COMPARISON OF THE ANALGESIC AND INTESTINAL EFFECTS OF FENTANYL AND MORPHINE IN RATS

Clinical studies report a low incidence of intestinal side effects wit h transdermally administered fentanyl (TTS-fentanyl) in comparison wit h oral morphine. To support these clinical data, analgesic and intesti nal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of cas tor oil-induced diarrhea only slightly (1.1 X) in the case of fentanyl (0.028 mg/kg) but markedly (36 X) in the case of morphine (0.22 mg/kg ). To reverse completely the antidiarrheal effect of equivalent analge sic doses of the opioids (their ED(50)s for analgesia lasting 2 hours) , much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 X) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 X) In the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral noses of the opioids (their ED(50 )s for analgesia lasting 2 hours), more naloxone was required in the c ase of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). R apid penetration of fentanyl into the brain is thought to be responsib le for the small dissociation between the analgesic and intestinal eff ect of this lipophilic opioid. The present data provide preclinical ev idence to support the relatively low incidence of intestinal side effe cts observed clinically with the use of TTS-fentanyl in comparison wit h orally administered morphine. (C) U.S. Cancer Pain Relief Committee, 1998.