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Original Investigation |

Hydromorphone Compared With Diacetylmorphine for Long-term Opioid Dependence A Randomized Clinical Trial

Eugenia Oviedo-Joekes, PhD1,2; Daphne Guh, MSc1; Suzanne Brissette, MD3; Kirsten Marchand, BSc1,2; Scott MacDonald, MD4; Kurt Lock, BA1; Scott Harrison, MA4; Amin Janmohamed, MSc1; Aslam H. Anis, PhD1,2; Michael Krausz, MD1,5; David C. Marsh, MD6; Martin T. Schechter, MD1,2
[+] Author Affiliations
1Centre for Health Evaluation and Outcome Sciences, Providence Health Care, St Paul’s Hospital, Vancouver, British Columbia, Canada
2School of Population and Public Health, Faculty of Medicine, University of British Columbia, Vancouver, Canada
3Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada
4Providence Crosstown Clinic, Providence Health Care, Vancouver, British Columbia, Canada
5Department of Psychiatry, University of British Columbia, Vancouver, Canada
6Northern Ontario School of Medicine, Sudbury, Canada
JAMA Psychiatry. 2016;73(5):447-455. doi:10.1001/jamapsychiatry.2016.0109.
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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

Figures in this Article

Figures

Place holder to copy figure label and caption
Figure 1.
Study Group Assignment and Retention Throughout the Trial

HCI indicates hydrochloride; ITT, intent to treat (included all randomized participants [using multiple imputation in case of missing assessments, except when data were missing owing to death]); MMT, methadone maintenance treatment; and PP, per-protocol (included all participants receiving treatment with injectables ≥20 days in the prior month of the main outcome assessment [the 6-month visit]).

aRefers to not respecting the clinic rules (eg, threats, verbal aggression).

bAmong those who did not discontinue the intervention.

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Figure 2.
Primary Efficacy Outcomes According to the Analysis Population at 6 Months

HCI indicates hydrochloride; ITT, intent to treat (included all randomized participants [using multiple imputation in case of missing assessments, except when data were missing due to death]); PP, per protocol (included all participants receiving treatment with injectables ≥20 days in the prior month of the main outcome assessment [the 6-month visit]). Street opioid use includes illicit use of heroin, morphine, hydromorphone, and speedball (combined street opioids and stimulants). The CI comparison approach is used, in which noninferiority was concluded when the lower bound of the 2-sided 90% CI (corresponding to a 1-sided 95% CI) lies within the noninferiority zone, represented by the shaded area that is defined by the margin. For days of street heroin and opioid use, the margin was −4 days. For the proportion of urinalyses positive for street heroin markers, the margin was −10% of the value for diacetylmorphine (ie, −0.03 for ITT and −0.032 for PP). For days of street heroin and opioid use, baseline values were adjusted.

aIndicates that noninferiority was concluded.

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