In Vitro and Clinical Assessments of Abuse-Deterrent Formulations in the Management of Chronic Pain

Faculty Perspectives in Chronic Pain: In Vitro and Clinical Assessments of Abuse-Deterrent Formulations for Chronic Pain
Gary M. Owens, MD

Opioid abuse and diversion are important issues for all payers, as they must balance access to opioids for those who truly need treatment with the potential that these drugs may not be used as intended. This issue is supported by the fact that in 2010, there were 16,651 opioid-related deaths in the United States, and by 2013, despite efforts to control the issue, that number remained higher than 16,000.1,2 For the decade prior to 2010, prescription opioid overdose deaths quadrupled in the United States, in parallel with prescription opioid sales.3,4 Additionally, a study of prescription opioid abusers in a drug rehabilitation program found that 80% of abusers tampered with opioid tablets by chewing or administering the drug intranasally or intravenously in order to accelerate drug release.5 These alarming statistics clearly show that concerted efforts are needed to combat this growing public health issue while preserving, and even expanding, appropriate treatment options for patients with chronic pain.

In the main article in this publication, the author noted: “Extended-release (ER) opioids, which were developed to provide long-acting, stable levels of medication for continuous treatment of pain, are particularly attractive to prescription drug abusers because of their relatively high opioid content and rapid onset of effect when manipulated.” Because of this, the US Food and Drug Administration (FDA) issued draft guidance on abuse-deterrent opioids in 2013. The guidance identified 4 areas that must be addressed by applicants6: laboratory-based in vitro manipulation and extraction studies (Category 1); pharmacokinetic studies (Category 2); clinical abuse potential studies (Category 3); and postmarketing studies (Category 4).

The article provides an excellent overview of the current status of manufacturers’ efforts to make long-acting opioids less desirable for abuse by a number of different methodologies, including tamper and crush resistance, the addition of aversive agents, and combinations with antagonists. However, what remains unknown is how much of an impact these strategies may have on abuse of long-acting opioid agents.

To address this issue, Larochelle and colleagues conducted a study to assess the 2010 launch of an abuse-deterrent formulation of an ER semisynthetic opioid and the impact of the FDA requirement to withdraw a separate opioid from the US market. That study, released on April 20, 2015, evaluated the association between these 2 temporally proximate changes in the opioid market with opioid-dispensing and overdose rates.7 The authors found a number of changes after 2 years7:

  • Total opioid dispensing decreased by 19% from the expected rate (absolute change, −32.2-mg morphine-equivalent dose/member/quarter)
  • The estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, −1.10/100,000 members/quarter)
  • Heroin overdose increased by 23% (absolute change, 0.26/100,000 members/quarter).

The authors concluded: “Pharmaceutical market interventions may have value in combating the prescription opioid overdose epidemic, but heroin overdose rates continue to increase. Complementary strategies to identify and treat opioid abuse and addiction are urgently needed.”7

As I have noted in this and previous perspectives on the subject, the issue of opioid abuse and the associated morbidity and mortality of this societal problem accompanied by the excess cost to the system are areas of great concern to payers. Payer organizations are an important stakeholder in these issues, but they cannot solve the problem alone. It will take a concerted effort by prescribers to engage in responsible prescribing, to be aware of patients who are potential abusers, and to become better educated on the management of chronic pain. Likewise, manufacturers will need to continue to develop products that can be used appropriately with minimal potential for abuse. Payers will need to make these products available on formularies for patients who need pain relief, but who are at risk for abuse. At the same time, payers must balance access to these agents with the increased cost that is likely to be incurred, and have policies in place to ensure that the right patient gets the appropriate treatment. Payers will need to work in collaboration with all involved stakeholders to continue to tackle this complex, costly, and difficult-to-manage area of medicine.

References

  1. Centers for Disease Control and Prevention. Opioids drive continued increase in drug overdose deaths [press release]. www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.html. 2013. Accessed April 16, 2015.
  2. Centers for Disease Control and Prevention. Drug Overdose in the United States: Fact Sheet. www.cdc.gov/drugoverdose/data/index.html; 2014. Accessed May 5, 2015.
  3. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309:657-659.
  4. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60:1487-1492.
  5. Passik SD, Hays L, Eisner N, Kirsh KL. Psychiatric and pain characteristics of prescription drug abusers entering drug rehabilitation. J Pain Palliat Care Pharmacother. 2006;20:5-13.
  6. US Food and Drug Administration. Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf. Accessed April 17, 2015.
  7. 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 Int Med. 2015;175:978-987.
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