Context and Policy Issues
Opioids have analgesic and central nervous system depressant effects and have been used as medication for pain relief.1 However, opioids also have the potential to cause euphoria and have been misused, resulting in opioid dependency and consequently increased morbidity and mortality.1 Opioid dependency is a serious problem and impacts public health with considerable clinical, social and economic implications.2,3 The Centers of Disease Control and Prevention estimated that in the US, the economic burden resulting from the misuse of prescription opioids is $78.5 billion per year (which includes costs for health care, productivity loss, treatment for dependency, and criminal justice involvement).2 In Canada, overdose deaths resulting from opioid dependency are on the rise and are a serious concern. It was estimated that in Canada in 2018, there were at least 4,460 deaths due to opioid overdose and 94% of these were determined to be unintentional overdose; this is a 9.4% increase in overdose deaths from 2017, and 48% increase from 2016.4
Opioid agonists have the ability to suppress opioid cravings and withdrawal symptoms from acute effects of other opioids, and have been used as a treatment option for opioid dependency. Opioid agonists include drugs such as methadone, buprenorphine, diacetylmorphine (DAM) and hydromorphone (HDM). In some individuals with opioid dependency, even with repeated treatment with oral opioid agonists no benefit was achieved.4 Injectable opioid agonists have shown some promise in treating opioid dependency in these individuals.4 Injectable opioid agonists have a rapid onset of action and shorter duration to reach peak values in comparison to oral opioid agonists, and hence there is potential for overdose issues. Administration of injectable opioid agonist under supervision would allow for immediate action to be taken in case of overdose to help ensure safety, although take-home dosing has also been studied.3,5
The purpose of this review is to summarize the evidence on the clinical effectiveness and cost-effectiveness of injectable opioid agonist treatment (with DAM or HDM, alone or in combination with methadone or buprenorphine/naloxone), compared with alternative pharmacological treatments or no treatment, for individuals with opioid dependency.
Research Questions
What is the clinical effectiveness of injectable opioid agonist treatment for patients with opioid dependence?
What is the cost-effectiveness of injectable opioid agonist treatment for patients with opioid dependence?
Key Findings
Five relevant reports were identified. These comprised one systematic review, two randomized controlled trials (RCT), and two economic evaluations.
One systematic review found that compared to patients treated with other treatments (i.e., methadone, or any other treatment program) those treated with injectable diacetylmorphine (DAM) (with or without the addition of methadone) had statistically significantly greater retention in treatment, reduction in illicit drug use, reduction in criminal activities, and fewer convictions and imprisonments, but no statistically significant difference in mortality and greater occurrence of adverse events.
One RCT showed that injectable hydromorphone (HDM) was not inferior to injectable DAM with respect to days of street opioid use, and proportions of urinalysis positives for street heroin metabolites in urine samples. There were no statistically significant between-group differences with respect to retention to treatment, criminal activity, and physical health and psychological health, however there was statistically significantly higher risk of adverse events related to the intervention in the DAM group compared to the HDM group.
One crossover RCT with 28 patients showed that there was statistically significant improvement after injectable DAM treatment compared to before treatment with respect to anxiety, anger, emotional excitement and well-being, and statistically significantly less heroin craving with injectable DAM compared to injectable placebo.
The results of the economic evaluations, considering a lifetime time horizon and societal perspective, indicated that DAM and HDM treatments each provided more benefits than methadone treatment, and at lower cost for individuals who had previously used other treatment options. Based on incremental cost-effectiveness ratios, it was found that both DAM and HDM dominated methadone. One evaluation reported that the probability of DAM being cost-effective was 76% at a willingness-to-pay (WTP) threshold of $0 per QALY gained, and 95% at a WTP threshold of $100,000 per QALY gained. The second evaluation did not report the WTP threshold.
Findings need to be interpreted with caution, considering the overall limited quantity of evidence, and that the economic evaluations were based on several assumptions.
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including PubMed, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were injectable opioid agonist treatment and opioid dependence. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and April 26, 2020.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in .
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in , they were duplicate publications, or were published prior to 2010. Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded. Primary studies retrieved by the search were excluded if they were captured in one or more included systematic reviews. Secondary analyses of included primary studies that did not include any additional relevant outcomes were excluded.
Critical Appraisal of Individual Studies
The included publications were critically appraised by one reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)6 for systematic reviews, the Downs and Black checklist7 for randomized studies, and the Drummond checklist8 for economic evaluations. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 140 citations were identified in the literature search. Following screening of titles and abstracts, 110 citations were excluded and 30 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these 32 potentially relevant articles, 27 publications were excluded for various reasons, and five publications met the inclusion criteria and were included in this report. These comprised one systematic review,3 two RCTs,9,10 and two economic evaluations.11,12 No relevant non-randomized studies were identified. Appendix 1 presents the PRISMA13 flowchart of the study selection.
Summary of Study Characteristics
The study characteristics are summarized below. Additional details regarding the characteristics of included publications are provided in Appendix 2. In the literature, various terms were used for “heroin”, such as diacetylmorphine (DAM) and diamorphine. For the purpose of consistency, we will use the term DAM throughout the main text. However, street heroin will be referred to as street heroin.
Study Design
The included systematic review3 was published in 2011. It had a broad focus and included eight studies of which seven studies were relevant for this review. These seven studies were RCTs published between 1980 and 2010. The systematic review conducted meta-analyses and reported pooled estimates when possible, and when not possible presented results of the individual studies separately.
Two relevant primary studies9,10 were identified. One was a double-blind, non-inferiority RCT9 published in 2016 and is also referred to as the Study to Assess Long-term Opioid Medication Effectiveness (SALOME). The second study was a cross-over RCT10 published in 2013.
Two relevant economic evaluations11,12 were identified. Both evaluations were cost utility analyses, with lifetime time horizons and societal perspectives. Both evaluations used semi Markov cohort models and conducted sensitivity analyses. The models included four states: treatment, relapse, abstinence, and death. Clinical and cost data were obtained from the North American Opiate Medication Incentive (NAOMI) trial, SALOME trial, published articles and databases for one evaluation,11 and from the NAOMI trial, other published articles and databases for the other evaluation.12
Country of Origin
The first author of the systematic review3 was from Portugal. Of the seven relevant studies, two studies were from the UK, and one study each was from Canada, Germany, the Netherlands, Spain, and Switzerland.
The first author of the RCT9 was from Canada and the study was conducted in Canada. The first author of the cross-over RCT10 was from Switzerland and the study was conducted in Switzerland.
The first authors of both economic evaluations11,12 were from Canada, and the studies on which the evaluations were based were conducted in Canada.
Patient Population
The included systematic review3 involved 1,793 participants who were chronically dependent on DAM. In the individual studies in this systematic review, the mean age in years ranged between 24 and 39 (4 studies), 18 to 65 (1 study), ≥25 (1 study), and >20 (1 study). The proportion of males ranged between 61% to 90% in five studies, and was not reported in two studies. History of drug use was greater than two years in six studies and 26.5 days in the past month in one study.
The RCT9 included 202 adults with opioid dependency. The mean age was 45 years, the proportion of males was 70%, and the mean history of street heroin use was 15 years. The crossover RCT10 included 28 adults with DAM dependency. The mean age was 41 years, proportion of males was 67%, and mean duration of dependency was seven years.
One economic evaluation11 involved adults with severe opioid use disorder (opioid dependency) who had been using illicit opioids, even though other treatment options were available (individuals who participated in the SALOME trial). The other economic evaluation12 involved adults with chronic opioid dependence refractory to treatment (individuals who participated in the NAOMI trial).
Interventions and Comparators
In the systematic review,3 the interventions in the included studies were injectable DAM, injectable DAM plus methadone, injectable DAM plus oral methadone, DAM maintenance, or self-injected DAM; the comparators were methadone, oral methadone, or waitlist (i.e., any other drug treatment program could be used). As the studies were pooled, in the rest of this report the various intervention will be collectively referred to as “injectable DAM”, and the various comparators will be collectively referred to as “other treatments”. In instances where the comparator group was methadone only it will be referred to as the methadone group. Treatment duration ranged between six months and 12 months.
In the RCT (the SALOME study)9 injectable hydromorphone (HDM) was compared with injectable DAM over a duration of six months, and in the crossover RCT10 injectable DAM was compared to injectable placebo, before and 60 minutes after treatment.
One economic evaluation11 compared injectable HDM, injectable DAM, and oral methadone. Comparisons between injectable HDM and injectable DAM were indirect, since this evaluation used data from one RCT (NAOMI) that compared DAM to methadone and another RCT (SALOME) that compared HDM to methadone (i.e., methadone was a common comparator). The other economic evaluation12 compared injectable DAM with oral methadone.
Outcomes
The systematic review3 reported on retention in treatment, relapse to street heroin, use of other substances, mortality, medical adverse events, criminal offense, incarceration, and social functioning.
The RCT (SALOME study)9 reported on street opioid use, urinalyses positive results, physical and mental symptoms (using Maudsley Addition Profile [MAP]), illegal activities, crack cocaine use, and adverse effects. The crossover RCT10 reported on drug cravings, state anxiety, state anger, emotional excitement, and well-being. The various assessment tools are described in Appendix 4, .
Both economic evaluations11,12 reported incremental cost-effectiveness ratios (ICER), i.e., cost per quality adjusted life year (QALY).
Summary of Critical Appraisal
An overview of the critical appraisal of the included publications is summarized below. Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
The systematic review3 was well-conducted overall, however details of the interventions and comparators were not clearly reported and there were some inconsistencies between information presented in the text and figures. A comprehensive literature search was conducted. The objective, the study characteristics, and article selection were described. Article selection and data extraction were done independently by two reviewers. Quality assessment of the studies was conducted and the risk of bias was generally low. Meta-analyses were conducted appropriately. It was unclear if publication bias was explored. The authors reported that there were no conflicts of interest.
In the RCT (SALOME study)9 the objective, and inclusion and exclusion criteria were stated; the patient population, intervention, and outcomes were described; the randomization procedure was described; and both patients and investigators were blinded to treatment groups. A sample size calculation was undertaken and the appropriate number of patients were recruited. Both intention-to-treat and per protocol analyses were conducted. The authors reported that there were no conflicts of interest.
In the cross-over RCT10 the objective, and inclusion and exclusion criteria were stated; and the patient population, intervention, and outcomes were described, but details of the outcome measures were sparse. The randomization procedure was not described. The patients and experimenter were blinded to the administered substance in the first session but were unblinded at the second session (i.e., after crossover). It was unclear if a sample size calculation was conducted. Intention-to-treat analyses were presented. The authors reported that there were no conflicts of interest.
Both economic evaluations11,12 were generally well described. The objectives, time-horizons, perspectives taken, sources for clinical and cost data, and discounting were reported. The models used were described, and assumptions were reported and appeared to be reasonable. Sensitivity analyses were conducted by varying different model parameters to ensure the validity of the model. Incremental analyses were reported. Conclusions were consistent with the results reported. In one economic11 evaluation it was reported that the authors had no conflicts of interest. In the other economic evaluation,12 of the nine authors, two authors had financial involvement with the pharmaceutical industry, hence potential for bias cannot be ruled out.
Summary of Findings
The main findings are summarized below. Appendix 4 presents details of the main study findings and authors’ conclusions.
Clinical Effectiveness of Injectable Diacetylmorphine or Hydromorphone
One relevant systematic review,3 one relevant RCT (SALOME study)9 and one relevant crossover RCT10 involving adults with opioid dependency were identified. Details of the major findings are presented in Appendix 4, (for the systematic review) and (for the primary studies).
Retention in treatment
The systematic review3 found that there was statistically significantly greater retention in treatment in the injectable DAM group compared to the methadone group or the other treatment group.
The RCT (SALOME study)9 showed that for adults with opioid dependency, injectable HDM was non-inferior to injectable DAM with respect to retention to treatment.
Illicit drug use or opioid craving
The systematic review3 found that there was a significantly greater reduction in illicit drug use in the injectable DAM group compared to the methadone group (three studies). Also, in this systematic review, four studies showed greater reduction in illicit drug use in the injectable DAM group compared to the other treatment group (statistically significant in three studies; no significant between-group difference in one study).
The RCT (SALOME study)9 showed that for adults with opioid dependency, injectable HDM was non-inferior to injectable DAM with respect to street opioid use (self-reported) and proportions of urinalyses positives found for street heroin metabolites.
In the cross-over RCT10 involving adults with opioid dependency, it was found that there was statistically significantly less craving for drugs with injected DAM compared to injected placebo.
Criminal activities and incarceration
In the systematic review3 there was greater reduction in criminal offenses in the injectable DAM group compared to the methadone group in three studies, with the between-group difference being statistically significant in two of these studies; and fewer convictions and imprisonments with injectable DAM compared to methadone (one study). Also, in this systematic review, it was reported that there were fewer charges in the injectable DAM group compared to the other treatment group (statistically significant in one study and statistical significance was not reported in one study); and statistically significantly greater improvement with injectable DAM in terms of imprisonment (2 studies).
The RCT (SALOME study)9 showed that for adults with opioid dependency, injectable HDM and injectable DAM were not statistically significantly different with respect to days of criminal activities.
Physical, psychological and social aspects
In the systematic review3 one study reported a slightly better (statistical significance was not reported) employment status in the injectable DAM group compared to the methadone group, one study reported statistically significant improvements in work status in both injectable DAM and methadone groups compared to before treatment, and two studies reported that there was no statistically significant difference in employment status between the injectable DAM group and the other treatment group (
The RCT (SALOME study)9 showed that for adults with opioid dependency, injectable HDM and injectable DAM were not statistically significantly different with respect to physical health and psychological health (based on Maudsley Addiction Profile).
In the cross-over RCT10 involving adults with opioid dependency, it was found that there was statistically significant improvements after injectable DAM treatment compared to before treatment with respect to anxiety, anger, emotional excitement and well-being; and statistically significantly less heroin craving with injectable DAM compared to injectable placebo. There was statistically significant increase in anger and emotional excitement but no statistically significant difference in anxiety and well-being after injectable placebo treatment compared to before treatment.
Mortality
In the systematic review3 it was reported that there was no statistically significant difference in mortality in the injectable DAM group compared to the methadone group (four studies pooled) or in the injectable DAM group compared to the other treatment group (5 studies).
Safety
In the systematic review3 it was reported that there was a statistically significant greater number of adverse events related to the intervention in the injectable DAM group compared to the methadone group (three studies).
The RCT (SALOME study)9 showed that for adults with opioid dependency, there was a statistically significantly higher risk of adverse events related to the intervention in the injectable DAM group compared to the injectable HDM group. The most common related adverse events included drowsiness, and minor or moderate histamine reactions. The most common related serious adverse events included seizures and opioid overdoses.
Cost-Effectiveness of Injectable Diacetylmorphine or Hydromorphone
Two relevant economic evaluations11,12 were identified. Details of major findings and author’s conclusions are presented in Appendix 4, .
Comparison between injectable hydromorphone, injectable diacetylmorphine and oral methadone
The economic evaluation11 suggested that over a lifetime time horizon both injectable DAM and injectable HDM provided more benefits than oral methadone and at lower cost; QALYs were 8.4 (7.4 to 9.5) for DAM and 8.3 (7.2 to 9.5) for HDM versus 7.4 (6.5 to 8.3) for methadone, and costs in Canadian dollars were 1.01 million (0.6 million to 1.59 million) for DAM, and 1.02 million (0.72 million to 1.51 million) for HDM versus 1.15 million (0.71 million to 1.84 million) for methadone. Based on ICERs, it was found that both DAM and HDM dominated methadone.
Comparison between injectable diacetylmorphine and oral methadone
The economic evaluation12 suggested that over a lifetime time horizon injectable DAM provided more benefit than oral methadone and at lower cost; QALYs were 7.92 (7.32 to 8.53) for DAM versus 7.46 (6.91 to 8.01) for methadone, and costs in Canadian dollars were 1.10 million (0.72 million to 1.71 million) for DAM versus 1.14 million (0.74 million to 1.78 million) for methadone. Based on ICERs it was found that DAM dominated methadone. Probabilistic sensitivity analysis showed that for lifetime, the probability of DAM being cost-effective was 76% at a WTP threshold of $0 per QALY gained, and 95% at a WTP threshold of $100,000 per QALY gained.
Limitations
Conclusions were based on statistical significance in the included publications; none of the studies mentioned what was considered a clinically important difference in outcomes. No studies were identified that compared injectable DAM and injectable HDM with other treatment options of interest such as buprenorphine or slow-release morphine. Many of the same sources of data were used for the two economic evaluations, so findings were not totally exclusive (i.e., some data were represented twice in this report).
One primary study included in the systematic review and one selected primary study were conducted in Canada, and the two economic evaluations were mostly based on Canadian data. Hence the findings can be generalized to the Canadian setting, however, it should be noted that generalizability is dependent on the assumptions on which the evaluations were based (Appendix 2, ).
Conclusions and Implications for Decision or Policy Making
Five relevant publications were identified regarding the clinical effectiveness and cost effectiveness of injectable opioid agonist treatment (with DAM or HDM, alone or in combination with methadone) compared with alternative pharmacological treatments or no treatment, for individuals with opioid dependency; these comprised one systematic review,3 two RCTs,9,10 and two economic evaluations.11,12
The systematic review3 found that patients in the injectable DAM group, compared to those in the methadone group or other treatment group, had significantly greater retention in treatment, reduction in illicit drug use, reduction in criminal activities, and fewer convictions and imprisonments; but no statistically significant difference in mortality and greater occurrence of adverse events.
The RCT (SALOME study)9 showed that for adults with opioid dependency, injectable HDM was not inferior to injectable DAM with respect to days of street opioid use and proportions of urinalysis positives for street heroin metabolites. There were no statistically significant between-group differences for injectable HDM compared to injectable DAM, with respect to retention to treatment, criminal activity, and physical health and psychological health, however there was statistically significantly higher risk of adverse events related to the intervention in the DAM group compared to the HDM group.
One crossover RCT10 showed that there was statistically significant improvement after injectable DAM treatment compared to before treatment with respect to anxiety, anger, emotional excitement and well-being, and statistically significantly less heroin craving with injectable DAM compared to injectable placebo.
One economic evaluation11 compared injectable DAM, injectable HDM, and oral methadone treatments, and found that over a lifetime time horizon, both DAM and HDM provided more benefits than methadone and at lower cost. Based on ICERs, it was found that both DAM and HDM dominated methadone. The WTP threshold was not reported. The other economic evaluation12 compared injectable DAM with oral methadone and found that over a lifetime time horizon DAM provided more benefit than methadone and at lower cost. The probability of DAM being cost-effective was 76% at a WTP threshold of $0 per QALY gained, and 95% at a WTP threshold of $100,000 per QALY gained.
An evidence brief14 on the effectiveness of supervised injectable opioid agonist treatments for opioid dependency was identified in the search but did not meet the inclusion criteria for this report (due to study design). The evidence brief summarized findings from a variety of study types and included findings from secondary analyses of primary studies and qualitative studies, which may provide some useful insights and are discussed here. It was reported that for treatment with injectable DAM there was better response in individuals with higher motivation at baseline, and reduced effect in individuals with psychiatric comorbidity. There was no significant advantage demonstrated with injected DAM compared to oral methadone for women participants, Indigenous participants, and participants with no prior maintenance experience. For comparison between injectable HDM and injectable DAM, it was reported that with both treatments there were significant improvements in use of street heroin, opioids, and crack cocaine in Indigenous participants; and there were no significant differences in outcomes between male and female participants. Findings from qualitative studies indicated that some participants found it less appealing injecting in a clinical environment, some participants treated with DAM under supervision perceived benefits of building a relationship with staff and having a collective identity with others at the clinic, and some participants thought that supervised injectable treatment gave them stability but found the scheduling demanding. The evidence brief reported that for individuals with opioid use disorder who had undergone methadone treatment in the past; both injectable DAM and injectable HDM demonstrated significant benefits for retention in treatment, reduction in street drug use, and reduction in illegal activities; and HDM was associated with fewer adverse events compared to DAM. The overall conclusions of this evidence brief are therefore in agreement with the conclusions of this current report.
Further research investigating long-term effects of DAM and HDM compared with other treatments for individuals with opioid dependency may provide a greater understanding of the effects of these treatments, and usefulness and feasibility of implementing such treatment programs. Also, studies investigating specific subgroups such as Indigenous people, and people with various psychiatric conditions, may allow identification of groups that are likely to benefit most. Economic evaluations exploring models considering different probabilities and frequency of entering the various health states, could provide greater insights.
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Abbreviations
- DAM
diacetyl morphine
- HDM
hydromorphone
- ICER
incremental cost effectiveness ratio
- Met
methadone
- NAOMI
North American Opiate Medication Initiative
- QALY
quality adjusted life year
- RCT
randomized controlled trial
- SALOME
Assessment of Long-term opioid Maintenance Effectiveness
- WTP
willingness-to-pay
Appendix 1. Selection of Included Studies
About the Series
CADTH Rapid Response Report: Summary with Critical Appraisal
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Suggested citation:
Injectable opioid agonist treatment for patients with opioid dependence: a review of clinical and cost-effectiveness. Ottawa: CADTH; 2020 May. (CADTH rapid response report: summary with critical appraisal).
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