The complex and intertwined dual epidemics of poorly treated pain and opioid addiction require a combined, artful approach to secure the best possible results for patients. The goal is to effectively treat pain while preventing prescription drug misuse, abuse, diversion/non-medical use, and overdose.
As part of an ongoing push to improve the assessment of new drugs or abuse deterrent formulations (ADFs) for their abuse potential, the FDA is placing much emphasis on rigorous science. The FDA's aim is to put in place appropriate controls to reduce the likelihood that a drug will be abused after marketing. That's one way how they hope to confront prescription drug abuse and misuse.
During September of 2017, the FDA issued letters to 74 manufacturers of Immediate Release (IR) opioid analgesics intended for use in an outpatient setting. In them, the FDA explained that their drugs would now be subject to a more stringent set of requirements under a Risk Evaluation and Mitigation Strategy (REMS). These drugs will now require that training be made available to those prescribing IR opioids. That will include mandatory education for safe prescribing practices and consideration of non-opioid alternatives.
The FDA continues to recognize the benefits of IR formulas to bring relief to many patients who follow prescribed courses of medication. However, once the new policy is fully implemented (in approximately a year), 277 IR opioid analgesics, in addition to the 64 ER opioid analgesic products, will be subject to these REMS requirements.
This is an important step to stem the tide of opioid abuse and misuse. It will be followed shortly with the issuance of guidelines for those who wish to submit an application for approval of generic versions of ADF opioids. While we’re fully aware that ADFs will not prevent people from taking too many tablets (which is one of the main ways in which IR opioids are misused), abuse deterrent technology should prevent deaths.
The science behind ADFs includes various technologies to discourage abuse. For example, one technology makes it difficult for users to crush or dissolve opioid pills (such as Morphabond ) to snort or inject the drug. Another technology uses an opioid antagonist (naloxone in the ER/LA opioid Targiniq and naltrexone in Embeda) that is released if the product is crushed, making the opioid ineffective if it is ingested, snorted, or injected. When taken properly, the drug releases only the opioid from the capsule. However, when the capsule is crushed, the opioid antagonist is released, blocking some of the euphoric effects of the opioid and possibly causing withdrawal in people who are physically dependent on opioids.
The FDA often requires a Human Abuse Potential study to assess the abuse potential of a New Chemical Entity (NCE) for a Central Nervous System (CNS) acting drug. A study is required to ascertain if an ADF can “meaningfully deter abuse," even if it does not "fully prevent abuse” (Abuse-Deterrent Opioids —Evaluation and Labeling Guidance for Industry, 2015). The FDA defines the term abuse as “intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect.”
Note that the phrase "abuse-deterrent" is used rather than "tamper-resistant." The latter often is used in connection with packaging of other medications and has an entirely different meaning that involves safety rather than abuse.
The science of ADFs is still relatively young, and technologies are continually evolving. Because of this, the FDA can adapt their methods of evaluation for abuse-deterrent properties of new molecular entities depending on the proposed route of administration. Abuse-deterrent technologies should target known and expected routes of administration of a proposed product and ensure that a product would not increase the potential of an abuser's moving to a riskier route of administration. Essentially, the FDA will look at what they term the “totality of evidence" when reviewing the results of studies evaluating the abuse-deterrent properties.
Abuse-Deterrent Opioids — Evaluation and Labeling Guidance for Industry identifies seven current categories for ADFs:
- Physical/chemical barriers – Physical barriers can prevent chewing, crushing, grating, cutting, or grinding of the dosage form.
- Agonist/antagonist combinations – An opioid antagonist can be added to interfere with, reduce, or defeat the euphoria associated with abuse (as mentioned previously in relation to naloxone and naltrexone).
- Aversion – Substances can be added to the product to produce an unpleasant effect if the dosage form is manipulated or is used at a higher dosage than directed.
- Delivery system (including use of depot injectable formulations and implants) – Certain drug release designs, or methods of drug delivery, can offer resistance to abuse.
- New molecular entities and prodrugs – The properties of an NME or prodrug could include the need for enzymatic activation, different receptor binding profiles, slower penetration into the central nervous system, or other novel effects.
- Combination – Two or more of the above methods could be combined to deter abuse.
- Novel approaches
There is still considerable room to advance research and assessment of ADFs. As ADF technology advances, labeling should also evolve.
Ultimately, we need to develop pain medicine with no rewarding properties—at least, with no rewarding properties within the dose range that provides the most pain relief. In the meantime, prevention of abuse, addiction, overdose, and death through ADFs, or other measures, is an important step forward. So, too, is keeping access to existing pain relief in its safest possible forms available for the millions of patients who need them.