Methodologic limitations of prescription opioid safety research and recommendations for improving the evidence base

PURPOSE: The ongoing opioid epidemic has claimed more than a quarter million Americans' lives over the past 15 years. The epidemic began with an escalation of prescription opioid deaths and has now evolved to include secondary waves of illicit heroin and fentanyl deaths, while the deaths due to prescription opioid overdoses are still increasing. In response, the Centers for Disease Control and Prevention (CDC) moved to limit opioid prescribing with the release of opioid prescribing guidelines for chronic noncancer pain in March 2016. The guidelines represent a logical and timely federal response to this growing crisis. However, CDC acknowledged that the evidence base linking opioid prescribing to opioid use disorders and overdose was grades 3 and 4. METHODS: Motivated by the need to strengthen the evidence base, this review details limitations of the opioid safety studies cited in the CDC guidelines with a focus on methodological limitations related to internal and external validity. RESULTS: Internal validity concerns were related to poor confounding control, variable misclassification, selection bias, competing risks, and potential competing interventions. External validity concerns arose from the use of limited source populations, historical data (in a fast-changing epidemic), and issues with handling of cancer and acute pain patients' data. We provide a nonexhaustive list of 7 recommendations to address these limitations in future opioid safety studies. CONCLUSION: Strengthening the opioid safety evidence base will aid any future revisions of the CDC guidelines and enhance their prevention impact.