Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel μ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys

Abstract

One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [V_E]) of heroin in five monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared with those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased V_E MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve rightward at least 10-fold. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 minutes after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared with those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 minutes, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than opioid receptor antagonists currently in use. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose.

Fig. 1.

Potency for heroin to decrease respiration across monkeys. The average of two heroin dose-effect curves determined in the absence of antagonist are shown with each symbol representing data from a different monkey. Because the potency of heroin varied across monkeys, the smallest dose of heroin that decreased V_E to <70% of control was designated dose X and used to normalize dose-effect curves to compare results of antagonism studies (Figs. 2 and 4). Abscissae: heroin dose in milligrams per kilogram of body weight. Ordinates: minute volume (V_E) in milliliters per minute (left) or expressed as a percentage of control, which was obtained from the last 5 minutes of the control period for that session (right).

Fig. 2.

Prevention of the respiratory-depressant effects of heroin in four monkeys. Heroin dose-effect curves were determined at various times after the administration of MCAM (upper) or naltrexone (lower). Data from OL, ME, CE, and GI are shown in the upper panel, whereas data from OL, ME, SC, and GI are shown in the bottom panel. Heroin doses were normalized across animals such that dose X is the smallest dose of heroin that decreased V_E to <70% of control (see Fig. 1 for individual doses). Abscissae: normalized heroin dose. Ordinates: minute volume (V_E) expressed as a percentage of control.

Fig. 3.

Reversal of the respiratory-depressant effects of heroin in four monkeys. A dose of heroin that decreased V_E to <70% of control when given as a bolus injection was administered with a second injection of either saline, MCAM, or naloxone given 30 minutes later. The dose of heroin needed to produce this effect varied across monkeys (OL: 0.1 mg/kg, ME: 0.32 mg/kg, SC: 0.56 mg/kg, and GI: 1 mg/kg). Asterisks indicate that data points obtained following administration of an antagonist are significantly greater than those obtained with heroin alone. Abscissae: time since administration of the second injection with time since heroin administration shown in parentheses. Ordinates: minute volume (V_E) expressed as a percentage of control.

Fig. 4.

Heroin dose-effect curves determined on various days after the MCAM or naloxone reversal tests shown in Fig. 3. Only the largest dose of naloxone is shown 1 day after the reversal test. Abscissae: normalized heroin dose. Ordinates: minute volume (V_E) expressed as a percentage of control.

Fig. 5.

Doses of heroin that decrease respiration to 75% at various times after administration of an antagonist. The upper panel, which shows results from the prevention experiments, summarizes dose-effect curves from Fig. 2, and the lower panel, which shows results from the reversal experiments, summarizes data from Fig. 4. Points above C indicate the ED₇₅ value obtained from heroin dose-effect curves in the absence of antagonist. Asterisks indicate that ED₇₅ values for heroin obtained after administration of an antagonist are significantly different from those obtained with heroin alone. Abscissae: days since antagonist administration. Ordinates: dose (milligrams per kilogram) of heroin needed to decrease V_E to 75% of control.