Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats

Abstract

Opioid use disorder affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. The Food and Drug Administration-approved opioid receptor antagonist naloxone (e.g., Narcan) is used currently to treat overdose; however, a short duration of action limits its clinical utility. Methocinnamox (MCAM) is a long-lasting opioid receptor antagonist that may reverse and prevent the ventilatory-depressant effects of fentanyl. This study compared the ability of naloxone (0.0001-10 mg/kg) and MCAM (0.0001-10 mg/kg) to reverse and prevent ventilatory depression by fentanyl and compared the duration of action of MCAM intravenously and subcutaneously in two procedures: ventilation and warm-water tail withdrawal. In male Sprague-Dawley rats (N = 8), fentanyl (0.0032-0.178 mg/kg, i.v.) decreased minute volume in a dose- and time-dependent manner with a dose of 0.178 mg/kg decreasing V_E to less than 40% of control. MCAM and naloxone reversed the ventilatory-depressant effects of 0.178 mg/kg fentanyl in a dose-related manner. The day after antagonist administration, MCAM but not naloxone attenuated the ventilatory-depressant effects of fentanyl. The duration of action of MCAM lasted up to 3 days and at least 2 weeks after intravenous and subcutaneous administration, respectively. MCAM attenuated the antinociceptive effects of fentanyl, with antagonism lasting up to 5 days and more than 2 weeks after intravenous and subcutaneous administration, respectively. Reversal and prolonged antagonism by MCAM might provide an effective treatment option for the opioid crisis, particularly toxicity from fentanyl and related highly potent analogs. SIGNIFICANCE STATEMENT: This study demonstrates that like naloxone, methocinnamox (MCAM) reverses the ventilatory-depressant effects of fentanyl in a time- and dose-related manner. However, unlike naloxone, the duration of action of MCAM was greater than 2 weeks when administered subcutaneously and up to 5 days when administered intravenously. These data suggest that MCAM might be particularly useful for rescuing individuals from opioid overdose, including fentanyl overdose, as well as protecting against the reemergence of ventilatory depression (renarconization).

Fig. 1.

Effects of fentanyl on ventilation. Minute volume is plotted as a function of time after administration of intravenous vehicle or fentanyl (0.0056, 0.0178, 0.056, and 0.178 mg/kg). After a 20-minute baseline period (see Table 1), rats received an intravenous infusion of vehicle or fentanyl (arrow at “0” minutes) followed 5 minutes later by an intravenous infusion of saline (arrow at “5” minutes). Data are presented as a percentage of the average minute volume during the 20-minute baseline period calculated individually for each rat. The inset summarizes the average minute volume during the 5 minutes immediately after infusion of saline or fentanyl (0.0032–0.178 mg/kg), and filled symbols represent doses not shown in the main figure; the gray bar represents the 95% CI for control conditions (i.e., saline infusions at “0” and “5” minutes). Ordinate: minute volume plotted as percent of control and averaged among eight rats ± 1 S.E.M. Abscissae: time in minutes. CI, confidence interval.

Fig. 2.

Reversal of the ventilatory-depressant effects of fentanyl by MCAM and naloxone. Rats received an intravenous infusion of 0.178 mg/kg fentanyl at “0” minutes (arrows) and a second infusion of vehicle, (squares, both panels), MCAM (left panels), or naloxone (right panels) at “5” minutes. Upper panels include data for vehicle, 0.1, 1.0, and 10.0 mg/kg; lower panels include data for vehicle, 0.0001, 0.001, and 0.01 mg/kg. The gray bar represents the 95% CI for minute volume under control conditions (saline followed by vehicle). Insets represent the area under the curve (AUC) for MCAM or naloxone curves compared with vehicle curves. Asterisks indicate that AUC obtained after the administration of an antagonist was significantly different from AUC after vehicle, P < 0.05. Ordinates: minute volume plotted as percent of control and averaged among eight rats ± 1 S.E.M. Abscissae: time in minutes. CI, confidence interval.

Fig. 3.

Dose-response curves summarizing the same data shown in Fig. 2 for MCAM and naloxone in reversing ventilatory-depressant effects of 0.178 mg/kg fentanyl intravenously. Each data point is the mean minute volume for 5 minutes after infusion of vehicle (V), MCAM, or naloxone and averaged (±1 S.E.M.) among eight rats. Ordinate: minute volume presented as a percent of baseline. Abscissa: dose of MCAM or naloxone in mg/kg body weight intravenously. C represents a control session in which rats received only vehicle.

Fig. 4.

Protection against the ventilatory-depressant effects of 0.178 mg/kg fentanyl by MCAM (left) and naloxone (right). The preceding day, rats received 0.178 mg/kg fentanyl intravenously followed by intravenous MCAM or naloxone. On the (next) test day shown in this figure, rats received an intravenous infusion of fentanyl at minute “0” and an infusion of vehicle intravenously at “5” minutes. The gray bar represents the 95% CI for minute volume under control conditions (saline followed by vehicle). Insets represent the area under the curve (AUC) for MCAM or naloxone curves compared with vehicle curves. Asterisks indicate that AUC obtained after the administration of an antagonist was significantly different from AUC after vehicle, P < 0.05. Ordinates: minute volume plotted as percent of control and averaged among eight rats ± 1 S.E.M. Abscissae: time in minutes. CI, confidence interval.

Fig. 5.

Protection against the ventilatory-depressant effects of 0.178 mg/kg fentanyl 1 and 3 days after intravenous (left) or subcutaneous (right) administration of MCAM. In contrast with data shown in Fig. 4, rats did not receive fentanyl on the day MCAM was administered (i.e., protection only and no rescue). On the test days shown, rats received an intravenous infusion of fentanyl at minute “0” and an infusion of vehicle intravenously at “5” minutes. The gray bar represents the 95% CI for minute volume under control conditions (saline followed by vehicle). Insets represent the area under the curve (AUC) for intravenous or subcutaneous MCAM compared with vehicle curves. Asterisks indicate that AUC obtained after the administration of an antagonist was significantly different from AUC after vehicle, P < 0.05. Ordinates: minute volume plotted as percent of control and averaged among eight rats ± 1 S.E.M. Abscissae: time in minutes. CI, confidence interval.

Fig. 6.

Time-response curves summarizing the same data shown in Fig. 5 and Table 2 for MCAM administered intravenously and subcutaneously in protecting against the ventilatory-depressant effects of 0.178 mg/kg fentanyl intravenously. Each data point is the mean minute volume for 5 minutes after infusion of fentanyl averaged (±1 S.E.M.) among eight rats. Asterisk indicates duration of MCAM (i.e., day) that was different between intravenous and subcutaneous administration, P < 0.05. Ordinate: minute volume presented as a percent of baseline. Abscissa: days after administration of MCAM. Vehicle points show data for fentanyl in rats that did not receive MCAM.

Fig. 7.

Effects of fentanyl on tail-withdrawal latency from warm water 1, 5, and 21 days after intravenous (left) or subcutaneous (right; replotted with permission from Gerak et al., 2019b) administration of 10 mg/kg MCAM. Inset summarizes data (maximum possible effect) for a cumulative dose of 0.1 mg/kg fentanyl under control conditions (C) and 1, 5, and 21 days after intravenous or subcutaneous administration of 10 mg/kg MCAM. Asterisks indicate tail-withdrawal latency that was different between MCAM administered intravenously or subcutaneously, P < 0.05. Ordinate: average latency (±1 S.E.M.) to remove tails from 50°C water expressed as a percentage of control and averaged among eight rats. Abscissae: dose of fentanyl administered intraperitoneally in mg/kg body weight. S represents the effects of saline.