Hydromorphone was as effective as pharmaceutical heroin for opioid addiction treatment, but it was associated with fewer serious side-effects, according to results from the SALOME trial presented at the 25th International Harm Reduction Conference (HR17) in Montréal.
These findings suggest that both hydromorphone and heroin should be included among the treatment options for opioid dependence, allowing providers to tailor treatment to the individual, said study co-investigator David Marsh of Northern Ontario School of Medicine.
Methadone and buprenorphine are the standard medications used for opioid substitution therapy, but they do not work for everyone. Around 15 to 25% of people who inject heroin will not respond well to methadone. European studies have found that diacetylmorphine – the active ingredient in heroin – can be more effective for this population.
Heroin-assisted treatment has a long history in the UK and is offered in European countries including Denmark, Germany, the Netherlands and Switzerland. Research has shown that it improves outcomes for selected patients, decreasing illicit drug use and its associated social and health-related harms. No one worldwide has ever died of an overdose in heroin-assisted treatment, Marsh said.
The NAOMI (North American Opiate Medication Initiative) study, a phase 3 randomised controlled trial conducted in Vancouver and Montréal, was the first major North American study comparing injectable diacetylmorphine versus oral methadone. As previously reported, participants who received heroin were more likely to stay on treatment and to reduce illicit drug use and other illegal activities.
But heroin remains illegal for this purpose in most countries. Hydromorphone (brand name Dilaudid) is a semi-synthetic morphine derivative that works similarly to heroin, but it is an approved painkiller and is widely legally available for medical use.
The phase 3 SALOME (Study to Assess Long-term Opioid Medication Effectiveness) trial, conducted at the Providence Health Crosstown Clinic in Vancouver's Downtown Eastside, evaluated whether hydromorphone is as effective as diacetylmorphine for the treatment of long-term opioid addiction.
The earlier NAOMI study included a small group of participants who received injectable hydromorphone to validate self-reports of ongoing drug use, because unlike diacetylmorphine it can be distinguished from illicit heroin on a urine test.
Some participants couldn't tell the difference between hydromorphone and diacetylmorphine, prompting researchers to conduct a larger study comparing these two drugs, Marsh said.
SALOME enrolled 202 participants between 2011 and 2013. About 70% were men, the mean age was 44 years and a third were of aboriginal origin; 60% reported being homeless or unstably housed. The participants were long-term chronic street opioid users, with at least a five-year history of heroin use (mean 15 years) and regular heroin or other opioid injection during the past year. On average they had been on methadone maintenance therapy for almost five years, but had been abstinent from illicit drugs for just seven months, Marsh said. Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone up to three times a day for six months, self-administered under the supervision of nurses at the clinic.
Nearly half of the hydromorphone recipients said they thought they were getting diacetylmorphine or were unsure, while a third of diacetylmorphine recipients thought they were getting hydromorphone or were unsure. Treatment retention was high and similar in both groups, at about 80%.
The study showed that hydromorphone was non-inferior to diacetylmorphine in reducing use of any illicit opioid, both in an intent-to-treat analysis (5.50 vs 3.15 days of use) and a per-protocol analysis that excluded people who did not complete treatment (4.08 vs 2.64 days of use). However, hydromorphone did not quite match diacetylmorphine in reducing street heroin use specifically in the intent-to-treat analysis.
Hydromorphone was statistically superior in decreasing positive urine tests, Marsh reported. In an intent-to-treat analysis 21% of urine tests were positive in the hydromorphone groups versus 30% in the diacetylmorphine group. Hydromorphone recipients also reported fewer days of illegal activity and less crack cocaine use.
Hydromorphone had a better overall adverse events profile than diacetylmorphine. In both groups the most common drug-related serious adverse event was opioid overdose, in all cases managed successfully on site. There were three overdoses in the hydromorphone group compared to 11 in the diacetylmorphine group. All 11 cases of seizures occurred in the diacetylmorphine arm.
"Where possible, both diacetylmorphine and hydromorphone should be incorporated into the addiction treatment repertoire for opioid dependence refractory to existing therapies," the researchers concluded. "In jurisdictions where diacetylmorphine is currently not available, hydromorphone provides a safe, effective and licensed alternative."
"We should by no means take the results of this trial to assume that heroin or hydromorphone would completely replace methadone," Marsh stressed. "Like any other health condition, we need to have multiple medications to be able to tailor a treatment regimen that matches the needs of the individual at that time."
NAOMI and SALOME not only demonstrated the effectiveness of alternatives to methadone, they also paved the way for heroin-assisted treatment in North America – an arduous process that even involved a lawsuit against the Canadian federal government.
NAOMI and SALOME participants have formed a lasting community that continues to advocate for ethical research involving drug users and to fight the stigma surrounding heroin use, whether in a clinical trial or on the streets.
Abstract 1
Background: Diacetylmorphine, the active ingredient in heroin, has been shown to be an effective treatment for people with long-term opioid dependence who have not benefitted from available treatments. However, due to political and regulatory barriers, diacetylmorphine is not available in many settings including the U.S. and Canada. This limits the treatment options for the most vulnerable street opioid users. The present study aimed to test if injectable hydromorphone is non-inferior to injectable diacetylmorphine in reducing illicit heroin and opioid use in chronic injection opioid users after six months of treatment.
Methods: SALOME (Study to Assess Longer-term Opioid Medication Effectiveness) was a phase III, double-blind, non-inferiority trial. Between December 2011 and 2013, the study randomized 202 long-term street opioid injectors in Vancouver (Canada) who were not benefitting from available treatments. Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone treatment (up to three times daily) for six months in a supervised clinic.
Results: Non-inferiority of hydromorphone was conclusive in both ITT and PP analyses of total street opioid use and positive urinalyses, and on PP analysis of street heroin use. Only the difference between ITT groups on street heroin use did not exclude the margin. The most common related serious adverse events were opioid overdoses (n=14) and seizures (n=11), all successfully treated on site without hospitalization. There were 3 overdoses in the hydromorphone group compared to 11 in the diacetylmorphine group, in 41,027 and 44,424 treatment episodes respectively. All 11 seizures occurred in 4 participants in the diacetylmorphine group.
Conclusions: Where possible, both diacetylmorphine and hydromorphone should be incorporated into the addiction treatment repertoire for opioid dependence refractory to existing therapies. In jurisdictions where diacetylmorphine is currently not available, hydromorphone provides a safe, effective and licensed alternative.
Authors
Eugenia Oviedo-Joekes, Daphne Guh, Suzanne Brissette, Kirsten Marchand, Scott MacDonald, Kurt Lock, Julie Foreman, Scott Harrison, David Marsh, Martin Schechter
Abstract 2
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.
Authors
Eugenia Oviedo-Joekes, Daphne Guh, Suzanne Brisette, Kirsten Marchand, Scott MacDonald, Kurt Lock, Scott Harrison, Amin Janmohamed, Aslam H Anis, Michael Krausz, David C Marsh, Martin T Schechter
[link url="http://www.aidsmap.com/Hydromorphone-works-as-well-as-heroin-assisted-drug-addiction-treatment/page/3139262/"]Aidsmap material[/link]
[link url="https://www.hri.global/abstracts/abstrct/222"]HR17 abstract[/link]
[link url="http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2512237"]JAMA Psychiatry abstract[/link]