# Treatment of IBS



## eric (Jul 8, 1999)

FYITREATMENTS OF IBSDouglas A. Drossman, MDCo-DirectorUNC Center for Functional GI & Motility DisordersINTRODUCTIONIn recent years, there has been increased interest by physicians and the pharmaceuticalindustry regarding newer treatments for IBS. Before discussing these new treatments, it isimportant to consider the overall management strategy in IBS. This is necessary becausepatients with IBS exhibit a wide spectrum of symptoms of varying frequencies and degreesof severity. There is no one ideal treatment for IBS, and the newer medications may workbest for only a subset of patients having this disorder. Therefore, the clinician must firstapply certain general management approaches and, following this, treatment choices willdepend on the nature (i.e., predominant diarrhea, constipation, or bloating, etc.) andseverity (mild, moderate, severe) of the symptoms.The symptoms of IBS may have any of several underlying causes. These can includea) abnormal motility (uncoordinated or excessive contractions that can lead todiarrhea, constipation, bloating)(







visceral hypersensitivity (lower pain threshold of the nerves that can produceabdominal discomfort or pain) resulting from the abnormal motility, stress or infection© dysfunction of the brainï¿½s ability to regulate these visceral (intestinal) activities.Treatments will vary depending on which of these possibilities are occurring. In general,milder symptoms relate primarily to abnormal motility, often in response to food, activity orstress, and/or visceral hypersensitivity. They are commonly treated symptomatically withpharmacological agents directed at the gut. However, more severe symptoms often relate todysfunction of the brain-gut regulatory system with associated psychosocial effects, andpsychological or behavioral treatments and antidepressants are frequently helpful.In addition to identifying treatments for the specific symptoms of IBS, therapeutic optionsalso depend on the severity of the symptoms reported, particularly when abdominal pain isprominent. The clinical profiles of patients with mild, moderate or severe symptoms areshown in Table 1 (1, 2-4) .The most frequently seen group of IBS patients has mild symptoms. They are seen inprimary care practices, usually maintain normal daily activities, have little or nopsychosocial difficulties (although they may have a flare of symptoms with stress), and donot over utilize health care services. Treatment involves education, reassurance anddietary/lifestyle changes, and prescription medications or psychological treatments are notnecessarily needed.A smaller proportion of patients have moderate symptoms that are usually intermittent,although at times are disabling. Symptoms may produce emotional distress and greaterphysiological gut reactivity (e.g., worse with eating, relieved by defecation). Treatmentsinvolve gut-acting pharmacological agents (e.g., anticholinergics, antidiarrheals, newer GItreatments etc.) and, if more persistent, possibly low dose tricyclic antidepressants (TCA)and/or psychological treatments.Finally, a very small proportion of patients have severe symptoms. They are mostly seen inreferral center, and frequently have severe, often constant pain, psychological distress(e.g., depression, anxiety) and other psychosocial difficulties (e.g., a history ofsexual/physical abuse, or maladaptive coping styles), with high health care use rates. Inthese cases, antidepressant medication and possibly mental health or pain center referralare needed, along with an ongoing relationship with the primary care physician to providepsychosocial support through brief, regular visits(5).Table 1Spectrum of Clinical Features among Patients with IBS (45)Clinical Feature Mild Moderate SevereEstimated Prevalence 70% 25% 5%Practice Type Primary Specialty ReferralCorrelation with Gut Physiology + + + + + +Symptoms Constant 0 + + + +Psychosocial Difficulties 0 + + + +Health Care Use + + + + + +Illness Behavior 0 + + + +Psychiatric Diagnoses 0 + + + +*0 = Generally Absent; + = Mild; + + = Moderate; + + + = MarkedGonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel syndrome: a largescaleaudit of a clinical service with examination of factors influencing responsiveness. Am JGastroenterol. 2002 Apr;97(4):954-61.Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severerefractory irritable-bowel syndrome. Lancet. 1984 Dec 1;2(8414):1232-4.GENERAL MANAGEMENT APPROACHESPhysician-Patient Relationship: An effective physician-patient relationship is thecornerstone of treatment. This relationship builds from a partnership. It involves aninteractive process where the physician and patient engage in a dialogue, with the goal ofenhancing the patientï¿½s knowledge of the illness and treatment options. Similarly, thephysician needs to understand more about the patientï¿½s illness experience, health concernsand treatment preferences in order to make optimal treatment recommendations. Theprocess for the clinician involves1) active listening to determine the patientï¿½s understanding of the illness and his or herconcerns(2) thoroughly explaining the specifics of the medical disorder(3) identifying and responding to the patientï¿½s concerns and expectations(4) helping to set realistic and consistent limits(5) involving the patient in the treatment strategy(6) establishing a long-term relationship (with a gastroenterologist or primary careprovider)(5,6).In turn, the patient has a responsibility to1) actively engage in this dialogue with the physician(2) take responsibility for asking questions and seeking clarifications as needed(3) share in the decision-making on treatment options presented.This type of approach is associated with reduced health care visits(7,8) and improved patientsatisfaction and, when diagnostic and prognostic information is provided, there is also areduction in symptoms(9).Dietary Modifications: It is often assumed that specific foods create the symptoms of IBSand that specific diets are important in treatment. Surprisingly, specific diets are not asimportant as with other GI disorders (e.g., avoiding gluten in celiac sprue, or nuts and seedsin diverticular disease). Rather, symptoms of IBS may occur more as a generalized responseto eating, and this is why some patients find the need to reduce the amount they eat or avoideating in the daytime to reduce the pain and diarrhea that may occur 15-30 minutes later. Ingeneral, eating small meals more frequently places less stress on the GI tract and can helpreduce post-prandial (i.e., after meal) symptoms. However there are some dietarysubstances that may aggravate IBS symptoms. This includes fatty foods (which delaystomach emptying but also stimulate the lower bowels leading to bloating and discomfortand diarrhea), beans and gas producing foods (which can produce bloating and diarrhea),as well as alcohol, caffeine and lactose in individuals with lactose intolerance. In somecases, even excess fiber can produce bloating or gaseousness, because the bacteria in theintestines can metabolize the cellulose to produce gas. In general, care should be taken toavoid an unnecessarily restrictive diet, and it is best to consult with a physician to identifythe best dietary plan.Symptom monitoring: It is frequently helpful to use a diary for 2-3 weeks to monitor thetiming and severity of symptoms, the presence of possible aggravating factors, and theemotional impact of the symptoms(5,10). The diary may also identify dietary indiscretions orspecific stressors not previously considered, and may also give the patient a greater level ofparticipation in the planning of care. Finally, it provides a basis to review the findings andconsider dietary, lifestyle or behavioral modifications. Maladaptive coping styles (e.g.,profound pessimism or feelings of ineffectiveness) may be identified(11), which can lead toreappraisal and modification, or referral for psychological treatments like cognitivebehavioraltherapy(12).TRADITIONAL TREATMENTS FOR IBSFor pain and bloating, antispasmodics (e.g., anticholinergics) are smooth muscle relaxingmedications that may be helpful, particularly when symptoms are worsened after meals.Available studies primarily in Europe suggest that many antispasmodics can be effective(13-15), although the trials may have been inadequate by modern standards(16). Furthermore,most of these medications (e.g., cimetropium bromide, trimebutine, octyloinium bromide,mebeverine, pinaverium bromide)(17), are not even available in the US, because they did notundergo sufficient testing to be approved by the Food and Drug Administration (FDA).Within the US, the commonly prescribed dicyclomine (Bentylï¿½) and hyosyamine (Levsinï¿½)have shown varying successes in clinical trials and seem to work best with mildersymptoms. Peppermint oil, commonly used as a medication in Europe and as over thecounter medications and teas, have also had varying success(18), but at a minimum are notharmful. In clinical practice, anticholinergic agents are best used on an as-needed basis upto three times per day for acute attacks of pain or before meals. They are taken as neededand become less effective with chronic use. Side effects are similar to antihistamines -- drymouth, blurring of vision and dizziness, particularly when arising. Low dose tricyclicantidepressants may be considered when the pain is more constant and/or disabling (seebelow).For constipation, increased dietary fiber (25 gm/day) is recommended for simpleconstipation, although its effectiveness, based on several studies, in reducing pain inconstipation-predominant IBS is mixed. If fiber is not helpful, osmotic laxatives such as milkof magnesia, sorbitol, or polyethylene glycol (Miralaxï¿½, PEG solution) may be used.For diarrhea, loperamide (Imodiumï¿½) taken in 2-to-4 mg. doses up to four times a day ordiphenoxylate (lomotilï¿½) which consists of 2.5 mg. diphenoxylate with .025 mg. atropinecan be taken up to 3 or 4 times a day. It can reduce loose stools, urgency and fecal soiling{Read, 1982 7205 /id}. Cholestyramine (Questranï¿½) may be considered for a subgroup ofpatients with cholecystectomy or who may have bile acid malabsorptionNEWER MEDICAL TREATMENTSNewer treatment of the diarrhea and pain/discomfort of IBS are based on certain new drugsthat block the 5-HT3 receptors. 5-HT3 receptors are found on the intestinal (enteric nerves)and on higher nerve locations, such as the vomiting center. Blocking these receptorsreduces visceral (i.e., GI) pain, colonic transit, and small intestinal secretion {Kozlowski,2000 7239 /id}. Alosetron hydrochloride (Lotronexï¿½), a selective 5-HT3 antagonist, iseffective in relieving pain and normalizing bowel frequency as well as reducing urgency indiarrhea-predominant, female patients with IBS(19). It is more effective than placebo ininducing adequate relief of pain and discomfort, and improvement in bowel frequency,consistency and urgency(20-22) in women with diarrhea-predominant IBS. The most commonadverse event is constipation, affecting up to 28% in clinical trials, but with only 10%withdrawing from these studies for this symptom. A significant adverse event with unclearrelationship to Alosetron is acute ischemic colitis, estimated to occur in 0.1 to 1%. The drugwas withdrawn from the market in November 2000 because of these side effects, but afterfurther evaluation was re-approved by FDA in Spring 2002, under restrictive guidelines thatrequire the physician and patient to sign a release form and the patient to be monitored bythe company for possible side effects. There is no clear evidence that this medication iseffective in men, but this may be because only a small proportion of men, relative to women,have been evaluated with this medication. The starting dose is 1 mg./day, which can beincreased to 1 mg. twice a day in a month, if there are no side effects.Another 5-HT3 antagonist, cilansetron (Calmactinï¿½), has demonstrated similar benefit to thatof Alosetron in early (i.e., Phase II) clinical trials(23), and was effective in male patients(possibly due to a larger number of male patients studied). This drug has completed PhaseIII trials and is under review by the FDA. If approved, this medication will be released laterthis year.For constipation-predominant IBS, the partial 5-HT4 agonists Tegaserod (Zelnormï¿½) can beconsidered. This medication resulted in global relief of IBS symptoms and constipation infemales(24). The effective dose of Tegaserod is 12 mg per day in two divided doses (6 mgb.i.d.). Tegaserod appears safe with no serious adverse events for females with constipationpredominant IBS. The drug is also being used clinically and trials are underway for otherindications, including constipation, esophageal reflux, dyspepsia, gastroparesis, andpseudo-obstruction.Other new approaches being explored in early (Phase II) studies include: newer type 3antimuscarinic agents, NK1 and NK3 receptor antagonists, cholecystokinin antagonists, thealpha2 adrenergic agonists, clonidine(25), a 5-HT1 agonist, buspirone(26), and an SSRI,citalopram(27,28). The value of these experimental treatments needs to be determined basedon their clinical efficacy, safety and cost.COMPLEMENTARY AND ALTERNATIVE TREATMENTSOver the past several years, the use of complementary and alternative treatments hasgained popularity(29-32). But, their efficacy has not been established in controlled trials(33).One exception is a placebo-controlled 16-week trial of Chinese herbal medicines thatshowed improved bowel symptom scores, global symptoms, and reduced IBS relatedinterference with life relative to placebo(34). Because many herbs were used, it is notpossible to make specific recommendations.PSYCHOLOGICAL TREATMENTSPsychological treatment is recommended when IBS symptoms are moderate to severe, therehas been failure to respond to medical treatments, or when there is evidence that stress orpsychological factors are contributing to the intensity of the GI symptom. It is important forthe patient to understand the rationale for psychological treatments, since motivation toengage in the treatment is critical to success. There are four major types of psychological orbehavioral treatments used in IBS1) Cognitive-Behavioral Treatment (CBT), where patients use diaries and do exerciseswith the therapist to modify ï¿½maladaptiveï¿½ thoughts as a means to increase or regaincontrol over the symptoms(2) ï¿½Psychodynamicï¿½ or interpersonal psychotherapy, commonly used in England,where patients identify and address difficulties in interpersonal relationships that maylead to worsening GI symptoms(3) Hypnosis, commonly done in England and at UNC where hypnotic suggestion isused to relax the bowel and reduce symptoms(4) Stress Management/Relaxation Training, which can be a component of the otherpsychological treatments, where imaging and relaxation methods are used to reduceautonomic (blood pressure, pulse) activity and muscle tension.Psychological treatment trials may have methodological limitations, because it is difficult toblind patients or the investigators as to the type of treatment, and it is difficult to find acredible placebo. In fact, not all studies have been controlle, or had sufficient numbers ofpatients to be certain of their efficacy(35,36). Recently, two well-designed studies involvinglarge numbers of patients have provided new information. In one study(37), usingpsychodynamic psychotherapy compared to paroxetine, an antidepressant and usualmedical care, it was found that both psychotherapy and paroxetine were superior to usualcare in improving health related quality of life. Furthermore, one year later, thepsychological treatment showed reductions in health care costs when compared to the othertreatments. In a Phase III multicenter trial done by our group at UNC and the University ofToronto(12), we found that CBT was significantly better than an educational comparison groupover 12 weeks of treatments. CBT was even effective for patients with more severesymptoms or with a history of abuse, but was not as effective if the patients had severedepression. This suggests for patients with severe depression, CBT may need to be doneeither for a longer period of time or in conjunction with an antidepressant. Also, it has beenproposed that patients who exhibit maladaptive coping styles or cognitions (e.g.,ï¿½catastrophizingï¿½) relative to their symptoms, or perceive an inability to decrease them,may be particularly responsive to CBT(11,38).An early placebo-controlled trial of hypnosis showed this treatment to be more effective forreducing abdominal pain and altered bowel habits compared to placebo tablets plusdiscussion of the role of emotion in symptoms(39). These results have been replicated byother investigators and are well-maintained at 5 years follow-up(40). A recent study publishedin Gastroenterology shows that hypnosis is also effective for functional dyspepsia and that itresults in decreased health care utilization and decreased use of prescribed medication(41).Currently, there is no evidence that one psychological treatment is superior to another.Favorable responses occur when patients have(42,43)1) awareness that stress worsens their bowel symptoms(2) some psychological distress associated with the symptoms(3) abdominal pain or diarrhea and not just constipation(4) abdominal pain that comes and goes in response to eating, defecation, or stressrather than being constant pain(5) symptoms are of relatively short duration.ANTIDEPRESSANTSMedical physicians commonly prescribe antidepressants for painful medical disorders,including migraine headache, fibromyalgia and moderate-to-severe IBS. Two classes ofantidepressants are most commonly used: tricyclic antidepressants/TCAï¿½s (e.g.,amitriptyline/Elavilï¿½, imipramine/Tofranilï¿½l, desipramine/Norpraminï¿½,nortriptyline/Pamelorï¿½, doxepin/Sinequanï¿½), and selective serotonin reuptakeinhibitor/SSRIs (e.g., fluoxetine/Prozacï¿½, sertraline/Zoloftï¿½, paroxetine/Paxilï¿½,citalopram/Celexaï¿½, escitalopram/Lexaproï¿½). Less frequently, novel antidepressants notbelonging to these two classes (such as, venlaxafine/Effexorï¿½, mirtazapine/Remeronï¿½) areprescribed. The rationale for antidepressant use relates to1) treatment of accompanying psychiatric diagnoses (e.g., major depression, anxietydisorders) associated with IBS (usually higher dosages are required)(2) their effects directly on the GI system to modify visceral sensitivity, motility andsecretion(3) most importantly, reduction of central pain perception arising from the intestines.There is also some evidence that antidepressants may enhance the effects ofpsychological treatments(35).Several randomized controlled trials of TCA medications in IBS have been published(36), andwere evaluated in a meta-analysis(44). Improvement in global GI symptoms against placebowas highly significant, and there was also improvement in pain score. Notably, the TCAdosages were lower than that used to treat major depression, suggesting that the benefitwas unrelated to the TCAï¿½s antidepressant effects. But, these studies had limitations due tosmall sample sizes, short study lengths, variable study design quality, and other difficulties,making it difficult to draw firm conclusions.More recently, our multi-center NIH-sponsored Phase III study(12) found that the benefit ofDesipramine, averaging 100 mg./day, was equivalent to our CBT treatment. However, it wasnot significantly greater than the placebo when all patients, including those who droppedout, were studied. The medication did produce side effects in about 30-40% of the patientstaking the medications, and the 30% who dropped out of the study were due primarily toside effects. Thus, when the study was analyzed to evaluate those who completed the 12weeks of treatment (per protocol analysis), there was significant benefit over placebo. Thesedata indicate that the medication is helpful for treating IBS, but only if the patient is able tostay on a full course of treatment. Thus, the physician and patient need to work together tofind the proper dosage that allows the patient to stay on the medication long enough for it towork.Antidepressants are generally used for patients with frequent or moderate-to-severesymptoms of pain and diarrhea, and must be given on a continuous rather than an ï¿½asneededï¿½ basis. Low doses of TCAï¿½s (e.g., 10-50 mg/day) are recommended because theyproduce fewer side effects, while still showing benefit. However, full dosages might beconsidered if the benefit is incomplete and there are no or few side effects. The side effectsare similar to anticholinergic drugs and include dry mouth, blurry vision, sexual difficulties,and dizziness. In general, the side effects tend to diminish after 1-2 weeks, while the benefitincreases over several weeks.There is only one published controlled study on the use of SSRIï¿½s or novel antidepressantsfor IBS. This study showed the effect of Paroxetine to be equivalent to psychodynamicpsychotherapy in terms of improved quality of life. A few other studies suggest clinicalbenefit particularly if there is associated anxiety, panic or phobic symptoms (e.g., fear ofeating because of pain or of leaving home because of inaccessibility of rest rooms, etc.). Incontrast to the TCAï¿½s, because SSRIï¿½s increase intestinal motility, they can be used forpatients with more diarrhea-type symptoms. They also have fewer side effects, which caninclude dizziness, anxiety at the beginning of treatment, and sleep and sexual disturbances.CONCLUSIONThere are a variety of treatments that can be used for treating patients with IBS. A generalapproach includes an effective physician-patient relationship, proper education, and dietaryor lifestyle modifications necessary for any treatment plan. In addition, the options fortreatment are based on the nature of the symptoms as well as their severity and frequency.The newer receptor active medications have added considerably to the treatment optionsthat can be considered and they focus primarily on the functioning of the GI system. Inaddition, psychological treatments and antidepressants are of particular value to patientswith more moderate to severe symptoms. Both physician and patient can work together todefine the clinical needs for treatment and then choose the best treatment strategy.References1) Drossman DA, Whitehead WE, Toner BB, Diamant NE, Hu YJB, Bangdiwala SI et al. Whatdetermines severity among patients with painful functional bowel disorders? Am J Gastroenterol.2000;95:974-80.(2) Drossman DA, Li Z, Toner BB, Diamant NE, Creed FH, Thompson DG et al. Functional BowelDisorders: A multicentercomparison of health status, and development of illness severity index. Dig Dis Sci. 1995;40:986-95.(3) Shapiro MS, Olden KW. 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