Assessment of nalmefene glucuronide as a selective gut opioid antagonist.
Opioid use often causes troublesome constipation as a side-effect. Selective antagonism of the intestinal actions of opioids might be useful in the treatment of opioid-induced constipation. We tested the inactive metabolite of nalmefene, nalmefene glucuronide, which showed promise of gut selectivity in rodent models, by administering ascending doses in single-blind, placebo-controlled fashion to five methadone-maintained, opioid-dependent male volunteers. Assessment of whether systemic or gut-selective opioid antagonist effects occurred was measured by vital signs, pupillary diameter, opioid withdrawal symptom scales, and bowel function. Oral nalmefene glucuronide precipitated symptoms and signs consistent with the opioid abstinence syndrome in all five subjects a mean of 9.0 h after dosing. We conclude that nalmefene glucuronide does not appear to exert sufficient gut selectivity to be useful in antagonizing constipation due to exogenous opioid administration without antagonizing systemic opioid effects.
National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
L J
LJ
Cheskin
T N
TN
Chami
R E
RE
Johnson
J H
JH
Jaffe
D000328:Adult; D001143:Arousal / Q000187:drug effects* / Q000502:physiology; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology; D003248:Constipation / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D009460:Neurologic Examination / Q000187:drug effects; D009293:Opioid-Related Disorders / Q000503:physiopathology / Q000534:rehabilitation*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D009292:Narcotic Antagonists; D009271:Naltrexone; C038981:nalmefene; D008691:Methadone