Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain

Abstract

Importance: Long-acting opioids increase the risk of unintentional overdose deaths but also may increase mortality from cardiorespiratory and other causes.

Objective: To compare all-cause mortality for patients with chronic noncancer pain who were prescribed either long-acting opioids or alternative medications for moderate to severe chronic pain.

Design, setting, and participants: Retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care.

Exposures: Propensity score-matched new episodes of prescribed therapy for long-acting opioids or either analgesic anticonvulsants or low-dose cyclic antidepressants (control medications).

Main outcomes and measures: Total and cause-specific mortality as determined from death certificates. Adjusted hazard ratios (HRs) and risk differences (difference in incidence of death) were calculated for long-acting opioid therapy vs control medication.

Results: There were 22,912 new episodes of prescribed therapy for both long-acting opioids and control medications (mean [SD] age, 48 [11] years; 60% women). The long-acting opioid group was followed up for a mean 176 days and had 185 deaths and the control treatment group was followed up for a mean 128 days and had 87 deaths. The HR for total mortality was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths (95% CI, 28.2-120.7) per 10,000 person-years. Increased risk was due to out-of-hospital deaths (154 long-acting opioid, 60 control deaths; HR, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years. For out-of-hospital deaths other than unintentional overdose (120 long-acting opioid, 53 control deaths), the HR was 1.72 (95% CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95% CI, 15.7-91.4) per 10,000 person-years. The HR for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95% CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95% CI, 4.6-65.3) per 10,000 person-years. The HR during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95% CI, 2.27-7.63) with a risk difference of 200 excess deaths (95% CI, 80-420) per 10,000 person-years.

Conclusions and relevance: Prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose, with a modest absolute risk difference. These findings should be considered when evaluating harms and benefits of treatment.

Figure. Mortality according to study drug duration, dose, and baseline use short-acting opioids

N indicates number of patients. An individual patient can be in multiple duration and dose categories during followup; thus, the numbers do not sum to the total cohort size. Adjusted hazard ratios and risk differences are shown are shown (95% confidence interval in parentheses) for current use of long-acting opioids versus current use of analgesic anticonvulsants or cyclic antidepressants. The estimates according to duration of use and study drug dose during follow-up are adjusted for a time-dependent disease risk score; those for baseline use of short-acting opioids are adjusted for baseline propensity score and age and calendar year during followup. Cutpoints for low (≤ cutpoint) versus high (> cutpoint) study drug dose were: 60 mg/day morphine equivalents, 600 mg/day gabapentin equivalents and 40 mg/day amitriptyline equivalents. For short-acting opioids, doses are in morphine equivalents.