Cardiovascular disorders associated with naloxone monotherapy and in fixed-dose combination with opioids: Data from international safety surveillance.

Background: The widespread use of opioids has resulted in sharp rise of associated complications, particularly opioid-induced constipation (OIC). Opioid receptor antagonists have been proposed to treat OIC, but could precipitate rapid opioid withdrawal. As cardiovascular safety data are lacking, we assessed disproportionate reporting of adverse cardiac events associated with naloxone across large, international pharmacovigilance systems.

Methods: Post-marketing data from the World Health Organization (WHO) and FDA Adverse Events Reporting System (FAERS) were evaluated for naloxone and the synthetic opioids oxycodone and tilidine. The proportional reporting ratio (PRR), a measure of reporting frequency analogous to an odds ratio, was assessed. The primary outcome was reporting frequency of the MedDRA System Organ Class (SOC) 'Cardiac Disorders' for naloxone alone and in fixed-dose combination with opioids. Opioid mono-preparations served as quasi-experimental controls. A PRR greater than 2.0 was considered significant.

Results: In total, 14,827,374 million adverse drug event reports were reviewed. In WHO, there were 1757 reports of SOC cardiac disorders among 10,866 total reports for oxycodone (PRR 2.38 [95% CI 2.28-2.49, χ(2)=1504]). For oxycodone-naloxone, there were 43/453 reports of SOC cardiac disorders (PRR 1.45 [95% CI 1.09-1.92, χ(2)=6.4]). For the synthetic opioid tilidine there were 13/179 reports (PRR 1.13 [95% CI 0.67-1.91, χ(2)=0.2]) and for tilidine-naloxone, 30/505 reports (PRR 0.92 [95% CI 0.65-1.31, χ(2)=0.2]). In FAERS, the PRR for SOC cardiac disorders was 0.95 [95% CI 0.89-1.01, χ(2)=2.1] for naloxone (all administration routes) and 1.16 [95% CI 0.93-1.45, χ(2)=1.3] for naloxone (oral only). In comparison, the PRR was 1.66 [95% CI 1.63-1.69, χ(2)=4278] for oxycodone and 1.52 [CI 1.28-1.80, χ(2)=1500] for oxycodone-naloxone.

Conclusions: Available pharmacovigilance data do not suggest disproportionate reporting of adverse cardiovascular events for opioid antagonists used to treat OIC.