Anticipated and unanticipated consequences of abuse deterrent formulations of opioid analgesics.

The paper by Hwang, et al. in this volume demonstrates that a reformulation of OxyContin (Purdue Pharma, Yonkers, NY, USA) in 2010, which had been intended to discourage opioid abuse, may have had the unintended consequence of discouraging its therapeutic use as well.1 This is an important finding, despite some flaws in the study, which raises important public health concerns. In this context, some history for those not well-versed in the current epidemic of prescription opioid abuse might be helpful. The abuse problem has its roots in two major developments in the 1990s. The first was a recommendation from the Joint Commission on Accreditation of Healthcare Organizations, which emphasized that pain should be treated as the fifth vital sign, and accordingly, there should be less trepidation about using potent opioids to relieve pain.2 This recommendation led to a surge in the use of opioid analgesics, which resulted in the inevitable diversion of some to those seeking their non-therapeutic effects.3 The second major factor was the introduction of a sustained release formulation of oxycodone—OxyContin— which contained large amounts of pure oxycodone. Sustained release preparations are meant to deliver a drug steadily for 12–24 h, and as a result, it was felt by the company and the Food and Drug Administration (FDA) that OxyContin had very little abuse potential.4,5 This judgment was based on the wellestablished Pavlovian concept that a delay in reinforcement (i.e., in this case, “getting high”) tends to be minimally effective in eliciting an operant response (i.e., drug taking). What the FDA and the manufacturer did not anticipate was the cleverness of illicit drug users. It was quickly established that the sustained release mechanism could easily be breached by crushing or solubilizing the oxycodone, making available large quantities of the active ingredient for snorting or IV injection. OxyContin quickly became the most widely abused and diverted prescription opioid, commanding very high prices on the black market.5,6 As the abuse crisis worsened over a 20-year span, intense government and other regulatory efforts grew to slow the supply of these drugs. Chief among the major steps was the adoption of prescription monitoring programs, which facilitated dual efforts to clamp down on script doctors and, most importantly, patients who “doctor shopped”.7 Other, equally strong measures were joint efforts by federal and state regulatory bodies to eliminate pill mills and the rise of police organizations across the country with dedicated programs to stop the diversion of prescribed substances.8 One additional measure, strongly supported by the FDA, was the development and introduction of abuse deterrent formulations (ADFs) of opioid analgesics.8 Because all drugs meant for oral consumption must be bioavailable and soluble in the gut, very little can be done to reduce abuse by the oral route. Rather, the exclusive purpose of these formulations is to make it difficult to extract the drug by chewing or crushing for inhalation or intravenous use, arguably the most harmful forms of substance abuse.9 Thus far, several products have been developed with abuse deterrent properties, a reformulated OxyContin ADF and Opana ER (oxymorphone, Endo Pharmaceuticals *Correspondence to: T. J. Cicero, Washington University, Psychiatry, 660 South Euclid Ave., Campus Box 8134, St. Louis, Missouri, United States, 63110. E-mail: [email protected]