Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS

Abstract

Transcutaneous electrical nerve stimulation (TENS) partially reduces primary hyperalgesia and is frequency dependent such that high frequency TENS produces approximately a 30% reduction in hyperalgesia whereas low frequency TENS has no effect. Both high and low frequency TENS completely reduce secondary hyperalgesia by activation of mu and delta- opioid receptors in the spinal cord and rostral-ventral medulla suggesting an opiate mediated analgesia. Clonidine in combination with opiates produces a synergistic interaction such that there is a potentiated reduction in hyperalgesia. Thus, we tested if combined application of clonidine with TENS would enhance the reduction in primary hyperalgesia. Male Sprague-Dawley rats were inflamed by subcutaneous injection of 3% carrageenan into one hindpaw. Withdrawal latency to radiant heat and withdrawal threshold to mechanical stimuli were assessed before and after inflammation and after administration of clonidine (0.002-2 mg/kg, intraperitoneal (i.p.)) with either low (4 Hz) or high (100 Hz) frequency TENS. Clonidine alone reduced both heat and mechanical hyperalgesia with ED50s of 0.02 and 1.0 mg/kg, respectively. In combination with either low or high frequency TENS, the dose-response curve shifted to the left and was significantly different from clonidine alone. The ED50s for heat and mechanical hyperalgesia following low frequency TENS with clonidine were 0.002 and 0.2 mg/kg, respectively and those following high frequency TENS with clonidine were 0.005 and 0.15 mg/kg, respectively. Thus, combined use of clonidine and TENS enhances the reduction in analgesia produced by TENS and enhances the potency of clonidine. It would thus be expected that one would reduce the side effects of clonidine and enhance analgesic efficacy with combinations of pharmaceutical and non-pharmaceutical treatments.