Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys

Abstract

There is evidence that blockade of Ca 2+ channels can modify the analgesia and respiratory depression produced by opioid drugs. The interaction between Ca 2+ channel blockade and drug-induced analgesia and respiratory depression was examined by administration of the L-type Ca 2+ channel blocker diltiazem together with various analgesic drugs. The antinociceptive effects of the drugs were evaluated using a warm-water (50°C) tail-withdrawal assay in rhesus monkeys, and the respiratory depressant effects were evaluated using a pressure-displacement plethysmograph. Pretreatment with diltiazem (10–40 mg/kg, i.m.) 30 min before administration of morphine (0.3 to 10 mg/kg) or heroin (0.03 to 1.0 mg/kg) produced a dose-dependent potentiation of the opioid-induced analgesia. The analgesic potency of morphine and heroin was increased by approximately 0.5 log unit in the presence of 40 mg/kg diltiazem. However, diltiazem failed to alter the analgesic potencies of the μ-opioid receptor agonists, fentanyl, etonitazene, nalbuphine, the κ-opioid receptor agonist, U-50,488 [( trans)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide], or the non-opioid, clonidine. Respiratory frequency, minute volume, and tidal volume were suppressed by morphine, heroin, and fentanyl, but these effects were not modified by pretreatment with diltiazem (40 mg/kg). These results suggest that diltiazem selectively potentiates morphine- and heroin-induced analgesia without modifying the effects of these opioids on respiration.