Background In response to the mounting public health crisis regarding opioid related deaths from misuse, the Food and Drug Administration (FDA) has issued guidance to pharmaceutical manufacturers on the development of abuse-deterrent formulations of opioids (1). This Fast Fact will focus on the different types of abuse-deterrent opioid formulations and their role in palliative care.
Opioid Abuse in the Palliative Care Population Opioid abuse is the intentional, nontherapeutic use of a drug product or substance, even once, to achieve a desired psychological or physiological effect (2). Opioids may be ingested, either whole or crushed, inhaled, via snorting, smoking, or vaping, or injected in an attempt to more quickly achieve a euphoric “high” (1,3). Previous literature suggests that 29-46% of palliative care patients possess risk factors for opioid misuse defined as a positive score (≥4 points) on the Screener and Opioid Assessment for Patients with Pain version 1.0—Short Form (SOAPP-SF) (4,5).
Opioid Abuse-Deterrent Categories
- Physical/Chemical Barriers: Physical barriers, such as polymers and high resistance coatings, can prevent mechanical manipulation, such as chewing, crushing, cutting, or grinding, of the medication. Chemical barriers, such as gelling agents, can resist dissolution of the opioid using common solvents (water, alcohol, or other organic solvents).
- Agonist/Antagonist Combinations: The addition of an opioid antagonist, most commonly naloxone or naltrexone, can interfere with the euphoria and analgesia associated with opioid abuse. Pharmaceutical designers often aim to sequester the antagonist so that it only becomes clinically active if the product is crushed for injection or snorting.
- Aversion: Substances can be added to the product to produce an unpleasant effect, such as irritation to the nasal mucosa, if the dosage form is manipulated or is used at a higher dosage than directed.
- Delivery System: Certain drug release and delivery methods, such as sustained-release depot injections and subcutaneous implants, can offer resistance to abuse as they cannot be tapered to quickly release the opioid and produce a drug high.
- New Molecular Entities and Prodrugs: These opioids require enzymatic activation, different receptor binding, slower penetration into the central nervous system, or other novel effects to thereby provide a chemical barrier to the in vitro conversion to the parent opioid, which may deter the abuse of the parent opioid by continuing to have controlled release of the drug even if it is crushed.
Opioid Abuse-Deterrent Formulations There are several brand-name extended release (ER) opioid formulations available with FDA-approved labeling describing abuse-deterrent properties (6,7). There is one immediate release oxycodone agent with abuse deterrent properties, but it does not possess FDA-approved labeling (8). Moving forward, greater availability of abuse deterrent opioid formulations is expected as the FDA has issued guidance on the development of generic versions (9).
Evidence To be considered abuse-deterrent by the FDA, formulations must undergo long term epidemiological study to assess their clinical abuse potential (17). Most often this is done utilizing a drug-liking and a subjective feeling of getting “high” scale of 0-100, where 0 represents maximum disliking, 50 represents a neutral response, and 100 represents maximum liking. FDA approved abuse deterrent agents showed statistically significant decreases in drug-liking and drug high when compared to other opioid formulations (10-16). Retrospective reviews found that 3.5 years after the reformulation of OxyContin®, opioid abuse, doctor-shopping, the amount of OxyContin® dispensed, and OxyContin-related fatalities were reduced (18,19). However, heroin overdoses increased by 23% during that same time (18). There is concern that even if these formulations reduce opioid-specific abuse, they may contribute to a shifting pattern of heroin abuse. No palliative care specific studies have yet been conducted.
Cost Effectiveness There is a lack of robust, controlled trials to determine if the expense of these formulations is justified. Most of these formulations are not covered by insurance policies. One cross-sectional study of Oklahoma Medicaid claims suggested that abuse-deterrent opioids may be related to slightly lower overall health care costs for members with ICM-9 codes associated with opioid abuse; this finding was not replicated among members without comorbidities of addiction (19).
Summary Abuse-deterrent opioids may have a role in the palliative care population, however cost may limit their use. These opioid formulations should be limited to opioid-appropriate patients who are at risk for opioid-specific problems.
- U.S. Food and Drug Administration (FDA) News Release: FDA takes important step to increase the development of, and access to, abuse-deterrent opioids. (2016, March 24). Accessed 3 August 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm492237.htm
- Denisco RA, Chandler RK, Compton WM. Addressing the intersecting problems of opioid misuse and chronic pain treatment. Exp Clin Psychopharmacol. 2008 Oct;16(5):417-28.
- Gasior M, Bond M, Malamut R. Routes of abuse of prescription opioid analgesics: a review and assessnemtn fo the potential impact of abuse-deterrent formulations. Postgrad Med. 2016 Jan;128(1):85-96.
- Childers JW, King LA, Arnold RM. Chronic pain and risk factors for opioid misuse in a palliative care clinic. Am J Hosp Palliat Care. 2015 Sep;32(6):654-9.
- Koyyalagunta D, Bruera E, Aigner C, Nusrat H, Driver L, Novy D. Risk stratification of opioid misuse among patients with cancer pain using the SOAPP-SF. Pain Med. 2013 May;14(5):667-75.
- U.S. Food and Drug Administration (FDA) Draft Guidance: General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (2016, March). Accessed 3 August 2016. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM492172.pdf
- U.S. Food and Drug Administration (FDA): Opioid Medications, Abuse-Deterrent Opioids (2016, July 7). Accessed 3 August 2016. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm337066.htm
- Product Information: OXAYDO(TM) oral tablets, oxycodone HCl oral tablets. Acura Pharmaceuticals, Inc. (per manufacturer), Palatine, IL, 2014. Product Information: OXYCONTIN® oral extended-release tablets, oxycodone HCl oral extended-release tablets. Purdue Pharma L.P (per FDA), Stamford, CT, 2015.
- U.S. Food and Drug Administration (FDA): FDA takes important step to increase the development of, and access to, abuse-deterrent opioids (2016, March). Accessed 12 December 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm492237.htm.
- Product Information: TARGINIQ ER® oral extended-release tablets, oxycodone HCl oral extended-release tablets. Purdue Pharma L.P (per FDA), Stamford, CT, 2015.
- Product Information: EMBEDA® oral extended-release capsules, morphine sulfate naltrexone HCl oral extended-release capsules. Pfizer Inc (per FDA), New York, NY, 2014.
- Product Information: HYSINGLA ER® oral extended-release tablets, hydrocodone bitartrate oral extended-release tablets. Purdue Pharma L.P. (per FDA), Stamford, CT, 2014.
- Product Information: MORPHABOND® oral extended-release capsules, morphine sulfate oral extended-release capsules. Inspirion Delivery Technologies LLC (per FDA), Valley Cottage, NY, 2015.
- Product Information: XTAMPZA ER® oral extended-release capsules, oxycodone HCl oral extended-release tablets. Patheon Pharmaceuticals (per FDA), Cincinnati, OH, 2016.
- 15.Product Information: Troxyca ER® oral extended-release capsules, oxycodone HCl naltrexone HCl oral extended-release capsules. Pfizer Inc (per FDA), New York, NY, 2016.
- 16.Coplan PM, Chilcoat HD, Butler SF, Sellers EM, et al. The Effect of an Abuse-Deterrent Opioid Formulation on Opioid Abuse-Related Outcomes in the Post-Marketing Setting. Clin Pharmacol Ther. 2016 May 12. doi: 10.1002/cpt.390. [Epub ahead of print]
- 17.U.S. Food and Drug Administration (FDA) Fact Sheet: FDA Opioids Action Plan (2016, Sept). Accessed 12 December 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm484714.htm.
- 18.Larochelle MR, Zhang F, Ross-Degnan D, Wharam JF. Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene. JAMA Intern Med. 2015 Jun;175(6):978-87.
- Keast SL, Owora A, Nesser N, Farmer K. Evaluation of Abuse-Deterrent or Tamper-Resistant Opioid Formulationson Overall Health Care Expenditures in a State Medicaid Program. J Manag Care Spec Pharm. 2016 Apr;22(4):347-56.
Authors’ Affiliation: University of Pittsburgh Medical Center
Conflicts of Interest: None
Version History: Originally edited by Sean Marks MD, first electronically published February 2017
Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.
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