Opioid dose and drug-related mortality in patients with nonmalignant pain

Context — Opioids are widely prescribed for chronic nonmalignant pain, often at doses exceeding those recommended in clinical practice guidelines. However, the risk-benefit ratio of high-dose opioid therapy is not well characterized.

Objective — To characterize the relationship between opioid dose and opioid-related mortality.

Design, Setting and Patients — The researchers conducted a population-based nested case-control study of Ontario residents aged 15 to 64 who were eligible for publicly-funded prescription drug coverage and received an opioid between August 1, 1997 and December 31, 2006 for nonmalignant pain.

Main Outcome Measures — The outcome of interest was opioid-related death, as determined by the investigating coroner. The risk of opioid-related death was compared among patients treated with various daily doses of opioids.

Results — Among 607,156 people aged 15 to 64 prescribed an opioid over the study period, the researchers identified 498 eligible cases whose deaths were related to opioids and 1,714 matched controls. After extensive multivariable adjustment, the researchers found that an average daily dose exceeding 200 mg morphine (or equivalent) was associated with a nearly threefold increase in the risk of opioid-related mortality (odds ratio 2.88, 95% confidence interval 1.79 to 4.63) relative to low daily doses (less than 20 mg morphine or equivalent). The researchers found significant but attenuated increases in opioid-related mortality with intermediate doses of opioids (50 to 99 mg of morphine: odds ratio 1.92 (95% confidence interval 1.30 to 2.85); 100 to 199 mg of morphine: odds ratio 2.04 (95% confidence interval 1.28 to 3.24)

Conclusions — Among patients receiving opioids for nonmalignant pain, the daily dose is strongly associated with opioid-related mortality, particularly at doses exceeding thresholds recommended in recent clinical guidelines.