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

Abstract

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.

The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig

“…Opioid activated μ-receptors disrupt GI function that leads to delayed gastric emptying, infrequent bowel movements and difficulty in rectal expulsion of stool. Webster et al 21 hypothesized the action of alvimopan as selective antagonism of peripheral μ-opioid receptors that leads to restoration of GI function and relieve opioid induced bowel dysfunction. Most of the studies suggested the activation of opioid receptors in the GI tract as a major cause of OIBD.…”

Avaliação do hábito intestinal em pacientes com câncer que utilizam morfina para o controle da dor

“…However, the effectiveness of the therapy should be analyzed with caution considering that, for ethical reasons, it would be impossible to have a control group. In addition, 40% of patients had constipation in spite of preventive measures, suggesting the need for studies with laxatives acting on specific intestinal receptors with higher effectiveness and few side effects [20][21][22] . During the study, nine clinical fecaloma were diagnosed and fecal desimpaction was a difficult stage of patients' management, generating pain and discomfort.…”

“…Patients with unsatisfactory therapeutic response received therapeutic options, such as the association of other laxatives or replacement of morphine by different opioids. 22 patients under morphine and meeting eligibility criteria. Mean age of patients was 16.7 years (5 to 35 years), being 54% males.…”

Mu-Opioid Receptor Antagonists and Their Role in Treatment of Chronic Constipation

“…It is also associated with improvements in straining, stool consistency, incomplete evaluation, decreased appetite, and abdominal bloating/discomfort [31].…”

“…A total of 6 metabolites are identified in plasma, urine and feces. These metabolites are formed via N-dealkylation, Odemethylation, oxidation and partial loss of the PEG chain [31]. The activity of the metabolites at the opioid receptor has not been determined.…”