Loss of analgesic effect of morphine due to coadministration of rifampin Martin F. Fromm*, Klaus Eckhardt, Shuxia Li, Gerhard Scha ¨nzle, Ute Hofmann, Gerd Mikus, Michel Eichelbaum Dr. Margarete Fischer-Bosch-Institut fu ¨r Klinische Pharmakologie, Auerbachstr. 112, 70376 Stuttgart, Germany Received 23 December 1996; revised version received 1 May 1997; accepted 12 May 1997 Abstract Methadone withdrawal symptoms have been reported in drug addicts treated with the tuberculostatic rifampin. Whereas this interaction can be explained by induction of phase I drug metabolism (CYP3A4), knowledge about induction of phase II metabolism (e.g., UDP- glucuronosyltransferases = UGTs) and its influence on drug effects in man, however, is very limited. The potent analgesic morphine is metabolized by more than one UGT to the active metabolite morphine-6-glucuronide and to morphine-3-glucuronide, which is devoid of analgesic activity. Thus, differential induction of UGTs involved in metabolism of morphine might lead to decreased or increased analgesic effects, depending on which UGT is preferentially induced. We therefore investigated the influence of the potent enzyme inducer rifampin on analgesic effects and pharmacokinetics of morphine, which is primarily eliminated by phase II metabolism. Ten healthy male volunteers participated in this double-blind, placebo-controlled study with double crossover design. Morphine (10 mg p.o.) and placebo were administered on two separate occasions before and near the end of 13 days of treatment with rifampin (600 mg/day). Blood samples were collected for 31 h. Morphine effects on pain sensation were determined using the cold pressor test. When morphine was given alone, the opioid elicted a significant increase in pain threshold and pain tolerance in comparison to placebo (P ≤ 0.05). However, following administration of rifampin no analgesic effect of morphine was observed. In agreement, the area under the serum concentration-time curve (AUC) of morphine and the maximum serum concentration of morphine were considerably reduced during coadministration of rifampin (-27.7 ± 19.3% and -40.7 ± 27.1%; P ≤ 0.01). Moreover, during treatment with rifampin a proportional reduction of AUCs of morphine- 3-glucuronide (P ≤ 0.01), morphine-6-glucuronide (P ≤ 0.05) and morphine was observed. Since urinary recoveries of both morphine-3- glucuronide and morphine-6-glucuronide were also reduced during administration of rifampin, there is no evidence for a contribution of UGT induction to the observed interaction. In summary, a major drug interaction was observed between morphine and rifampin, which could not be attributed to induction of UGTs, but resulted in a complete loss of analgesic effects of the opioid.  1997 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Morphine; Morphine-6-glucuronide; Rifampin; Enzyme induction; Pain; Cold pressor test 1. Introduction Symptoms of methadone withdrawal have been observed in drug addicts on maintenance therapy, who were treated with the tuberculostatic rifampin (Kreek et al., 1976; Bend- ing and Skacel, 1977; Holmes, 1990). Therapeutic failure occurs in these cases due to induction of a phase I drug metabolizing enzyme (CYP3A4), which is involved in a major pathway of methadone metabolism (Iribarne et al., 1996) and is inducible by rifampin in intestine and liver (Combalbert et al., 1989; Kolars et al., 1992; Fromm et al., 1996). The importance of phase I drug metabolism cat- alyzed by cytochrome P450 enzymes and its modification by inducers has intensively been studied. In contrast, there are only very limited data on the occurrence and extent of induction of phase II drug metabolizing enzymes (e.g., UDP-glucuronosyltransferases; UGTs) in man and on its consequences for drug effects (for review see Kroemer and Klotz, 1992). Several human UGTs have been identified Pain 72 (1997) 261–267 0304-3959/97/$17.00  1997 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959(97)00044-4 * Corresponding author. Present address: Vanderbilt University School of Medicine, Division of Clinical Pharmacology, 532 Medical Research Building I, Nashville, TN 37232–6602, USA. Tel.: +1 615 3223304; fax: +1 615 3434522.