers or
dependent.

Develop in house pharmacy based brief interventions at point of sale
along with supported detoxification in pharmacies.

Provide needle and syringe exchange services targeting opiate
injecting.
18
Monitoring and Surveillance of Codeine
The monitoring and surveillance of codeine dispensing activity and
estimations of levels of customer misuse (both intentional and non-intentional)
remains problematic. In addition to therapeutic dependence and such forms of
non-compliant use, the diversion, tampering, home manufacture and injecting
of over the counter and prescribed pharmaceuticals (containing codeine and
other opioids) is a pharmacy, drug surveillance and public health issue (Azbel,
Dvoryak, & Altice, 2013).
Recommendations for monitoring and surveillance:

Develop prescription drug monitoring and national online prescription
systems.

Develop and evaluate real time integrated monitoring of the dispensing
of prescribed and over the counter use of codeine based products in
community pharmacies.

Ensure routine enquiries by health professionals of patients with regard
to prescribed and over the counter codeine medication use.

Monitor the use of prescription opioids in vulnerable groups (patients
with chronic non-malignant pain, patients with cancer pain and illicit
drug users) to identify if opioids are substituting for or complicating
mental health and addiction treatment outcomes, thereby minimising
risk of overdose.

Share information in relation to codeine sales and consumers by
pharmacists with other pharmacists.

Develop and evaluate ‘early warning systems’ in relation to codeine
use, misuse and dependence (i.e. recording of adverse events).

Consider further development and roll-out to other countries of
initiatives which are similar to the South African Codeine Care Project,
using The TrustaTAG™

Monitor and manage conflicts between commercial and customer
interests; and between pharmacy, non-pharmacy and internet
pharmacy outlets.
Recommendations for Future Research
A number of key areas are identified for further research in relation to
prescribed and over the counter codeine use, misuse and dependence.
Research recommendations are listed under six headings: (1) patterns of use,
misuse and dependence; (2) prevalence; (3) treatment/interventions; (4) risk;
(5) epidemiology and (6) policy.
19
Patterns of Use, Misuse and Dependence
Research, evaluation studies and reviews are needed to:

Quantify the extent of prescribed and over the counter codeine use,
misuse and dependence, whether intentional or non-intentional. This
work should enable the creation of user profiles in relation to patterns
and estimations of codeine use, misuse and dependence.

Explore the views and experiences of users and misusers of various
codeine and other products to better understand product interactions
and illegal drug and poly pharmaceutical use patterns.

Systematically review studies of poly medication use, for example,
benzodiazepines, codeine, comorbidity and drug injecting transitions.

Investigate motives for codeine misuse which range from self-treating
of pain (physical and emotional), sleep and anxiety problems, pleasure
and ease of access and personality types, for example, addictive
personality.

Explore the experiences of general practitioners of misuse of
prescribed drugs, particularly codeine. These studies should
investigate: the challenges encountered by primary care staff,
incidence of problematic use, the drugs used in treatment, other
treatments considered and referral patterns.

Systematically review studies and conduct further studies to establish
the risk of driving accidents with opioid and codeine use, including the
effect of these drugs on driving ability on people with different genetic
polymorphisms and on aging drivers. The effects of higher doses of
codeine require particular investigation.

Explore the views and experiences of the injecting user of home
produced drugs made from codeine. These studies should pay
particular attention to perceptions of harm, user practices, trajectories
of use and experiences of services. Drug testing of field samples is
warranted to establish content.
Prevalence
 Estimate the prevalence of use, misuse and dependence within the
broad and ‘hidden’ spectrum of therapeutic and non-therapeutic
patterns of codeine use and misuse. The literature is still unclear as to
why the misuse of codeine occurs despite various levels of legislative
control and preventative strategies in various countries.
20

Estimate the prevalence of codeine misuse and dependence among
methadone patients and opiate drug users.

Estimate the prevalence of internet availability and purchase of
medications without a legitimate prescription, including identification of
customer characteristics.

Estimate the prevalence and incidence of persistent and problematic
use of codeine in patients with non-cancer chronic pain or non-pain
patients.

Estimate the prevalence and effects of parental social medication of
children using codeine products.

Estimate the prevalence of use of home-made drug solutions made
from codeine containing pharmaceuticals.
Treatment/Interventions
 Establish the evidence base for the continued use of codeine
compared to non-steroidal anti-inflammatory drugs in the management
of mild to moderate pain. Overall the evidence presented to support
codeine use as opposed to non-steroidal anti-inflammatory drugs is
inconclusive and requires further study.

Establish the effectiveness (benefits and harms) of codeine compared
to alternative medications.

Explore doctors’ and other prescribers’ preferences for prescribing
codeine rather than alternative medications and their views on a
standard starting dose and subsequent dose titration.

Establish the effectiveness (benefits and harms) of long-term treatment
with short-acting weak opioids.

Establish the frequency with which prescribers co-prescribe codeine
with benzodiazepine or Z drugs.

Evaluate health professional training in the recognition and
management of codeine aberrant behaviours such as forged or lost
scripts, requesting certain medications, describing unresolved pain,
visiting multiple pharmacies merits further study across a variety of
regulatory systems.

Establish the efficacy and effectiveness of non-pharmacological
responses to pain management.

Synthesise evidence from related fields to guide the development of
specific treatment and referral pathways for individuals with codeine
21
dependence. Although general treatment for opiate dependency is
primarily detoxification and psychosocial therapy, there is limited
evidence available to guide specific policy development and
implementation, management initiatives and the development and
provision of specific referral and treatment pathways for over the
counter codeine misuse and dependence.

Synthesise evidence from related fields to guide the development of
specific treatment protocols for codeine-users who have issues with
pain management, have developed problematic opioid use or are codependent on benzodiazepines or Z-drugs.

Explore the self-perception of codeine dependent individuals many of
whom do not view themselves as needing help for their codeine
dependence and their experience of interventions (counselling,
community detoxification, switching onto other medication) in the
management of codeine misuse.

Identify treatment seeking barriers and experiences of people with
codeine dependence.

Evaluate therapeutic interventions, for example, brief interventions, and
their efficacy in treating people who present with codeine related
misuse and addiction problems.

Establish the effectiveness of dihydrocodeine in maintenance, cross
over and detoxification treatment of opiate dependency, to ensure a
favourable risk/benefit ratio.
Risk
 Identify predictors of risk of codeine misuse and dependence and
protective factors. Results could inform practices to minimise risk of
dependence, guidelines for early detection and management of
dependence and the pharmaceutical development of safer products.

Identify genetic risk factors for opioid dependence, opioid induced
hyperalgesia as potential targets for medication therapy and
pharmaceutical development of abuse deterrent opioid formulations.

Explore the characteristics and habits of opioid shoppers in clinical
practices and the relationship between prescriber characteristics and
risk.

Synthesise studies of clinical profiles of people who are dependent on
prescribed and over the counter codeine to identify subtypes of users
at risk of adverse consequences and associated motives and
trajectories of use.

Establish levels of risk and impairment as a result of codeine use and
misuse.
22
Epidemiology
 Develop pharmaco-epidemiological methods to investigate misuse,
non-medical use, abuse and dependence on codeine based drugs for
self-medication. This would facilitate real time monitoring of prescribing
and dispensing activity with data linked to national medicines abuse
systems.

Investigate self-medication and patterns of codeine use among the
following key groups: youth, older people, problematic drug users, pain
patients, individuals prescribed antianxiety medication, methadone
maintenance treatment patients and individuals accessing internet
forums.

Estimate street pricing of diverted prescription codeine and homemade drug solutions produced using codeine based pharmaceuticals.
Policy
 Guide the development of accessible and specific regulatory,
pharmaceutical, treatment and community detoxification protocols for
codeine misuse and dependence.
23
Chapter 1
Introduction
This chapter will present background contextual information in relation to
codeine use, misuse and dependence. It will described what codeine is, its
uses in ‘normal’ medical practice and adverse effects and highlight lack of
consensus surrounding terminology such as ‘misuse’, ‘abuse’ and
‘dependence’.
Chapter 2 describes the methods used for the review and findings from the
review are presented and discussed through chapters 3 to 9.







Chapter 3 - Production, manufacture consumption and regulation of
codeine internationally.
Chapter 4 - Prevalence rates of codeine use, overuse, misuse and
dependence and associated risk factors.
Chapter 5 – Use and efficacy of within healthcare practice.
Chapter 6 - Consequences of codeine use, misuse and abuse.
Chapter 7 - Prevention of codeine misuse, abuse and dependence.
Chapter 8- Interventions/Treatments and codeine dependence.
Chapter 9 - Recommendations and implications for policy, practice and
research.
Aim of Scoping Review:
To report what is known about the regulation, production, distribution,
prevalence, consequences and prevention in relation to the use, misuse
and dependence of codeine in the partner countries (Ireland, UK, South
Africa), across the EU and internationally and to identify gaps in the
evidence base.
Specific objectives are:
 To map the existing literature examining codeine use, misuse and
dependence.
 To identify gaps in the evidence base and make recommendations
for future research.
 To provide an overview of the healthcare system, prescribing of
codeine and addiction treatment in the three partner countries.
 To make recommendations for practice and policy to promote
improved understanding and awareness of codeine misuse and
dependence
24
1.1 Codeine
Codeine or 3-methylmorphine is the most commonly consumed opiate
worldwide, widely used for its analgesic, antitussive and anti-diarrhoeal
properties (Derry et al., 2013; Tremlett et al., 2010). The name codeine is
derived from the Greek word kodeia (κώδεια) for ‘poppy head’ and it is found
naturally in the poppy plant ‘Papaver somniferum var. album’. Codeine (Fig 1)
is a phenanthrene derivative extracted from opium or produced synthetically
by the methylation of morphine.
Fig 1.1: Chemical Structure of Codeine Base
1.1.1 Available Formulations
Codeine exists as a base and a number of salts, but is used mainly as
codeine phosphate, which occurs in a number of hydrated forms. It is usually
a white or near white crystalline solid that is freely soluble in water. It is
formulated in a number of ways for use in various conditions and by different
routes of administration (Martindale, 2014). Uses and formulations vary in
different countries, as do the laws that control its supply. ‘Over-the-counter’
supply varies from total prohibition to minimal regulation on supplies from
community pharmacies. Typically preparations containing codeine of 30mg
and above classify as a ‘prescription only medicine’ (Derry et al., 2013). The
maximum recommended dosage is 240mg daily, and increasing the dose
above 60mg four times a day does not increase efficacy (Campbell, 2006).
The main pharmaceutical form is the tablet (60%) but codeine is also
available as a capsule, effervescent tablet, syrup, suppository and solution
(EMA, 2013). Codeine products may also be marketed for subcutaneous or
intramuscular injection. Intravenous use is not advised as it may cause
hypotension and grand mal convulsions. Table 1.1 details the preparations
and uses listed in the British National Formulary No.66 September 2013.
Over the counter codeine based products contain typically between 8 and
15mg of codeine per tablet, and may be marketed as a single ingredient drug
or more commonly in combination with Non-Steroidal Anti-Inflammatory Drugs
such as ibuprofen (e.g. Nurofen Plus®), aspirin, paracetamol, caffeine and
buclizine in order to enhance the synergistic effect of drug compounds
(Tremlett et al., 2010). Examples of codeine containing over the counter
medicines in the UK are shown in Table 1.2.
25
Table 1.1: Codeine preparations listed in the British National Formulary No 66 September 2013
Preparation
Indication
Route of
Administration
Oral
Dose
Codeine Phosphate
Tablets 15mg, 30mg,
60mg
Mild to Moderate
Pain
Codeine Phosphate
Injection 60mg/ml
1ml Ampoule
Codeine Phosphate
Syrup 25mg/5ml
Mild to Moderate
Pain
Intramuscular
Injection
Mild to Moderate
Pain
Oral
ADULT over 18 years, 30–60 mg every 4 hours when necessary, to
a max. of 240 mg daily
CHILD 12–18 years 30–60 mg every 6 hours when necessary;
max. 240 mg daily; max. 3 days
Codeine Phosphate
with Paracetamol
Tablets/Capsules/
Dispersible Tablets
(Co-codamol )
8/500mg, 15/500mg,
30/500mg
Codeine Linctus BP
15mg/5ml
Mild to Moderate
Pain
Oral
ADULT over 18 years, 1–2 tablets in water every 4–6 hours when
necessary; max. 8 tablets daily
Cough
Suppressant
Oral
ADULT over 18 years 5–10 ml 3–4 times daily
ADULT over 18 years, 30–60 mg every 4 hours when necessary, to
a max. of 240 mg daily
CHILD 12–18 years 30–60 mg every 6 hours when necessary;
max. 240 mg daily; max. 3 days
ADULT over 18 years, 30–60 mg every 4 hours when necessary
26
Table 1.2: Examples of Codeine Containing Medicines available Over-the-Counter in the UK
Product
Ingredients
Indication
Co-codamol
Tablets
Paracetamol 500mg
Codeine Phosphate 8mg
Co-codamol® is indicated in children older than 12 years of age for the
treatment of acute moderate pain, which is not considered to be relieved
by other analgesics such as paracetamol or ibuprofen (alone).
Solpadeine
Plus® Tablets
Paracetamol 500 mg
Codeine Phosphate
Hemihydrate 8mg
Caffeine 30.0 mg.
Codeine is indicated in patients older than 12 years of age for the
treatment of acute moderate pain, which is not considered to be relieved
by other analgesics such as paracetamol or ibuprofen alone.
Solpadeine Plus®. Tablets are recommended for the relief of migraine,
headache, backache, rheumatic pain, period pains and dental pain.
Solpadeine
Max® Tablets
Paracetamol 500 mg
Codeine phosphate
hemihydrate 12.8 mg.
Migraleve®
Pink Tablets:
paracetamol 500mg
Codeine Phosphate 8mg
buclizine 6.25mg
Codeine is indicated in patients older than 12 years of age for the
treatment of acute moderate pain, which is not considered to be relieved
by other analgesics such as paracetamol or ibuprofen alone.
Solpadeine Max ®Tablets are recommended for the relief of migraine,
headache, dental pain, period pain, backache, arthritic & rheumatic pain,
strains & sprains and sciatica.
For the short term treatment of acute moderate pain which is not relieved
by paracetamol, ibuprofen or aspirin alone such as migraine attacks
including the symptoms of migraine headache, nausea and vomiting.
Yellow Tablets:
paracetamol 500mg
codeine phosphate 8mg
27
Nurofen Plus®
Ibuprofen 200mg
codeine phosphate
12.8mg
Co-codaprin
Effervescent
Tablets
aspirin 400mg
codeine phosphate 8mg
Codeine Linctus
BP
codeine phosphate
15mg/5ml
Nurofen Plus® (which contains codeine) is indicated in patients older
than 12 years of age for the short term treatment of acute, moderate pain
(such as rheumatic and muscular pain, backache, migraine, headache,
neuralgia, period pain and dental pain) which is not considered to be
relieved by other analgesics such as paracetamol, ibuprofen or aspirin
alone
1) For the relief of headaches, toothache, migraine, neuralgia, sore throat
and period pains.
2) For the symptomatic relief of influenza, feverishness, rheumatic pains,
sciatica, lumbago, fibrositis, muscular aches and pains.
Indicated in adults for relief of the symptoms of dry or irritating coughs
28
1.1.2 Pharmacodynamics and Pharmacokinetics
Codeine is a short acting weak to mid-range opiate that has a low affinity and
low intrinsic activity at the opioid receptors (Iedema, 2011). It is effectively a
pro-drug meaning that the body must metabolize it to active metabolites
before it becomes effective as a painkiller. The major metabolite is codeine-6glucoronide, but most of the analgesic action is due to the production of
morphine in the liver by the enzyme Cytochrome P450 2D6. The metabolism
is by 0- and N- demethylation.
Codeine has high oral ⁄ parenteral potency ratio with peak plasma
concentrations occurring at 60 minutes, and with a plasma half-life of 3 to 3.5
hours in adults (Arora & Herbert, 2001; Band, Band, Deschamps, Besner, &
Coldman, 1994). Through the oral route of administration, codeine is
effectively absorbed by the GI tract with approximately 50% of the dose
undergoing first pass metabolism (Tremlett et al., 2010), and with minimal loss
of drug potency (in direct contrast with morphine which loses up to 90%
potency). Speed of absorption via intramuscular route is similar to rectal
administration (McEwan et al., 2000). Codeine and its metabolites are
excreted almost entirely by the kidney (Campbell, 2006; Martindale, 2014). Of
note is that the pharmacokinetics of codeine are poorly described in children,
despite use over many years (Anderson, 2013). Intravenous use is
contraindicated due to lack of first-pass metabolism by the liver inhibiting the
drug outcome.
The analgesic effect of opioids is primarily mediated by mu-receptors in the
central nervous system and to a lesser extent in the periphery. They act by
inhibiting the transmission of nociceptive impulses caused as a result of
damage to the tissues. Morphine also reduces the affective component of
pain by a supraspinal action, possibly in the limbic system. This effect known
as ‘opioid analgesia’ alters the perception and emotional response to pain.
Opioids have poor efficacy in the management of pain with a neuropathic
component (Rang, Ritter, Flower, & Henderson, eds., 1999; Williams, Patel, &
Howard, 2002). Conversion to morphine by endogenous enzymes (human
cytochrome P450 2D6) results in the analgesic effect (Kelly & Madadi, 2012),
known as the ‘opioid analgesia’ which alters perception and emotional
responses to pain (euphoric or dreamy feelings), and stimulatory effects by
blocking neurotransmitters (Williams et al., 2002). In therapy, there is a
codeine:morphine potency ratio of about 1:10 which means that 60mg of
codeine has a morphine equivalence of 6mg (Anderson, 2013). However, it
does have the advantage of relatively mild side effects (Martindale, 2014).
Genetic variations in activity of human cytochrome P450 2D6 vary rates
(approximately 2-20%) of conversion to morphine (Cartabuke et al., 2013;
Cascarbi, 2003; Iedema, 2011; Kelly & Madadi, 2012; Zhou, 2009) with 5% of
the population not having the enzyme to convert codeine to morphine, with
codeine preparations neither effective for pain relief, nor likely to cause
dependence (Chew, White, Somogyi, Bochner, & Irvine, 2001). More than 60
alleles in the CYP2D6 gene have been identified leading to significant enzyme
polymorphism. Phenotypes are classified as poor, intermediate, extensive or
29
ultra-rapid metabolizers. 7-10% Caucasians are slow metabolizers, but this
varies with ethnicity and geographic origin (Table 1.3).While some ultraextensive metabolizers can convert about 15% of a codeine dose into
morphine, the majority of the population will convert between 1% and 10%.
Population
Ultra-rapid
Metabolisers%
African/Ethiopian
African American
African
Asian
Caucasian
Greek
Hungarian
Northern European
Western European
Southern European
Arabian
29%
3.4% to 6.5%
5-30%
1.2% to 2%
3.6% to 6.5%
6.00%
1.90%
1%-2%
8-10%
Slow Metabolisers
0-20%
7-10%
1-4%
7-10%
up to 20%
Table 1.3: CYP2D6 phenotypes by ethnicity (Iedema, 2011; Madadi & Koren,
2008; Actavis, 2014).
The toxicity of codeine relates to its opioid effect (EMA, 2013). Codeine has
minimal analgesic activity in slow CYP2D6 metabolizers due to their inability
to produce sufficient morphine to incur the analgesic effect. However, adverse
effects such as sedation, nausea or pruritus still occur, especially if the dose
is raised or combination products are used (Anderson, 2013). Fast CYP2D6
metabolizers or ‘extensive metabolizers’ are at risk of opioid toxicity
syndrome, and particularly respiratory depression (Derry et al., 2013;
Ingelman-Sundberg, Sim, Gomez, & Rodriguez-Antona, 2007; Madadi et al.
2008; Somogyi, Barratt, & Coller, 2007; Willmann, Edginton, Coboeken, Ahr,
& Lippert, 2009). This risk is also exacerbated if poly pharmacy is evident in
co-consumption of other drugs such as benzodiazepines and phenobarbitone
(Derry et al., 2013; Ingelman-Sundberg et al., 2007; Madadi, 2008; Somogyi,
Barratt, & Coller, 2007; Willmann et al., 2009).
In addition to CYP2D6, other genetic factors affecting morphine metabolism,
transit via blood brain barriers and opioid receptor kinetics can affect
individual responses to codeine (Iedema, 2011). As patient responses vary,
the dosage must be monitored on an individual basis, with the usual dose by
mouth for adults is 30-60mg every four hours, to a maximum of 240mg per
day (Derry et al., 2013). Medications such as phenytoin, rifampicin and
dexamethasone can enhance the effect through enzymic induction of
CYP450, with antidepressant drugs such as fluoxetine, paroxetine, sertraline
and citalopram potentially compromising the analgesic effect through enzymic
inhibition of CYP450 (Derry et al., 2013; Iedema, 2011).
30
1.2 Use of Codeine within Normal Medical Practice
1.2 1 Use in Adults
Codeine was used originally for the treatment of cancer pain, and
extrapolated for the management of mild to moderate pain in adults and
children (Campbell, 2006; Iedema, 2011; Kelly & Madadi, 2012; Cartabuke et
al., 2013; EMA, 2013; Hall, Morant, Carroll, Gabriel, & McQuay, 2013;
Anderson, 2013).
It is listed as step 2 in the WHO Analgesic Ladder after paracetamol and nonopioid analgesics for the treatment of cancer pain, although the step is
sometimes omitted if deemed clinically appropriate (NICE, 2013; Cartabuke et
al., 2013). It is also used as part of a stepwise approach for the management
of mild to moderate non-cancer pain in combination with paracetamol and/or
Non-Steroidal Anti-inflammatory Drugs after there is inadequate pain control
with the agents alone (NICE, 2010). Recent discourse has suggested to skip
‘step 2’ due to problems with codeine (and tramadol) (Anderson, 2013;
MacDonald & MacLeod, 2010), with guidelines generally not recommending
codeine for management of pain, due to limited evidence of effectiveness,
variations in metabolism and availability of more predictable opioids. It
continues to be used for postoperative pain management (Stoneham &
Walters, 1995), as it causes less sedation and potential respiratory
depression than morphine, despite morphine incurring a safer, more potent
and longer lasting effect (Goldsack, Scuplak, & Smith, 1996).
The advised dose of codeine is 30-60mg every four hours up to a maximum of
240mg daily (British National Formulary, 2013). Increasing the dose above
60mg does not increase its efficacy, as there is a ceiling effect at a daily dose
of 240mg (Campbell, 2006). Lower doses (15mg) are recommended in the
elderly, who are more susceptible to the side effects of weak opioids, in
people with hypothyroidism and adrenocorticoid insufficiency and in moderate
to severe renal impairment, where metabolites can accumulate (NICE, 2010).
Also of note is that cough suppression does not correlate with analgesic and
respiratory depressant activity of opioids, with the mechanism at receptor
level remaining unclear. Codeine suppresses cough at sub-analgesic doses
and is widely contained in cough medicines.
1.2.2 Use in Children
Codeine was prescribed for paediatric use, due to the lower incidence of
opioid-related side-effects in situations where airway management and
neurological assessment are critical (Semple, Russel, Doyle, & Aldridge,
1999). Codeine given its ease of administration as an oral syrup, capsule,
suppository or tablet for post-operative, has been used in mild to moderate
pain management in children (Tremlett et al., 2010). A recently published
serial cross-sectional analysis of emergency department visits for patients
between the ages of three and 17, drawn from a nationally representative
Canadian sample found a small decline in codeine prescriptions issued (from
3.7% to 2.9% of all prescriptions issued) over a 10 years period, from 20012010 (Kaiser et al., 2014). This study found that the odds of codeine
31
prescription was higher for children aged 8 to 12 years and this did not decline
significantly over the study period. The odds of codeine prescribing was lower
for non-Hispanic black children, or those from low income families covered by
a social healthcare programme (Medicade); possibly reflecting general opioid
prescriber avoidance for these groups. Prescribing of codeine for cough or
upper respiratory infection did not decline following the publication in 2006 of
national guidelines recommending against its use; this is in line with other
studies which show that practice guidelines have limited impact on prescriber
behaviour for a variety of reasons, including lack of awareness and familiarity
with established prescribing practice.
According to Tremlett et al. (2010), ‘the pharmacokinetics of codeine is poorly
described in children despite use over decades’. Commentaries have
expressed concerns for morbidity and mortality in paediatric use, especially
considering the variability of the effects in patients and relating to ethnicity,
body composition and physiology (Cartabuke et al., 2013; Madadi & Koren,
2008). It was originally considered a suitable analgesic for children after
adenotonnesillectomy.
Countries employ different regulations around the minimum age for codeine
use, with the UK Medicine and Healthcare Products Regulatory Agency
(2010) advising that codeine cough preparations should not be used by
people under 18 years of age. In July 3013 a number of Medicines Regulatory
Agencies issued restrictions prohibiting its use for this indication in children
less than 18 years. This followed reports of deaths in children having a
procedure for sleep apnoea, who died of respiratory depression. The children
who died were ultra-rapid metabolizers of codeine and developed morphine
toxicity.
In 2013, the European Medicines Agency (EMA) commissioned a report on
the paediatric use of codeine amid concerns regarding toxicity and lack of
consistent risk minimisation measures. They reported on the lack of data on
the influence of childhood development on the efficacy and side-effects of
codeine, highlighted the risks associated with some children who are ultrarapid or extensive codeine to morphine metabolizers (EMA, 2013) and pointed
to the need to exercise caution when interpreting the effect of age, genetic
polymorphism and increasing enzymatic activity in young people. In their
view, codeine is: contraindicated in paediatric patients up to 18 years that
undergo tonsillectomy and/or adenoidectomy for Obstructive Sleep Apnoea
Syndrome due to increased risk of loss of consciousness and respiratory
arrest; contraindicated in patients known to be CYP2D6 ultra-rapid
metabolizers; and is not recommended for use in children with neuromuscular
disorders, severe cardiac or respiratory conditions, upper respiratory or lung
infections, multiple trauma or after extensive surgical procedures.
The EMA (2013) recommends that codeine should be used only in children
over 12 years for acute moderate pain, where paracetamol and ibuprofen
have been ineffective. The maximum dose should not exceed 240mg with a
minimum of 6 hours between doses for a maximum duration of 3 days.
Parents should be given warning signs of codeine toxicity and advised to stop
32
treatment and seek immediate medical attention if they occur. Warning signs
include: reduced levels of consciousness; lack of appetite; somnolence;
constipation; respiratory depression; ‘pin-point’ pupils; nausea and vomiting.
Also of concern is the over the counter use of codeine containing preparations
by parents, so called parental ‘social medication’, to incur positive child
behaviour, control behaviour, and reduce the inconvenience of neonate and
child sickness (for example teething) (Allotey, Reidpath, & Elisha, 2004).
There is also the potential for unintentional paediatric overdoses, usually as
unsupervised ingestions (Schillie, Shehab, Thomas, & Budnitz, 2009).
1.2.3 Use in Pregnancy and Lactation
Codeine has been prescribed and used over the counter during pregnancy as
it is considered a safer option to other opiates. It is also is prescribed for
obstetric purposes (Glover, Amonkar, Rybeck, & Tracey, 2003). However, its
metabolites do cross the placental barrier and have been linked with neonatal
abstinence syndrome and cerebral infarction. This problem is difficult to
accurately describe as many women do not consider over-the-counter
medicines to be dangerous and exact medication histories are problematic to
obtain (Reynolds, Riel-Romero, & Bada, 2007). Codeine was originally viewed
as having minimal risk to mothers and breast feeding infants (Seaton,
Reeves, & McLean, 2007) however recent commentaries have presented
serious concerns for morbidity and mortality in paediatric use (Cartabuke et
al., 2013, Chang et al. 2012). Madadi & Koren (2008) have commented on the
lack of empirical evidence available to support its use in children and breast
feeding mothers, and emphasised variability in the efficacy of codeine in these
patients.
Neonatal abstinence syndrome and cerebral infarction following maternal
codeine use during pregnancy have been observed (Au et al., 2007; Reynolds
et al., 2007; Van Leeuwen, Guthrie, & Stange, 1965). Breastfeeding is
cautioned and requires close monitoring if codeine is prescribed for
breastfeeding mothers, given the potential risks associated with CYP2D6
ultrafast metabolism (Kennedy, 2011). Codeine use while breastfeeding is
associated with events in breast-fed infants, including apnea, bradycardia,
drowsiness, and cyanosis (Darnall, Stacey, & Chou, 2012). Women with a
rarer CYP2D6 genotype rapidly metabolize codeine into morphine, resulting in
high breast milk and plasma levels in neonates, and can potentially cause
infant death due to opioid toxicity (Madadi et al., 2007; 2011). Genetic
screening is not standard practice, so contributing to a lack of clinician
awareness of the potential for neonate opioid toxicity (Madadi et al., 2011).
As part of the warnings issued by the Medicines Regulatory Agencies in 2013
concerning the use of codeine in children, it was stated that ‘codeine should
not be used by breastfeeding mothers because it can pass to the baby
through breast milk and potentially cause harm’ (MHRA, 2013). In North
America, it is standard practice to use codeine combined with paracetamol in
obstetrics for the treatment of pain immediately post-partum, following
caesarean section, the use of episiotomy or after 3 rd or 4th degree tears of
33
perineal tissue. However, considering the recent recognition of the problems
with codeine use in breastfeeding there have been calls to limit its use in
favour of Non-Steroidal Anti-Inflammatory Drugs, which are shown to have a
better risk-benefit ratio (Nauta, Landsmeer, & Koren, 2009).
1.2.4 Use in Older People
Misuse of pharmaceuticals among the older population is largely overlooked,
under reported and hidden (McGrath, Crome, & Crome, 2005). Codeine
specific literature is scant. The use of opioid analgesics increases with age
(Roumie & Griffin, 2004). Pharmaco-genetic variability in older people and
reduced renal function leading to an accumulation of active metabolites (Derry
et al., 2013), may result in increased susceptibility to opioids (Derry et al.,
2013). Research shows that the prevalence of opioid misuse is highest in
women, particularly if widowed, less educated, with lower income, in poor
health and with reduced social supports (Francis et al., 2005). Older people
are more likely to have pain issues, and are at greater risk of codeine related
adverse events (Cherubino, Sarzi-Puttini, Zuccaro, & Labianca, 2012).
Increases in the problematic use of over the counter codeine containing
products have been observed amongst older people (Moore, 2008).
Contraindications of codeine use include concurrent use of other medications,
with associated heightened risk of sedation, confusion and collapse
(Buckeridge et al., 2010; Iedema, 2011). Other adverse consequences
include the risk of falls, fractures, injuries and impaired driving and road
crashes (Amato et al., 2013; Bachs, Skurtveit, & Mørland, 2003; Bachs,
Engeland, Morland, & Skurtveit, 2009; Buckeridge et al., 2010; Francis et al.,
2005; Leung, 2011; Mailis-Gagnon et al., 2012; Vestergaard, Rejnmark, &
Mosekilde, 2006).
1.2.5 Use in the treatment of opiate dependence
Codeine, dihydrocodeine and oxycodone can be prescribed for use in
substitution treatment and detoxification (Kurdyak et al., 2012). Oral short
acting dihydrocodeine (half-life: 4 h) has been viewed as a viable alternative
to methadone as substitution treatment for opiate dependence (Banberry,
Wolff, & Raistrick, 2000; Krausz et al., 1995; Krausz, Verthein, Degkwitz,
Haasen, & Raschke, 1998; Robertson et al., 2006). Some preference is
shown for the prescribing of dihydrocodeine by general practitioners
particularly within specialist drug services because it is considered: safe;
offering a lower risk of addiction; having potential for retaining patients in
treatment; efficacy for patients with less severe dependence (despite lack of
data on positive clinical outcomes); avoids the need for frequent dosing;
lessens the risk of patients oscillating between sedation and withdrawals,
lessens the potential of poly drug use diversion and fatalities (Backmund,
Meyer, Eichenlaub, & Schütz, 2001; Banbery et al., 2000; Robertson,
Witcomb, Roberts, & Egan, 1990; MacLeod. Whittaker, & Robertson, 1998;
Seymour, Black, Jay, & Oliver, 2001; Sheard et al., 2007; Stark & Gregory,
2005; Zamparutti, Schifano, Corkery, Oyefeso, & Ghodse, 2010).
34
1.3 Diversionary Use of Codeine outside of Normal Medical Practice
1.3.1 Non Medicinal and Recreational use of Codeine
Research shows that awareness of codeine’s abuse potential within
problematic drug using networks is higher than in the general population, and
that it has the potential to alleviate withdrawals from stronger opiates such as
heroin (Agyapong et al., 2013; Cooper, 2013b). Recreational codeine use is
characterised by consumption of high doses of codeine in ‘binge’ episodes
with nasal, rectal, oral, inhalation and subcutaneous use most common
(Ernest et al., 2010).
Reported forms of recreational use for intoxication include consumption of
codeine cough syrups along with anti-nausea preparations such as
promethazine and codeine crushed within caffeine laced drinks (i.e. Red Bull)
popular in the US (Ernest et al. 2010), and in Thailand, the home production
of ‘Kratom Cocktails’ (Chittrakarn, Penjamras, & Keawpradub, 2012). In the
US, codeine has been labelled ‘Hillbilly Heroin’ with free base smoked on
aluminium foil (similar to heroin ‘chasing the dragon’). Poly drug taking
represents an additional confounding health consequences and drug
outcomes for the recreational misuse of codeine (Reed et al., 2011).
According to Bardhi, Sifaneck, Johnson, Dunlap (2007) increased use and
abuse of prescription pharmaceuticals (including vicodin, percocet, codeine,
xanax, valium, adderall and so forth) have been documented, particularly
among young, white, middle class, college educated women, who also report
recreational poly drug use (marijuana, cocaine, ecstasy and alcohol). These
authors reported on three forms of controlled pill use, recreational, quasi
medical and legal medical, with awareness of side effects and shifting
patterns described. Poly substance use using pills to enhance the effects of
other drugs and reduce negative outcomes of illicit drugs was reported. No
respondents in this study reported the temptation to use heroin. Few reported
that their pill use interfered with employment and family life, and none
reported contact with the police, or seeking treatment.
Amongst illicit drug users, extra medical use of pharmaceuticals including
codeine occurs in varying degrees. Wilkins, Sweetsur, & Griffiths (2011),
reported that amongst frequent users of ecstasy, there were low levels of
morphine, methadone and ‘home bake’ morphine, but sizable levels of
reported methylphenidate, benzodiazepines and codeine use. These
prescription drugs are most commonly sourced from doctors/pharmacies,
drug dealers, family members, and with opioids most commonly used for pain
and withdrawal in street drug user regimes (Davis & Johnson, 2008).
1.3.2 Tampering with codeine containing pharmaceuticals
Drug or formulation tampering is defined as ‘physical or chemical alteration of
a specific drug formulation for purposes of enhancing drug effect, increasing
speed of onset of effects, eliminating undesirable actives and excipients, and
chemically modifying actives’ (Cone, 2006). Tampering with pharmaceutical
drug formulations by physical or chemical alteration is conducted to enhance
35
the psychoactive drug effect, heighten onset of drug effects, eliminate
undesirable active substances and excipients, and chemically modify certain
active substances (Budman, Grimes Serrano, & Butler, 2009; Cone, 2006
Vosburg et al., 2012; Webster, 2009). The extent of this form of drug misuse
and dependence is unknown and is partly due to a lack of data and monitoring
systems by health and drug professionals (UNODC, 2013).
With regard to the diversionary use of codeine, instructions on how to crush,
separate excipients from undesirable actives, overcome time release
formulations, purify and chemically alter formulations and intended route of
administration, alongside recommended optimal routes of administration and
dosage are readily available on the Internet (Cone, 2006; Raffa & Pergolizzi,
2010; Srimurugan, Su, Shum, Murugan, & Chen, 2012). Online user forums
provide information for users on how to extract codeine from combination
products by splitting tablets with a sharp blade, discarding the side containing
ibuprofen and consuming the tablet side marked N+, and how to conduct ‘cold
water extraction’ (CWE) processes using multi filtration of the product in order
to yield the codeine base.
A review of the tampering of pharmaceutical formulations is beyond the scope
of this study. Readers are referred to Cone’s (2006) excellent review on
tampering with pharmaceuticals.
1.3.3 Home produced drugs made from codeine
In 2011, the European Monitoring Centre for Drugs and Drug Abuse
(EMCDDA) reported on the rising illicit market of opioids other than heroin, for
example pain relievers (morphine, fentanyl, codeine, oxycodone,
hydrocodone) and substitution drugs used in the treatment of heroin
dependence (methadone, buprenorphine). In South Asia namely Afghanistan,
Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka, the
diversion, extra medical and injecting use of pharmaceutical opioids
(buprenorphine, codeine, nalbuphine, dextropropoxyphene) is related to
inadequate prescribing for pain, and a recent decline in natural opiate
availability (Larance et al., 2011).
Of interest is the misuse of over the counter available medicinal preparations
from pharmacies, despite efforts to regulate the sale of certain medicines,
most notably codeine, pseudoephedrine, pentazocine, promethazine
hydrochloride and dextromethorphan. These compounds are used to
manufacture home- made amphetamine and opiate type drug solutions. Initial
reporting of ‘home-made’ drug solutions’ often commences via the media, with
scientific research somewhat slow to follow.
This new phenomenon of home production of drug solutions, often for
injecting drug users centres on the use of cheap and readily available
materials, low costs of production, and cheaper drugs with similar effects as
heroin (Balakireva et al., 2006). The popularity of certain ‘home-made’ drugs
depends on the ease of sourcing of ingredients, preparation and synthesis, its
36
market status relative to other available drugs, and the relative cost-benefit
ratio of its use (Heimer, 2013).
In New Zealand, the small scale production of injectable heroin substitutes is
known as ‘Home Bake’, and commonly made from morphine and codeine
based pharmaceuticals (Bedford, Nolan, Onrust, & Siegers, 1987; Grund,
Latypov, & Harris, 2013; Robinson, Kemp, Lee, & Cranston, 2000). The
conversion process from morphine sulphate to diacetylmorphine or heroin is a
relatively simple process that produces a product with few impurities and
requires a spoon, heat source, baking soda, citric acid, water and acetic
anhydride (AA) (Kemp & Aitken, 2004). AA or ‘double’ whilst strictly regulated
(UNODC 2011), is readily available via illicit sources (Grund et al., 2013). In
contrast, converting codeine based pharmaceuticals to diacetylmorphine is
relatively complex, and involves additional reagents (Grund et al., 2013). This
home produced opiate is then sold as powder for acetylation with AA, or in
liquid form, and is reportedly relatively pure (Bedford et al., 1987).
The Soviet tradition of homemade substances is viewed as contributory to the
production of new, accessible and affordable drug solutions (Azbel et al.,
2013). Recent reports indicate that injecting drug users in Russia, Ukraine
and other countries no longer source poppies or raw opium for home
produced injectables and have diverted their attention to available
medications containing codeine in pharmacies (Grund et al., 2013). A homemade product called ‘Braun’ is made from pharmaceuticals containing a
mixture of morphine and codeine such as Alnagon ® ,Korynal ® Kodynal,
Ipecarin ® (Zábranský, 2007).
Desomorphine (5a-17-methyl-4, 5-epoxymorphinan-3-ol) is generated from
codeine (3-methylmorphine) via 2 intermediate steps (α- chlorocodide and
desocodeine). Over the counter codeine medications (‘Codelac ®’ and
‘Terpincod ®’) are used for reduction of codeine using iodine, lighter fluid,
hydrochloric acid, gasoline, industrial cleaning oil and red phosphorus in a
similar short process to that of methamphetamine from pseudoephedrine
(Gahr et al., 2012, a,b,c; Savchuk, Barsegyan, Barsegyan, & Kolesov, 2008;
Skowronek, Celiński, & Chowaniec, 2012; UNODC, 2012).
The home production of desomorphine known as ‘Russian Magic’ or better
known as ‘Krokodil’ (крокодил or crocodile), emerged in Russia in 2003
(Savchuk et al., 2008)3. The rise in Russian ‘Krokodil’ addicts fuelled a shift
toward regulation of codeine containing tablets in June 1st 2011. Print screen
and online media reporting, whilst sensationalist and for the most part
reporting on isolated cases have reported suspected clinical presentations
and fatalities in the UK, Germany, Poland, Czech Republic, France, Belgium,
Sweden, Norway and other European countries with Russian populations
(Gahr et al., 2012b; Skowronek et al., 2012) and in late 2013 in the US.
3
The extensive review conducted by Grund, Latypov and Harris (2013) reports in its use in
Russia, Ukraine, Georgia and Kazakhstan and comments on ‘Krokodil’ as a relatively new
phenomenon, with estimates of between 20,000 and 100,000 injectors of the drug in 2011,
and most commonly used opiate amongst OST patients in Georgia.
37
The presence of contaminants and residues of iodine, phosphorus, heavy
metals and other chemicals such as iodocodeine, caffeine, paracetamol,
diphenhydramine (an opioid potentiator); and co-injecting use of other drugs
such as fentanyl (UNODC, 2012), tianeptine (an antidepressant) or
tropicamide (eyedrops) further compound abuse trajectories.
1.4 Common side effects of codeine
1.4.1 Opioid Side Effects
Common side–effects are often a result of the action of codeine and its
metabolites at the opioid receptors. Codeine is a weak agonist at mu-, kappaand delta-opioid receptors. Its analgesic effect is primarily mediated through
its metabolite morphine, which is a much stronger mu-agonist (Rang et al.,
1999). It is assumed that the actions of codeine are largely due to morphine.
However, there is evidence that some effects are related to codeine or its
other metabolites (Bachs et al., 2003).
Drowsiness and nausea are common side effects with oral doses of 30-60mg
and with regular dosing constipation is seen with 8-16mg (Campbell, 2006). At
high dose it has a depressive effect on respiration and alertness, but to a
lesser extent than morphine (Amato et al., 2013). Codeine is linked to an
increase in motor accidents where opioids are implicated causing sedation,
cognitive impairment and mental clouding (Bachs et al., 2003). Codeine
toxicity syndrome with risk of coma or death occurs at very high oral doses,
when part of poly drug or pharmaceutical use, and when injected
intravenously (Dobbin & Tobin 2008; Heard, Sloss, Weber, & Dart, 2006;
McAvoy et al., 2011; Paulozzi & Ryan, 2006; Zamparutti et al., 2010).
The effect of codeine on the central nervous system depends on dose, route
of administration, previous exposure and genetic factors of the patient. Dose
dependent effects include visual disturbances, mood changes, dependence,
itching, nausea, vomiting, constipation, drowsiness, pupil constriction,
bradycardia, tachycardia, palpitation, oedema, reduced breathing rate,
sweating, flushing, clammy skin, postural hypotension, sexual difficulties,
tremors, irritation, depression, ureteric spasm, miosis, dry mouth, urinary
retention, sleep disturbances, headache, constipation, hallucinations, vertigo,
euphoria, dysphoria, confusion, drowsiness, difficulty with micturition, urinary
retention, rash, urticaria, pruritus and seizures (Iedema, 2011; McDonough
2011; Olesen et al., 2006; Williams, 2005). Tolerance and dependence can
occur, especially with prolonged high dosage (Sanofi, 2014). Long term use
for pain relief and/or high dosage over time results in adverse effects such as
constipation and sedation, with dose related respiratory depression (Derry et
al., 2013). There is a risk of respiratory depression, coma and death resulting
from codeine toxicity at very high doses, after oral over-dosage, when
injected, and used in combination with alcohol or other drugs (Bellville &
Seed, 1968; Dobbin & Tobin, 2008).
Codeine is often used to manage headache, especially in the form of overthe-counter preparations. In common with other analgesics, misuse in the
38
form of repetitive daily use has been known to contribute to increased
headaches known as ‘Medication Overuse Headache’ (Bendtsen et al., 2012).
Other research comments on the use of analgesic drugs such as codeine to
treat headache and to assist patients in coping with life (Ferrari et al., 2006).
The extent of self-medicating behaviour for headache is unknown due to
inconsistent patient contact with medical professionals, and inaccurate or the
under reporting of this form of drug use (Leong & Lachenmeyer, 1996). Outpatient drug withdrawal therapy is required to treat patients with medication
overuse headache followed by structured acute therapy and initiation of
migraine prophylactic treatment (Diener & Katasarva, 2001; Linton-Dahlöf, P.,
Linde, M., & Dahlöf, 2000).
The effects on the gastrointestinal tract are complex and mediated by a
number of mechanisms. Studies have shown that there is little difference
between poor and extensive metabolisers of codeine on gastrointestinal
transit and nausea, suggesting that total or at least some effects are due to
itself or metabolites other than morphine (Bachs, Skurtveit, & Mørland, 2003).
Nausea and vomiting are common side effects at higher doses and the site of
action is the chemoreceptor trigger zone, a region of the medulla where
chemical stimuli induce the effect. There is also increased tone and reduced
motility in many parts of the gastrointestinal system through stimulation of muopioid receptors and to a lesser extent delta- and kappa-. This can add to the
feelings of nausea but also contribute to constipation, an effect that is
occasionally used in the treatment of diarrhoea. It can also slow the
absorption of other drugs.
1.4.2 Tolerance and Dependence
Codeine produces less euphoria than morphine and the risk of dependence is
low with normal use. Euphoria appears to be mediated through mu-receptors
and is balanced by the dysphoria associated with kappa-receptor activation.
The euphoria produced by morphine depends considerably on the
circumstances of the patient. In acute pain, a powerful sense of contentment
and well-being is invoked, which helps mitigate the agitation and anxiety that
is often a feature of the condition. However, in patients who have become
accustomed to chronic pain, analgesia occurs without the euphoric effect and
some patients even report restlessness under these conditions (Rang et al.,
1999).
Tolerance to the effect of morphine, including analgesia develops rapidly via a
number of mechanisms including metabolic degradation, reduced affinity for
the opioid receptor and down regulation of opioid receptors. This means that
the amount of opioid required for effective analgesia increases with time and
physical and psychological dependence develop. It also means that
dependents or people who have built tolerance can take large doses without
problems such as respiratory depression occurring. An abstinence syndrome
characterizes physical dependence, where patients show symptoms
resembling severe influenza, with yawning, pupillary dilation, fever, sweating,
piloerection, nausea, diarrhoea and insomnia. The symptoms are maximal for
39
about two days and mostly disappear after 8-10 days. Re-administration of
the opioid rapidly alleviates the abstinence syndrome. Psychological
dependence is associated with craving, lasting for months or years. It rarely
occurs in patients being given opioids as analgesics (Rang et al., 1999).
Dependence has been reported in prescribed analgesics containing codeine
(McBride & Meredith-Smith, 1995), with low risk of dependence in over the
counter codeine preparation if taken as directed (Cooper, 2013b). Conflicting
views exist with regard to codeine’s potential for addiction, particularly when
considering combination products and the potential effects of other active
ingredients such as ibuprofen, paracetamol and caffeine (Frei et al., 2010).
Although effects are milder than heroin, abuse potential remains of concern,
with tolerance and neuro-adaptation occurring with regular use over a short
period of time (Mattoo, Basu, Sharma, Balaji, & Malhotra, 1997; Nielsen et al.,
2008; 2010; Orriols, Gaillard, Lapeyre-Mestre, & Roussin, 2009). Withdrawal
effects in the case of physical dependency on codeine include classic opiate
dependence symptomatologies, albeit less severe than with morphine, such
as cravings, preoccupation with seeking and taking codeine, lack of control of
consumption patterns despite negative side effects, insomnia, restlessness,
runny nose, stomach pains, diarrhoea and chills (Cooper, 2013b).
Psychological criteria of codeine dependence are less evoked than
physiological dependence symptoms (tolerance and withdrawals) in noncancer pain patients (Vallejo, Barkin, & Wang, 2011). Prolonged use of
codeine is strongly associated with depression and dysphoric mood states
(Romach et al., 1999).
1.4.3 Non-Opioid Side Effects
Codeine has effects on the body that are not mediated by opioid receptors.
There is a dose-related release of histamine from mast cells, which can cause
urticaria and itching, particularly at injection sites in the face and neck areas. It
can also lead to anaphylaxis in rare cases and contribute to hypotension.
Large doses have been known to have an action on the medulla causing
bradycardia and further hypotension. Effects on smooth muscle other than
that of the gastrointestinal tract are slight, though spasm of the ureters,
bladder and uterus sometimes occur (Martindale, 2014; Rang et al., 1999).
Codeine can interact with other medication taken by patients. Alcohol and
other central nervous system depressants can lead to increased sedation,
respiratory depression and other central nervous system effects. Respiratory
depression can occur with phenobarbital, which although not contraindicated,
warrants caution and monitoring. Drugs that affect CYP2D6 can potentially
affect the outcome of codeine. Enzymic inducers such as rifampicin,
phenytoin and carbamazepine can increase the metabolism to its active
metabolites, increasing adverse effects. Conversely, inhibitors of the enzyme
such as fluoxetine, paroxetine, sertraline and citalopram slow down the
metabolism, compromising analgesic activity (Baxter & Preston (eds.), 2014).
40
Serious chronic health consequences, particularly in the case of excessive or
long term use of combination products containing ibuprofen and paracetamol
include gastric ulcers, gastrointestinal bleeding, hepatotoxicity, hypokalaemia,
inflammatory bowel conditions, and profound hypokalaemia associated with a
severe myopathy, and often in users with no history of substance use
disorders and co-morbidity (Barreto et al., 2011; Chetty et al., 2003; Dobbin &
Tobin, 2008; Dutch, 2008; Dyer et al., 2004; Ernest et al., 2010; Evans,
Chalmers-Watson, & Gearry, 2010; Frei et al., 2010; Ford & Good, 2007;
Hastier et al., 2000; Hou et al. 2011; Lambert & Close, 2005; McAvoy et al.,
2011; Ng et al., 2011; Tormey, Sabah, & Moore, 2013). Contraction of the gall
bladder and constriction of the biliary sphincter increases the pressure in the
biliary tract. This can lead to increased pain in patients with gallstones, rather
than bring relief (Rang et al., 1999). Convulsions and acidosis have been
associated with codeine and antihistamine (diphenhydramine) in antitussive
medicine (Murao, Manabe, Yamashita, & Sekikawa, 2008). Other potential
complications associated with long term use include symptoms of anxiety and
depression (Dobbin & Tobin, 2008; Romach et al., 1999). Codeine may also
be an iatrogenic cause of psychiatric disturbances (Manchia et al., 2013).
Excessive doses of over the counter analgesics containing codeine in patients
accessing emergency admissions have been recorded (Heard et al., 2006).
1.5 The problem of codeine misuse
The global misuse of pharmaceutical opioid analgesics is of increasing public
health and drug monitoring concern (Forman, Woody, McLellan, & Lynch,
2006; Compton & Volkow, 2006; Fry, Smith, Bruno, O Keefe, & Miller, 2007;
UNODC, 2011). Misuse of prescribed and over the counter opioid analgesic
medication4, (including codeine) is driven by a host of factors which include
pharmaceutical marketing tactics, inappropriate and increased prescribing,
access to licit and illicit drug sourcing, governmental responses, public
misconceptions around safety, social influences, self-medication of emotional
and physical pain and recreational popularity (UNODC 2011, 2013). Emerging
patient demand for access to efficient analgesic drugs without consultation
with medical professionals has contributed to the displacement of prescription
only drugs to over the counter status, with resultant problems relating to the
self-selection of opioid analgesic drugs by consumers (Peterson, 2005).
In their review of ‘Misuse of Medicines in the European Union’, Casati et al.
(2012), underscore that whilst awareness of the misuse of opioid analgesics
such as codeine is on the increase, data on the extent of the problem in the
EU is scant, with similar global observations made by the UNODC in 2011.
Given that these pharmaceuticals are legally dispensed to patients for
treatment of medical conditions such as pain, and are more widely available
and accessible to the public, epidemiological efforts to capture hidden
patterns of non-medical use are difficult (UNODC 2011). Experts suggest that
cohorts of pharmaceutical opioid misusers remain hidden, and reasons for
non-compliant medicinal use, overuse and intentional misuse for euphoric and
4
Drugs available from pharmaceutical sources,i.e. manufactured by the pharmaceutical industry or made up by a pharmacist.
Caffeine, antihistamines, codeine (an opiate) and alcohol are the most common psychoactive constituents of over-the-counter
drugs.
41
other effects are not well understood, despite potential for dependence, poly
use of other drugs, and adverse health consequences (Manchikanti & Singh,
2008; Nielsen et al., 2010).
Deregulation of medicines like codeine has created increased patient
convenience, self-management, response to advertising and pharmacist
empowerment in health decision making (Albsoul-Younes et al., 2010; Francis
et al., 2005). However emergence of misuse and abuse of non-prescription
medicine has increased along with associated harms (Bond & Hannaford,
2003; Eccles, 2006; Hughes, McElnay, Hughes, & McKenna, 1999; Hughes,
McElnay, & Fleming, 2001). Patient demand for access to efficient analgesic
drugs such as codeine without medical consultation, has contributed to high
numbers of products being available ‘over-the-counter’.
1.6 Misuse, Abuse and Dependence
1.6.1 Terminology
There is a lack of consensus in the literature as to definitions of the terms
misuse and abuse. This is further compounded by pharmaceuticals supplied
on prescription or over the counter and how these may differ to other
substances obtained illicitly (Barrett, Meisner, & Stewart, 2008). The variation
in the legal control of over the counter and prescription medicines such as
codeine creates difficulty in creating a consistent terminology resulting in
many terms used, for example, ‘nonmedical use, problem use, harmful use
and inappropriate use’. A lack of consensus of what constitutes associated
harm further compounds this problem (Casati et al., 2012).
Motives for use, whether medical, non-medical, recreational, problematic,
abuse or dependence exists within a dynamic continuum of use. The
variability of definitions across studies makes interpretation of results and
comparisons difficult. The interpretation of clinical findings and
characterisation of the issue are complicated by use of multiple criteria for
misuse and by lack of differentiation between them (Barrett et al., 2008). Such
variability of definitions across studies makes interpretation of results across
studies and comparisons difficult.
Here follows the range of terminology used in the literature:
Inappropriate medication use is defined on the basis of user characteristics
(e.g. any non-prescribed use), reason for use (e.g. recreation) or the presence
of clinically significant symptoms (e.g. diagnostic criteria for abuse and
dependence) (Barrett et al., 2008).
Variation in determining misuse and dependence exists (Hughes, Pillitteri,
Callas, Callahan, & Kenny, 2004), with Cooper (2013a) commenting on the
generic use of the term ‘misuse’ to describe all forms of problematic over the
counter use, with little delineation between misuse, abuse and dependence
(Akram, 2000; Ajuoga, Sansgiry, Ngo, & Yeh, 2008; MacFadyen, Eadie, &
42
McGowan, 2001; Matheson, Bond, & Pitcairn, 2002; Myers, Siegfried, &
Parry,. 2003; Pates, McBride, Li, & Ramadan, 2002)
Wazaify et al. (2005), describe the misuse of an over the counter product as
use for legitimate medical reasons but in higher doses or longer than advised,
with abuse representing the non-medical use of over the counter preparations
such as codeine for the euphoric effect. Fleming, McElnay, & Hughes, (2004)
observe that misuse can apply to all medicines, with abuse relating to specific
drugs such as codeine.
This review adopts Casati et al.’s, (2012) broad definition of ‘misuse’ which is:
‘The problematic consumption of codeine where risks and adverse
consequences outweigh the benefits, and which includes use of codeine
with or without prescription, outside of acceptable medical practice or
guidelines, for recreational reasons, when self-medicating, with higher
doses and for longer than advisable’
Albsoul-Younes et al. (2010) define abuse as:
‘The use of drugs for nonmedical purposes, i.e., to experience their
mind-altering effects, while “misuse” is applied to the use of a drug for
legitimate medical purposes, but in an incorrect manner, i.e., its use for
longer duration than prescribed or in a higher dose than recommended
on the packet’.
For the term ‘abuse’ the DSM-IV definition and criteria is used:
‘A pattern of maladaptive substance use that is associated with recurrent
and significant adverse consequences’.
A diagnosis of substance abuse requires meeting at least one of the following
four criteria due to recurrent substance use:




Failure to fulfil obligations at home/school/work
Use in situations that are physically hazardous
Legal problems
Social or interpersonal problems
It should be noted that few empirical studies of ‘pharmaceutical medication’
assess according to these criteria, often because the user does not perceive
their use as abuse (Barrett et al., 2008).
Of interest is the inter-changeability of the term ‘patient’ for those attending
hospital services (Mattoo et al., 1997; Myers et al., 2003), ‘client’ in pharmacy
based interventions (Fleming et al., 2004), and ‘customer’ in studies of over
the counter supply (Albsoul-Younes et al,. 2010; McBride, Pates, Ramadan,
McGowan, 2003).
43
There is distinct variation in the literature in terms of “pharmacodependence”
(Orriols et al., 2009). The term ‘addiction’ is sometimes used (Hughes, 2003;
Reay, 2009) or ‘dependence’ is the term of choice for codeine specific studies
(Tinsley & Watkins, 1998; Orriols et al., 2009).
DSM V (American Psychiatric Association, 2000) combines previous DSM IV
categories of substance abuse and substance dependence into a single
disorder - substance use disorder, which is measured on a continuum from
mild to severe.
Substance use disorders are patterns of symptoms resulting from use of a
substance which the individual continues to take, despite experiencing
problems as a result. These disorders span a wide variety of problems arising
from substance use, and cover 11 different criteria:
1. Taking the substance in larger amounts or for longer than the you
meant to
2. Wanting to cut down or stop using the substance but not managing to
3. Spending a lot of time getting, using, or recovering from use of the
substance
4. Cravings and urges to use the substance
5. Not managing to do what you should at work, home or school, because
of substance use
6. Continuing to use, even when it causes problems in relationships
7. Giving up important social, occupational or recreational activities
because of substance use
8. Using substances again and again, even when it puts the you in
danger
9. Continuing to use, even when the you know you have a physical or
psychological problem that could have been caused or made worse by
the substance
10. Needing more of the substance to get the effect you want (tolerance)
11. Development of withdrawal symptoms, which can be relieved by taking
more of the substance.
Two or three symptoms indicate a mild substance use disorder, four or five
symptoms indicate a moderate substance use disorder, and six or more
symptoms indicate a severe substance use disorder.
Substance use disorders are one of two groups of substance-related
disorders identified in DSM 5. The other group is substance-induced
disorders, which are symptoms caused directly from the use of a substance
that an individual continues to take, in spite of experiencing problems as a
result; for example, intoxication, withdrawal and substance induced mental
disorders.
When diagnostic criteria for dependence are met, along with tolerance and/or
withdrawal, a physical dependence is diagnosed (Barrett et al., 2008). Of
note, in the case of pharmaceutical dependence, this can occur following long
term prescribed use and in the absence of intentional misuse (for example for
44
pain), and in illicit drug users as substitute medication (for example heroin)
(Barrett et al., 2008).
Transitioning between misuse and abuse, in the form of involuntary addiction
is less explored in the literature (Reay, 2009). Non-prescribed’ medication use
includes a range of consumptive behaviours, motives, risk behaviours and
user characteristics (Barrett et al., 2008). Non-prescribed use with therapeutic
intentions is problematic due to lack of medical supervision, and often lack of
medical diagnosis, but not as risky as forms of recreational use (Barrett et al.,
2008).
Terminology is further complicated by the recognition that trajectories and
symptoms differ, with use often for longer than intended, withdrawal on
cessation, and with recreational users presenting unique consumptive
patterns and symptoms of use. Indeed, “Not all drug users are necessarily
addicted to drugs or are chaotic users, and many manage their drug use as
part of their normal daily routine. Such misuse is termed recreational use”
(Scottish Specialist in Pharmaceutical Public Health, 2004, p.24).
Poly substance users who misuse pharmaceuticals seek formulations which
enhance the effect of other substances, for example the co-administration of
opiates and stimulants, minimise undesirable effects, for example comedown
symptomatology such as insomnia, and for prolonging drug episodes (Barrett
et al., 2008).
1.6.2 Characteristics of codeine misusers
Whilst the potential for misuse and dependence on codeine is established in
the literature, research on prevalence and incidence of persistent and
problematic use of this weak opioid in patients with non-cancer chronic pain or
non-pain patients is scant (Roussin, Bouyssi, Pouche, Pourcel, & LapeyreMestre, 2013; Skurtveit, Faru, Borchgrevink, Handal, & Fredheim, 2011).
Individuals who misuse prescription or over the counter pharmaceuticals may
not identify themselves as addicts, because of an inferred degree of safety
and sanctioning by prescribers and pharmacies. Moreover, there are different
legal consequences of misuse in comparison to illicit drug use. It is important
to recognise variance in groups of non-compliant codeine users and misusers
so that initiatives to prevent misuse can be targeted appropriately.
Cooper (2011) identifies three distinctive groups of over the counter codeine
medicine user based on quantity of consumption. They are (1) users that
never exceed the maximum dose; (2) users who sometimes consume slightly
higher than the recommended dose; and (3) those who consume significantly
higher doses than recommended. No displacement between these three
types was observed.
In terms of codeine dependence, two distinct cohorts of dependent user are
identified. The first cohort commence codeine use for pain management
(either prescribed or via pharmacy sale). They use it initially in an appropriate
manner and intentionally or unintentionally increase their dosage or length of
time administered in order to ease discomfort. This may be due to a lack of
45
awareness or poor pharmacy/health professional advice (Ford & Good, 2007;
Hughes et al., 1999). The second cohort are opiate dependent and use
codeine to manage withdrawals when unable to secure either heroin or
prescribed methadone (Heard et al., 2006; National Council on Patient
Information & Education, 2002; Reed et al., 2011; Roumie & Griffin 2004).
The prevalence of this public health issue remains unclear, with rates of
dependence on pharmaceutical drugs such as codeine used for pain
management lower than expected (Dobbin & Tobin, 2008; Fishbain, Cole,
Lewis, Rosomoff & Rosomoff, 2008). Quantitative studies have found that
individuals dependent on codeine are young and rate their health poorer than
nondependent users, report chronic pain, and represent greater numbers of
females, when compared with other groups of opioid dependent individuals
(Nielsen et al., 2011; Sproule, Busto, Somer, Romach, & Sellers, 1999).
Nielsen et al. (2011), in their web survey of individuals self-reporting over the
counter codeine use in Australia, reported that codeine dependent individuals
differed from non-dependent users as follows; consumption of well above the
recommended dose of over the counter codeine, for longer periods of time,
younger, lower levels of employment and education, and with family history of
substance dependence. This study also observed differences with other
populations of opioid dependents.
More recently, three distinct types of codeine dependent users were identified
using DSM-IV criteria for substance dependence. This ‘hidden’ population of
codeine users includes those with ‘iatrogenic’ dependence following medical
use of codeine for pain, anxiety or insomnia over time (Nielsen et al., 2010).
Pseudo-addiction is defined as the under-treatment of pain (Bell & Salmon,
2009). An identified ‘blurring between therapeutic and problematic use’ serves
to compound the individual’s problematic codeine use, particularly when
opioid withdrawal symptoms are experienced, and individuals consume
codeine to self-medicate (Nielsen et al., 2010).
The three subtypes of codeine dependent user are:
(1) Therapeutic dependence
This type of user is characterised by not exceeding therapeutic doses but
still demonstrates features of codeine dependence and often having a
picture of worsening pain. Some are consistent with descriptions of
medication overuse headache.
(2) Non-medical/recreational users:
This type of user is characterised by use that is specifically for the
euphoric effects of codeine. This group usually seeks and shares
knowledge to reduce harms.
(3) High dose dependence:
This type of user is characterised by the use of high doses (multiple
packets per day) and experiencing serious adverse effects from their use.
Their use almost always stems from therapeutic use with users often
having limited insight into their dependence for an extended period of time.
46
In some cases, use began for therapeutic use and escalated rapidly once
euphoric effects of codeine were experienced.
Of note, pharmaceutical dependence on codeine can occur following long
term prescribed use and in the absence of intentional misuse (for example for
pain), and in illicit drug users as substitute medication (for example heroin)
(Barrett et al., 2008). Estimations of this public health issue remain cloudy,
with rates of dependence on pharmaceutical drugs used for pain management
lower than expected (Dobbin & Tobin 2008; Fishbain et al., 2008). A
qualitative study conducted in the UK (Cooper, 2013b) described over the
counter medicine dependents as aware of their addiction, but not identifying
with the stereotypical drug user. They also reported self-blame in losing
control over the medicine taken initially for medical use. Codeine contained in
combination products was the main medicine used, and with subsequent use
characterised by internet and multiple pharmacy sourcing, and centring on the
opiate effect (‘the buzz’). Withdrawals were described, along with work and
health problem inversely related to dosage, and concerns centred on standard
forms of treatment available for opiate addicts.
1.6.3 Factors leading to misuse of codeine
A range of pharmacological, physiological, social and economic harms are
associated with over the counter medicine misuse (Cooper, 2013). Misuse is
related to the increasing dose of codeine, which increases abuse potential
and likelihood of adverse effects, even when combined with safer analgesics
such as paracetamol. The relationship between the misuse of over the
counter medicines such as codeine containing products such as Nurofen Plus
(ibuprofen and codeine) and illicit drug use, and the diversion of codeine to
street drug markets has been reported in several studies (Levine, 2007;
Matheson et al., 2002; Reay, 2009; Sproule et al., 1999). Motives for use
range from self-treatment for physical or emotional pain consistent with
intended uses, to recreational and problematic drug use (Boyd, McCabe,
Cranford, & Young, 2006; Boyd & McCabe, 2008; Compton & Volkow, 2006a,
b; Daniulaityte et al., 2006; Lankenau et al., 2007; McCabe, Cranford,
Morales, & Young, 2006; McCabe & Teter, 2007; Teter et al., 2006, 2005;
Volkow & Swanson, 2003) with greater prevalence of recreational motives
among men (McCabe, Boyd, &. Teter, 2009).
Repeated administration of codeine in the absence of pain causes tolerance
and dependence (Derry et al., 2013). A Canadian study reported that codeine
dependents are more likely to report chronic pain, and likely to use codeine
for its pleasurable effect, to relax or reduce stress. Over half the sample
reported using over the counter products with average doses of 179mg per
day, and 80% of the sample reported using codeine 5 or more days per week
(Sproule et al., 1999). In Frei’s study (Frei et al., 2010), individuals reported
consuming between 435 and 602mg of codeine phosphate and 6800 to
9400mg of ibuprofen, and most had no previous history of substance use
disorder.
Continued use can occur in response to withdrawals in the case of physical
dependency on codeine and which include classic opiate dependence
47
symptomatologies albeit less severe than with morphine such as cravings,
preoccupation with seeking and taking codeine, lack of control of consumption
patterns despite negative side effects, insomnia, restlessness, runny nose,
stomach pains, diarrhoea and chills (Cooper, 2013b). Dependence has been
reported in prescribed analgesics containing codeine (McBride & MeredithSmith, 1995), with risk of dependence low in over the counter codeine
preparation if taken as directed (Cooper, 2013b). Individuals with codeine
dependence often commence codeine use in an effort to manage pain (Frei et
al., 2010; Tennant & Rawson, 1982; with others describing ‘chemical coping’
in the case of codeine use for stress (Nielsen et al., 2010). That said,
according to Pates et al. (2002), a “discrete group of possibly dependent
users who may fail to seek help” due to a lack of identification of their use as
potentially problematic may, nevertheless be aware of their increased use
1.6.5 Behavioural indicators of codeine misuse
Behavioural indicators of misuse and diversion of pharmaceuticals containing
codeine include requesting certain drugs, hoarding of medications, use of
multiple doctors and pharmacies, forging prescriptions, selling prescription
opioids, stealing prescription opioids from other patients, injecting
formulations, sourcing on the street, concurrent abuse of other licit and illicit
drugs, multiple unsanctioned dose escalations, and repeated lost or stolen
prescriptions (Chou et al., 2009; UNODC, 2011). As a result, health
professionals may become unintentionally involved in diversion (Sheridan &
Butler, 2008).
1.7 Conclusion
Codeine is an opiate widely used in the management of pain, cough and
diarrhoea. It is prescribed by healthcare professionals on prescription and can
also be bought over-the-counter in pharmacies. Its opiate analgesic effect
means that there is potential for misuse, abuse and dependence and is
becoming a global concern. The purpose of this scoping review is to map
what is known about codeine with regard to regulation, production,
distribution, prevalence, prevention and consequences of use. The next
chapter outlines the methods used for this review.
48
Chapter 2
Methods
2.1 Introduction
This chapter outlines the methods used for this scoping review of codeine
use, misuse and dependence. A key objective of the review was to map key
concepts underpinning this area of study as situated within medical, pharmacy
and treatment practices. This work was undertaken by a team of researchers
from both academic and pharmacy practice backgrounds that were recruited
to the CODEMISUSED project.
2.2 Approach
Scoping study methods are increasingly common and used for broad
searching of literature on a specific topic (Arksey & O’Malley, 2005; Daudt et
al., 2013; Levac et al., 2010). The scoping review was guided by Arksey &
O’Malley’s framework using six stages (Arksey & O’Malley, 2005). Figure 2.1
(flow diagram) on the following page represents the broad framework used.
2.3 Methods
A broad search was conducted in order to achieve a comprehensive scope of
the field (Daudt et al., 2013). Databases searched included PubMed, EBSCO
Host, Science Direct, EMBASE, PsycINFO, Cochrane library and Medline
from 1994 to 2014. Search terms used were in English and included: codeine;
dihydrocodeine; opiate medication; opioid misuse/abuse/diversion/addiction;
opioid dependence; over the counter codeine/medicine; analgesics;
prescription opioids; self-medication; pain; pharmacy; medical; treatment’.
Follow up search strategies included hand searching, searching of
pharmaceutical, health, medical, drug related websites, and contacting key
organisations such as the World Health Organisation (WHO), International
Narcotics board (INCB) European Medicines Agency (EMA), European
Monitoring Centre for Drugs and Drug Abuse (EMCDDA), authorised
medicine boards in each of the European membered states, The Federal
Drugs Agency (FDA) USA, the Canadian pharmacy authority, and the
National Health Service (NHS) in the UK.
A spreadsheet was created to chart relevant data (data collection categories
included author, setting, study aim and design/intervention, sample size, and
results/outcomes), to enable the identification of commonalities, themes, and
gaps in the literature. No restrictions were placed on inclusion so long as the
article reported the results of research (collecting qualitative or quantitative
data) or other systematic enquiry into the use or misuse of codeine. Two
reviewers independently screened titles and abstracts to determine inclusion
status. A second screen of the full-text of each article, again by two
independent reviewers, ensured that the studies were relevant to the focus of
the review and, through a charting exercise (as per Levac et al. 2010),
49
identified the specific areas of the review to which they could contribute and
extracted article data manually into a database. Disagreements were resolved
through discussion.
A hand search of reference lists from published peer reviewed studies was
also undertaken. Articles beyond the search years (1995-2013) were
reviewed to establish their relevance to the review.
Identifying the research questions
Compehensive search of the
literature
Screening of the literature using
predefined inclusion and exclusion
criteria
Screening of the literature,
identifying themes and charting of
the results
Collating, summarising and
reporting of the results, including
thematic analysis
Consultation (CODEMISUSED
Partners and Expert Panel to
inform and validate study findings)
Figure 2.1- Framework utilised in the scoping review (adapted from Arskey &
O’Malley, 2005)
Inclusion and exclusion criteria were set to determine the relevance of the
literature with regard to the aim and objectives of the review.
Inclusion criteria
 Research studies of prevalence or incidence of prescribed and over the
counter codeine use, misuse, abuse, diversion, treatment and
dependence in adult populations.
 Research studies that describes the tampering of codeine containing
medicines.
50








Reports of interventions for the treatment of codeine dependence.
Reports of pharmacy based interventions for codeine use and misuse.
Research studies of at risk groups and other illicit drug users that use,
misuse or is dependent on codeine.
Research studies which examine the effectiveness of codeine in pain
management
Research studies examining pharmacovigilance, pharmacodynamics
and pharmacokinetics with particular reference to codeine.
Literature in relation to the sale, consumption and manufacture of
codeine.
Policy documents on the scheduling of codeine medicines products.
Policy documents and guidelines with a particular reference to codeine.
Exclusion criteria
 Anecdotal and opinion based literature about prescribed and over the
counter codeine use, misuse, abuse, diversion, treatment and
dependence in adult populations.
 Literature not available in English.
 Articles where full text was not available.
 Empirical studies examining codeine in animal populations.
Two researchers screened literature titles and abstracts to determine their
inclusion status. Full text articles were reviewed and screened by two
independent researchers to ensure they met the inclusion criteria. Full text
articles were placed in a shared file by author, year and title of study to avoid
duplication. References were managed by the citation manager Endnote®.
This software facilitated the recording and organisation of all relevant
literature. This allowed the cross checking of data records, removal of
duplicates and extraction of information from the papers included in the
review.
Initial screening identified a total of 3,105 articles, of which 475 met the
inclusion criteria. They were manually uploaded onto the shared folder and
the Endnote database. Eight broad categories were identified to assist in the
organisation of the literature and data extraction - see Table 2.1.
Table 2.1- Broad categories used to organise literature included in the review
Categories relating to codeine
Production, manufacture, consumption and regulation of codeine
Characteristics and profiles of codeine users
Therapeutic use of codeine within healthcare
Prevalence of codeine use, overuse, misuse and dependence
Prevention of codeine overuse, misuse and dependence.
Consequences of codeine use/misuse(health and society)
Over the counter and internet sale of codeine medication
Interventions and treatment for codeine misuse
51
The following information was extracted for each paper included in the review
and tabulated: author; year; country of origin; study aims; methodology;
sample size and setting; outcome measures; results and author’s conclusions
and specificity to codeine. Data was extracted for each paper by a single
researcher and checked by a second researcher to ensure that data
extraction was accurate and comprehensive. A qualitative synthesis of the
literature was carried out within categories and sub-categories.
A stakeholder consultation stage from addiction, nursing, psychiatry,
psychology, health, pharmacy, drug control and pharmacovigilent
backgrounds (Arksey & O’ Malley, 2005; Daudt et al., 2013; Levac et al.,
2010) with CODEMISUSED partners and the CODEMISUSED Expert Panel
was undertaken and contributed to extraction of multifaceted perspectives
from the extant literature on codeine throughout the review process.
2.4 Results of the search
Figure 2.2 presents the flow diagram for the literature included in and
excluded from the review.
3105 articles identified through databse
searching
475 total number after
duplictes and non
language english
removed
475 articles screened for inclusion criteria
242 full text articles
retrieved
22 other records
included (reviews
papers, reports etc
233 abstract identified
and exlcuded for
charting
91 record excluded for
lack of specificty to
codeine
149 studies included in the final
review and synthesis under main
thematic headings
Final screening and
further removal of
non-specific articles
n=33
Final number of articles charted =
117
52
2.5 Conclusion
This chapter outlined the methods used for the scoping review. Arksey &
O’Malley’s framework using six stages was used to guide this process. The
findings were synthesized under seven broad categories as outlined in table
2.1. The stages of this scoping review were similar to that of a systematic
review, in that our search and review efforts aimed to achieve systematic
selection, retrieval and synthesis of extant knowledge within a broad thematic
remit (Mays, Roberts, & Popay, 2001). The process of navigating and
redefining the findings was iterative, and we engaged with each stage in a
reflexive manner, by fine tuning and repeating steps so as to ensure
comprehensive synthesis of literature.
53
Chapter 3
Production, Manufacture, Consumption
and Regulation of Codeine
3.1 Introduction
This chapter reports on the global production, manufacture, consumption and
regulation of codeine. The reported figures are taken directly from the
statistics produced by the International Narcotics Control Board (INCB) (INCB,
2012; INCB, 2013). Figures quoted are in metric tonnes.
3.1.1 Definition of terms
The following are definitions of terms as outlined by the INCB:
 Consumption: - act of supplying a narcotic drug to any person or
enterprise for retail distribution, medical use or scientific research.
 Utilisation – refers to the use of codeine for the manufacture of other
drugs.
 Drug - substances included in Schedules I or II of the 1961 Convention,
whether natural or synthetic.
 Manufacture- all processes, other than production (see definition
below) by which drugs may be obtained and includes refining as well
as the transformation of drugs into other drugs.
 Preparation - any mixture, solid or liquid, subject to international control
owing to the fact that it contains a drug under international control.
Preparations listed in Schedule III of the 1961 Convention are
exempted from some control measures (when compounded with one or
more other ingredients and containing not more than 100 milligrams of
the drug per dosage unit and with a concentration of not more than 2.5
per cent in undivided preparations).
 Production - refers to the separation of opium, coca leaves, cannabis
and cannabis resin from the plants from which they are obtained.
 Stocks - refers to the amounts of drugs held in a country or territory for
domestic consumption, manufacture of other drugs or export.
3.2 Global stocks and requirements
In 2010, the global stock of codeine was 173 tonnes, with approximately 59%
being held by five countries (United States, United Kingdom, Australia, France
and India). Similarly for 2011, global stocks of codeine were 176 tonnes with
56% (approximately) of this global stock being held by four countries United
States (36 tonnes); United Kingdom (25 tonnes); France (19 tonnes) and India
(18 tonnes) - see figures 3.1 & 3.2. Fourteen other countries held quantities of
codeine greater than 1 ton and included Australia, Japan, Canada, Hungary,
Romania, Norway, Switzerland, Spain, Germany, South Africa, Italy, Russia,
China and Turkey (INCB, 2012).
54
Table 3.1 presents the estimated world requirements of codeine and
dihydrocodeine in grams for 2013 for Europe and other countries with high
global stock requirements (INCB, 2013).
Figure 3.1 – Major stockists (countries) of codeine 2010-2011
Major Stockists (countries) of Codeine 2010-2011
40
36
35
30
29.2
Tons
25
24.4
25
22.3
19
20
18
15
15
11.6
10
5
0
2010
United States
2011
Australia
France
United Kingdom
India
Table 3.1 – Codeine and dihydocodeine estimated requirements in grams
2013
Country
Albania
Australia
Austria
Belgium
Belarus
Bosnia and
Herzegovina
Codeine (grams)
35 000
9 800 000
500 000
4 700 000
3 000 000
78 000
Dihydrocodeine (grams)
Brazil
3 600 001
1 000
Bulgaria
Canada
China
China -Hong Kong
Croatia
Cyprus
Czech Republic
Denmark*
Egypt
4 000 000
29 231 000
10 400 000
4 501 000
205 000
35 000
1 080 000
1 000 000
450 000
40 000
200
450 000
6 001
285 000
650 000
482 000
1 000
10
3 000
55
Estonia
Finland
France
Germany
Greece*
Hungary
Iceland
India
Ireland
Italy
Japan
Latvia
Lithuania
Luxembourg
Malta
Montenegro
New Zealand
Norway
Poland
Portugal
The Netherlands
Romania
Serbia
Slovenia
Slovakia
Spain
South Africa
Sweden
Switzerland
United Kingdom
United States of
America
Ukraine
300
1 230 000
30 100 000
6 010 001
700 000
12 220 000
130 000
65 000 000
5 500 500
14 000 000
15 230 000
301
2
110
4
1
1 681 300
3 908 600
1 550 000
450 000
250 000
1 214 890
50
40 240
3 386 215
8 200 000
10 860 000
714 000
2 200 000
76 887 000
83 201 856
500
1 000
96 500
1 510 000
1 100 000
601 000
1 000 000
12 515 000
1
360 000
1
60 000
237 831
21 001
500
50 000
395 000
25 001
2 630 000
90 000
4 693 342
3.3 Global consumption
Globally, the demand for codeine remains high and has risen by
approximately 27% over the last decade. Recent reported figures estimate
that consumption reached an all-time high at 269 tonnes in 2011 and
compares to 164 tonnes in 1992 (INCB, 2012). Approximately 225 tonnes and
240 tonnes of codeine were consumed in 2008 and 2007 respectively.
Codeine remains the second most widely administered opiate in medical
practice and its total defined daily dose (assumed average maintenance dose
per day for a drug used for its main indication in adults) is recorded at
2.7billion (S-DDD) (INCB 2012). (Figure 3.2 – below details the emerging
trend of codeine consumption over the years 2007-2011).
56
Figure 3.2 – Global consumption of codeine 2007-2011
Global consumption of Codeine (Tons)
280
270
260
Tons
250
Global consumption of
Codeine in (Tons)
240
Linear (Global
consumption of Codeine
in (Tons))
230
220
210
200
2007
2008
2009
2010
2011
3.4 Global manufacture, exports and imports
It is estimated that approximately 90-95% of codeine manufactured globally is
obtained from morphine through a semi-synthetic process. Codeine is mainly
used for the manufacture of preparations under schedule III of the 1961
convention and to a lesser extent for the manufacture of dihydrocodeine and
hydrocodone. Preparations listed under Schedule III accounts for 99% of the
consumption of codeine (INCB, 2012). Codeine manufacture reached a peak
of 381 tonnes in 2011 compared to 349 tonnes in 2007 (INCB, 2012).
In 2011, figures highlight that the UK was the highest codeine manufacturer
(85 tonnes representing 22% of global manufacture); followed by France (78.3
tonnes - 21%); United States (64.6 tonnes - 17%) and Australia (31.9 tonnes 8%). Figure 3.3 shows the global manufacture by tonnage for the four main
countries in 2011.
World exports of codeine have continued to rise reaching 168.4 tonnes in
2011, highest level ever recorded. This figure is up from 160 tonnes in 2010
and almost double from the previous decade. France was the principal
exporter of codeine at 28% (46.8 tonnes). Australia was the next leading
exporter (16% - 26.3 tonnes), followed by the UK (13% - 21.1 tonnes) and
Iran (10% - 16.8 tonnes).
The main countries importing codeine in 2011 were India (48.9 tonnes),
Canada (20.2 tonnes), Switzerland (13 tonnes) and Germany (9 tonnes) – see
figures 3.4 and 3.5.
57
Figure 3.3 – Global manufacture of codeine in 2011 (tonnes)
Global Manafacture of Codeine (Tonnes)
2011
31.9
85
United Kingdom
France
64.6
United States
Australia
78.3
58
Figure 3.4: Codeine Exports 2011
Figure3.5: Codeine Imports 2011
Codeine Export (Tonnes)
Iran
Codeine Imports (Tonnes)
16.8
United
Kingdom
Germany
9
Hungary
9.3
21.2
Codeine
Export (Tons)
Australia
Switzerland
Codeine
Imports (Tons)
13
26.3
Canada
France
46.8
0
20
40
20.2
India
48.9
0
60
20
40
3.5 Codeine utilisation
Sixty eight percent (68%) of codeine used for the manufacture of schedule III
drug preparations in 2011 was listed in six countries (India, UK, France, Iran,
US, and Canada). It should be noted that utilization of codeine does not
indicate consumption of these preparations. The major manufactures were
India (50.3 tonnes) and the UK (50 tonnes). Each country has seen a rise in
utilisation since 2010 with a 3.6% increase in manufacture in India, 2.9%
(Iran), 1.7% (US) 1.6% (France) 1.4%(UK), and 0.2%(Canada). Figure 3.6
highlights codeine utilisation in 2010 for manufacture of preparations listed in
Schedule III of the 1961 convention.
Utilisation of codeine for other preparations such as dihydrocodeine and
hydrocodone has declined since 2007 (81.8 tonnes). In 2010, utilisation
decreased to 52.6 tonnes but increased to 62.3 tonnes in 2011. The main
reason was for the manufacture of hydrocodone in the US in 2011 (30.1
tonnes), 2010 (25.4 tonnes)), while the remaining was used for the
manufacture of dihydrocodeine in Japan, the UK and Italy (INCB, 2012).
59
60
Figure 3.6 – Utilisation of codeine preparations for manufacture of
preparations
Utilisation of codeine for the manafacture of preparations
0
17.50%
India
18.90%
United Kingdom
France
2.10%
2.80%
Iran (Islamic Republic)
United States
3.00%
Canada
3.60%
18.80%
3.00%
China
Australia
Hungary
6.20%
Spain
6.80%
7.20%
10.10%
Germany
INCB 2012
3.5.1 Utilisation, exports, imports and stocks of codeine in Ireland,
South Africa and UK
This section presents data in relation to codeine utilisation for the manufacture
of schedule III preparations and other drugs, exports, imports and stocks for
each of the three participating countries (Ireland, South Africa and UK) for the
past five years. The information presented is in response to a communication
with the INCB (Stefano Berterame, Chief, Narcotics Control & Estimates
Section, personal communication to Professor Charles Parry).
Over this five year period there was a decrease of just over 1 tonne (metric) in
the utilisation of codeine in the manufacture of schedule III preparations in
Ireland, while utilisation increased by over 1 metric tonne in South Africa and
18 metric tonnes in the UK - see figure 3.7.
60
Figure 3.7- Quantity utilized for manufacture of preparation 2008-2012
Quantity utilized for the manafacture of schedule III
preparations (2008-2012)
60.000
Codeine (Tons)
50.000
40.000
Ireland
30.000
South Africa
20.000
United Kingdom
10.000
0.000
2008
2009
2010
2011
2012
Utilisation of codeine for preparation of other drugs was only recorded in the
UK. While there have been some fluctuations in use recorded over the 5 year
period, it remains at just over 12 metric tonnes - see Figure 3.8.
Figure 3.8 – Quantity utilized for the manufacture of other drug (UK 20082012)
Codiene (Tons)
Quantity utilized for the manafacture of other drugs
(United Kingdom 2008-2012)
20.000
18.000
16.000
14.000
12.000
10.000
8.000
6.000
4.000
2.000
0.000
United Kingdom
2008
2009
2010
2011
2012
UK imports for codeine showed significant fluctuations between 2008-2012,
peaking at just under 14.5 metric tonnes in 2010. South Africa has seen
limited importation at just 0.248kg in 2008 and zero in 2012. In Ireland imports
have slightly decreased from 5.5 metric tonnes in 2008 to 3.9 metric tonnes in
2012. Figure 3.9 highlights codeine imports for each country in Kgs
61
Figure 3.9- Imports of Codeine 2008-2012
codieine Imports KGs
Codeine Imports 2008-2012
16,000.000
14,000.000
12,000.000
10,000.000
8,000.000
6,000.000
4,000.000
2,000.000
0.000
Ireland
South Africa
UK
2008
2009
2010
2011
2012
5,532.162
5,081.817
5,135.167
3,865.606
3,978.820
0.248
0.044
0.000
0.000
0.000
6,261.361
8,387.116 14,445.828 3,336.679
4,160.297
Codeine exports were highest in the UK ranging from over 26 metric tonnes in
2008 to 33.6 metric tonnes in 2012. Ireland’s exports of codeine peaked in
2008 at 67kg and have seen a sharp decrease since. Exports of codeine are
rising in South Africa, but are significantly less than the UK at just 2.2kg in
2012. Figure 3.10 presents the exports of codeine from 2008-2012
Figure 3.10 – Exports of codeine 2008-2012
40,000.000
Exports of Codeine 2008-2012
35,000.000
Exports in Kgs
30,000.000
25,000.000
20,000.000
15,000.000
10,000.000
5,000.000
0.000
2008
2009
2010
2011
2012
Ireland
67.675
19.405
0.942
49.824
0.007
South Africa
0.000
3.700
0.024
0.289
2.220
26,157.511
21,240.940
18,630.374
18,768.586
33,600.090
UK
The total codeine stock held between all three countries in 2012 was 25.5
metric tonnes, with the UK holding the majority share. In 2012, Ireland held
571Kg of codeine stock with South Africa and the UK each holding 4.9 and 20
metric tonnes respectively. Figure 3.11 details the codeine stock in each of
the countries from 2008-2012.
62
Figure 3.11 – Codeine Stocks 2008-2012
Codeine Stocks
30,000.000
Codeine Kgs
25,000.000
20,000.000
15,000.000
10,000.000
5,000.000
0.000
Ireland
2008
2009
2010
2011
2012
1,068.411
673.909
158.597
663.944
571.188
3,099.188
3,441.794
2,974.266
4,943.089
South Africa 2,065.048
UK
18,243.624 14,863.904 14,973.760 24,995.000 20,000.000
3.6 Over-The- Counter consumption of codeine preparations
Over the counter sales of codeine containing medications is not easy to
determine due to commercial sensitivity, trade exemptions or where such
disclosure of information might prejudice the commercial interests of any
person or public authority. The major pharmaceutical manufacturing
companies were contacted 5 (Adlock Ingram, Johnson &Johnson, Sanofi,
Glaxosmithkline, Pharagen, Teva) and requested to provide approximate
figures for their sales of over the counter codeine products. All declined and
quoted ‘commercial sensitivity’. IMS healthcare were also contacted but a
subscription to this service was required.
UK market figures indicate that the over the counter drug market is worth over
553.3million sterling, with adult analgesia accounting for approximately 350
million of all over the counter sales (PAGB, 2012). Walker, Evans and
Meacham (2009) examined physical dependence and addiction to
prescription and over the counter medication in Wales (UK) and obtained data
from IMS heath (Institute for Healthcare Informatics) on the consumption of 3
particular drugs: Nurofen plus® (ibuprofen 200mg +codeine 12.8mg),
Solphadine plus® and Ultamol® (paracetamol 500mg, 8mg codeine) across
628 of the 714 pharmacies in Wales (Walker et al., 2009). Mean sales figures
for Nurofen ® during 2005-2008 was shown to be 6 packs per 1000 of the
population, however some areas in Wales reported sales as high as 18 packs
per 1000. Solpadeine Plus® and Soluble Ultramol had a mean number of
packs at 24 per 1000 of the population based on the combined figures of
2005-2008. In one district of Wales - Blaenau Gwent in 2008, sales of these
products was 400 packs per 1000 population.
5
Contact was made by members of the CODEMISUSED team during November and December 2013
63
An attempt to quantify the sales of codeine by number of tablets or capsules
per carton was carried out in England (Reed et al., 2011). The Propriety
Association of Great Britain, the UK trade association for manufacturers of
branded over-the-counter medicines and food supplements provided sales
figures. These figures do not reveal how the medicines were used when sold
but they do provide a useful indicator of the overall extent of use in the UK
during this period. Table 3.2 was reproduced with permission from the
Propriety Association of Great Britain. It should be noted that these data are
prior to the introduction of restrictions on over the counter codeine in the UK.
It is now permissible to sell only a maximum supply of 32 tablets in any single
transaction.
Table 3.2 – The sales of over the counter codeine preparations
Sales of codeine products by
2006
2007
number of tablets or capsules
per carton (Propriety Association
of Great Britain 2009)
(Reproduced with permission)6
Pack size (no. of tablets)
10
392,748
303,360
12
2,621,434
1,844,933
16
263,767
1,298,902
20
1,809,488
1,610,965
24
3,126,146
1,690,097
30
2,536,960
2,580,571
32
5,390,315
10,604,674
48
734
327
60
2,128,283
125,117
100
1,328,271
1,385,378
Total
19,598,146 21,444,324
2008
297,718
1,229,799
1,577,164
1,486,898
1,346,093
2,680,489
11,152,623
240
5,980
1,467,327
21,244331,
3.7 Regulation of Codeine
Codeine is a listed narcotic drug held under international control and
regulated by the regulatory authority of medicines in individual countries. Pure
Codeine is listed under Schedule II, of the 1961 convention on Narcotic drugs.
However, most codeine products are classified under Schedule III due to
being compounded with one or more other ingredients and not containing
more than 100 milligrams of the drug per dosage unit with a concentration of
not more than 2.5 per cent in undivided preparations (INCB, 2011).
Codeine preparations classified under Schedule III are pharmacy only. Under
this schedule a prescription is required and must include full details of the
form and strength of the preparation and the total quantity written in both
6
Sales of codeine products by number of tablets or capsules per carton ( Propriety Association of Great Britain
2009) (Reproduced with permission) Pack size (no. of tablets) (Reed et al. 2011)
64
words and figures. It is the ‘prescribers’ responsibility to minimise the risk of
dependence and quantities of drugs should match the likely needs of the
patient until their next clinical review.
Under Schedule III there is no requirement to keep controlled registers. In
some countries codeine preparations are available without prescription in
combination preparations (paracetamol, ibuprofen or aspirin) from licensed
pharmacies in doses up to 12.8 mg of codeine phosphate. Concentrations of
up to 28mg are permissible in some countries under pharmacy supervision.
Over the counter (OTC) sales of products containing codeine generally must
be supervised by the pharmacist. Some countries restrict the visual display
and advertisement of over the counter codeine preparations to the consumer.
New regulations restricting the prescribing of codeine preparations to children
are now in place. Codeine is now contraindicated in children (less than 18
years) undergoing surgical removal of tonsils or adenoids, in ultra-rapid
cytochrome CYP2D6 metabolizers and breastfeeding women. The use of
codeine is not recommended in children whose respiratory function may be
compromised by respiratory conditions, trauma or extensive surgical
procedures and should only be used where benefits outweigh the risks (EMA,
2013).
Table 3.3 details the scheduling of codeine across the EU, Australia, Canada,
United States of America, Asia and South Africa. This information is taken
from a number of sources. Information obtained through direct
communications with the medicines agencies in the listed countries is
indicated by a reference. The country, regulatory agency and regulation of
over the counter and prescription codeine are detailed. Dihydrocodeine is
listed where data were available.
65
Table 3.3 –Regulation of codeine, over the counter (over the counter) and prescribed (including dihydrocodeine)
Country
Regulatory
agency
Standard for the
Uniform
Scheduling of
Medicines and
Poisons
(SUSMP).
Over the counter preparations (over the counter)
codeine/dihydrocodeine preparations sold in pharmacies
Preparations fewer than 12.5mg of codeine less than 5 days can
only be sold under pharmacist’s supervision.
Cannot be advertised directly to the consumer.
Labelled with a recommended total daily dose of up to 100mg
codeine (128 mg codeine phosphate).
Austria
Austrian federal
office for safety in
Healthcare.
Belgium
Federal agency
for medicine and
health products.
Bulgarian drugs
agency
Generally not sold as an over the counter product but some
provincial and municipal relegation which allows cities and provinces
to regulate the selling of least regulated schedule of drugs as
defined by the substance narcotic law.
Pharmacy is self-regulating and can control sale and item quantities.
Not sold as an over the counter medicine.
Australia
Bulgaria
Canada
National Drug
Scheduling
Advisory
Committee.
Sold as an over the counter in combined preparations.
Main products include
Aceffeine® tablets (250mg paracetamol/ 250mg Acetylsalicylic
acid/10 mg codeine phosphate /50mg caffeine
Solpadeine® caps/soluble 8mg codeine phosphate/500mg
paracetamol/30mg caffeine
Paracofdal® tablet – 200mg paracetamol/300mg metamizole
sodium/20mgcodeine phosphate /caffeine 30mg
Caffetine forte® - 250mg paracetamol/210 mg propyphenazone /10
mg codeine phosphate and 50mg Caffeine.
Products can be displayed in the pharmacy and sold without
pharmacist’s supervision. There is no restriction on the number of
tablets sold but must include warning of addiction.
Over the counter codeine combination products available up to 8mg
or its equivalent of codeine phosphate per tablet or per unit in other
solid form or not more than 20 mg or its equivalent of codeine
phosphate per 30 mL in a liquid preparation. Products may not be
displayed and must be kept out of view of the consumer.
No pharmacist shall sell or provide a preparation if the pharmacist
has reasonable grounds to believe that the preparation is to be used
66
Prescription only medicine (POM) codeine/dihydrocodeine
POM when containing more than 5 days treatment and greater than
12mg of codeine (15.4mg codeine phosphate) per dosage unit.
Labelled with a recommended total daily dose of up to 100mg codeine
(128 mg codeine phosphate).
Preparations containing pure codeine (e.g., codeine phosphate tablets
or codeine phosphate linctus are considered controlled drug (CD)
(Controlled Drug (Possession without authority is illegal).
Dispensing of products containing codeine and similar drugs,
dihydrocodeine, requires a prescription order from a doctor or the
discretion of the pharmacist.
Plain codeine hydrochloride tablets are controlled drugs as well as other
non-injectable forms of codeine and must be dispensed in this way.
As of the 17 June 2013, all medicines containing codeine or codeine
derivatives can only be issued on a medical prescription.
Prescription only medicine in higher doses usually 30mg of codeine
phosphate.
Other product Sedalgin –neo ® 300mg paracetamol/150mg metamizole
sodium/10mg codeine phosphate/15mg phenobarbital/50mg caffeine.
No pure codeine products available in Bulgaria.
Stronger doses of greater than 8mg of codeine phosphate must be
prescribed by a medical practitioner.
Non-compounded Codeine is a schedule one drug in Canada and can
only be prescribed by a medical professional.
for purposes other than recognized medical or dental purposes.
Over the counter cough suppressant available up to 0.1% (5mg/5ml)
of active drug from licensed pharmacies.
Regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous
Drugs Ordinance. It can be used legally only by health professionals.
Must only be dispensed as a prescription item. Anyone who supplies
the substance without a prescription or traffics the drug can be fined
and or jailed.
Codeine containing medicines are available on prescription only, 3 main
medicines available, Caffetin®, Codeine phosphatis and Plivadon®.
China -Hong
Kong
Pharmaceutical
service –
Department of
Health (HK).
Croatia
Agency for
medicinal
products and
medical devices of
Croatia.
State Institute for
drug control.
Not sold as an over the counter medicine.
Not sold as an over the counter medicine.
All codeine containing products are medical prescription drugs only.
Danish health and
medical authority.
State agency of
medicines
Sold as an over the counter medicine as combination products up to
9.6mg of codeine.
Sold as combination drug up to 8mg of codeine. 2 main products
Co-Codamol® (codeine phosphate paracetamol 8/500) and
Solpadeine® (codeine phospahate, paracetamol codeine 8/500/30).
Prescription only medicine in preparations greater than 9.6mg.
Finland
Finnish medicines
agency
Over the counter codeine preparations are not sold in Finland
France
French national
agency of
medicine and
health products
safety.
Germany
German central
authority for
health protection
with regards to
medicines
products and
medical devices
National
organisation for
Over the counter codeine preparations sold as combinations under
supervision at community pharmacies up to 20mg per dose.
Thirteen analgesic formulations of drugs containing codeine can be
requested without limit of duration of use.
These drugs are placed behind the dispensing counter in the
pharmacies, and patients must request them from a member of the
pharmacy staff.
Generally not sold as an over the counter product but some
provincial and municipal relegation which allows cities and provinces
to regulate the selling of least regulated schedule of drugs as
defined by the substance narcotic law.
Pharmacy is self-regulating and can control sale and item quantities.
Czech
Republic
Denmark
Estonia
Greece
Not sold as an OCT medicine.
Prescription only above a concentration of 8mg of codeine phosphate.
30/500 codeine phosphate/paracetamol combination, 30/400
codeine/ibuprofen combination.
1 dihydrocodeine product licenced containing 60mg of active drug.
10 codeine preparations licenced for use. Combination products with
paracetamol (Pamol®, Paraceon® (500/30mg) and ibuprofen®
(30mg/400) is only available on a medical prescription.
Combinations containing codeine over 20mg must be prescribed by a
medical practitioner.
Dispensing of products containing codeine and similar drugs
dihydrocodeine requires a prescription order from a doctor or the
discretion of the pharmacist.
Plain codeine hydrochloride tablets are controlled drugs as well as other
non-injectable forms of codeine and must be dispensed in this way.
Codeine is classed as an illegal drug in Greece and is a controlled drug.
There is also strict regulation on importation. It is sold only with a
67
medicines.
Hungary
Iceland
India
Ireland
Italy
Latvia
National Institute
for quality and
organisational
development in
healthcare and
medicines.
Icelandic
medicines
agency.
Only 1 over the counter product sold called Erigon szirup (cough
syrup).
Central drug
standards control
organisation
(CDSCO).
Irish medicine
board.
Guided under the
misuse of drugs
act 1977.
Not sold as an over the counter product.
Italian Medicines
Agency.
State Agency of
Medicines of the
Republic of Latvia.
Malta
Medicines
Authority of Malta.
New Zealand
New Zealand
Medicines and
Not sold as an over the counter product.
Over the counter sales permissible in regulated pharmacies under
supervision of the pharmacists without prescription Usually in
8mg/500 and 12.8mg/500 combination drugs containing analgesics
such as paracetamol and aspirin.
Cannot be visually displayed or advertised to the consumer.
Patient must be advised on its use at point of sale
Must contain warning of addiction on pack.
Not available over the counter.
Non-prescription medicinal products available over the counter
Co-Codamol® 500 mg/8 mg tablets.
Solpadeine® 500 mg/8 mg/30 mg tablets (effervescent and table).
Sirupus Pini compositus syrup (Calcium lactate
64 mg, Codeine phosphate - 3 mg, Celandine liquid extract - 10 mg)
Sirupus Tussipini (in 100 g syrup): Calcium lactate - 1 g, Codeine
phosphate - 0.05 g, Celandine liquid extract, 0.16 g, Fennel tincture
- 1 g, Pine liquid extract - 6.60 g.
Over the counter sales permissible in low doses less than 10mg of
codeine per single dose.
Must be sold in a pharmacy and under pharmacy supervision.
Over the counter in doses less than 15 milligrams of codeine per
solid dosage unit or per dose of liquid with a maximum daily dose
68
doctor's prescription - two main combination products Lonarid-N®
(500mg paracetamol, codeine phosphate 10mg and caffeine 50mg,
Lonalgal®(500mg paracetamol, 30mg codeine phosphate)
All other codeine containing medications must be prescribed by a
medical practitioner and dispensed by a pharmacist.
Preparations of paracetamol and codeine require a medical prescription
in Iceland.
Main products known as Parkódín® – codeine 10mg/paracetamol
500mg.
Medicines containing codeine are only dispensed on prescription of
Registered medical practitioner. There is a requirement to keep all
documents, batch no., patient no and their address which required for
auditing by drug inspector.
Higher strength codeine formulations 15/300, 30/500 of codeine
phosphate/paracetamol combinations- are prescription only medicines.
Codeine is also available combined with Ibuprofen; a common
formulation is 12.8 mg Codeine alongside 200 mg Ibuprofen.
Preparations containing pure codeine (e.g., codeine phosphate tablets
is considered controlled drug (CD) (Controlled Drug (Possession
without authority is illegal).
Available on prescription for pain relief and cough
Medical prescription required for all drugs over 8mg of codeine
phosphate.
No pure codeine products.
Higher dose require a medical prescription.
If more than 100mg of codeine they are considered as controlled drugs
with special prescription.
Prescription Only above 15mg of codeine phosphate and must be
prescribed by a medical professional.
Medical Devices
Safety Authority
Norway
Norwegian
Medicine agency.
Poland
Main
Pharmaceutical
Inspectorate
The
Netherlands
Medicines
evaluation board.
Russia
Russian
medicines board.
Spanish
medicines
agency.
South African
medicines
agency.
Spain
South Africa
not exceeding 100 milligrams of codeine, when combined with 1 or
more active ingredients. Pack of not more than 5-6days supply
Must be sold under supervision of a pharmacist.
Over the counter sales of codeine are not permissible in Norway.
Certain products are available Over the counter in combination with
other drugs. Maximum dose found in listed products is up to 20mg.
Regulation states that Codeine when compounded with one or more
other ingredients and containing not more than 50 milligrams of the
drug per dosage unit and with a concentration of not more than 1.5
per cent in undivided preparations are permissible. The pharmacist
can refuse sales if it is considered that the health of the patient is
endangered.
Only one over the counter available ‘(Natterman Melrosum extra
sterk stroop (RVG 03732)’. This cough suppressant product is in the
category Pharmacy and Drugstore only (PDO) and must be under
the supervision of the pharmacist. This product has low concentrate
codeine (2.5mg).
Not available over the counter
Not available as an over the counter, but may be sold with discretion
of the pharmacist.
Over the counter preparations in combination with one or more
therapeutically active substances, and containing 10 milligrams or
less of codeine (calculated as base) per dosage unit.
Pack sizes sold can contain up to 100 doses.
Sold under supervision of the pharmacists.
Sales of codeine containing products must be recorded in the
pharmacy.
69
Available on prescription only from a medical prescriber. Mainly
supplied as combination formulations.
Five Common drugs include Codalgin®, Codaxol®, Paralgin®,
Paramax® and Pinex®.
Above 20mg is only available on prescription.
No special prescription requirements.
Register of supply is required.
Products containing codeine/dihydrocodeine in the Netherlands are only
available on prescription from doctor of specialist.
All sales require a prescription.
Medical prescription required.
POM medicine in doses over 10mg of codeine per dosage unit and are
only available on medical prescription.
Sweden
Medical products
agency
Over the counter sales of codeine are not permissible.
POM medicine only. 16 approved drug for use mainly in combination
formulations with paracetamol and consisting of a dosage of 30mg/500.
One combination product containing a lower dose of 15mg/500.
Kodein Recip 25 mg tablet, is the only pure codeine containing drug
which is classed as narcotic according to list III and is a controlled drug.
United
Kingdom,
United States
of America
Medicine and
healthcare
products
regulatory
authority
Controlled under
the Medicine of
Drugs Act 1971.
Federal drug
Agency.
Over the counter sales permissible in regulated pharmacies under
supervision of the pharmacists without prescription. Usually in 8/500
and 12.8/500 combination drugs containing analgesics such as
paracetamol and aspirin.
1 over the counter Dihydrocodeine product containing 7.46mg of
active ingredient.
Only 1 pack x 32 tablets allowed per customer transaction unless
sanctioned by the pharmacist.
Can be visually displayed and advertised to the consumer at the
point of sale.
Must contain warning of addiction on pack.
Federal regulations state that certain preparations containing not
more than 200 milligrams of codeine per 100 millilitres or per 100
grams that also include a sufficient proportion of nonnarcotic active
medicinal ingredients providing medicinal qualities beyond those
possessed by codeine alone, are exempt from prescription
requirements
Local regulation of over the counter codeine occurs in various
states, with further detail found at http://www.nabp.net/boards-ofpharmacy/
Higher strength codeine formulations 15/300, 30/500 of codeine
phosphate/paracetamol combinations are prescription only medicines
(POM). Codeine is also available combined with Ibuprofen; a common
formulation is 12.8 mg Codeine alongside 200 mg Ibuprofen.
Preparations containing pure codeine (e.g., codeine phosphate tablets
is considered a controlled drug (CD). (Possession without authority is
illegal).
No longer permitted for use under the age of 18years (codeine
containing linctus for cough).
Majority of codeine containing drugs are only available on medical
prescription.
Quantities over 90mg per single dose unit are list under the controlled
drug schedule.
Websites of each of the regulatory agencies for Human Medicines were accessed to retrieve information about the regulation and
sale of codeine. Each regulatory agency was contacted individually by a member of the research team.
70
Chapter 4
Prevalence Rates of Codeine Use, Misuse
and Dependence and Associated Risk
Factors
4.1 Introduction
This chapter explores prevalence in relation to codeine use, misuse and
dependence and associated risk factors. The literature highlights a number of
issues in relation to the prevalence of codeine use, misuse and dependence.
These include paediatric use of codeine, codeine prescribed for pain, misuse
of over the counter forms of codeine (i.e. Codeine Cough Syrups); codeine
use in pregnancy, codeine products used to manufacture home-made drug
solutions such as desomorphine and recreational use of codeine. This nonmedical use of prescription opioids is associated with severe psychological
distress and misuse of other medications, with tailoring of specific
interventions for targeted high risk groups needed (Wang et al., 2013).
There is a gap in the evidence base in relation to the extent of inappropriate
use of codeine, misuse and dependent use of over the counter analgesics
containing codeine. For example, studies relating to codeine are often
combined with general prescription opioid studies and therefore are not
specific to codeine alone. We recommend greater education of codeine users
about variations in metabolism, and risks of long term use, risks associated
with polypharmacy intake to challenge the widely held but misinformed
perception that codeine based products are low risk in terms of their potential
for dependence. Greater concentration of policy and practice focus on
prevention, referral and support strategies for those who are at risk of or are
currently problematic opioid users is required.
4.2 Prevalence of codeine use
EU prevalence data on codeine use, misuse and dependence is at present
confined to French and Norwegian studies, and it is not known whether
prevalence rates are similar in other European countries (Casati et al., 2012;
Fredheim et al., 2009). Sales trends of opioid analgesic drugs like codeine in
nine European countries recorded the highest consumption of codeine in the
UK in the period 2001-2003 (De Conno et al., 2005). The prevalence of the
non-medical use of prescription opioids in the USA (2008-2009) found that a
substantial number of individuals reported using combination products
containing codeine with paracetamol (Wang et al., 2013).
Codeine is the most common opioid consumed in several European countries,
particularly in Norway (Fredheim et al., 2009). The prevalence rates of
codeine use in Norway in the year 2006 for men and women was estimated to
be 7.3% and 9.3% respectively, with 12% of women and 9% of men being
71
moderate to high consumers (120 defined daily doses in 2006). It was
estimated that 50% of the moderate to high consumers were also dispensed
benzodiazepines or carisoprodol. Codeine use was mainly sporadic but a
large sub-group was dispensed repeated prescriptions of the drug in
combination with potential other drugs of abuse (Bachs, Bramness, Engeland,
& Skurtveit, 2008). Prescribed combined codeine analgesics were most
common in Norway, with an average of 30 defined daily doses per year
consumed. Greater proportions of women reported weekly use that was
sporadic, which increased for both men and women with age, with greatest
use reported in older women (Eggen & Andrew, 1994).
A Norwegian prescription database (2004-2006) highlighted that one in 10
adults were dispensed codeine in 2005. A majority (58%) received codeine
only once which was most likely for acute pain. However, a small minority
(0.5%) of individuals on a minimum of one codeine prescription exceeded the
maximum recommended dose of 730 defined daily doses of codeine per year,
indicating problematic opioid use (Fredheim et al., 2009). This study highlights
the need for more clinical trials to establish whether patients benefit from longterm treatment with short-acting weak opioids. Additionally, research on the
treatment of codeine-using patients who appear to have developed
problematic opioid use is required. Instead of making codeine less available,
the analysis of this prescription database suggests that greater focus on
prevention and helping those who are at risk of or are problematic opioid
users is needed (Fredheim et al., 2009). A study in Iceland reported
substantial increases in codeine sales and also in the number of treatment
cases for over the counter codeine abuse (Almarsdóttir & Grimsson, 2000).
In France, a cross-sectional study sampling 53 pharmacy customers found
that among those reporting codeine use in the past month, 15.1% misused it
and/or used it for a non-medical reason, and 7.5% reported dependence as
per the DSM-IV criteria (Orriols et al., 2009; Roussin et al., 2013) A French
study reported that misuse and dependence on codeine analgesics was
significantly higher than for paracetamol, with 19.5% reporting daily use of
codeine for more than six months. Armand et al. (2004) in France recorded a
continuous decrease in neocodion (codeine antitussive preparation with
psychoactive effects) consumption between 1992 and 2002 (community
pharmacy and the French drug dependence-monitoring program OPPIDUM
data), but observed that 86% of those misusing neocodion were poly drug
users, and that the product was less sought after for opiate maintenance than
for its psychoactive effect.
Quantitative studies have found that codeine dependents are young and rate
their health poorer than nondependent users, report chronic pain, and
represent greater numbers of females, when compared with other groups of
opioid dependent individuals (Nielsen et al., 2011; Sproule et al., 1999). In
Australia, Nielsen et al. (2010) survey of 909 codeine users reported that
17.3% were likely to be codeine dependent. Codeine users were more likely
to report consumption of well above the recommended dose of over the
counter codeine, for longer periods of time, and were younger, with lower
levels of employment and education, and more likely to have a family history
72
of substance dependence than members of the general population. This study
also observed differences with other populations of opioid dependents.
To establish the prevalence of addiction to over the counter pharmaceuticals
containing codeine, studies have sampled a range of groups and group
perspectives which include those of pharmacists, pharmacy customers, the
public and dependent individuals (Cooper, 2013b). The literature highlights
the prevalence of use and abuse of codeine to specific groups of people.
Studies have reported a wide profile of individuals misusing codeine
medicines ranging from the parental medication of children with codeine
products (Allotey et al., 2004), the misuse of codeine cough mixtures among
youth and drug users (Agnich, Stogner, Miller, & Marcum, 2013; Arndt et al.,
2011; Banerij & Anderson, 2001; Chittrakarn et al., 2012; Elwood, 2001; Ford,
2009; Hart et al., 2013; Kitabayashi et al., 2000; Lam & Shek, 2006; Lao et al.,
2010; Miyatake et al., 2002; Peters et al., 2003: 2007a,b,c; Shek & Lam,
2006:2008; Tang et al., 2012; Wilson et al., 2010), prescribed and over the
counter codeine use among university students (Acocella 2005, Steinman
2006), adult male customers and treatment patients (Albsoul-Younes et al.,
2010; Sweileh et al., 2004; Tetrault et al., 2007; Yang & Yuan, 2008), middle
aged women accessing pharmacies (Akram, 2000), psychiatric patients
(Agyapong et al., 2013) older people (Agaba, Agaba, & Wigwe, 2004; Roumie
& Griffin, 2004) and ketamine injectors who frequently misuse codeine
(Lankenau et al., 2007).
Tetrault et al. (2007) found that more men reported non-medical use of
prescription opioids in the past year compared to women with men commonly
using Percocet, Codeine, Oxycontin, Demerol, Morphine and Methadone.
Sweileh et al. (2004) reported that males aged 20-40 years were more likely
to misuse over the counter products including codeine. However, among the
student population, females were more likely to misuse over the counter
medicines containing codeine than males, with misuse higher in older, white
and Native American students (Steinman 2006). With regard to pharmacist’s
perspectives, Sweileh et al. (2004) reported males aged 20 -40 years was
more likely to misuse over the counter products including codeine. Pates et al.
(2002) observed that pharmacists were aware of all types of potential over the
counter misusers. In terms of the student population, Steinman (2006)
reported that females were more likely to misuse over the counter medicines
containing codeine than males, with misuse higher in older white and Native
American students.
Of note is that older people are the largest consumer group of prescribed and
over the counter opioid analgesics (Francis et al., 2005). Sole misuse of
prescribed opioid analgesics is prevalent among educated, high earning
women who are over 35 years of age and do not report any other drug use or
misuse (UNODC, 2011). Greater trends of non-medicinal use of opioid
analgesics in students are reported (Fischer et al., 2013; Lord, Agaba, &
Wigwe, 2011) with significant gaps in knowledge in adolescents using over
the counter analgesics (Wilson et al., 2010). Tormoehlen, Mowry, Bodle, &
Rusniak (2011) reported on an increase in adolescent risk to abuse of
73
prescription and over the counter opioid analgesics relating to availability and
reduced perception of risk (Levine, 2007).
Fry et al., (2007) investigation of the prevalence and relationship between
benzodiazepines, pharmaceutical opioid use and crime in Australia found that
27% of participants used codeine in the previous 6 months. Prescription drugs
were reportedly relatively easy to obtain on the street with a low level of
reported organised criminal activity related to the procurement of prescription
pharmaceuticals. The study concludes that there may be a relationship
between the use of prescription drugs, dependence and some criminal
activity. A comprehensive national prescription drug misuse prevention
monitoring system is proposed.
4.2.1 Codeine related deaths
A number of studies have explored the prevalence of drug poisoning deaths in
relation to codeine use. Risk of fatal overdoses due to medicinal opioids
(buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone,
oxycodone, tramadol) are present with poisonings by weak opioids (codeine
and tramadol) associated with large, suicidal and accidental overdoses,
particularly among females (Gerostamoulos, Burke, & Drummer, 1996;
Hakkinen, Launiainen, Vuori, & Ojanpera, 2012; Wazaify et al., 2005). Co
administration
of
dihydrocodeine
with
heroin,
methadone
and
benzodiazepines may increase risk of overdose (Wazaify et al., 2005;
Zamparutti et al., 2010).
Morgan et al. (2006) found in the UK that there was an increase of codeine
deaths from 26 in 1999 to 54 in 2004. The incidence and role of codeine in
drug-related deaths was also examined in Victoria, Australia over a 5-year
period. A total of 107 cases involving codeine, representing 9% of all drugrelated deaths in this period in Victoria were examined. Six fatalities in which
codeine was considered the major poison was identified with paracetamol the
most common other drug found (Gerostamoulos et al., 1996). Paracetamol is
usually combined with codeine and propoxyphene in many preparations for
the treatment of pain and common colds. It is suggested that free codeine
concentrations >0.4 mg/L and total codeine concentrations >2.0 mg/L may be
sufficient to cause death in the absence of any other contributing factors
(Gerostamoulos et al., 1996).
An analysis of the prevalence of opioid-related deaths in Finland from 2000 to
2008 found that of the 14–44 year-olds (n=12,891), 10,182 were men
(Hakkinen et al., 2012). Several opioids were detected in 1363 cases (1103
men). For codeine use poisoning the manner of death was 43% accidental,
40% suicide and 16% unclear. There were no single drug codeine poisonings.
Benzodiazepines were found more frequently than other opioids in codeine
poisonings. Poisonings by the weak opioids, for example, codeine and
tramadol, were found to be associated with large and often suicidal overdoses
resulting in high drug blood concentrations (Hakkinen et al., 2012).
74
Zamparutti et al. (2010) analysed the prevalence of dihydrocodeine in
fatalities that occurred in the UK among individuals with a history of opiate
misuse. Data covering the period 1997–2007 was voluntarily supplied by
coroners and analysed. 646 cases were identified as dihydrocodeine -related
deaths. Dihydrocodeine, either alone or in combination with other drugs, was
identified in 584 fatalities. In 44% of cases it was directly implicated in the
cause of death. Typical dihydrocodeine cases identified were white males in
their early thirties. Accidental deaths (96%) were likely to involve
dihydrocodeine in combination with other psychoactive agents, for example,
heroin, morphine, benzodiazepines and methadone. These findings highlight
the importance of alerting opiate/opioid misusers about the risks associated
with poly drug intake and for prescribers to consider alternative
pharmacological interventions to dihydrocodeine (e.g. methadone,
buprenorphine) when managing and treating opiate/opioid addiction.
4.2.2 Misuse of Codeine Cough Syrups
Whilst codeine is abused in pill or syrup form (Compton & Volkow, 2006b), the
abuse of codeine cough syrup is well documented in the US (Blakley &
Schilling, 2008), India (Mattoo et al., 1997; Wairagkar et al. 1994), Hong Kong
(Lam et al., 1996; Shek & Lam, 2008), and Japan (Ishigooka, Yoshida, &
Murasaki, 1991; Kitabayashi et al., 2000; Miyatake et al., 2002; Seno et al.
1996). Over the counter and prescribed forms of codeine cough syrup exists
and contains varied percentages of codeine, dextromethorphan and
promethazine hydrochloride, an antihistamine with sedative properties. In the
US, and particularly in Southern States, codeine cough syrup is mixed with
alcohol or soft drinks (i.e. Sprite) and called ‘Purple Drank’, ‘Syrup,’ ‘Barre’,
‘Purple Tonic’, ‘Sizzurp’; ‘Texas tea’, ‘Tsikuni’ and ‘Lean or Southern Lean’
(nicknamed for the slumped posture in intoxicated users) (Elwood, 2001;
Peters et al., 2010, 2007a, 2003)
Poly drug users in the US report using codeine syrup due to its lack of legal
sanction, is perceived to be safe, is free or inexpensive with Medicaid or
private insurance and can be widely procured from doctors and hospital
emergency rooms (Elwood et al. 2001). The purple-ish hue of ‘Purple Drank’
comes from the dyes in the cough syrup. Males, other drug users and those
who prefer rap/hip hop music have significantly higher likelihood of using
‘Purple Drank’ (Hart et al., 2013). Southern rap music is inspired by
intoxication on codeine and promethazine, with ‘chopped and screwed’ beats,
typically significantly slower, skipped and relaxed, and characteristic of the
codeine cough syrup induced cardiovascular depressant effect (Elwood,
1999).
When consumed in large quantities fatigue, loss of coordination, sedation,
dissociation and altered levels of consciousness are reported (Elwood et al.
2001, Peters et al. 2003). Amongst younger cohorts, codeine cough syrup
users’ beliefs centre on perception low risk and lack of adverse consequences
or potential for dependence (Darboe 1996; Hou et al., 2011; Lam & Shek,
2006; Shek & Lam, 2008; Peters et al., 2007a, c: 2003).
75
Gaps in knowledge have been reported in adolescent use of over the counter
analgesics containing codeine (Wilson et al., 2010). But prevalence rates are
high among Native Americans, Hispanics, males, LGBT and urban students
(Agnich et al., 2013). However, Tormoehlen et al. (2011) identified an
increase in adolescent risk to abuse of prescription and over the counter
opioid analgesics, which suggests a possible decrease in codeine use
compared to other opioids.
Codeine cough syrup use is evident among males in urban black ethnic
groups and lesbian, gay, bisexual, transgender (LGBT) minorities, and is
associated with poly substance use, high levels of sexual activity and use of
new psychoactives (Agnich et al., 2013; Elwood, 2001; Peters et al.,
2007a,b,c, 2003; Peters et al., 2007a,b,c;). A survey assessing the
prevalence of misuse of codeine cough syrup of 2,349 students was
conducted in the USA (Agnich et al., 2013). The sample comprised White
(69%), African American (24%), Hispanic (3%), Native American (3%) and
Asian (1%) people with an average age of 20. Findings from this study
highlighted that significant gaps in treatment may exist for both Hispanic and
Native American students. They suggest also that urban male youth of all
racial backgrounds are potential misusers of codeine cough syrup and that
misuse may be most common within the LGBT community.
A retrospective study of cough mixture abuse (2009-2011) examined the
medical records of patients with a diagnosis of cough mixture dependence
who attended the substance abuse clinics at the Prince of Wales and North
District Hospitals in Hong Kong (Tang et al. 2012). A total of 63 patients with
the diagnosis of cough mixture abuse were identified. 89% were male with an
average age of 34 and 83% reported being unemployed. The average age of
onset of cough mixture abuse was 20 ± 5 years. The most common
substances in the urine samples at first presentation were promethazine
(75%), pseudoephedrine (67%), codeine (60%), ephedrine (57%), zopiclone
(17%), and hydrocodone (16%). The study suggests that psychotic disorders
are the most frequent psychiatric diagnosis associated with cough mixture
abuse. Paranoid psychosis manifesting as persecutory delusions and
derogatory hallucinations are common among users who abuse cough
mixtures containing promethazine, ephedrine, pseudoephedrine, codeine and
hydrocodone. Psychiatric symptoms develop at any time between two and 13
years after onset of abuse (Tang et al., 2012).
Similar forms of cough syrup misuse include the home production of ‘Kratom
Cocktails’ in Thailand, and consisting of boiled kratom leaves, Coca-Cola, a
codeine cough syrup, and sometimes the addition of alpraxolam. This mixture
is popular amongst youth and served with ice, yoghurt or coffee. Active
ingredients of ‘Kratom Cocktails’ reportedly include mitragynine, caffeine,
codeine, chlorpheniramine (antihistamine) and phenylephrine (decongestant)
(Chittrakarn et al., 2012). Kratom leaves contain over 25 alkaloids including
mitragynine, paynantheine, mitraphylline, and 7-hydroxymitragynine, with
mitragynine the major psychoactive constituent (Chittrakarn et al., 2012).
‘Kratom Cocktails’ are illegal in Thailand but not in Europe or the US, where
the herbal mixture of kratom leaves and tramadol (a synthetic opioid
76
analgesic) dubbed ‘Krypton’ is popular (Arndt et al., 2011). Kratom is typically
sold on the internet, and in smart or headshops in the form of whole or
crushed green leaves, or green powder and capsules.
4.2.3 Codeine use in pregnancy
Codeine is prescribed for obstetric purposes (Glover et al., 2003). Codeine
was originally viewed as having minimal risk to mothers and breast feeding
infants (Bar-Oz et al., 2003; Seaton et al., 2007) however recent
commentaries have raised serious concerns about the risk of morbidity and
mortality in paediatric use (Cartabuke et al., 2013; Chang, Cheng, & Chang,
2012). Madadi & Koren (2008) have commented on the lack of empirical
evidence available to support its use in children and breast feeding mothers,
and emphasised variability in the efficacy of codeine in these patients. The
use of codeine by breastfeeding mothers has been found to cause adverse
central nervous system events in breastfed infants (Madadi et al., 2008a, b).
Arguably, physicians need to recognize codeine use during breastfeeding as
a cause of central nervous system depression in infants, and breastfeeding
mothers should be made aware of the possibility of adverse events before
being offered codeine (Madadi et al. 2008 a, b).
There is a lack of data with regard to use of codeine during pregnancy. This
problem is difficult to accurately describe as many women do not consider
over-the-counter medicines to be dangerous and exact medication histories
are problematic to obtain (Reynolds et al., 2007). However, it is known that he
use of ibuprofen is quite common and consumed at unexpectedly high rates
although is contraindicated in pregnancy (Glover et al., 2003). For example, a
longitudinal study (26 months) of medication usage and discontinuation to
identify medications that are consumed by a rural obstetric population (n=578)
during pregnancy was conducted in the USA (Glover et al., 2003). 2,086
interviews were conducted in relation to the use of prescription, over-thecounter and herbal medicines. 96% of the participants reported taking
prescription medications; 93% self-medicated with over-the-counter
medications and 45% used herbal medications. Over time, consumption of
over-the-counter medications exceeded prescription medication use. 15% of
the pregnant women took ibuprofen at some point during the pregnancy (5.7%
in the third trimester). 8% of the women were noncompliant with 20% of these
poorly compliant with prenatal vitamin and mineral formulations.
4.2.4 Pain
Individuals with codeine dependency often commence codeine use in an
effort to manage pain (Frei et al., 2010; Tennant & Rawson, 1982). Patients
with co-existing pain and addiction may have decreased pain tolerance,
increased anxiety, depression and insomnia. A high rate of cross dependence
(18%) on codeine has been reported and suggests that chronic pain requires
better medical care, in particular chronic cephalalgia, with subsequent
prevention of drug-related chronic headache (Roussin et al., 2013). Pan, Ho,
Lu, Lin, & Wang (2013) investigated the prevalence of opioid consumption in
Taiwan and found that prescriptions and expenditure increased steadily from
2002-2007 similar to nearby Asian countries, but remained much lower than in
77
developed countries. Notably, 67% of patients took codeine for cancer pain in
2002 compared to 73% in 2007.
Other research points with regards to the self-medicating use of codeine to
manage emotional pain, anxiety or stress (Nielsen et al., 2010). Sproule et al.
(1999) found that codeine dependents are more likely to report chronic pain
and will use codeine for its pleasurable effects, to relax or reduce stress,
otherwise referred to as ‘chemical coping’ (Nielsen et al., 2010). Sproule et al.
(1999) identified that over half of their sample using over the counter products
had average doses of dependence of 179mg per day, with 80% using codeine
5 or more days per week. Frei et al. (2010) suggested that users were
consuming mean daily doses of between 435 and 602mg of codeine
phosphate and 6800 to 9400mg of ibuprofen, with the majority having no
previous history of substance use disorder.
Repeated administration of codeine in the absence of pain causes tolerance
and dependence (Derry et al., 2013). However, research on prevalence and
incidence of persistent and problematic use of this weak opioid in patients
with non-cancer chronic pain or non-pain patients is limited (Roussin et al.,
2013; Skurtveit et al., 2011). Misuse in the form of repetitive daily use has
been known to contribute to increased headache called “Medication Overuse
Headache”. This withdrawal headache is also one of the most frequent
reasons for persistent daily use leading to misuse and dependence on
codeine analgesics. Roussin et al. (2013) reported that half of daily codeine
users reported headaches, with headache also reported as a reason for use
in codeine dependents.
For those with pain management issues, often stimulating initial misuse of
codeine, the re-emergence of pain creates a barrier to successful treatment
completion (Tennant & Rawson, 1982), and highlights the need for coexisting
pain management supports (Dobbin & Tobin, 2008; Fishbain et al., 2008). The
misuse of opioid analgesic medication can complicate chronic pain
management (Ives et al. 2006). Chronic use of prescription opioids for noncancer pain is higher in patients with mental health or substance use
disorders (Edlund et al., 2010). Indeed, long term opioid use is particularly
prevalent in women with chronic pain (Darnall et al.; 2012). Studies describe
poor long term outcomes for codeine dependents at 12 month follow up (Otto
et al., 2009; Zahradnik et al., 2009).
4.2.5 Recreational Use
Recreational codeine use is characterised by consumption of high doses of
codeine in ‘binge’ episodes (Ernest et al., 2010). Reported forms of misuse for
recreational purposes include consumption along with anti-nausea
preparations promethazine, codeine linctus, products with higher proportions
of codeine, and crushed within caffeine laced drinks (i.e. Red Bull). Codeine
can also be smoked as free base, Poly drug taking represents an additional
risk in terms of potential drug outcomes and adverse health consequence on
recreational misuse of codeine (Reed et al., 2011). Online user forums
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provide information on how to split tablets and extract codeine using the cold
water extraction methods for removal of additives.
Whilst codeine is abused in pill or syrup form (Compton & Volkow, 2006b), the
abuse of codeine cough syrup is well documented in the US (Blakley
&Schilling, 2008); India (Mattoo et al., 1997; Wairagkar et al., 1994), Hong
Kong (Lam et al., 1996; Shek & Lam, 2008), and Japan (Ishigooka et al.,
1991; Kitabayashi et al., 2000; Miyatake et al., 2002, Seno et al., 1996).
These syrups contain codeine, dextromethorphan and promethazine
hydrochloride.
As outlined earlier, this form of legitimate misuse of oral codeine syrup is
known as ‘Purple Drank’, ‘Syrup,’ ‘Barre’, ‘Purple Tonic’, ‘Sizzurp’; ‘Texas tea’,
‘Tsikuni’ and ‘Lean or Southern Lean’ (nicknamed for the slumped posture in
intoxicated users) (Elwood, 2001; Peters et al., 2010, 2007a, 2003) .
4.2.5 Illicit drug use
The relationship between the misuse of over the counter medicines containing
codeine such as Nurofen Plus® (ibuprofen and codeine), illicit drug use and
the diversion of codeine to street drug markets is reported (Levine 2007,
Matheson et al., 2002; Reay, 2009; Sproule et al., 1999). Research shows
that awareness of codeine’s abuse potential within problematic drug using
networks is relatively high with use potentially to alleviate withdrawals from
stronger opiates such as heroin (Agyapong et al., 2013; Cooper, 2013b).
Amongst illicit drug users, extra medical use of pharmaceuticals occurs in
varying degrees (Wilkins et al., 2011). Wilkins et al. (2011) reported that
amongst frequent users of ecstasy, low levels of morphine, methadone and
‘home bake’ morphine, and sizable levels of methylphenidate,
benzodiazepines and codeine use are reported. Furthermore, Wilkins et al.,
(2011) found that many injecting drug users tend to get prescriptions for
codeine (41%) and benzodiazepines (41%) as a means for using extra
medical pharmaceuticals and occurs in varying degrees.
In terms of using over the counter and black market sourced codeine,
increasing trends relating to home manufacture of injecting drug solutions has
been observed in Eastern Europe, Russia, South Asia, Australia and New
Zealand (Harris, 2013). Popularity of these home drug solutions made from
codeine appears dependent on the availability of natural opiates such as
heroin, levels of policing and user awareness of harms (Booth, 2013; Grund et
al., 2013). The Soviet tradition of homemade opiate type substances such as
‘Braun’ and ‘Krokodil’ is viewed as contributory to the production of new,
accessible and affordable drug solutions (Azbel et al., 2013). In New Zealand,
‘Home Bake’ is made from morphine and codeine based over the counter and
illicitly sourced pharmaceuticals (Grund et al., 2013).
According to Gahr et al. (2012b) no scientific qualitative chemical analysis of
the solution known as ‘Krokodil’ exists. Savchuk et al. (2008) in their work
(part i) observed the synthesis of desomorphine using different recipes and
conditions, and identified four synthetic analogues of desomorphine, of
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codeine and other compounds in ‘desomorphine’ samples, and ranging from
trace to 75%. They commented on the different procedures and conditions
involved in the synthesis of desomorphine in various regions of Russia. Grund
et al. (2013) emphasize the need for field testing of samples and continued
efforts for empirical research on ‘Krokodil’’s synthetic pathways, the effect of
presence of certain medicines, chemicals and reagents on chemical reactions
and manufacturing processes.
4.3 Conclusion
Codeine is one of the most prevalent opioids consumed worldwide. The
prevalence of the non-medical use of prescription opioids suggests that
significant numbers use codeine with paracetamol. Issues in relation to
codeine use, misuse and dependence include codeine related deaths; oral
misuse of codeine cough syrups; codeine use in pregnancy, codeine
prescribed for pain, recreational use of codeine and codeine used in
problematic injecting drug use. Psychotic disorders, especially paranoid
psychosis, are a frequent psychiatric diagnosis associated with codeine cough
mixture abuse with dysphoric mood states associated with sustaining longterm codeine use.
Relatively little is known about the use of over the counter analgesics
containing codeine. Codeine misusers would benefit from education about the
risks associated with poly drug intake to challenge widely held but
misinformed perceptions that codeine based products are low risk in terms of
their potential for dependence.
Clinical trials to establish the benefits or otherwise from long-term treatment
with short-acting weak opioids are warranted. Research is also needed into
treatments for codeine-users who have developed problematic opioid use and
to evaluate as prevention strategies to help those who are at risk of or are
currently problematic opioid users. Harm reduction and clinical treatment
warrants further development in response to the injecting use of codeine
containing home-made drug solutions.
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Chapter 5
Use and Efficacy of Codeine within
Healthcare Practice
5.1 Introduction
This chapter explores the evidence with regard to the use of codeine within
healthcare practice and its effectiveness when compared to other
medications. The frequency with which codeine is prescribed and the reasons
why people misuse are briefly examined.
The World Health Organisation has placed codeine as a ‘step 2’ (weak opioid)
on its pain ladder (Cartabuke et al., 2013). It was originally used for treatment
of cancer pain, and extrapolated for the management of mild to moderate pain
in adults and children (Campbell, 2006; Cartabuke et al., 2013; EMA, 2013;
Hall et al., 2013; Kelly & Madadi, 2012; Iedema, 2011). It is frequently used in
the management of mild to moderate pain in adults (often dental or postpartum) and under strict monitoring in children (Campbell, 2006; Cartabuke et
al., 2013; EMA, 2013; Kelly & Madadi, 2012). Some commentaries have
speculated on its therapeutic uses and limited role in palliative care
(Therapeutic Guidelines, 2007). Recent discourse has suggested to skip ‘step
2’ due to problems with codeine (and tramadol), with guidelines generally not
recommending codeine for management of pain, due to limited evidence of
effectiveness, variations in metabolism and availability of more predictable
opioids.
The main therapeutic indications for codeine are the relief of mild to moderate
pain and cough suppression (British National Formulary, 2013). While codeine
is widely used7 in healthcare, its effectiveness and role in the treatment of
minor and moderate pain is debatable. In general, codeine is thought to be
effective in the treatment of non-cancer pain over short periods of time (less
than 6 months). Long-term treatment with codeine is not supported as the
evidence of effectiveness is variable and the risk of misuse and abuse
increases significantly over time (Trescot et al., 2008).
Codeine is available over the counter in combination preparations with
paracetamol or ibuprofen. It has been shown that combination effects of
different analgesics have additive effects (Moore, Derry, Derry, Straube, &
McQuay, 2012). However, there is limited evidence suggesting that
combination preparations are better than same doses of either medication
taken together (Derry et al., 2013). A reason for selling over the counter
products as a combined preparation is to decrease their addictive and abuse
potential.
7
Background information on the therapeutic use of codeine is described in chapter one.
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The effectiveness of codeine or combined codeine based products for postoperative treatment, chronic pain, opiate dependency treatment and
detoxification medication, children and breastfeeding are now explored.
5.2 Post-operative treatment
A meta-analysis of six studies concluded that a combined formulation of
codeine (25.6 mg to 60mg) and ibuprofen (400mg) as a single dose treatment
for post-operative treatment has good analgesic efficacy (Derry et al., 2013).
This finding was for use of high doses of codeine only with limited available
data on low and medium doses. However, there are some concerns in
prescribing combined preparations because of the potential for the misuse of
over the counter preparations containing codeine (Derry et al., 2013).
Franceschi et al. (2013) suggest that codeine-paracetamol combined
preparations should be the treatment of choice for mild to moderate pain
rather than using non-steroidal anti-inflammatory drugs. They argue that the
effectiveness of codeine and paracetamol combinations is not inferior to nonsteroidal anti-inflammatory drugs and that the risks from non-steroidal antiinflammatory drugs side effects and their ability to induce potentially lifethreatening conditions is greater than codeine and paracetamol based
combinations. This recommendation is especially directed for use in older
people and those with chronic pain requiring long-term treatment (Franceschi
et al., 2013).
A systematic review by Nauta et al. (2009) found non-steroidal antiinflammatory drugs to be equipotent to paracetamol-codeine preparations.
However, there is a better risk/benefit ratio when using non-steroidal antiinflammatory drugs compared to paracetamol-codeine combination as fewer
adverse effects were reported.
No difference has been found in the efficacy of the relief of post-operative
pain in dental patients and headaches between the use of aspirin and
paracetamol-codeine combinations (Abt, 2012). A single dose of
dihydrocodeine used for the treatment of post-operative pain was found to be
less effective in providing adequate pain relief (Moore et al., 2011). Moreover,
ibuprofen (400mg) was shown to be statistically superior to dihydrocodeine
(30mg, or 60mg) for relief of pain (Moore et al., 2011). It continues to be used
for postoperative pain management (Stoneham & Walters, 1995), as it causes
less sedation and potential respiratory depression than morphine, although
morphine is safer, more potent and has a longer lasting effect (Goldsack et
al., 1996).
Despite clinical arguments against the use of codeine, it still holds an
important place in mild to moderate pain treatment (Tremlett et al., 2010).
Overall the evidence in support of codeine use as opposed to non-steroidal
anti-inflammatory drugs is inconclusive.
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5.3 Chronic pain
Codeine is commonly used to manage dental pain (Gatoulis, Voelker, &
Fisher, 2012) and post-partum pain (Nauta et al., 2009) Codeine and
paracetamol combination was assessed against hydrocodone and ibuprofen
for effectiveness in the treatment of chronic pain (Palangio et al., 2000).
Hydrocodone is six to eight times more effective than codeine. The dose of
two tablets of the combined preparation of codeine (30mg) and paracetamol
(300mg) was as effective as a dose of one tablet of hydrocodone (7.5mg) and
ibuprofen (200mg), but less effective than a dose of two tablets of
hydrocodone and ibuprofen. The authors concluded that hydrocodone
(7.5mg) and ibuprofen (200mg) combination is a therapeutic alternative to
codeine (30mg) and paracetamol (300mg) (Palangio et al., 2000).
The misuse of opioid analgesic medication can complicate chronic pain
management (Ives et al., 2006). Chronic use of prescription opioids for noncancer pain is higher in patients with mental health or substance use
disorders (Edlund et al., 2010) with long term opioid use being particularly
prevalent in women with a chronic pain condition (Darnall et al., 2012).
5.4 Opiate replacement treatment
The use of codeine and dihydrocodeine as an opiate replacement treatment
has not been widely studied. Oral short acting dihydrocodeine (half-life: 4 h)
has been viewed as a viable alternative to methadone as substitution
treatment for opiate dependence (Banberry et al., 2000; Krausz et al., 1998;
1995; Robertson et al., 2006). Dihydrocodeine and codeine are particularly
useful within the primary care and prison settings, for substitution treatment
and for use in cross over detoxification from methadone (Backmund et al.
2001; Banbery et al., 2000; MacLeod et al. 1998; Robertson et al., 1990;
Seymour et al., 2001; Sheard et al., 2007; Stark & Gregory, 2005; Zamparutti
et al., 2010). Strang et al. (2005) have reported on dihydrocodeine prescribing
in UK based primary care services for the treatment of opiate dependence,
and as a drug of choice for opiate withdrawals for those in police custody
(Pearson, Robertson & Gibb, 2000). Preference is shown for the prescribing
of dihydrocodeine for patients with less severe opiate dependence by general
practitioners due its reduced toxicity with shorter half-life and more rapid onset
of action, reduced abuse potential and potential for injecting use, perceived
safety, potential retention of patients, its flexibility and portability thereby
impacting less negatively on the patient’s lifestyle, and its capacity to reach
wider groups of opiate dependent drug users (Krausz et al., 1998; MacLeod et
al., 1998; Robertson et al., 1990, 2006; Swadi, Wells, & Power,. 1990). Some
studies have measured the efficacy of dihydrocodeine as an alternative
maintenance and detoxification treatment. Banberry et al. (2000) report that
on consecutive use a “steady-state” condition for dihydrocodeine is achieved
and weaning can be achieved successfully with minimal complications within
a few days. Dihydrocodeine maintenance treatment is typically low threshold,
less bureaucratic, increases patient choice and retention, and is prescribed by
general practitioners in the form of capsules and juice (Krausz et al., 1998).
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The use of both codeine and dihydrocodeine in maintenance or detoxification
of opiate addicts is unlicensed in the UK (British National Formulary, 2013).
The National Institute for Health and Care Excellence has produced a
guideline for UK health professionals, which states that dihydrocodeine could
be used in opioid detoxification treatment. However, it is not a first-line
treatment and should not be used routinely for that purpose (NICE, 2007).
Krausz et al. (1998) examined the use of codeine in detoxification and
maintenance of opiate addicts in Germany. The results in maintenance
treatment were promising and comparable to methadone (Krausz et al.,
1998). However, codeine was inferior to methadone for drug users completing
a detoxification program (Backmund et al., 2001).
Unfavourable results for the use of dihydrocodeine treatment of opiate
detoxification compared to buprenorphine has been reported (Wright et al.,
2007). Robertson et al. (2006) found no difference in outcomes between
dihydrocodeine and methadone when used for maintenance treatment.
Despite this weak evidence, the unlicensed use of dihydrocodeine is
recommended by the UK Department of Health in the ‘Drug Misuse and
Dependence guideline’ as an alternative, but not routine treatment for
maintenance of opiate dependence. (Department of Health, 2007).
This recommendation was shown to be ignored by forensic physicians who
were found to routinely prescribe dihydrocodeine as a treatment of choice for
withdrawal symptoms (Stark & Gregory, 2005). The efficacy of dihydrocodeine
in maintenance and detoxification treatment of opiate dependency, to ensure
a favourable risk/benefit ratio has yet to be established.
There are however concerns of concomitant dihydrocodeine use amongst
problematic drug users and potential for street diversion (Robertson et al.,
1990; Seymour et al., 2001). Lower rates of compliance with dihydrocodeine
and its misuse have also been reported, compared to rates recorded in
methadone maintenance studies (Elias, 1990; Friessem & Tashner; 1991,
Swadi et al., 1990). Dihydrocodeine can be prescribed as a painkiller to
individuals with opiate dependence even post detoxification (Larson et al.,
2007). Nordmann et al. (2013) have described regional trends in France of
doctor shopping for dihydrocodeine for pain related reasons. Concomitant
consumption of dihydrocodeine with heroin, methadone and benzodiazepines
is a major problem in patients with opioid dependence (Backmund et al.,
2005) and may increase risk of overdose (Wazaify et al., 2005; Zamparutti et
al., 2011).
5.5 Children and Breastfeeding
Codeine was originally viewed as having minimal risk to mothers and breast
feeding infants (Seaton et al., 2007). However, recent commentaries have
presented serious concerns in relation to morbidity and mortality in paediatric
use (Cartabuke et al., 2013; Chang et al., 2012). There is a lack of evidence
to support codeine use in children and breast feeding mothers, and variability
in the efficacy of codeine in this group of users (Madadi & Koren, 2008).
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Commencing in 2012 the EMA conducted a review led by the
Pharmacovigilance Risk Assessment Committee (PRAC) under Article 31
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_documen
t/Codeine_containing_medicinal_products/Procedure_started/WC500133297.
pdf . The (PRAC) was requested to give its opinion on whether the marketing
authorisations for codeine-containing medicinal products indicated in the
management of pain in children, should be maintained, varied, suspended or
withdrawn.
The report highlighted: the risks associated with some children who are ultrarapid or extensive codeine to morphine metabolisers (EMA, 2013); and the
need to exercise caution when interpreting the effect of age, genetic
polymorphism and increasing enzymatic activity with age. The report
concluded that codeine should only be administered at the lowest effective
dose for the shortest period possible, and limited to 3 days with maximum of
240mg per day. In their view, codeine is contraindicated in paediatric patients
under 18 years that undergo tonsillectomy and/or adenoidectomy for
Obstructive Sleep Apnoea Syndrome due to increased risk of loss of
consciousness and respiratory arrest and also contraindicated in patients
known to be CYP2D6 ultra-rapid metabolisers (EMA, 2013).
It is recommended that codeine should not be used in children with
neuromuscular disorders, severe cardiac or respiratory conditions, upper
respiratory or lung infections, multiple trauma or extensive surgical
procedures. The report also recommends codeine be contraindicated in
breastfeeding women (EMA, 2013). Furthermore, Cartabuke et al. (2013)
highlight that parents need to be educated to recognize the potential side
effects of codeine such as respiratory depression when prescribed for children
and calculations of dose should be based on ideal body weight and not actual
body weight.
5.6 Frequency of codeine prescribing versus other analgesics
This review could only find limited empirical evidence in relation to adherence
of doctors to pain management guidelines in non-cancer patients. This
represents a knowledge gap in determining how doctors decide which
patients receive opioid treatments; the frequency doctors prescribe codeine
rather than other analgesics and what is regarded as a standard starting
dose.
It was noted, however, that doctors follow advice from the World Health
Organisation Analgesic Ladder, when making decisions in relation to
treatments for pain. Also, it was suggested that countries generate their own
guidelines, for example, ‘Opioids for Persistent Pain: Good Practice’ released
by The British Pain Society (The British Pain Society, 2010). This document
was drafted to support prescribing doctors and to assist them to use
interventions that are evidence based. This guide specifies when opioid
treatments are appropriate and when to prescribe them.
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5.7 Motives for misuse of codeine
Motives for misuse of opioid pharmaceuticals including codeine range from
self-treatment for pain consistent with the drug’s main indication to
recreational use (Boyd & McCabe, 2008; Boyd, McCabe, Cranford, & Young,
2006; Compton & Volkow, 2006 a, b; Daniulaityte et al., 2006; Lankenau et
al., 2007; McCabe et al., 2006, 2007; McCabe & Teter, 2007; Teter, McCabe,
LaGrange, Cranford, & Boyd, 2006; Volkow & Swanson, 2003) with greater
prevalence of recreational motives among men (McCabe et al. 2009).
The number of studies that specifically examine what motivates people to
overuse and misuse codeine is limited. Two studies specific to motives of
codeine misuse are identified. Daniaulaityte et al. (2006) conducted in-depth
interviews with 24 people who had a history of opioid abuse. Their use of
codeine was connected with self-medicating for physical pain associated with
daily tasks and to psychological well-being. Some started taking codeine for
genuine reasons and over time developed their addiction; while others took
codeine to feed their already established addiction to heroin, especially when
heroin was not readily available (Daniulaityte, 2006).
Similar findings are reported by McCabe et al. (2009) who identified motives
for codeine misuse ranging from self-treatment of pain (physical and
emotional), sleep and anxiety problems and pursuit of pleasure. Ease of
access and personality types (for example, addictive personality) may also
play a role. Use of codeine for its pleasurable effects, to relax or reduce stress
was also reported (Nielsen et al., 2010).
A qualitative study investigating over the counter medicine abuse which
included codeine in the UK (Cooper, 2013b) revealed that individuals
considered themselves ‘addicted’, and different to illicit drug dependents by
virtue of social and economic activity. Self-blame for perceived loss of control
was described, with medicine use (codeine, decongestant and antihistamine)
commencing for genuine reasons. Subsequent use occurred for opiate
effects, and with little difficulty sourcing from pharmacies and online.
Withdrawal symptoms for all dose ranges were reported, and work/health
problems occurred within higher dose ranges. Standard drug treatment was
viewed as inappropriate.
Research highlights that awareness of codeine’s abuse potential within
problematic drug using networks is relatively high with use potentially to
alleviate withdrawals from stronger opiates such as heroin (Agyapong et al.,
2013; Cooper, 2013b). These issues need further study given the high levels
of misuse and abuse of prescription medications (Boyd et al., 2006).
5.8 Conclusion
This chapter explored the evidence with regard to the use of codeine within
healthcare practice and its effectiveness when compared to other
medications. The frequency with which codeine is prescribed and the reasons
why people are misusing are briefly examined. The evidence is inconclusive
86
and there is a need to explore these issues further given the high levels of
misuse and abuse of prescription opioid medications.
87
Chapter 6
Consequences of Codeine Use, Misuse and
Dependence
6.1 Introduction
Like all drugs, codeine is not free of problems. Consequences such as
dependence and side effects in the use of opiates are thought to influence the
way in which they are prescribed, with clinicians opting to err on the side of
caution and prescribe lower doses than required to produce analgesic effects
(Benyamin et al., 2008). Codeine is considered to be an unpredictable drug
with increased risk of toxicity in combination products (Iedema, 2011).
The potential for overuse and misuse of codeine containing medications is not
only detrimental for a person’s health but has broader consequences in terms
of its cost and implications for the wider society (Feinberg, 2006). In this
review a total 26 papers were found examining the consequences of codeine
use, misuse and abuse. These studies are grouped under four main
categories: (1) impairment (2) injury (3) adverse health effects and (4)
dependence.
6.2 Impairment
Three studies looked specifically at impairment as a consequence of codeine
use. The literature suggests that codeine metabolises partly to morphine by
the liver enzyme CYP2D6 and that the analgesic effects of codeine are due to
the morphine metabolite. However, codeine effects other than analgesia have
not been extensively investigated and it is suggested that sedation, for
example, might be independent of morphine formation.
Bachs et al. (2003) examined the effects of codeine alone, without
concomitant presence of morphine, on a clinical test for drunkenness
performed in relation to suspected drugged driving. 43 cases of suspected
drugged drivers from a national database were examined that tested positive
for codeine in blood samples but negative for morphine and other drugs.
Codeine appeared to have a dose-dependent effect on the central nervous
system that may have led to impairment as judged by the clinical test for
drunkenness measurement, independent of measurable blood morphine
concentrations. These findings support the view that some codeine effects do
not seem to be mediated by morphine.
A recent double-blind, randomized, placebo-controlled study examined
impairment in driving with 16 healthy young adults to evaluate the dose–effect
relationship of three therapeutic doses of codeine/paracetamol (Amato et al.,
2013). Driving performance, responses to psychomotor vigilance tests, and
88
scales reflecting alertness were evaluated the morning after drug intake.
Findings did not reveal any significant impairment in performance of driving or
vigilance nor demonstrate a dose effect relationship with the usual therapeutic
doses of codeine/paracetamol in a single intake. However, some correlations
suggested a blood concentration effect, which is important to take into
account because the metabolism of codeine is genetically polymorphic. The
study suggests that while epidemiological studies point to an elevated risk of
driving accidents with opioid and codeine use, further research is needed to
quantify the effects of these drugs on driving ability, such as those on different
genetic polymorphisms or on aging drivers. The effects that higher doses of
codeine may have require further investigation (Amato et al., 2013).
Hou et al. (2011) conducted an experimental study comparing brain images of
codeine cough syrup addicts and matched healthy individuals. Brain scans
and the volume and weight of the bilateral corpus striatum and the ratio of the
corpus striatum to the whole brain were measured in the 22 codeine cough
syrup addict participants and compared to 27 healthy individuals. The study
showed changes to the bilateral corpus striatum and decreased weight and
volume and ratio to the whole brain in the codeine cough syrup addict
participants. The result of the scans suggested alterations in the dopaminergic
system responsible for cognitive and motor action. The study concludes that
chronic codeine cough syrup abuse may cause serious damage to the brain
and neuroimaging findings further illustrate the mechanism of codeine cough
syrup dependence.
While these studies have small sample sizes they are nevertheless specific to
codeine use. Further evidence is required to determine the exact levels of
impairment as a result of codeine use.
6.3 Injury
Medications that have central nervous system side effects, for example,
sedation and compromised coordination are known to intensify the risk of
injury particularly in older adults. Buckeridge et al. (2010) examined hospital
and medical service records from 2001-2003 in Quebec, the second largest
province in Canada. Population-based health databases were used to
measure pre-existing risk factors for injuries in 2001/02 and drug use and
injuries during follow-up in 2003. The records examined included prescription
medications, quantity, duration, diagnosis, procedure and location (e.g.,
emergency, department, intensive care unit). In total 403,339 adults over 65
were followed up over a one year period to estimate the risk of injury
associated with opioid use.
The results demonstrated that 3.7% of the total population sustained an injury,
with fractures and lacerations being the most common. 15.3% of this
population were prescribed an opiate of which 10.8% was codeine. Following
adjustment for patient characteristics and other risk factors there was an
increased risk of injury associated with opioid use (p<0.05) and a 127%
increase in risk per one adult dose within the group prescribed codeine
combinations (Hazard ratio 2.27, 95% CI 2.21-2.34). The study concludes that
89
older adults commonly use opioids along with other medications that have
sedating side effects. Higher doses of low-potency opioids, particularly
codeine combinations, were prevalent and result in twice the risk of injury.
Early detection and intervention in the increasing use of opioids for pain
management may reduce the risk of injury (Buckeridge et al., 2010).
In Denmark, a study that examined the effects of morphine and opiates on
fracture risk suggested that codeine was amongst opiate medication
associated with an increase in overall fracture risk (OR, 1.16, 95% CI 1.121.20) (Vestergaard et al., 2006). This study examined all subjects on a
nationwide register in the year 2000 (n=124,655) who were taking opiate
medication and were matched to three cases of the general population. While
the study may not have measured medication compliance, issues of misuse
or other pre-existing conditions, it concludes that an increased fracture risk is
seen in users of morphine and opiates and this may be related to the risk of
falls due to central nervous system effects, for example, dizziness.
6.4 Adverse health effects
The harmful effects of codeine abuse are well recognised by the medical
community (Davis, Baum, & Graham, 1991; Gerostamoulos et al., 1996; Hou
et al., 2011; Romach et al., 1999). Adverse health effects as a result of
codeine use are reported by a significant number of studies. In general
reported health outcomes of excessive, long term or dependent use of
codeine and combination codeine products include perforated gastric ulcers,
gastrointestinal bleeding, hepatotoxicity, hypokalaemia, inflammatory bowel
conditions, and profound hypokalaemia associated with a severe myopathy,
and often in users with no history of substance use disorders and co-morbidity
(Chetty et al., 2003; Dutch, 2008; Dyer et al. 2004; Ernest et al. 2010; Frei et
al. 2010; Lambert & Close 2005; Lewis et al. 2005; Nielsen et al. 2010;
Robinson et al., 2010). Serious chronic health consequences relating to
gastrointestinal haemorrhage, nephro-toxicity, hypokalaemia and opioid
dependence are associated with the misuse of ibuprofen-codeine combination
products (Chetty et al., 2003; Ernest et al., 2010; Frei et al., 2010; Ng et al.’
2011). Many of these health effects are a result of additives in combination
products.
Madadi et al (2007) reported the death of a new-born male after his mother
was prescribed Co-Codamol (30/500mg) post-partum. While it appears the
mother was consuming normal therapeutic doses of codeine, the findings of
the case report revealed that both the mother and infant were fast
metabolisers of morphine, the metabolite of codeine producing a higher than
normal levels of metabolite resulting in the infant’s death. Reynolds et al.
(2007) assessed the effects of maternal drugs and medications on neonates.
They reported two separate case studies involving neonatal death which
found that codeine containing cough medicine had been given to the mothers
during pregnancy and was subsequently identified as the cause of neonatal
abstinence syndrome. The study recommends that doctors need to ask about
maternal medication use, including codeine-containing cough preparations,
when evaluating new-born infants with evidence of cerebral infarction.
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A quantitative mechanistic modelling study conducted in Germany on the risk
to the breast-fed neonates from codeine treatment to the mother
demonstrates that mother’s codeine and morphine clearance rates and
neonate’s morphine clearance rates are the most critical determinants of
morphine accumulation in infants. They conclude that unmonitored use of
codeine for post-labour pain in breast-feeding mothers should not be
considered a safe practice (Willmann, 2009).
The use of codeine for dental pain management is not uncommon. A reported
case of a 19 year old male who received erythromycin and cocodamol®(30/300mg) following dental pain for one week experienced a rare
psychotic episode which subsequently resolved with discontinuation of the
drugs and a 5 day course of antipsychotic therapy. Arguably, a
pharmacokinetic interaction occurred between both medications and resulted
in the psychotic disturbance. While psychiatric disturbances are often
experienced by those who abuse opiate medication, the result of this adverse
event is considered rare and it was impossible to ascertain if this incident was
as a result of a medication interaction only. However, clinicians should be
aware that these commonly prescribed drugs may have an iatrogenic cause
for psychiatric disturbances and that these adverse events are more likely to
occur during their concomitant use (Manchia et al., 2013).
Furthermore, Lam, Lee, Shum, & Chen (1996) from a retrospective chart
review of psychiatric admissions of 27 patients admitted with psychiatric
disorders over a 54 month period, either suffering from acute organic brain
syndrome, psychosis or affective episodes found all were misusing codeine
cough syrup. They suggest that in cases where substance misuse psychiatric
disorders are suspected, a high index of suspicion for cough mixtures
misuse/abuse is warranted (Lam et al., 1996). Paranoid psychosis
manifesting as persecutory delusions and derogatory hallucinations can occur
in patients abusing cough mixtures containing promethazine, ephedrine,
pseudoephedrine, codeine, and hydrocodone (Tang et al., 2012).
Over and prolonged use of non-steroidal anti-inflammatory drugs combined
with codeine to give additional analgesic effects can result in adverse health
effects, such as gastrointestinal problems and renal tubular acidosis. Ng et al.
(2011) examined four cases of life-threatening hypokalaemia associated with
ibuprofen and identified that all 4 patients had taken excessive amounts of
ibuprofen over a prolonged period with 2 of the patients having taken
ibuprofen combined with codeine. The four patients had developed
hypokalaemia due to ibuprofen-induced renal tubular acidosis. Ibuprofen
cessation and support therapy allowed complete recovery within days for all.
The study concluded that opioid addiction with the misuse of ibuprofencodeine combinations is common and needs to be considered in patients
presenting with severe hypokalaemia (Ng, 2011).
A number of other case studies found similar outcomes in relation to
hypokalaemia and codeine use. For example, Ernest and colleagues reported
severe hypokalaemia in a patient who consumed 72 Nurofen Plus® in 3 days,
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24 cans of Red Bull® energy drink, 2.5 litres of a homeopathic preparation in
addition to taking prescribed medications (galoperidol, diazepam, alprazolam
and salbutamol). While, the cause of the patient’s hypokalaemia was clouded
by the unusually high doses of multiple substances ingested, the authors
consider that the patient’s hypokalaemia was most probably attributable to the
significant ingestion of Nurofen Plus®. The codeine content and the ready
availability of Nurofen Plus® as an over-the-counter medication make it a
potential drug for misuse (Ernest et al., 2010). Other cases of
Ibuprofen/codeine induced hypokalaemia are also reported in the UK
(Lambert & Close, 2005).
Barreto et al. (2011) found from a retrospective analysis of patients presenting
with acute pancreatitis in Australia, that five of the 11 confirmed cases were
associated with drug ingestion and were most likely due to codeine
medication use (Barreto et al., 2011). Similarly, Hastier et al. (2000), reported
four cases of acute pancreatitis in France which had resulted after all patients
had taken therapeutic doses of codeine 1-3 hours before the onset of
symptoms (Hastier et al., 2000). The death of a female in the UK in 2013 as a
result of toxic levels of codeine coupled with methadone and morphine is also
reported (Tormey et al., 2013). Additionally, the misuse of Nurofen Plus® in
two patients in Australia resulted in perforated gastric ulcers (Dutch, 2008).
Chronic headache is also reported among those who use/misuse codeine.
Eng and Lachenmeyer (1996) describe a patient with chronic headache
resulting from a history of 25 years of self-medication of paracetamol/codeine.
Their study highlights the need to identify patients who are in need of
psychological services to assist in pain management and highlight the value
of psychological treatments, for example, cognitive-behavioural therapy,
biofeedback, and relaxation techniques for the treatment of chronic headache
(Eng & Lachenmeyer, 1996). Furthermore, a study of 12 female patients with
chronic daily headaches revealed cellular changes caused by prolonged
misuse, and withdrawal from the prescribed analgesics (codeine) resulted in a
decrease of mediators involved in headache pain for a majority over a 4 week
period which was significantly more improved one month further (Hering et al.,
1993).
Co administration of dihydrocodeine with heroin, methadone and
benzodiazepines can also potentially increase risk of fatal poisoning (Wazaify
et al., 2005; Zamparutti et al., 2010) and are associated with large, suicidal
and accidental overdoses, particularly among females (Gerostamoulos et al.,
1996; Häkkinen et al., 2012; Wazaify et al., 2005).
Home produced drug solutions based on codeine and other over the counter
compounds are associated with a myriad of dangers relating to contamination
and high risk injecting practices (Booth, 2013; Grund et al., 2013). The risk of
blood borne virus transmission (BBV) such as HIV and HCV is high, when
considerate of needle sharing and use of open containers of homemade drug
solutions. Perhaps most concerning, as outlined by Grund et al. (2013), is the
excessive harms reported by ‘Krokodil’ users whereby the skin of the user
becomes scale like, discoloured (green, black) and ulcerated. High and
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multiple injecting without a filter (particularly in the case of ‘Krokodil’) causes
great harm to the user in the form of severe and life-threatening phlegmon,
gangrene or internal damage to parenchymatous organs or muscles (Gahr. et
al. 2012a, b; Grund et al., 2013).
6.5 Dependence
A limited number of studies examine dependence on codeine, with much of
the evidence focusing on opioids as a group of medications only. Therefore, it
is a challenge to determine the extent of codeine dependence among drug
dependent users. Conflicting views exist with regard to codeines potential for
addiction, particularly when considering combination products and the
potential effects of other active ingredients such as ibuprofen, paracetamol
and caffeine (Frei et al., 2010; Wills 2005). Although effects are milder than
heroin, tolerance occurs with regular use over a short period of time (Mattoo
et al., 1997; Nielsen et al., 2008, 2010; Orriols et al., 2009). Withdrawals
include classic opiate dependence symptomatologies albeit less severe than
with morphine such as cravings, preoccupation with seeking and taking
codeine, lack of control of consumption patterns despite negative side effects,
insomnia, restlessness, runny nose, stomach pains, diarrhoea and chills
(Cooper, 2013b).
Estimations of the levels of codeine dependence in the public remain cloudy,
with rates of dependence on pharmaceutical drugs used for pain management
lower than expected (Dobbin & Tobin, 2008; Fishbain et al., 2008). As outlined
in Chapter 1, dependence in the case of codeine has been identified by
Nielsen et al. (2010:5) as three distinct types of codeine user, namely (direct
cite);
1. Therapeutic dependence; characterised by not exceeding therapeutic
doses but still demonstrating features of codeine dependence and often
having a picture of worsening pain. Some cases were consistent with
descriptions in the literature of medication overuse headache.
2. Non-medical/recreational users; characterised by use specifically for the
euphoric effects of codeine. This group were generally seeking and sharing
knowledge to reduce harms.
3. High dose dependence; characterised by the use of high doses (multiple
packets per day) and experiencing serious adverse effects from their use. Use
almost always stemmed from therapeutic use with participants often having
limited insight into dependence for an extended period of time. In some cases
use began for therapeutic use and escalated rapidly once euphoric effects of
codeine were experienced.
Dependent codeine users can also be categorised as either: those who
commence codeine use for pain management (either prescribed or via
pharmacy sale), initially use appropriately and who intentionally or
unintentionally due to lack of awareness or pharmacy/health professional
advise increase their dosage or length of time administered in order to ease
discomfort (Good & Ford, 2007; Hughes et al., 1999); or those who are opiate
dependent, may be in methadone maintenance treatment, and using codeine
to manage withdrawals when unable to secure either heroin or prescribed
93
methadone (National Council on Patient Information and Education, 2002;
Heard et al., 2006; Reed et al., 2011; Roumie & Griffin, 2004).
A prospective cohort study following patients recorded on a national database
from 2005 to December 2008 was conducted in Norway to determine the
extent in which new users of weak opiates develop persistent or problematic
use (Skurtveit et al., 2011). 245,006 patients were new users of weak opioids
of which 216,902 were prescribed codeine. Although not exclusive to codeine
medication, on examination, 191 subjects met the criteria for probable
problematic opioid use. 0.3% and 0.08% developed prescription patterns
indicating persistent opioid use and problematic opioid use respectively. The
study concluded that only a very small minority of patients starting with weak
opioids develop a prescription pattern indicating persistent use or probable
problematic use of opioids. Therefore, it is argued that the fear of developing
problematic opioid use should not hamper the use of weak opioids for
moderate or severe acute pain (Skurtveit et al., 2011).
Fleming et al. (2007) examined substance dependence in 801 patients from
235 family practices in the USA (Fleming, Balousek, Klessig, Mundt, & Brown,
2007). The aim of the research was to present a comprehensive picture of
substance use disorders in a sample of patients receiving opioid therapy from
primary care physicians. Additionally, the study tried to determine the
relationship of positive urine screens and aberrant drug behaviours to opioid
use disorders. Of the 801 patients, 68 (8.6%) were prescribed 30/500mg cocodamol. While the study was not specific to codeine only, the frequency of
opioid use disorder was four times higher in patients prescribed an opioid
when compared to the general population and linked aberrant behaviour to
opioid use disorders.
A study examining dependence on legal psychotropic drugs among 130
alcohol dependent users found that 29% had developed a high dose
dependence on codeine (Johansson, Berglund, Hanson, Pohlen, & Persson,
2003). When this group were compared to a control group of 120, 13% were
dependent on codeine compared to 1% of the normal population. More than
half of the alcohol and codeine dependent users were also dependent on
benzodiazepines.
Busto et al. (1998) in a mixed method study in Canada found high
dependence on codeine in a group of opioid dependent patients (n=58)
admitted for treatment (Busto, Sproule, Knight, Romach, & Sellers, 1998). The
most commonly used opioids were codeine at 52% with doses at between
343 and 554mg per day.
Daniaulaityte et al. (2006) conducted in-depth interviews with 24 people who
had a history of opioid abuse. Their use of codeine was connected with selfmedicating for physical pain associated with daily tasks and to psychological
well-being. Some started taking codeine for genuine reasons and over time
developed their addiction; others took codeine to feed their already
established addiction to heroin, especially when heroin was not readily
available.
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In conclusion, a limited number of studies examine dependence on codeine,
with much of the evidence focusing on opioids as a group of medications only.
The relationship between the misuse of over the counter available medicines
such as codeine containing products such as Nurofen Plus (ibuprofen and
codeine) and illicit drug use, and the diversion of codeine to street drug
markets warrants further investigation (Levine, 2007; Matheson et al., 2002;
Reay, 2009; Sproule et al., 1999). It is important to recognise variance in
groups of codeine misusers and target research, policy and practice initiatives
appropriately.
6.6 Conclusion
Codeine is considered to be an unpredictable drug with increased risk of
toxicity in combination products (Iedema, 2011). The potential for overuse and
misuse of codeine containing medications is not only detrimental for a
person’s health but has broader consequences in terms of its cost and
implications for the wider society (Feinberg, 2006). This review examined the
consequences of codeine use, misuse and abuse and four main categories
were identified: (1) impairment, (2) injury, (3) adverse health effects and (4)
dependence. Recommendations for practice and areas for further research
are offered.
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Chapter 7
Prevention of Codeine Misuse, Abuse and
Dependence
7.1 Introduction
The misuse, abuse and dependence on codeine products are an emerging
public health challenge in many countries throughout the world. Deregulation
has contributed to compounding the issue, with codeine present in a range of
over the counter medicines (Cooper, 2013a; Robinson et al., 2010). Much of
the evidence on codeine misuse and dependence originates from the United
States (US) where codeine based products are now not available over the
counter. However, there are a growing number of studies now emerging in
other parts of the world on over the counter codeine use and misuse, for
example, in the United Kingdom (UK) and Australia. The literature in relation
to the medical prescribing of codeine and pharmacy related activities are
presented with regard to the prevention of codeine misuse, abuse and
dependence. Some innovative approaches for managing such issues are
offered.
7.2 Medical Practice and Pharmacovigilance
Increased pharmacovigilance in primary care is advised (Kahan et al., 2006;
Jones et al., 2012). There is increased emphasis on responsible prescribing in
the literature on the misuse of prescribed opioid analgesics (including
codeine) to include risk assessments, prescribing agreements and treatment
contracting without compromising legitimate access to opioids for analgesia
(Ling et al., 2011; Maxwell, 2011).
Education in administration of paediatric medication containing codeine is
needed (Cartabuke et al., 2013). Those caring for paediatric patients taking
codeine should be advised to seek medical assistance if symptoms of toxicity
occur (EMA, 2013; Ng et al., 2011; Schillie et al., 2009).
Health professionals involved in prescribing need to monitor use in vulnerable
groups (patients with chronic non-malignant pain, patients with cancer pain
and illicit drug users).
The objective of such monitoring is to identify if opioids such as codeine are
substituting for or complicating pain, mental health and addiction treatment
outcomes, thereby minimising risk of overdose (Edlund et al., 2010;
Manchikanti & Singh, 2008; Roxburgh, Bruno, Larance, & Burns, 2011).
Indeed, dependence by health professionals themselves to both prescribed
and over the counter opioids such as codeine are also issues of concern (Des
Roches et al., 2010).
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7.2.1 Co-prescribing and effects on health
Frequent co-prescribing, for example benzodiazepines and opioids, can have
negative consequences for health, potential overdose lethality and treatment
outcomes and requires patient monitoring and responsible prescribing
practices (Maxwell, 2011). Practitioners need to be aware of excessive
consumption of combination products, with health consequences relating to
additives in causing severe hypokalaemia complicated by myopathy (Chetty
et al., 2003; Ernest et al., 2010; Frei et al., 2010; Ng et al., 2011), and also the
iatrogenesis of psychiatric disturbances relating to codeine use (Manchia et
al., 2013).
7.2.2 Pain
Pseudo-addiction is defined as the under-treatment of pain (Bell & Salmon,
2009). Concerns are evident for the under treatment of patients in pain, due to
fears of addiction, and complications in estimating prevalence and
characteristics of dependents according to DSM-IV criteria particularly among
chronic pain patients (Brands, Blake, Sproule, Gourley, & Bust, 2004).
Medical practitioners can be reluctant to treat such patients due to concerns
relating to over prescribing (Olsen & Daumit, 2002). The National Institute on
Drug Abuse (NIDA) in the US has observed the under prescribing of codeine
due to general practitioners’ overestimation of patient potential for addiction
(otherwise known as ‘opiophobia’), which can result in the sub management
of pain (Bell & Salmon 2009; Brennan, Carr, & Cousins, 2007; Rupp &
Delaney, 2004 ). However, in other studies, pain management specialists
observe a low incidence of misuse and dependence, with risks outweighing
the potential for improved functioning and quality of life (Cowan, Allan, &
Griffiths, 2002). Despite this, the emergence of patient dependence on opioids
such as codeine is viewed as compromising therapeutic relations due to the
belief that “pain exists whenever the patient says it does” which hampers
detection of deception and increases the risk of inadequate pain control and
overdose (Modesto-Lowe, Johnson, & Petry, 2007).
Bailey, Hurley, & Gold (2010), describes the crossroads of pain and opioid
dependence as characterised by: travelling long distances to the pain clinic;
inability or unwillingness to obtain records; requests for medications with
abuse potential; use of street vernacular; focus on opioids; activity in street
dealing; obtaining medication from friends and relatives; doctor shopping;
unwillingness to consider non opioid adjuncts; interventional treatment
modalities and physical therapy; aversions or allergies to non-opioid
medication; unwillingness to produce urine for screening; physical signs of
illicit drug use; appearance not correlating with physical dysfunction and
hepatitis B or C. Future preventative strategies need to be aware of such user
characteristics.
7.2.3 Prescription drug monitoring
Studies recommend the development of prescription drug monitoring and
national online prescription systems (Francis et al., 2005; Maxwell, 2011;
Roxburgh et al., 2011,). Pharmaceutical opioid seeking behaviours are often
97
characterised by visiting multiple prescribers, feigning prescription loss,
requesting early refills of prescriptions, seeking strong opioids, avoiding
combination products and paying in cash (Brands et al., 2004; Cepeda et al.,
2013, 2012a, b; Fountain et al., 1998; Kamien, 2004). Prescribers aged 70-79
years, male and prescribing stronger opioids have increased likelihood of
having opioid shoppers as patients (Cepeda et al., 2012b). Nordmann et al.
(2013) have described regional trends in France of doctor shopping for
dihydrocodeine and oxycodone.
In terms of codeine cough syrup, students suggest that doctors and
pharmacists are the greatest facilitators of acquisition (Peters et al. 2007).
Many doctors do not question patients around over the counter use of
analgesics, resulting in undetected problems, and the increased availability of
over the counter analgesics such as codeine in certain countries may
contribute to patient delays in consulting their doctors for potentially serious
conditions (Francis et al., 2005). Furthermore, a survey conducted by ‘OverCount’ estimated that the majority of codeine misusers are female and that
their first purchase of codeine products was to treat minor ailments; most
often sourcing the products via the Internet with low rates of support from
doctors (Reay, 2009).
General practitioners report that they often receive ‘verbal threats’ from
patients with prescribed drug problems and that tactics adopted by them to
manage such threats include the documentation of incidents, suggestion of
alternative drugs and cessation of prescribing such drugs (commonly
benzodiazepines and opioids) (Sheridan, Jones, & Aspden, 2012). Primary
care treatment strategies should promote the availability of disposal
containers for unused prescriptions and referral to addiction services
(Lessenger & Feinberg 2008).
7.2.4 Screening
Standard screeners, for example, the Screener and Opioid Assessment Tool
for Patients with Pain (SOAPP), the Opioid Risk Tool (ORT) (Bailey et al.
2010), the Prescription Misuse Index (Knisely, Wunsch, Cropsey, & Campbell,
2008) and the current opioid misuse measure are used for pain patients on
long term opioid therapy to screen for patient aberrant behaviours (Butler et
al., 2007). Management of aberrant opioid behaviours requires patient
education, monitoring, testing, adjunct support, treatment of comorbid
conditions with a primary focus on treatment of dependence (Bailey et al.,
2010).
Breastfeeding is cautioned and requires close screening and monitoring if
prescribing codeine to breastfeeding mothers, given the potential risks
associated with CYP2D6 ultrafast metabolism (Kennedy, 2011). Codeine use
while breastfeeding is associated with events in breast-fed infants, including
apnoea, bradycardia, drowsiness and cyanosis (Darnall et al., 2012). Women
with the cytochrome P450 2D6 (CYP2D6) genotype rapidly metabolize
codeine into morphine, resulting in high breast milk and plasma levels in
neonates, and can potentially cause infant death due to opioid toxicity
98
(Madadi et al. 2007; 2011). However, genetic screening is not standard
practice, thus contributing to a lack of clinician awareness of potential for
neonate opioid toxicity (Madadi et al., 2011). Screening and education in the
administration of paediatric medication is needed (Cartabuke et al., 2013).
Health professionals caring for paediatric patients taking codeine should be
advised to seek medical assistance if symptoms of toxicity occur (EMA, 2013;
Ng et al., 2011; Schillie et al., 2009).
7.2.5 Clinical presentations of injecting use of home produced drug
solutions
The diversion, tampering, home manufacture and injecting use of over the
counter and prescribed pharmaceuticals (containing codeine and other
opioids) remains a public health and drug monitoring concern (Azbel et al.,
2013). Tampering with pharmaceutical formulations and home production of
opiates using pharmaceuticals containing codeine impacts on primary care
and treatment provisions. Simple procedures to alter medication formulations
are preferred by substance users (Cone, 2006), with users generally deterred
by homemade drugs which are difficult to produce (Katz et al., 2006) or inject
(Partanen, Wunsch, Cropsey, & Campbell, 2009). Pharmaceutical drug
formulation technologies are continuously developing in order to create
disincentives to reduce the incidence of product tampering and abuse
(Coleman et al. 2005; Coleman, Schuster, & DuPont, 2010; Cone 2006;
Hamed & Moe, 2010; Katz et al., 2011).
Drug monitoring systems, drug workers and clinicians should be aware of
potential presentations for emerging and harmful forms of home produced
drug abuse, particularly in the case of injecting drug use (Gahr et al., 2012a,
b). The adverse health consequences associated with these tampered
substances demands provision of coordinated services comprising medical
support, counselling, HIV counselling and testing, wound and infection
management, outreach support and rehabilitation (Elovich & Drucker, 2008;
Gahr et al., 2012a, 2012b; Harris et al., 2002; Skowronek et al., 2012).
Research in countries experiencing diffusion of homemade codeine
containing drug use and injecting have reported on the negative impact of
policing effective drug treatment (Azbel et al., 2013; Grund et al., 2013;
Mimiaga et al., 2010; Sarang, Rhodes, Sheon, & Page, 2010), with evidence
suggesting inequitable treatment of injecting drug users by health
professionals with subsequent reluctance of users to access treatment
(Booth, 2013; Grau et al., 2002; Harris et al., 2002; Wolfe, 2007; Wolfe et al.,
2010).
A proactive approach to developing appropriate harm reduction tactics
(needle exchange, bleach distribution, hygiene, provision of filters, foil packs
to encourage route reversals, and safer injection facilities), screening,
treatment and therapy (opiate substitution therapy, antiretroviral therapy) and
prevention programmes is therefore essential (Alistar, Owens, & Brandeau,
2011; Bojko, Dvoriak, & Altice, 2013; Chintalova-Dallas, Case, Kitsenko, &
Lazzarine, 2009; Hallinan, Osborn, Cohen, & Dobbin, 2011; Hedrich, Kerr, &
99
Dubois-Arber, 2010; Pizzey & Hunt, 2008; Wolfe et al. 2010). The
development of strategies to manage access and treatment barriers in relation
to the reluctance of injecting drug users to access treatment is of concern.
7.3 Pharmacy Practice and Preventative Strategies
The de-regulation of prescription only medicines to pharmacy status over the
counter drugs has evolved to reduce government drug budgets, general
practitioner’s workloads, and to extend the screening and patient education
roles of community pharmacists (Cooper, 2011b; MacFadyen et al., 2001;
Robinson et al., 2010).
Pharmacists are regarded as a trusted source of information in relation to over
the counter medications (Wawruch et al. 2013). However, the literature
suggests that a significant number of people who consume medications
cannot identify the active ingredients in their chosen medications (Roumie &
Griffin 2004). This is despite high reported public awareness of the abuse
potential of over the counter medicine (Wazaify et al., 2005, 2005a) and
pharmacists’ concerns in relation to safety and codeine misuse, abuse and
dependence (Albsoul-Younes et al., 2010; Ball & Wilde, 1989; Hughes et al.,
1999; MacFayden et al., 2001; Matheson et al., 2002; Pates et al., 2002;
Paxton & Chapple, 1996; Reed et al., 2011; Roumie & Griffin, 2004; Wazaify
et al., 2005).
A minority of customers appear willing to accept the risks associated with
increased access to pharmaceuticals (Alexander et al. 2005). Perceptions of
risk amongst over the counter users generally do not conform to current
medical thinking or correlate with self-reports of analgesic usage, with users
who view analgesics as necessary reporting analgesic use, at greater doses
and frequencies (French & James, 2008). However, customers who are selfselecting and purchase products online have inadequate access to
information and advice at point of sale (Bessell, Anderson, Silagy, Sansom, &
Hiller, 2003).
Other concerns regarding patient awareness of overuse of over the counter
codeine and lack of translation into appropriate codeine consumption by
disregarding product packaging or simple lack of patient comprehension that
dosage is excessive have been recorded in emergency departments. Clearer
product labelling of active ingredients in over the counter codeine has been
advised (Heard et al., 2006, Roumie et al., 2004). Recent research on
codeine misuse and customer awareness in Australia by Nielsen et al. (2010)
identified three distinct forms of codeine misuse, namely:
individuals conscientiously disobeying product instructions so as to
experience a drug induced euphoric effect from the codeine present.
individuals becoming addicted to codeine based products, aware of their
dependence but continuing to use them in response to cravings and to avoid
withdrawals.
individuals unknowingly misusing codeine based products within the
recommended limits but frequently and regularly using them to treat druginduced withdrawal symptoms such as headache.
100
Screening and patient education roles for community pharmacists have
resulted as a consequence of the de-regulation of prescription only medicines
to pharmacy status over the counter drugs (Basak, van Mil, &
Sathyanarayana, 2009; Cooper 2013b, 2011; MacFadyen et al., 2001,
Robinson et al., 2010). Furthermore, pharmacists’ decision-making in relation
to product selection and the role of clinical evidence suggests that safety and
patient demand for certain products influences their decision making
processes. Hanna & Hughes (2010)’s research into pharmacists’ decisionmaking processes regarding product selection and the role of clinical
evidence in reaching such decisions, found that safety and patient demand for
certain products influenced the recognition of patient demands. Evidence of
effectiveness of the selected product was rarely part of the decision-making
process. Communication between medicines counter assistants and
customers in community pharmacies in the UK is promoted as source of
primary care advice, and viewed as a complex process relating to retail,
medical and pharmaceutical sources of information despite being
characterised by conflict (Banks, Shaw, & Weiss, 2007). Although the selfmedication of non-prescription drugs is beneficial to patients, health
professionals, pharmaceutical industries and governments (Orriols et al.,
2009; Wawruch et al., 2013), monitoring of certain populations and products,
data recording and patient monitoring is required to promote safer use of
medicines (Hughes, 2003).
In France, Orriols et al. (2009) conducted a cross sectional pharmacoepidemiological study using pharmacy customer data to explore non-medical
use, misuse, abuse and dependence on self-medicated drug use. Statistically
significant differences in non-medical use and misuse, abuse and
dependence were present for codeine based products. Nielsen et al. (2013)
investigated perspectives of over the counter codeine users who met DSM-IV
criteria for dependence about dependence in the pharmacy setting.
Participants reported that ease of access to codeine was related to better
appearance and presentation, and also commented on standard pharmacist
questioning, minimal interventions from staff and occasional refusals to
supply. Codeine users in this study did not describe pharmacy staff offering
advice and reported employing tactics including wearing business suits to
promote product acquisition (Nielsen et al., 2013). This study also found that
the ‘hassle’ of pharmacy shopping was an important driver for eventual
treatment seeking.
7.3.1 Pharmacy Preventative Strategies
Research by Hamer, Spark, Wood, & Roberts (2013) describes challenges in
pharmacy management of codeine dependent individuals. Community
pharmacies can solve or partly solve drug related problems without
involvement of general practitioners (Frøkjær et al. 2012). Pharmacists
commonly observe opioid intoxication and aberrant opioid behaviours in their
practice, but report difficulties in the communication of concerns to doctors
(Kahan et al. 2011).
101
Communications between counter sales assistants and customers in
community pharmacies are promoted as a medium for providing
pharmaceutical advice despite consultations sometimes being characterised
by conflict (Banks et al,. 2007). Challenges in relation to the pharmacy
management of codeine dependent users are described (Hamer et al., 2013).
For certain populations who use over the counter products, for example,
codeine, data recording and user monitoring are required so that safer use of
such medicines is realised (Hughes, 2003). Safety is central to pharmacists’
decision making with regard to medication supply (Hanna & Hughes, 2010).
Pharmacy practice strategies 8 that promote safety include the removal of
potential products of abuse from sight; brief interventions to raise user
awareness of potential harms; refusing sales; doctor referral and in some
instances the supply of small amounts of the requested drug (Albsoul-Younes
et al., 2010; Matheson et al., 2002; Pates et al.’ 2002). Broader strategies
have been proposed that centre on the monitoring of web sales, raising
visibility of warnings on product labels and restrictions in relation to
advertising (McBride et al., 2003). Clearer product labelling of the active
ingredients in over the counter codeine is a concern expressed by emergency
room staff following patient presentations in relation to the overuse of over the
counter codeine as a result of disregarding product packaging or lack of
understanding of therapeutic dose ranges (Heard et al., 2006; Roumie &
Griffin, 2004).
There is a need for further protective mechanisms in the pharmacy profession
in order to track and monitor codeine misuse in so called ‘respectable
addicts’, in order to provide support and treatment options for those affected,
along with the option for pharmacy led treatment withdrawal (Cooper, 2011;
2013a;b). Research has underscored how the de-regulation of prescription
only medications toward pharmacy status medications has moved toward selfcare and the reduction of GP workloads, and reciprocally spotlighted the need
for an ‘early warning system’ in pharmacies, along with inter agency
educational, screening, life skills and harm reduction initiatives to reduce
codeine misuse (Basak et al,. 2009; Gruenewald et al. 2009; Hughes et al.
1999; MacFadyen et al., 2001; McBride et al., 2003; Wazaify et al., 2006).
The expansion of the clinical role of the community pharmacist should include
a thorough assessment of the customers’ problem prior to counter prescribing
(Francis et al., 2005). Fleming et al. (2004) developed a harm reduction tool to
identify and treat over the counter drug misuse and abuse by community
pharmacists. This harm reduction tool consists of three phases: (1) patient
identification and recruitment, (2) treatment and referrals, and (3) data
collection/outcomes measurement.
The potential use of real-time online prescribing information systems of
prescribed records could be a possible medium for effective monitoring of
codeine use, misuse and abuse (Chee & Schneberger, 2003; Dobbin & Tobin,
8
See Chapter 3, table 1- Regulation of Codeine over the counter and Prescribed
102
2008; UNODC, 2011; Wrobel, 2003). While a minority of users appear willing
to accept the risks associated with increased access to pharmaceuticals
(Alexander et al., 2005), those who are self-selecting and purchasing products
online have inadequate access to information and advice at point of sale
(Bessell et al., 2003). Innovative developments based on national integrated
prescriber and pharmacy monitoring of medicines using real time reporting
(RTR) analysis have emerged in the US, Canada, South Africa and Australia
(Le Roux, 2013; Shand et al., 2013; UNODC, 2011).
7.4 Conclusion
The misuse, abuse and dependence of codeine products is an emerging
public health issue (Cooper, 2013a; Robinson et al., 2010). Of note is that
pharmaceutical opioid misusers already have regular contact with health
professionals, thereby highlighting the preventative and monitoring role of
pharmacists and prescribing doctors using real-time online prescribing
information systems of prescribed records (Dobbin & Tobin, 2008; Chee &
Schneberger, 2003; UNODC, 2011; Wrobel, 2003). Continuing interdisciplinary training for counter assistants, pharmacists and health
professionals is required (Basak et al., 2009; Bissell et al., 2000; Butler &
Sheriden, 2010; Wazaify et al., 2005). The literature in relation to the medical
prescribing of codeine and pharmacy related activities highlights the need for
more preventative strategies in relation to codeine overuse, misuse and
dependence. Some innovative approaches for managing such issues are at
an early stage of development.
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Chapter 8
Interventions/Treatment and Codeine
Dependence
8.1 Introduction
This chapter describes interventions used in the initiation and treatment of
codeine dependence. Increases in treatment uptakes relating to codeine
dependency and concerns for appropriate design of treatment protocols have
been recorded across a variety of countries (Bell, 2010; Cooper, 2011a, b;
EMCDDA Annual Report, 2011; Roche, McCabe, & Smyth, 2011; Romelsjo et
al., 2010; SAMHSA, 2009; Thekiso & Farran, 2010). Many codeine dependent
individuals do not view themselves as needing help (Cooper 2013b, Nielsen
et al., 2010) and the evidence base for treatment of codeine dependence is
limited. With regard to treatment interventions, there is varying uptake by
individuals dependent on codeine in drug services due to issues relating to
treatment stigma and poor consideration of needs (Reed et al., 2011). The
potential for ‘discrete’ groups of codeine dependents who fail to seek help due
to lack of recognition of their dependence or identification of their codeine use
as a problem is described (Pates et al., 2002). We describe here the stages of
potential intervention on prevention of pharmaceutical tampering, initial
identification, referral and uptake into treatment.
8.2 Extractability Rating System (ERS)
In a non-codeine specific intervention, Katz et al. (2006) describe the
development of an Extractability Rating System for use by the pharmaceutical
industry and regulators. The ERS was used to evaluate the extractability of
five prescription opioids. The motivation for this project was to develop abuseresistant formulations. Extractability is the extent to which extraction
procedures are performed on a drug product that results in quantities of active
ingredients relevant to substance abuse.
The development of the ERS followed five stages. Open-ended interviews
were conducted with an initial group of experts that included professionals in
the field of substance abuse as well as individuals who had abused opioid
medications. Several experts in the field were participants in subsequent
stages to further develop and refine the ERS. The main outcome of the study
was the creation of a comprehensive inventory of extraction techniques used
by substance abusers. The authors acknowledge limitations in the study and
that the ERS requires further work to improve standardisation and reliability.
8.3 Harm-Minimisation Intervention Model
The harm-minimisation intervention model was developed and piloted by
Fleming et al. (2004). This model is designed to be used by community
pharmacists in conjunction with other healthcare professionals. It addresses
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the abuse and misuse of opioid, antihistamine and laxative-containing product
groups which are highlighted as problematic by pharmacists in practice. The
model has three elements:
(1) To identify those at risk of abuse
Identification is via an information campaign and by keeping records of
sales. Once the pharmacist has identified a customer suspected of
abusing or misusing over the counter medicines, they are approached.
This approach utilises communication techniques, for example,
motivational interviewing and details of all approaches are recorded on a
record sheet designed for the purpose.
(2) How and when to intervene and propose treatment
This involves two treatment algorithms showing possible treatment paths.
The treatment path chosen depends on the product involved and if the
product is being abused or misused.
(3) To measure the overall outcome of the intervention
Individualised confidential records are initiated. These include details of
the client’s demographics, history of product use and treatment
interventions (including details of medications dispensed). These records
are updated each time the customer attends the pharmacy so enabling the
pharmacist to monitor the customer’s progress and outcomes.
Two pharmacists participated in a pilot study of the model. They were
provided with training which incorporated the use of communication
techniques. While identifying abusing/misusing customers was relatively
simple due to the initiated record keeping, implementation of the intervention
was more problematic as customers were generally uncomfortable in taking
part in any discussion regarding misuse/abuse.
A total of 18 customers suspected of abusing/misusing products were
identified and the two pharmacists discussed inappropriate over the counter
use with 14 of them. Both pharmacists reported that it was easier to approach
clients whom they suspected were misusing products, as opposed to those
suspected of abusing products. While it was agreed that the training in
communication skills had been helpful, a more intensive training programme
on this aspect of the model was recommended (Fleming et al., 2004).
A limitation of this intervention appears to be the reluctance of customers to
take part. Abuse/misuse of over the counter products is a sensitive subject
and it is not surprising that customers were disinclined to have documented
their history of product use. It is likely that customers who are highly motivated
will benefit from this intervention (Fleming et al., 2004).
Although successful in a number of areas, the completion of the pilot has
identified opportunities for further refinement of the model. Future work
focusing on improving pharmacists’ communication skills, particularly in the
area of motivational interviewing was recommended (Fleming et al., 2004).
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Wazaify et al. (2006) examined the use of the harm-minimisation intervention
model in a follow up study conducted in six community pharmacies in Belfast,
Northern Ireland. This study included testing the model and exploring the
experiences of pharmacists conducting the intervention. As recommended by
the pilot study (Fleming et al., 2004), the participating pharmacists received
two full days of training before commencing the study. Training included
motivational interviewing techniques which are known to support change in
behaviours, particularly in alcohol and substance abuse/misuse management.
Pharmacists identified 196 cases of suspected abuse/misuse. They
approached 70 of the identified clients during the six month study. Some
clients agreed to stop using the product of abuse/misuse, use an alternative,
or switch to maintenance prescription under general practitioner supervision.
No client proceeded to completion of the follow-up phase (e.g. health-related
quality of life).
The study concluded that some difficulties were encountered in implementing
the harm minimisation model, but these may be alleviated by further training
and more collaborative working by all concerned. The harm-minimisation
model should be considered for wider implementation within community
pharmacies.
8.4 Assessment and Management of Codeine Dependence
Research has previously called for the use of standardised criteria to
determine client codeine dependence (Tinsley & Watkins 1998). There is also
a lack of evidence to guide development of specific treatment and referral
pathways for over the counter codeine dependence (Cooper, 2011; 2013a, b;
Reed et al., 2011; Thekiso & Farren, 2010,).
Clinical profiles of codeine dependents vary but are over represented by
females, those in middle to late age, poly substance users, alcohol users and
those with underlying psychiatric conditions (Agyapong et al., 2013;
Johansson et al., 2003; Otto et al., 2009; Thekiso & Farren, 2010; Robinson
et al., 2010). Codeine misusers in Ireland were more likely to be older, male
and with a longer drug dependence history (Cohen, Unoh, Barry, O'Connor,
2009). Research in South Africa shows that combination codeine product
abuse may also present as a secondary problematic substance and was
ranked second to benzodiazepine dependency, with primary over the
counter/prescription medication abuse most common in females aged over 40
years, and secondary over the counter/prescription medication abuse most
common in males over 40 years (Myers et al., 2003).
In another study, average daily intake of codeine in psychiatric patients
diagnosed with harmful over the counter codeine dependence was 261mg per
person, with greater trends in those who were older, male and with co morbid
psychiatric, physical and poly substance illnesses (Thekiso & Farren, 2010).
Codeine cough mixture treatment patients are primarily young (Wairagkar et
al., 1994). Another study observed dependence trajectories for young codeine
cough syrup treatment seeking patients, often initiated through friends and for
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curiosity, with daily use progressing in less than 6 months to higher than
therapeutic doses (Mattoo et al., 1997)
Research by McAvoy et al. (2011) reported on high average over the counter
codeine analgesic tablet consumption amongst patients attending
detoxification (49-65 tablets daily), long duration of misuse, and a history of
prior alcohol or other drug misuse or mental health disorder. Brands et al.
(2004) found that those patients dependent on prescribed opioids alone,
reported an average consumption of 21 tablets of codeine daily, and were
less likely to use illicit non opioid drugs or report injecting drug use. Those that
used prescription opioids only or initially before using heroin reported ongoing
pain problems and psychiatric treatment. In Ireland, regulatory controls on
non-prescribed over the counter available codeine medication were observed
to have the potential to reduce abuse among psychiatric patients (Agyapong
et al., 2013).
Codeine dependence can be managed with residential treatment
programmes, opiate substitution therapy or lofexidine (an alpha-2 agonist
used to attenuate opiate withdrawal effects) in community detoxification (Kelly
& Madadi, 2012; Mattick et al., 2008). Additionally, patients suspected of
opioid misuse can be treated with time restricted structured opioid therapy in
the form of weekly dispensing, urine testing and tapering of dose, if not
seeking opioids from other sources (Kahan et al., 2006).
Codeine dependent individuals need to taper their use under medical
supervision. The primary modes of treatment are similar to that of heroin
dependence and focus on a variety of detoxification modalities ranging from
no medical support, the prescribing of sedatives, (benzodiazepines and
sedative anti-psychotic medication), the prescribing of Lofexidine (i.e.
Britoflex®) and buprenorphine (i.e. Subutex®) (Frei et al. 2010). Rehabilitation
involves inpatient and cognitive behavioural therapy. Other options include
maintenance therapy in the form of opioid substitution treatment using
naloxone or dihydrocodeine. Psychosocial support and regular aftercare is
vital for positive treatment outcomes (Backmund et al., 2001; Otto et al.,
2009). Websites such as ‘Over-Count’ and ‘Codeine Free Me’ offer useful
support for individuals experiencing codeine dependence (Reay, 2009).
A limited number of papers relating to interventions to treat the misuse of
analgesics were identified for review. However, a harm-minimisation model for
the identification and treatment of over-the-counter over the counter drug use
and misuse that could be used by community pharmacists in conjunction with
other health care professionals is described (Fleming et al., 2004; Wazaify et
al., 2006). The development of the Extractability Rating System for use by the
pharmaceutical industry and regulators to assist drug developers who wish to
develop opioid products that are abuse-resistant is also available (Katz et al.
2006). ‘Withdrawal Therapy’ , an intervention for patients with chronic daily
headache and frequent long-term use of headache symptomatic medication
is also reported (Linton-Dahlöf, 2000).
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A retrospective analysis of an intervention using drug withdrawal therapy of
patients with chronic daily headache with frequent long-term use of headache
symptomatic medication reported the following results (Linton-Dahlöf, 2000).
One hundred and one adult patients (74 women and 27 men, aged between
16 and 72 years), were evaluated 1±3 months after total drug withdrawal
therapy without substitution. The total withdrawal period was approximately
eight weeks. Results indicated that 57 (56%) patients were significantly
improved (defined as at least 50% reduction in number of headache days).
Patients with misuse of codeine (n=14) were also able to accomplish outpatient withdrawal and report a similar pattern of abstinence symptoms in
comparison with patients with misuse of non-psychotropic drugs. Patients who
experienced no improvement after drug withdrawal therapy were offered
treatment with amitriptyline and 36% experienced a significant (50%)
reduction of headache days. The study concluded that out-patient drug
withdrawal therapy is the treatment of choice in patients with chronic daily
headache. It is estimated that about one quarter of chronic daily headache
patients do not respond to drug withdrawal therapy only.
Reed et al. (2011) conclude their review on codeine based products by
highlighting the need to consider the wide variety of clinical profiles and harms
incurred for codeine users, misusers and dependents, and the need for timely
evidence to guide the development of treatment policy for over the counter
codeine misuse or dependence. Comprehensive training programmes and
coordinated supports for pain and addiction specialists in the assessment and
management of coexisting addiction and chronic non-malignant pain via
didactic and experiential training requires further development (Bailey et al.,
2010, Daniulaitye et al., 2006, Maxwell, 2011, Roxburgh et al., 2011).
8.5 Barriers to Treatment Completion
Myers et al. (2003) points to the need to develop primary health care
protocols for detection, management and referral of patients misusing over
the counter/prescription drugs and the need to debate the re-scheduling of
codeine as a prescription-only substance.
Studies describe poor long term outcomes for codeine dependents at 12
month follow up (Otto et al. 2009, Zahradnik et al. 2009). However, for those
with pain management issues, a re-emergence of pain creates a barrier to
successful treatment completion (Tennant & Rawson, 1982), and highlights
the need for coexisting pain management supports (Dobbin & Tobin, 2008,
Fishbain et al., 2008). Patients with co-existing pain and addiction may have a
‘syndrome of pain facilitation’ characterised by decreased pain tolerance,
increased anxiety, depression and insomnia (Compton et al. 2001). Even
when detoxified, pharmaceutical opiate dependents may need help for pain
(Larson et al., 2007) and may have abnormal pain perception (Pud et al.,
2006), leading to drug cravings (Ren et al., 2009). .
Concomitant consumption of benzodiazepines and opioids is a major barrier
in treating patients with opioid dependence and is associated with daily
alcohol or barbiturate use, early onset of opioid use, unemployment, family
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history of dependence and history of imprisonment, with codeine dependents
reporting significantly greater daily intake than heroin dependents (Backmund
et al., 2006). A review of codeine based products has highlighted the need to
consider the wide variety of clinical profiles and harms incurred for codeine
users, misusers and dependents, and the need for timely evidence to guide
the development of treatment policy for over the counter codeine misuse or
dependence (Reed et al., 2011).
8.6 Conclusion
Many codeine dependent individuals do not view themselves as needing help
for their codeine dependence. Indeed, the literature in relation to the use of
interventions in the management of codeine misuse is limited, lacks specificity
and requires further research and development. Despite the use of criteria to
establish dependency, recent research has commented on the lack of
evidence to guide development of specific treatment and referral pathways for
over the counter codeine dependence. With this in mind, there is a need for
further research to guide the development of treatment policy for over the
counter codeine misuse and dependence.
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Chapter 9
Conclusions and Implications for Practice,
Policy and Research
9.1 Introduction
This chapter provides a discussion of the findings of this scoping review of
codeine use, misuse and dependence. Key recommendations are addressed
under the headings: (1) raising awareness; (2) detecting and managing risk;
(3) dispensing practices and (4) monitoring and surveillance. Some key areas
for further research are identified and presented under six headings: (1)
patterns of use, misuse and dependence; (2) prevalence; (3) treatment/
interventions; (4) risk; (5) epidemiology and (6) policy. Additionally, the
limitations of the review are discussed, in order that the findings are
interpreted in context.
9.2 Improved Understanding and Pharmacovigilance
A global emergence of ‘respectable addiction’ has occurred alongside a
heightened awareness by the general public and health professionals with
regard to this addiction issue (Cooper 2013a, 2011; EMCDDA 2011). There is
a societal need for improved understanding in relation to the risks of codeine
use, misuse and dependence. The potential risks relating to prescribed and
over the counter codeine use, misuse and dependence, and the impact that
pharmacy controls and interventions may have is an area that requires further
development (Agyapong et al., 2013; Reed et al., 2011; Wazaify et al., 2005).
Prescribed misuse, diversion, deregulation and over the counter availability of
codeine compounds the potential for user adverse consequences and medical
and pharmacy practice interventions (Ferner & Beard, 2008; Pawaskar &
Balkrishnan, 2007). Health professionals need to be more aware of public lay
drug definitions around pharmaceutical opioid use, both prescribed and over
the counter, in order to avoid misunderstandings within their practice
(Björnsdóttir, Almarsdóttir, Traulsen, 2009).
This scoping review has revealed that while the appropriate directed use of
codeine based products incurs little risk, excessive or long term use of such
products contributes to dependence, associated side effects and adverse and
life threatening situations. The unpredictable nature of codeine’s
pharmacokinetics gives rise to concerns in relation to safety (MacDonald &
McLeod, 2010, Tremlett et al., 2010). Continuous review and
pharmacovigilance of codeine based products is an essential activity that
needs to be adhered to by both medical and pharmaceutical healthcare
professionals.
Prescribed opioid drug use is grounded in a mutual responsibility for
transparent communication between service users and health professionals
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(Francis et al., 2005). Coordinated responses are required to address drug
compliance of service users (Robinson et al., 2011). Medical practitioners are
advised to question those receiving opioid therapy about current, past and
family histories with regard to misuse and addiction (Kahan et al., 2006), and
their levels of over the counter and prescribed opioid use (Bradley et al. 1998,
Lessenger & Feinberg, 2008).
Raising professional awareness with enhanced efforts to improve skills,
confidence and commitment in relation to codeine misuse and dependence is
required (Cooper 2013a; Lessenger & Feinberg, 2008; Bride et al., 2003;
Reay 2009; Williams & Kokotailo 2006). Management of codeine related
issues requires a concerted effort by all stakeholders (prescribers,
pharmacists, wholesalers, treatment specialists and drug education
specialists). Therefore, a number of specific recommendations in relation to
codeine use, misuse and dependence are presented.
9.3 Key recommendations:
Recommendations are presented under the following four headings (1) raising
awareness; (2) detecting and managing risk; (3) dispensing practices and (4)
monitoring and surveillance of codeine.
9.3.1 Raising Awareness
A significant number of people who consume medications cannot identify the
active ingredients in their chosen medications (Roumie & Griffin, 2004). A
minority of customers appear willing to accept risks associated with increased
access to over the counter medications containing codeine and other active
ingredients (Alexander et al. 2005). This is despite high public awareness of
the abuse potential of over the counter medicine (Wazaify et al., 2005, 2005a)
and pharmacists’ concerns in relation to safety and codeine misuse and
dependence. Pharmacists are a trusted by the public as a source of
information about over the counter medications (Wawruch et al., 2013).
Dobbin & Tobin (2008) have described particular characteristics of individuals
misusing codeine containing pharmaceuticals, whereby they may not identify
as an addict, the medication prescribed infers safety and sanctioning by the
prescriber, and with the products purchased having different legal
consequences in comparison to illicit drug users. It is important to recognise
variance in groups of codeine misusers and target patient and customer
awareness initiatives appropriately.
Recommendations for raising public and professionals’ awareness of
prescribed and over the counter codeine use, misuse and dependence:
Professional education and public awareness campaigns should seek to:
 Promote recognition and early detection by healthcare professionals of
signs of dependence and withdrawals in relation to codeine based
products.
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
Promote drug monitoring systems, drug workers and clinicians should
be aware of potential presentations for emerging and harmful forms of
home produced drug abuse, particularly in the case of injecting drug
use.

Develop and disseminate key health related messages about the risks
of exceeding therapeutic dosages of codeine based products.

Promote improved awareness by professionals in relation to coprescribing and effects on health.

Heighten public awareness about the risks surrounding the use of
codeine based products whilst driving.

Increase awareness and access to psychological treatments, for
example, cognitive-behavioural therapy, biofeedback, and relaxation
techniques for the treatment of chronic headache. (Eng &
Lachenmeyer, 1996).
In addition we recommend the further development of:

Brief interventions at point of sale to raise customer awareness of
potential risk of tolerance and dependence over time.

Parenting classes to highlight the potential side effects of codeine such
as respiratory depression when prescribed for children. The evidence
suggests that codeine should not be used for children with
neuromuscular disorders, severe cardiac or respiratory conditions,
upper respiratory or lung infections, multiple trauma or extensive
surgical procedures and be contraindicated in breastfeeding women.
Moreover, calculations of dose should be based on ideal body weight
and not actual body weight.
9.3.2 Detecting and Managing Risk
Evidence on the extent of use, non-compliant use and misuse of
pharmaceuticals containing codeine is limited. We recommend more
education for codeine misusers about the risks associated with poly use of
medication and intake of alcohol and illicit drugs to challenge misinformed
perceptions that codeine based products are low risk in terms of their potential
for dependence.
Recommendations for detecting and managing risk are as follows:

Develop community pharmacy practice strategies that promote safety
and include the removal of potential products of abuse from point of
sale or sight.

Develop and improve referral mechanisms to primary care teams for
people suspected to be misusing codeine or to be dependent.
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
Identify patients who are in need of psychological services to assist in
pain management.

Develop strategies to detect deception especially in pain related cases
thereby minimising risk for failing to improve or overdose.

Increase availability of disposable containers for unused prescriptions.

Incorporate routine enquiries about maternal medication use, including
codeine-containing cough preparations, when evaluating new-born
infants with evidence of cerebral infarction into assessment protocols.

Assess opioid addiction with the misuse of ibuprofen-codeine
combinations when assessing patients presenting with severe
hypokalaemia, pancreatitis and medication overuse headache.

Develop strategies to manage access and reduce treatment barriers in
relation to codeine misuse and dependence. For example, the
reluctance of problem opiate users to access treatment is an
immediate concern.

Develop clearer guidelines for interpretation of DSM V criteria for
abuse and dependence in chronic pain patients, especially in cases of
‘maladaptive or aberrant behaviour’.

In cases where substance misuse psychiatric disorders are suspected,
a high index of suspicion for cough mixtures misuse/abuse is
warranted.

Develop appropriate harm reduction tactics (needle exchange, bleach
distribution, hygiene, provision of filters, foil packs to encourage route
reversals, and safer injection facilities), screening, treatment (opiate
substitution therapy, antiretroviral therapy), therapy and prevention
programmes which target injecting drug users who inject home drug
solutions made from codeine.
9.3.3 Dispensing Practices
Safety is central to pharmacists’ decision making with regard to medication
dispensing (Hanna & Hughes, 2010). Pharmacy practice strategies that
promote safety in relation to codeine dispensing practices are detailed in
chapter 3, table 1.
Recommendations for dispensing practices:
We recommend that dispensing practices
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

Continue to expand the clinical and public health role of the community
pharmacist with on-going inter-disciplinary training for counter
assistants, pharmacists and other health professionals.
Adopt a ‘universal precautions’ systematic approach for each codeine
sale, rather than a selective approach based on customer appearance.

Introduce short term restricted dispensing practices of codeine based
products.

Provide clearer product labelling of the active ingredients in over the
counter and prescribed products.

Remove potential products of abuse from sight in community
pharmacies.

Refuse sales of codeine to users who are problematic misusers or
dependent.

Develop in house pharmacy based brief interventions at point of sale
along with supported detoxification in pharmacies.

Provide needle and syringe exchange services targeting opiate
injecting.
9.3.4 Monitoring and Surveillance of Codeine
The monitoring and surveillance of codeine dispensing activity and
estimations of levels of customer misuse (both intentional and non-intentional)
remains problematic. In addition to therapeutic dependence and such forms of
non-compliant use, the diversion, tampering, home manufacture and injecting
of over the counter and prescribed pharmaceuticals (containing codeine and
other opioids) is a pharmacy, drug surveillance and public health issue (Azbel
et al., 2013).
Recommendations for monitoring and surveillance:

Develop prescription drug monitoring and national online prescription
systems.

Develop and evaluate real time integrated monitoring of the dispensing
of prescribed and over the counter use of codeine based products in
community pharmacies.

Ensure routine enquiries by health professionals of patients with regard
to prescribed and over the counter codeine medication use.

Monitor the use of prescription opioids in vulnerable groups (patients
with chronic non-malignant pain, patients with cancer pain and illicit
drug users) to identify if opioids are substituting for or complicating
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mental health and addiction treatment outcomes, thereby minimising
risk of overdose.

Share information in relation to codeine sales and consumers by
pharmacists with other pharmacists.

Develop and evaluate ‘early warning systems’ in relation to codeine
use, misuse and dependence (for example the recording of adverse
events).

Consider further development and roll-out to other countries of
initiatives which are similar to the South African Codeine Care Project,
using The TrustaTAG™

Monitor and manage conflicts between commercial and customer
interests; and between pharmacy, non-pharmacy and internet
pharmacy outlets.
9.4 Recommendations for Future Research
A number of key areas are identified for further research in relation to
prescribed and over the counter codeine use, misuse and dependence.
Research recommendations are listed under six headings: (1) patterns of use,
misuse and dependence; (2) prevalence; (3) treatment/interventions; (4) risk;
(5) epidemiology and (6) policy.
9.4 1 Patterns of Use, Misuse and Dependence
Research, evaluation studies and reviews are needed to:

Quantify the extent of prescribed and over the counter codeine use,
misuse and dependence, whether intentional or non-intentional. This
work should enable the creation of user profiles in relation to patterns
and estimations of codeine use, misuse and dependence.

Explore the views and experiences of users and misusers of various
codeine and other products to better understand product interactions
and illegal drug and poly pharmaceutical use patterns.

Systematically review studies of poly medication use, for example,
benzodiazepines, codeine, comorbidity and drug injecting transitions.

Investigate motives for codeine misuse which range from self-treating
of pain (physical and emotional), sleep and anxiety problems, pleasure
and ease of access and personality types, for example, addictive
personality.
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
Explore the experiences of general practitioners of misuse of
prescribed drugs, particularly codeine. These studies should
investigate: the challenges encountered by primary care staff,
incidences of problematic use, the drugs used in treatment, other
treatments considered and referral patterns.

Systematically review studies and conduct further studies to establish
the risk of driving accidents with opioid and codeine use, including the
effect of these drugs on driving ability on people with different genetic
polymorphisms and on aging drivers. The effects of higher doses of
codeine require particular investigation.

Explore the views and experiences of the injecting user of home
produced drugs made from codeine. These studies should pay
particular attention to perceptions of harm, user practices, trajectories
of use and experiences of services. Drug testing of field samples is
warranted to establish content.
9.4.2 Prevalence
 Estimate the prevalence of use, misuse and dependence within the
broad and ‘hidden’ spectrum of therapeutic and non-therapeutic
patterns of codeine use and misuse. The literature is still unclear as to
why the misuse of codeine occurs despite various levels of legislative
control and preventative strategies in various countries.

Estimate the prevalence of codeine misuse and dependence among
methadone patients and opiate drug users.

Estimate the prevalence of internet availability and purchase of
medications without a legitimate prescription, including identification of
customer characteristics.

Estimate the prevalence and incidence of persistent and problematic
use of codeine in patients with non-cancer chronic pain or non-pain
patients.

Estimate the prevalence and effects of parental social medication of
children using codeine products.

Estimate the prevalence of use of home-made drug solutions made
from codeine containing pharmaceuticals.
9.4.3 Treatment/Interventions
 Establish the evidence base for the continued use of codeine
compared to non-steroidal anti-inflammatory drugs in the management
of mild to moderate pain. Overall the evidence presented to support
codeine use as opposed to non-steroidal anti-inflammatory drugs is
inconclusive and requires further study.
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

Establish the effectiveness (benefits and harms) of codeine compared
to alternative medications.
Explore doctors’ and other prescribers’ preferences for prescribing
codeine rather than alternative medications and their views on a
standard starting dose and subsequent dose titration.

Establish the effectiveness (benefits and harms) of long-term treatment
with short-acting weak opioids.

Establish the frequency with which prescribers co-prescribe codeine
with benzodiazepine or Z drugs.

Evaluate health professional training in the recognition and
management of codeine aberrant behaviours such as forged or lost
scripts, requesting certain medications, describing unresolved pain,
visiting multiple pharmacies merits further study across a variety of
regulatory systems.

Establish the efficacy and effectiveness of non-pharmacological
responses to pain management.

Synthesise evidence from related fields to guide the development of
specific treatment and referral pathways for individuals with codeine
dependence. Although general treatment for opiate dependency is
primarily detoxification and psychosocial therapy, there is limited
evidence available to guide specific policy development and
implementation, management initiatives and the development and
provision of specific referral and treatment pathways for over the
counter codeine misuse and dependence.

Synthesise evidence from related fields to guide the development of
specific treatment protocols for codeine-users who have issues with
pain management, have developed problematic opioid use or are codependent on benzodiazepines or Z-drugs.

Explore the self-perception of codeine dependent individuals many of
whom do not view themselves as needing help for their codeine
dependence and their experience of interventions (counselling,
community detoxification, switching onto other medication) in the
management of codeine misuse.

Identify treatment seeking barriers and experiences of people with
codeine dependence.

Evaluate therapeutic interventions, for example, brief interventions, and
their efficacy in treating people who present with codeine related
misuse and addiction problems.
117

Establish the effectiveness of dihydrocodeine in maintenance, cross
over and detoxification treatment of opiate dependency, to ensure a
favourable risk/benefit ratio.
9.4.4 Risk
 Identify predictors of risk of codeine misuse and dependence and
protective factors. Results could inform practices to minimise risk of
dependence, guidelines for early detection and management of
dependence and the pharmaceutical development of safer products.

Identify genetic risk factors for opioid dependence, opioid induced
hyperalgesia as potential targets for medication therapy and
pharmaceutical development of abuse deterrent opioid formulations.

Explore the characteristics and habits of opioid shoppers in clinical
practices and the relationship between prescriber characteristics and
risk.

Synthesise studies of clinical profiles of people who are dependent on
prescribed and over the counter codeine to identify subtypes of users
at risk of adverse consequences and associated motives and
trajectories of use.

Establish levels of risk and impairment as a result of codeine use and
misuse.
9.4.5 Epidemiology
 Develop pharmaco-epidemiological methods to investigate misuse,
non-medical use, abuse and dependence on codeine based drugs for
self-medication. This would facilitate real time monitoring of prescribing
and dispensing activity with data linked to national medicines abuse
systems.

Investigate self-medication and patterns of codeine use among the
following key groups: youth; older people, elderly, problematic drug
users, pain patients, individuals prescribed anti-anxiety medication,
methadone maintenance treatment patients and individuals accessing
internet forums.

Estimate street pricing of diverted prescription codeine and homemade drug solutions produced using codeine based pharmaceuticals.
9.4.6 Policy
 Guide the development of accessible and specific regulatory,
pharmaceutical, treatment and community detoxification protocols for
codeine misuse and dependence.
118
9.5 Limitations of the review
This scoping review was conducted as an exercise aiming to provide a
starting point for future research in the area of codeine use, misuse and
dependence by mapping the existing evidence base and capturing what
challenges are presented. The management of codeine related issues
requires a concerted effort by all stakeholders and this is a varying global
challenge specific to individual countries. A number of specific
recommendations in relation to codeine use, misuse and dependence are
presented.
The review of the literature followed a systematic process but cannot claim to
be exhaustive in its coverage. In particular, there may be ongoing, as yet
unpublished pieces of research not described here. It must also be
acknowledged that while our search was comprehensive and included an
extensive body of literature, across varying populations, conditions and study
designs, that some literature may have been missed. Furthermore, social
media is constantly evolving leading to challenges in keeping the search
updated. While many specific topic areas were identified, further analysis of
these areas is now required. For example, peer reviewed publications in
relation to prevalence and codeine, and the development and implementation
of policy to guide treatment and practice for over the counter codeine use,
misuse and dependence are needed.
119
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148
Appendix 1Characteristics of the research studies included in the
review
149
Author,
Year,
Country
Research aim
Design
Participants
Intervention
/
outcome
measure
Findings
Author’s conclusions/
recommendation
Theme
Abt 2012,
USA
Pain treatment
with aspirin versus
paracetamol with
codeine
Randomized
controlled
study
302
patients in
this dental
pain study,
676
patients in
the
headache
study
The 2 main
outcome
measures
were the
sum of pain
intensity
differences
from
baseline
over 6 h
and the
sum of pain
relief
scores at
30 min, 1, 2,
3, 4,
5, and 6 h
after taking
medication.
Prevalence
rates
For the dental study, aspirin and paracetamol
with codeine showed a statistically
significant benefit when compared to placebo
at all-time points.
Aspirin provides a
statistically significant
benefit for relief of dental
pain and tension-type
headaches compared to
placebo, and similar pain
relief when compared to
paracetamol and codeine.
Therapeu
tic useeffectiven
ess when
compare
d to other
drugs or
placebo
Significant gaps in treatment
may exist for both Hispanic
and Native American
students practitioners
should consider urban male
youth of all racial
backgrounds as potential
misusers of codeine cough
syrup, and note that misuse
may be more common within
the LGBT community.
Prevalenc
e of
cough
mixture
misuse students
over the counter
medications are used as a
What is
known
Agnich et
al. 2013,
USA
Allotey et
al. 2004,
To determine the
prevalence and
characteristics of
purple drank users
among a sample of
college students in
the United States.
To identify the
patterns of use of
Quantitative
survey
assessing
misuse of
codeine cough
syrup
Qualitative
study using in-
2,349
students
The sample
was 51.6%
female,
68.9%
White,
24.4%
African
American,
2.8%
Hispanic,
and 3.0%
Native
American,
had a mean
age of 20.06
(SD = 3.01),
40 parents
with
In the tension-type headache study, both
aspirin and paracetamol with codeine were
significantly better than placebo at all-time
points but were not significantly different
from each other.
Purple drank use was :
1) Much higher among students from urban
areas (12.2% urban versus 7.3% suburban,
4% rural)
2) Lowest use was reported among African
Americans, (5%) along with Asian Americans.
(5.1%) 3) Hispanics (15.65) and Native
Americans (16.7%) were significantly higher.
Students who had lower GPAs, identified as a
member of the LGBT community, and used
marijuana and alcohol were more likely to
report purple drank use.
Patterns of
use in over
There were 3 striking and readily apparent
themes in the use of over the counter
150
Australia
over-the-counter
medications
among children
depth
interviews.
Snowball
sampling was
utilized
children <5
years of
age
the counter
medicines
Almarsdo
ttir &
Grimsso
n 2000,
Denmark
To investigate the
impact of
increased access
of over-thecounter codeine
on its use in
Iceland
Inferences
about the
impact of the
legislation are
based on an
interrupted
time series that
contrasts the
monthly use of
over-thecounter pain
relievers
containing
codeine before
and after the
legislation took
effect.
Monthly
sales data
of codeine
medication
sold over
the counter
Behavioural
changes in
purchasing
codeine
over the
counter
Amato et
al. 2013,
France
Effects of three
therapeutic doses
of codeine/
paracetamol on
driving
performance, a
Psychomotor
Vigilance Test ,
and subjective
Balanced
cross-over
randomised,
double-blind
placebo
controlled
study.
16 subjects
(50%
female)
with
minimum 2
years
driving
experience
Gelatin
capsules
containing
Codeine/
Paracetamo
l
20mg/400m
g,
40/800mg,
medications among children. Codeine was
given in 8 cases.
One was the administration of over the
counter medications as a
form of “social medication,” to give parents
control over children’s behaviour that they
perceived as fractious and irritating.
A related theme was the use of over the
counter medications to reduce the
inconvenience to the parents of having a sick
child, again giving parents greater control
and better time-management abilities.
Finally, paracetamol was considered by many
parents to have almost miraculous properties
in calming, sedating, and lifting the mood of
children.
The total use of over the-counter pain
relievers containing codeine as well as those
containing paracetamol and codeine has
risen steadily throughout the period under
study. The interrupted time series did not
show a substantial effect from the legislative
change on the use of all over-the-counter
codeine pain relievers, paracetamol with
codeine, and aspirin with codeine
combinations.
No statistical difference on the driving tests
or relating to dose. However, significant,
though modest, correlations were observed
between the driving parameters and both
morphine and codeine blood concentrations.
Statistical dose-related difference in the
subjective Karolinska Sleepiness Scale
(20mg/400mg vs. 40mg/800mg).
151
form of social medication for
the control and maintenance
of “good” behaviour among
children. The use of over the
counter medications for the
treatment of minor ailments
among children is
widespread, despite the lack
of evidence.
about
over the
counter
codeine;
use of
over the
counter
meds in
children
The assumption that
increased access leads to
irrational use of over-thecounter medicines is not
substantiated in the case of
over-the-counter pain
relievers containing codeine.
Impact of
access
on over
the
counter
sales
Study did not demonstrate a
dose-effect relationship, but
did suggest a blood
concentration – effect
relationship. This is
important to take into
account because
metabolism of codeine is
genetically polymorphic.
Consequ
ences of
Codeine
use,
misuse
and
Abuse –
Impairme
nt of
feelings
Backmun
d et al.
2001,
Germany
Basu et
al. 2010,
India
Bachs et
al., 2003
Norway
60/1200mg
or placebo
Moreover, the
pharmacokinetic
modification
linked to aging or some
elimination pathologies may
increase blood
concentrations of codeine
and morphine in certain
persons.
performa
nce
Completion of
detoxification
program using
methadone or
codeine in
interventions
heroin users
To document
changes in
patients registered
in a de-addiction
centre in north
India over three
decades.
Retrospective
study of heroin
users in
detoxification
programme
1070
patients
Completed
detoxificati
on program
Rates of completion 50.4% (OR 1.8) of
methadone substituted , 45.5% (OR1.5) of
codeine substituted patients and 35.9%(OR 1)
of injecting illicit heroin users(control)
This was statistically significant P= 0.006
Drug users treated with
methadone have better
outcome in detoxification
treatment
Therapeu
tic use –
detoxifica
tion
Retrospective
study
Use of
opioids;
Dependenc
e on
opioids
The number of registered subjects increased
eight-fold over the decades, and age of the
subjects presenting for the treatment
decreased.
The percentages of subjects presenting for
the treatment with opioid dependence were
36.8% 42.9 % and 53.2% respectively for the
three decades.
The proportion of subjects using natural
opioids decreased
over the three decades with a concomitant of
newer and prescription opioids such as
buprenorphine, codeine and
dextropropoxyphene
Our results showed major
shifts in the patterns of
substance abuse in clinicattending patients in north
India over the three decades
from 1978 till 2008. These
have important implications
for all the stakeholders
concerned with combating
the challenge of
psychoactive substance
abuse in our society.
Profile of
individual
s at
substanc
e abuse
clinic
The effects of
codeine alone and
not due to its
morphine
metabolite on
clinical test for
drunkenness
Review of
database at
National
Institute for
Forensic
Toxicology,
Oslo, Norway
Case notes
of all
patients
registered
in the
centre from
September
1978 till
December
31, 2008
was
reviewed.
Compariso
ns were
made
among
three
decades.
43 cases of
suspected
drugged
drivers with
codeine in
blood
samples
but no
morphine
Codeine
blood
concentrati
on was
compared
with the
conclusion
s from the
correspondi
23 were judged as ‘‘not impaired’’, and 20 as
‘‘impaired’’
There was a statistically significant
difference in concentration between the two
groups.
The odds ratios for being judged as impaired
were 6 (95% CI 1–32, P=0.04) and 19 (95% CI
2–182, P=0.01) for a ‘‘medium high”
concentration group and a ‘‘high’’
Codeine appears to have
some dose-dependent effect
on the central nervous
system that may lead to
impairment as judged from a
Clinical Test for
Drunkenness, independent
of measurable blood
morphine concentrations.
Consequ
ences of
Codeine
use,
misuse
and
Abuse –
Impairme
nt of
152
or other
drug.
Bachs et
al. 2008,
Norway
Barreto
et al.
2011,
Australia
Brands et
al. 2004,
Canada
To explore the use
of codeine
analgesics in
individual patients
in Norway, giving
special attention to
the 10% who
consume the
highest amounts.
Norwegian
Prescription
Database on
patients who
were dispensed
at
least one
codeine
analgesic
prescription
during 2006.
.
386,836
patients
To analyse druginduced acute
pancreatitis
A retrospective
analysis of
patients
presenting with
acute
pancreatitis
328
patients
admitted to
hospital
between
January
2006 and
April 2011
To characterize
prescription opioid
dependent
patients in a
methadone
maintenance
treatment (MMT)
program
Detailed
retrospective
chart review of
new
admissions
178 new
admissions
: Four
groups
were
identified:
24% had
used
prescriptio
n opioids
only; 24%
used
prescriptio
n
ng Clinical
Test for
Drunkennes
s.
Age and
gender
specific 1year
periodic
Prevalence
rates.
concentration group, respectively, relative to
a ‘‘moderate’’ concentration group
To measure
the
incidence,
presentatio
n, course
and
outcome of
druginduced
acute
pancreatitis
Profiles of
opioid
users
based on
social class
11 patients out of the 328 were found to have
pancreatitis associated with drug ingestion. 5
of these were probably due to codeine.
2 of these patients had a history of
pancreatitis following codeine ingestion that
wasn’t recognized as a factor at the time. 1 of
the codeine patients had a prior
cholecystectomy. Codeine was the drug most
commonly associated with the causation of
acute pancreatitis.
In the year 2006, a total of 386,836 individuals
filled at least one prescription for codeine
analgesics excluding cancer patients. The
crude prevalence for the use of codeine
analgesics was 7.3% and 9.3% of the male
and female Norwegian population,
respectively. 12%
of women and 9% of men who filled codeine
prescription received 120 defined daily doses
(DDD) or more of codeine analgesics in 2006
(moderate to high consumers). 50% of those
patients (21,759) were also dispensed large
amounts of benzodiazepines or carisoprodol
over the same period.
DSM IV dependent codeine users were
relatively common.
Those dependents on prescription opioids
such were codeine (45.5%) and oxycodone
(46.6%) respectively.
There were no significant differences found
amongst the groups in measures of social
stability. Those dependent on prescription
opioids alone were less likely to use illicit
non-opioid drugs or to be associated with
injection drug use.
Those that used prescription opioids only or
initially were more likely to have ongoing
153
This supports the view that
some codeine effects do not
seem to be mediated by
morphine.
High percentage of the
Norwegian population used
codeine analgesics. Oneyear prevalence use of
codeine increased with age
and was higher for women at
all ages. Our study showed
that codeine use was mainly
sporadic, but that a
relatively large sub-group of
users were dispensed
repeated prescriptions of the
drug in combination with
other potential drugs of
abuse.
Routine prescription drugs,
as an aetiological factor,
accounted for 3.4% of cases
of acute pancreatitis. This is
likely to be an underestimated due to the
stringent criteria to
determine causality
performa
nce
Pain is a common feature of
those on prescription
opioids in the methadone
programme
Character
istics of
prescripti
on opioid
dependen
t patients
Better understanding of the
complex relationships
between pain, mental health
and addiction in order to
develop optimal prevention
and treatment strategies for
prescription opioid
dependence.
Prevalenc
e of
codeine
analgesic
use in
Norway
Adverse
health
effects
opioids
initially and
heroin
later; 35%
used heroin
first and
prescriptio
n opioids
subsequent
ly and 17%
had used
heroin only
Buckerid
ge et al.
2010,
Canada
Risk of Injury
Associated with
Opioid Use in
Older Adults
A historical
cohort study
403,339
adults over
65 years on
a database
held by a
universal
public
health
insurance
programme
Busto et
al. 1998,
Canada
A mixed method
study of the
characteristics,
patterns of drug
use, treatment and
outcome of
patients severely
dependent on
opioids
Prospective
structured
interviews
Additional
information
from charts
58 patients
admitted
consecutiv
ely to the
medical
unit of an
addiction
research
foundation
with a
diagnosis
of severe
oral opioid
dependenc
e
pain problems and to be involved in
psychiatric treatment.
Over a 1year followup period
the
database
was
analysed to
estimate
the risk of
fall-related
injuries
associated
with the use
of opioids
Levels of
dependenc
e
During the study 15.3% were prescribed an
opioid with codeine containing products
being the most common (10.8%)
After adjustment for patient characteristics,
there was a statistically significantly greater
risk of injury with opioid use.
Within low- potency opioids, codeine
combinations were associated with the
greatest risk, a 127% increase in risk of injury
per one adult dose increase
Higher doses of low-potency
opioids, particularly codeine
combinations, are prevalent
and result in twice the risk of
injury. Early detection and
intervention in increasing
use of opioids for pain
management may be
beneficial in reducing the
risk of injury.
Injury
Most commonly used opioids were codeine
(52%) and oxycodone (40%)
Codeine doses were 554 +/- 343mg/day
Mean duration at current dose was 81
months
Other substance abuse was common
Family history of drug abuse was high
Follow-up was required by 74% of patients,
and 26% had a documented relapse
Severe oral opioid
dependence is part of
multiple substance pattern
and occurs more frequently
than has been previously
recognized
There are no clear
guidelines on the treatment
of severe opioid dependence
Common practice is to use
tapering regimens with
substitutes.
Long-term outcomes are
poor. Better strategies are
needed including nonpharmacological
interventions
Depende
nce
154
Butler &
Sheridan
2010,
Australia
Cartabuk
e et al.
2013,
USA
Cooper
2011, UK
To understand
issues for primary
care health
practitioners in
relation to
prescription drug
misuse (PDM), by
exploring the
attitudes and
experiences of
healthcare
professionals
with respect to
PDM.
Use of codeine by
Paediatricians
To describe and
understand
current issues
relating to over the
counter medicine
addiction by
investigating the
experiences of
Crosssectional.
Qualitative
interviews to
explore
attitudes to
PDM
Quantitative
survey
examining
differences in
paediatric
codeine
prescribing
among medical
and healthcare
professionals.
Qualitative,
semistructured
interviews by
telephone, inperson -audio
recorded and
one participant
General
practitioner
s (17),
community
pharmacist
s (16) and
‘key
experts’
(18)
298
participants
- response
rate 26.7%
Three
purposively
sampled
groups.
First group
of 16 key
stakeholder
s from
Attitudes to
abuse
Experience
s of abuse
Main types of prescription medicines
identified as being misused were opioids
such as dihydrocodeine, codeine and
pethidine
Major theme that was identified was that of
two different types of patients involved in
PDM, as described by participants - the
‘abuser’ and the ‘overuser’. The ‘abuser’ was
believed to acquire prescription medicines
through deception for their own use or for
selling on to the illicit market, to use the
drugs recreationally, for a ‘high’ or to stave
off withdrawal from illicit drugs. ‘Overusers’
were characterised as having become
‘addicted’ through inadvertent overuse and
over prescribing, and were generally viewed
more sympathetically by practitioners.
Impact of
years of
experience
on
prescribing
practice
Evaluate
opinion
over the
counter use
Practitioners’ attitudes may have impacted
on whether any harm reduction interventions
might be offered.
43.3% prescribed codeine for pain
management in children. There was no
significant difference among providers based
on years of experience.
98% of sample used actual body weight
instead of ideal body weight. All respondents
stated that they instructed parents to contact
the physician if their child became lethargic
or unresponsive,
10.9% did not specifically counsel parents to
seek assistance if their child developed
difficulty breathing.
Individuals referred to themselves as
‘addicts’ or ‘addicted’ and all described the
use of an opiate – usually codeine containing medicine.
over the counter medicines described as
being used for genuine medical reasons to
treat symptoms that included headaches,
155
There is a need for further
exploration of ‘over users’
whose needs may not be
being met by mainstream
drug services, and issues of
stigma in relation to
‘abusers’.
Health
professio
nals
perceived
attitudes
of
character
istics of
prescripti
on drug
misusers
- codeine
Calculations of dose should
be based on ideal body
weight. Parents should be
educated to recognize the
potential side effects of
codeine such as respiratory
depression.
Therapeu
tic usePaediatri
c
prescribi
ng
Three distinct types of over
the counter medicine
addiction were identified
based upon the quantity of
medicine taken: type
Involved those who never
exceeded the maximum
dose; type II involved those
Addiction
/misuse/a
buse of
over the
counter
medicine
s
individuals
affected by over
the counter
medicine addiction
in the United
Kingdom (UK),
pharmacists and
medicines counter
assistants (MCAs),
and key UK
stakeholders.
Additional aims
involved exploring
the role of the
internet, pharmacy
involvement, and
different types of
medicine use.
Cooper
2013b,
UK
To describe the
experiences and
views of those
self-reporting over
the counter
medicine abuse,
and why
medicines were
taken, how they
were obtained and
associated
treatment and
support sought.
requested
email/textbased
communication
.
Qualitative
study using indepth mainly
telephone
interviews.
organizatio
ns and
employmen
t related to
over the
counter
medicine
addiction.
Second
group of 10
pharmacist
s and 7
MCAs.
Third group
of 25
individuals
recruited
via two UK
on-line
medicine
addiction
support
groups
(Over count
and
Codeine
Free)
A
purposive
sample of
25 adults,
aged
20–60s, 13
women.
migraine, and period, joint or post-operative
pain.
Recurrent patterns of drug-seeking
behaviour were described, including
purchasing and use rituals such as brand
specificity, deception and secretiveness,
anxiety when supplies diminished, and
intentionally varying the pharmacies.
Individuals raised safety concerns about
internet-supplied medicines. All individuals
had attempted to stop but some were still
taking an over the counter medicine. None
sought pharmacy advice, and some explicitly
rejected medical help or support from help
forums due to concerns about their addiction
being recorded, concerns about lack of GP
understanding, or a desire to hide their
addiction. Individuals were aware of risks
associated with over the counter
who sometimes took slightly
higher than recommended
doses; and type III included
those who took significantly
higher doses than
recommended. All three
types
described withdrawal
symptoms and using the
product
for different reasons than
clinically indicated
Stakeholders held mixed views about
pharmacists and their role, and viewed the
internet availability of medicines as a
currently small but significant future issue.
Pharmacists could be grouped into those
who were negative about pharmacy
involvement in supporting over the counter
medicine abuse or addiction,
View on
taking over
the counter
medicines
Individuals considered themselves
‘addicted’, but socially and economically
active and different from illicit substance
misusers. They blamed themselves for losing
control over their medicine use, which
usually began for genuine medical reasons
and not experimentation and was often linked
to the cessation of, or ongoing, medical
prescribing. Codeine, in compound
analgesics, was the main medicine
implicated with three distinct dose ranges
emerging with decongestant and sedative
antihistamine abuse also being reported.
156
Greater awareness of the
addiction potential
of over the counter
medicines is needed for the
public, pharmacists
and medical prescribers,
along with appropriate
communication about, and
reviews of, treatment and
support options, for this
distinct group.
Addiction
/misuse/a
buse of
over the
counter
medicine
s
Cooper
2013a,
UK
To explore the
experiences and
views of
community
pharmacy staff to
over the counter
medicine abuse
Qualitative
study using
semistructured
interviews with
10 pharmacists
and 7 medicine
counter
assistants
Experience
s and views
Daniulait
ye et al.
2006,
USA
To develop
appropriate
treatment and
prevention
programs, the
population of
pharmaceutical
Exploratory
study based on
qualitative
interviews
24 people
in the
Dayton/
Columbus,
Ohio, area
Participants
ranged in
To explore
the
experience
s and views
of
community
pharmacy
staff in
relation to
current
practices
and
concerns,
manageme
nt and
support
relating to
over the
counter
medicine
abuse
Subsequent use was for the ‘buzz’ or similar
effects of the opiate, which was obtained by
having lists of pharmacies to visit and
occasionally using internet suppliers.
Perceived withdrawal symptoms were
described for all three dose ranges, and work
and health problems were reported with
higher doses. Mixed views about different
treatment and support options emerged with
standard drug treatment services being
considered inappropriate for over the counter
medicines and concerns that this ‘hidden
addiction’ was recorded in medical notes.
Most supported the continued availability of
over the counter medicines with appropriate
addiction warnings.
A surveillance role was apparent for
assistants, who placed emphasis on
regulations, procedure and monitoring
frequency of purchases to manage abuse,
with referral on to pharmacists. Frequency of
purchase was central to assistants’ definition
of those suspected of over the counter
medicine abuse, which pharmacists also
utilised as well as a distinction between
intentional abuse and unintentional medicine
misuse. A lack of information about
customers, easy access to, and poor
communication between community
pharmacies were emergent barriers to
pharmacists providing more support.
Participants
discussed a number of different reasons,
including self-medication of emotional and
physical pain, legitimate medical
prescriptions related to chronic pain
management, social influences, recreation,
and easy access to pharmaceutical opioids.
157
Policy implications include
the need for improved
knowledge for community
pharmacy staff about
signposting to relevant
services, increased
awareness
of who might be affected,
and a review of how
pharmacists can
have more information about
patients to inform over the
counter medicine sales.
Views/ex
perience
on over
the
counter
medicine
use/abus
e
Interventi
on
developm
ent
opioid abusers has
to be well
understood
Davis, &
Johnson.
2008,
USA
Derry et
al. 2013,
UK
To document
patterns of
(prescription
opioid) PO use,
misuse, and
diversion among
street drug users,
and begins to
indicate how drug
culture practices
interact with the
legitimate
therapeutic goals
of PO
prescriptions (e.g.
pain management).
Brief interviews
on the various
motivations or
aims for PO
use.
Treatment of acute
postoperative pain
with a single dose
oral ibuprofen plus
codeine
Meta-analysis
of 4 studies
age from 18
to 48 years;
the majority
was White
and
male.
586
participants
recruited
from
outreach
and locales
frequented
by
heroin/meth
adone
users.
1342
participants
from six
studies
On the basis of participant age and lifetime
experiences with pharmaceutical opioid and
other drug misuse, six user groups were
identified that faced unique risks and
prevention/treatment challenges.
Pattern of
use and
diversion
Methadone was used (71.9%) and sold
(64.7%) at a higher level than OxyContin,
Vicodin, and Percocet.
33% used codeine and 18.5% sold it
Compared
ibuprofen
plus
codeine
with
placebo
and with
the same
dose of
ibuprofen
alone
In four studies
(443 participants) using ibuprofen 400 mg
plus codeine 25.6 to 60 mg (high dose
codeine) 64% of participants had at least
50%maximum pain relief with the
combination compared to 18% with placebo.
The NNT was 2.2 (95% CI 1.8 to 2.6). In three
studies (204 participants) ibuprofen plus
codeine (any dose) was better than the same
dose of ibuprofen (69% versus 55%) but the
result was only borderline significant with a
relative benefit of 1.3 (95% CI 1.01 to 1.6).
POs are an important
component of street drug
users’ drug-taking regimes,
especially those who are
Physically Ill Chemical
Abusers
Prevalenc
e of
prescripti
on opioid
use in
street
drug
users
The combination of
ibuprofen 400 mg plus
codeine 25.6 to 60 mg
demonstrates good
analgesic efficacy. Very
limited data suggest that the
combination is better than
the same dose of either drug
alone. Use of combination
analgesics that contain
codeine has been a source
of some concern because of
misuse from over-thecounter preparations.
Therapeu
tic useeffectiven
ess when
compare
d to other
drugs or
placebo
The Nurofen Plus® had
caused the perforated
Adverse
health
In two studies (159 participants) ibuprofen
plus codeine appeared to be better than the
same dose of codeine alone (69% versus
33%)
Dutch
2008,
Misuse of Nurofen
Plus® leading to
Case Reports
Two adult
patients
One patient
had a
Both patients were found to have confirmed
perforated gastric ulcers
158
Australia
perforated gastric
ulcers
admitted to
A&E, one
with
epigastric
and one
with
abdominal
pain
Dyer et
al. 2004,
UK
Case report of
hypokalaemia with
ibuprofen and
codeine
Case Report
Eggen, &
Andrew
1994,
Norway
To investigate the
use of controlled
analgesics in a
general
population.
All
prescriptions
dispensed
during one year
were
quantitatively
analysed.
All
prescriptio
ns for
controlled
analgesics
dispensed
from the
three
pharmacies
in the
municipalit
y of Troms,
Norway.
5354
persons
had 10 824
prescriptio
history of
high use of
Nurofen
Plus® for
three weeks
and the
other had
taken ‘a
packet a
day’ for the
previous
year
Hypokalae
mia
following
suspected
Nurofen
Plus®
(Ibuprofen
and
Codeine)
ingestion.
Patient
denied
taking on
some
occasions
Number of
prescription
dispensed
in 1 year
ulcers. Tighter controls are
needed for this over the
counter product due to the
high concentration of
codeine leading to abuse
potential and the lack of
perceived toxicity of the
ibuprofen compared to
paracetamol combinations
effects
There were complicating factors with this
case such as the patient’s denial of Nurofen
Plus® usage, psychiatric history and
substance misuse. However, there is a
possibility that the ibuprofen lead to the
hypokalaemia
Ibuprofen use should be
considered in patients
presenting with
hypokalaemia, especially
considering it combination
with a drug with abuse
potential, codeine in an over
the counter formulation
Adverse
health
effects
About 8 % of the population had obtained
one or more prescriptions of controlled
analgesics.
The sporadic users were in the majority.
About 8 % of the population had obtained
one or more prescriptions of controlled
analgesics. Combined codeine preparations
were by far the most frequently prescribed
sub-groups. The users of buprenorphine and
entazocine differed in several aspects from
the codeine users.
The
Monitoring of prescribing
and use of controlled
analgesics according to
certain criteria may uncover
possible misuse.
Use of controlled analgesics
is common, but sporadic
use is dominant. Drug use
increases with age, and
women use more drugs than
men.
Prevalenc
e of
codeine
analgesic
s in a
general
populatio
n
159
Elwood
2001,
USA
To explore
emerging drug
trend of codeine
syrup abuse and
codeine overdose
leading to fatalities
A literature
search of
scientific
journals and
news media,
interviews with
community
authorities, and
guided
interviews with
25 adults who
reported using
codeine cough
syrup in the 30
days preceding
their interviews
Eng &
Lachenm
eyer
1996,
USA
Codeine selfmedication in a
headache patient
Case report of
a chronic
headache
patient.
Ernest et
al. 2010,
Australia
To analyse
profound
hypokalaemia due
to Nurofen Plus®
and Red Bull
misuse
Case Report
ns
dispensed.
Comprised
3083women
(58 %) and
2223 men
(42 %)
between 10
and 99
years of
age.
Guided
qualitative
interviews
with 25
adults who
reported
using
codeine
cough
syrup in the
30 days
preceding
their
interviews
54-year old
patient with
25-year
history of
paracetamo
l and
codeine
selfmedication
39-year-old
Adult male
presenting
to A&E with
hypokalae
mia,
Views on
trends in
codeine
cough
syrup
abuse
The procurement and misuse of codeine
cough syrup in Houston has increased over
the past three years.
The procurement and
misuse of prescription
cough syrup
is a sticky business that
requires prevention,
treatment, and social welfare
precautions to ameliorate
the problem .
Character
istics of
codeine
misusers
After
detoxificati
on
program,
the patient
began
cognitivebehavioral
treatment
72 Nurofen
Plus®
tablets
ingested
during the
previous 3
Study highlights the need to identify patients
who are in need of psychological services to
assist in pain management.
The value of psychological
treatments and cognitivebehavioral, biofeedback, and
relaxation techniques for
headache treatment should
be explored.
Adverse
health
effects
The cause of the patient’s hypokalaemia was
clouded by the unusually high doses of
multiple substances ingested. The authors
consider that the patient’s hypokalaemia was
most probably attributable to the significant
ingestion of Nurofen Plus.
The codeine content and
ready availability of Nurofen
Plus® as an over-thecounter medication make it a
potential drug for misuse.
Nurofen Plus should be
Adverse
health
effects
It appears that lean/
syrup use has grown in response to the poor
quality of illegal drugs and the relative ease
of its procurement without fear of arrest.
160
associated
with severe
myopathy
Evans et
al. 2010,
New
Zealand
Combination nonsteroidal antiinflammatory drugs
codeine
preparations and
gastrointestinal
toxicity
Case Study
Fitzcharl
es et al.
2011,
Canada
To evaluate the
reported use
of opioids and the
associations
there of in patients
A chart review
of all patients
referred to a
tertiary care
pain centre
35-year-old
Adult male
admitted to
hospital
and
admitted
taking 100
Nurofen
Plus® per
day for
back pain
for an
unspecified
duration
All patients
referred to
a tertiary
care pain
centre
days. The
patient was
also taking
prescribed
haloperidol,
diazepam,
alprazolam
and
salbutamol
for various
conditions.
He had also
ingested 24
cans of Red
Bull energy
drink and
2.5 bottles
(1875mL) of
the
homeopathi
c
preparation,
Nervatona
Calm over
three days
The patient
was
prescribed
a reducing
codeine
dose as an
opiate
substitute.
Another potential contributor to the
hypokalaemia and myopathy may have been
the caffeine from the Red Bull.
The Nervatona Calm may have contributed to
the myopathy
considered in patients
presenting with otherwise
unexplained hypokalaemia.
Gastroscopy revealed a significant
gastrointestinal pathology secondary to the
gross overuse of combination non-steroidal
anti-inflammatory drug /codeine products
It is known that non-steroidal
anti-inflammatory drugs can
cause multiple adverse
effects. The addition of
codeine causes an addictive
potential.
It is hoped that the re
classification to Pharmacistonly will reduce the abuse
potential and subsequent
clinical adverse effects as
seen in this patient
Adverse
health
effects
Use of
opioids
Characteris
tics of
opioid
Opioid use by 32% of 457 patients referred to
a multidisciplinary fibromyalgia clinic, with
over two thirds using strong opioids. 16% of
this sample used codeine.
Any physician prescribing
opioids for a patient with
fibromyalgia should practice
responsible
prescribing behaviours with
Character
istics of
opioid
users
161
referred with a
diagnosis of
fibromyalgia to a
multidisciplinary
pain centre.
Fleming,
McElnay,
&
Hughes
2004,
Netherlan
ds
To develop and
pilot a harmminimisation
model for the
identification and
treatment of overthe-counter (over
the counter) drug
abuse/misuse by
community
pharmacists.
clinic with a
referring
diagnosis of
fibromyalgia
was conducted
to evaluate use
of opioid
medications.
Focus group
study with
24 experts
consisting of
GPs,
pharmacists,
health
promotion
practitioners ,
sociologist and
psychiatrics
clinic with a
referring
diagnosis
of
fibromyalgi
a
Intervention
for over the
counter
misuse
users
The model
is designed
to be used
by
community
pharmacist
s in
conjunction
with other
healthcare
professiona
ls. It
focuses on
the
abuse/misu
se of
opioids,
laxatives
and
antihistami
nes and can
be broadly
divided into
three
phases,
namely:
patient
identificatio
n and
recruitment,
treatment/re
ferrals and
Opioid use was more commonly associated
with lower education, unemployment,
disability payments, current unstable
psychiatric disorder, a history of substance
abuse, and previous suicide attempts.
Some success was noted in that clients
agreed to stop using the product and/or to try
safer alternatives. As expected, some sales
had to be refused, as the client was unwilling
to accept the pharmacist’s intervention.
162
attention to function
and psychological status,
use of screening tools or
treatment agreements where
appropriate, and be alert to
any indication
of aberrant drug behaviour.
The use of opioids in
fibromyalgia requires further
study in order to examine
health outcome parameters.
Although successful in a
number of areas, the
completion of the pilot has
identified opportunities for
further refinement of the
model. Future work will
focus on improving
pharmacist communication
skills, particularly in the area
of motivational interviewing.
Interventi
ons
over the
counter
(includes
codeine)
(may also
be
included
under the
over the
counter
heading)
Fleming
et al.
2007,
USA
Looking at
Substance Use
Disorders in a
Primary Care
Sample
Relationship of
positive urine
screens and
aberrant drug
behaviours to
opioid use
disorders
A quantitative
study using a
15 point scale
for chronic
pain , 12 point
aberrant scale
,Prescription
medication
survey
Substance
dependence
severity scale
and addiction
severity index
801
participants
from the
primary
care
practices of
235 family
physicians
Forman
et al.
2006,
USA
To
determine the
availability of web
sites offering
to sell opioid
medications
without
prescriptions and
to develop basic
knowledge about
parameters
affecting the types
of web sites
obtained in
searches.
To investigate
morbidity related
to misuse of overthe-counter (over
the counter)
Codeineibuprofen
analgesics.
Forty-seven
Internet
searches
were
conducted
2
researchers
Prospective
case series
collected from
Victorian
hospital-based
Addiction
medicine
specialists
between May
Twentyseven
patients
with
serious
morbidity
were
included,
mainly with
Frei et al.
2010,
Australia
data
collection/o
utcome
measureme
nt.
Dependenc
e on
opioids
Codeine was prescribed (30/500 for 68 of the
patients 8.6% of the group)
Depende
nce
The 6 most common pain diagnoses were
degenerative arthritis, low back pain,
migraine headaches, neuropathy, and
fibromyalgia
The point prevalence of current (DSM-IV
criteria in the past 30 days) substance abuse
and/or dependence was 9.7% (n =78) and
3.8% (30) for an opioid use disorder
This study found that the
frequency of opioid use
disorders was 4 times higher
in patients receiving opioid
therapy compared with
general population samples
(3.8% vs 0.9%)
The study also provides
quantitative data linking
aberrant drug behaviours to
opioid use disorders
No of Hits
for opioid
search
terms
In searches with terms such as “no
prescription codeine” and “Vicodin,” over
50% of the links obtained were coded as “No
Prescription Website (NPW).” The proportion
of links yielding NPWs was greater when the
phrase “no prescription” was added to the
opioid term. More than 300 opioid NPWs were
identified and entered into a database
The emergence of NPWs
introduces a new vector for
unregulated access to
opioids. Research is needed
to determine the effect of
NPWs on prescription opioid
use initiation, misuse, and
dependence.
Web
sales of
over the
counter
medicine
s
Morbidity
associated
with
codeine–
ibuprofen
misuse.
The patients were taking mean daily doses of
435–602mg of codeine phosphate and 6800–
9400mg ibuprofen. Most patients had no
previous history of substance use disorder.
The main treatment was opioid substitution
treatment with buprenorphine–naloxone or
methadone.
Although codeine can be
considered a relatively weak
opioid analgesic, it is
nevertheless addictive, and
the significant morbidity and
specific patient
characteristics associated
with overuse of codeine–
ibuprofen analgesics
Addiction
/misuse/a
buse of
over the
counter
medicine
s;
Consequ
ences of
163
2005 and
December
2008.
Fredheim
et al.
2009,
Norway
To determine
whether codeine is
primarily used for
acute pain or
whether there is a
prescription
pattern indicating
problematic opioid
use.
3 years of
prescription
data 2004-2006
in Norway
Fry et al.
2007,
Australia
Understanding of
the relationship
between
benzodiazepine
and
pharmaceutical
opioid use and
crime.
Multiple
methods:
Qualitative key
informant
interviews;
quantitative
survey; and
data collection
law
enforcement
and health
sectors in three
select
Australian
jurisdictions
(Melbourne,
Hobart, Darwin)
gastrointest
inal
haemorrha
ge and
opioid
dependenc
e.
All users of
codeine
compounds
recorded in
the Norway
prescriptio
n data base
(NorPD)
during the
years 2004,
2005 and
2006.
Stage 1: A
total of 33
key
informant
Stage 2: a
face-to-face
survey of
people who
inject drugs
n=303
support further awareness,
investigation and monitoring
of over the counter codeine–
ibuprofen analgesic use.
use
Patterns of
codeine use
for nonmalignant
pain
About one in 10 adult persons in Norway
were dispensed codeine in 2005. A majority
(58%) received codeine only once, most likely
for acute pain, whereas a small minority
(0.5%) had a prescription pattern indicating
problematic opioid use.
Clinical trials are needed in
order to establish whether
patients benefit from such a
long-term treatment with
short-acting weak opioids.
Research is also needed on
the treatment of the small
but important group of
codeine-using patients who
appear to have developed
problematic opioid use.
Instead of making codeine
less available, the results of
this study indicate that one
should concentrate on
preventing and helping
those who are at risk of or
have already developed
problematic opioid us
Prevalenc
e of
prescripti
on
codeine
use
Crime rate
based on
27% of participants used codeine in the
previous 6 months
Prescription drugs are reportedly relatively
easy to obtain on the street. Low level of
reported organised criminal activity related to
the procurement of prescription
pharmaceuticals.
There may be some
relationship between the use
of prescription drugs,
dependence and some
criminal activity. Poly-drug
use as a feature of illicit
prescription pharmaceutical
markets. There remains a
need in Australia for a type
of comprehensive national
prescription drug misuse
prevention monitoring
system.
Prevalenc
e of
opioid
misuse
who
participat
e in crime
164
where there is
evidence of
illicit
prescription
pharmaceutical
markets.
Furlan et
al. 2006,
Canada
Gerosta
moulos
et al.
1996,
Australia
Effectiveness and
side effects of
opioids in
treatment of
chronic noncancer pain
To investigate the
incidence and role
of codeine in drugrelated deaths in
Victoria over a 5year period.
Meta-analysis
Case studies autopsy
reports
6019
patients
from 41
randomized
trials
There were
a total of
107 cases
involving
codeine,
representin
g 8.8% of
all drugrelated
deaths in
this period
in Victoria.
There were
only six
fatalities in
which
codeine
was
considered
the major
poison.
These 6
case
studies are
Outcomes
measures
included
pain,
function or
side effects
Number of
death
Opioids were more effective than placebo for
both pain and functional outcomes in
patients with nociceptive or neuropathic pain
or fibromyalgia. Strong, but not weak,
opioids were significantly superior to
naproxen and nortriptyline, and only for pain
relief. Among the side effects of opioids, only
constipation and nausea were clinically and
statistically significant.
Despite the relative shortness of the trials,
more than one third of the participants
abandoned treatment.
Findings of 6 case studies:
The mean (±SD) blood concentration of total
codeine was 4.0 ± 2.3 mg/L.
Findings of 101 other fatalities: Cause of
death was given as toxicity due to codeine
and other drugs.
These cases had a mean blood total codeine
concentration of 1.8 ± 3.3 mg/L (range, 0.0426 mg/L).
Paracetamol was the most common of the
“other” drugs found. Paracetamol is usually
combined with codeine and propoxyphene in
many preparations for the treatment of pain
and common colds.
165
Weak and strong opioids
outperformed placebo
for pain and function in all
types of chronic non cancer
pain.
Other drugs produced better
functional outcomes than
opioids, whereas for pain
relief they were
outperformed only by strong
opioids.
Free codeine concentrations
>0.4 mg/L and total codeine
concentrations >2.0 mg/L
may be sufficient to cause
death in the absence of any
other contributing factors.
Therapeu
tic useeffectiven
ess when
compare
d to other
drugs or
placebo
Occurren
ces of
death due
to
codeine
Glover et
al. 2003,
USA
To identify the
medications that is
consumed by a
rural obstetric
population during
pregnancy.
Hall et al.
2013, UK
Epidemiology and
treatment of
neuropathic pain
Hamer et
al. 2013,
Australia
To explore how the
up scheduling of
over the counter
combination
analgesics
containing codeine
(CACC)
Longitudinal
study (26
months) of
medication
usage and
discontinuation
. 2086
qualitative
interviews
concerning the
use of
prescription,
over-the
counter and
herbal
medicines.
Observational
descriptive
study
A descriptive
qualitative
design was
used, with data
collected via
face-to-face
semistructured
discussed
in detail
and the
remaining
101
578
(pregnant
women)
5,920
patients
with postherpetic
neuralgia
(PHN),
5,340 with
painful
diabetic
neuropathy
(PDN), and
185 with
phantom
limb pain P
(PLP)
11
pharmacist
s
Level of
consumptio
n
95.8% of the participants took prescription
medications, 92.6% of the participants selfmedicated with over-the-counter
medications, and 45.2% of the participants
used herbal medications. Over time,
consumption of over-the-counter
medications exceeded prescription
medication use. Fifteen % of the pregnant
women took ibuprofen at some point during
the pregnancy (5.7% in the third trimester).
Eight %
of the women were noncompliant and 20%
incompletely compliant with prenatal vitamin
and mineral formulations.
Medication use was
substantial in this
population. Medications (eg,
ibuprofen) that are
contraindicated
in pregnancy were used at
unexpectedly high rates. Of
the three medication
classes, over the counter
medications were used most
frequently.
Consump
tion
during
pregnanc
y
Recording
of
neuropathic
back and
postoperative
pain.
First line treatment of PDN & PLP is with
amitriptyline or gabapentin. PHN pain treated
with amitryptaline or Co-Codamol® co-.
Paracetamol, co-dydramol (paracetamoldihydrocodeine) and capsaicin were also
prescribed in one or more condition.
The UK incidence of
diagnosed PHN has
increased with the incidence
of back-pain and postoperative pain unclear.
While use of licenced
antiepileptics increased,
prescribing of therapy with
little evidence of efficacy in
neuropathic pain is still
common. Treatment was
often not in-line with current
guidance.
Therapeu
tic useadult
prescribi
ng
Experience
s in supply
of over the
counter
codeine
Pharmacists were found to monitor the
supply of over the counter CACC by
recording sales and to intervene when they
felt that the medication was being used too
frequently. They perceived a number of
challenges surrounding the provision of over
the counter CACC including; supply from
other pharmacies, establishing
A number of challenges
faced by community
pharmacists to ensure the
safe provision of over the
counter
CACC and to assist codeine
dependent people were
identified, highlighting the
Impact of
access to
over the
counter
meds
166
interviews
Hart et al.
2013,
USA
To examine the
relationship
between musical
preferences and
experimentation
with purple drank.
Cross sectional
survey in a
large university
in the south
eastern United
States of
America
2,349
students
Substance
use and
related high
risk
behaviours
based on
musical
preference
Hastier et
al. 2000,
France
Case Reports of
Codeine-induced
acute pancreatitis
Case Reports
4 confirmed
cases of
acute
pancreatitis
Use of
codeine
prior to the
onset of
symptoms
of
pancreatitis
Hering et
al. 1993,
UK
Cellular changes
in patients with
chronic daily
headaches caused
by ergotamine and
analgesic misuse
Assays of
blood and 3
visits to the
clinic.
12 female
patients
Number of
headache
days per
month was
recorded.
Hou et al.
2011,
China
The neurological
effects of CodeineContaining Cough
Syrup ) addiction
Experimental
study
comparing
Brain Scan
images of
codeine
containing
cough syrup dependent
subjects with
22
dependent
subjects
and 27
healthy
volunteers
The volume
(V) and
weight (W)
of bilateral
corpus
striatum as
well as the
ratio of
corpus
striatum to
therapeutic need, managing codeine
dependent people, lacking confidence in
discussing misuse with people, being unsure
where to refer dependent people for help and
purchaser resentment towards pharmacist
involvement in all sales.
Those who prefer rap/hip-hop music and
rock/alternative have the highest risk for
reporting purple drank use.
Males, other drug users, and those that
prefer rap/hip-hop music have a significantly
higher likelihood of using purple drank.
All patients had taken therapeutic doses of
codeine 1-3 hours before the onset of
abdominal symptoms. All cases had a history
of cholecystectomy.
3/4 had a history of pancreatitis after codeine
ingestion
need for more effective ways
of monitoring the use of
over the counter CACC and
intervening in over the
counter codeine
dependence.
Establishing whether
rap/hip-hop lyrics influence
users to experiment with
drugs, or whether the
increasing popularity of
certain drugs leads rappers
to discuss them in their
lyrics should be explored in
future research.
Codeine ingestion leads to
acute pancreatitis in some
individuals. Previous
cholecystectomy seems to
predispose to codeineinduced pancreatitis
Character
istics of
misusers
of
codeine
syrup.
Adverse
health
effects
All patients stopped the offending medication
and,
at the end of four weeks, 8 out of 12 patients
had
experienced relief from chronic daily
headache. Withdrawal of analgesics
produced a significant decrease in thrombinstimulated inositol
phosphate production at one month; this was
further decreased a month later.
These results provide
evidence of an
adaptation in transduction
with misuse of analgesics
and ergotamine which
correlates with headache
frequency
Adverse
health
effect
The study showed changes to the
appearance of the bilateral corpus striatum,
with decreases in weight , volume and ratio
to whole brain, in codeine containing cough
syrup-dependent subjects
CCS abuse may induce
significant neurological
changes. The dopaminergic
system alterations may play
a role on the
pathophysiology of codeine
containing cough syrup
dependence.
More research is required
Consequ
ences of
Codeine
use,
misuse
and
abuse –
Impairme
nt of
performa
167
Hakkinen
,
Launiain
en,
Vuori,&
Ojanpera
2012,
Finland
To evaluate the
drug and alcohol
findings as well as
the cause and
manner of death in
opioid-related
post-mortem
cases in Finland
from 2000 to 2008.
Hughes
et al.
Northern
Ireland
(UK)
To investigate
abuse of over the
counter products
in Northern Ireland
Ives et al.
2006,
USA
To determine the
one-year incidence
and predictors of
opioid misuse in a
cohort of patients
enrolled in a
chronic pain
disease
management
program within an
academic general
internal medicine
practice.
matching
healthy
volunteers
Quantitative
analysis of all
deaths in
Finland in
which a case
was registered.
the whole
brain
14–44-yearolds. 12,891
cases
(10,182
men).
Death rate
Cross –
sectional study
using
Questionnaire
with 509
community
pharmacists
253
participants
Frequency
of over the
counter
abuse
experience
d in the
pharmacy
Observational
cohort study
196 opioidtreated
patients
with
chronic,
non-cancer
pain of at
least three
months
duration.
The mean
patient age
was 52
years, 55%
were male,
Predictors
of opioid
use
nce
Of the 14–44-year-olds, 12,891 cases (10,182
men), several opioids were detected in 1363
cases (1103 men).
In codeine use poisoning; 43% were accident
and 40% were suicide and was higher than
other cause of death but not statistically
significant However no deaths were reported
for codeine use alone
The perception of pharmacists was that the
abuse of over the counter was on the
increase. The suspected number of patient
that were abuse ranged from 0-700 (median
10) with 55 persons being regular customers.
The most common technique described to
combat abuse was to keep the product out of
site. The participants agreed that their role
could be expanded with regards to misuse of
over the counters
Sixty-two (32%) patients committed opioid
misuse. Detection of cocaine or
amphetamines on UTS was the most
common form of misuse (40.3% of
misusers).Misusers were more likely than
non-misusers to be youngers, have past
alcohol abuse, past cocaine abuse, or have a
previous drug or DUI conviction
Race, income, education, depression score,
disability score, pain score, and literacy were
not associated with misuse.
168
Noticeable differences in the
manner of death, showing
evidence of very few
suicides by methadone and
buprenorphine as opposed
to tramadol and codeine.
Codeine poisonings could
be well distinguished from
other causes of death based
on a high codeine
concentration, and tramadol
poisonings could be
distinguished based on high
tramadol and Odesmethyltramadol
concentrations
over the counter is
perceived to be common in
Prevalenc
e of
opioidrelated
deaths
Patients with a history of
alcohol or cocaine abuse
and alcohol or drug related
convictions should be
carefully evaluated and
followed for signs of misuse
if opioids are prescribed.
Character
istics of
opioid
misusers
- includes
codeine
Frequenc
y of
abuse of
over the
counter
and 75%
were white.
Johanss
on et al.
2003,
Sweden
A quantitative
study of the
dependence on
legal psychotropic
drugs among
alcoholics
Anonymous
questionnaires
given to
alcoholics in
open and
institutionalize
d care.
130
alcoholics
in open
care, 23
alcoholics
in
institutional
ized care
and 120
healthy
control
subjects
Levels of
dependenc
e
Kahan et
al. 2011,
Canada
To explore
pharmacists’
beliefs, practices,
and experiences
regarding opioid
dispensing.
Cross-sectional
emailed survey
652
pharmacist
s
Pharmacist
s’
experience
s and
interactions
with
physicians
Katz et
al. 2006,
USA
Describe the
development of an
Extractability
Rating System for
use by the
pharmaceutical
industry and
regulators.
Five stages.
(eg. Concept
mapping,
development of
rating system).
Stage one was
qualitative
interviews.
Information
was gathered
from opioid
abusers
Nine
prescriptio
n opioid
abusers
with a
range of
extraction
experience
and six
experts
participated
in this
Extractabilit
y of
prescription
opioid
products.
Alcoholics were more often psychotropic
drug dependent (17%) than were healthy
controls (2%).
Benzodiazepines were the most common
psychotropic drug
3% of the open care and 13% of the
institutionalized alcoholics were dependent
on codeine. This is compared to 1% of the
healthy volunteers.
29% of the codeine-dependent alcoholics had
developed high dose dependence.
More than half of the codeine-dependent
subjects were also dependent on
benzodiazepines
86% of pharmacists reported they were
concerned about several or many of their
patients who were taking opioids.
Participants’ most common concerns in the 3
months before the survey were patients
coming in early for prescription refills (39%),
suspected double-doctoring (12%), and
requests
for replacement doses for lost medication
(16%).
Pharmacists reported difficulty in reaching
physicians directly by telephone (43%), and
indicated that physicians frequently did not
return their calls promptly (28%).
Alcoholics are more
dependent on psychotropic
drugs than their healthy
controls. Benzodiazepines
are the most common, but
small percentage use
codeine.
Depende
nce
Pharmacists commonly
observe opioid intoxication
and aberrant drug-related
behaviour in their patients
but have difficulty
communicating their
concerns to physicians.
System-wide strategies
are urgently needed to
improve the safety of opioid
prescribing and to
enhance communication
between physicians and
pharmacists.
Prevalenc
e of
prescripti
on
codeine
use
The majority of users preferred oral intake
(45.4%) to injection (36.4%) or
smoking/inhalation (0%) in this small group.
Extractions are performed mostly by
individual opioid abusers (as opposed to
“street chemists”). The qualitative phases
were extremely informative and shaped our
understanding of the prescription opioid
abuse problem as it relates to the
extractability of prescription opioids, as well
as caused a shift in our thinking about how a
tool could be the most clinically and socially
Despite several limitations,
this effort serves as a call
for standardized testing and
reporting so that products
can be accurately rated, and
should help establish goals
for drug developers who
wish to develop “abuseresistant” opioid products.
Interventi
on
Prescripti
on opioid
abuse
169
regarding the
actual
phenomenolog
y of
extractability.
Krausz et
al. 1998,
Germany
Kurdyak
et al.
2012,
Canada
Use of codeine for
maintenance
treatment of opiate
addicts
To determine the
extent to which
other opioids are
prescribed to
patients receiving
methadone
Three-year
follow-up study
with use of
Standardised
interviews,
medical
examinations
and patients’
questionnaires.
Retrospective
cohort study
stage
Among the
opioid
abusers,
four were
female and
five male,
age ranged
from 26 to
48 years
(mean 37),
eight were
white and
one was
AfricanAmerican,
and seven
had
completed
at least the
twelfth
grade.
199 people
18759, age
group 15-64
years old
meaningful.
Measures
of health,
living
conditions,
employmen
t, criminal
activities
and drug
use were
collected at
baseline
and followup.
Improvement in general health and mental
problems. The living and working situation
remained more or less unchanged and
stabilized at a satisfactory level. The same
applies to the consumption of drugs.
The primary
outcome
was the
proportion
of
methadone
18.4% received at least one prescription for
non-methadone opioids for more than 7 days
duration. Most frequently used opiate was
codeine.
Many patients receiving methadone
170
The patients’ progress
shown in this study was
comparable to that achieved
by methadone maintenance
in similar geographical
regions.
Codeine has a weaker
pharmacological effect and
our results suggest that
codeine maintenance
treatment deserves more
attention and controlled
trials to assess the benefits
compared with methadone
(or other opioids).
Co-prescription of other
opioids with methadone is
common despite current
practice guidelines for drug
monitoring during MMT. This
problem could be mitigated
Therapeu
tic useadult
prescribi
ng
Prevalenc
e of
opioids
prescribe
d to
patients
Lambert
and
Close
2005,
UK
Case report of
hypokalaemia
with ibuprofen and
codeine
Case Report
Repeated
admissions
of one
patient to
A&E
Lam et al.
1996,
Hong
Kong
A review of
psychiatric
admissions due to
cough medicine
misuse
Retrospective
chart review of
psychiatric
admissions
27 subjects
identified
from a 54
month
period
Lankena
u et al.
2007,
USA
To check
prevalence and
patterns of
prescription drug
misuse among
young ketamine
injectors
Cross
sectional.
Multiple
methods:
Quantitative
survey and key
informant
interviews
213 young
injection
drug users
(IDUs)
recipients
who filled at
least one
prescription
for more
than 7 days
of a nonmethadone
opioid
during the
observation
period.
Hypokalae
mia
following
large
amounts of
Nurofen
Plus®
Cough
medicine
misuse in
patients
admitted for
psychiatric
conditions
Rates of
use of
prescription
drugs
maintenance therapy in Ontario receive
overlapping prescriptions for other opioids,
often for extended periods. This suggests
that many such prescriptions may be
duplicitous.
largely by real-time access
to prescription data for both
physicians and pharmacists
prior to writing and filling
prescriptions
receiving
methado
ne
The ibuprofen had caused type 2 proximal
renal tubular acidosis and life threatening
hypokalaemia
The case is an important
issue to raise as the
ibuprofen was bought overthe-counter and abuse of
such preparations can go
unnoticed.
Adverse
health
effects
The main psychiatric presentations included
acute organic brain syndrome,
schizophreniform psychosis and affective
episode
From the observations
reported, a wide range of
psychiatric symptoms could
be associated with cough
mixture misuse.
Adverse
health
effects
Higher rates of lifetime nonmedical
prescription drug use compared to NSDUH
data.
New polydrug combinations, such as
injecting OxyContin and ketamine, which
were associated with drug overdoses.
Future research studies
should report misuse of
multiple classes of
prescription drugs.
Prevalenc
e of
prescripti
on drug
misuse in
young
adults
The most frequently prescribed drugs were
codeine and oxycodone
Codeine was among one of the frequently
misused medication 62% (L.A)and 51%(New
York)
Nonmedical prescription
drug use was not an
ancillary practice an integral
part of drug using
behaviours.
Simultaneous and/or sequential use of
prescription drugs in various polydrug
combinations.
Lankena
u et al.
2012b,
To describe
patterns of
initiation into
Quantitative
design using
face to face
213 young
adults
between 16
Patterns of
use
High lifetime history of receiving a
prescription for an opioid, tranquilizer, or
stimulant which commonly preceded misuse.
171
Patterns of drug use among
high-risk young adults in
Los Angeles and New York
Prevalenc
e of
prescripti
USA
prescription drug
misuse amongst
young IDUs in Los
Angeles and New
York.
interviews
LintonDahloÈ,
Linde,&
Dahloef
2000,
Sweden
To analyse the
effect of drug
withdrawal therapy
in patients with
chronic daily
headache
associated with
long-term misuse
of headache
medication.
Retrospective
analysis of the
effect of drug
withdrawal
therapy in
patients with
chronic daily
headache ) and
frequent longterm use of
headache
symptomatic
medication.
Lord et
al. 2011,
USA
To (1) assess
the feasibility of
implementing a
survey study
about
prescription
medication misuse
with college
students on
Facebook and (2)
identify the
characteristics,
motivations,
beliefs, and
attitudes
associated with
Mixed method.
A quantitative
and qualitative
survey of
motives and
attitudes
associated with
patterns of
nonmedical
prescription
opioid
medication use
among college
students was
conducted on
Facebook.
and 25
years old
who had
engaged in
misuse of a
prescriptio
n drugs
One
hundred
and one
adult
patients (74
women and
27 men,
aged
between 16
and 72
years,
mean age
43 years)
were
evaluated
1±3 months
after drug
withdrawal
therapy had
been
initiated.
689 college
students.
41% female,
83% White
(nonHispanic),
7%
Hispanic,
2.5% Asian
and 1%
Black with
3% from
other
racial/ethni
c group.
Initiation of opioids occurred before heroin
and initiation of prescription stimulants
happened prior to illicit stimulants.
Combining prescription and illicit drugs
during drug using events was commonly
reported.
appear to be linked to
differences in local markets
in each city for illicit drugs
and diverted prescription
drugs.
on drug
misuse in
young
adults
Drug
withdrawal
therapy.
Treatment
with
amitriptylin
e was
offered to
patients in
whom no
improveme
nt had been
achieved.
Fifty-seven (56%) patients were significantly
improved (defined as at least 50% reduction
in number of headache days) after a period of
drug withdrawal therapy. Based on the
outcome of the drug withdrawal therapy. Ten
of those 22 patients offered amitriptyline
(36%) experienced a significant (i50%)
reduction of headache days.
Out-patient drug withdrawal
therapy is the treatment of
choice in patients with
chronic daily headache and
frequent long-term use of
headache symptomatic
medication, and that about
one quarter of these
patients do not respond to
drug withdrawal therapy
only.
Interventi
on
Misuse of
headache
medicatio
n
(includes
codeine)
Reasons for
using
prescription
medication
s.
Codeine was amongst the drugs used.
Codeine combined with paracetamol was one
of the most frequently misused prescription
opioids and Tylenol® with codeine was 43%
Three motives were related to a higher
likelihood of regular misuse: to get high, to
manage chronic pain, and to cope with
depression or anxiety.
There is a need for
prevention programming for
college students that builds
awareness about the risks of
prescription drug use,
challenges
positive beliefs and outcome
expectancies related to
misuse, and fosters
motivation and skills to
avoid
non-medical use of
prescription drugs.
Reasons
for
misusing
prescripti
on
opioids includes
codeine
Feasibility
of using a
web based
survey
Need for Programming for
health practitioners that
172
experimental
versus regular
misuse of
prescription opioid
analgesic
medications.
builds awareness about the
risk potential of prescription
drug misuse and promotes
development of policy
initiatives that direct
attention to prescription
drug misuse on campuses
MacFady
en et al.
2001,
Scotland
To explore
community
pharmacists’
experience of
over-the-counter
medicine misuse
in Scotland
Postal
questionnaire
87
pharmacist
s
Attitudes to
the range of
over the
counter
medicines
being
misused in
Scotland.
The study found that over the counter
medicines misuse was common and the
estimated mean number of patients
suspected of misusing medicines in a typical
week was 5.63.
Pharmacists expressed a
need for support in
managing over the counter
misuse and in organizing
‘early warning systems’ to
share information locally.
Views/ex
perience
on over
the
counter
medicine
use/abus
e
Madadi et
al. 2007,
Canada
Safety of codeine
in breast feeding
Case Report
New-born
male infant
Genotype analysis revealed that the mother
was an ultra-fast metabolizer of codeine to
morphine and both the infant and mother
were fast metabolizers of morphine to its
more potent metabolite, morphine-6glucuronide. The subsequent high levels of
these substances in the infant lead to death.
The widespread perception
that codeine is safe in
breast-feeding is not the
case in subjects with
polymorphisms in enzymes
that lead to the ultra-fast
metabolism.
Adverse
health
effects
Manchia
et al.
2013,
Canada
Repeated
Erythromycin/Cod
eine-Induced
Psychotic Mania
Case Report
19 year old
male
admitted
for
psychotic
episode,
one week
after tooth
extraction
To study the
socio-
Observational;
case series.
46
consecutiv
The temporal relationship between his taking
erythromycin, paracetamol
with codeine, and the onset of psychiatric
symptoms and
the rapid offset of symptoms with
discontinuation of these drugs points to the
diagnosis of substance-induced mood
disorder with psychosis. It is proposed that a
pharmacokinetic interaction between
erythromycin and codeine could explain the
observed association with symptoms of
psychotic mania. Complete resolution of
psychosis within 5 days following
antipsychotic therapy.
Mean age of starting for codeine containing
cough syrups use was 23 years. Initiated
Adverse events of psychotic
mania have been rarely
reported with erythromycin
and paracetamol with
codeine, despite
been commonly prescribed
medications. Clinicians
should be aware that these
drugs may be an iatrogenic
cause of psychiatric
disturbances and that these
adverse events are more
likely to occur during their
concomitant use.
The combination of an
opioid and a
Adverse
health
effects
Mattoo et
al. 1997,
Mother
prescribed
CoCodamol®
(30/500mg)
postpartum
which lead
to the death
of the infant
30 tablets in
one week of
paracetamo
l (300mg)/
codeine
(30mg)/caff
eine (15mg)
Erythromyc
in 800mg
before and
400mg six
hours post
dental
procedure.
Type of
client group
173
Character
istics of
India
demographic and
clinical profile of
patients seeking
treatment for
abuse of codeinecontaining cough
syrups .
Semistructured
interviews for
patients and
their family
covering sociodemographic
and clinical
variables
e treatmentseeking
patients of
DSM-III-Rdiagnosed
dependenc
e on
codeine
containing
cough
syrups
seeking
treatment
for abuse
commonly through friends and often for
curiosity 89% of the patients progressed to
daily use of codeine containing cough syrups
in less than 6 months..
McAvoy
et al.
2011,
New
Zealand
To describe the
characteristics of
clients addicted to
over-the-counter
(over the counter)
codeine
analgesics
presenting to an
Auckland clinic;
clients to a New
Zealand
detoxification unit,
and in the
Australian
community.
Cross-sectional
study of clients
presenting to a
regional, openaccess
detoxification
clinic covering
the Greater
Auckland area
between 1
January and 31
March 2010.
Demograph
ics
information
on
codeine
consumptio
n patterns,
associated
morbidity,
relevant
history and
manageme
nt
Cases in each cohort were consistent with
those in the published literature, and appear
to be similar to each other both
demographically and in terms of the high
average tablets consumption (49–65 tablets
per day), the serious non-steroidal antiinflammatory drug adverse drug reactions
identified, and the long duration of misuse.
Many had a history of alcohol or other drug
use and mental health disorder.
McBride
et al.
2003,
UK
To explore the
views of experts
within the fields of
pharmacy and
addiction
on the value of
current strategies
and possible
alternatives and to
reach an
agreement on best
practice in the sale
Using a
modified Delphi
approach, three
stage postal
questionnaire
was conducted
that generated
both qualitative
and
quantitative
data.
Fifteen
clients were
analysed,
and
compared
to 77
similar
clients
identified in
Victoria and
five other
Australian
States, and
7 clients
admitted to
a New
Zealand
detoxificati
on unit.
47 experts
completed
all three
stages
Expert
views on
strategies
of over the
counter
medicines
A consensus was reached on the strategies
considered the most important and effective.
Key areas include improving access to
current information, improved staff training,
addressing the issues of non-pharmacy
outlets and Internet pharmacy sites.
Concerns were expressed regarding the
possible conflict between commercial and
customer interests.
Opioid-like withdrawal was reported by 92%.
Concurrent use of other substances,
psychiatric co-morbidity and HIV-related risk
behaviour were present in 72%, 24% and
45%, respectively. Most of the patients
reported a 'stimulant' effect of codeine
containing cough syrups .
174
sympathomimetic agent in
the codeine containing cough
syrupmay cause a special,
distinct euphoric effect. This
effect, along with the low
price, easy availability and
'pure' preparation of codeine
containing cough syrups , may
be responsible for the
rapidly rising popularity of
the codeine containing cough
syrups as drugs of abuse in
India.
over the counter codeine
analgesics in both countries
are not sufficient to limit
non-medical use of these
products. As a
result, cases identified in
these two countries
escalated the number of
self-administered tablets
taken daily for misuse,
resulting in codeine
dependence and serious
non-steroidal anti-inflammatory
drugs toxicity secondary to
this dependence.
misuse
Findings suggest a need for
improvements to existing
strategies, including
national policies with central
co-ordination, a greater
emphasis on training and
improved communication
between primary health-care
professionals. The panel
wisely reminds us that new
policies and practices
cannot prevent all over the
Strategie
s for best
practice
on over
the
counter
supply
Addiction
/misuse/a
buse of
over the
counter
medicine
s
McCabe
et al.
2009,
USA
Moore et
al. 2011,
UK
of over-thecounter (over the
counter)
medicines which
are liable to
misuse.
To use three
characteristics
(i.e., motive, route
of administration,
and co-ingestion
with alcohol) of
nonmedical
prescription drug
misuse across
four separate
classes (i.e., pain,
sedative/
anxiety, sleeping,
and stimulant
medications) to
examine subtypes
and drug related
problems
Treatment of acute
postoperative pain
with a single dose
of oral
dihydrocodeine
counter misuse.
A selfadministered
randomised
design Web
survey
3639
undergradu
ate
students
(53.6%
women and
46.4%
men).
attending a
large
Midwestern
U.S.
university.
Characteris
tics by
subtype
Nonmedical prescription drug misuse
including codeine was 20% and 13%,
respectively.
Approximately 13% of those who reported
any nonmedical
prescription drug misuse were classified in
the recreational subtype, while 39% were
classified in the self-treatment subtype and
48% were classified in the mixed subtype
based on motive, route of administration, and
co-ingestion with alcohol
Future clinical and research
efforts should differentiate
between subtypes of
nonmedical prescription
drug misuse because
subtypes can be associated
with different rates of drug
use and drug related
problems, especially for pain
medication.
Character
istics of
prescripti
on drug
misusers
-includes
codeine
A single 30 mg dose of
dihydrocodeine is not
sufficient to provide
adequate pain relief in
postoperative pain.
Statistical superiority of
ibuprofen 400 mg over
dihydrocodeine (30 mg or 60
mg) was shown.
Therapeu
tic useeffectiven
ess when
compare
d to other
drugs or
placebo
There were significant differences in the
subtypes in terms of gender, race and
prescription drug class.
Approximately 50% of those in subtypes
other than self-treatment screened positive
for drug abuse. The odds of substance use
and abuse were generally lower among selftreatment subtypes than other subtypes.
Meta-analysis
194
participants
from three
reports
compared
dihydrocod
eine
with
placebo
and one
(120
participants
) compared
dihydrocod
For a single dose of
dihydrocodeine 30 mg in moderate to severe
postoperative pain the NNT for at least 50%
pain relief was 8.1.
Pooled data showed significantly more
participants to have reported adverse effects
with dihydrocodeine 30 mg than with
placebo.
When compared to ibuprofen 400 mg both
dihydrocodeine 30 mg and 60 mg were
significantly inferior.
175
Morgan
et al.
2006,
England
& Wales
To report trends in
death due to drug
misuse 1993 -2004
National deaths
database
Myers et
al. 2003,
South
Africa
To provide
community-level
public health
surveillance
information on
over-the-counter
(over the counter)
and
prescription
medicine misuse
A retrospective
study of over
the counter and
prescription
medicine
misuse.
Nielsen
et al.
2011,
Australia
To compare the
characteristics
of an Australian
drug treatment
sample presenting
Cross
sectional. A
structured
quantitative
interview
eine (30 mg
or 60 mg)
with
ibuprofen
400 mg.
Drug
poisoning
deaths are
extracted
from the
national
deaths
database
Death rate
Between 1993 and 2004 there were 12,687
deaths related to drug misuse among males
and 3,401 deaths among females.
Mortality rates were highest in young adults.
Codeine deaths were reported at 26 in 1999
to 54 in 2004
Drug-misuse-related
poisoning is a significant
cause of mortality in
England and Wales.
Meaningful interpretation of
surveillance data needed to
plan effective strategies to
reduce the number of drugmisuse-related deaths
depends on understanding
the size of the drug using
population and the risk of
fatal poisoning among drug
users.
Prevalenc
e of
deaths
due to
drug
misuse
9 063
patients
(forms)
from 23
specialist
substance
abuse
treatment
centres in
Cape Town,
South
Africa,
between
1998 and
2000.
Use of over
the counter
medicines
over the counter and prescription medicine
misuse places a burden on health and social
services in South Africa. Analgesic misuse is
most often accounted for by the use of
codeine-containing medicines, many of
which are available over the counter. Patients
using over the counter/prescription
medicines as their primary drug of abuse are
significantly more likely to be female, and
aged over 40 years. In contrast, patients
using over the counter/prescription medicine
as an additional drug of abuse tend to be
male and over 40 years of age.
Addiction
/misuse/a
buse of
over the
counter
medicine
s
A
convenienc
e sample of
192
treatment
Compariso
n between
profiles of
injecting
and non-
Most treatment entrants reported a history of
injection drug use and use of both heroin and
POA. Minority (13%) were using codeine as
their primary POA.
This study points to the
need to develop primary
health care protocols for
detection, management and
referral of patients misusing
over the
counter/prescription drugs
and the need to debate the
re-scheduling of codeine as
a prescription-only
substance. The study also
points to the need for further
community-based research
on the nature and extent of
over the
counter/prescription drug
misuse among the general
population.
There are many similar
characteristics between
those with primary problems
with heroin and POA.
This finding contrasts with
176
Character
istics of
misusers
of opioid
analgesic
with
pharmaceutical
opioid analgesics
(POA) as their
primary drug of
concern and a
sample presenting
with heroin as
their primary drug
of concern.
collected data
on
demographic
characteristics,
substance use,
Self-perceived
mental and
physical health,
crime and
harms resulting
from drug use.
entrants
were
recruited
from
alcohol and
drug
treatment
services in
four
Australian
jurisdiction
s.
Nielsen
et al.
2010, UK
Understanding the
nature of
dependence to
over the counter
codeine.
A web survey,
qualitative,
semistructured
interviews with
primary
healthcare
practitioners
and other key
experts‟ as
well as
qualitative
interviews with
codeine
dependent
people.
Sampling for
both groups
was purposive.
web
surveyn=800 ;
qualitative
interviews
n=20 and
Key expert
interviews
Nielsen
et al.
2013,
Perspectives of
over-the-counter
(over the counter)
Qualitative
research
methodology
20
participants
injecting
heroin
users
However, those with primary POA problems
were less likely to report an overdose history
and more likely to initiate opioid use for pain
than those with primary heroin problems.
While most of the POA group were similar to
heroin users in demographics, health and
injecting drug use, there was a small, distinct
group of primary POA problem users that did
not typically inject and who commonly
initiated opioid use for pain and also
experienced elevated physical and mental
health disability. For the non-injecting group
few had problems with heroin (8%) instead
the problem drug was typically codeine (35%)
Experience
s of over
the counter
Web survey: Participants classified as
codeine dependent were found to be more
likely to report chronic pain, have higher
ratings of psychological distress, have
experienced alcohol and drug treatment and
have used doses higher than the maximum
dose. Participant interviews: three types of
codeine users were identified I. Therapeutic
dependence II. Non-medical/recreational
users III. High dose dependence. Blurring
between therapeutic and problematic use
was also a feature where participants
described being in a viscous cycle of
medicating opioid withdrawal thinking they
were medicating pain. Key Expert Interviews:
Pharmacist’s descriptions were based more
on appearance than other characteristics,
consistent with descriptions of over the
counter codeine users reporting appearance
being related to codeine supply. Reporting
appearance being related to codeine supply.
Pharmacists also highlighted the challenges
in responding to codeine dependence with
information available with current systems.
Key themes identified included experience of
participants acquiring over the counter
codeine and participants’ interactions with
177
reports of a growing
population of opioiddependent people with
characteristics that
are distinct from traditional
opioid-dependent
populations, which may
reflect the orientation of
current treatment systems in
Australia towards injection
drug users.
s
Pharmacist can play an
important role in raising
general awareness
regarding potential over the
counter codeine
dependence and harms.
Requirement for greater
interaction between the
pharmacist and the public
for over the counter codeine
purchases
Addiction
/misuse/
abuse of
over the
counter
medicine
s
and
views/
experienc
e on over
the
counter
medicine
use/abus
e
Barriers exist to effective
interventions for over the
counter codeine
Opportun
ities and
challenge
Australia
codeine users and
issues relating to
codeine
dependence in the
community
pharmacy setting.
using
interviews with
over the
counter
codeine users
and met DSM
IV criteria for
codeine
dependence.
Case Reports
Ng et al.
2011,
Australia
To look at cases of
life-threatening
hypokalaemia
associated with
ibuprofen
Noysk et
al. 2012,
Canada
To identify
changes in the
availability of
Prescription
Opioids and other
illicit drugs among
drug users in a
Canadian setting.
Data were
derived from
the baseline
assessments of
a series of
ongoing open
prospective
cohort studies
involving illicit
drug users
1871
participants
31% Female
Nuesch
et al.
2009, UK
Treatment of
osteoarthritis of
the knee or hip
Meta-analysis
2268
participants
4 patients
admitted to
hospital
with lifethreatening
hypokalaemia
dependenc
e
pharmacists. The over the counter codeinedependent participants found it generally
easy to access over the counter codeine,
describing ‘standard’ questioning, minimal
intervention from pharmacists and only
occasional refusal to supply. A better
appearance and presentation was generally
linked to easy codeine supply.
dependence. Targeted
interventions are required to
reduce over the counter
codeine harm.
s in over
the
counter
codeine
All 4
patients
had taken
excessive
amounts of
ibuprofen
over a
prolonged
period. 2 of
the patients
had taken
the
ibuprofen
combined
with
codeine
The four patients had developed
hypokalaemia due to ibuprofen-induced
Renal Tube Acidosis
Ibuprofen cessation and support therapy
allowed complete recovery within a few days
for all the patients
Opioid addiction with the
misuse of ibuprofen-codeine
combinations is common. It
should be considered in
patients presenting with
severe hypokalaemia
Adverse
health
effects
Availability of codeine increased from 17% to
40% from 2006-2010. Codeine and other
drugs were more immediately to people over
45
Immediate availability of POs increased
significantly from 2006 to 2010. These
increases persisted after adjustment for
changes in the characteristics of individuals
entering the cohorts under study.
Policy and programmatic
responses should
acknowledge that POs may
be used as a primary drug of
abuse, as a temporary
solution to opioid
withdrawal, or as genuine
pain relief.
The demand, and context of
the use of prescribed
opioids requires closer
consideration
The small to moderate
beneficial effects of nontramadol opioids are
outweighed by large
increases in the risk of
adverse events.
Nontramadol opioids should
Availabilit
y of
codeine
Effectivene
ss of opioid
preparation
s against
placebos
Overall, opioids were more effective than
control interventions in terms of pain relief
(SMD -0.36, 95% CI -0.47 to -0.26) and
improvement of function (SMD -0.33, 95% CI 0.45 to -0.21).
No substantial differences in effects
according to type of opioid, analgesic
178
Therapeu
tic useadult
prescribi
ng
Pan et al.
2013,
Taiwan
To investigate
opioid
consumption
patterns in Taiwan,
compare the
results with those
from selected
countries, identify
differences
between patients
with and without
cancer, and
determine the
associated
expenditure.
Taiwan
National Health
Insurance
Research
Database for
2002-2007.
Data on
prescriptio
ns for three
so-called
strong
opioids
(fentanyl,
morphine,
and
pethidine
[meperidine
]) and one
so-called
weak opioid
(codeine)
were
obtained
DDD per
million
inhabitants
Reynolds
et al.
2007,
USA
To assess effects
of maternal drugs
and medications
on neonates
2 case studies
2 neonates
Occurrence
of a
cerebral
infarction
Palangio
et al.
2000,
USA
Treatment of
chronic pain with a
combination of
hydrocodone and
ibuprofen versus
combination of
codeine and
paracetamol
Randomized,
parallel-group,
double-blind,
repeated-dose,
active
comparator,
4-week,
multicentre
study
469
patients
Efficacy of
drug.
potency (strong or weak), daily dose,
duration of treatment or follow up,
methodological quality of trials, and type of
funding.
From 2002 to 2007, opioid consumption in
Taiwan increased by 55% from 362 to 560
defined daily dose for statistical purposes
per million inhabitants per day. Among the
investigated opioids, prescriptions for
transdermal fentanyl and oral morphine
increased markedly from 2002 to 2007.
33% took codeine in 2002 and 27% in 2007 for
non-cancer patient
67% took codeine for cancer pain in 2002 and
73% in 2007
Codeine-containing cough preparations
given to pregnant mothers have been
identified as a cause of neonatal abstinence
syndrome. However, many women do not
consider prescription cough syrups when
asked about drug use. Maternal medication
or illicit drug use has been identified as a
cause of perinatal arterial stroke.
The overall mean daily pain relief score was
significantly greater in the HI2 group (2.25 f
0.89) than in the HII group
(1.98 * 0.87) (P = 0.003) or the CA group (1.85
f 0.96) (P < 0.001).
179
therefore not be routinely
used, even if osteoarthritic
pain is severe.
Opioid prescriptions and
expenditure increased
steadily from 2002 to 2007 in
Taiwan, as in nearby Asian
countries, but remained
much lower than in
developed countries.
Pethidine (meperidine) was
predominantly prescribed to
non-cancer patients,
whereas morphine and
fentanyl were mainly
prescribed for cancer
patients.
Prevalenc
e of
opioid
consump
tion in
Taiwan
Physicians should ask about
maternal medication use,
including codeinecontaining cough
preparations, when
evaluating new-born infants
with evidence of cerebral
infarction.
The results of this study
suggest that 2-tablet doses
of combination hydrocodone
7.5 mg and ibuprofen 200
mg may be more effective
than either l-tablet doses of
this combination or 2-tablet
doses of combination
codeine 30 mg and
paracetamol 300 mg.
Moreover, 1 -tablet
doses of combination
hydrocodone 7.5 mg and
ibuprofen 200 mg may be as
Adverse
health
effect
Therapeu
tic useeffectiven
ess when
compare
d to other
drugs or
placebo
effective as 2-tablet doses of
combination codeine 30mg
and paracetamol 300mg.
Piccoliori
et al.
2013,
Italy
Robinson
et al.
2010,
New Zealand
Roussin
et al.
2013,
France
Management of
low back pain in
general practice
Observational
study using
quality
indicators
To review cases of
codeine
dependency from
over-the-counter
(over the counter)
combination
analgesics
admitted to a
hospital
detoxification unit.
Case records
of all
admissions
following an
index case
were reviewed
over a
2-year period.
To investigate the
prevalence of
misuse, abuse,
and dependence
on nonprescription
psychoactive
drugs.
Crosssectional.
Quantitative
survey to
investigate
misuse/abuse
of nonprescription
drugs
475
patients
7 cases
Managemen
t of LBP
was judged
by predefined
quality
indicators
based on
guideline
recommend
ations.
Complicatio
ns of over
the counter
medicines
In 93.3% of those receiving a medication,
88.3% had non-steroidal anti-inflammatory
drugs , 6.3% Paracetamol, 10.4% Paracetamol
combined with Codeine, and 9% muscle
relaxants. 50% of GPs did not fully follow
locally established guidelines.
Gross deviations of GP
management of LBP from
current guidelines.
There were 7 cases reporting chronic excess
of Nurofen Plus® , of which 6 had prior or
current histories of alcohol dependency.
Complications which were likely contributed
by excessive ibuprofen consumption
included: gastric ulcer (4 patients),
gastrointestinal bleeding (3), hepatotoxicity
(1), and inflammatory bowel conditions (2).
These cases likely represent
the severer end of the
spectrum of codeine
dependency acquired from
over the counter pharmacy
sources. The paucity of
evidence to support
additional benefit from the
inclusion of codeine in
analgesic combination
products is concerning.
There is a need for
increased
pharmacovigilance around
these and other over the
counter medications.
These results support the
fact that chronic pain
requires better medical care,
in particular chronic
cephalalgia, which in turn
will help prevent drugrelated chronic headaches.
These patients described patterns of visiting
multiple pharmacies, sometimes travelling
considerable distances, to obtain the Nurofen
Plus®. Many of the patients suffered
significant opioid withdrawal symptoms
despite treatment with ancillary medications.
383
questionnai
res handed
out in
pharmacies
were
available
for
analysis.
Number of
misusers/
abusers
Misuse and dependence on codeine
analgesics concerned 6.8%
Headache was the most frequent reason for
persistent daily use.
High rate of dependence on codeine (18% of
users).
180
Two different types of
deviators –GPs (50%) who
partially followed the
guidelines and those who
did not.
Therapeu
tic useadult
prescribi
ng
Addiction
/misuse/
abuse of
over the
counter
medicine
s
Prevalenc
e of
misuse,
abuse,
and
dependen
ce on
nonprescripti
on
psychoac
tive
drugs.
Stark &
Gregory
2005,
UK
Skurtveit
et al.
2011,
Norway
The clinical
management of
substance
misusers in police
custody
To what extent
does a cohort of
new users of weak
opioids develop
persistent or
probable
problematic opioid
use
Quantitative
questionnaire
examining
current
practice in
managing
substance
misuse
detainees and
attitude to drug
addiction and
management in
custody.
409
members of
the
Association
of Forensic
Physicians
Prospective
cohort study
following
patients
recorded on a
national
database from
2005 to
December 2008
245,006
patients
who were
new users
of weak
opioids in
2005
(216,902
codeine,
26,326
tramadol,
1778
dextroprop
oxyphene)
Dependenc
e on
opioids
143 active
clients on
the register
for opiate
addiction,
99 men and
44 women,
with mean
ages of 30
No of
misuser of
DF118
Probable
problematic
opioid use
defined as
receiving
opioids at least
once a year
from 2005 to
2008 and in
2008:
Swadi et
al. 1990,
UK
To report the
results of an
investigation
into the level of DF
118 misuse
(excluding other
dihydrocodeine
preparations)
among opiate
The clinic
notes of all
opiate addicts
at a central
London drug
dependency
treatment
centre were
inspected for
Use of
substance
for
methadone
replacemen
t
The mean dose of dihydrocodeine prescribed
by doctors was 313mg in 24hours
44 doctors prescribe doses between 201 and
300mg
Max dose they were willing to prescribe was
960mg in 24hr period
80% of doctors thinking substance misuser
are unreliable and deceitful
65% of doctors felt that substances misusers
did not comply with treatment
686 patients were dispensed more than 365
defined daily doses of opioids in 2008 and
are probably persistent users
There were 191 subjects who met the criteria
for probable problematic opioid use
Among the 143 clients positive urine tests
were recorded for the following substances:
DF 118 31, amphetamine 21, barbiturates 79,
benzodiazepines one, cocaine one, codeine
38, heroin 122, methadone 71, morphine 101,
phenothiazine’s 11, morphine 101,
phenothiazines 11,
181
The majority of respondents
did not follow guidelines on
prescribing
Therapeu
tic use
Large variation in practice
between doctors
Doctors display negative
attitudes to those who are
misusing substances
In a cohort of new opioid
users who started treatment
with weak opioids, only 0.3%
and 0.08% developed
prescription patterns
indicating persistent opioid
use and problematic opioid
use, respectively.
Depende
nce
The potential for DF 118
misuse was confirmed by
clients, who reported that it
is widely misused and
preferred to other
dihydrocodeine
preparations.
Prevalenc
e of
misuse
among
opiate
addicts
addicts at a
London treatment
centre.
Tang et
al. 2012,
Hong
Kong
To explore the
following:
1) The content of
the local cough
mixture (Cough
mixture is the third
most commonly
abused substance
in patients
attending the
Prince of Wales
Hospital
Substance Abuse
Clinic.)
2) Paranoid
psychosis
manifesting as
persecutory
delusions and
derogatory
hallucination, as
well as mood
symptoms, which
are common in
these patients.
3)The natural
history and
outcome of such
psychoses
associated with
cough mixture
abuse
the results of
their first pretreatment urine
test.
Retrospective
study of cough
mixture abuse
in Hong Kong
and 28
years
respectivel
y.
The
medical
records of
patients,
with a
diagnosis
of cough
mixture
dependenc
e according
to the ICD10 Mental
and
Behavioural
Disorders1
0 criteria
who
attended
the
substance
abuse
clinics of
the PWH,
Alice Ho
Miu Ling
Nethersole
Hospital,
and North
District
Hospital
from
October
2009 to
December
2011, were
reviewed.
Abuse rates
Total of 63 patients with the diagnosis of
cough mixture abuse were identified in the
database; 89% were male. The mean age of
the patients was 34.4; 67% were single and
83% were unemployed. The mean age of
onset of cough mixture abuse was 20 ± 5
years. Psychiatric symptoms developed a
mean of 7.6 ± 6.0 years after onset of abuse.
According to the ICD-10 Mental and
Behavioural Disorders criteria, the top
psychiatric diagnoses were substanceinduced psychotic disorder (67%),
schizophrenia (19%), depressive disorder
(11%), and dysthymia (10%). The most
common ingredients in the urine sample at
first presentation were promethazine (75%),
pseudoephedrine
(67%), codeine (60%), ephedrine (57%),
zopiclone (17%), and hydrocodone (16%).
Additionally, 16% of patients were in the
priority follow-up group.
182
Promethazine, ephedrine,
pseudoephedrine, codeine,
and hydrocodone are the
most common ingredients of
cough mixture abused in
this locality. Psychotic
disorders are the most
frequent psychiatric
diagnosis associated with
cough mixture abuse.
Prevalenc
e of
abuse
(over the
counter
also)
Tobin et
al. 2013,
Australia
Analysis of the
policy response by
Australia’s
National Drugs
and Poisons
Schedule
Committee
(NDPSC) and
comparison with
recommendations
by expert advisory
committees in New
Zealand and the
United Kingdom.
Analysis of
public policy
documents of
relevant
regulatory
authorities was
conducted.
Tormey
et al.
2013,
UK
To determine the
effects of
methadone and
codeine on acute
haemorrhagic
necrotising
pancreatitis
Case Report
written as a
letter to editor
37 year old
female
found dead
at home
Data were
extracted
regarding
changes to
over-thecounter
(over the
counter)
codeine
analgesic
scheduling,
indications,
maximum
unit dose,
maximum
daily dose,
maximum
pack size,
warning
labels,
consumer
medicine
information
and
advertising.
80ml
methadone
from
detoxificati
on
programme,
Benzodiaze
pines from
the street.
Paracetamo
l and
codeine
Expert advisory committees in Australia, NZ
and the UK defined the policy problem of
over the counter codeine misuse and harm
as small relative to total use and responded
by restricting availability. Pharmacist
supervision was required at the point-of-sale
and pack sizes were reduced to short-term
use.
Comparison with
recommendations by expert
advisory committees in NZ
and the UK suggests the
NDPSC’s actions in
response to over the counter
codeine misuse were
appropriate given the
available evidence of misuse
and harm, but highlights
opportunities to utilise
additional regulatory levers.
Views/ex
perience
on over
the
counter
medicine
use/abus
e
Toxic levels of codeine with potentially lethal
levels of methadone and morphine were
found in the blood
Benzodiazepine levels were insignificant
Paracetamol levels were difficult to interpret
but were compatible with those seen taken
for pain relief
The data in this case may
represent a co-incidence of
poisoning with codeine and
methadone in a case of
acute pancreatitis or may
represent an example of
opiates as the cause of the
pancreatitis. Whether
opiates caused the
pancreatitis or were the
consequence of selfmedication for pain is
impossible to differentiate.
Adverse
health
effects
183
Tormoehl
en et al.
2011,
USA
Vesterga
ard et al.
2006,
Denmark
Wanga et
al. 2013,
USA
This study was
undertaken to
determine the
number and
severity of
prescription
opioid-related
cases in
adolescents
reported to the
Indiana Poison
Center (IPC)
between the years
1994 and 2007.
Fracture risk
associated with
opiates
Retrospective
case series of
opioid
exposures
To (1) describe the
prevalence of
nonmedical use of
prescription
opioids in urban
and rural counties,
(2) determine the
correlates of
nonmedical use of
prescription
opioids
among urban and
rural residents, (3)
describe the
differences
2008–2009
National
Survey on Drug
Use and Health
in USA.
Case control
study
1634
adolescent
opioidrelated
cases with
187 cases
developing
medical
complicatio
ns.
Poisonings,
medical
complicatio
ns and
number of
deaths
1)Calls to the Indiana Poison centre (IPC)
related to adolescent opioid exposures
significantly increased. (OR 1.69) however a
decrease was observed in codeine use)
2)There was an increase in the number of
medical complications related to opioids
noted (n=187)
3) There was also a significant increase in the
number of deaths involving opioids and
adolescents
The increased reported
opioid cases and associated
complications following
JCAHO pain initiative
correlates with increased
drug availability.
All subjects
with any
fracture
sustained
in 2000 on a
nationwide
register (n
= 124,655)
compared
with
matches in
the general
population
(n =
373,962)
75,964
respondent
s
Use of
morphine
or opiates
in subjects
with
fracture
Codeine (1.16, 95% CI 1.12–1.20) was
associated with an increase in overall
fracture risk
No change in risk was seen for combinations
of aspirin and codeine
An increased fracture risk is
seen in users of morphine
and opiates. The reason for
this may be related to the
risk of falls due to central
nervous system effects such
as dizziness.
Injury
Prevalence
of nonmedical use
of
prescription
opioids
3.5% of rural respondents versus 1.9% of
urban respondents admitted to use of
codeine with paracetamol. Urban and rural
residents with severe psychological distress
and nonmedical use of other prescription
medications were more likely to report nonmedical use of opioids. Urban residents
whose first use of illicit drugs was between
the age of 18 and 25 and who reported
alcohol use were more likely to report
nonmedical use. Black and Hispanic urban
residents were less likely to use prescription
opioids non-medically compared to white
urban residents.
Rural residents were more likely than urban
Prevention and treatment
interventions may need to
be tailored for specific
communities.
Prevalenc
e of
nonmedic
al use of
prescripti
on
opioids
Correlates
of use
184
Drug prevention campaigns
should simultaneously
promote awareness of the
dangers of these drugs to
adolescents.
Prevalenc
e of
prescripti
on
opioidrelated
poisonin
g in
adolesce
nts
between urban and
rural residents
who use opioids
nonmedical
and (4) determine
which opioids are
used most
frequently in urban
and rural counties.
residents to use paracetamol with
propoxyphene and
methadone and paracetamol with codeine.
Wairagka
r et al.
1994,
India
To ascertain the
drug use pattern in
both states
(Assam &
Nagaland) and to
assess the
magnitude and
patterns of this
form of drug
abuse.
cross-sectional
study using the
proforma
adopted from
Ministry of
Health and
Family
Welfare's
ICMR- AIIMS
study
Assam 48
cases and
Nagland 49
cases
Consumpti
on based
on
demographi
cs variables
Consumption was dependent on the
concentration of codeine in cough syrups
and brands with a higher concentration and
easy availability seemed to be popular.
Abuse of cough syrups might be due to their
addictive potential, easy availability over the
counter, lesser expenditure involved milder
forms of withdrawals and also due to the
ease in consuming cough syrup without the
need for privacy. Mild forms of physical and
psychiatric disorders were reported
Easy over-the-counter
availability, lesser
expenditure, milder
withdrawals and ease of
consumption without
secrecy were some of the
reasons for the emergence
of this new form of addiction
in Assam and Nagaland.
Addiction
/misuse/
abuse of
over the
counter
medicine
s
Wawruch
et al.
2013,
Slovak
Republic
To evaluate the
perception of the
risk of over the
counter
medications by
elderly patients.
To identify patient
associated
characteristics
which determine
elderly persons
who consider
over the counter
medications as
safe.
54-item
Questionnaire
survey
519
participants
Attitudes to
over the
counter
Majority (75.5 %) of the respondents
considered over the counter medications as
safe. over the counter medicines were used
daily (OR 2.09). Prepared a wide range of
products in pharmacies (OR 2.86).
Considered over the counter medications as
effective OR(10.33). Obtaining information
on over the counter drugs from pharmacists
(OR1.91), willingness to possibly purchase
over the counter medicines outside of
pharmacy (OR0.23).
The survey identified
various factors that
influenced the perceptions
of the safety of over the
counter medications by the
elderly and indicated that
pharmacists represent the
most trusted source of
information about over the
counter medications.
Views/ex
perience
on over
the
counter
medicine
use/abus
e
185
Wazaify
et al.
2006,
Northern
Ireland
Wazaify
et al.
2005,
UK
To test an
intervention model
which sought to
minimise over-thecounter (over the
counter) drug
misuse and abuse
in community
pharmacies
Intervention
study using
motivational
interviewing
and strategies
to promote
health
behaviours
To investigate the
general public’s
opinion and
perceptions of
over the counter
medicines,
including the
misuse/abuse of
such preparations.
Survey using
structured
interview
technique.
6
pharmacist
s in six
community
pharmacies
in the
Greater
Belfast area
1000
members of
the public
in 10 study
sites in
Northern
Ireland
The
intervention
model
consisted
of client
identificatio
n and
recruitment,
treatment
and
referrals,
and finally
follow-up
data
collection
and
outcome
measureme
nts.
Pharmacists identified 196 cases of
suspected abuse/misuse. Pharmacists
approached 70 of the identified clients during
the six month study; some clients agreed to
stop using the product of abuse/misuse,
used an alternative, or had been switched to
a maintenance prescription under general
practitioner (GP) supervision. No client
proceeded to completion of the follow-up
phase
Some difficulties were
encountered in
implementing the harm
minimisation model, but
these may be alleviated by
further training and greater
collaborative working.
Attitudes
towards
community
pharmacy
Attitudes
towards the
use of over
the counter
medicines;
Views on
over the
counter
medicines;
Knowledge
and
opinions of
abuse/misu
se of over
the counter
medicines.
The majority of participants (74.6%) visited a
community pharmacy at least once per
month. Almost one-third (32.2%) of
participants reported buying over the counter
drugs at least once per month and the
majority (86.4%) would always or often follow
the directions on the product. The general
public were highly aware of the abuse
potential of some over the counter drugs,
with the majority naming painkillers as the
products most liable for abuse. Almost one
third of the participants reported having
personally encountered cases of over the
counter abuse.
This survey revealed that the
general public had a high
level of awareness of the
abuse potential of over the
counter medicines. These
findings indicate that
pharmacists could be more
proactive in the
management of
inappropriate over the
counter drug use.
186
Notwithstanding the
challenges faced in the
study, this approach to harm
minimisation should be
considered for wider
implementation in
community pharmacy.
Interventi
on
Misuse of
over the
counter
headache
medicatio
n
(includes
codeine)
Views/ex
perience
on over
the
counter
medicine
use/abus
e
Wilkins
et al.
2011,
New
Zealand
Williams
et al.
2002, UK
To examine the
rates of
pharmaceutical
drug use, and level
of prescription use
and injection of
pharmaceutical
drugs by frequent
injecting drug
users (IDU),
frequent
methamphetamine
users and frequent
ecstasy users in
New
Zealand for 2006–
2009
Treatment of pain
in paediatric
patients after
adenotonnesillecto
my
Review of
findings from
the 2006, 2007,
2008 and 2009
Illicit Drug
Monitoring
System
(IDMS).The
IDMS
interviews used
purposive
sampling and
‘snowballing’.
Three
groups of
frequent
illegal drug
users (i.e.
IDU,
methamphe
tamine
users and
ecstasy
users)
To
determine
usage of
methamphe
tamine,
ecstasy and
drug used
by IDUs.
Pharmaceutical morphine rather than heroin
was the principal opioid used by the IDU. Few
of the IDU or frequent methamphetamine
users had prescriptions to use morphine. The
injection of methadone by IDU and
methamphetamine users was common. All
three groups of frequent drug users were
involved in the extra-medical use of
methylphenidate and benzodiazepines. Some
of the frequent injecting drug users had
prescriptions for codeine (41%) and
benzodiazepines (41%) in 2009.
Extra-medical use of
pharmaceuticals occurred
among all three groups of
frequent illegal drug users to
varying degrees. Differences
between the three groups in
the level and type of extramedical pharmaceutical
drug use suggest that
different control strategies
may be effective for each
group.
Prevalenc
e of
prescripti
on
opioids
use
among
substanc
e misuse
patients
Randomized
double-blind
study
96 children
Plasma
morphine
level
47% of children had genotypes associated
with reduced enzyme
Activity. Mean (SD) morphine concentrations
were significantly lower (P<0.001) after
codeine
[4.5 (0.3) ng ml±1] than after morphine [24.7
(1.5) ng ml±1], and morphine and its
metabolites were not detected in 36% of
children given codeine.
Plasma morphine
concentration 1 h after
codeine is very low, and
related to phenotype.
Therapeu
tic usepaediatric
prescribi
ng & how
effective
is
codeine
in
treating
pain
Concentrati
on of
codeine
and
morphine in
blood
plasma of
neonate
The simulations demonstrated that the
mother’s codeine and morphine clearances
and the neonate’s morphine
clearance are the most critical determinants
of morphine accumulation in the neonate
The results support the
validity of the questions that
have recently been raised
regarding the unmonitored
use of codeine in breastfeeding mothers.
Unmonitored use of codeine
for post-labour pain in
breast-feeding mothers
should not be considered a
safe practice.
Adverse
Health
Effects
Prevalence
of use of
opioids
Opioid prescriptions (12.8%) were most
frequently involved in multiple provider
episodes
Opioids were involved in
multiple providers
prescribing more frequently
Prevalenc
e of
multiple
Willmann
et al.
2009,
Germany
Risk to the BreastFed Neonate From
Codeine Treatment
to the Mother
A Quantitative
Mechanistic
Modelling
Study
Wilsey et
al. 2010,
USA
To determine the
prevalence of
multiple providers
Secondary data
analysis of the
California PMP,
Four wholebody
physiology
–based
pharmacoki
netic
models for
codeine
and
morphine in
mother and
neonate
were used
28,893,404
cases
187
Codeine analgesia is less
reliable than morphine, but
was not well correlated with
either phenotype or plasma
morphine in this study.
Wright et
al. 2007,
UK
Zamparut
ti et al.
2010, UK
for different
controlled
substances
the Controlled
Substance
Utilization
Review and
Evaluation
System
(CURES)
collected
during 2007
Use of
Buprenorphine
versus
dihydrocodeine for
opiate
detoxification
Open label
randomized
controlled trial
To analyse
involvement of
dihydrocodeine in
fatalities that
occurred between
1997 and 2007
among individuals
with a history of
opiate/opioid
Data covering
the period
1997–2007
voluntarily
supplied by
coroners were
analysed.
Benzodiazepines (4.2%), stimulants (1.4%),
and anorectics (0.9%), respectively. The
greatest associations with multiple provider
episodes were simultaneously receiving
prescriptions for different controlled
substances.
60 patients
646 cases
identified
as
dihydrocodei
ne -related
deaths in
This opiate/
Opioid
misusers’
Primary
outcome
was
abstinence
from illicit
opiates at
final
prescription
, during
detoxificati
on and at
three and
six months
post
detoxificati
on as
indicated
by a urine
sample.
Death rates
Only 23% completed the prescribed course of
detoxification medication and gave a urine
sample on collection of their final
prescription. Risk of non-completion of
detoxification was reduced if allocated
buprenorphine (68% vs 88%, RR 0.58 CI 0.35–
0.96, p = 0.065).
than other controlled
substances. The likelihood
of using multiple providers
to obtain one class of
medications was
substantially elevated as
patients received additional
categories of controlled
substances from the same
provider or from multiple
practitioners. Polypharmacy
represents a signal that
requires additional vigilance
to detect the potential
presence of doctor
shopping.
Buprenorphine is superior to
dihydrocodeine for opiate
detoxification.
providers
for
different
controlle
d
substanc
es includes
codeine
Opiate/opioid misusers
should be educated about
risks associated with
polydrug intake and
prescribers should carefully
consider a pharmacological
intervention alternative to
Dihydrocodeine (e.g.
methadone, buprenorphine)
Prevalenc
e of
dihydroco
deine
involvem
ent in
fatalities
of opioid
misusers
Therapeu
tic useadult
prescribi
ng
A higher proportion of people allocated to
buprenorphine provided a clean urine sample
compared with those who received
dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–
3.21, p =0.028) and were more abstinent at
three months (10 vs 4, RR 1.55 CI 0.96–2.52)
and six months post detoxification (7 vs 3,
RR 1.45 CI 0.84–2.49).
Dihydrocodeine, either alone or in
combination, was identified in 584
Fatalities. In 44% of cases it was directly
implicated in the cause of death.
Typical dihydrocodeine cases identified were
White males in their early thirties. Accidental
deaths
(96%) were likely to involve dihydrocodeine
in combination with other psychoactives
188
misuse.
population
mainly heroin/morphine, hypnotics/sedatives
and
methadone.
189
when managing and treating
opiate addiction