Randomized placebo-controlled trial of the activity of the morphine glucuronides

Background Morphine‐6‐glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity. Morphine‐3‐glucuronide (M3G), the most prevalent metabolite, has minimal affinity for opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2000-12, Vol.68 (6), p.667-676
Main Authors: Penson, Richard T., Joel, Simon P., Bakhshi, Krishna, Clark, Simon J., Langford, Richard M., Slevin, Maurice L.
Format: Article
Language:English
Subjects:
Adult
Analgesics
Analgesics, Opioid - adverse effects
Analgesics, Opioid - pharmacokinetics
Analgesics, Opioid - pharmacology
Biological and medical sciences
Conscious Sedation
Cross-Over Studies
Double-Blind Method
Drug Interactions
Female
Humans
Male
Medical sciences
Morphine - adverse effects
Morphine - pharmacokinetics
Morphine - pharmacology
Morphine Derivatives - adverse effects
Morphine Derivatives - pharmacokinetics
Morphine Derivatives - pharmacology
Neuropharmacology
Pain - drug therapy
Pain - prevention & control
Pain Measurement - drug effects
Pharmacology. Drug treatments
Placebos
Pulmonary Ventilation - drug effects
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Summary:Background Morphine‐6‐glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity. Morphine‐3‐glucuronide (M3G), the most prevalent metabolite, has minimal affinity for opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G. Methods We performed a double‐blind placebo‐controlled trial with 10 healthy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphine, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg/70 kg of M6G; all were give by slow intravenous bolus. Analgesia was assessed with the use of the submaximal ischemic pain model. The effects were quantified on numerical and visual analogue scales. Respiratory parameters and response to steady state 5% carbon dioxide challenge were assessed with spirometry, mass spectroscopy, and earlobe blood gas analysis. Results Morphine and M6G produced significant pain relief compared with placebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26). Pain relief with morphine and M6G were not significantly altered by M3G (P = .59 and P = .28, respectively). Significant and similar dysphoria and sedation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo (morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively). Conclusions M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine. (Clin Pharmacol Ther 2000;68:667‐76.) Clinical Pharmacology & Therapeutics (2000) 68, 667–676; doi: 10.1067/mcp.2000.111934
ISSN:0009-9236
1532-6535
DOI:10.1067/mcp.2000.111934