Challenges Facing Abuse-Deterrent Formulations
PPM: Clinicians may be hesitant to prescribe second-generation ADFs of opioids, which combine naltrexone or naloxone, over concern that the core active ingredient may become inactive or push an abuser into withdrawal. Can you describe this hesitation and how these second-gen mechanisms of action work?
Cohen: The concern has had an anecdotal quality to it; I have heard from pain physicians that “they are aware of failures” with other prescribers/patients using second-gen ADFs but have not experienced themselves. The mechanisms of action in these combination products, known as agonist/antagonist combination pills, retain analgesic properties when swallowed. In this example, the antagonist (naloxone) is not effectively absorbed into the bloodstream when swallowed as intended; this works by allowing the naloxone to pass through the system unabsorbed. When swallowed, the pill is excreted naturally.
However, when snorted or injected intravenously, the antagonist portion of the pill will reduce or counteract opioid-induced euphoria. So if a user crushes the tablet, the naloxone is released, and any desired “high” after ingesting the drug is defeated. If the user is an opioid addict and succeeds in defeating the ADF property, the combination product could throw the misuser into sudden withdrawal with known adverse consequences.
The “fear of failure” for a patient on chronic opioid therapy using the product as prescribed is unwarranted. If a physician suspects that his/her patient may be misusing the product, then another ADF-approved opioid may be more appropriate.
PPM: Third-generation abuse-deterrent technologies (ie, prodrugs) were designed to change at the molecular level, thereby offering no advantage to potential abusers. However, these products are facing an uphill battle in terms of payer coverage. What’s your take?
Cohen: Physicians are well aware of the advantages of prodrugs, as a significant portion of available medications have a prodrug capability. A physician will not prescribe a product that a patient cannot “fill” at the pharmacy. If a pharmacy benefit manager refuses to cover a prodrug, using “fail first” or “step edit” policies, adoption is delayed. All ADF products are hampered by payer refusal to broadly cover these products, which aim to reduce the risk of abuse, misuse, and diversion, as these qualities offer a public health benefit – and not a medical benefit.
PPM: How do currently patented technologies play a role in moving ADFs forward? For example, Oxycontin is patented through 2030.
Cohen: The ultimate key to deploying new and better technologies is for both payers to adopt currently existing abuse-deterrent technology and for FDA to mandate a market conversion to these technologies. Future technologies are dependent on the adoption of current products, which are less abusable than the products credited with causing the opioid crisis.
PPM: The FDA recently issued a Complete Response Letter (CRL) denying the marketing application of a new oxycodone extended-release, abuse-deterrent medication (Remoxy ER, Pain Therapeutics), noting that the data presented did not demonstrate that the benefits of the drug outweighed its risks. The rejection has led the company to shift its tamper-resistant opioid formulations away from pain management and toward treating Alzheimer’s disease. What’s your take on this trend?
Cohen: The CRL issued to Remoxy does not yet constitute a trend, in fact, the request for additional data is consistent with other FDA decisions on the approval or denial of other new drug applications presented for approval. The increased availability of “new” ADF opioids on the market would not impact use, nor should it change the appropriate prescribing of any opioid for patient treatment. More options for the physician to “right size” a script to the most appropriate treatment requires more ADF opioid options to be made available.
