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

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 w arm water tail withdrawal procedure using 50 degrees C and 52 degrees C wat er (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezoc ine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of an tinociception 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 antinocicep tion alone, these opioids dose-dependently antagonized the effects of morph ine. When levorphanol, dezocine, and buprenorphine were combined with morph ine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was ad ministered 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 stimu lus intensity. Furthermore, the level of antinociception produced by the op ioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. Implications: Compared with high-efficacy opi oids, lower efficacy opioids produce lower levels of pain relief, especiall y in situations of moderate to severe pain. When opioids are given in combi nation, the effects can only be predicted on the basis of the antinocicepti on obtained when the drugs are administered alone.