Opioid activity and distribution of fentanyl metabolites.

Fentanyl, a short-term analgesic frequently used in neuroleptanalgesia, has in a number of cases been reported to cause unexpected, severe postanesthetic respiratory depression which can successfully be treated with naloxone. Several explanations for this rebound effect produced by fentanyl (in combination with other drugs) have been proposed, though so far none has proved completely satisfactory. The possibility that this effect may be due to a secondary accumulation of fentanyl or fentanyl metabolites with opioid activity in the brain has led us to investigate the relative opioid potency of several known or proposed metabolites by measuring their inhibitory action on the contraction of guinea-pig ileum in comparison with that of morphine, pethidine, and fentanyl itself. Two proposed metabolites containing the phenethyl sidechain were found to possess an opioid activity lying between that of morphine and pethidine, whereas metabolites without the side-chain were generally less active than pethidine. Using thin-layer chromatography, it was possible to detect one of these proposed active metabolites in vivo in rats. This result may have some relevance for the understanding of the fentanyl rebound. However, the possibility that multiple doses of fentanyl, such as may be given during neuroleptanalgesia, or interactions with other drugs, e.g. tranquilizers and general anesthetics, may be the cause of fentanyl rebound, remains open.