Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 300, Issue 1, Pages 118-123Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.300.1.118
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Funding
- NCI NIH HHS [R01 CA79042] Funding Source: Medline
- NCRR NIH HHS [M01 RR00055] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA079042] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000055] Funding Source: NIH RePORTER
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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 subcutaneous 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 &PLUSMN; 49.1 min to 140 &PLUSMN; 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.
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