Disclosures Learning Objectives - American Pharmacists Association

Transcription

Resisting Temptation: Can AbuseDeterrent Formulations Curb Opioid
Abuse?
Disclosures
• Dr. Keast declares no conflicts of interest, real or apparent, and no financial
interests in any company, product, or service mentioned in this program,
including grants, employment, gifts, stock holdings, and honoraria.
• Dr. Fudin declares the following
Shellie Keast, PharmD, PhD
Assistant Professor
University of Oklahoma College of Pharmacy
Pharmacy Management Consultants
• Kaléo (Speakers Bureau, Advisory
Board)
• KemPharm (Consultant)
• Millennium Health, LLC (Speakers
Bureau)
Jeffrey Fudin, PharmD, DAAPM, FCCP, FASHP
Clinical Pharmacy Specialist & PGY2 Pain Residency Director;
Stratton VA Medical Center
•
•
•
•
Remitigate, LLC (Founder, Owner)
Scilex Pharmaceuticals (Consultant)
Zogenix (Consultant)
Faculty (PainWeek; PainWeekEnds)
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.
Adjunct Affiliations; Albany College of Pharmacy & Health Sciences,
Western New England University, UCONN School of Pharmacy
1
2
Learning Objectives
• Target Audience: Pharmacists
1. Explain how altering opioid formulations for abuse affects
• ACPE#: 0202-0000-16-072-L01-P
2. Compare and contrast tamper-deterrent opioid formulations
their kinetics and increases overdose risks
and other pharmacological approaches to deter abuse
3. Describe validated risk assessment tool applicability for
• Activity Type: Knowledge-based
4.
5.
employing universal precautions and how this could apply to
tamper-deterrent preference
Describe national and state efforts to curb abuse and misuse
Describe issues surrounding the selection of tamperresistant products for individual patients
3
Which of the following factors does not influence the
likability of opioids for abuse?
A.
B.
C.
D.
Embeda and Suboxone are examples of which type of
approach to abuse-deterrent formulations (ADFs)?
Media attention
High first-pass metabolism
Tampering susceptibility
Peer preferences
A.
B.
C.
D.
5
© 2016 by the American Pharmacists Association. All rights reserved.
4
Physical barrier
Viscosity management
Sequestered antagonist
Aversion agent
6
What 2 pharmacokinetic properties are exploited to
increase abuse potential?
Which of the following national organizations have
developed plans to curb misuse of prescription opioids?
A. Half-life and elimination factor
B. Maximum plasma concentration and time to peak
concentration
C. Receptor binding affinity and excretion factor
D. Enzyme degradation and pro-drug metabolism
A. Center for Disease Control and Prevention
B. Center for Medicare and Medicaid Services
C. Office of the President
D. All of the above
7
8
Which of the following characteristics is NOT associated
with high nonmedical opioid use or use disorders?
A.
B.
C.
D.
Sedative use disorder
Disabled for work
Private insurance
Depression
Introduction
Current State of Prescription Drug Abuse
Epidemic
Dr. Shellie Keast
9
The Prescription Drug Abuse
Epidemic
10
Nonmedical Use of Pain Relievers
(NMPR)
• 4.3 million used prescription pain relievers for nonmedical
•
•
Source: National Institute on Drug Abuse; National Institutes of Health;
U.S. Department of Health and Human Services.
11
purposes (1.6% of population)1
Use has decreased from 2002, but plateaued beginning in
20131
Marijuana, prescription pain relievers, and cocaine remain
the main issues of concern1,2
12
National Overdose Deaths
Heroin Use
•
•
•
•
•
•
460 people aged 12 or over start using heroin every day
Mortality has increased since 2000
Use remains below 0.3% of the 12 or over population2
Strong association between NMPR and past year initiation
of heroin
Recent use of heroin was 19 times higher for those with
NMPR use
Although gateway theory is supported, most NMPR users
do not progress to heroin use3
Number of Deaths from Prescription
Opioid Pain Relievers
20,000
18,000
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
0
Total
Female
Male
Source: National Center for Health Statistics, CDC Wonder
13
National Overdose Deaths
Abuse-Deterrent Formulations
Number of Deaths from Heroin
12,000
Total
Female
14
• Food and Drug Administration (FDA) Guidance to Industry4
• Considers development of products with abuse-deterrent
Male
10,000
properties a priority
• Products with properties that “meaningfully deter abuse”
8,000
through non-oral routes
6,000
• Full prevention of abuse is not a requirement
4,000
2,000
0
Source: National Center for Health Statistics, CDC Wonder
15
16
References (for Introduction slides)
1.
2.
3.
4.
Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States:
Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927,
NSDUH Series H-50). Retrieved from http://www.samhsa.gov/data/.
R.N. Lipari and A. Hughes. The NSDUH Report: Trends in Heroin Use in the United States: 2002 to 2013.
(2015). Substance Abuse and Mental Health Services Administration, Center for Behavioral Health
Statistics and Quality. Rockville, MD.
Muhuri PK, Gfroerer JC, Davies MC. (2013, August). CBHSQ Data Review: Associations of nonmedical
pain reliever use and initiation of heroin use in the United States. Rockville, MD: Substance Abuse and
Mental Health Services Administration, Center for Behavioral Health Statistics and Quality.
U.S. Food and Drug Administration. Abuse-deterrent opioids - evaluation and labeling. Guidance for
industry. April 2015.
Risk Assessment
Validated Risk Tools and Monitoring
Dr. Jeffrey Fudin
17
18
Risk
Question Indications
Assessment Formats
Tools
Risk Assessment Tool
• Why is it important to assess risks?
Advantages
Disadvant Scoring
ages
Validated
SOAPP1
5, 14, 24
1° Care, Assess for
high abuse risk,
suitability for long
term opioid tx,
preferable to ORT in
high-risk
populations
Best
psychometrics,
less susceptible
to deception, 5-10
minutes
Dependent on
patient
reporting,
Copyrighted
Numeric, simple
to interpret
Yes, 14 quest ion
studied in 396
pts
SOAPP-R2
24
Primary Care
5 minutes, Crossvalidated, Less
susceptible to
overt deception
c/t SOAPP
Less sensitive
and less
specific than
SOAPP
Numeric, simple
to interpret
Yes, 283 pts
ORT3
5
Categorizes
patients as low risk,
moderate risk, and
high risk
Less than 1
minute, simple
scoring, high
sensitivity &
specificity when
stratifying
patients
1 question in
the ORT is
limited by
patient’s
knowledge of
family history
of substance
abuse
Numeric, simple
to interpret
Yes, (male and
female),
Preliminary
Validation in 185
patients at 1 pain
clinic, high
degree of
sensitivity and
specificity
DIRE4
7, by pt
interview
risk of opioid abuse
and suitability of
candidates for long
term opioid therapy
2 minutes, score
correlates well
with patient’s
compliance&
efficacy of long
term opioid
therapy
Prospective
validation
needed
Numeric, simple
to interpret
?, Retrospective
validation only
of 61 pts over 38
months
– Safety
– Public health (diversion, death, naloxone access)
• What are the risks?
– Drug interactions (anticipated and unanticipated)
– Aberrant behaviors and UNIVERAL PRECAUTIONS
• Collaboration with Clinics/providers
– Role of the pharmacist (clinic and community)
• Assess risk, patient monitoring, UDT, community outreach,
in-home naloxone qualification
• Opioid Risk Stratification Tools Summarized (next slide)
– Available at http://paindr.com/wp-content/uploads/2012/05/Riskstratification-tools-summarized_tables.pdf
19
Opioid
Misuse
Tools
Question
Formats
Indications
Advantages
Disadvan Scoring
tages
N/A
To streamline the
assessment of
outcomes in
patients with
chronic pain, 2
sided chart note
based on 4-A’s*
5 minutes,
Documents
progress over
time,
Complements a
comprehensive
clinical evaluation
Not intended
to be
predictive of
drug-seeking
behavior or
predict
positive or
negative
outcomes to
opioid therapy
PADT5
17
COMM6
20 questions
ABC7
N/A
Validated
Further studies
needed to
confirm the
reliability and
validity, Studied
in 388 patients
by 27 clinician
1.
J Pain Symptom Manage 2006;32:287–93
2.
J Pain. 2008 April; 9 (4): 360-372
3.
Pain Med 2005;6:432–42
4.
J Pain 2006;7:671–81
20
Street Value Perspective
• 120 Percocet 5/325 (brand name)
• $600.00
• 120 Lortab 10/500 (any brand)
• $600.00
To assess
aberrant
medication
related behaviors
of chronic pain
patients
10 minutes,
Useful in
assessing &
reassessing
adherence to
opioid RX(s)
Long term
reliability is
unknown
Numeric
Ongoing clinical
assessment of
chronic pain
patients on
opioid therapies
Concise and easy
to score
Studied in the VA
setting
Needs
validation in
non-VA
setting.
Score of ≥3
indicates
possible
inappropriate
opioid based on
Y/N answers
222 pts, Long
term reliability is
unknown,
Validated in
small study,
needs to be
replicated
Studied 136
veterans in a
multidisciplinary
VA Chronic Pain
Clinic
5. Clin Ther 2004; 26:552–61
6. Pain. 2007 July; 130(1‐2):144‐156 7. J Pain Symptom Manage 2006;32:342‐351 21
• 60 Oxycontin 80mg
• $1500.00
• 120 Actiq Lollipop 200mcg
• $3240.00
• Knowing when your patient is diverting drug…
• PRICELESS!
http://streetrx.com/
22
Do you sell these?
https://www.google.com/webhp?tab=mw&ei=k2dtVpTdOoHZyAOAibT
YDw&ved=0EKkuCAQoAQ#q=urine+drug+screen+kit+cvs
23
The Clean Whiz Kit
(http://www.youtube.com/watch?v=91knqnsu_hU)
24
Urine Drug Testing (UDT) Rationale
Urine Drug Testing (UDT) Rationale
• Supports justification for closer monitoring
• Guidelines recommend UDT as standard of care when (more frequent visits / lab monitoring)
•
prescribing chronic opioid therapy, especially for CNCP1‐5
• Helps to ensure compliance and mitigate risk1‐5
Supports behavior modification and referral to
psychologist
• Detects presence of illicit substances
• Detects absence of prescribed medication
Potential Pitfalls6-8
• Helps to justify continual prescriptions
• Patient reliability to report compliance, use and misuse is
• Supports clinician decision to discontinue controlled substance dubious and often poor
• Behavior alone is unreliable for identifying patients at risk
medication non-compliance, abuse, misuse, and diversion
25
References (for UDT slides)
26
Types of Urine Drug Testing
1. Chou R, Fanciullo G, Fine P et al. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic
Noncancer Pain. American Pain Society & American Academy of Pain Medicine Opioids Guideline Panel.
Pain. 2009; 10(2):113-130.
2. Gourlay DL, Heit HA, Caplan YH. Urine Drug Testing in Clinical Practice: the Art and Science of Patient
Care. 2010. Stamford, CT: PharmaCom Group, Inc.
3. Federation of State Medical Boards of the United States. Model Policy for the Use of Controlled
Substances for the Treatment of Pain. J Pain & Palliative Care Pharmacotherapy. 2005; 19(2):73-78.
4. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP)
Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part 2-Guidance. Pain
Physician. 2012; 15:S67-S116.
5. VA/DoD. Clinical Practice Guideline For Management of Opioid Therapy For Chronic Pain. 2010. [Online]
Published May 2010. Accessed March 26, 2014. Available at
http://www.va.gov/painmanagement/docs/cpg_opioidtherapy_fulltext.pdf
6. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self-reported drug use in chronic pain
patients. Clin J Pain 1999;15:184-191.2.
7. Berndt S, Maier C, Schultz HW. Polymedication and medication compliance in patients with chronic
nonmalignant pain. Pain 1993;52:331-339j.
8. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients
receiving long-term opioid therapy. Anesth Analg 2003;97:1097-1102.
Immune Assay (IA)
•
•
•
•
•
•
•
In office or send out
Inexpensive
Results are quick (minutes)
Helps for initial detection
False negatives/positives
False patient accusations
Easier for pts to manipulate
low sensitivity, esp w/ synthetics
• Presence/absence of RX class
only
• No option for synthetics,
designer drugs, and unique
natural products
Chromatography
•
•
•
•
•
•
•
Usually send-out
More expensive
24 hours to 1 week (per lab)
Final result
Definitive testing
Justifies RX decisions
99.999 percent reliability
high sensitivity
• Presence/absence of RX
metabolites
• Custom option for synthetics,
designer drugs, and unique
natural products
27
Phenyl-Propylamines
Opioid Chemistry and Cross-sensitivity
Paindr.com; RESOURCES TAB; Opioid Chemistry
28
29
Paindr.com; RESOURCES TAB; Opioid Chemistry
30
Fudin J. Interview: New App Helps Interpret Urine Drug Test
Results. Practical Pain Management. 2015 July/Aug; 15(6); 84-87.
31
32
Mr. Bad Urine Test
Ms. Dedicated LPN
Dr. Smith
Positive amphetamine is plausible because I am prescribing carbidopa which Unitel lists as false positive. The patient may be taking an unprescribed opioid and benzodiazepine, as indicated by Urintel below. The other unexpected results are possible because of prescribed medications.
33
Printout
35
34
Printout continued
36
Recent National Efforts to Curb
Misuse
• 2010 – First abuse-deterrent opioid introduced (oxycodone
Efforts to Curb
Misuse
extended-release)
• 2011 – Obama Administration detailed a response to the
drug abuse crisis1
• 2012 – CMS issues strategies to reduce diversion in
Medicaid2
Recent National and State Efforts
Dr. Shellie Keast
• 2013 – FDA required changes to long-acting and extended
release opioid pain medications and released draft
guidance on abuse-deterrent opioids3
37
Recent National Efforts to Curb
Misuse, Cont.
State Efforts
• 2015 – Issues final guidance to industry regarding abuse•
•
38
deterrent opioids4
2015 – Obama Administration announced new steps to
increase access to drug treatment5
2015 – CDC launches Prescription Drug Overdose:
Prevention for states6
• States have also initiated efforts to curb abuse
• Kentucky enacted a strict mandate for PDMP (2012)
• Massachusetts developed a comprehensive strategy to
end opioid abuse (2014)
• Arizona issued opioid prescribing guidelines (2014)
• Wisconsin begins “Dose of Reality” media campaign
(2015)
• The list goes on…..
39
40
Research on Effect of AbuseDeterrent Opioids
Oklahoma’s History
• Medicaid policies to curb abuse and misuse7:
• Largely centered around oxycodone extended-release8-17
• Changes in use of oxycodone extended-release after
– 2003 to 2015: 13 unique policies implemented
– Various levels of success
release of new formulation18
• Governor's task on prescription opioid abuse (2012)
• Senate study on opioids with abuse-deterrent properties
–
–
–
–
(2015)
• General agreement that solution requires collaborative
Decrease from 46% to 26% in past-month use in first year
33% of abuser of original formulation continued to abuse new
33% of abusers of original changed drugs
5% indicated new influenced decision to stop abusing drugs
• Most who continued abusing either changed to oral route
effort between state agencies and communities
or defeated the abuse-deterrent mechanism
• 70% who switched drugs turned to heroin
41
42
• Introduction of new formulation of oxycodone extended-
• Han and colleagues18:
•
release resulted in reduced sales, but did not result in a
statistically significant change in overall opioid market3
Hwang and colleagues13:
– Percentage of nonmedical use of prescription opioids decreased
– High-risk measures increased
– No decreases in intensity outcomes from 2011 to 2013
• “Until we deal with the demand side of the epidemic, we
– Large portion of opioid abusers use oral route which abusedeterrent opioids do not effect
– New agents may cause practitioners to have a false sense of
security in prescribing new formulations
will still see use of these drugs in inappropriate ways.”8
43
44
12-Month Summary of Costs per
Enrollee in US dollars: Median (IQR)
• Review of oxycodone extended-release, plus
•
•
•
Generic
(N=541)
hydromorphone* and oxymorphone* with additional
deterrent properties, in Oklahoma Medicaid
Overall total healthcare costs higher in users of newer
formulations, no decrease in medical expenditures, with
increase in prescription expenditures
No difference in emergency department visits
More opioid prescriptions filled for users of new
formulations
Rx Costs
$3,854 (5,097)
New
Formulations
(N=397)
$12,167 (10,745)
Opioid Rx Costs
$1,532 (1,747)
$9,922 (7,138)
$9,306 (17,187)
$10,015 (19,622)
0.38
$15,043 (22,996) $24,979 (34,971)
<0.01
Medical Costs
Healthcare
Costs
p-value
<0.01
<0.01
*Not considered abuse-deterrent by FDA
Keast S, Owora A, Nesser N , Farmer K. Evaluation of abuse-deterrent or tamper
resistant opioid formulations on overall healthcare expenditures in a state Medicaid
program. In Press JMCP.
45
Keast S, Owora A, Nesser N , Farmer K. Evaluation of abuse-deterrent or tamper
resistant opioid formulations on overall healthcare expenditures in a state Medicaid
program. In Press JMCP.
46
References (for Efforts to Curb Misuse slides)
References (for Efforts to Curb Misuse slides)
1.
2.
11. Cassidy TA, DasMahapatra P, Black RA, Wieman MS, Butler SF. Changes in prevalence of prescription
opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med;2014 Mar;15:440-51.
12. Sessler NE, Downing JM, Kale H, Chilcoat HD, Baumgartner TF, Coplan PM. Reductions in reported
deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent
formulation. Pharmacoepidemiology and Drug Safety 2014;23:1238-46.
13. Hwang CS, Chang H-Y, Alexander GC. Impact of abuse-deterrent OxyContin on prescription opioid
utilization. Pharmacoepidemiology and Drug Safety 2015;24:197-204.
14. Severtson SG, Bartelson BB, Davis JM, et al. Reduced Abuse, Therapeutic Errors, and Diversion
Following Reformulation of Extended-Release Oxycodone in 2010. The Journal of Pain 2013;14:1122-30.
15. Butler SF, Cassidy TA, Chilcoat H, et al. Abuse Rates and Routes of Administration of Reformulated
Extended-Release Oxycodone: Initial Findings From a Sentinel Surveillance Sample of Individuals
Assessed for Substance Abuse Treatment. The Journal of Pain 2013;14:351-8.
16. Coplan PM, Kale H, Sandstrom L, Landau C, Chilcoat HD. Changes in oxycodone and heroin exposures
in the National Poison Data System after introduction of extended-release oxycodone with abusedeterrent characteristics. Pharmacoepidemiol Drug Saf;2013 Dec;22:1274-82.
17. Winegarden W. Estimating the Net Economic Benefit of Abuse-Deterrent Opioids: EconoSTATS at
George Mason University; 2015 March 2015.
18. Cicero TJ, Ellis MS. Anticipated and unanticipated consequences of abuse deterrent formulations of
opioid analgesics. Pharmacoepidemiology and Drug Safety 2014.
19. Han B, Compton WM, Jones CM, Cai R. Nonmedical prescription opioid use and use disorders among
adults aged 18 through 64 years in the united states, 2003-2013. JAMA 2015;314:1468-78.
Office of the President. Epidemic: responding to America's prescription drug abuse crisis. 2011.
Drug Diversion in the Medicaid Program State Strategies for Reducing Prescription Drug Diversion in
Medicaid. In: Center for Medicare and Medicaid Services; 2012.
3. FDA announces safety labeling changes and postmarket study requirements for extended-release and
long-acting opioid analgesics. 2013. (Accessed November 25, 2015, at
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm367726.htm.)
4. U.S. Food and Drug Administration. Abuse-deterrent opioids - evaluation and labeling. Guidance for
industry. April 2015.
5. FACT SHEET: Obama Administration Announces Public and Private Sector Efforts to Address
Prescription Drug Abuse and Heroin Use
6. Centers for Disease Control and Prevention. Prescription Drug Overdose Prevention for States.
(Accessed November 25, 2015 at http://www.cdc.gov/drugoverdose/states/state_prevention.html.)
7. Keast SL, Nesser N, Farmer K. Strategies aimed at controlling misuse and abuse of opioid prescription
medications in a state Medicaid program: a policymaker's perspective. Am J Drug Alcohol Abuse
2015;41(1):1-6.
8. Rossiter LF, Kirson NY, Shei A, et al. Medical cost savings associated with an extended-release opioid
with abuse-deterrent technology in the US. Journal of Medical Economics 2014;17:279-87.
9. Cicero TJ, Ellis MS. Abuse-deterrent formulations and the prescription opioid abuse epidemic in the united
states: Lessons learned from oxycontin. JAMA Psychiatry 2015.
10. Havens JR, Leukefeld CG, DeVeaugh-Geiss AM, Coplan P, Chilcoat HD. The impact of a reformulation of
extended-release oxycodone designed to deter abuse in a sample of prescription opioid abusers. Drug
and Alcohol Dependence 2014;139:9-17.
47
48
Comparison of oral drug formulations that deter or prevent misuse and abuse 1-4
Product
Active Drug
Exalgo
Compare and Contrast
ADF Abuse Deterrent Formulations
Dr. Jeffrey Fudin
Dosage
Form
ER tablet
Manufacturer
Physical
Barrier
Nucynta ER
Hydromorphoone
HCl
Tapentadol
Mallinckrodt
Pharmaceuticals, Inc.
Janssen
Endo
Purdue Pharma, L.P.
ER tablet
Opana ER
Oxymorphone HCl
ER tablet
Oxycontin
Oxycodone HCl
CR tablet
Xartemis XR
Embeda
Oxycodone HCl
ER tablet
and acetaminophen
Morphine sulfate
ER capsule
Mallinckrodt
King Pharmaceuticals,
Inc. (a Pfizer co.)
Suboxone
Buprenorphine HCl SL film
X
Abuse-Deterrent Methods
Viscosity
Sequestered
Management
Opioid
Antagonist
X
X
X
Intac and PEO matrix
X
X
Intac and PEO matrix
X
HPMC and PEO matrix
X
Acuform and PEO
matrix
Pellets of morphine
surrounding an inner
core of naltrexone
Co-formulated with
sequestered naloxone
Co-formulated with
Co-formulated with
Co-formulated with
Co-formulated with
homatropine
methylbromide
Aversion and PEO
matrix
X
Talwin NX
Pentazocine HCL
IR tablet
Targiniq ER
Oxycodone HCl
ER tablet
Purdue Pharma, L.P.
X
Zubsolv
Buprenorphine HCl SL tablet
Orexo US, Inc.
X
Monarch
(a Pfizer co.)
King Pharmaceuticals,
Inc. (a Pfizer co.)
Tussigon
Hydrocodone
bitartrate
IR tablet
Oral syrup
Oxycodone HCl
IR tablet
Remoxy
Oxycodone HCl
ER capsule
Xtampza
Oxycodone HCl
ER capsule
OROS
X
Reckitt Benckiser
Sanofi-Aventis LLC.
Oxecta
Type of Technology
Aversive
Agent
X
X
X
X
X
PDF printable version is available at
http://paindr.com/wp-content/uploads/2016/01/Comparison-ofPO-RX-Formulations-that-deter-or-prevent-Misuse-and-Abuse.pdf
Hysingla ER
Pain Therapeutics
(a Durect Corporation
co.)
Collegium
Pharmaceutical, Inc.
Purdue Pharma, L.P.
?
X
ORADUR and SAIB
matrix
?
DeteRx
Hydrocodone
ER tablet
X
X
PEO matrix and HPC
bitartrate
RESISTEC
Hydrocodone
ER capsule Pernix Therapeutics,
X
PEO matrix BeadTek
bitartrate
LLC.
MS Contin
Morphine sulfate
ER tablet
Purdue Pharma, L.P.
Avinza
Morphine sulfate
ER capsule Purdue Pharma, L.P.
X
Kadian
Morphine sulfate
ER capsule Actavis Pharma, Inc.
X
OROS, Osmotic extended-Release Oral delivery System; PEO, polyethylene oxide; HPMC, hydroxypropyl methylcellulose; SAIB, sucrose acetate isobutyrate;
HPC, hydroxypropyl cellulose
Zohydro ER
49
Physical Barriers
Viscosity Management
• Excipient
• Swelling and Increased Viscosity
• Shelter “or “entrap” the active drug
• Control or avert enhancement of delivery
– Characteristics of barriers
• Resist physical manipulation
– crushing / grinding
• As a result, mitigate against
– Snorting
– Smoking
– Extraction
» for “dose dumping”
» for rapid absorption via intravenous administration
Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 1
- development of a formulation-based classification system. Expert
opinion on drug metabolism & toxicology. Feb 2015;11(2):193-204.
– water-soluble/swellable cellulose derivatives
• polyethylene oxide, gums, clays and polyacid
carbomers
–consequential increase in solution viscosity
–drug trapping in a gel-like substance
»prevents syringe extraction for
intravenous use
51
Viscosity Management (continued)
– physical and chemical process by which one substance becomes
attached to another. Options include…
1. ion-exchange resins to bind and trap free drug if tamper
attempted
2. drug already attached to crush-resistant resin particles
– prevents rapid release of the drug in common, extraction
solvents
3. Modification of solubility (temperature, pH, particle size and
solvent)
– To affect drug’s absorption
» Example: meglumine, a basic solubilizing agent
» in the presence of methadone, can increase the pH
causing methadone to precipitate out rendering it
more difficult for extraction for oral liquid or injection
52
In vivo Processes
• Sorption Processing
References:
1. Lourenco LM, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-medical use? Expert opinion on drug delivery. Feb
2013;10(2):229-240.
2. Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 1 - development of a formulation-based classification system. Expert opinion on drug metabolism & toxicology. Feb 2015;11(2):193204.
3. Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 2: commercial products and proprietary technologies. Expert opinion on pharmacotherapy. Feb 2015;16(3):305-323.
4. Stanos SP, Bruckenthal P, Barkin RL. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic
deterrents to tampering. Mayo Clinic proceedings. Jul 2012;87(7):683-694.
• Modifying or interfere with drug binding or metabolism
following the administration of a product into the body
– Opioid antagonists
– Prodrugs
– Enzyme inhibitors
• Examples
–
–
–
–
–
53
Talwin NX (pentazocine + naloxone)
Suboxone (buprenorphine + sequestered naloxone)
Embeda (morphine + sequestered naltrexone)
Zubsolv (buprenorphine + naloxone)
Targiniq ER (oxycodone + naloxone)
54
Other In vivo Options
Modifying Drug Favorability
Inactive prodrug mitigates against…
– Parenteral
– Nasal
– Smoking
• Pharmacokinetic advantages…
– Extends time to peak
• Possibly lessen the euphoric effects
Enzyme inhibitors
– Inhibit or slow the transformation to drug to active metabolite
Sequestered metabolic blocking agents
– Released upon administration of a tampered product
• deter abuse by crushing or chewing for snorting or parenteral
administration
• Advantage over antagonist formulations, blunted immediate
withdrawal
• Oxecta has 2 unique abuse deterrent properties
– Sodium lauryl sulfate - snorting becomes unpleasant
– Excipient results in gel formation with attempt to dissolve
• Previous to Oxecta
– Acurox
• Oxycodone + niacin
• Other Aversive Options
– constituents that trigger unpleasant and very noxious SEs
• laxatives (ex. bisacodyl, casanthanol, senna), nauseants (zinc
salts, ipecac, cephaeline), bittering agents (ex. menthol,
eucalyptus oil, denatonium benzoate, denatonium saccharide),
and mucous membrane irritants (resiniferatoxin, olvanil, sodium
lauryl sulfate)
55
56
Right Drug for the Right Patient
• Choosing the proper patient for an abuse-deterrent product
may not be straightforward
• Choice may be based more on who is most likely to abuse
Patient Selection
opioids
• Characteristics associated with high nonmedical use or use
disorders (Han 2015):
Dr. Shellie Keast
–
–
–
–
–
Sedative use disorders
Other substance disorders (nicotine, etc)
Disabled for work
Medicaid as primary insurance
Depression, mental health diagnoses
57
58
Right Drug for the Right Patient
•
•
•
•
•
Incorporate risk assessment tools before prescribing
Perform frequent Urine Drug Testing
Utilization of PDMP monitoring systems by all providers
Have a plan to discontinue opioids prior to initiation
Pain management patient contracts
Manipulating the ADF
– http://www.aafp.org/fpm/2001/1100/fpm20011100p47-rt1.pdf
– Provide structure, support, and monitoring1
And Altered Pharmacokinetics
Dr. Jeffrey Fudin
• Know the demographics and abuse rates in your practice
area
• Remember that abuse-deterrent opioids can still be abused
by oral route of administration
1. Hariharan J, Lamb GC, Neuner JM. Long-Term Opioid Contract Use for Chronic
Pain Management in Primary Care Practice. A Five Year Experience. Journal of
General Internal Medicine 2007;22:485-90.
59
60
Where to buy them…
One step forward, two steps back
61
https://www.youtube.com/watch?v=XemdKyIrWUo
62
Overcoming Abuse Deterrent Tablets
https://drugs-forum.com/forum/showthread.php?t=255151
63
Pharmacist & Community Service
64
Trying to help other addicts…
Can we help?
https://www.youtube.com/results?search_query=evzio+fudin
https://www.youtube.com/watch?v=2pnfuz2_y0Y
65
https://www.youtube.com/watch?v=KE8NFd4TUVc
66
Key Points
Key Points
• Nonmedical use of pain relievers continues to be an
•
•
•
•
•
important medical and societal problem.
Abuse-deterrent formulations are being developed to
“meaningfully deter abuse” through non-oral routes.
Patients with increase substance abuse risk include male
gender, family and/or personal hx substance abuse,
smoker, alcoholism, PTSD, schizophrenia
National and state entities are actively involved in efforts to
curb misuse
Current research into abuse-deterrent formulations indicate
some decrease in non-oral misuse, but heroin use may be
increasing
ADF’s do not prevent abuse; they mitigate risks
• Selecting the right patient for these formulations is
challenging – planning and monitoring are the key
• ADF’s are not created equal
–
–
–
–
Some deter abuse by injecting oral formulations
Some deter abuse by snorting
Some deter dose-dumping when ingested with alcohol
All can be taken in large quantities and cause death
• Newer formulation on the way may overcome this
67
Which of the following factors does not influence the
likability of opioids for abuse?
A.
B.
C.
D.
68
Embeda and Suboxone are examples of which type of
approach to abuse-deterrent formulations (ADFs)?
Media attention
High first-pass metabolism
Tampering susceptibility
Peer preferences
A.
B.
C.
D.
• ANSWER: B. Factors that influence opioid abuse
Physical barrier
Viscosity management
Sequestered antagonist
Aversion agent
ANSWER: C. Embeda and Suboxone contain
sequestered naltrexone and naloxone, respectively.
attractiveness include media attention, peer preferences,
low cost, availability, tampering susceptibility, and a high
attractiveness quotient (high Cmax, low Tmax).
69
70
What 2 pharmacokinetic properties are exploited to
increase abuse potential?
Which of the following national organizations have
developed plans to curb misuse of prescription opioids?
A. Half-life and elimination factor
B. Maximum plasma concentration and time to peak
concentration
C. Receptor binding affinity and excretion factor
D. Enzyme degradation and pro-drug metabolism
A. Center for Disease Control and Prevention
B. Center for Medicare and Medicaid Services
C. Office of the President
D. All of the above
ANSWER: B. An increased maximum plasma
concentration (Cmax) and decreased time to maximum
concentration (Tmax) increase abuse potential.
ANSWER: D. All of the listed organizations have
developed plans to curb misuse. States have also
developed localized plans to curb misuse.
71
72
Which of the following characteristics is NOT associated
with high nonmedical opioid use or use disorders?
A.
B.
C.
D.
Sedative use disorder
Disabled for work
Private insurance
Depression
ANSWER: C. Medicaid as primary insurance is a
characteristic associated with high nonmedical opioid use
or use disorder.
73

Disclosures Learning Objectives - American Pharmacists Association

Transcription

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