An antiemetic for irritable bowel syndrome? A drug used for cancer patients may provide some relief to patients with IBS. Practice changer: Consider prescribing ondansetron up to 24 mg/d for patients who have irritable bowel syndrome with diarrhea (IBS-D)

Corbo, Jason M.

Levy, Robert

Prasad, Shailendra

English

University of Missouri: MOspace

600 The Journal of family PracTice  |   ocToBer 2014  |   Vol 63, no 10Priority updates from the research literature from the family Physicians inquiries networkPURLs®Robert Levy, MD; Jason Corbo, PharmD, BCPS; Shailendra Prasad, MBBS, MPHNorth Memorial  Family Medicine Residency, University of Minnesota, Minneapolis (Drs. Levy and Prasad); Family Medicine Residency Program, UPMC St. Margaret, Pittsburgh, Pa (Dr. Corbo)P U R L s  E D i t o RBernard Ewigman, MD, MSPHDepartment of Family Medicine, The University  of ChicagoAn antiemetic for irritable bowel syndrome? A drug used for cancer patients may provide some relief to patients with IBS. PRACTICE CHANGERConsider prescribing ondansetron up to 24 mg/d for patients who have irritable bowel syndrome with diarrhea (IBS-D).1 StRENGtH oF RECoMMENDAtioNB: Based on a well-done double-blind, placebo-controlled randomized controlled trial (RCT).Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondan-setron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625.ILLUSTRATIVE CASEa 23-year-old woman who was diagnosed with irritable bowel syndrome (iBS) comes to your clinic with complaints of increased frequency of defecation with watery stools and general-ized, cramping abdominal pain. She also notes increased passage of mucus and a sensation of incomplete evacuation. She says the only thing that relieves her pain is defecation. She has tried loperamide, acetaminophen, and ibupro-fen without relief. She does not have crohn’s disease or ulcerative colitis. What else can you offer her that is safe and effective?IBS is a chronic, episodic functional gas-trointestinal disorder characterized by abdominal pain or discomfort and al-tered bowel habits (constipation [IBS-C], diarrhea [IBS-D], or alternating periods of both—mixed [IBS-M]).2 It is diagnosed based on Rome III criteria—recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with ≥2 of the following: improvement with defecation, on-set associated with a change in frequency of stool, and onset associated with a change in form (appearance) of stool.3 IBS often is un-recognized or untreated, and as few as 25% of patients with IBS seek care.4 IBS-D affects approximately 5% of the general population in North America.5,6 IBS-D is associated with a considerably decreased quality of life and is a common cause of work absenteeism.7,8 Because many conditions can cause diarrhea, patients typically undergo numerous tests before receiving an accurate diagnosis, which creates a financial burden.9For many patients, current IBS treat-ments, which include fiber supplements, laxatives, antidiarrheal medications, antispas-modics, and antidepressants such as tricyclics and selective serotonin reuptake inhibitors, are unsatisfactory.10  Alosetron, a 5-hydroxy-tryptamine 3 (5HT3) receptor antagonist, has been used to treat IBS-D,11 but this medi-cation was voluntarily withdrawn from the US market in 2000 due to concerns of isch-emic colitis and severe constipation.12 It was reintroduced in 2002, but can be prescribed only by physicians who enroll in a prescribing program provided by the manufacturer, and the drug has restrictions on its use. Ondansetron—a different 5HT3 receptor antagonist used to treat nausea and vomiting caused by chemotherapy—may be another option for treating IBS-D. Garsed et al1 recent-ly conducted a RCT to evaluate the efficacy of ondansetron for patients with IBS-D.601JfPonline.com Vol 63, no 10  |  ocToBer 2014  |  The Journal of family PracTiceSTUDY SUMMARYondansetron improves stool  consistency, severity of iBS symptomsIn a 5-week, double-blind crossover RCT, Garsed et al1 compared ondansetron vs place-bo for symptom relief in 120 patients who met Rome III criteria for IBS-D. All patients were ages 18 to 75 and had no evidence of inflam-matory bowel disease. Exclusion criteria were pregnancy or breastfeeding, unwillingness to stop antidiarrheal medication, prior abdomi-nal surgery other than appendectomy or cho-lecystectomy, or being in another trial. Patients were started on ondansetron 4 mg/d with dose titration up to 24 mg/d based on response; no dose adjustments were allowed during the last 2 weeks of the study. There was a 2- to 3-week washout between treatment periods.The primary endpoint was average stool consistency in the last 2 weeks of treatment, as measured by the Bristol Stool Form (BSF) scale.13 The BSF is a visual scale that depicts stool as hard (Type 1) to watery (Type 7); types 3 and 4 describe normal stools. The study also looked at urgency and frequency of defeca-tion, bowel transit time, and pain scores. Treatment with ondansetron resulted in a small but statistically significant improve-ment in stool consistency. The mean differ-ence in BSF score between ondansetron and placebo was -0.9 (95% confidence interval [CI], -1.1 to -0.6; P<.001), indicating slightly more formed stool with use of ondansetron. The IBS Severity Scoring System score (maxi-mum score 500 points, with mild, moder-ate, and severe cases indicated by scores of 75-175, 175-300, and >300, respectively) was reduced by more points with ondansetron than placebo (83 ± 9.8 vs 37 ± 9.7; P=.001). Although this mean difference of 46 points fell just short of the 50-point threshold that is considered clinically significant, many pa-tients exceeded this threshold. Compared to those who received place-bo, patients who took ondansetron also had less frequent defecation (P=.002) and lower urgency scores (P<.001). Gut transit time was lengthened in the ondansetron group by 10 hours more than in the placebo group (95% CI, 6-14 hours; P<.001). Pain scores did not change significantly for patients taking ondansetron, although they experienced significantly fewer days of urgency and bloating. Symptoms typically improved in as little as 7 days but returned after stopping ondansetron, typically within 2 weeks. Sixty-five percent of patients reported adequate re-lief with ondansetron, compared to 14% with placebo. Patients whose diarrhea was more severe at baseline didn’t respond as well to ondansetron as did those whose diarrhea was less severe. The only frequent adverse effect was constipa-tion, which occurred in 9% of patients receiving ondansetron and 2% of those on placebo. WHAT’S NEWAnother option for iBS patients  with diarrheaA prior, smaller study of ondansetron that used a lower dosage (12 mg/d) suggested benefit in IBS-D.14 In that study, ondansetron decreased diarrhea and functional dyspepsia. The study by Garsed et al1 is the first large RCT to show significantly improved stool consistency, less frequent defecation, and less urgency and bloating from using ondansetron to treat IBS-D.CAVEATSondansetron doesn’t appear  to reduce painIn Garsed et al,1 patients who received ondanse-tron did not experience relief from pain, which is one of the main complaints of IBS. However, this study did find slight improvement in formed stools, symptom relief that approached—but did not quite reach—clinical significance, fewer days with urgency and bloating, and less frequent defecation. This study did not evalu-ate the long-term effects of ondansetron use. However, ondansetron has been used for other indications for more than 25 years and has been reported to have a low risk of adverse effects.15CHALLENGES TO IMPLEMENTATIONRemember ondansetron  is not for iBS patients with constipationProper use of this drug among patients with IBS is key. The primary benefits of ondan-setron are limited to IBS patients who suffer from diarrhea, and not constipation. Ondan-For patients  with iBS-D,  ondansetron  reduced  frequency of defecation and bloating, but did not relieve pain. 602 The Journal of family PracTice  |   ocToBer 2014  |   Vol 63, no 10PURLs®setron should not be prescribed to IBS pa-tients who experience constipation, or those with mixed symptoms.                 JFPACkNowLEDGEMENtThe Purls Surveillance System was supported in part by Grant number ul1rr024999 from the national center for research resources, a clinical Translational Science award to the univer-sity of chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the national center for research resources or the national institutes of health.copyright © 2014. The family Physicians inquiries network. all rights reserved.references 1.   Garsed K, Chernova J, Hastings M, et al. A randomised trial of on-dansetron for the treatment of irritable bowel syndrome with diar-rhoea. Gut. 2014;63:1617-1625. 2.   Hahn BA, Yan S, Strassels S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion. 1999;60:77-81. 3.   Drossman DA, Dumitrascu DL. Rome III: New standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006;15:237-241. 4.   Luscombe FA. Health-related quality of life and associated psy-chosocial factors in irritable bowel syndrome: a review. Qual Life Res. 2000;9:161-176. 5.   Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol. 2000;95:2816-2824. 6.   Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel syn-drome in general practice: prevalence, characteristics, and refer-ral. Gut. 2000;46:78-82. 7.   Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the al-ternating bowel habit subtype in patients with irritable bowel syn-drome. Am J Gastroenterol. 2005;100:896-904. 8.   Schuster MM. Diagnostic evaluation of the irritable bowel syn-drome. Gastroenterol Clin North Am. 1991;20:269-278. 9.   Sandler RS, Everhart JE, Donowitz M, et al. The burden of se-lected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511. 10.   Talley NJ. Pharmacologic therapy for the irritable bowel syn-drome. Am J Gastroenterol. 2003;98:750-758. 11.   Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytrypta-mine (serotonin) type 3 antagonists on symptom relief and consti-pation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545-555. 12.   Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006;101:1069-1079. 13.   Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol. 1994;19:28-30. 14.   Maxton DG, Morris J, Whorwell PJ. Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther. 1996;10:595-599. 15.   Gill SK, Einarson A. The safety of drugs for the treatment of nausea and vomiting of pregnancy. Expert Opin Drug Saf. 2007;6:685-694.in “colicky baby? here’s a surprising remedy” (J Fam Pract. 2011;60:34-36), we summarized a 2010 double-blind randomized controlled trial (rcT) that found the probiotic Lactobacillus reuteri  DSm 17938 reduced daily crying time in colicky, exclusively breastfed infants.1 a recently published rcT of the same probiotic by Sung et al2 adds to the body of evidence and suggests that the jury may still be out as to the value of probiotics for colicky babies. The newer study (which also measured colic using modified Wessel’s criteria) included babies who were formula-fed as well as those who were breastfed. When researchers looked at all babies as a single group, those who received probiotics fussed significantly more than those who received placebo at nearly all of the postinter-vention time points. however, when they delved deeper, the researchers noted that an increase in fussing occurred only among infants on formula. on the other hand, the time that breastfed infants spent crying or fussing did not vary significantly between those who received probiotics and those who received placebo. Both the 2010 and 2014 studies used valid rcT meth-ods with low risk for bias, so we’re not clear why the re-sults (especially for breastfed infants) differed. The 2010 study was done in italy and required breastfeeding moms to avoid cow’s milk, while the 2014 Sung et al2 study was conducted in australia and did not have this requirement, so environmental factors may have played a role. The re-porting method in the Sung et al2 study—a well-validated, detailed diary of infant behaviors—may have led to less parent recall error than the diary used in the 2010 study. all in all, we can only conclude that it is unclear whether probiotics work to reduce crying in colicky infants. a safe bet may be to avoid recommending probiot-ics for colicky formula-fed infants, since no study of this population has shown probiotics are effective, and in the Sung et al2 study, they appeared to worsen symptoms. for breastfed babies, there is no evidence of harm, and mixed evidence on whether probiotics help. Debra B. Stulberg, MD, MA; Kate Rowland, MD, MSThe University of Chicago   1.  Savino F, Cordisco L, Tarasco V, et al. Lactobacillus reuteri DSM 17938 in in-fantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics. 2010;126:e526-e533.   2.  Sung V, Hiscock H, Tang ML, et al. Treating infant colic with the probiotic Lac-tobacillus reuteri: double blind, placebo controlled randomised trial. BMJ. 2014;348:g2107.Probiotics for colic? A PURL update

An antiemetic for irritable bowel syndrome?

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An antiemetic for irritable bowel syndrome?

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