(421) CR845, a novel peripherally-acting kappa opioid receptor agonist, has low abuse potential compared with pentazocine

Abstract

CR845, a potent, peripherally-acting, selective kappa opioid receptor agonist, is being developed for the treatment of acute and chronic pain. This study examined the relative abuse potential of CR845 compared to placebo or pentazocine, a schedule IV opioid analgesic. Recreational polydrug users with experience with opioids and hallucinogenic agents were enrolled in this single-center, randomized, double-blind, active- and placebo-controlled study. Thirty-nine subjects received a single bolus IV dose of the following 4 treatments in random order: CR845 5 mcg/kg (therapeutic dose), CR845 15 mcg/kg (supra-therapeutic dose), placebo, and pentazocine 0.5 mg/kg. Treatments were separated by 48-hour washout period. Drug liking bipolar Visual Analog Scale (VAS) was the primary measurement, and was assessed periodically between 5 minutes and 8 hours after dosing. This trial met the primary endpoint with drug liking scores for pentazocine significantly greater than that of placebo and either doses of CR845 (P<0.0001 for each comparison to pentazocine). The least squares (LS) mean for the maximum drug liking VAS (Emax) scores (±standard error of LS mean) were 87.6±1.9 for pentazocine, 65.3±1.9 for CR845 5 mcg/kg, 66.9±1.9 for CR845 15 mcg/kg, and 52.4±1.9 for placebo, indicating that both doses of CR845 had significantly lower drug liking response compared to pentazocine. Additional bipolar VAS measurements were lower for CR845 compared with pentazocine for “overall drug liking” (P<0.0001 for both doses of CR845) and “take drug again” (P<0.0003 for CR845 5 mcg/kg and P<0.0001 for CR845 15 mcg/kg). These VAS scores for CR845 were equivalent for both doses and were similar to those of placebo. These results suggest that the novel and selective peripherally acting kappa agonist CR845 may present a low risk for abuse liability in humans. Sponsored by Cara Therapeutics. CR845, a potent, peripherally-acting, selective kappa opioid receptor agonist, is being developed for the treatment of acute and chronic pain. This study examined the relative abuse potential of CR845 compared to placebo or pentazocine, a schedule IV opioid analgesic. Recreational polydrug users with experience with opioids and hallucinogenic agents were enrolled in this single-center, randomized, double-blind, active- and placebo-controlled study. Thirty-nine subjects received a single bolus IV dose of the following 4 treatments in random order: CR845 5 mcg/kg (therapeutic dose), CR845 15 mcg/kg (supra-therapeutic dose), placebo, and pentazocine 0.5 mg/kg. Treatments were separated by 48-hour washout period. Drug liking bipolar Visual Analog Scale (VAS) was the primary measurement, and was assessed periodically between 5 minutes and 8 hours after dosing. This trial met the primary endpoint with drug liking scores for pentazocine significantly greater than that of placebo and either doses of CR845 (P<0.0001 for each comparison to pentazocine). The least squares (LS) mean for the maximum drug liking VAS (Emax) scores (±standard error of LS mean) were 87.6±1.9 for pentazocine, 65.3±1.9 for CR845 5 mcg/kg, 66.9±1.9 for CR845 15 mcg/kg, and 52.4±1.9 for placebo, indicating that both doses of CR845 had significantly lower drug liking response compared to pentazocine. Additional bipolar VAS measurements were lower for CR845 compared with pentazocine for “overall drug liking” (P<0.0001 for both doses of CR845) and “take drug again” (P<0.0003 for CR845 5 mcg/kg and P<0.0001 for CR845 15 mcg/kg). These VAS scores for CR845 were equivalent for both doses and were similar to those of placebo. These results suggest that the novel and selective peripherally acting kappa agonist CR845 may present a low risk for abuse liability in humans. Sponsored by Cara Therapeutics.