Interaction of clonidine and morphine with lidocaine in mice and rats

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.