resize_shutterstock_256514542Long-acting opioid medications are associated with an increased risk for death among patients treated for non-cancer pain in comparison with patients treated with other pain medications, including gabapentin (multiple brands) and cyclic antidepressants, particularly in the first month after starting therapy, the results of a large US study reveal 1,2,3. In a study of more than 45,000 prescription episodes, Wayne A. Ray, PhD, of the Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee, and colleagues found that use of long-acting opioids was associated with a 90% increased risk for all-cause mortality. The risk was increased more than fourfold in the first 30 days of treatment with the long-acting opioid drugs 1, 2,3. The significantly increased mortality risk with the drugs held even after taking into account unintentional overdoses. The overall risk appeared to be partially explained by an increased risk for cardiovascular deaths.

“It is well known that long-acting opioid analgesics increase the risk of fatal overdose,” said lead author Wayne A. Ray, PhD, an epidemiologist and professor of health policy at Vanderbilt University School of Medicine, in Nashville, Tenn. “However, we were concerned that the focus on overdose could underestimate the harms of these medications, given the broad scope of their physiologic effects.”1 Dr Ray told Medscape Medical News that the findings “reinforce the recent guideline by the Centers for Disease Control and Prevention that, for many patients, opioids should be a last resort for patients with chronic pain who don’t have cancer or aren’t in end-of-life or palliative care.”3
The study utilized a retrospective cohort review occurring between 1999 and 2012 of Tennessee Medicaid patients with chronic non-cancer pain2. To ensure that patients with critical illnesses did not influence the findings, the investigators excluded patients receiving end-of-life or palliative care, as well as those with recorded evidence of drug abuse 1, 3.

The researchers identified 23,308 new episodes of prescriptions for long-acting opioids and 131,883 new episodes of control medication prescriptions. Using propensity scoring, the team matched 22,912 long-acting opioid episodes with an equal number of control medication episodes. The mean age of the matched patients was 48 years, and 60% were women. The most common chronic pain diagnosis was back pain (75% of patients), followed by other musculoskeletal pain (63%) and abdominal pain (18%). The most commonly prescribed study medications were morphine SR, gabapentin, and amitriptyline (multiple brands).

For patients receiving long-acting opioids, during a mean follow-up period of 176 days, there were 185 deaths, compared with 87 deaths during a mean follow-up of 128 days for patients receiving control medications. The hazard ratio for mortality with long-acting opioids was 1.64, at a risk difference of 68.5 excess deaths per 10,000 person-years. Crucially, the risk for death was highest during the first 30 days after starting therapy, at a hazard ratio of 4.16 and a risk difference of 200 excess deaths per 10,000 person-years. The increased mortality risk among patients receiving long-acting opioids was primarily attributable to out-of-hospital deaths, at a hazard ratio vs control medications of 1.90 and a risk difference of 67.1 excess deaths per 10,000 person-years. This translated into a hazard ratio for out-of-hospital deaths with causes other than unintentional overdose of 1.72 and a risk difference of 47.4 excess deaths per 10,000 person-years. Patients taking long-acting opioids also had an increased risk for cardiovascular deaths compared with those taking control medications, at a hazard ratio of 1.65, or a risk difference of 28.9 excess deaths per 10,000 person-years.1, 2, 3

“We were surprised that 70% of the excess deaths in the long-acting opioid group were for causes other than unintentional overdose,” Dr. Ray said. “This suggests that current thinking may have underestimated the harms of these medications.” The 65% increase in risk for cardiovascular death “may be due to the adverse effects of opioids on nocturnal respiration,” according to the researchers.
The higher number of early deaths in the long-acting opioid group “may be due to a subset of particularly susceptible patients,” Dr. Ray said. “Therefore, when starting a long-acting opioid, consider reducing doses or eliminating concurrent short-acting opioids. Also, use an even lower starting dose than now is recommended and titrate slowly up.”1

Readers of this blog are highly encouraged to completely read the references/links listed for the entire context of these articles. Additionally, references are provided for your information and additional data is readily available in the public domain for healthcare professionals and other interested parties to research and review this topic in more thorough detail.


  2. Ray WA, et al JAMA. 2016; 315(22):2415-2423. doi:10.1001/jama.2016.7789 (Abstract).

Additional References: