Abstract
Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. However, the effects of subcutaneous methylnaltrexone, a more convenient route of administration, have not been evaluated. In this controlled trial, we evaluated the efficacy of subcutanous methylnaltrexone in antagonizing morphine-induced delay in oral-cecal transit time. In addition, opioid-induced unpleasant subjective effects and pharmacokinetics were studied. We observed that in the first group (n = 6) morphine (0.05 mg/kg intravenously) increased the transit time from a baseline level of 85 ± 20.5 min to 155 ± 27.9 min (mean ± S.D., P < 0.01). After 0.1 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 110 ± 41.0 min. In the second group (n = 6), morphine increased the transit time from a baseline level of 98 ± 49.1 min to 140 ± 58.2 min (P < 0.01). After 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 108 ± 59.6 min (P < 0.05 compared with placebo plus morphine). In addition, subcutaneous methylnaltrexone significantly decreased morphine-induced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.
Footnotes
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Supported in part by Grant R01 CA79042 from the U.S. Public Health Service and Grant M01 RR00055 from the U.S. Public Health Service General Clinical Research Center.
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Methylnaltrexone was originally formulated and subsequently modified by faculty at the University of Chicago. The University of Chicago and Drs. Yuan and Foss stand to benefit financially from the further development of methylnaltrexone.
Abbreviations
- AUC
- area under the curve
- Tmax
- time to peak plasma concentration
- Received August 10, 2001.
- Accepted September 17, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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