Loss of analgesic effect of morphine due to coadministration of rifampin

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 elicited a significant increase in pain threshold and pain tolerance in comparison to placebo (P < or = 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 < or = 0.01). Moreover, during treatment with rifampin a proportional reduction of AUCs of morphine-3-glucuronide (P < or = 0.01), morphine-6-glucuronide (P < or = 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.

Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

“…Rifampin is a common interacting drug involved in glucuronidation-mediated DDI (13)(14)(15)(16)(17)(18). In our study, the C max and AUC of morinidazole in healthy subjects were decreased significantly, by around 20% to 30%, after pretreatment with rifampin, while only the C max of M8-1was increased 1.3-fold, without a change of AUC.…”

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…Induction of intestinal and/or hepatic MRP2 has been implicated to play a role in the interactions observed clinically between rifampin and morphine, mycophenolate mofetil, ezetimibe, and carvedilol (Fromm et al, 1997;Giessmann et al, 2004b;Oswald et al, 2006). Carbamazepine also increased talinolol elimination in humans, most likely by induction of P-gp and MRP2 (Giessmann et al, 2004a).…”

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

“…A significant drug interaction has been observed between morphine and rifampicin. In a clinical study with ten healthy volunteers receiving an oral dose of morphine (10 mg), the serum concentrations of morphine, glucuronide-3-morphine, and glucuronide-6-morphine were measured before and after the treatment with rifampicin 600 mg once daily for 13 days (194). There was only a moderate decrease in the serum concentrations of morphine after the treatment with rifampicin.…”