Cardiovascular Disorders Associated with Naloxone Monotherapy and in Combination with Opioids: Safety Data from International Surveillance

Background: The United States Food and Drug Administration (FDA) convened a public advisory committee to discuss cardiovascular risk associated with opioid receptor antagonists to treat opioid-induced constipation. Randomized trials evaluating opioid antagonists would require large sample sizes for this population at low cardiovascular risk and are therefore unlikely to be performed. Alternatively, 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 from market introduction of each drug until 2015. The proportional reporting ratio (PRR), a measure of reporting frequency analogous to an odds ratio was assessed. The primary outcome was disproportionate reporting of System Organ Class (SOC) cardiac disorders for naloxone monotherapy and in fixed-dose combination with opioids. Opioid mono-preparations served as a quasi-experimental control. A PRR value greater than 2.0 was considered significant.

Results: Over 16-million reports were reviewed. In WHO (Figure), there were 1757 SOC cardiac disorder reports for oxycodone among 10,866 total reports (PRR 2.38 [95% CI 2.28-2.49, χ2 = 1504.08]). For oxycodone-naloxone, there were 43/453 total reports (PRR 1.45 [95% CI 1.09-1.92, χ2 = 6.366]). For tilidine there were 13/179 total reports (PRR 1.13 [95% CI 0.67-1.91, χ2 = 0.21]) and for tilidine-naloxone, 30/505 total reports (PRR 0.92 [95% CI 0.65-1.31, χ2 = 0.21]). The PRR in FAERS was 0.95 [CI 0.89-1.01, χ2 = 2.1] and 1.16 [CI 0.93-1.45, χ2 = 1.3] for naloxone (all routes) and naloxone (oral route), respectively. In comparison, the PRR was 1.66 [CI 1.63-1.69, χ2 = 4278] for oxycodone and 1.52 [CI 1.28-1.80, χ2 = 1500] for oxycodone-naloxone.

Conclusions: Available pharmacovigilance data do not suggest an adverse cardiovascular safety signal for opioid antagonists. This supports potential regulatory approval of naloxone to treat opioid-induced constipation.