Opioid-induced Loss of Local Anesthetic Potency in the Rat Sciatic Nerve

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Previous evidence suggests that opioid-tolerant patients are less responsive to local anesthetics (LAs) for postoperative pain management.


To determine whether this apparent loss of LA potency is due to an intrinsic change in the peripheral nerve, the effect of systemic morphine was assessed on the potency of lidocaine-induced block of the compound action potential in isolated rat sciatic nerves. Analgesic efficacy was assessed with the heat withdrawal assay.


While acute administration of 10 mg/kg morphine had no detectable influence on lidocaine potency, seven daily subcutaneous injections of morphine produced a three-fold decrease in potency (EC50 for block A and C waves for naive rats were [mean ± SD] 186 ± 32 μM [n = 6] and 201 ± 31 μM [n = 6], respectively, vs. 608 ± 53 μM [n = 6] and 613 ± 42 μM [n = 6], respectively [P < 0.001], in nerves from rats that had received seven daily injections of morphine [10 mg/kg]). This loss in potency was both dose-dependent and injection number dependent, such that the magnitude of the loss of lidocaine potency was significantly (n = 6; P < 0.01) correlated (r2 = 0.93) with the development of morphine tolerance. Interestingly, despite the complete recovery of analgesic efficacy within days after cessation of morphine administration, the morphine-induced decrease in lidocaine potency was fully manifest even 35 days after the last morphine injection. Coadministration of naloxone (1 mg/kg, intraperitoneally), but not of naloxone methiodide (1 mg/kg, subcutaneously), with each of seven daily injections of morphine blocked the decrease in lidocaine potency.


These preclinical data suggest that the morphine-induced decrease in LA potency is due, at least in part, to the intrinsic changes in the peripheral nerve. Identification of the underlying mechanisms may suggest strategies for more effective postoperative pain management in the growing population of opioid-tolerant patients.

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