Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor

Rationale: A common treatment strategy for the management of severe pain in volves the co-administration of multiple opioid analgesics. Due to the incr easing popularity of this practice, it is becoming increasingly important t o understand the interactions between clinically employed opioids under a w ide range of conditions. Objective: The purpose of the present investigatio n was to examine the effects of opioid combinations following acute and chr onic administration of the low-efficacy mu-opioid butorphanol, and to deter mine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. Methods: In a warm-water, tail-withdrawal proced ure, rats were restrained and the latencies to remove their tails from 50 d egrees C (low temperature) and 55 degrees C (high temperature) water were m easured following both acute and chronic administration of butorphanol. Opi oids possessing both high (etorphine, levorphanol, morphine) and low [dezoc ine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. Results: Under acute conditions, etorphine, levorphanol, morphin e and dezocine increased tail-withdrawal latencies at both low and high tem peratures, whereas (-)-pentazocine, nalbuphine and butorphanol increased la tencies only at the low temperature. A dose of 30 mg/kg butorphanol increas ed the effects produced by these opioids at the low temperature, but antago nized the effects of etorphine, levorphanol, morphine and dezocine at the h igh temperature. During chronic treatment with 30 mg/kg per day butorphanol , tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids pos sessing low efficacy at the mu receptor. During butorphanol treatment, etor phine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperatu re, and (-)-pentazocine, nalbuphine and butorphanol failed to increase late ncies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine d uring chronic treatment, and these effects were observed at both water temp eratures. Conclusions: These findings indicate that the interactions betwee n butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most in stances, however, these interactions can be predicted from the effects of t he drugs when administered alone.