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Alosetron was effective and safe for relieving abdominal symptoms in women with irritable bowel syndrome
  1. Arvey I Rogers, MD,
  2. Vikas Khurana, MD
  1. University of Miami, Miami, Florida, USA

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

    Design

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

    Setting

    119 centres in the US.

    Patients

    647 women ≥18 years of age (mean age 46 y, 93% white) who had IBS for ≥6 months, had normal colonic anatomy, were diarrhoea predominant or had alternating bowel patterns (diarrhoea 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 concentrations; 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 (ie, 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}.

    Alosetron v placebo in women who have had irritable bowel syndrome >3 months‡

    Conclusion

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

    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 et al 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 diarrhoea 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 treatments.

    Many new treatments 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 et al involved an impressive number of women who had abdominal pain and principally diarrhoea 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 US Food and Drug Administration, prompted by postmarketing reports of serious adverse effects, including severe constipation, ischaemic 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 treatments that selectively antagonise the factors responsible for IBS symptoms adds a scientific dimension to the management of a very common, poorly understood, and challenging disorder.

    References

    View Abstract

    Footnotes

    • 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 +1 919 483 8614.

    • * See glossary.

    • p Values calculated from data in article.

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