In patients given opioids for nonmalignant pain, the daily dose is strongly associated with opioid-related mortality, particularly at doses over thresholds recommended in recent clinical guidelines, according to the results of a population-based, nested, case-control study reported in the April 11 issue of the Archives of Internal Medicine.
“Opioids are widely prescribed for chronic nonmalignant pain, often at doses exceeding those recommended in clinical practice guidelines,” write Tara Gomes, MHSc, from the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada, and colleagues. “However, the risk-benefit ratio of high-dose opioid therapy is not well characterized. The objective of this study was to characterize the relationship between opioid dose and opioid-related mortality.”
The study population consisted of 607,156 residents of Ontario, Canada, 15 to 64 years old, who were eligible for publicly funded prescription drug coverage and who had received an opioid from August 1, 1997, through December 31, 2006, for nonmalignant pain. Opioid-related death, as diagnosed by the investigating coroner, was the main study endpoint.
The investigators compared the risk for opioid-related mortality among patients treated with various daily doses of opioids using a case-control design of 498 eligible patients with opioid-related deaths and 1714 matched control participants.
Compared with low daily opioid doses (< 20 mg of morphine, or equivalent), an average daily dose of 200 mg or more of morphine or equivalent was associated with close to a 3-fold increase in the risk for opioid-related mortality (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.79 – 4.63), after extensive multivariable adjustment. With intermediate doses of opioids, increases in opioid-related mortality risk were still significant but somewhat attenuated (50 – 99 mg/day of morphine: OR, 1.92; 95% CI, 1.30 – 2.85, and 100 – 199 mg/day of morphine: OR, 2.04; 95% CI, 1.28 – 3.24).
“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,” the study authors write.
Limitations of this study include lack of generalizability to other populations; possible misclassification of opioid-related deaths; and inability to identify unused prescription drugs, those obtained illicitly, and those paid for out of pocket. In addition, the indication for opioid therapy could not be determined, and case patients and control participants differed on several baseline characteristics that could be associated with the risk for addiction and drug-related adverse events.
“Our findings have important implications, largely because most opioid-related deaths were avoidable and occurred in young people,” the study authors conclude. “We believe physicians should carefully assess the appropriateness of long-term use of opioids to treat chronic, noncancer-related pain, particularly at high doses.”
In an accompanying invited commentary, Mark D. Sullivan, MD, PhD, from the Department of Psychiatry and Behavioral Sciences at the University of Washington in Seattle, notes that opioid therapy has other harms associated with prescribed daily dose, including opioid misuse, alcohol- and drug-related medical encounters, fractures, and opioid and other drug abuse.
“Professional organizations and patient advocacy groups see any limitation to opioid dosing as an unnecessary constraint on the ability of prescribers to provide pain relief for the most distressed patients,” Dr. Sullivan writes. “But at this time, we have clearer evidence of the harm provided to patients through high-dose opioid therapy than we do of the benefits. As long as there are means to override dosing guidelines in appropriate cases through specialist review (as is the case in Washington), some effort to limit the risk associated with high-dose opioid therapy seems reasonable.”
The Ontario Ministry of Health and Long-Term Care (MOHLTC) Drug Innovation Fund and the Institute for Clinical Evaluative Sciences, a nonprofit research institute sponsored by the Ontario MOHLTC, supported this study. One of the study authors (Muhammad M. Mamdani, PharmD, MA, MPH) has received honoraria from Pfizer Inc. Another study author (Irfan A. Dhalla, MD, MSc) receives salary support in the form of a postdoctoral fellowship from the Canadian Institutes of Health Research. Dr. Sullivan has disclosed no relevant financial relationships.