Misuse and abuse of opioids pose serious public health and safety risks. A hydrocodone bitartrate extended-release (ER) tablet, formulated with CIMA® Abuse-Deterrence Technology, provides resistance against rapid release of hydrocodone when tablets are manipulated or taken with alcohol, potentially reducing abuse liability when misused or abused. This study examined the relative abuse potential of manipulated intranasal hydrocodone ER in healthy nondependent adults with a history of recreational and intranasal opioid use. Subjects able to tolerate a 45-mg intranasal dose of hydrocodone active pharmaceutical ingredient (API) powder and discriminate effects of hydrocodone from placebo were randomized into a double-blind, 5-period crossover, treatment phase to assess abuse potential. Subjects received each of the following: intranasal manipulated hydrocodone ER 45 mg, intranasal hydrocodone API 45 mg, intact oral hydrocodone ER 45 mg, intranasal manipulated Zohydro 45 mg (commercially available hydrocodone ER capsule), and placebo. Forty-five subjects were enrolled; 34 were evaluable for pharmacodynamic assessments performed through 48 hours after administration of study drug. Maximum effect (Emax) of “at this moment” drug liking based on a bipolar Visual Analog Scale (VAS; primary endpoint) was significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (72.8 vs. 80.2 and 83.2, respectively) and significantly (P<0.001) higher vs. oral hydrocodone ER (57.3) and placebo (58.6). Emax of end-of-day/next-day Overall Drug Liking VAS (co-primary endpoint) was also significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (68.5 vs. 77.1 and 79.8, respectively) and significantly (P≤0.001) higher vs. oral hydrocodone ER (57.8) and placebo (57.7). No new safety signals were observed. Abuse potential via the intranasal route, one of the two most common routes of abuse, was significantly lower with hydrocodone ER compared with non–abuse-deterrent opioid products, including Zohydro. When administered as intended (intact orally), liking scores for hydrocodone ER were similar to placebo. Misuse and abuse of opioids pose serious public health and safety risks. A hydrocodone bitartrate extended-release (ER) tablet, formulated with CIMA® Abuse-Deterrence Technology, provides resistance against rapid release of hydrocodone when tablets are manipulated or taken with alcohol, potentially reducing abuse liability when misused or abused. This study examined the relative abuse potential of manipulated intranasal hydrocodone ER in healthy nondependent adults with a history of recreational and intranasal opioid use. Subjects able to tolerate a 45-mg intranasal dose of hydrocodone active pharmaceutical ingredient (API) powder and discriminate effects of hydrocodone from placebo were randomized into a double-blind, 5-period crossover, treatment phase to assess abuse potential. Subjects received each of the following: intranasal manipulated hydrocodone ER 45 mg, intranasal hydrocodone API 45 mg, intact oral hydrocodone ER 45 mg, intranasal manipulated Zohydro 45 mg (commercially available hydrocodone ER capsule), and placebo. Forty-five subjects were enrolled; 34 were evaluable for pharmacodynamic assessments performed through 48 hours after administration of study drug. Maximum effect (Emax) of “at this moment” drug liking based on a bipolar Visual Analog Scale (VAS; primary endpoint) was significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (72.8 vs. 80.2 and 83.2, respectively) and significantly (P<0.001) higher vs. oral hydrocodone ER (57.3) and placebo (58.6). Emax of end-of-day/next-day Overall Drug Liking VAS (co-primary endpoint) was also significantly (P=0.004) lower for hydrocodone ER vs. hydrocodone API and Zohydro (68.5 vs. 77.1 and 79.8, respectively) and significantly (P≤0.001) higher vs. oral hydrocodone ER (57.8) and placebo (57.7). No new safety signals were observed. Abuse potential via the intranasal route, one of the two most common routes of abuse, was significantly lower with hydrocodone ER compared with non–abuse-deterrent opioid products, including Zohydro. When administered as intended (intact orally), liking scores for hydrocodone ER were similar to placebo.