Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain.
Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.
Webster
Lynn
L
Lifetree Clinical Research and Pain Clinic, 3838 South 700 East, Ste. 200, Salt Lake City, UT 84106, USA Schwerpunktpraxis für Schmerztherapie und Ambulante Anästhesie, Berlin, Germany The Pain Treatment Center of the Bluegrass, Lexington, KY, USA Manna Research, Toronto, Ont., Canada Swedish Medical Center, Seattle, WA, USA The Leuven Centre for Algology & Pain Management, University Hospital, Leuven, Belgium GlaxoSmithKline, Research Triangle Park, NC, USA.
Jansen
Jan Peter
JP
Peppin
John
J
Lasko
Ben
B
Irving
Gordon
G
Morlion
Bart
B
Snidow
Jerry
J
Pierce
Amy
A
Mortensen
Eric
E
Kleoudis
Christi
C
Carter
Eric
E
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D003085:Colic / Q000139:chemically induced / Q000503:physiopathology; D003248:Constipation / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D016896:Treatment Outcome
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010880:Piperidines; D010919:Placebos; D017450:Receptors, Opioid, mu; C419502:alvimopan