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Authors; Kwakye Peprah, and Hannah Loshak.
Appraisal of Guidelines for Research and Evaluation II
Canadian Coalition for Seniors Mental Health
cost-effectiveness acceptability curve
Canadian Research Initiative in Substance Misuse
diacetylmorphine
Grades of Recommendation Assessment, Development, and Evaluation
hydromorphone
incremental cost-effectiveness ratio
methadone maintenance treatment
North American Opiate Medication Initiative
opioid use disorder
quality-adjusted life-year
randomized controlled trial
Randomized Injectable Opiate Treatment Trial
Study to Assess Long-term Opioid Maintenance Effectiveness
slow-release oral morphine
Opioid dependence has an enormous burden on individuals and society due to the association between opioid use disorder (OUD) and criminal activity, incarceration, deterioration in overall health and social functioning, quality of life, and overdose-related death.1-3 First-line treatment for most patients with OUD includes pharmacotherapy with an opioid agonist or antagonist and adjunct psychosocial treatment.4 Methadone maintenance treatment (MMT) and buprenorphine, for example, have been shown to be effective in improving physical and psychological health, decreasing drug use, infectious disease transmission, illegal activity, and death in many individuals.5,6 However, a subpopulation of individuals with severe OUD fail to benefit and continue to inject heroin regularly, necessitating alternative approaches with enhanced effectiveness.3,5,7 There is emerging evidence suggesting that individuals who do not respond to or relapse from the effect of these first-line drug treatments may benefit from supervised injectable opioids such as prescription diacetylmorphine (heroin),2,3 hydromorphone,1 or other oral alternatives.8
While the expanded OUD treatment options may lead to better outcomes, it comes with challenges such as the risk of adverse effects, restricted access, and increased resource pressure on health services with an associated cost.7 In 2017, CADTH produced a report summarizing abstracts of publications concerning the comparative clinical effectiveness, cost-effectiveness, and evidence-based recommendations for using the various formulations for use in OUDs.9 The objective of this Rapid Response report is to review current full-text evidence regarding the cost-effectiveness of various opioid agonist interventions for treating OUDs and summarize identified evidence-based guidelines recommendations for their use. The clinical effectiveness of opioid substitution treatment is being reviewed in a separate report.10
A limited literature search was conducted by an information specialist on key resources including MEDLINE, 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 controlled vocabularies, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were opioid substitution therapies. CADTH-developed search filters were applied to limit retrieval to economic studies and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English documents published between January 1, 2012, and November 4, 2021.
One reviewer screened citations and selected studies. In the first screening level, 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, they were duplicate publications, or were published before 2012. Guidelines8,11 with relevant portions adapted into another guideline that is more recent and more comprehensive were omitted.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: the Drummond checklist12 for economic evaluations and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument13 for guidelines. Summary scores were not calculated for the included studies; instead, the strengths and limitations of each included publication were described narratively.
A total of 300 citations were identified in the literature search. After screening titles and abstracts, 287 citations were excluded, and 13 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 the 13 articles, 8 publications were excluded for various reasons, and 5 papers that met the inclusion criteria were included in this report. These comprised 3 economic evaluations7,14,15 and 2 evidence-based guidelines.16,17 Appendix 1 presents the PRISMA18 flow chart of the study selection.
Additional details regarding the characteristics of included publications are provided in Appendix 2.
All the 3 included economic evaluations7,14,15 were based on randomized controlled trials. One each used data from the Study to Assess Long-term Opioid Maintenance Effectiveness (SALOME),14 the Randomized Injectable Opiate Treatment Trial (RIOTT),7 and the North American Opiate Medication Initiative (NAOMI)15 trials. Each study evaluated estimated incremental costs, quality-adjusted life-years (QALYs) and cost-effectiveness ratios from a societal perspective, considering costs borne by the health care,7,14,15 social services,7,14,15 and criminal justice systems,7,14,15 as well as out-of-pocket costs borne by society.14,15 QALYs were calculated using the Euroqol EQ-5D tool as a utility measure. The considered time horizons for analyses were 26 weeks,7,14 1 year,15 5 years,15 10 years,15 and a lifetime.14,15 Lifetime analysis was based on average additional years lived following entry into the model of 14.515 to 14.9,14 17.5,14 and 15.4515 to 18.414 for patients treated with MMT, injectable hydromorphone (HDM), and injectable diacetylmorphine (DAM), respectively. All the 3 economic evaluations7,14,15 sourced clinical and costs data from the respective RCTs, administrative sources, and the published literature. A decision-analytic approach was used in all the economic evaluations, with 2 studies14,15 stating that a semi-Markov model was applied. In contrast, 1 study7 did not specify the model used in the analysis.
Two evidence-based guidelines16,17 were included in this report. The Canadian Coalition for Seniors Mental Health developed 1 of the guidelines,16 and the Canadian Research Initiative in Substance Misuse developed the other guideline.17 Both guidelines16,17 were developed using evidence from relevant literature identified through systematic literature searches. The recommendations were developed through consensus. The quality of evidence and the strength of recommendations were rated and reported according to the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) tool.16,17 The evidence quality was ranked as high, moderate, low, and very low. A high rate indicates strong confidence that the actual and estimated effects are close. A very low rank means very little confidence in the effect estimate because the true and estimated effects are likely to be substantially different.17 A moderate rating signifies moderate confidence because the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. A low-quality rank denotes a limited confidence because the true and estimated effects may be significantly different. In 1 of the guidelines,16 the low and very low scores were joined together and reported as low.
Two of the 3 economic evaluations were conducted in Canada,14,15 and 1 was conducted in the UK.7 Both of the included evidence-based guidelines16,17 were developed in Canada.
Patients who participated in the trials that formed the basis for the included economic evaluations were adults who had received previous treatments with opioid agonists, including MMT but were still injecting street heroin (diacetylmorphine) as at the time of enrolment into the various studies.7,14,15 Sample sizes of the source trials were 251 (for NAOMI),2,15 127 (for RIOTT),7 and 202 (for SALOME).14 The mean age of the patients was between 37 and 40 years old, and most were male (≤ 61%).7,14,15 The mean duration for which the patients had been injecting drugs was between 13.7 and 16.5 years.7,14,15 In 1 study,7 eligible patients had been on conventional oral MMT for at least 6 months but continued to inject street heroin regularly (≥ 50% of days in the preceding 3 months). Another study15 required that patients should have had at least 2 previous opioid substitution treatment attempts and been out of treatment for at least 6 months before trial entry.
The target population of 1 of the guidelines was older adults (i.e., ≥ 65 years) with OUD.16 In the other guideline,17 the target population was adults with severe OUD relapsed or unsuccessful on a previous oral opioid agonist treatment, or whose circumstances and risks indicated that they might benefit from injectable opioid agonist treatment. Both guidelines16,17 were intended for use by health care professionals in Canada.
One economic evaluation14 was based on the SALOME trial that randomized patients to treatment with injectable hydromorphone (HDM) or injectable diacetylmorphine (DAM). Doses were presented in diacetylmorphine equivalents up to 400 mg per dose.1 A patient could receive up to 3 doses per day, but not exceeding 1,000 mg per day.1
One economic evaluation was based on the RIOTT trial in which patients were randomly assigned to DAM, injectable methadone, or optimized oral methadone (oral methadone).7 The DAM was given twice daily titrated on an individual basis to a typical stabilizing daily dose of between 300 mg/day and 600 mg/day, to a maximum of 900 mg/day.7 Injectable methadone was administered once daily, titrated individually to a maximum of 200 mg/day.7
Another economic evaluation15 was based on the NAOMI trial in which patients were randomly allocated to injection-assisted treatment (55%) or methadone maintenance alone (45%). Patients in the injection group were randomly assigned to receive hydromorphone HDM or DAM.2 The doses of the individual drugs were not specified.
Pharmacological interventions considered within 1 of the guidelines16 included buprenorphine maintenance, buprenorphine-naloxone, MMT, naltrexone alone, slow-release oral morphine (SROM). The other guideline17 focused on DAM and HDM.
For economic evaluations,7,14,15 reported outcomes were costs and QALYs gained, and incremental cost-effectiveness ratios (ICER). One of the studies assessed cost-effectiveness at specified willingness-to-pay thresholds using cost-effectiveness acceptability curves (CEAC). For guidelines,16,17 major outcomes considered by the guideline panels included a reduction in illicit heroin or any street opioid use, premature death, nonfatal overdose, blood-borne infectious diseases, involvement in sex work and criminal activity, as well as improvement in treatment retention rates, overall health, and social functioning.
The 3 included economic evaluations7,14,15 stated research objectives and their economic importance, and provided the perspective and time horizons used in analyses. Each of the studies7,14,15 compared relevant alternatives, described the rationale for choosing them and reported incremental effects due to their use. Two of the economic evaluations14,15 stated and justified the type of analysis and modelling approach used in the evaluation were described and justified. Although authors of the other study7 reported that their analysis used a decision-making approach, the evaluation model and its parameters were not adequately described, and its selection was not justified. All the included economic evaluations7,14,15 reported the sources of data for effectiveness estimates. The supporting RCTs were adequately referenced, and the population of interest was described for each evaluation. The studies7,14,15 stated the primary outcome measure and reported methods of estimating quantities, unit cost, and value of benefits.
Two economic evaluations14,15 applied discount rates to adjust for inflation, although no justification was provided for the chosen rates. One study7 did not adjust for inflation in the analysis, although it was based on cost data from a study conducted at least 3 years earlier. Therefore, the reported cost of providing the OUD treatments in that study7 may have been underestimated. In 1 of the economic evaluations,14 the lifetime analysis extrapolated costs and outcomes data from multiple sources and applied an indirect comparison approach. However, the methods of data synthesis were not provided. The major outcomes in all the included economic evaluations7,14,15were presented in both disaggregated and aggregated forms, and the approaches to sensitivity analysis were described clearly. For each economic evaluation, the discussion of the results considered the study's limitations, and the conclusions reflected the evidence used to derive them.
The included guidelines16,17 had clear objectives to answer specific health questions in well-described populations. They were developed based on evidence from a systematic review of relevant literature. Although for 1 guideline16 the criteria for selecting the evidence and provision of advice or tools on applying the recommendations were unclear, each of the guidelines16,17 demonstrated strengths in all the 6 domains in the AGREE II instrument.13 Overall, both guidelines16,17 ranked positively regarding scores for scope and purpose, stakeholder involvement, development rigour, presentation clarity, applicability, and editorial independence. Thus, they provide essential details, such as an explicit link between recommendations and supporting evidence, criteria for selecting evidence, strengths and limitations of the body of evidence, and methods for formulating recommendations. Both guidelines16,17 were externally peer-reviewed and had input from a broad base of stakeholders, including intended professional users and targeted populations representatives. Furthermore, each guideline16,17 provided information about facilitators, barriers, and potential resource implications for applying the recommendations and stated monitoring approaches to ensure the recommendations were up to date.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
Appendix 4 presents the main study findings and authors’ conclusions.
No relevant evidence regarding the cost-effectiveness of SROM for OUD was identified; therefore, no summary can be provided.
No relevant evidence regarding the cost-effectiveness of oral hydromorphone for OUD was identified; therefore, no summary can be provided.
One economic evaluation14 found that in the short term (up to 6 months), treatment with HDM dominated (i.e., providing more benefit at less cost than) DAM in OUD patients who were refractory to treatments (ICER HDM versus DAM = 6,683,925 CN$/QALY). The outcomes were not discussed in terms of decision-makers’ willingness-to-pay threshold. In analysis extrapolating data over a lifetime, the study14 found that compared with MMT, the probability of providing more benefit at less cost in treating OUD was higher with HDM (67%) and DAM (75%).
One economic evaluation7 with 26 weeks’ time horizon showed that at a willingness-to-pay threshold of £30,000 per QALY, both DAM and injectable methadone dominated oral methadone. At the same willingness-to-pay level, injectable methadone was more likely to be more cost-effective than DAM (80% versus 20%).7 Sensitivity analysis showed that the relative cost-effectiveness was sensitive to the price of DAM. However, the DAM price needed to fall considerably (≥ 84%) before being more cost-effective than injectable methadone.7 However, DAM had a probability of being more cost-effective than injectable methadone at a higher willingness-to-pay threshold (i.e., ≥ £70,000).
One economic evaluation15 that compared DAM and MMT over 1-year, 5-year, 10-year, and lifetime horizons found that DAM was a dominant strategy over MMT to treat OUD in each of the time horizons. Sensitivity analysis showed that DAM's cost-effective probability was 76% and 95% at a willingness-to-pay thresholds of $0 per QALY gained and $100,000 per QALY gained, respectively.
No relevant evidence regarding the cost-effectiveness of fentanyl patches or fentanyl buccal tablets for OUD was identified; therefore, no summary can be provided.
The CCSMH guideline16 recommends that SROM be considered with caution for treating OUDs in older adults with adequate renal function in whom buprenorphine and methadone maintenance have been ineffective or could not be tolerated. The recommendation is weak and is supported by low-quality evidence from 1 guideline, 1 consensus statement of an International Expert Panel, and 1 animal study.16 According to the recommendation, the treatment should be initiated by first starting the patient on supervised short-acting morphine before transitioning to maintenance with the long-acting, 24-hour SROM formulation.
The CRISM guideline17 recommends that for patients who are determined to be likely to benefit from injectable opioid agonist treatment, both DAM and HDM are acceptable treatment options. The recommendation was rated as strong, although supported by low-quality evidence from 2 systematic reviews and 1 RCT.17 According to the authors, the strong rating was based on expert consensus, substantial clinical experience in British Columbia, reduced risk of adverse events for HDM compared with DAM, and the lack of regulatory and supply barriers affecting access to HDM.17 The CRISM guideline also recommends that treatment with injectable opioid agonists be provided on an open-ended basis, with decisions to transition to oral opioid agonists made collaboratively with the patient.17 The recommendation was rated as strong despite being supported by low-quality evidence because it aligns with the WHO's recommendation that opioid agonists be provided as open-ended treatment for OUD, and the open-ended approach potentially reduces a patient’s risk of exposure to fentanyl-contaminated illicit opioid use.17
No evidence-based guidelines with recommendations regarding the use of oral hydromorphone, fentanyl patches, or fentanyl buccal tablets for OUD treatment were identified; therefore, no summary can be provided.
A key limitation for the included cost-effectiveness studies7,14,15 is that the actual observed data came from trials with short-term follow-up duration. Although 2 out of the 3 economic evaluations14,15 provided longer-term outcomes, they were based on extrapolations beyond the supporting studies, and 1 study14 indirectly compared interventions from multiple sources without giving details about the data synthesis approach. Thus, there is some uncertainty about the reported long-term cost-effectiveness outcomes. Further, the long-term evaluations were limited to comparisons between MMT and either HDM14 or DAM.14,15 Therefore, it is unknown if the reported short-term cost-effectiveness dominance of HDM14 and injectable methadone7 over DAM could be replicated in analysis with a longer time horizon. One of the economic evaluations7 was based on a study conducted in the UK with the cost data denominated in the British pound sterling and analysis not adjusted for inflation. Therefore, in addition to a likely underestimation of the costs, the generalizability of the reported findings in the Canadian context is unknown. Also, besides methadone, none of the economic evaluations considered other important oral opioid agonist interventions such as slow-release morphine or buprenorphine preparations.
No relevant cost-effectiveness evidence or guidelines with recommendations regarding the use of oral hydromorphone, fentanyl patches, or fentanyl buccal tablets for OUD treatment were identified; therefore, no summary can be provided.
Three included economic evaluations7,14,15 based on data from RCTs, and 2 evidence-based guidelines16,17 were included in this Rapid Response report. Results of cost-effectiveness analyses from the studies showed that in the short term (up to 6 months), HDM provided more benefit than DAM at less cost,14 and injectable methadone had a greater probability of being more effective than DAM (80% versus 20%).7 Two of the economic evaluations showed that MMT had a lower likelihood of being more cost-effective for the treatment of OUD compared with HDM14 or DAM14,15 in a lifetime analysis14,15 or over shorter time horizons (i.e., 1-year, 5-year, or 10-years horizons).15 There is some uncertainty about the reported long-term cost-effectiveness outcomes due to data extrapolations14,15 and lack of clarity about how data from multiple sources were synthesized.14 Further, the long-term evaluations were limited to comparisons between MMT and either HDM14 or DAM.14,15 Thus, it is unknown if the reported short-term cost-effectiveness dominance of HDM14 or injectable methadone7 over DAM could be replicated in analysis with a longer time horizon.
One guideline16 recommends using SROM in older adults with adequate renal function in whom buprenorphine and methadone maintenance have been ineffective to treat OUD or could not be tolerated. Another guideline recommends using injectable opioid agonists for individuals with severe, treatment-refractory OUD engaging in illicit injection opioid use, adding that HDM and DAM are acceptable treatment options.
No relevant cost-effectiveness evidence or guidelines with recommendations regarding the use of oral hydromorphone, fentanyl patches, or fentanyl buccal tablets for OUD treatment were identified; therefore, no summary can be provided.
Given the limitations discussed here and elsewhere in this report, future economic evaluations comparing the various opioid agonist therapies for OUD over the short- and long-terms are needed. Similarly, there is a need for evidence-based recommendations regarding the use of different opioid agonist treatment options for OUD.
Selection of Included Studies.
Characteristics of Included Economic Evaluations.
Characteristics of Included Guidelines.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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