Opioids with abuse-deterrent properties: A regulatory and technological overview

J. David Haddox, DDS, MD

doi:10.5055/jom.2017.0417

Authors

J. David Haddox, DDS, MD

DOI:

https://doi.org/10.5055/jom.2017.0417

Keywords:

analgesics, opioid, drug abuse, drug delivery systems, chemistry, pharmaceutical

Abstract

Three concurrent public health problems coexist in the United States: endemic nonmedical use/misuse of opioid analgesics, epidemic overdose fatalities involving opioid analgesics, and endemic chronic pain in adults. These intertwined issues comprise an opioid crisis that has spurred the development of formulations of opioids with abuse-deterrent properties and label claims (OADP). To reduce abuse and misuse of prescription opioids, the federal Food and Drug Administration (FDA) has issued a formal Guidance to drug developers that delineates four categories of testing to generate data sufficient for a description of a product's abuse-deterrent properties, along with associated claims, in its Full Prescribing Information (FPI). This article reviews the epidemiology of the crisis as background for the development of OADP, summarizes the FDA Guidance for Industry regarding abuse-deterrent technologies, and provides an overview of some technologies that are currently employed or are under study for incorporation into OADP. Such technologies include physical and chemical barriers to abuse, combined formulations of opioid agonists and antagonists, inclusion of aversive agents, use of delivery systems that deter abuse, development of new molecular entities and prodrugs, and formulation of products that include some combination of these approaches. Opioids employing these novel technologies are one part of a comprehensive intervention strategy that can deter abuse of prescription opioid analgesics without creating barriers to the safe use of prescription opioids. The maximal public health contribution of OADP will probably occur only when all opioids have FDA-recognized abuse-deterrent properties and label claims.

Author Biography

J. David Haddox, DDS, MD

Vice President, Health Policy, Purdue Pharma L.P., One Stamford Forum, Stamford, Connecticut; Adjunct Associate Professor, Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts

References

Substance Abuse and Mental Health Services Administration (SAMHSA): Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17-5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, SAMHSA. 2017. Available at: https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2016/NSDUHFFR1-2016.htm. Accessed October 26, 2017.

The Substance Abuse and Mental Health Services Administration (SAMHSA): 2016 National Survey on Drug Use and Health: Survey Materials. Available at https://www.samhsa.gov/data/sites/default/files/NSDUHmrbShowcards2016.pdf. Accessed December 20, 2016.

The Substance Abuse and Mental Health Services Administration (SAMHSA): Results from the 2014 National Survey on Drug Use and Health. Available at http://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs2014/NSDUHDetTabs2014.htm#tab7-44a. Accessed October 10, 2016.

Center for Behavioral Health Statistics and Quality: 2015 National survey on drug use and health: summary of the effects of the 2015 NSDUH questionnaire redesign: Implications for data users. Substance abuse and mental health services administration, Rockville, MD. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-TrendBreak-2015.pdf. Accessed November 30, 2016.

The Substance Abuse and Mental Health Services Administration (SAMSHA): Results from the 2015 National Survey on Drug Use and Health: Detailed tables. Available at https://www.samhsa.gov/data/sites/default/files/NSDUHDetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.htm. Accessed December 26, 2016.

Centers for Disease Prevention and Control: US Standard Certificate of Death: Available at https://www.cdc.gov/nchs/data/dvs/death11-03final-acc.pdf. Accessed December 20, 2016.

Chen LH, Hedegaard H, Warner M: Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. Available at http://www.cdc.gov/nchs/data/databriefs/db166.htm. Accessed November 30, 2016.

World Health Organization: International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Available at http://apps.who.int/classifications/icd10/browse/2016/en. Accessed December 26, 2016.

Drug Enforcement Administration: National Heroin Threat Assessment Summary- Updated: Available at https://www.dea.gov/divisions/hq/2016/hq062716_attach.pdf. Accessed December 20, 2016.

Centers for Disease Prevention and Control: Nonpharmaceutical fentanyl-related deaths--multiple states, April 2005-March 2007. MMWR Morb Mortal Wkly Rep. 2008; 57 (29): 793-796.

Centers for Disease Prevention and Control: Increases in fentanyl drug confiscations and fentanyl-related overdose fatalities. Available at http://emergency.cdc.gov/han/han00384.asp. Accessed November 30, 2016.

World Health Organization: Acetyl fentanyl. Expert Committee on Drug Dependence: Thirty-seventh meeting-Agenda item 5.2, Geneva 2015. Available at http://www.who.int/medicines/access/controlled-substances/5.2_Acetylfentanyl_CRev.pdf. Accessed December 27, 2016.

Rudd RA, Seth P, David F, et al.: Increases in Drug and Opioid-Involved Overdose Deaths—United States, 2010–2015. MMWR Morb Mortal Wkly Rep. ePub: December 16 2016. DOI: http://dx.doi.org/10.15585/mmwr.mm655051e1.

Rudd RA, Aleshire NA, Zibbell JE, et al.: Increases in drug and opioid overdose deaths–United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2016; 64 (50-51): 1378-1382.

Erensen JG, Haddox JD: Opioid deaths or polydrug/multicause deaths? Poster presented at: College on Problems of Drug Dependence (CPDD) Annual Meeting; June 14-19, 2014; San Juan, Puerto Rico. Abstract 199. Available at http://cpdd.org/wpcontent/uploads/2016/07/CPDD14AbstractBook.pdf. Accessed August 15, 2017.

Oregon Department of Human Services: Methadone deaths (and distribution) on the rise: CD Summary. 2003; 52 (14). Available at http://public.health.oregon.gov/DiseasesConditions/CommunicableDisease/CDSummaryNewsletter/Documents/2003/ohd5214.pdf. Accessed November 30, 2016.

Faul M, Bohm M, Alexander C: Methadone Prescribing and Overdose and the Association with Medicaid Preferred Drug List Policies – United States, 2007-2014. MMWR Morb Mortal Wkly Rep 66(12): 320-323.2017 Available at https://www.cdc.gov/mmwr/volumes/66/wr/mm6612a2.htm. Accessed April 6, 2017.

The White House Office of National Drug Control Policy: Continued rise in opioid overdose deaths in 2015 shows urgent need for treatment. Available at https://www.whitehouse.gov/thepress-office/2016/12/08/continued-rise-opioid-overdose-deaths-2015-shows-urgent-need-treatment. Accessed December 12, 2016.

US Food and Drug Administration: FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use [press release]. Silver Spring, MD: FDA Office of Media Affairs; August 31, 2016. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518697.htm. Accessed October 31, 2016.

Institute of Medicine (now National Academy of Medicine): Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Available at http://www.nationalacademies.org/hmd/Reports/2011/Relieving-Painin-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx. Accessed November 8, 2016.

Nahin RL: Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015; 16 (8): 769-780.

Centers for Disease Control and Prevention: Opioid painkiller prescribing. Available at http://www.cdc.gov/vitalsigns/opioid-prescribing/. Accessed December 13, 2016.

IMS Institute: Medicine use and shifting costs of healthcare: A review of the use of medicines in the U.S. in 2013. Available at http://www.imshealth.com/en/thought-leadership/quintilesimsinstitute/reports/use-of-medicines-in-the-us-2013. Accessed November 30, 2016.

IMS Health NPA Market Dynamics: Monthly opioid analgesic patient counts. Data on file.

Office of National Drug Control Policy: Epidemic: responding to America's prescription drug abuse crisis. Available at https://www.whitehouse.gov/sites/default/files/ondcp/policyand-research/rx_abuse_plan.pdf. Accessed November 30, 2016.

National Drug Control Strategy: FY 2016 Budget and Performance Summary. Available at https://www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/fy_2016_budget_summary.pdf. Accessed December 20, 2016.

US Department of Health and Human Services, Food and Drug Administration: Abuse-deterrent opioids–evaluation and labeling: Guidance for industry. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf. Accessed November 30, 2016.

American Society of Addiction Medicine: Public Policy Statement on Public Safety and the Healthcare and other Licensed Professional with Addictive Illness. Available at https://www.asam.org/docs/default-source/public-policystatements/101pip_overview_4-11.pdf?sfvrsn=0. Accessed August 15, 2017.

Food and Drug Administration Consumer Updates: A guide to safe use of pain medicine. Available at https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm095673.htm. Accessed August 15, 2017.

National Institute of Health-National Institute on Drug Abuse: How can prescription drug abuse be prevented? Available at https://www.drugabuse.gov/publications/researchreports/misuse-prescription-drugs/how-can-prescription-drugmisuse-be-prevented. Accessed August 15, 2017.

Code of Federal Regulations. Available at https://www.gpo.gov/fdsys/pkg/USCODE-2015-title21/pdf/USCODE-2015-title21-chap9-subchapII-sec321.pdf. Accessed December 2, 2016.

Katz R: FDA: Evidentiary standards for drug development and approval. NeuroRx. 2004; 1 (3): 307-316.

US Department of Health and Human Services, Food and Drug Administration: General principles for evaluating the abuse deterrence of generic solid oral opioid drug products: guidance for industry. Draft guidance. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM492172.pdf. Accessed December 12, 2016.

US Food and Drug Administration: Drugs@FDA Web site. Available at http://www.accessdata.fda.gov/scripts/cder/daf/. Accessed November 8, 2016.

Katz N, Dart R, Bailey E, et al.: Tampering with prescription opioids: Nature and extent of the problem, #health |consequences, and solutions. Am J Drug Alcohol Abuse. 2011; 37 (4): 205-217.

Alexander L, Mannion RO, Weingarten B, et al.: Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol Depend. 2014; 138: 1-6.

Upjohn WE: Inventor: Process for making pills. United States Patent 312041A. February 10, 1885.

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 Clin Proc. 2012; 87 (7): 683-694.

Collegium Pharmaceuticals: DETERx® technology. Available at http://www.collegiumpharma.com/technology/overview. Accessed December 1, 2016.

Mastropietro DJ, Omidian H: Abuse-deterrent formulations: Part 1–development of a formulation-based classification system. Expert Opin Drug Metab Toxicol. 2015; 11 (2): 193-204.

Elite Pharmaceuticals: Technology overview. Available at http://www.elitepharma.com/how-it-works/. Accessed November 11, 2016.

Pfizer Inc: Embeda® Technology. Available at https://www.pfizerpro.com/product/embeda/hcp/technology. Accessed November 30, 2016.

Schaeffer T: Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics. J Med Toxicol. 2012; 8 (4): 400-407.

Mastropietro DJ, Omidian H: Abuse-deterrent formulations: Part 2: Commercial products and proprietary technologies. Expert Opin Pharmacother. 2015; 16 (3): 305-323.

Titan Pharmaceuticals: Probuphine®. Available at http://www.titanpharm.com/pipeline/probuphine. Accessed November 2, 2016.

Webster L, Smith S, Silowsky J, et al.: Abuse potential assessment of novel opioid analgesic NKTR-181: Implication for labeling and scheduling. Poster presented at: College on Problems of Drug Dependence (CPDD) Annual Meeting; June 15-20, 2013; San Diego, CA.

Comer SD, Ashworth JB, Sullivan MA, et al.: Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag. 2009; 5 (4): 203-212.

Hale ME, Moe D, Bond M, et al.: Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain. Pain Manag. 2016; 6 (5): 497-508.

Everitt BJ, Robbins T: Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nat Neurosci. 2005; 8 (11): 1481-1489.