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CADTH Health Technology Review
Authors; Khai Tran, and Danielle MacDougall.
Opioid dependence has devastating consequences for individuals, families, and society. Between January 2016 and September 2021, 26,690 Canadians died from opioid-related toxicity.1 In 2021, there were approximately 20 opioid toxicity deaths per day in Canada compared with 7 deaths per day in 2016 and 12 deaths per day in 2018.1 Almost all (98%) of those deaths were accidental, and 88% of these accidental deaths occurred in British Columbia, Alberta, or Ontario.1 From January 2016 to September 2021, there were 29,228 hospitalizations due to opioid-related poisoning in Canada and 12,977 hospitalizations due to stimulant-related poisoning.1 Opioid-related poisoning hospitalizations increased by 27% in the first year of pandemic (April 2020 to March 2021) compared with the previous year (April 2019 to March 2020).1
Maintenance therapy with oral opioid agonist treatment medications, such as methadone or buprenorphine, can be effective in decreasing drug use and preventing mortality and illegal activity in many individuals with opioid use disorder.2 However, a subset of individuals with severe opioid use disorder who used to inject opioids may not benefit from oral maintenance treatment, therefore alternative approaches are needed.3 In 2009, the North American Opiate Medication Initiative (NAOMI) trial conducted in Canada found that injectable diacetylmorphine (DAM) was more effective than oral methadone maintenance therapy (MMT) for higher retention and response rates in addiction treatment, and reduction in rates of illicit opioid use or illegal activity in long-term users of injectable heroin.4 However, DAM had more serious adverse events compared with oral MMT.4 At that time, DAM was not available in Canada.5 A subsequent trial, the Study to Assess Long-term Opioid Maintenance Effectiveness (SALOME), was designed to find an acceptable alternative to DAM, and showed that injectable hydromorphone (HDM) was noninferior to injectable DAM and had fewer adverse events.6 Health Canada has recently approved DAM as an injectable opioid agonist therapy for adult patients with severe opioid use disorder who use injectable opioids and have failed previous opioid agonist therapy, including oral MMT.7 DAM is delivered in a supervised setting due to its risk of serious adverse events, such as overdose and seizure.4,7 Injectable DAM can be provided in combination with oral MMT to prevent withdrawal symptoms.7
This report aims to summarize the evidence on the clinical effectiveness and cost-effectiveness of DAM for injection versus methadone or buprenorphine for adults with opioid dependence. Additionally, this report also aims to summarize the recommendations from evidence-based guidelines regarding the use of DAM for injection for adults with opioid dependence.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were injectable diacetylmorphine and opioid dependence. No filters were applied to limit the retrieval by study type. Conference abstracts were excluded. If possible, retrieval was limited to the human population. The search was completed on June 1, 2022, and limited to English-language documents published since January 1, 2017.
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 Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1 or they were published before 2017. Guidelines with unclear methodology were also excluded.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: The Drummond checklist8 for economic evaluations, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument9 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 326 citations were identified in the literature search. Following screening of titles and abstracts, 320 citations were excluded and 6 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search for full-text review. Of these 6 potentially relevant articles, 4 publications were excluded for various reasons, and 2 publications met the inclusion criteria and were included in this report. These comprised 1 economic evaluation study and 1 evidence-based guideline. The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA)10 flow chart of the study selection is presented in Appendix 1.
Additional details regarding the characteristics of the included economic evaluation study11 (Table 2) and evidence-based guideline12 (Table 3) are provided in Appendix 2.
The economic evaluation study by Bansback et al. (2018)11 used an existing semi–Markov cohort model13 to assess the cost-effectiveness of HDM or DAM compared with oral MMT for treatment of severe opioid use disorder in adults. The clinical data were from the SALOME6 and NAOMI4 trials, and data from an 11-year population study of methadone recipients in British Columbia.14 The SALOME trial6 found that HDM was noninferior to DAM for all clinical outcomes, with the exception that HDM had lower rates of adverse events compared to DAM. The NAOMI trial4 found DAM to be superior to oral MMT. A mixed treatment comparison approach was used to compare HDM and DAM with oral MMT. Resource use included utilization of drugs, non-protocol visits the health professionals, and other health care resources (hospitalizations, and criminal involvement and charges). All costs were calculated by multiplying resource use by respective costs, adjusted to 2015 Canadian dollars, and discounted at 5% per year. Health-related quality of life (HRQoL) was incorporated in terms of utility values on a scale from 0 (death) to 1 (full health), combined with life-years to generate quality-adjusted life-years (QALYs), which was discounted at 5%. The analyses were conducted from a Canadian societal perspective over a 50-year life-time horizon. A series of scenario analyses including the Ministry of Health perspective were conducted to explore the sensitivity of the results to specific parameter uncertainty, alternative assumptions, and sources of data.
The included evidence-based guideline12 was developed by the Canadian Research Initiative in Substance Misuse (CRISM), which provides recommendations on defining the patient population considered for injectable opioid agonist treatment and outlining considerations for medication selection and length of treatment. A systematic search of the literature was conducted, and the quality of evidence and the strength of recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
The economic evaluation study11 and the guideline12 was conducted by authors from Canada.
Patients considered in the economic evaluation study11 were from the cohorts of adults with severe opioid use disorder from the SALOME trial6 and the NAOMI trial.4 In the SALOME trial,6 patients had mean age of 44 years, 70% were men and 30% were women, and the average duration of usage was described as “15 years of injecting street heroin.” In the NAOMI trial,4 patients had mean age of 40 years, 61% were men and 39% were women, and the average duration of usage was 17 years of injection-drug use.
The target population of the CRISM guideline12 is adults with severe opioid use disorder, while the intended users are Canadian health professionals with clinical recommendations and guidance for the treatment of severe opioid use disorder with injectable opioid agonist treatment.
HDM was compared with DAM using within-trial analysis from the SALOME study,6 and HDM was indirectly compared with oral MMT using DAM as a common comparator from the NAOMI trial.4
The CRISM guideline12 formulated its recommendations concerning the injectable opioid agonist treatment (i.e., DAM or HDM).
The outcomes in the economic evaluation study11 were incremental costs, QALYs, and incremental cost-effectiveness ratio (ICER), which was calculated as the incremental cost per QALY change.
Major outcomes considered in the CRISM guideline12 were high retention rates, reduction of street opioid use, and adverse events.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3 (Table 4).
The economic evaluation study by Bansback et al. (2018)11 clearly stated the objective, the economic importance of the research question, the rational for choosing the alternative comparators (i.e., DAM versus oral MMT, HDM versus oral MMT, and HDM versus DAM), and the type of economic evaluation (i.e., cost-effectiveness analysis) that was conducted. An existing semi–Markov cohort model for the purposes of the life-time analysis was further developed with a societal perspective. For data collection, the study clearly stated the source of effectiveness estimates with details of the design and findings (i.e., from 2 clinical trials, and data from an 11-year population study of methadone recipients in British Columbia), and the resource use and costs. The study clearly stated the outcome measures for economic evaluation (i.e., incremental costs, QALYs, and ICER). A Markov model was presented with all parameters used in the analysis. For the analysis and interpretation of results, the study clearly stated the time horizon of costs and benefits, statistical tests and confidence intervals, justification for the choice of variables for sensitivity analysis, and the ranges over which the variables were varied. A 5% discounting rate was applied for all costs and QALYs with a 50-year life-time horizon. The study reported incremental analysis and presented major outcomes in a disaggregated as well as aggregated form. Probabilistic analysis was used to estimate the means and 95% confidence intervals (CIs) of total costs, QALYs, and ICERs to reflect parameter uncertainty. The conclusion in the study was based on the data reported and was accompanied by the appropriate caveats. Overall, the study was of good methodological quality with respect to the study design, data collection, and analysis and interpretation of results.
The CRISM guideline12 was explicit in terms of scope and purpose (i.e., objectives, health questions, and populations), and had clear presentation (i.e., specific and unambiguous recommendations, different options for management of the condition or health issue, and easy to find key recommendations). In terms of stakeholder involvement, the guidelines clearly defined target users and the development groups. The views and preferences of the target population (e.g., patients, public) were sought. For rigour of development, the guideline reported systematic methods used to search for evidence, criteria for selecting evidence, explicit links between recommendations and the supporting evidence, and methods of formulating the recommendations. The guideline considered health benefits, side effects, and risks in formulating the recommendations, and it was externally peer-reviewed before publication. The guideline assessed the quality of evidence and graded the level of recommendations using the GRADE tool. For clarity, the recommendations in the guideline are specific and unambiguous, provide different options for management of the condition, and are easily identifiable. For applicability, the guideline was explicit in terms of facilitators and barriers to application, advice on how the recommendations can be put into practice, and resource implications (e.g., considering costs in recommendations). For editorial independence, the guideline reported competing interests of the guideline development group members and that the views of the funding body did not have influence on the content of the guidelines. Overall, the guideline was of good methodological quality.
The main study findings and authors’ conclusions are presented in Appendix 4.
No clinical studies comparing the clinical effectiveness of DAM for injection versus methadone or buprenorphine for adults with opioid dependence were identified; therefore, no summary can be provided.
Because the comparisons of HDM with DAM and HDM with oral MMT were not in scope in this review, only the cost-effectiveness results of DAM compared with oral MMT are presented here. Results for the comparisons of HDM with DAM and HDM with oral MMT are presented in Table 6 of Appendix 4.
The model results suggested that injectable DAM provided 3.5 additional years of life compared with oral MMT (18.4 years versus 14.9 years). When combining life-years with quality of life, the injectable DAM strategy provided a greater benefit in comparison to the oral MMT strategy (8.4 QALYs versus 7.4 QALYs; difference = 1.0 QALY). For total costs, DAM was less expensive compared with oral MMT ($1.01 million versus $1.15 million; difference = –$0.14 million) during the life-time. More than 90% of the cost was attributable to involvement in property and violent crime, and less than 3% attributable to treatment. The DAM strategy had a decrease in criminal charges for property crime per person-year of 0.5 compared with MMT and had 5.4 fewer involvements with property crimes per person-year (9.6 versus 15.0). Therefore, injectable DAM was considered to dominate oral MMT (ICER = dominates; 95% CI, dominates to 306.8) due to more benefit and less cost. Probabilistic analysis showed that injectable DAM had a 75% probability of dominating oral MMT. The results were consistent with all scenarios, with the exception of the Ministry of Health perspective.
The CRISM guideline12 provided 3 key recommendations based on the existing literature on injectable opioid agonist treatment. First, the guideline recommends that injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use. This recommendation was rated conditional based on moderate quality of evidence. Second, the guideline suggests that both DAM and HDM are acceptable treatment options for individuals who are likely to benefit from injectable opioid agonist treatment. This recommendation was considered strong despite low quality of evidence, based on expert consensus, clinical experience in British Columbia, low risk of adverse events of HDM compared with DAM, and the unavailability of prescribed DAM in Canada at that time. Third, the guideline recommends that injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral opioid agonist treatment. This recommendation was considered strong despite low quality of evidence based on the risk of fentanyl-contaminated illicit opioid use and WHO’s recommendation for opioid agonist treatment as an open-ended treatment.
The economic evaluation study11 had several limitations. First, not all data were able to capture costs related to possession or dealing of drugs, disorderly conduct, sex work, driving violations, or illegal activities. Including these costs may further improve the cost-savings from treatment with DAM or HDM. Second, the study made several assumptions for transitions between treatment states that were beyond the trial data. However, various scenario analyses found that all were insensitive to the assumptions. Third, other oral opioid agonist treatment strategies such as buprenorphine or slow-release morphine, which are important options to improve the effectiveness of opioid agonist treatment, were not included in the model analysis and their inclusion in the model could affect the results on the cost-effectiveness of DAM or HDM. Lack of accessibility of these agents may limit the generalizability of rates of retention included in the model. Fourth, the model assumed only 1 state for relapse (defined by opioid use outside of treatment) and the individual left the treatment during relapse. In reality, some people may decide to remain on treatment despite relapse, and those who stay in treatment may have health advantage over those who do not.
The included guideline12 recognized that the recommendations were made based on the low- to moderate-quality evidence because of the low number of studies and the discrepancy in evidence supporting each medication (i.e., DAM and HDM).
This review did not identify recent studies on the clinical effectiveness of DAM for injection in comparison with methadone or buprenorphine.
This report identified 1 economic evaluation study11 and 1 evidence-based guideline12 conducted by authors in Canada. The economic evaluation study results suggested that injectable DAM might provide more benefits and lower costs compared with oral MMT in patients with severe opioid use disorder. The majority (> 90%) of cost-saving was largely from reduced involvement in criminal activity. The findings of this economic evaluation study11 on the comparison of DAM with oral MMT were inconsistent with those in previous studies in Canada and Europe.13,15,16 No cost-effectiveness studies of injectable DAM compared with buprenorphine were identified. The CRISM guideline12 provided 3 key recommendations on the patient populations considered for injectable opioid agonist treatment, medication selection, and treatment end date. The guideline recommends that both injectable DAM and HDM should be considered as treatment options for patients with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use, and that the injectable opioid agonist treatment should have an end date to transition to oral opioid agonist treatment. The findings from the economic evaluation study and the recommendations of the CRISM guideline may be applicable to the Canadian context despite some limitations. Future studies are needed to compare the clinical effectiveness and cost-effectiveness of injectable DAM with other opioid agonist treatment strategies such as buprenorphine, slow-release morphine, or agents with any formulations.
Canadian Research Initiative in Substance Misuse
diacetylmorphine
hydromorphone
health-related quality of life
incremental cost-effectiveness ratio
methadone maintenance therapy
North American Opiate Medication Initiative
quality-adjusted life year
Study to Assess Long-term Opioid Maintenance Effectiveness
Selection of Included Studies.
Characteristics of the Included Economic Evaluation.
Characteristics of the Included Guideline.
Note that this appendix has not been copy-edited.
Strengths and Limitations of the Economic Evaluation Using the Drummond Checklist.
Strengths and Limitations of the Guideline Using AGREE II.
Note that this appendix has not been copy-edited.
Summary of Findings of the Included Economic Evaluation.
Summary of Recommendations in the Included Guideline.
Note that this appendix has not been copy-edited.
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