Differential Reversal of the Ventilatory‐Depressant Effects of Fentanyl and its Derivatives by Naloxone in Monkeys

Abstract

Opioid overdose deaths continue to rise with fatalities involving synthetic opioids, such as fentanyl and its derivatives, increasing sharply in 2020 and accelerating further during the COVID‐19 pandemic. Many lives have been saved by administering naloxone to reverse ventilatory depression, the fatal effect of opioids; however, these effects of fentanyl derivatives are reportedly more difficult to reverse with naloxone than those of other opioids like heroin. The current study examined the ability of naloxone to reverse ventilatory depression produced by fentanyl and 2 of its derivatives. Minute volume (VE) was measured using head plethysmography in 4 rhesus monkeys breathing air. On separate occasions, monkeys received saline or naloxone (0.032 mg/kg) 30 min after administration of the smallest dose of fentanyl, 3‐methylfentanyl or carfentanil that decreased VE to <70% of control. Fentanyl and its derivatives dose‐dependently decreased ventilation, although their potency varied markedly; carfentanil was 10‐fold more potent than 3‐methylfentanyl and 100‐fold more potent than fentanyl. For each opioid, the dose that decreased VE varied slightly across individual monkeys (fentanyl: 17.8‐56 µg/kg; 3‐methylfentanyl: 3.2‐5.6 µg/kg; carfentanil: 0.32‐0.56 µg/kg), although those doses reliably decreased ventilation within 30 min such that VE ranged from 57‐63% of control. Ventilatory depression was evident for at least 90 min. Naloxone reversed the ventilatory‐depressant effects of fentanyl and 3‐methylfentanyl with the mean VE increasing to 112% and 120% of control, respectively, within 15 min; however, this attenuation by naloxone did not last long, beginning to wane 30 min after its administration. In contrast, naloxone was not as effective in reversing the ventilatory‐depressant effects of carfentanil; VE was <70% of control 15 min after naloxone and remained <90% at all time points. Thus, reversal of the ventilatory‐depressant effects of fentanyl and 3‐methylfentanyl was similar to each other and to that obtained previously with heroin, supporting the effectiveness of naloxone in attenuating ventilatory depression involving these opioids. Differences between carfentanil and pharmacologically equivalent doses of other opioids suggest that naloxone is not equally potent, and might not be equally effective, in reversing all opioids and underscores the importance of developing novel treatment options for opioid overdose.