A Canadian systematic review of 28 observational studies has identified 10 strong predictors of fatal and nonfatal prescription opioid overdose.
Published in CMAJ, the analysis found the risk of fatal and nonfatal opioid overdose was notably tied to such factors as high-dose and fentanyl prescriptions, multiple opioid prescribers or pharmacies, and several mental health issues. High-certainty evidence from 14 studies involving more than a million patients showed a linear dose-response relationship with opioid overdose.
“Our findings suggest that awareness of, and attention to, several patient and prescription characteristics may help reduce the risk of opioid overdose among people living with chronic pain,” wrote a research team led by Li Wang, PhD, a researcher at the Michael G. DeGroote Institute for Pain Research and Care and the department of anesthesia at McMaster University, Hamilton, Ont.
Predictors of fatal and nonfatal overdose
Reporting on studies of 103 possible predictors in a pooled cohort of almost 24 million patients, the review found moderate- to high-certainty evidence for large relative associations with the following 10 criteria:
- A history of overdose (odds ratio, 5.85; 95% confidence interval, 3.78-9.04).
- A higher opioid dosage (OR, 2.57; 95% CI, 2.08-3.18 per 90-mg increment).
- Three or more prescribers (OR, 4.68; 95% CI, 3.57-6.12).
- Four or more dispensing pharmacies (OR, 4.92; 95% CI, 4.35-5.57).
- Prescription for fentanyl (OR, 2.80; 95% CI, 2.30-3.41).
- Current substance use disorder (OR, 2.62; 95% CI, 2.09-3.27).
- Any mental health diagnosis (OR, 2.12; 95% CI, 1.73-2.61).
- Depression (OR, 2.22; 95% CI, 1.57-314).
- Bipolar disorder (OR, 2.07; 95% CI, 1.77-2.41).
- Pancreatitis (OR, 2.00; 95% CI,1.52-2.64).
Absolute risks in patients with the predictor ranged from 2 to 6 per 1,000 for fatal overdose and 4 to 12 per 1,000 for nonfatal overdose.
The authors noted that chronic pain affects 20% of the world’s population worldwide, and a 2021 meta-analysis of 60 observational studies revealed that opioids are prescribed for 27% of adults living with chronic pain, with a higher prevalence of prescribing in North America than in Europe.
International review
A total of 28 observational studies comprising 23,963,716 patients (52% female) with mean age of 52 years were enrolled. All used administrative databases. Twenty-four studies were conducted in the United States, three in Canada, and one in the United Kingdom. Twenty-one studies included only patients with noncancer chronic pain, while seven included patients with either cancer-related or noncancer chronic pain. Twenty-two studies accepted patients with previous or current substance use disorder and three excluded patients with comorbid substance use disorder. Twenty-three studies included patients with comorbid mental illness and five exclusively recruited veterans.
The median sample size was 43,885. As a limitation, 25 studies (89%) were at high risk of bias for at least one criterion, the authors acknowledged. Moderate-certainty evidence showed the pooled prevalence of fatal opioid overdose after prescription for chronic pain was 1.3 per 1,000 (95% CI, 0.6-2.3 per 1,000) for fatal overdose and 3.2 per 1,000 (95% CI, 2.0-4.7 per 1,000) for nonfatal overdose.
“Awareness of these predictors may facilitate shared decision-making regarding prescribing opioids for chronic pain and may inform harm-reduction strategies,” Dr. Wang and associates wrote.
This study was supported by a grant from Health Canada’s Substance Use and Addictions Program. Coauthor Dr. Corey Hayes was supported by Veterans Affairs Health Services Research and Development and the National Institute on Drug Abuse Clinical Trials Network. Dr. Jason Busse is supported by the Canadian Institutes of Health Research. Dr. David Juurlink has received travel support for presentations from the CIHR, Stanford University, and Texas Tech University Health Sciences Center.