Long-Acting Opioids: Mortality in Patients with Chronic Noncancer Pain

Study shows frequent opioid reliance despite lack of evidence of benefit and increased risk.

Long-acting opioids increase the risk of unintentional overdose deaths, but there has been a lack of strong research comparing their overall safety with other medications prescribed for noncancer pain. This was the focus of a research study conducted by investigators from the departments of Medicine, Health Policy and Pharmacology at Vanderbilt University Medical Center.

The retrospective cohort study, published in JAMA, evaluated all causes of mortality for Tennessee Medicaid patients between 1999 and 2012 with chronic noncancer pain and no evidence of palliative or end-of-life care. Propensity scores were developed by matching new episodes of prescribed therapy for long-acting opioids or control medications (either analgesic anticonvulsants or low-dose cyclic antidepressants) with total and cause-specific mortality as determined from death certificates.

“There is a very high prevalence of chronic noncancer pain,” said Leslie Crofford, M.D., director of the Division of Rheumatology and Immunology at Vanderbilt, “and patients frequently use long-acting opioids despite lack of evidence for benefit. This study employs state-of-the-art methodology to further underscore the risks associated with use of these agents.”

The Cohort

The study excluded persons 75 years of age or older, patients with cancer and other life-threatening diseases, nursing home residents and those with evidence of palliative or end-of-life care, as these patients have higher baseline risk and could be more susceptible to adverse medication effects. The cohort also excluded patients with any recorded evidence of drug abuse, thus underestimating the potential for overdose.

Patients in the two study groups were tightly matched according to potential confounders, including chronic pain diagnoses; patterns of prior use of short-acting opioids and other analgesics; use of benzodiazepines and other psychotropic drugs associated with increased risk of overdose deaths; and cardiovascular, respiratory and other comorbidities.

After matching, the cohort included 22,912 long-acting opioid episodes and an equal number of control medication episodes. The most commonly prescribed medications in the cohort were morphine SR, gabapentin and amitriptyline. The median doses at the time of cohort entry were 50 mg morphine-equivalents for the long-acting opioids, 600 mg gabapentin-equivalents for the analgesic anticonvulsants and 25 mg amitriptyline-equivalents for the cyclic antidepressants.


Patients prescribed therapy for a long-acting opioid had a risk of all-cause mortality 1.64 times greater than that for matched patients starting an analgesic anticonvulsant or a low-dose cyclic antidepressant. This difference was explained by a 1.90 times greater risk of out-of-hospital deaths. More than two-thirds of the additional deaths in patients using long-acting opioids were due to causes other than unintentional overdose; of these, more than one-half were cardiovascular deaths. The increased risk of cardiovascular death could be related to adverse respiratory effects of long-acting opioids, especially sleep-disordered breathing.

“The results of this important study show an alarming increase in all-cause mortality associated with use of long-acting opioids compared to other agents that may benefit patients with noncancer pain.”

These study findings reinforce the conclusion of the CDC guidelines that “nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain.” Although all prescribing decisions should be based on an evaluation of the source and severity of the patient’s pain and a discussion of the known risks and benefits of opioid therapy, the CDC’s guidelines suggest that the efficacy of nonopioid pain management for many chronic conditions is at least equal to that of opioids. These findings should be considered when evaluating the risks and benefits of treatment.

“The results of this important study show an alarming increase in all-cause mortality associated with use of long-acting opioids compared to other agents that may benefit patients with noncancer pain,” Crofford said. “The investigators carefully matched patients to control for other factors that could explain their results, increasing confidence in their findings. The study strongly supports current CDC guidelines to avoid chronic opioids in patients with chronic pain.”