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No contribution of morphine-6-glucuronide to clinical morphine effects after short-term administration
J Lötsch1, G Kobal, G Geisslinger
1Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
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.
Insights
Morphine-6-beta-glucuronide (M-6-G), a morphine metabolite, did not significantly affect the central nervous system (CNS) in healthy volunteers during short-term intravenous administration. Its contribution to morphine
Area of Science:
- Pharmacology
- Neuroscience
- Clinical Research
Background:
- Morphine-6-beta-glucuronide (M-6-G) is a primary metabolite of morphine.
- M-6-G is suggested to contribute to morphine's overall effects.
- Investigating M-6-G's independent central nervous system (CNS) effects is crucial.
Purpose of the Study:
- To evaluate the central nervous system (CNS) effects of morphine-6-beta-glucuronide (M-6-G) after short-term intravenous (i.v.) administration.
- To compare the CNS effects of M-6-G with those of morphine.
- To determine M-6-G's contribution to the clinical effects of morphine.
Main Methods:
- Twenty healthy volunteers received placebo, morphine, M-6-G at three dose levels, or a combination of morphine and M-6-G.
- Administration involved i.v. bolus followed by a 4-hour i.v. infusion.
- Central nervous system (CNS) effects were assessed using electroencephalograph (EEG) power spectra analysis and clinical observations.
Main Results:
- Morphine significantly increased alpha 1 and delta EEG power, and induced subjective effects like tiredness and drowsiness.
- M-6-G did not produce any significant changes in EEG parameters or clinical signs at tested doses.
- M-6-G plasma concentrations were elevated to 1, 2, or 3 times those seen with morphine administration.
Conclusions:
- Short-term intravenous administration of M-6-G does not appear to affect the central nervous system (CNS) in humans at the tested doses.
- The contribution of M-6-G to the immediate clinical effects of morphine is questionable.
- Limited CNS penetration of M-6-G may explain the lack of observed effects in short-term studies.