Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Alosetron was effective and safe for relieving abdominal symptoms in women with the irritable bowel syndrome

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ACP J Club. 2001 Jan-Feb;134:19. doi:10.7326/ACPJC-2001-134-1-019

Related Content in this Issue
• Companion Abstract and Commentary: Review: Smooth-muscle relaxants treat abdominal pain and loperamide reduces diarrhea in the irritable bowel syndrome


Source Citation

Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet. 2000 Mar 25;355:1035-40. [PubMed ID: 10744088]


Abstract

Question

What is the effectiveness and safety of alosetron in women with the irritable bowel syndrome (IBS)?

Design

Randomized (allocation concealed*), blinded (clinicians, patients, outcome assessors, and statisticians),* placebo-controlled trial for 12 weeks with 1-month follow-up.

Setting

119 centers in the United States.

Patients

647 women ≥ 18 years of age (mean age 46 y, 93% white) who had IBS for ≥ 6 months, had normal colonic anatomy, were diarrhea predominant or had alternating bowel patterns (diarrhea and constipation), had a mean daily abdominal pain and discomfort score between 1.0 and 3.3 on a 5-point scale (0 = none to 4 = severe), and a mean daily stool consistency score ≥ 2.5 on a 5-point scale (1 = very hard to 5 = watery). Exclusion criteria were constipation-predominant IBS; pregnancy, breast-feeding, or potential for childbearing; unstable medical or other gastrointestinal disorder; major psychiatric disorder; substance abuse in the previous 2 years; abnormal aspartate aminotransferase, alanine aminotransferase, or serum creatinine levels; hyperthyroidism or hypothyroidism; non-skin malignancy in the previous 5 years; investigational drug use 30 days before study; or use of specified drugs. Follow-up was 80%.

Intervention

Women were allocated to twice-daily oral alosetron, 1 mg (n = 324), or placebo (n = 323) for 12 weeks. Study drugs were taken before meals.

Main outcome measures

Adequate relief of abdominal pain and discomfort; improvements in urgency, stool frequency, and stool consistency; and adverse events.

Main results

Analysis was by intention to treat. Alosetron had a higher rate of achieving adequate relief of abdominal pain and discomfort {P = 0.001}† (Table) and decreased urgency, stool frequency, and stool consistency (i.e., increased stool firmness) (P < 0.001) than did placebo. Alosetron was associated with a higher risk for constipation than was placebo {P < 0.001}† (Table), but groups did not differ in the rate of reporting ≥ 1 adverse events {P = 0.07}†.

Conclusion

Alosetron was effective and well tolerated in relieving abdominal pain and discomfort in women with the irritable bowel syndrome.

*See Glossary.

P values calculated from data in article.

Source of funding: Glaxo Wellcome Research and Development.

For correspondence: Dr. A.W. Mangel, Gastroenterology Clinical Development, Glaxo Wellcome, Research Triangle Park, NC 27709, USA. FAX 919-483-8614.


Table. Alosetron vs placebo in women who have had the irritable bowel syndrome > 3 months‡

Outcomes at 1-month follow-up Alosetron Placebo RBI (95% CI) NNT (CI)
Relief of abdominal symptoms 41% 29% 41% (14 to 75) 8 (5 to 22)
RRI (95% CI) NNT (CI)
Constipation 30% 3% 854% (415 to 1685) 4 (3 to 5)

‡Abbreviations defined in Glossary; RBI, RRI, NNT, and CI calculated from data in article.


Commentary

IBS is still a diagnosis of exclusion despite the fact that criteria for making a positive diagnosis have been established and widely disseminated. Organic lesions that resemble symptoms commonly seen in IBS must be excluded before initiating treatment (1). The traditional treatment for IBS has been a combination of symptomatic therapy, reassurance, education, and lifestyle modification. Patients with milder disease can usually be managed conservatively, even for the short term. Other patients can be prescribed a combination of psychotherapy, psychopharmacotherapy, and pharmacotherapy, which generally has variable success.

The review by Jailwala and colleagues evaluates the available therapeutic trials. Considering the varied presentation of IBS, lack of uniform diagnostic criteria, and initial difficulties in defining the condition, a substantial number of trials did not meet rigorous scientific standards. The authors stated that smooth-muscle relaxants for abdominal pain and loperamide for diarrhea were the only agents with clinical effectiveness. Although results for other therapeutic agents were inconclusive, the authors expressed an optimistic view that, as the pathophysiology of IBS becomes better understood, it is likely that subgroups of patients with specific sets of symptoms may be responsive to targeted therapies.

Many new therapies that focus on modulating neurotransmitters in the “brain-gut” axis are currently being studied. Recent interest in serotonin receptors and serotonin-mediated motor activity in the gut has led to the development of new treatment options for the management of the more distressing symptoms associated with IBS. The type-3 serotonin receptor (5-HT3) stimulates extrinsic enteric sensory nerves, thereby lowering visceral pain thresholds, a generally accepted component of IBS (2).

The study by Camilleri and colleagues involved an impressive number of women who had abdominal pain and principally diarrhea-predominant IBS. The authors were able to show reasonable, although not overwhelmingly impressive, therapeutic efficacy of the 5-HT3 antagonist alosetron for control of mild-to-moderate symptoms. Alosetron (Lotronex) is the first serotonin-subtype antagonist to be examined in a large clinical trial. Unfortunately, alosetron's adverse effects have led to its recent voluntary withdrawal by its manufacturer, Glaxo Wellcome. This decision followed discussions with the U.S. Food and Drug Administration, prompted by postmarketing reports of serious adverse effects, including severe constipation, ischemic colitis, and death (unproved association).

IBS is a chronic disorder with frequent relapses and substantial morbidity, although no mortality is caused by the disease itself. Therefore, the decision to initiate long-term pharmacotherapy should not be taken lightly. Only further trials and postmarketing surveillance strategies will determine whether the class of drugs represented by the ill-fated alosetron will be safe and better than smooth-muscle relaxants and loperamide and their combination with other interventions.

As investigators more accurately classify various subgroups of IBS, understand their unique pathophysiologies, and study the effects of the emerging therapeutic agents, targeted therapeutic interventions will become better defined. A supportive physician-patient relationship is necessary regardless of the therapeutic regimen. The availability of therapies that selectively antagonize the factors responsible for IBS symptoms adds a scientific dimension to the management of a very common, poorly understood, and challenging disorder.

Arvey I. Rogers, MD
Vikas Khurana, MD
University of Miami
Miami, Florida, USA


References

1. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997;112:2120-37.

2. De Ponti F, Malagelada JR. Functional gut disorders: from motility to sensitivity disorders. A review of current and investigational drugs for their management. Pharmacol Ther. 1998;80:49-88.