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Psychiatry Research Review

Sanjay Gupta, MD
Released: November 18, 2021

Association of Opioid Agonist Use With All-Cause Mortality: Systemic Review and Meta-analysis

Santo T, et al. JAMA Psychiatry. 2021;78:979-993.

Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the United States, and patients with OUD have higher mortality than the general population treatment-resistant depression An effective treatment for opioid dependence is opioid agonist treatment (OAT), but the relationship between OAT and specific causes of mortality has not been established. This study estimated the association of OAT with mortality.

The Embase, MEDLINE, and PsycINFO databases were used to identify clinical trial registries and previous reviews. Randomized clinical trials and observational studies were included if they collected data on all-cause or cause-specific mortality among people with OUD being treated with or without OAT. In total, 15 randomized clinical trials, including 3852 participants, and 36 primary cohort studies, including 749,634 participants, were analyzed. Participant, study, and treatment characteristics were extracted in the analysis, and treatment with methadone and buprenorphine OAT were specifically evaluated. The main outcomes were all-cause and cause-specific mortality by setting and participant characteristics.

All-cause mortality during treatment with OAT was more than one half of the rate seen without OAT and was consistent across participant sex, age, and geographic location and treatment with methadone vs buprenorphine. Treatment with OAT was associated with a reduced risk of mortality related to suicide, drugs, alcohol, cancer, and cardiovascular factors. In the 4 weeks after OAT cessation, the rate of all-cause mortality was 6 times higher than during therapy with OAT; after 4 weeks, and for the remainder of time that patients did not receive OAT, the rate of all-cause mortality remained twice as high. The rates of all-cause mortality and drug-related poisoning in the first 4 weeks of methadone treatment were almost twice that for the remainder of OAT, but this association was not observed for treatment with buprenorphine.

Although this study found an association between OAT and reduced mortality, access to and insurance coverage of treatment with OAT are limited. There may be population-level benefits in mortality if access to OAT is improved globally.

Clinical Commentary
The COVID-19 pandemic has resulted in an increase in OUD and related mortality in many countries, particularly in North America, where there have been substantial increases in overdoses. Patients who were previously stable have been destabilized by remote telehealth or telephone visits and also have been receiving reduced monitoring from urine drug screenings at many clinics. This study is an eye-opener for all healthcare professionals, indicating that OAT treatment reduces mortality, and it is the first study to associate OAT with reductions in all-cause and cause-specific mortality. One limitation of this study is that it did not take into account the long-acting formulations of buprenorphine.

Clinical Insights

  • OAT was associated with a 50% lower risk of all-cause mortality and drug-related deaths.
  • People with opioid dependence were at a substantially lower risk of suicide, cancer, and drug-related, alcohol-related, and cardiovascular-related mortality during OAT compared with time while not receiving OAT.
  • Viral hepatitis mortality was higher among those who received OAT.

In my professional opinion, healthcare professionals should begin thinking of OUD as a disease state akin to diabetes and treat it aggressively with OAT to reduce mortality from all causes and comorbid medical conditions. Mental health care professionals should increase focus on screening and treating OUDs with OATs (buprenorphine and methadone). It is important to note that it serves the patient well if the same healthcare professional (psychiatrist, nurse practitioner, or physician assistant) prescribes psychiatric medications and OAT, and it should also reduce the coprescription of opiates and benzodiazepine (which has an FDA boxed warning).

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