title: No contribution of morphine-6-glucuronide to clinical morphine effects after short-term administration.
abstract: The primary metabolite of morphine, morphine-6-beta-glucuronide (M-6-G), is reported to contribute to the effects of morphine. The authors investigated the effects of M-6-G on the central nervous system (CNS) after short-term intravenous (i.v.) administration by employing both electroencephalograph (EEG) power spectra analyses and clinical signs as indicators of opioid effects. Three dosages of M-6-G, one dosage of morphine (bolus 10 mg/70 kg and 3.5 mg/70 kg/hour for 4 hours), a combination of morphine and M-6-G, and placebo were administered to 20 healthy volunteers as i.v. bolus plus i.v. infusion for 4 hours. M-6-G was dosed to produce steady state plasma concentrations that were either identical, 2 times, or 3 times higher than the M-6-G plasma concentrations observed after administration of morphine. The EEG background activity and clinical effects were recorded 3.5 hours after the infusion started. M-6-G failed to produce effects on any of the investigated EEG or clinical parameters at the doses tested. In contrast, morphine produced a significant increase in the alpha 1 and delta power of the EEG. In addition, morphine increased the subjects' ratings of tiredness, sickness, vertigo, and drowsiness, and decreased their level of performance in a tracking task. It was concluded that after short-term i.v. administration, M-6-G does not affect the CNS at the doses tested. Therefore, its contribution to clinical effects of morphine after short-term administration is questionable. The missing CNS effects were probably caused by the slow brain permeability of M-6-G, which in short-term treatment might not attain effective CNS concentrations.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lötsch
authors.forename: G
authors.initials: G
authors.lastname: Kobal
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D008297:Male; D009020:Morphine / Q000097:blood / Q000494:pharmacology; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine