Tolerance to the analgesic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine

Purpose. The increased use of opioids in the chronic treatment of pain, especially with oncologic patients, encourages the search for drugs with potent analgesic activity, but with minimal induced tolerance and cross-tolerance to morphine. Methods. Four agonist-antagonist opioid derivatives (buprenorphine, butorphanol, nalbuphine, and cyclorphan) were examined. Tolerance to the analgesic effect of the four drugs and their cross-tolerance effects with morphine were evaluated in ICR albino mice by the "hot plate method". Measurements of the analgesic effect were taken before and after chronic treatment (of 14 days duration) with these drugs, as well as morphine. Results. All tested drugs produced tolerance after 14 days of treatment. Chronic treatment with morphine reduced the effects of nalbuphine and cyclorphan, but not those of buprenorphine and butorphanol. After 14 days treatment with buprenorphine and cyclorphan, the analgesic action of morphine was reduced, but this reduction did not occur after butorphanol and nalbuphine treatments. Conclusion. Of the four agonist-antagonists tested, butorphanol seems to be least likely to produce cross-tolerance with morphine.