The push to provide better pain care and ensure adequate analgesia for patients living with chronic pain led to liberalized opioid prescription practices that have been accompanied by a massive increase in the abuse, misuse, and diversion of prescription opioids. Efforts to combat this include technological remedies such as "abuse-deterrent" formulations of opioids and educational approaches such as the REMS program approved by the FDA in 2012.
The US Food and Drug Administration (FDA) is tasked with protecting the health, safety, and welfare of the American people. Over the past 15 years, a massive effort has been made to improve pain control for millions of people living and suffering with chronic pain. Multidisciplinary pain treatment, once so popular and effective, is mostly gone and most people with chronic pain have it managed through interventions and opioids, with an occasional referral to physical therapy.
With the increase in opioid prescribing there was an unintended consequence of opioid-related abuse, diversion, overdose, and death. Congress directed the FDA to make the dying stop, resulting in passage of the Food and Drug Administration Amendment Act of 2007 (FDAAA 2007), and ultimately to the current efforts by the pharmaceutical industry to provide opioid education as part of a class-wide Risk Evaluation and Mitigation Strategy (REMS) for extended-release (ER) and long-acting (LA) opioid formulations. Additionally, opioid makers now have draft “Guidance for Industry: Abuse-Deterrent Opioids-Evaluation and Labeling” to utilize if they wish to obtain label changes.
These proposed guidelines, issued in January 2013, lay out a blue print for opioid analgesic manufacturers that wish to develop opioid formulations with potentially abuse-deterrent properties. While immediately acknowledging that prescription opioid analgesics are an important component of modern pain management, the FDA admits that these same medications have created a serious and growing public health problem. They pledge to address the problem while ensuring that patients suffering with chronic pain have appropriate access to opioid analgesics. In other words, the FDA is trying to put the genie back into the bottle.
The “Guidance for Industry” document is quite thorough in defining all of the currently available abuse-deterrent technologies and formulations: physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, pro-drug, and combinations of strategies. “To obtain a full and scientifically rigorous understanding of the impact of a technology or technologies on a product’s abuse potential,” the FDA proposes categories of testing involving: laboratory-based in vitro manipulation and extraction studies (Category 1), pharmacokinetic studies (Category 2), clinical abuse potential studies (Category 3), and post-marketing data analysis to assess the impact of an abuse-deterrent formulation on actual abuse (Category 4).
In laying out the criteria and rationale for testing of abuse-deterrent formulations, the FDA’s “Guidance for Industry” document unfortunately also provides information that could potentially be used to defeat or compromise controlled release mechanisms, prepare immediate-release formulations for alternative routes of administration, and separate an opioid antagonist, if present, from the opioid agonist. The FDA describes specific extractability and solubility studies to be designed and specifically names water, vinegar, ethanol, isopropanol, acetone, mineral spirits, and other solvents, while also mentioning relevant solvent characteristics such as pH, polarity, and protic vs. aprotic. Spend a few minutes on Google and you will understand what these mean. Route-specific information about snorting, smoking, and intravenous administration of manipulated opioids is provided.
Much of the FDA’s “Guidance for Industry” document is technical and standardizes what testing should be performed, what pharmacokinetic characteristics should be considered, who should be tested in studies, how comparisons should be done, what determines drug liking, and what statistical methods should be used. The net result will be the development of four tiers of claims made regarding the potential abuse-deterrent properties of a product: formulated with physiochemical barriers (Tier 1), expected to reduce or block effect of the opioid when manipulated (Tier 2), expected to result in a meaningful reduction in abuse (Tier 3), and demonstrated reduced abuse in the community (Tier 4). Just taking more medication than intended orally will not be addressed by any of the current available strategies or proposed labeling tiers, and realistically may never occur.
Manipulating formulations to deliver drug more rapidly is one thing, but stopping people from just overdosing with oral pills and tablets is nearly impossible to prevent. There is no viable way to make people who are willing to do anything to get high (even die) refrain from taking more medication than is prescribed unless all opioid analgesics available in the US are dispensed only in unit doses on a daily basis (as is done in methadone maintenance clinics). This is so cost-ineffective and burdensome for the health care system that it will never happen.
The FDA is now considering the Drug Enforcement Administration’s (DEA) request for scheduling hydrocodone as a CII (it is now a CIII). The FDA Drug Safety and Risk Management Advisory Committee voted in favor of making this change, so it may yet come to pass. The state of New York is taking this action in 2013 regardless of what the FDA or DEA decide to do. Inevitably, moving hydrocodone to Schedule II will reduce the number of prescriptions generated as all refills would require a new written prescription from a physician (no more telephone or faxed refill requests). Likely, the opioid problem will shift to codeine or heroin, but won’t go away.
On February 7-8, 2013, the FDA held hearings on the role of opioid analgesics, and considered a proposal by the Physicians for Responsible Opioid Prescribing (PROP) that calls for several radical changes in the way opioids are marketed and prescribed (more on this here, here, and here). If the PROP proposal is implemented there will be “stop” points for maximum opioid doses, limits on the duration of treatment, and the need for other considerations when prescribing opioids for those with chronic non-cancer pain. Missing from the “put the genie back in the bottle” process will be any real measures to provide multidisciplinary care for most Americans in pain. The debate will go on about the appropriateness of opioid analgesics, the need for more interventions, and options to spare patients from opioids, but I predict very little thought will be given to providing multidisciplinary care with an emphasis on rehabilitation.
At some point in the 1990s it was determined somehow that long-term treatment with opioids, repeated use of interventional procedures, and performing definitive surgeries was more important than restoring people in pain to productive lives. Instead of comprehensive programs utilizing behavioral services, physical and occupational therapies, graded exercise, and work hardening, with individualized tailoring of medication and judicious use of interventional methods, we now fit patients into standard regimens.
The FDA hopes that, through the REMS program, 320,000 US prescribers of opioid analgesics will receive voluntary education on the use of ER/LA opioid analgesic in the next four years. The FDA also hopes that the makers of these medications will do what they can to “harden” opioid analgesics to resist common forms of manipulation. Perhaps when/if hydrocodone is scheduled at the same level as hydromorphone, meperidine, methadone, morphine, oxycodone, and oxymorphone US prescribers will think twice about “phoning in” several hundred hydrocodone and acetaminophen tablets with five refills.
Sadly, the genie is out of the bottle. Millions of Americans are now dependent upon opioid analgesics for their ability to perform activities of daily living, and a certain amount of collateral damage may have to be tolerated.
It took the FDA from late 2007 (when FDAAA 2007 was passed) until July 2012 to get the ER/LA opioid REMS education defined. It was only in 2013 that educational providers were identified, and it remains unlikely that any education will commence by 3/1/2013, as directed by the FDA’s July 2012 “guidelines.” Will manufacturers with short patent lives remaining undertake the testing programs envisioned by the “Guidance for Industry” document? Will the FDA seriously consider allowing generic manufacturers to bring back “soft” opioid formulations that have now been “hardened” to resist common forms of manipulation? Perhaps around 2018 we will know.
B. Eliot Cole, MD, MPA, is a member of the Pain Management editorial advisory board. He has served in executive positions for several prominent pain management organizations and societies, including the American Society of Pain Educators and the American Academy of Pain Management. He has been a pain management fellow, clinician, educator, and advocate for nearly 30 years and has practiced in a variety of settings serving a wide range of patients.