Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

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 ϭ 6) morphine (0.05 mg/kg intravenously) increased the transit time from a baseline level of 85 Ϯ 20.5 min to 155 Ϯ 27.9 min (mean Ϯ S.D., P Ͻ 0.01). After 0.1 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 110 Ϯ 41.0 min. In the second group (n ϭ 6), morphine increased the transit time from a baseline level of 98 Ϯ 49.1 min to 140 Ϯ 58.2 min (P Ͻ 0.01). After 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 108 Ϯ 59.6 min (P Ͻ 0.05 compared with placebo plus morphine). In addition, subcutaneous methylnaltrexone significantly decreased morphineinduced 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.

In Vitro Metabolism and Identification of Human Enzymes Involved in the Metabolism of Methylnaltrexone

“…Thus, it reduces the peripheral side effect of opioids without reversal of analgesia or the induction of opioid withdrawal. In healthy volunteers, intravenous MNTX effectively blocked acute morphineinduced delay in oral-cecal transit time without affecting analgesia (Yuan et al, 1996(Yuan et al, , 2002. A significant reversal of the gut transit delay in subjects dependent on chronic methadone treatment was also observed with intravenous MNTX (Yuan et al, 1998(Yuan et al, , 1999(Yuan et al, , 2000.…”

Randomized placebo-controlled study of intravenous methylnaltrexone in postoperative ileus

“…Only the pharmacist was unblinded at each site; the patients and investigators remained blinded during the study. The dose of 0.3 mg/kg methylnaltrexone was selected based on previous studies15,16. The first dose of study drug was administered within 90 min after the end of the surgical procedure.…”

O papel dos antagonistas periféricos dos opióides no tratamento da dor e nos cuidados perioperatórios

“…Para que se pudesse usar o fármaco de forma a garantir previsibilidade, desenvolveu-se formulação para administração subcutânea. Após a administração subcutâ-nea, as alterações no trânsito oral-cecal ocorreram em período de 15 minutos nos voluntários 24 . Portanto, as diversas vias de administração, ou seja, oral, venosa e subcutânea, diferem quanto ao seu início de ação e duração.…”

“…In order to utilize the drug in a fashion that conferred predicatability a subcutaneous route was developed. After subcutaneous administration, changes in oral cecal transit time occurred over a period of about 15 minutes in volunteers 24 . Thus, the several routes for administration; oral, intravenous, or subcutaneous, have various onset of action and duration times.…”