A Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Study to Evaluate the Abuse Potential of Oxymorphone Compared to Other Mu Opioid Agonists in Physically Dependent Opioid Users with Moderate-Severe Opioid Use Disorder

Oxymorphone (14-hydroxydihydromorphinone) is a semisynthetic ì-opioid agonist, structurally similar to oxycodone and hydromorphone, which displays a very high degree of ì-opioid receptor specificity and intrinsic activity. Oxymorphone is currently marketed in the United States as a prescription analgesic for the treatment of moderate-to-severe pain. However, as oral oxymorphone prescribing and availability has increased over the past several years, rates of diversion, abuse and overdose deaths involving oxymorphone have also increased. In 2011, Endo Pharmaceuticals introduced a new version of the extended-release oral formulation for approval as an abuse-deterrent formulation (ADF). During this time and since approval of the newly formulated ER oxymorphone formulation, significant public health concerns have arisen from the misuse of Opana ER® (outbreak of HIV infection, Opana® injection-related blood disorders). Both of these health complications were the result of crushing and preparing the oral formulation (with excipients) for intravenous use and confirmed that absence of protection against intravenous preparation of this purported abuse deterrent formulation and a propensity for drug users to misuse this formulation specifically by the intravenous route. In June 2017, the FDA requested the Sponsor to remove the Opana ER® from the market, and the Sponsor quickly followed with a refusal to comply. While it is clear that there have been significant unintended public health harms related to the misuse of oxymorphone by those with intent to misuse the drug, the factors contributing to these observations are incompletely known. There are a number of issues that could contribute to the observed shift from intranasal misuse to intravenous misuse of Opana ER and its observed abuse potential. However, one possible contributing factor is the intrinsic activity of oxymorphone itself when administered by the intravenous route. Whether the abuse liability of intravenous oxymorphone is similar to or different from other full mu opioid agonists is unknown and is the focus of this study. This inpatient, randomized, double-blind placebo-controlled study will enroll active opioid users (n=10 completers) who are physically dependent on opioids to evaluate the relative reinforcing effects of oxymorphone (0, 10, 18, 32, and 56 mg/70 kg, intravenous, i.v.) compared to oxycodone (0, 10, 18, 32, and 56 mg/70 kg, i.v.), morphine (0, 10, 18, 32, and 56 mg/70 kg, i.v.), and fentanyl (0, 0.056, 0.1, 0.18, and 0.32 mg/70 kg, i.v.) by using laboratory models of drug taking (e.g., drug self-administration) and drug choice (e.g., drug vs. drug assessments). Secondary outcomes will include full time-action curves for subjective and physiological effects of each drug condition. A dose finding/pilot analysis (n=3 completers) will be conducted prior to the main study to determine dose equivalency of the test compounds. Overall, this study will allow us to evaluate the relative reinforcing efficacy and the subjective and physiological effects of intravenous oxymorphone, providing some of the first controlled data in humans on this important public health topic.