Carisoprodol: an underrecognized drug of abuse in north India

Transcription

Carisoprodol: an underrecognized drug of abuse in north India
Available online at www.sciencedirect.com
General Hospital Psychiatry xx (2012) xxx – xxx
Carisoprodol: an underrecognized drug of abuse in north India☆,☆☆
Naresh Nebhinani, M.D., D.N.B. a,⁎, Munish Aggarwal, M.D. b , Surendra Kumar Mattoo, M.D. b ,
Debasish Basu, M.D., D.N.B., M.A.M.S. b
a
b
Department of Psychiatry, Postgraduate Institute Medical Science, Rohtak, Haryana, 124001, India
Department of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh, 160012, India
Received 7 June 2012; accepted 29 July 2012
Abstract
Background: There is limited literature on clinical profile of subjects abusing carisoprodol.
Methods: Our series of 34 subjects shows that a typical subject was an unmarried, unemployed, urban resident from a nuclear family set up;
was a substance abuser before being introduced to carisoprodol by another substance abuser; initiated the use to get a better “kick” and after
regular use reported craving and withdrawal symptoms.
Results: The effect of carisoprodol was dose dependent: a majority reported a feeling of general wellbeing on consuming up to three tablets;
a hypomanic state with 4–10 tablets and confusion, disorientation and drowsiness with N10 tablets at a time.
Conclusion: Thus being an underrecognized drug of abuse, carisoprodol is in need of wider awareness and regulatory measures to prevent its
emergence as a greater menace in the future.
© 2012 Elsevier Inc. All rights reserved.
Keywords: Carisoprodol; Meprobamate; Abuse; Dependence
1. Introduction
Carisoprodol or N-isopropylmeprobamate (brand names
Carisoma and Soma) is a centrally acting muscle relaxant
indicated in acute painful musculoskeletal conditions [1]. It
was developed and promoted as a congener of meprobamate
emphasizing better muscle relaxing properties, lower risk of
overdose, and less potential for abuse [2]. Initially it was
thought to be devoid of abuse potential [2]. However, later
experience has established that it is associated with both
abuse and impairment (i.e., increased risk of automobile
accidents) [3].
It is usually prescribed for administration three times
daily and at night in dosage formulations of 250 and 350 mg
[4]. The onset of action is rapid (about 30 minutes) and the
effects last about 2–6 hours. Metabolized in the liver via the
cytochrome P450 oxidase isozyme CYP2C19, and excreted
☆
Funding: None.
Conflict of interest: None to declare.
⁎ Corresponding author. Tel.: +91 8059434515; fax: +91 01262
211162.
E-mail address: drnaresh_pgi@yahoo.com (N. Nebhinani).
☆☆
0163-8343/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.genhosppsych.2012.07.011
by the kidneys, it has a half-life of about 8 hours. The abuse
potential can be attributed to a considerable proportion being
metabolized to meprobamate, a known drug of abuse and
dependence [5].
Tachycardia, involuntary movements, hand tremor, and
horizontal gaze nystagmus may be specific carisoprodol
intoxication effects [6]. Serotonergic and GABAergic
systems are implicated for some of the symptoms and
signs of carisoprodol intoxications [7]. This may have
implications for the clinical evaluation and treatment of such
intoxications [8].
Recreational users of carisoprodol seek its muscle
relaxing, anxiolytic, and sedating effects. Also, because of
its potentiating effects on narcotics, it is often abused in
conjunction with opioid drugs. Additionally, it is used as
sexual performance enhancer and to prevent withdrawal
among opioid addicted users [9–11]. It is believed that
carisoprodol has gained reputation among drug abusers as an
agent whose use begins as benign substitute for “harder”
drugs and then escalates gradually for its own psychic
effects. The “carry-over” phenomenon of dissemination of
information from one addict to another makes the abuse of
carisoprodol self-sustained. This is said to explain the
2
N. Nebhinani et al. / General Hospital Psychiatry xx (2012) xxx–xxx
spreading popularity of carisoprodol and it getting established as an addictive substance by itself [12].
In India carisoprodol was not considered a problem drug
till recently. In 1999, the Ministry of Social Justice and
Empowerment, Government of India (MSJE, GOI) and the
United Nations International Drug Control Program, Regional
Office for South Asia (UNIDCP, ROSA) started a large scale
national survey for the extent, pattern and magnitude of
substance abuse in India. The National Household Survey
(NHS), a major component of this survey reported the
following nationwide current prevalence profile: Alcohol was
the commonest substance (21.4%), followed by cannabis
(3%) and opioids (0.7%). Drug Abuse Monitoring Survey
(DAMS) component of this survey, obtained from consecutive new patients/treatment seekers contacting various
treatment facilities, again revealed alcohol as the commonest
substance (43.9%), followed by opioids (26%) and cannabis
(11.6%). Possibly because it was not listed in any of the
survey forms that were to be filled by the data collectors,
carisoprodol abuse was not reported by this survey [13].
However, all over the world in the past 2 decades, concern
among the medical professionals about the abuse of
carisoprodol has increased steadily [9–12,14–24]. Most of
this literature consists of case reports of single or few cases
with abuse or dependence [9,10,12,14–20]; in the last
decade, a few reviews have been added [11,21,22].
Sikdar et al. [12] mentioned dose-related variable effects,
i.e., 1–3 tablets (each tablet of 350 mg), general relaxation
and drowsiness; 4–10 tablets, hypomania and N10 tablets,
acute organic brain syndrome-like state.
Resultantly it is schedule IV controlled substance in
several European countries [25,26] and since January
2012 in the US, too; but in India, carisoprodol is still
freely available in the drug stores. This is mainly because
it is not listed in Narcotic Drug Psychotropic Substance
Act [27], as under this act, it is illegal for a person to
produce/manufacture/cultivate, possess, sell, purchase,
transport, store and consume the listed narcotic drug or
psychotropic substance.
Data about therapeutic, toxic and withdrawal effects of
carisoprodol intake in Indian setting are limited. The present
research aimed to study the sociodemographic and clinical
profile of subjects abusing carisoprodol.
2. Methodology
The study was conducted at the Drug De-addiction and
Treatment Centre (DDTC) of a multispecialty tertiary-care
teaching hospital providing services to a major area of north
India. Most patients came by family or self-referral, and
some were referred from other hospitals or other departments
of our Institute.
The study was approved by the institutional research
ethics committee. Patients reporting carisoprodol use were
recruited consecutively from the patients who attended the
DDTC between May 2010 and December 2011 (20 months).
The data intake were done by N.N. Diagnosis of substance
dependence was made by a consultant psychiatrist as per
ICD-10 [28].
A written informed consent was obtained from the
patients taken up for the study. The inclusion criteria were
patients who were using carisoprodol and gave informed
consent for participation in the study; thus, those not using
carisoprodol or not consenting were excluded from the
study. An open-ended clinical interview was conducted to
obtain the data on demographics and substance use,
including carisoprodol.
2.1. Measures
Demographic form: it was used to record sex, age, mean
years of education, occupation, marital status, religion,
family and locality.
Clinical Form: specially developed for the study, it was
used to collect information regarding ages of initiating any
substance and carisoprodol, durations of carisoprodol use
and dependence, onset and duration of carisoprodol action,
dose and frequency of carisoprodol intake, source and reason
of initiating carisoprodol, and carisoprodol related craving,
tolerance, withdrawal, intoxication, harmful use etc.
2.2. Data analysis
The data were analyzed using SPSS version 14.0 for
Windows (Chicago, IL, USA). Descriptive data were
analyzed by percentage, mean, and standard deviation.
3. Result
Between May 2010 and December 2011 a total 3202
patients were registered in the DDTC and out of them 34
patients (nearly 1%) were using carisoprodol. All carisoprodol using patients were male with mean age of 27 years and
formal education of 12 years. Majority were single (67%),
from urban (70%), nuclear family (58%) and unemployed
and Sikh by religion (55% each) (Table 1).
As mentioned in Table 2, most of the patients started
using any substance at age 18 years, took nearly 5 years to
start carisoprodol (23.5 years) and reported to us after
another 5 years (including 3.6 years of using carisoprodol in
a dependent pattern). Majority were also using opioids (88%;
mainly heroin and dextropropoxyphene), and nearly half
were using one or another form of tobacco (55.9%); while
alcohol (17.6%), cannabis (17.6%) and sedatives (8.8%)
remained less common substances.
Most of the patients were introduced to carisoprodol by
friends or co-addicts (88.2%). Majority (70%) were using up
to 10 tablets in a day (3500 mg) in two to three divided doses.
Majority were taking carisoprodol to get better ‘kick’ (58%)
or to combat withdrawal of mainly opioids (32%) or just out
N. Nebhinani et al. / General Hospital Psychiatry xx (2012) xxx–xxx
Table 1
Sociodemographic profile
Variable
Frequency/mean (S.D.)
Age (y)
Education (y)
Marital status
Single
Married
Occupational status
Working
Not working
Religion
Hindu
Sikh
Family type
Nuclear
Extended/joint
Locality
Urban
Rural
27 (5.9)
12.38 (2.32)
23 (67.6)
11 (32.4)
15 (44.1)
19 (55.9)
15 (44.1)
19 (55.9)
20 (58.8)
14 (41.2)
24 (70.6)
10 (29.4)
of curiosity (8.8%). Majority reported craving (97%) and
tolerance (85%) for carisoprodol.
Most of the subjects reported dose-dependent effects of
carisoprodol. Consumption of one to three tablets produced a
feeling of general wellbeing and feeling energetic, while
consumption of 4–10 tablets produced a hypomanic state
3
characterized by overcheerfulness, psychomotor excitement,
increased socialization and self-confidence. Higher one-time
dose (N10 tablets) produced an acute organic brain
syndrome-like state with confusion, disorientation, and
partial amnesia for the events during such intake. Increased
energy and pleasurable effects at all doses and escalating
with dose increase were reported by 5 subjects (14.7%).
Acute confusional state at relatively lower doses (seven to
eight tablets) was reported by four subjects (11.8%).
More than two thirds of subjects (70%) reported one or
another form of withdrawal symptoms; the commonest being
restlessness (35%), followed by weakness/reduced energy
(23%), aches and pains (20.5%), irritability (20%), reduced
sleep (17.6%), lack of pleasure (11.7%), drowsiness (5.8%),
watery stools (5.8%) and reduced appetite (2.9%).
Half of the subjects reported harmful use of carisoprodol
(50%), though only minority (11.8%) had shifted to
carisoprodol as the preferred substance. Also, less than half
reported history of intoxication (41%) with the commonest
manifestations being in the form of gait disturbance (35%),
followed by tremors (32%), speech impairment (26%),
impaired consciousness (26%), impaired vision (11.7%) and
nystagmus (8.8%). Most of subjects (91%) knew other
persons in the community who were using carisoprodol.
4. Discussion
Table 2
Carisoprodol related details
Variable
Frequency/ Mean (SD)
Age of initiating any substance (years)
Age of initiating carisoprodol (years)
Duration of carisoprodol use (years)
Duration of carisoprodol dependence (years)
Onset of carisoprodol action (minutes)
Duration of action of carisoprodol (hours)
Dose of carisoprodol (daily)
Up to 5 tabs
6–10 tabs
N10 tabs
Frequency of carisoprodol
N4 times/day
2–3 times/day
Once daily
Once a week
Introduced by
Friends/co-addicts
Local chemist
Reason for initiation
To combat the withdrawal
To get better kick
Curiosity
Craving-present
Tolerance-present
Withdrawal symptoms, present
Intoxication, present
Impaired control, present
Harmful use, present
Shift to carisoprodol as the preferred substance
Knowledge of other person taking carisoprodol
Carisoprodol current use, present
18.85 (5.7)
23.55 (4.9)
5.13 (5.33) [median-2.75]
3.69 (4.5) [median-1.5]
14.44 (7.09)
3.70 (2.22)
10 (29.4)
14 (41.2)
10 (29.4)
5 (14.7)
22 (64.7)
5 (14.7)
2 (5.9)
30 (88.2)
4 (11.8)
11 (32.4)
20 (58.8)
3 (8.8)
33 (97.1)
29 (85.3)
24 (70.6)
14 (41.2)
24 (70.6)
17 (50)
4 (11.8)
31 (91.2)
32 (94.1)
A typical study subject was a young male, single, school
educated and from an urban nuclear family. Majority were
introduced to carisoprodol by friend/co-addicts. They
initiated carisoprodol to get a better “high” from their preexisting opioid and tobacco use. However, later they
experienced the distinct reinforcing effect of carisoprodol
and gradually became also dependent on it.
Carisoprodol has been reported to have tolerance and
antagonist-precipitated withdrawal, suggesting it may have
an addiction potential similar to benzodiazepine or barbiturate compounds [29]. Similar to earlier case reports/series
[9,14,19] we also found frequent withdrawal symptoms and
toxic effects with carisoprodol. While one study reported
seizures in one-forth of sample [20], none of our subjects
reported seizure, respiratory depression and coma. Similarly,
none of our subjects reported withdrawal delirium as
reported by one earlier study at discontinuing a high dose
of 10.5 g [23].
Similar to an earlier study [30], majority of our patients
(88%) were also abusing opioids in addition to carisoprodol.
Due to lack of facilities, we did not analyze drug and
metabolites in body fluids [20,31], which would have
confirmed the use of carisoprodol and other substances.
In comparison to the earlier study from our centre [12], the
present study was a prospective one, covered a 20 month
period (vs. postal contact with 15 years period patient pool)
and a larger sample size (34 vs. 16), reported a higher mean
age (27 vs. 24 years) and education (12.3 vs. 10 years), a
4
N. Nebhinani et al. / General Hospital Psychiatry xx (2012) xxx–xxx
higher age of initiating substance abuse (18.8 vs. 17 years), a
longer period for shifting from initial drug abuse to
carisoprodol intake (4.5 vs. 3.5 years), and a longer period
of carisoprodol intake (61 vs. 33 months). Also in comparison
to our previous study [12] the most common initiator to
carisoprodol intake was co-addicts (vs. local chemist), and
the most common reason for initiating carisoprodol was for
better “kick” (vs. to combat aches). Dose-dependent effect
(general wellbeing→ hypomania→confusional state) and
craving, tolerance, toxic and withdrawal (physical and
psychological) effects were common to our two studies [12].
The results of the present study must be seen within its
limitations. The sample size was small, and it was conducted
at a single site; hence, the results can't be generalized to other
primary care and community settings. The information
collected by patients' self-reports raises the possibility of
individual patients over-/under-reporting; however, selfreports of substance users are said to be fairly acceptable [32].
Most of the available literature on carisoprodol users is
based on those who were co-using other substances. Hence,
the future research on carisoprodol should investigate the
specific clinical manifestations of carisoprodol as a standalone drug. It would also be important to study the genetic
variability of the CYP2C19 liver enzyme and neurobiological basis of any specific carisoprodol effects.
The reporting by many of our subjects of other persons
in community using carisoprodol is indicative of the
actual community prevalence being much higher compared to the much smaller “tip of the iceberg” seen in the
clinics. This makes carisoprodol an underrecognized drug
of abuse and reflects a need for increasing awareness and
regulatory measures.
References
[1] Harveys C. Hypnotics and sedatives. In: Gilman AG, Goodman LS,
Rall TW, Murad F, editors. Goodman and Gilman's the pharmacological basis of therapeutics. New York: Macmillan; 1985,
pp. 364–5.
[2] Berger F, Kletzkin M, Ludwig B, Margolin S. The history, chemistry,
and pharmacology of carisoprodol. Ann N Y Acad Sci
1959;86:90–07.
[3] Fraser HF. Evaluation of carisoprodol and phenyramidol for addictiveness. Bull Narc 1961;13:3–7.
[4] Zacny JP, Paice JA, Coalson DW. Characterizing the subjective and
psychomotor effects of carisoprodol in healthy volunteers. Pharmacol
Biochem Behav 2011;100:138–43.
[5] Olsen H, Koppang E, Alvan G, Mørland J. Carisoprodol elimination in
humans. Ther Drug Monit 1995;16:337–40.
[6] Bramness JG, Skurtveit S, Mørland J. Impairment due to intake of
carisoprodol. Drug Alcohol Depend 2004;74:311–8.
[7] Gonzalez LA, Gatch MA, Taylor CM, Bell-Horner CL, Forster MJ,
Dillon GH. Carisoprodol-mediated modulation of GABAA receptors:
in vitro and in vivo studies. J Pharmacol & Exp Ther 2009;329:
827–37.
[8] Bramness JG, Mørland J, Sørlid HK, Rudberg N, Jacobsen D.
Carisoprodol intoxications and serotonergic features. Clin Toxicol
(Phila) 2005;43:39–45.
[9] Reeves RR, Carter OS. Use of carisoprodol by substance abusers to
modify the effects of illicit drugs. South Med J 1999;92:441.
[10] Reeves RR, Carter O, Pinkofsky HB, Struve FA, Bennett DM.
Carisoprodol (Soma): abuse potential and physician awareness. J Addict
Dis 1999;18:51–6.
[11] Reeves RR, Liberto V. Abuse of combinations of carisoprodol and
tramadol. South Med J 2001;94:512–4.
[12] Sikdar S, Basu D, Malhotra AK, Varma VK, Mattoo SK. Carisoprodol
abuse: a report from India. Acta Psychiatr Scand 1993;88:302–3.
[13] Pal HR, Kumar A. Epidemiology of substance use. In: Lal R, editor.
Substance use disorder: Manual for Physicians. 1st ed. New Delhi:
National Drug Dependence Centre, All India Institute of Medical
Science; 2005, pp. 9–14.
[14] Mose RM, Chua L. Carisoprodol dependence: a case report. Am J
Drug Alcohol Abuse 1978;5:527–30.
[15] Luehr JG, Meyerle KA, Larson EW. Mail-order (veterinary) drug
dependence. JAMA 1990;263:657.
[16] Elder NC. Abuse of skeletal muscle relaxants. Am Fam Physician
1991;44:1223–6.
[17] Wyller TB, Korsmo G, Gadeholt G. Dependence on carisoprodol
(Somadril)? A prospective withdrawal study among prisoners. Tidsskr
Nor Laegeforen 1991;111:193–5.
[18] Rust GS, Hatch R, Gums JG. Carisoprodol as a drug of abuse. Arch
Fam Med 1993;2:429–32.
[19] Reeves RR, Pinkofsky HB, Carter OS. Carisoprodol: a drug of
continuing abuse. J Am Osteopath Assoc 1997;97:723–4.
[20] Bailey DN, Briggs JR. Carisoprodol: an unrecognized drug of abuse.
Am J Clin Pathol 2002;117:396–400.
[21] Reeves RR, Parker JD. Somatic dysfunction during carisoprodol
cessation: evidence for a carisoprodol withdrawal syndrome. J Am
Osteopath Assoc 2003;103:75–80.
[22] Logan BK, Case GA, Gordon AM. Carisoprodol, meprobamate, and
driving impairment. J Forensic Sci 2000;45:619–23.
[23] Ni K, Cary M, Zarkowski P. Carisoprodol withdrawal induced
delirium: a case study. Neuropsychiatr Dis Treat 2007;3:679–82.
[24] Rohatgi G, Rissmiller DJ, Gorman JM. Treatment of carisoprodol
dependence: a case report. J Psychiatr Pract 2005;11:347–52.
[25] Reeves RR, Burke RS. Is it time for carisoprodol to become a
controlled substance at the federal level? South Med J 2008;101:
127–8.
[26] Reeves RR, Burke RS. Carisoprodol: abuse potential and withdrawal
syndrome. Curr Drug Abuse Rev 2010;3:33–8.
[27] Government of India, Ministry of Law and Justice. Narcotic Drugs and
Psychotropic Substances Act, 1985. New Delhi: Controller of
Publications; 1985.
[28] World Health Organization. The ICD-10 Classification of Mental and
Behavioural Disorders — clinical descriptions and diagnostic
guidelines. Geneva: WHO; 1992.
[29] Gatch MB, Nguyen JD, Carbonaro T, Forster MJ. Carisoprodol
tolerance and precipitated withdrawal. Drug Alcohol Depend 2012;
123:29–34.
[30] Bramness JG, Furu K, Engeland A, Skurtveit S. Carisoprodol use and
abuse in Norway. A pharmacoepidemiological study. Br J Clin
Pharmacology 2007;64:210–8.
[31] Backer RC, Zumwalt R, Mcfeeley P, Veasev S, Wohlenberg N.
Carisoprodol concentrations from different anatomical sites: three
overdose cases. J Anal Toxicol 1990;14:332–4.
[32] Darke S. Self-report among injecting drug users: a review. Drug
Alcohol Depend 1998;51:253–63.