Evidence is growing that two key factors help determine the risks of death in patients being treated for opioid dependence: which medication the patients are—or have been—taking, methadone or buprenorphine; and whether the patients are currently in or out of treatment.
A new study that has delved into these two factors suggests ways of lowering patients’ risks of death—especially during times of highest risk (defined below).
The study was published in BMJ April 26 under the title, “Mortality Risk During and After Opioid Substitution Treatment: Systematic Review and Meta-Analysis of Cohort Studies.”
Study Details
| Group | Patients with opioid dependence |
| Objective | Compare risks of death from all causes during and after methadone or buprenorphine treatment
Characterize trends in risks of death after treatment begins and after it ends |
| Data Sources | Literature search |
| Periods Covered | Time in or out of treatment with methadone or buprenorphine, 1974 to 2016 |
| Patient Population | Methadone: 122,885 patients, treated 1.3 to 13.9 years
Buprenorphine: 15,831 patients, treated 1.1 to 4.5 years |
| Daily Dose | Methadone, 47 mg to 116 mg; buprenorphine, 10 mg to 12 mg |
Study Findings
Treatment with either methadone or buprenorphine lowered the risk of death to less than one-third of what would be expected without treatment.
Phases of Treatment
Induction and Treatment. The risk of death with methadone was initially high during the four weeks of induction. Risk dropped from its high point during the four weeks, eventually stabilized, then remained unchanged during the rest of treatment.
This did not happen with buprenorphine. Instead, the number of deaths remained stable during induction and throughout the rest of the treatment period. The authors commented, however, that findings with buprenorphine are preliminary; buprenorphine treatment probably reduces deaths, but further studies are needed for verification.
Treatment Cessation. With both medications, cessation of treatment clearly was a danger period. The authors noted: “The mortality risk in the four weeks immediately after cessation of either treatment is high . . . ” [emphasis added]. This increased risk could be due to patients’ return to heroin, after having lost their tolerance to its toxic effects. Other factors could be involved, such as patients being out of contact with therapists who might have guided them back into treatment, although the authors did not mention this specifically.
| Key Periods for Lowering the Risks Of Drug-Related Deaths:
Methadone:
Both drugs:
With methadone: focus on preventing drug-related deaths during the first four weeks; with both drugs: focus on the first four weeks after patients discontinue therapy. |
Implications of the Findings
The authors recommended using clinical strategies and public health measures to mitigate risks during periods of high and highest risk. They also suggested modifications in study design that could yield additional data.
Authors’ specific recommendations:
- Carefully assess patients’ opioid tolerance before treatment begins; use the information to establish a safe induction dose
- Monitor for mental and physical problems during induction; consider adjusting the dosage accordingly
- Prevent patients from using illicit opioids (they did not elaborate on how to accomplish this)
- Educate patients about the risk of overdose and the use of naloxone
- Consider using buprenorphine for induction, then transitioning to methadone
- Look for ways to improve patient retention
- Coordinate the exchange of information between health care professionals, social and legal services, and patients
- Have both medications widely available worldwide, to “reduce the social harm associated with opioid use”
The Dangers of Cycling
Patients who cycle—go in and out of treatment—face a high risk of death, possibly because they are repeatedly exposed to high-risk periods. The specific risks could involve fatal overdose, but this has not been proven.
Limitations and Comments
Despite the potential importance of their findings, the authors cautioned that further research is needed. Specifically, such studies would be directed toward several methodological shortcomings the authors encountered in the indexed studies. These shortcomings, which may have impacted their estimates, include a loss to follow-up and a lack of studies in low- and middle-income countries.
BMJ published three comments contributed by outsiders not involved in the study. Two concerned the study design. The third, by Richard Saitz, MD, MPH, amounted to a critique of the article’s title. (The linked editorial in BMJ also included a gentle criticism of the article’s use of the term “opioid substitution treatment,” pointing out, as did Dr. Saitz, that the preferred term is “opioid agonist treatment.”)
Our Comment: Dr. Saitz is editor of the Journal of Addiction Medicine, the official journal of the American Society of Addiction Medicine. He’s also no stranger to these pages. Dr. Saitz often speaks out against stigma, and last year we quoted his writings several times in our four-part series on that topic. So we weren’t surprised to see his comment accompanying the current paper.
In criticizing the term “opioid substitution treatment,” Dr. Saitz points out that, unlike heroin, opioid agonists such as methadone reduce mortality and produce no euphoria or endocrine derangements. And people do not use the agonists compulsively.
A better term than substitution, Dr. Saitz suggests, would be “opioid agonist treatment.” Or more generally “medication treatment. Or medication for addiction treatment. Or just buprenorphine and methadone.”
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RESOURCES
Sordo L, Barrio G, Bravo MJ, et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017;357:j1550 http://dx.doi.org/10.1136/bmj.j1550.
Manhapra A, Rosenheck R, Fiellin DA. Opioid substitution treatment is linked to reduced risk of death in opioid use disorder [Editorial]. BMJ. 2017; Apr 26;357:j1947. doi: 10.1136/bmj.j1947. http://www.bmj.com/content/357/bmj.j1947.
Saitz R. Time to avoid inaccurate terms in this field: it’s not substitution, it is opioid agonist treatment. http://www.bmj.com/content/357/bmj.j1550/rr.