The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study

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1 Aliment Pharmacol Ther 2005; 22: doi: /j x The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study H.VAHEDI,S.MERAT,A.RASHIDIOON,A.GHODDOOSI&R.MALEKZADEH Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran Accepted for publication 9 January 2005 SUMMARY Background: Irritable bowel syndrome has been treated with selective serotonin reuptake inhibitors but there is not enough evidence from controlled trials to prove their effectiveness. Aim: To compare the effects of fluoxetine and placebo in the treatment of pain and constipation-predominant irritable bowel syndrome in a double-blind randomizedcontrolled trial. Methods: Forty-four cases meeting Rome II criteria for irritable bowel syndrome with predominance of pain and constipation were included in this study. Organic causes were ruled out by detailed history, physical examination, laboratory tests and colonoscopy. Participants were then randomly assigned to receive either fluoxetine or placebo for 12 weeks. Symptoms addressed by the Rome II criteria were recorded during treatment and 4 weeks after termination of treatment. Results: Fluoxetine was significantly more effective than placebo in decreasing abdominal discomfort, relieving feeling and sense of bloating, increasing frequency of bowel movements and decreasing consistency of stool. Mean number of symptoms per patient decreased from 4.6 to 0.7 in the fluoxetine group vs. 4.5 to 2.9 in controls (P < 0.001). Conclusions: Fluoxetine is an effective and well-tolerated short-term treatment for pain and constipation-predominant irritable bowel syndrome. INTRODUCTION Irritable bowel syndrome (IBS) is an exceedingly common condition. IBS and its variants, collectively called functional gastrointestinal disorders, constitute 40 5 of all the patients seen by gastroenterologists in western countries. 1 The mainstays of pharmacotherapy when necessary are loperamide for diarrhoea, fibre and osmotic laxatives (such as magnesium salts or lactulose) for constipation, and anticholinergics or muscle relaxants for pain, gas and bloating, and antidepressants such as imipramine, Correspondence to: Dr R. Malekzadeh, Digestive Disease Research Center, Shariati Hospital, N. Kargar St, Tehran 14114, Iran. malek@ams.ac.ir fluoxetine and many others. More recently tegaserod, a serotonin 5-HT4 receptor agonist, has also been used. 1, 2 Among patients with significant psychological or psychiatric components, low-dose tricyclic antidepressants have also been effective in relief of pain, depression and diarrhoea. 1 In one large study trimipramine appeared to be effective in relief of abdominal pain, nausea and diarrhoea. 3 Unfortunately, in constipationpredominant IBS tricyclic antidepressants do not appear to be very useful and occasionally aggravate the constipation. 1 Current treatments for constipation-predominant IBS are not optimal. High amounts of fibre, more than 20 g daily, often causes massive flatulence and gas production. Tricyclic antidepressants effectively relieve pain and diarrhoea, but may worsen constipation. Other Ó 2005 Blackwell Publishing Ltd 381

2 382 H. VAHEDI et al. antidepressants, with the possible exception of selective serotonin reuptake inhibitors (SSRIs), do not appear to be very useful. Finally, laxatives, which are effective in controlling constipation, have little effect on pain. There is a tendency towards using SSRIs in pain and constipation-predominant IBS but case controlled studies are sparse. 4 6 Psychological factors, neurotransmitters such as serotonin and receptors such as 5-HT3 and 5-HT4 are involved in the pathogenesis of IBS. Fluoxetine has long been used as an effective treatment for many psychological disorders such as depression and obsessive compulsive disorders. 7 Considering the increasingly identified role of serotonergic neurotransmitters in pathogenesis of IBS, fluoxetine would be expected to have therapeutic effect in this condition. Randomized-controlled trials on IBS are scarce. There is one study on the effect of fluoxetine on IBS patients which has found it effective only on abdominal pain and only in hypersensitive patients and not effective in other subgroups and other symptoms. 8 In this study, all IBS subgroups were included which would probably dilute effects on certain subgroups. We designed a study to compare therapeutic effects of fluoxetine and placebo on common complaints of pain and constipationpredominant IBS patients in a randomized-controlled, double-blind trial. PATIENTS AND METHODS Consecutive patients referring to the gastroenterology clinic of Shariati Hospital, Tehran, were evaluated for eligibility. Cases with pain and constipation-predominant IBS as defined by the Rome II criteria were included. Patients were excluded if they had any organic disease proven by clinical examination, laboratory tests, or colonoscopy. Laboratory tests included complete blood count, sedimentation rate, renal and liver function tests, thyroid function tests, stool examinations and serological tests for coeliac disease. 9 Patients were also excluded if they did not consent to the study or had any of the following features: disease onset after age 50, progressively increasing severity of symptoms, frequent awakening by symptoms, fever, weight loss, dehydration, opium abuse, pregnancy, consumption of laxatives and prokinetic agents, dementia or severe psychological disorder. Patients were randomly assigned according to a computer-generated randomization table to receive fluoxetine (Abeidi Pharmaceuticals, Tehran, Iran) 20 mg daily (study group) for 12 weeks or an identical looking placebo (control group). Both patients and researchers were unaware of the true identity of the prescribed medicine. Five major symptoms addressed by the Rome II criteria were studied: significant abdominal discomfort, significant sense of bloating, hard stool consistency, frequency of bowel movement <3 times a week, and change in bowel habit. A significant abdominal discomfort and sense of bloating was defined as when it interfered with daily activities. During the study, patients were visited every other week. A final visit was performed 4 weeks after the end of treatment. At each visit, the presence of the above symptoms was recorded. The study protocol was approved by the ethics committee of Tehran University of Medical Sciences. Sample size calculation In case control studies on IBS, a 5 response to placebo is frequently observed. In open-label studies on antidepressants response rates of up to 89% have been observed. 10 Using these numbers and with a power of 8, a sample size of 22 was obtained for each group. Statistical methods Analysis was done using spss for Windows version Comparisons were made using independent sample t-test or chi-square as appropriate. RESULTS Sixty-four patients with constipation-predominant IBS were assessed for eligibility. A total of 14 were excluded because of failure to meet the eligibility criteria: two with onset at age of over 50, two pregnant, one suspicious to inflammatory bowel disease, three noncompliant, four opiate addicts, three severe melancholic depression and one suspected malignancy. Another six cases did not consent to the study protocol. The remaining 44 patients were randomly assigned to the study or control group. The mean age of participants was 34.9 ± 10.0 years (17 males and 27 females). The age and sex distribution betweeen the two groups was not significantly different. The baseline symptoms were also similar between the two groups (Table 1).

3 FLUOXETINE IN IRRITABLE BOWEL SYNDROME 383 Table 1. Initial characteristics of patients* Placebo group Fluoxetine group Total Age (years; mean ± s.d.) 32.8 ± ± ± 10.0 Male/female 11/11 6/16 17/27 Subjects with significant abdominal discomfort (%) Subjects with significant sense of bloating (%) Subjects with hard stool consistency (%) Subjects with <3 bowel movements per week (%) Subjects with change in bowel habit (%) Number of symptoms per subject (mean ± s.d.) 4.46 ± ± ± 0.63 * None of the differences between the two groups is significant. All 44 recruited patients continued and finished the study. Thus, intention-to-treat and per-protocol numbers are similar. At week 4 of treatment, all five symptoms were significantly less frequent between the fluoxetine group vs. the placebo group (P < 0.05 for each symptom). This advantage continued till the end of treatment at week 12. Interestingly even 4 weeks after end of treatment, four of the five symptoms were still significantly less frequent in the fluoxetine group. Only change in bowel habit was equally frequent between the two groups at week 16, 4 weeks after end of treatment. The mean number of symptoms per subject dropped very significantly in the fluoxetine group when compared with the placebo group from week 2 (P < 0.005) and continued throughout the study till week 16 (P < 0.001). The frequency of different symptoms and the mean number of symptoms per subject during the treatment and follow-up period are shown in Figure 1. Adverse events observed during the study were not significantly different between the two groups (Table 2). No adverse event was severe enough to lead to discontinuation of medications. DISCUSSION Treating IBS patients has always been a challenge to the gastroenterologist. The currently employed treatments for constipation-predominant IBS consist of increased fibre intake or laxatives to relieve constipation and antidepressants to relieve sense of bloating and abdominal discomfort. Unfortunately, there are many problems with these treatments. Fibre intake, particularly if over 20 g/day, often results in aggravation of gas and bloating. Tricyclic antidepressants, which are effective for pain and bloating, tend to make constipation worse. Laxatives may relieve the constipation but have never been demonstrated to ameliorate abdominal pain. Administration of antidepressants in IBS is a common practice, although evidence is sparse. Antidepressants can decrease the accompanying psychological symptoms especially depression and anxiety which can intensify the digestive complaints of IBS patients. Furthermore, antidepressants are central analgesics and there is significant evidence of central nervous system (CNS) disorders in IBS. These drugs also have some local effects on the gastrointestinal tract which 11, 12 may improve sensory motor function of the bowel. Serotonin (5-HT) may play an important role in the regulation of colonic motility in humans. However, it is not definitely known whether alterations in the colonic 5-HT system are involved in the pathophysiology of IBS. In one study on colonic mucosal specimens obtained from patients with IBS the overall mean mucosal 5-HT concentrations obtained from patients with constipation-predominant IBS were significantly higher than those obtained from the control subjects and patients with diarrhoea-predominant IBS. 13 It has also been shown that SSRIs can shorten the oroceacal transit time. 11 It is thus tempting to use SSRIs in constipationpredominant IBS. In the present study, we demonstrated that low-dose fluoxetine is effective in controlling symptoms in constipation-predominant IBS. As seen in Figure 1, most improvements are observed within the first 4 6 weeks. Furthermore, the improvement lasted 4 weeks after discontinuing fluoxetine. The half-life of fluoxetine is 4 6 days but its active metabolite, norfluoxetine, has a half-life of up to 15 days. 14 So some levels of activity remain in the patient s body for a relatively long time. It can be concluded that lower doses of fluoxetine may be able to maintain IBS patients once the symptoms are controlled. Another possible

4 384 H. VAHEDI et al. Placebo Fluoxetine Subjects with significant abdominal discomfort Subjects with significant sense of bloating Subjects with hard stool consistency Subjects with less than 3 weekly bowel movements Subjects with change in bowel habit Number of symptoms per subject Figure 1. Symptoms in patients treated with fluoxetine vs. placebo for 12 weeks and followed till week 16. Table 2. Adverse events observed in irritable bowel syndrome (IBS) patients treated with fluoxetine vs. placebo Adverse event Fluoxetine Placebo Nausea 4 3 Anorexia 5 1 Diarrhoea 3 1 Nervousness 3 2 Tremor 4 2 Anxiety 3 1 Insomnia 2 3 Headache 5 4 Abdominal cramp 4 2 Oesophagitis 2 0 explanation for the continued effect of fluoxetine may be that once symptoms are controlled, the threshold for recurrence is increased. Of course both these explanations need confirmation in well-designed studies. It is probable that intermittent treatment with fluoxetine may be a reasonable option to improve the quality of life in pain and constipation-predominant IBS patients. Paroxetine, another SSRI, has also been studied. In a study conducted on 258 cases with severe IBS there was a significant decrease in the number of days with abdominal pain in the paroxetine-treated group. 15 A placebo-controlled trial of paroxetine also showed benefit in pain and constipation-predominant IBS patients. 16 The mechanism of action of SSRIs is not clear. In one study, non-depressed patients took benefit of paroxetine as well as depressed patients, arguing against antidepressive effects being the mechanism of action. 16 In another study by Kuiken et al., it was shown that fluoxetine did not affect rectal sensitivity in IBS patients, arguing against visceral analgesic effects. 8 In this study, 40 patients with IBS were randomized to receive 6 weeks of placebo or fluoxetine. Symptoms and rectal sensitivity was analysed at the end of the study. No significant improvement was observed in the fluoxetine group vs. placebo. Kuiken et al. had included all IBS subgroups and only 11 of the 40 patients were constipation-dominant IBS. We believe the possible beneficiary effect of fluoxetine on the constipationpredominant subgroup may have been diluted and thus not recognized in this study. Although Kuiken et al. did observe that abdominal pain in a subgroup of these

5 FLUOXETINE IN IRRITABLE BOWEL SYNDROME 385 patients, hypersensitive patients only, does significantly respond to fluoxetine. 8 Adverse events were minimal in our patients and were not significantly more frequent in the fluoxetine group. Of course, the number of patients in our study was too small to allow effective evaluation of adverse events. Tremor and oesophagitis was observed in four and two patients of the fluoxetine group respectively. All six were relieved by week 4 without any specific treatment. An important adverse event of fluoxetine is gastrointestinal bleeding. 17, 18 The risk is especially higher when nonsteroidal anti-inflammatory agents are also used. We did not observe this adverse event among our cases. Our results support the use of fluoxetine as an effective and well-tolerated antidepressant for pain and constipation-predominant IBS patients. However, there is a need for further studies with larger sample sizes and longer follow-up to verify our results. ACKNOWLEDGEMENT This study was supported by a grant from the Digestive Disease Research Center of Tehran University of Medical Sciences. REFERENCES 1 Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ther 2001; 15: Muller-Lissner S, Holtmann G, Rueegg P, Weidinger G, Loffler H. Tegaserod is effective in the initial and retreatment of irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2005; 21: Myren J, Lovland B, Larssen SE, Larsen S. A double-blind study of the effect of trimipramine in patients with the irritable bowel syndrome. Scand J Gastroenterol 1984; 19: Camilleri M. Management of the irritable bowel syndrome. Gastroenterology 2001; 120: Jackson JL, O Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med 2000; 108: O Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract 1999; 48: Gram L. Fluoxetine. N Engl J Med 1994; 331: Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebocontrolled study. Clin Gastroenterol Hepatol 2003; 1: Shahbazkhani B, Forootan M, Merat S, et al. Coeliac disease presenting with symptoms of irritable bowel syndrome. Aliment Pharmacol Ther 2003; 18: Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther 1994; 8: Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther 1994; 8: Talley NJ. SSRIs in IBS: sensing a dash of disappointment. Clin Gastroenterol Hepatol 2003; 1: Miwa J, Echizen H, Matsueda K, Umeda N. Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits. Digestion 2001; 63: Hirsch M, Birnbaum RJ. Pharmacology and use of antidepressants. In: Rose, BD, ed. UpToDate. Wellesley, MA, USA: UpToDate, Creed F, Fernandes L, Guthrie E, et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 2003; 124: Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol 2004; 99: Aranth J, Lindberg C. Bleeding, a side effect of fluoxetine. Am J Psychiatry 1992; 149: Yaryura-Tobias JA, Kirschen H, Ninan P, Mosberg HJ. Fluoxetine and bleeding in obsessive-compulsive disorder. Am J Psychiatry 1991; 148: 949.

Selective serotonin reuptake inhibitors for the management of irritable bowel syndrome: A meta-analysis of randomized controlled trials

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