An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity

Anesth Analg. 1999 Feb;88(2):407-13. doi: 10.1097/00000539-199902000-00035.


We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.

Implications: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic
  • Buprenorphine / administration & dosage
  • Buprenorphine / pharmacology
  • Butorphanol / administration & dosage
  • Butorphanol / pharmacology
  • Cycloparaffins / administration & dosage
  • Cycloparaffins / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Levorphanol / administration & dosage
  • Levorphanol / pharmacology
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Nalbuphine / administration & dosage
  • Nalbuphine / pharmacology
  • Narcotics / administration & dosage
  • Narcotics / pharmacology*
  • Nociceptors / drug effects*
  • Pain / physiopathology
  • Physical Stimulation
  • Rats
  • Rats, Long-Evans
  • Receptors, Opioid, mu / drug effects*
  • Tetrahydronaphthalenes


  • Analgesics, Opioid
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cycloparaffins
  • Drug Combinations
  • Narcotics
  • Receptors, Opioid, mu
  • Tetrahydronaphthalenes
  • Levorphanol
  • Buprenorphine
  • Morphine
  • Nalbuphine
  • Butorphanol
  • dezocine