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Suboxone versus Methadone for the Treatment of Opioid Dependence: A Review of the Clinical and Cost-effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2013 Nov 14.

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Suboxone versus Methadone for the Treatment of Opioid Dependence: A Review of the Clinical and Cost-effectiveness [Internet].

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SUMMARY OF EVIDENCE

Quantity of Research Available

One hundred and twenty-one articles were identified from the literature search. Upon screening titles and abstracts, 28 potentially relevant articles were selected for full-text review. Of these, 19 did not satisfy the inclusion criteria and were excluded. The nine included reports of eight unique clinical studies and comprised four RCTs (a secondary analysis on data from one RCT was performed), two non-RCTs and two economic evaluations. No relevant health technology assessments, systematic reviews or meta-analyses were identified. The selection process is described in Appendix 1.

Summary of Study Characteristics

Characteristics of the included clinical trials and economic evaluations are summarized below and details are provided in Appendix 2.

Clinical Effectiveness

In the included RCTs and non-randomized trials, the baseline patient characteristics such as demographics, drug history, treatment history were similar between two treatment groups.

Randomized-controlled trials

Four relevant RCTs comparing Suboxone with methadone were identified.1518 Three RCTs15,17,18 were published from the US, and one16 was published in 2012 from Georgia. The number of recruited patients in these studies ranged between 54 to 1,269. Drugs being misused included heroin, cocaine, cannabis, amphetamines and other prescription opioids. The mean duration of drug use ranged from 20 days to 12 years. Treatment durations in these trials ranged between three to six months. All RCTs reported retention in treatment and use of opioids at study end (assessed by self-report or urine test). Safety data were reported in all but one RCT.15 One American study17 evaluated the effects of Suboxone or methadone on liver health, and indicated that results on drug use will be analyzed in a future paper. In addition, secondary analysis on data from this RCT was performed and the results were published in a different journal.19 Two patients from the original RCT were excluded from the analysis due to pregnancy and change in treatment plan during the study.

Non-randomized-controlled trials

Two prospective cohort studies comparing Suboxone with methadone in adult patients were identified.20,21 One20 was published in 2013 from the UK, and another one21 was published in 2007 from Finland. The number of patients enrolled in these non-RCTs ranged from 33 to 71. These studies reported on days of opioid use and change in cognitive performance (attention, working memory and verbal memory) after the treatment with Suboxone or methadone.

Cost-Effectiveness

A recent economic evaluation was conducted in Greece, to evaluate the cost-effectiveness of opioid substitution treatment (mainly methadone and buprenorphine) in this country.22 The investigated study drugs were methadone and buprenorphine monotherapy, and Suboxone. The data used were retrospectively retrieved from the local health authority databases. The expenses included personnel, drugs/consumables, medical consultations/diagnostic investigations, maintenance of equipment and buildings, and overheads. No discount rates were applied. Prices (in Euros) were those of the Greek National Health System in 2008. The clinical effectiveness was assessed using the completion of treatment and the number of deaths that were related to the use and/or overdose of illicit opioid drugs.

An economic evaluation by Doran et al.23 was performed in Australia to examine the cost-effectiveness of high-dose buprenorphine, Suboxone, low-dose buprenorphine, and methadone. A treatment provider perspective was adopted with a reference year of 1998 to 1999. Resources use was identified at both the patient and facility level, which included staff time, diagnostics, medications, supplies, equipment, and ancillary services. The summation of patient and facility resource use provided an estimate of total cost of each patient’s treatment episode. Three economic models were examined: comparison of methadone with low dose buprenorphine, comparison of methadone with high dose buprenorphine, and comparison of methadone with Suboxone. The third model is relevant to our review. The primary measure of clinical effectiveness was the change in number of heroin-free days between the month prior to treatment and the 6th month.

Summary of Critical Appraisal

The strengths and limitations of the included studies are summarized in Appendix 3.

Randomized controlled trials

All four RCTs1518 clearly stated the objective and the selection criteria and described patient characteristics, interventions and outcomes. One RCT was a double-blind, double-dummy RCT and described the methods of blinding clearly.18 Two stated that they had an open-label design.15,17 For one RCT, it was unclear whether it was a blinded trial.16 A sample size calculation was reported in one RCT.18 In the largest RCT enrolling 1269 patients,17 the authors indicated that the US Food and Drug Administration required a minimum of 300 evaluable participants on each medication, hence a power calculation was not performed. No power calculation was reported for the other two RCTs.15,16 All of the four RCTs reported results for patients who had completed the study or had evaluable data. Intention-to-treat analysis was not specified in any of these trials. The proportion of patients who completed the study was generally low. One RCT, conducted in Georgia,16 reported a completion rate of higher than 80% in the randomized population. In the other three RCTs, the completion rates ranged between 20% to lower than 50% in the overall population. The dropout rates were comparable between treatment groups, except for the Saxon study (more patients with Suboxone dropped out the study than those with methadone, 54% versus 26%, respectively). Generalizability was limited as it was uncertain as to whether the study patients were representative of all patients.

Non-randomized-controlled trials

Both of the non-randomized studies20,21 were prospective studies. However, it was unclear if the outcome assessors or patients were blinded to the treatment. Patient characteristics were described in one study. Both studies described the interventions and outcomes. Both studies provided P-values though not always for all outcomes. Generalizability was uncertain as to whether the study patients were representative of all patients. Both studies had small sample size.

Economic evaluations

The economic evaluation reports22,23 were considered to be of high methodological quality according to the Drummond checklist. The research question was well defined and the analysis method was clearly stated. The key parameters on which the analysis was based were justified and the time horizons were clearly specified. Sensitivity analyses were performed in both reports. One limitation of the Australian report was that the investigators based their analyses on retrospective data (cost and efficacy data) collected almost 10 years ago. In addition, the discount rate was not reported in this analysis. The generalizability of the study results to Canadian setting is uncertain due to the relatively old data. The long-term cost-effectiveness of the selected treatments is unclear since the time horizon in both economic evaluations was relatively short (six months to one year).

Summary of Findings

The overall findings are summarized below and detailed findings from the individual clinical studies are provided in Appendix 4.

What is the comparative clinical effectiveness of Suboxone compared with methadone for the treatment of patients with opioid dependence?

Opioid use

Randomized-controlled trials

In one RCT including 54 patients,15 clinical outcomes were reported for patients who completed the six month treatment with Suboxone or methadone. In 26 patients (48.1%, 13 in each group) who remained in the study, five patients in the Suboxone group compared with 0 from the methadone group reported illicit opioid use (P = 0.039). The between-group difference in positive urine test for opioid use was not found to be statistically significant (five patients in the Suboxone group compared with 2 in the methadone group, P > 0.05).

In the double-blind RCT by Kamien et al.,18 patients in the combined Suboxone groups (low dose and high dose groups combined) reported numerically fewer days of heroin use in the past 30 days, when compared with combined methadone groups, P = 0.05. Higher doses of Suboxone or methadone were associated with larger reduction in days of heroin use, compared with lower doses Suboxone or methadone; however, statistical tests of differences in days of heroin use between Suboxone and methadone in respective high- or low-dose group were not performed.

Non-randomized-controlled trials

One non-RCT20 in patients who had already received 6 months treatment with Suboxone or methadone at study entry found that significantly more Suboxone-treated patients reported “abstinent from heroin use in the past 90 days” compared with those treated with methadone (71.4% versus 37.7%). “Days of heroin use in the past 90 days” were similar at 6-months, however those in the Suboxone group reported significantly fewer days of heroin use after 14 months of treatment, compared with the methadone group (Suboxone: reduced from 38.64 days to 8.5 days; methadone: reduced from 37.40 days to 24.15 days). In terms of “treatment motivation”, significantly more patients with methadone viewed their drug use as a problem and indicated their intention to adhere to treatment. Attrition from 8-month assessment was similar between methadone and Suboxone.

Retention in treatment

Randomized-controlled trials

In the Neumann study,15 there was no significant difference in the numbers of patients who had completed the treatment of SUB or MET, 13 patients in each group.

In the Saxon study,17 patients in the Suboxone group completed fewer weeks of treatment (mean 18.5 weeks) as compared to those in the methadone group (mean 25.8 weeks), P < 0.0001. In the secondary analysis using data from this RCT,19 significantly fewer Suboxone patients (46%) than methadone patients (74%) completed treatment at 24 weeks, P < 0.01.

Kamien and coworkers reported similar retention time between Suboxone and methadone: 12.1 weeks, 13.2 weeks, 12.5 weeks and 12.3 weeks for patients in low dose Suboxone, high dose Suboxone, low dose methadone and high dose methadone groups, respectively.18 The between-group differences in retention time were not statistically significant.

Non-randomized-controlled trials

In the non-RCT by McKeganey,20 there were no statistically significant differences in rates of attrition from the 8-month follow-up assessment (rates of attending: 67.9% for Suboxone versus 62.3% for methadone, P > 0.05).

Patient perceptions toward disease and treatment

In the non-RCT by McKeganey,20 at study entry (after six months treatment with Suboxone or methadone), significantly higher scores of the Texas Christian University Self-Rating Form (TUC/SRF) were reported in patients treated with methadone than those with Suboxone, indicating that they were more likely to view their drug use as a problem and show readiness for adherence to treatment.

Cognitive performance

One non-RCT evaluated the effects of Suboxone or methadone on patient’s cognitive abilities using specific tests.21 Results showed that Suboxone was superior to methadone in attention testing. Similar test results were observed in the Suboxone group and the methadone group for working memory and verbal memory.

Safety

Randomized-controlled trials

The Neumann study reported similar rates of self-reported adverse effects between the Suboxone group and the methadone group, eight patients (61.5%) versus nine patients (69.2%), respectively.15 However, no further descriptions on adverse events were provided.

Significantly more adverse events were reported in the Suboxone group than the methadone group in a Georgia study,16 108 events versus 80 events, respectively, P = 0.003. The most commonly reported events in both groups were insomnia, constipation and depression, but were mild to moderate in intensity. There were no reports of deaths, overdoses, suicide attempts or other serious adverse events.

In one RCT which focused on liver health,17 rates of serious adverse events (SAEs) were not significantly different between treatment groups, 38 patients (5.2%) in the Suboxone group versus 45 (8.7%) in the methadone group. The SAEs reported for Suboxone included persistent headache, non-cardiac chest pain, spontaneous abortion, suicidal ideation, suicidal threat, cholecystitis, accidental benzodiazepine overdose, and suicide plan by heroin overdose; while SAEs observed for methadone included alprazolam overdose, drug intoxication requiring hospitalization, hospitalization for vomiting, bradycardia, change in metal status, inadvertent methadone overdose, gastric ulcer, and one death from accidental acute combined use of cocaine and methadone.

In the Kamien study,18 SAEs were experienced by one patient treated with Suboxone and four patients treated with methadone. There were no other safety data reported in this study.

Non-randomized-controlled trials

None of the non-randomized studies examined the safety of the use of Suboxone.

What is the cost-effectiveness of Suboxone compared with methadone for the treatment of patients with opioid dependence?

In the Greek cost-effectiveness analysis, the estimated patient total costs for one year were 2,876 euros for treatment with Suboxone, while it was 5,626 euros for treatment with methadone. In terms of the clinical effectiveness, Suboxone increased the percentage of treatment completion approximately 1.5-fold, and percentage of deaths in the Suboxone group was 2.5-fold smaller compared with that in the methadone group. As a result, the cost-effectiveness analysis demonstrated that Suboxone therapy was dominating the other two drugs, methadone and buprenorphine monotherapy. The incremental cost-effectiveness ratio (ICER) for Suboxone versus methadone was −795.03 euros with respect to “treatment completion”, and was −1,410.7 euros with respect to “percentage of avoided deaths”.

In the Australian economic evaluation, the mean treatment costs over a 6-month period were AUD$1,593 for Suboxone, and AUD$1,415 for methadone. The changes in the number of heroin-free days between the month prior to treatment (baseline) and the sixth month were 7.34 days for Suboxone and 6.84 days for methadone. Therefore, the ICER for the comparison between Suboxone and methadone was AUD$357 (confidence interval: −1,520 to 2,367). The results suggested that the combination of buprenorphine and naloxone was more expensive but more effective than methadone for patients with opioid dependence. However, the between-treatment difference in cost-effectiveness was not statistically significant.

Limitations

Most of the included clinical trials had small sample size and power calculations were not described. Results from these underpowered studies should be interpreted with caution, since a difference between treatment groups may not be detected. In addition, all studies reported results from the evaluable population, or from patients who had completed the study. However, the proportions of patients that remained in the study were low. Effectiveness of Suboxone in patients who withdrew the study earlier is uncertain.

Adverse effects were insufficiently reported and not all studies reported on adverse events. Infection was reported in a number of studies but the reporting of infection varied (e.g. catheter related infection, blood stream infection, and exit site infection). Also, the studies were not powered to detect adverse events, so differences in rare event rates may not be detectable. The studies were conducted at single centers, mainly tertiary hospitals so generalizability of the findings may be limited.

None of the clinical trials or economic evaluations was conducted in Canada, so applicability to the Canadian setting is unclear.

Copyright © 2013 Canadian Agency for Drugs and Technologies in Health.

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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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