Reformulated OxyContin Fails to Show Less Abuse 10 Years After FDA Approval

The opioid overdose epidemic remains a substantial public health challenge in the U.S., with rates of opioid-related overdose fatalities rising despite efforts by federal and state governments to address this deadly scourge.[1] The most recent national data show that in the 12 months leading up to April 2020, overdose deaths connected to prescription opioids exceeded 54,000.[2] Because of this risk and the related risk of addiction, opioids in the U.S. are regulated as dangerous substances to be used only under the care of a licensed health care professional.

Oxycodone was first approved in the U.S. in 1950 but only became widely used for pain after the Food and Drug Administration (FDA) approval in 1995 of the brand-name product OXYCONTIN, which is a controlled-release formulation designed to deliver a steady dose of oxycodone for a period of 12 hours.[3],[4] OxyContin is marketed by Purdue Pharma, and by 2004 it was the leading drug of abuse in the U.S. By 2007 it yielded a total of $35 billion in sales for Purdue, and by 2013 it represented nearly one-third of the U.S. prescription opioid market.

In 2019, Purdue declared bankruptcy in the face of mounting legal judgments regarding its harmful marketing of OxyContin, which thus far have racked up over $8 billion in criminal and civil penalties.[5] It is unclear whether such claims will ever be fully paid by the company or by members of the Sackler family who own the company,[6],[7] but for the moment Purdue continues to operate by selling OxyContin[8] and other products that, somewhat ironically, include remedies for opioid overdose or dependence.[9],[10]

Purdue recently submitted for FDA review the results of studies to assess their latest “abuse-deterrent formulation” of OxyContin.[11] Those studies were required by the FDA when abuse-deterrent OxyContin was approved in 2010. That reformulation was engineered to inhibit crushing or dissolving of the tablets to purportedly discourage misuse or abuse via snorting or injecting.

This article reviews the four postmarketing studies Purdue submitted to the FDA that evaluated the alleged abuse-deterrent properties of reformulated OxyContin and the agency’s independent assessment of the studies’ results.

The four studies

All four postmarketing safety studies were observational. They relied on non-random samples of subjects exposed to OxyContin or other opioid drugs (comparator opioids).[12] Two involved over 63,000 assessments each at substance abuse treatment centers across the U.S. A third used data from over 308,000 intentional opioid exposure calls received by poison centers across the country, and the fourth study was of nearly 958,000 Medicaid or commercial health insurance claimants who were dispensed OxyContin or at least one comparator opioid.

Comparator opioids across the first three studies included non-abuse-deterrent forms of oxycodone, hydrocodone, oxymorphone, hydromorphone or morphine. For the Medicaid or commercial insurance population study, the comparators were slightly different but overlapping with the other three studies including morphine, transdermal (patch) fentanyl and methadone, all of which are long-available alternatives to OxyContin.[13]

Across these four studies, various statistical analyses were conducted to assess trends from two years before abuse-deterrent OxyContin was approved in 2010 to up to five years after that approval.[14] These analyses sought to test the hypothesis of Purdue scientists that the abuse-deterrent form had indeed reduced the abuse of OxyContin in the real world. Their results, however, were mostly inconclusive or negative in that regard per the FDA and the agency’s expert advisory committee that reviewed the studies in September 2020.

Analyses of the two substance-abuse-treatment-center studies revealed what the FDA said was “fairly compelling” evidence that the reformulation reduced abuse of OxyContin, but only via non-oral routes of administration, and also primarily in the narrow population of those with advanced substance use disorders.[15] Across the substance-abuse-treatment-center and poison-center populations (the first three studies), evidence was “not robust” for any meaningful reduction in overall OxyContin abuse via any route, a conclusion that FDA reviewers said was clouded by changes over time in opioid use trends which were separate from OxyContin’s reformulation (for example, changes in prescribing habits).

The study of Medicaid and commercial insurance claimants did not demonstrate that the reformulated OxyContin reduced the risk of opioid overdose, fatal or otherwise.[16] This finding specifically led the FDA review team to conclude that “It is unclear whether [OxyContin’s] reformulation reduced opioid overdoses or had a net public health benefit.” Citing several published studies, the FDA reviewers further noted that some individuals substituted other legal or illegal opioids after OxyContin was reformulated and that overdoses tied directly to this reformulation may well have been more than offset by overdoses of other opioids.

Finally, it is notable that the FDA’s 888-page briefing document for the September 2020 advisory committee review concluded with a short memo summarizing results from a survey of 320 health professionals (physicians, physician assistants, nurse practitioners and dentists) who prescribed opioids to at least five different individuals during the preceding month. Those professionals were typically confused as to the meaning of “abuse deterrent formulation.” Nearly half wrongly thought that abuse-deterrent forms have been proven to reduce oral abuse or were less addictive, and only one-third knew that abuse-deterrent forms had the same addiction potential as other opioids.[17]

During the FDA advisory committee meeting, at least two public commenters, both physicians, encouraged the FDA to eliminate use of the abuse-deterrent designation in opioid product labeling because it is confusing and tied to pharmaceutical marketing deception. For OxyContin specifically, one physician suggested that alternative labeling should simply state that the tablets are made with materials to make powderizing (for snorting) or dissolving (for injecting) difficult to discourage dangerous use.

At the FDA advisory committee meeting, Public Citizen’s Health Research Group testified that the data from the four studies submitted by Purdue did not demonstrate that OxyContin’s reformulation is any safer than its predecessor.[18] The advisory committee concurred by voting overwhelmingly (26 to 2) in opposition to the premises that the reformulation yielded meaningful reductions in overall abuse or opioid overdose.[19]

The FDA has said they will issue a final determination about this matter pursuant to conclusion of the advisory committee process. The agency’s internal and external experts point toward a decision that should prevent Purdue from claiming (in its labeling or other marketing materials) that OxyContin has general abuse-deterrent properties.

What You Can Do

To manage noncancer pain, talk to your doctor about nondrug options (such as exercise, physical therapy or behavioral therapy) or non-opioid medications (such as ibuprofen [ADVIL, IBU-TAB, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN] or acetaminophen [TYLENOL]). If such options are not possible (for example, after surgery) or they have not provided adequate pain relief and your doctor recommends an opioid medication, ask your doctor to prescribe the lowest effective dose of an immediate-release (instead of an extended-release or long-acting) opioid and discuss with him or her how long you need to take this medication and when you can stop it.

Be aware that all opioid pain medications (including abuse-deterrent forms) can lead to addiction and, even if you do not become dependent, taking too much of such drugs can cause respiratory depression (impaired breathing), overdose and death, especially when the drugs are taken simultaneously with other substances such as alcohol or benzodiazepines.
 

References

[1] Ellerbeck A. The Health 202: Biden will also have the opioid epidemic to deal with amid the coronavirus pandemic. The Washington Post. November 16, 2020. https://www.washingtonpost.com/politics/2020/11/16/health-202-biden-will-also-have-opioid-epidemic-deal-with-amid-coronavirus-pandemic/. Accessed December 2, 2020.

[2] Center for Disease Control and Prevention. National Center for Health Statistics. Nation Vital Statistics System. Vital statistics rapid release. Provisional drug overdose death counts. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm#dashboard. Accessed December 2, 2020.

[3] Purdue Pharma L.P. Label: oxycodone extended release (OXYCONTIN). October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022272s043lbl.pdf. Accessed December 2, 2020.

[4] Jones GH, Bruera E, Abdi S, Kantarjian HM. The opioid epidemic in the United States-Overview, origins, and potential solutions. Cancer. 2018;124(22):4279-4286.

[5] Randazzo S. Purdue Pharma reaches $8.34 billion settlement over opioid probes. Wall Street Journal. October 21, 2020. https://www.wsj.com/articles/purdue-pharma-reaches-8-34-billion-settlement-over-opioid-probes-11603292613. Accessed December 8, 2020.

[6] Scurria S, Brickley A. Democratic senators object to ‘rebranding’ of Purdue as a public asset. Wall Street Journal. November 10, 2020. https://www.wsj.com/articles/democratic-senators-object-to-rebranding-of-purdue-as-a-public-asset-11605022508. Accessed December 2, 2020.

[7] Randazzo S. Purdue Pharma reaches $8.34 billion settlement over opioid probes. Wall Street Journal. October 21, 2020. https://www.wsj.com/articles/purdue-pharma-reaches-8-34-billion-settlement-over-opioid-probes-11603292613. Accessed December 8, 2020.

[8] Purdue Pharma L.P. Healthcare professionals. Purdue products. https://www.purduepharma.com/healthcare-professionals/products/#prescription-opioids. Accessed December 2, 2020.

[9] Purdue. Restructure. On September 15, 2019, Purdue Pharma L.P. announced a preliminary agreement to settle the opioid litigation facing the company. https://www.purduepharma.com/restructure/. Accessed December 2, 2020.

[10] Scurria S, Brickley A. Democratic senators object to ‘rebranding’ of Purdue as a public asset. Wall Street Journal. November 10, 2020. https://www.wsj.com/articles/democratic-senators-object-to-rebranding-of-purdue-as-a-public-asset-11605022508. Accessed December 2, 2020.

[11] Food and Drug Administration. FDA briefing document. Joint meeting of the Drug Safety and Risk Management (DSaRM) Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC). Oxycontin abuse deterrent formulation (ADF). Oxycontin Abuse Deterrent Formulation (ADF). September 10-11, 2020. https://www.fda.gov/media/141914/download. Accessed December 2, 2020.

[12] Purdue Pharma L.P. Joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee. OxyContin (oxycodone hydrochloride) extended-release tables NDA 022272. Postmarketing requirement briefing Document. Advisory committee meeting. September 10-11, 2020. https://www.fda.gov/media/141916/download. Accessed December 2, 2020.

[13] Purdue Pharma L.P. Joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee. OxyContin (oxycodone hydrochloride) extended-release tables NDA 022272. Postmarketing requirement briefing Document. Advisory committee meeting. September 10-11, 2020. https://www.fda.gov/media/141916/download. Accessed December 2, 2020.

[14] Ibid.

[15] Food and Drug Administration. FDA briefing document. Joint meeting of the Drug Safety and Risk Management (DSaRM) Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC). Oxycontin abuse deterrent formulation (ADF). September 10-11, 2020. https://www.fda.gov/media/141914/download. Accessed December 2, 2020.

[16] Ibid.

[17] Food and Drug Administration. FDA briefing document. Joint meeting of the Drug Safety and Risk Management (DSaRM) Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC). Oxycontin abuse deterrent formulation (ADF). September 10-11, 2020. https://www.fda.gov/media/141914/download. Accessed December 2, 2020.

[18] Wolfe S. Testimony before the FDA’s Drug Safety and Risk Management Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee regarding reformulated Oxycontin. September 11, 2020. https://www.citizen.org/article/testimony-before-the-fdas-drug-safety-and-risk-management-advisory-committee-and-anesthetic-and-analgesic-drug-products-advisory-committee-regarding-reformulated-oxycontin/. Accessed December 2, 2020.

[19] Food and Drug Administration. Final Summary Minutes of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee Joint Meeting. September 10-11, 2020. https://www.fda.gov/media/143918/download. Accessed December 7, 2020.