Eugenia Oviedo-Joekes1, Daphne Guh2, Suzanne Brissette3, Kirsten Marchand1, Scott MacDonald4, Kurt Lock2, Scott Harrison4, Amin Janmohamed2, Aslam H Anis1, Michael Krausz5, David C Marsh6, Martin T Schechter1. 1. Centre for Health Evaluation and Outcome Sciences, Providence Health Care, St Paul's Hospital, Vancouver, British Columbia, Canada2School of Population and Public Health, Faculty of Medicine, University of British Columbia, Vancouver, Canada. 2. Centre for Health Evaluation and Outcome Sciences, Providence Health Care, St Paul's Hospital, Vancouver, British Columbia, Canada. 3. Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. 4. Providence Crosstown Clinic, Providence Health Care, Vancouver, British Columbia, Canada. 5. Centre for Health Evaluation and Outcome Sciences, Providence Health Care, St Paul's Hospital, Vancouver, British Columbia, Canada5Department of Psychiatry, University of British Columbia, Vancouver, Canada. 6. Northern Ontario School of Medicine, Sudbury, Canada.
Abstract
IMPORTANCE: Diacetylmorphine hydrochloride (the active ingredient in heroin), delivered under supervision, is effective for the treatment of severe opioid use disorder. However, owing to political and regulatory barriers, it is not available in many settings around the world, which limits the options for many long-term street opioid injectors not attracted into or retained in available treatments. OBJECTIVE: To test if injectable hydromorphone hydrochloride is noninferior to injectable diacetylmorphine in reducing illicit heroin use for chronic injection opioid users after 6 months of intervention. DESIGN, SETTING, AND PARTICIPANTS: The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) was a phase 3, double-blind, noninferiority trial. The study randomized 202 long-term street opioid injectors in Vancouver, British Columbia, Canada. Eligible participants were recruited between December 19, 2011, and December 18, 2013. Both intent-to-treat (ITT) and per-protocol (PP) analyses were conducted. INTERVENTIONS: Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone (up to 3 times daily) for 6 months under supervision. MAIN OUTCOMES AND MEASURES: Primary and coprimary efficacy outcomes were self-reported days of street heroin use (primary), days of any street-acquired opioids in the prior 30 days (noninferiority margin, 4 days), and the proportion of urinalyses positive for street heroin markers (margin, 10% of the observed rate in the diacetylmorphine group). The mean differences between diacetylmorphine and hydromorphone for the ITT and PP analyses were reported. RESULTS: The study included 202 participants; 100 randomized to receivehydromorphone and 102 to diacetylmorphine. Their mean (SD) age was 44.33 (9.63) years, and 30.7% (62 of 202) were women. Noninferiority of hydromorphone was confirmed in the PP analysis (-1.44; 90% CI, -3.22 to 0.27) for street heroin use, although the margin of 4 days was not excluded in the ITT analysis (-2.34; 90% CI, -4.14 to -0.52). Noninferiority was confirmed for any street opioids in the ITT analysis (-0.85; 90% CI, -2.97 to 1.25) and the PP analysis (-0.15; 90% CI, -2.09 to 1.76), as well as for the urinalyses (0.09; 90% CI, -0.02 to 0.19 for the ITT analysis and 0.13; 90% CI, 0.02-0.24 for the PP analysis). There were 29 SAEs considered to have some relationship with the injection medication, 5 in the hydromorphone group and 24 in the diacetylmorphine group (rate ratio, 0.21; 95% CI, 0.06-0.69). Seizures and overdoses accounted for 25 of the 29 related SAEs. CONCLUSIONS AND RELEVANCE: This study provides evidence to suggest noninferiority of injectable hydromorphone relative to diacetylmorphine for long-term opioid dependence. In jurisdictions where diacetylmorphine is currently not available or for patients in whom it is contraindicated or unsuccessful, hydromorphone could be offered as an alternative. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01447212.
RCT Entities:
IMPORTANCE: Diacetylmorphine hydrochloride (the active ingredient in heroin), delivered under supervision, is effective for the treatment of severe opioid use disorder. However, owing to political and regulatory barriers, it is not available in many settings around the world, which limits the options for many long-term street opioid injectors not attracted into or retained in available treatments. OBJECTIVE: To test if injectable hydromorphone hydrochloride is noninferior to injectable diacetylmorphine in reducing illicit heroin use for chronic injection opioid users after 6 months of intervention. DESIGN, SETTING, AND PARTICIPANTS: The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) was a phase 3, double-blind, noninferiority trial. The study randomized 202 long-term street opioid injectors in Vancouver, British Columbia, Canada. Eligible participants were recruited between December 19, 2011, and December 18, 2013. Both intent-to-treat (ITT) and per-protocol (PP) analyses were conducted. INTERVENTIONS:Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone (up to 3 times daily) for 6 months under supervision. MAIN OUTCOMES AND MEASURES: Primary and coprimary efficacy outcomes were self-reported days of street heroin use (primary), days of any street-acquired opioids in the prior 30 days (noninferiority margin, 4 days), and the proportion of urinalyses positive for street heroin markers (margin, 10% of the observed rate in the diacetylmorphine group). The mean differences between diacetylmorphine and hydromorphone for the ITT and PP analyses were reported. RESULTS: The study included 202 participants; 100 randomized to receive hydromorphone and 102 to diacetylmorphine. Their mean (SD) age was 44.33 (9.63) years, and 30.7% (62 of 202) were women. Noninferiority of hydromorphone was confirmed in the PP analysis (-1.44; 90% CI, -3.22 to 0.27) for street heroin use, although the margin of 4 days was not excluded in the ITT analysis (-2.34; 90% CI, -4.14 to -0.52). Noninferiority was confirmed for any street opioids in the ITT analysis (-0.85; 90% CI, -2.97 to 1.25) and the PP analysis (-0.15; 90% CI, -2.09 to 1.76), as well as for the urinalyses (0.09; 90% CI, -0.02 to 0.19 for the ITT analysis and 0.13; 90% CI, 0.02-0.24 for the PP analysis). There were 29 SAEs considered to have some relationship with the injection medication, 5 in the hydromorphone group and 24 in the diacetylmorphine group (rate ratio, 0.21; 95% CI, 0.06-0.69). Seizures and overdoses accounted for 25 of the 29 related SAEs. CONCLUSIONS AND RELEVANCE: This study provides evidence to suggest noninferiority of injectable hydromorphone relative to diacetylmorphine for long-term opioid dependence. In jurisdictions where diacetylmorphine is currently not available or for patients in whom it is contraindicated or unsuccessful, hydromorphone could be offered as an alternative. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01447212.
Authors: John Strang; Nora D Volkow; Louisa Degenhardt; Matthew Hickman; Kimberly Johnson; George F Koob; Brandon D L Marshall; Mark Tyndall; Sharon L Walsh Journal: Nat Rev Dis Primers Date: 2020-01-09 Impact factor: 52.329