Opioid related adverse events in clinical trials- indicators for abuse liability

      Opioids are effective at managing moderate to severe pain; however, several liabilities are associated with their use including abuse potential and risk for dependence. Detecting abuse signals early on can guide future clinical development and influence trial design around the understanding of those liabilities. One approach involves collecting abuse-related AEs in studies with recreational opioid users, who are particularly sensitive to positive opioid effects. This analysis explores the potential for AEs to signal abuse and other liabilities early on. Adverse Event and PD data for opioids were obtained from single-dose, randomized, double-blind crossover studies in recreational opioid users (8 Studies; N=185). Opioids included Hydromorphone (4, 8, 16mg); Hydrocodone 60 mg; Morphine 120mg; Oxymorphone 15 and 30mg; Oxycodone 30, 40, and 60mg3; and intravenous Hydromorphone 30μg/kg and Oxycodone 0.07mg/kg. AEs were coded and categorized as Actual Abuse/Dependence [AD] and those suggestive of Mood-Elevating (ME) or Sedative (SED) effects. Percentage of AE incidence (% of subjects) across treatments was summarized and correlations between PD measures and AEs were performed. No AD adverse events were reported in >750 exposures. The highest incidence of ME events was observed with oxycodone (50%) followed by hydromorphone (∼25%). Sedative effects were reported less often than ME effects. The highest incidence of sedative effects was reported in oxycodone (∼45%) followed by placebo (24%) and oxymorphone (∼21%). Across opioids, the most common ME event was ‘euphoric mood', and ‘somnolence’ was the most common SED event. Drug Liking/Overall Drug Liking scores were higher in subjects who reported euphoric mood as an AE. There was a significant correlation (p<0.001) between median Drug Liking/Overall Drug Liking scores and euphoric mood AE incidence. This evaluation indicated that AEs were generally consistent with PD results suggesting that clinical trial AE patterns may be useful for detecting abuse liability in early drug development.