The Opioid Crisis
A NATIONAL PUBLIC HEALTH EMERGENCY
SAFERx Pharmaceuticals’ new class of alcohol-resistant opioids fits into three of the FDA proposed abuse-deterrent formulation categories: 'Novel approaches', 'Aversion', and (conceptually) 'Agonist/Antagonist combination; these latter two categories are characterized as follows:
'Substances can be added to the product to produce an unpleasant effect if the dosage form is manipulated or is used in a manner other than directed. '
By including an aldehyde dehydrogenase inhibitor with the opioid analgesic in a single tablet, the proposed FDCs represent a novel, ‘alcohol-proof’ class of opioid. This is because if the medication is taken as directed- that is, without concurrent consumption of alcohol- the opioid component will exert its typical profile of analgesic effects and the aldehyde dehydrogenase inhibitor component will exert no effect and go unnoticed by the patient. But if, against medical advice, alcohol is consumed in conjunction with the opioid medication, the presence of the aldehyde dehydrogenase inhibitor (which prevents the metabolism of alcohol) will result in a powerful noxious reaction characterized by severe flushing, nausea, and vomiting (referred to as the disulfiram-alcohol reaction), thereby limiting additional alcohol consumption.
'Antagonists can be added to interfere with, reduce, or defeat the euphoria associated with abuse.'
Although the proposed fixed-dose combinations do not contain an antagonist ligand per se, the mechanism of deterrence is also conceptually consistent with the ‘agonist-antagonist combination’ ADF category, as the addition of an aldehyde dehydrogenase inhibitor antagonizes the metabolism of ethanol, thereby interfering with/reducing (via discouragement) or defeating the euphoria associated with alcohol co-administration (via induction of the disulfiram-alcohol reaction).
The FDA has recently encouraged the development of prescription opioids with abuse-deterrent formulations (ADFs) to help combat the opioid crisis.
The FDA Initiative to Enhance Prescription Opioid Safety
The agency recognized that abuse-deterrent opioids are not abuse-proof, but are a step toward products that may help reduce abuse, and in March 2015 issued, “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling”. The agency has since broadly publicized its position that, “The FDA looks forward to a future in which most or all opioid medications are available in formulations that are less susceptible to abuse than the formulations that are on the market today. To achieve this goal, FDA is taking steps to incentivize and support the development of opioid medications with progressively better abuse-deterrent properties.”
In their guidance to industry, the FDA indicates, "Opioid products can be abused in a number of ways… Abuse-deterrent technologies should target known or expected routes of abuse relevant to the proposed product. As a general framework, abuse-deterrent formulations can currently be categorized as follows: Physical/chemical barriers; Agonist/antagonist combinations; Aversion; Delivery system; New molecular entities and prodrugs; and "Novel approaches".
Existing ADF opioid products have largely focused on the 'physical/chemical barrier' category, and in general are designed to hinder the crushing/chewing/snorting or IV administration routes of abuse. And while these are well-established methods of prescription opioid abuse, the extent to which they contribute to overdose-related mortality is unknown. To date, no opioid ADF other than the new class of fixed-dose combinations developed by SAFERx PHARMACEUTICALS prevents/limits the concurrent consumption of alcohol with the opioid. This new technology is therefore felt to represent a paradigm-shifting advance in the science of abuse-deterrence, which when used in at-risk patient populations has the potential to save nearly 4000 American lives annually, and thousands more around the world.