Abuse liability of oral formulations of hydromorphone in opioid-experienced, recreational drug users: importance of onset of effect

Abstract

Rate of onset is an important determinant of the abuse liability of opioid formulations. OROS hydromorphone ER is a once-daily opioid formulation that releases hydromorphone at a controlled rate. The objective of this study was to compare the abuse-related effects of various formulations of hydromorphone, with particular emphasis on early time intervals after drug administration. This was a double-blind, placebo-controlled, randomized study in subjects (N=28) with a history of recreational opioid use. In phase A, subjects received immediate-release (IR) hydromorphone 8 mg, intact OROS hydromorphone ER 16 and 32 mg, a milled preparation of OROS hydromorphone ER 8 mg, and placebo in a crossover design. In phase B, subjects who tolerated all treatments in Phase A received single doses of IR hydromorphone (8 mg) and OROS hydromorphone ER (64 mg). Time to maximum effect (TEmax) and area under the effect curve at 2 hours (AUE0-2) were assessed for subject-rated outcomes of “high”, “drug liking”, and “euphoria”. All formulations produced effects significantly different than placebo (P<0.05). For all subject-rated outcomes, the TEmax for all intact doses of OROS hydromorphone ER (range: 7.8-13.3 hours) was greater than the TEmax for 8 mg IR hydromorphone (range: 2.4-3.5 hours) (P<0.05). For AUE0-2, all intact doses of OROS hydromorphone ER produced significantly lower levels of “high” and “euphoria” compared with 8 mg hydromorphone IR (P<0.05). The effects of milled OROS hydromorphone ER were similar to those of IR hydromorphone. The slower onset of effect and decreased reports of “high” and “euphoria” suggest that OROS hydromorphone ER may have less abuse liability than IR hydromorphone when intact tablets are taken whole. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO. Rate of onset is an important determinant of the abuse liability of opioid formulations. OROS hydromorphone ER is a once-daily opioid formulation that releases hydromorphone at a controlled rate. The objective of this study was to compare the abuse-related effects of various formulations of hydromorphone, with particular emphasis on early time intervals after drug administration. This was a double-blind, placebo-controlled, randomized study in subjects (N=28) with a history of recreational opioid use. In phase A, subjects received immediate-release (IR) hydromorphone 8 mg, intact OROS hydromorphone ER 16 and 32 mg, a milled preparation of OROS hydromorphone ER 8 mg, and placebo in a crossover design. In phase B, subjects who tolerated all treatments in Phase A received single doses of IR hydromorphone (8 mg) and OROS hydromorphone ER (64 mg). Time to maximum effect (TEmax) and area under the effect curve at 2 hours (AUE0-2) were assessed for subject-rated outcomes of “high”, “drug liking”, and “euphoria”. All formulations produced effects significantly different than placebo (P<0.05). For all subject-rated outcomes, the TEmax for all intact doses of OROS hydromorphone ER (range: 7.8-13.3 hours) was greater than the TEmax for 8 mg IR hydromorphone (range: 2.4-3.5 hours) (P<0.05). For AUE0-2, all intact doses of OROS hydromorphone ER produced significantly lower levels of “high” and “euphoria” compared with 8 mg hydromorphone IR (P<0.05). The effects of milled OROS hydromorphone ER were similar to those of IR hydromorphone. The slower onset of effect and decreased reports of “high” and “euphoria” suggest that OROS hydromorphone ER may have less abuse liability than IR hydromorphone when intact tablets are taken whole. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO.