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Systematic review

Alternative opioid agonists in the treatment of opioid dependence: a systematic review

  • Year: 03.2017
  • By: Folkehelseinstituttet
  • Authors Mosdøl A, Ding KY, Hov L.
  • ISBN (digital): 978-82-8082-812-5
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In this review, we have looked at treatment with slow release oral morphine and levomethadone. These treatments are compared to the three medications used in Norway: buprenorphine with naloxone, buprenorphine or methadone.

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Key message

Opioid maintenance treatment can help people with opioid dependence to improve their lives. The treatment is effective, but people often experience side effects. Sometimes it may help to change the medication used in treatment.

In this review, we have looked at treatment with slow release oral morphine and levomethadone. These treatments are compared to the three medications used in Norway: buprenorphine with naloxone, buprenorphine or methadone.

We found six relevant studies - three for slow release oral morphine and three for levomethadone. All compared these treatments with methadone. Almost all studies examined effect on use of illicit drugs and at least some possible adverse effects. Some studies reported if people stayed in treatment or how satisfied they were. No studies examined effect on crime.

When treatment with either slow release oral morphine or levomethadone was compared to treatment with methadone for opioid maintenance treatment, the researchers did not find evidence that these have different effects. However, the evidence is too limited and uncertain to conclude whether the treatments are equivalent.

Summary

Background

The Norwegian Directorate of Health revises the national guideline for the treatment of opioid dependence. Opioid Maintenance Treatment (OMT) has become the dominant form of treatment for people with opioid dependence. The current Norwegian OMT guideline recommends buprenorphine with naloxone as the first choice of medication, secondly buprenorphine monoformulation or methadone. However, all OMT drugs have several side effects. There is a need to diversify the possible medications available. The objective of this report is to assess the effect of using slow-released oral morphine or levomethadone in OMT for opioid dependence compared with the three medications used today.  

Method

We first searched for systematic reviews and found one systematic review on treatment with slow-release oral morphine. We decided to use this as a basis with updated search for new primary studies. Subsequently, we searched for primary studies in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL and PsycInfo through June 2016. Two people independently examined 2210 references and assessed 15 articles in full-text. We included three studies on treatment with slow-release oral morphine and three studies on levomethadone. The relevant study population was adults receiving OMT for opioid dependence. The intervention was either treatment with slow-release oral morphine or levomethadone. Control was treatment with methadone, buprenorphine or buprenorphine with naloxone. Relevant outcomes were retention in treatment, patient satisfaction, use of opioids and other addictive drugs, adverse effects and crime. We looked for randomized controlled trials or controlled studies with both pre- and post-measurements. Two reviewers independently assessed risk of bias.  One person retrieved data from the studies, analysed and assessed our confidence in the effect estimates, and another person checked the data and analyses. We used the GRADE-methodology (Grading of Recommendations Assessment, Development, and Evaluation) to indicate our certainty in the effect estimates. The certainty may be high, medium, low, or very low.

Results

We found six relevant studies conducted in Germany, Switzerland, Austria and Nederlands. All studies recruited persons with long-term opioid dependence who had received OMT for some years. We considered that all studies had unclear risk of bias.

Three studies, with in total 460 recruited participants, compared receiving slow-release oral morphine with receiving methadone. One of these also compared treatment with buprenorphine. We found that when people are treated with slow-release oral morphine as compared to methadone:

  • There is probably little or no difference in retention in treatment (Relative risk 0.97, 95% confidence interval 0.90 - 1.04, moderate certainty).

  • There may be little or no difference in the use of illicit opioids and drugs as measured in urine and self-reported (low certainty).

  • About 4 of 5 participants in these studies experienced at least one side effect (any severity) during treatment with slow-release oral morphine or methadone. Two of the studies reported that the overall prevalence of serious adverse events was 4% and 0% respectively. One person, treated with methadone at the time of event, died of an overdose. There may be little or no difference in the occurrence of adverse events between these treatments, but we have low to very low certainty in these estimates.

  • The evidence is too uncertain to estimate effect on patient satisfaction.

  • We found no studies that looked at effect on crime.

The evidence is sparse regarding the effect of treatment with slow-release oral morphine as compared to buprenorphine.

Further three studies compared receiving levomethadone with receiving methadone among 141 recruited participants. We could not calculate effect on retention in treatment when people were treated with levomethadone compared to methadone. The evidence is too uncertain to estimate the effect on any differences in patient satisfaction, use of both illicit opioids and other drugs, and in the prevalence of adverse events (very low certainty evidence). We found no studies that looked at effect on crime. 

Discussion

The evidence is more comprehensive for slow-release oral morphine than for levomethadone. Most of the studies compared the alternative treatment to treatment with methadone. All the included studies had weaknesses in how the studies were performed and presented. Due to these weaknesses, we assessed the certainty in most of the evidence of effect as low or very low. Low certainty in evidence of effect does not mean that the treatments are ineffective or differ, but that the available evidence is insufficient to reliably estimate the true comparative effect.

Only one of the studies related their design and interpretation of findings to features of equivalence and non-inferiority study designs. The other studies provided insufficient information to judge the effects against equivalence and non-inferiority margins.

Overall, when the evidence is viewed across all the presented outcomes, the studies do not indicate any major differences in effects of treatment with slow-release oral morphine or levomethadone as compared to methadone for OMT. However, the evidence is too uncertain and limited to conclude whether the treatments are equivalent or non-inferior to standard treatments.

Conclusion

When treatment with either slow release oral morphine or levomethadone for OMT was compared to treatment with methadone, we did not find evidence suggesting substantially different effects between treatments. However, the evidence is too limited and uncertain to conclude whether the treatments are equivalent.