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

Abstract

Rationale: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions.

Objective: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus.

Methods: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined.

Results: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high 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 possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures.

Conclusions: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.