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14 Articles in Volume 18, Issue #7
A 2018 Update: The Federal Pain Research Strategy
A Commentary on Medical Cannabis
Are Abuse-Deterrent Opioids Appropriate for Your Pain Patient?
Behind the AHRQ Report
Challenges Facing Abuse-Deterrent Formulations
Demystifying Opioid Abuse-Deterrent Technologies
Editorial: Our Clinical Pain Neighborhood
Independent Pain Practice: A Case Example
Inside Performing Arts Medicine
Letters to the Editor: ACT Therapy; Compounded Topicals
Nerve Growth Factor and Targeting Chronic Pain
Pain Control for Athletes: What Works?
Quality Training: One Center’s Experience with Pain Assessment
The Importance of Developing Professional Relationships in Pain Practice

Demystifying Opioid Abuse-Deterrent Technologies

A review of existing and emerging ADF products – and their potential implications on the opioid epidemic.
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Continued struggles within the United States regarding the opioid epidemic has prompted the FDA and other government agencies to support change in the way opioid drugs are manufactured.1 A major effort in this regard is FDA’s support of the pharmaceutical industry’s development of new technologies and innovations that may allow for the safer prescribing of opioids. One such innovation is abuse-deterrent formulations (ADFs) of opioids, which began to enter the market in 2010 after the agency approved an ADF formulation of OxyContin; these formulations are geared toward deterring prescription opioid misuse and abuse by making the final substances difficult to crush, chew, gel, or dissolve.

Bumpy roadThe road ahead for integrating abuse-deterrent opioids into everyday pain practice may be bumpy. (Source: 123RF)

The purpose of this review is to outline the reasoning behind the emphasis on improving ADFs, the current FDA approval process for including ADF information in package inserts, and to highlight unique ADF technologies, including key differences that may impact prescribing and use.

Support for ADFs

In 2016, the CDC labeled prescription opioid misuse and abuse in the United States as an epidemic, citing that more than 3.8 million people in 2014, 12 years or older, reported illicit use of prescription opioid analgesics.2,3 In addition, the number of overdose deaths involving overall opioid analgesics (alone or combined with other substances, both legal and illicit) had increased by over 4.5-fold between 1999 and 2014.4 Not only did these trends result in significant morbidity and mortality, but they were also extremely cost-exhaustive. In 2009, it was estimated that the US dollar cost of prescription opioid abuse to society was around $55.7 billion; a number that has likely increased.5

The significant societal and economic impact caused by this crisis has led to serious rethinking of different formulation approaches. While the standard of care still supports the use of non-opioid pharmacologic and non-pharmacologic modalities as a first-line approach to manage pain, there are millions of patients who have significant and complex pathology that warrants long-term opioid analgesic use. Best practices also promote the use of extended-release opioids to help reduce baseline chronic pain, with the intermittent use of immediate-release (IR) opioids to help manage breakthrough pain as needed.

Notably, the 2016 CDC Guideline on Prescribing Opioids for Chronic Pain controversially suggested that extended-release (ER) opioids be used only after immediate-release products have been utilized.6 ER opioids are distributed into the bloodstream at a steady rate over a prolonged period of time and therefore contain, on average, 8 to 24 hours of opioid doses in a single oral formulation, or 3 to 7 days in transdermal patch formulations, when compared to their IR counterparts; IR formulations contain 3 to 6 hours, on average, of medication in a single unit. Thus, if ER dosage forms are manipulated in such a way that bypasses their ER mechanism, a higher payload of opioid may be immediately accessed, and thus, abused or misused. For this reason, ADFs are being emphasized as a potential means to help reduce prescription opioid abuse and misuse.

The definition of an ADF includes opioids that have one or more properties that work to increase the difficulty of abuse, making abuse less attractive, and/or less rewarding.1, 7 There are seven designated categories outlined by FDA for guidance on the development of ADFs, including:

  • physical/chemical barriers
  • agonist/antagonist combinations
  • aversion technologies
  • delivery system technologies
  • new molecular entities and prodrugs
  • different combinations of ADFs
  • novel approaches.1

See Tables I and II for details.1,7 Although the FDA’s regulation of ADF technology is still evolving, the agency has provided a framework for how a developer may pursue approval for product labeling indicating that their ADF opioid is likely to reduce abuse by specific routes of administration.1,7

Types of Abuse-Deterrent Properties(Table provided by author)

Table II has been corrected from its original printed version.

FDA-Approval of Abuse-Deterrent Labeling

To obtain FDA approval for abuse-deterrent labeling, sufficient evidence must be presented that indicates that the opioid’s abuse-deterrent properties are effective.1 In 2015, the agency released guidance for industry to describe how these new formulations are to be evaluated, including recommendations for how specific studies should be conducted and analyzed, and how labeling claims may be made given the results of these studies. The three premarket studies required include:

  • laboratory based in vitro manipulation and extraction studies (Category 1)
  • pharmacokinetic studies (Category 2)
  • clinical abuse potential studies (Category 3).1

The results of these premarket studies must then be confirmed by post-market trials (Category 4). The major difference between the three premarket categories and the post-market studies is that premarket studies focus on assessing the abuse-deterrent properties in a controlled setting.1 The major goal for the post-market studies is to determine whether the commercial availability of the product actually results in significant reductions in abuse, misuse, and adverse clinical outcomes in real-world scenarios.1 All post-market trial results have to be submitted to the FDA along with the results of Category 1-3 studies. To date, no pharmaceutical company or product has achieved Category 4 status.

Available Abuse-Deterrent Opioids with FDA-Approved Labeling

The following FDA-approved opioid products have product labeling that includes information regarding how their specific ADF technology may reduce abuse by specific routes of administration, including these branded medications:

Last updated on: October 24, 2018
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Challenges Facing Abuse-Deterrent Formulations