# Digest winter 2003 2004



## eric (Jul 8, 1999)

UNC Center for Functional GI & Motility DisordersTREATMENTS OF IBSWinter 2003/2004INDEXTreatments of IBS ................................. 1 - 8Does Desipramine Dose Matter inthe Treatment of Functional BowelDisorders? ................................. 9 - 12, 24Center News ...... 8,13-14, 16-17, 24, 28-29Farewell To Carlar Blackman ........... 13 - 14Lactose Intolerence and Small BacterialOvergrowth in IBS ..................... 15,18- 22Ask the Expert - New to the Newsletter 23Parentsï¿½ Thoughts and Worries AboutRecurrent Abdominal Pain .............. 25 - 28Role of Physicianï¿½s Assistant ................... 29Patient Symposium ..................................... 8Chat with the Experts ................................. 8Advancing the Treatment of Fecal andUrinary Incontinence Through Research ................................................................. 30Support the Center .................................... 31Donations/Thank You! .............................. 32Our People ................................................ 14Continued on page 2Our Missionis to advancethe biopsychosocialunderstanding and careof patients withfunctional GIand motility disordersthroughresearch, training,and education.Douglas A. Drossman, MDCo-Director, UNC Center for Functional GI & Motility DisordersINTRODUCTIONIn recent years, there hasbeen increased interest byphysicians and thepharmaceutical industryregarding newer treatmentsfor IBS. Before discussingthese new treatments, it isimportant to consider theoverall managementstrategy in IBS. This isnecessary because patientswith IBS exhibit a widespectrum of symptoms of varying frequencies and degrees of severity. Thereis no one ideal treatment for IBS, and the newer medications may workbest for only a subset of patients having this disorder. Therefore, the clinicianmust first apply certain general management approaches, and followingthis, treatment choices will depend on the nature (i.e., predominant diarrhea,constipation, or bloating, etc.) and severity (mild, moderate, severe) of thesymptoms.The symptoms of IBS may have any of several underlying causes. Thesecan includea) abnormal motility (uncoordinated or excessive contractions thatcan lead to diarrhea, constipation, bloating),(







visceral hypersensitivity (lower pain threshold of the nerves thatcan produce abdominal discomfort or pain) resulting from the abnormalmotility, stress or infection, and© dysfunction of the brainï¿½s ability to regulate these visceral (intestinal)activities.Thus the treatments will vary depending on which of these possibilities areoccurring. In general, milder symptoms relate primarily to abnormal motility,often in response to food, activity or stress, and/or visceral hypersensitivity,Page 2 DigestTable 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 constantPsychosocial difficulties Health Care Use Illness Behavior Psychiatric diagnoses Generally Absent; Mild; Moderate; MarkedGonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel syndrome: a large-scale audit of a clinical servicewith examination of factors influencing responsiveness. Am J Gastroenterol. 2002 Apr;97(4):954-61.Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome.Lancet. 1984 Dec 1;2(8414):1232-4.TREATMENTS OF IBS, CONT.Continued from page 1and they are commonly treated symptomatically withpharmacological agents directed at the gut. However, moresevere symptoms often relate to dysfunction of the brain-gutregulatory system with associated psychosocial effects, andpsychological or behavioral treatments and antidepressantsare frequently helpful.In addition to identifying treatments for the specific symptomsof IBS, therapeutic options also depend on the severity ofthe symptoms reported, particularly when abdominal pain isprominent. The clinical profiles of patients with mild,moderate or severe symptoms are shown in Table 1(1, 2-4)(below). The most frequently seen group of IBS patientshas mild symptoms. They are seen in primary care practices,usually maintain normal daily activities, have little or nopsychosocial difficulties (though may have a flare ofsymptoms with stress) and do not overutilize health careservices. Treatment involves education, reassurance anddietary/lifestyle changes, and prescription medications orpsychological treatments are not necessarily needed. Asmaller proportion of patients have moderate symptoms thatare usually intermittent, though at times are disabling.Symptoms may produce emotional distress, and greaterphysiological gut reactivity (e.g., worse with eating, relievedby defecation). Treatments involve gut-actingpharmacological agents (e.g., anticholinergics, antidiarrheals,newer GI treatments etc.), and if more persistent, possiblylow dose tricyclic antidepressants and/or psychologicaltreatments. Finally, a very small proportion of patients havesevere symptoms. They are mostly seen in referral centers,and frequently have severe, often constant pain, psychologicaldistress (e.g., depression, anxiety) and other psychosocialdifficulties (e.g., a history of sexual/physical abuse, ormaladaptive coping styles), with high health care use rates.Here, antidepressant medication and possibly mental health orpain center referral are needed along with an ongoingrelationship with the primary care physician to providepsychosocial support through brief, regular visits(5).GENERAL MANAGEMENT APPROACHESPhysician-Patient Relationship: An effective physicianpatientrelationship is the cornerstone of treatment. Thisrelationship builds from a partnership. It involves an interactiveprocess where the physician and patient engage in a dialoguewith the goal being to enhance the patientï¿½s knowledge of theillness and treatment options. Similarly, the physician needs tounderstand more about the patientï¿½s illness experience, healthconcerns and treatment preferences in order to make optimaltreatment recommendations. The process for the clinicianinvolves1) active listening to determine the patientï¿½s understandingof the illness and his or her concerns,(2) thoroughly explaining the specifics of the medicaldisorder,(3) identifying and responding to the patientï¿½s concernsand expectations,(4) helping to set realistic and consistent limits,(5) involving the patient in the treatment strategy, and(6) establishing a long-term relationship (by agastroenterologist or primary care provider)(5,6).In turn, the patient has the responsibility to1) actively engage in this dialogue with the physician,(2) take responsibility for asking questions and seekingclarifications as needed, andDigest Page 3(Continued on page 4)TREATMENTS OF IBS, CONT.(3) share in the decision-making of treatment optionspresented.This type of approach is associated with reduced health carevisits(7,8) and improved patient satisfaction, and when diagnosticand prognostic information is provided, there is also a reductionin symptoms(9).Dietary Modifications: It is often assumed that specific foodscreate the symptoms of IBS, and that specific diets areimportant in treatment. Surprisingly, specific diets are not asimportant as with other GI disorders (e.g., avoiding gluten inceliac sprue, or nuts and seeds in diverticular disease). Rather,symptoms of IBS may occur more as a generalized responseto eating, and this is why some patients find the need to reducethe amount they eat, or avoid eating in the daytime to reducethe pain and diarrhea that may occur 15-30 minutes later. Ingeneral, eating small meals more frequently places less stresson the GI tract and can help reduce post-prandial (i.e., aftermeal) symptoms. However there are some dietary substancesthat may aggravate symptoms. This includes fatty foods (whichdelay stomach emptying but also stimulate the lower bowelsleading to bloating and discomfort and diarrhea), beans andgas producing foods (which can produce bloating and diarrhea),as well as alcohol, caffeine, and lactose in individuals withlactose intolerance. In some cases even excess fiber canproduce bloating or gaseousness because the bacteria in theintestines can metabolize the cellulose to produce gas. Ingeneral, care should be taken to avoid an unnecessarilyrestrictive diet, and it is best to consult with the physician toidentify the best dietary plan.Symptom monitoring: It is frequently helpful to use a diaryfor 2-3 weeks to monitor the timing and severity of symptoms,the presence of possible aggravating factors and the emotionalimpact of the symptoms(5,10). The diary may also identifydietary indiscretions, or specific stressors not previouslyconsidered, and may also give the patient a greater level ofparticipation in the planning of care. Finally, it provides a basisto review the findings and consider dietary, lifestyle orbehavioral modifications. In addition, maladaptive coping styles(e.g., profound pessimism, or feelings of ineffectiveness) maybe identified(11), which can lead to reappraisal and modification,or referral for psychological treatments like cognitivebehavioraltherapy(12).TRADITIONAL TREATMENTS FOR IBSFor pain and bloating, antispasmodics (e.g., anticholinergics)are smooth muscle relaxing medications that may be helpful,particularly when symptoms are worsened after meals.Available studies primarily in Europe suggest that manyantispasmodics can be effective(13-15), although the trials mayhave been inadequate by modern standards(16). Furthermore,most of these medications (e.g., cimetropium bromide,trimebutine, octyloinium bromide, mebeverine, pinaveriumbromide)(17), are not even available in the US because they didnot undergo sufficient testing to be approved by the Food andDrug Administration. Within the US, the commonly prescribeddicyclomine (Bentylï¿½) and hyosyamine (Levsinï¿½) have shownvarying successes in clinical trials, and seem to work bestwith milder symptoms. Peppermint oil, commonly used as amedication in Europe and as over the counter medications andteas have also had varying success(18), but in the least are notharmful. In clinical practice, anticholinergic agents are bestused on an as-needed basis up to 3 times per day for acuteattacks of pain or before meals. They are taken as needed,and become less effective with chronic use. Side effects aresimilar to antihistamines with dry mouth, blurring of vision anddizziness, particularly when arising. Low dose tricyclicantidepressants may be considered when the pain is moreconstant and/or disabling (see below).For constipation, increased dietary fiber (25 gm/day) isrecommended for simple constipation, although itseffectiveness, based on several studies, in reducing pain inconstipation-predominant IBS is mixed (see dietarymodification section). If fiber is not helpful, osmotic laxativessuch as milk of 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 or diphenoxylate (lomotilï¿½) whichconsists of 2.5 mg. diphenoxylate with .025 mg. atropine canbe 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 subgroupof patients with cholecystectomy or who may have bile acidmalabsorptionNEWER MEDICAL TREATMENTSNewer treatment of the diarrhea and pain/discomfort ofIBS are based on certain new drugs that block the 5-HT3receptors. 5-HT3 receptors are found on the intestinal, orenteric nerves, and on nerve locations higher such as thevomiting center. Blocking these receptors reduces visceral (i.e.,GI) pain, colonic transit, and small intestinal secretion{Kozlowski, 2000 7239 id}. Alosetron hydrochloride(Lotronexï¿½), a selective 5-HT3 antagonist, is effective inrelieving pain and normalizing bowel frequency and reducingurgency in diarrhea-predominant, female patients with IBS(19).It was more effective than placebo in inducing adequate reliefPage 4 Digest(Continued from page 3)TREATMENTS OF IBS, CONT.of pain and discomfort, and improvement in bowel frequency,consistency and urgency(20-22) in women with diarrheapredominantIBS. The most common adverse event wasconstipation, affecting up to 28% in clinical trials, but withonly 10% withdrawing from these studies for this symptom.A significant adverse event with unclear relationship toAlosetron is acute ischemic colitis, estimated to occur in 0.1to 1%. The drug was withdrawn from the market in November2000 because of these side effects, but after further evaluationwas reapproved by FDA in spring, 2002, under restrictiveguidelines that require the physician and patient to sign arelease form and for the patient to be monitored by thecompany for possible side effects. There is no clear evidencethat this medication is effective in men, however, that may bebecause only a small proportion of men, relative to women,have been evaluated with this medication. The starting doseis 1 mg./day, which can be increased to 1 mg. twice a day ina month if there are no side effects.Another 5-HT3 antagonist, cilansetron (Calmactinï¿½), hasdemonstrated similar benefit to that of 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 Phase III trials and is under reviewby the Food and Drug Administration. If approved, thismedication will be released later this year.For constipation-predominant IBS, the partial 5-HT4 agonistsTegaserod (Zelnormï¿½) can be considered. This medicationresulted in global relief of IBS symptoms and constipationalso in females(24). The effective dose of Tegaserod is 12 mgper day in two divided doses (6 mg b.i.d.). Tegaserod appearssafe with no serious adverse events for females withconstipation predominant IBS. The drug is also being usedclinically, and trials are underway for other indicationsincluding constipation, esophageal reflux, dyspepsia,gastroparesis and pseudo-obstruction.Other new approaches being explored in early (phase II)studies include: newer type 3 antimuscarinic agents, NK1 andNK3 receptor antagonists, cholecystokinin antagonists, thealpha2 adrenergic agonists, clonidine(25), a 5-HT1 agonist,buspirone(26), and an SSRI, citalopram(27,28). The value of theseexperimental treatments needs to be determined based on theirclinical efficacy, safety and cost.COMPLEMENTARY AND ALTERNATIVE TREATMENTSOver the last few years, the use of complementary andalternative treatments has gained popularity(29-32). However,their efficacy has not been established in controlled trials(33).One exception is a placebo-controlled 16 week trial of Chineseherbal medicines that showed improved bowel symptom scores,global symptoms, and reduced IBS related interference withlife relative to placebo(34). Because many herbs were used, itis not possible to make specific recommendations.PSYCHOLOGICAL TREATMENTSPsychological treatment are recommended when IBSsymptoms are moderate to severe, have failed to respond tomedical treatments, or when there is evidence that stress orpsychological factors are contributing to the intensity of theGI symptom. It is important for the patient to understand therationale for psychological treatments, since motivation toengage in the treatment is critical to success. There are 4major types of psychological or behavioral treatments used inIBS1) Cognitive-Behavioral Treatment (CBT), wherepatients use diaries and do exercises with the therapist tomodify ï¿½maladaptiveï¿½ thoughts as a means to increaseor regain control over the symptoms,(2) ï¿½Psychodynamicï¿½ or interpersonal psychotherapy,commonly used in England, where patients identify andaddress difficulties in interpersonal relationships that maylead to worsening GI symptoms,(3) hypnosis, commonly done in England and at UNCwhere hypnotic suggestion is used to relax the bowel andreduce symptoms, and(4) stress management/relaxation training, which can bea component of the other psychological treatments whereimaging and relaxation methods are used to reduceautonomic (blood pressure, pulse) activity and muscletension.Psychological treatment trials may have methodologicallimitations because it is difficult to blind patients or theinvestigators as to the type of treatment, and it is difficult tofind a credible placebo. In fact, not all studies have beencontrolled, or had sufficient numbers of patients to be sure oftheir efficacy(35,36). Recently, two well-designed studiesinvolving large numbers of patients have provided newinformation. In one study(37), using psychodynamicIt is important for the patient tounderstand the rationale forpsychological treatments, sincemotivation to engage in the treatmentis critical to success.Digest Page 5TREATMENTS OF IBS, CONT.psychotherapy compared to paroxetine, an antidepressant andusual medical care, it was found that both psychotherapy andparoxetine were superior to usual care in improving health relatedquality of life. Furthermore, one year later the psychologicaltreatment showed reductions in health care costs when comparedto the other treatments. In a phase III multicenter trial done byour group at UNC and the University of Toronto(12), we foundthat CBT was significantly better than an educational comparisongroup over 12 week of treatments. CBT was even effective forpatients with more severe symptoms, or with a history of abuse,but was not as effective if the patients had severe depression.This suggests for patients with severe depression, CBT may needto be done either for a longer period of time or in conjunctionwith an antidepressant. Also, it has been proposed that patientswho exhibit maladaptive coping styles or cognitions (e.g.,ï¿½catastrophizingï¿½) relating to their symptoms, or perceive aninability to decrease them, may be particularly responsive tocognitive-behavioral treatment(11,38).An early placebo-controlled trial of hypnosis showed thistreatment to be more effective for reducing abdominal pain andaltered bowel habits compared to placebo tablets plus discussionof the role of emotion in symptoms(39). These results have beenreplicated by other investigators and are well-maintained at 5years follow-up(40). A recent study published in Gastroenterologyshows that hypnosis is also effective for functional dyspepsiaand that it results in decreased health care utilization and decreaseduse of prescribed medication(41).Currently, there is no evidence that one psychological treatmentis superior to another. Favorable responses occur when patientshave(42,43)1) awareness that stress worsens their bowel symptoms,(2) some psychological distress associated with thesymptoms,(3) abdominal pain or diarrhea and not just constipation,(4) the abdominal pain comes and goes in response to eating,defecation, or stress rather than being constant pain, and(5) the symptoms are of relatively short duration.ANTIDEPRESSANTSMedical physicians commonly prescribe antidepressantsfor painful medical disorders, including migraine headache,fibromyalgia and moderate to severe IBS. Two classes ofantidepressants are most commonly used: tricyclicantidepressants (TCAï¿½s) (e.g., amitriptyline/Elavilï¿½,imipramine/Tofranilï¿½l, desipramine/Norpraminï¿½,nortriptyline/Pamelorï¿½, doxepin/Sinequanï¿½), and selectiveserotonin reuptake inhibitor (SSRIs) (e.g., fluoxetine/Prozacï¿½, sertraline/Zoloftï¿½, paroxetine/Paxilï¿½, citalopram/Celexaï¿½, escitalopram/Lexaproï¿½). Less frequently, novelantidepressants not belonging to these two classes(venlaxafine/Effexorï¿½, mirtazapine/Remeronï¿½) areprescribed. The rationale for antidepressant use relatesto1) treatment of accompanying psychiatric diagnoses(e.g., major depression, anxiety disorders) associatedwith IBS (usually higher dosages are required),(2) their effects directly on the GI system to modifyvisceral sensitivity, motility and secretion, or(3) most importantly, reduction of central painperception arising from the intestines. There is alsosome evidence that antidepressants may enhance theeffects of psychological treatments(35).Several randomized controlled trials of tricyclicantidepressant medications in IBS have been published(36),and were evaluated in a meta-analysis(44). Improvementin global gastrointestinal symptoms against placebo washighly significant, and there was also improvement in painscore. Notably, the TCA dosages were lower than thatused to treat major depression, suggesting that the benefitwas unrelated to the TCAï¿½s antidepressant effects.However, these studies had limitations due to small samplesizes, short study lengths, variable study design quality, andother difficulties, making it difficult to draw firmconclusions.More recently, our multi-center NIH phase III study(12)found that the benefit of desipramine, averaging 100 mg./day was equivalent to our CBT treatment. However, itwas not significantly greater than the placebo when allpatients, including those who dropped out were studied.The medication did produce side effects in about 30-40%of the patients taking the medications and the 30% dropoutswere due primarily to side effects. Thus when the studywas analyzed to evaluate those who completed the 12weeks of treatment (per protocol analysis), there wassignificant benefit over placebo. These data indicate thatContinued on page 6Antidepressants are generally used forpatients with frequent or moderate tosevere symptoms of pain and diarrhea,and must be given on a continual ratherthan an ï¿½as neededï¿½ basis.Page 6 Digestthe medication is helpful for treating IBS, but only if the patient is able to stay on a full course of treatment. Thus, the physicianand patient need to work together to find the proper dosage that allows the patient to stay on the medication long enough forit to work.Antidepressants are generally used for patients with frequent or moderate to severe symptoms of pain and diarrhea, and mustbe given on a continual rather than an ï¿½as neededï¿½ basis. Low doses of TCAï¿½s (e.g., 10-50 mg/day) are recommendedbecause they produce fewer side effects, while still showing benefit. However, full dosages might be considered if the benefitis incomplete and there are no or few side effects. The side effects are 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 antidepressants for IBS. This study showed theeffect of paroxetine to be equivalent to psychodynamic psychotherapy in terms of improved quality of life. A few otherstudies suggest clinical benefit particularly if there is associated anxiety, panic, or phobic symptoms (e.g., fear of eatingbecause of pain or of leaving home because of inaccessibility of rest rooms, etc.). In contrast to the TCAï¿½s, because SSRIï¿½sincrease intestinal motility, it can be used for patients with more diarrheal type symptoms. They also have fewer side effects,which can include 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 general approach includes an effectivephysician- patient relationship, proper education, dietary or lifestyle modifications necessary for any treatment plan. In addition,the options for treatment are based on the nature of the symptoms as well as their severity and frequency. The newer receptoractive medications have added considerably to the treatment options that can be considered and they focus primarily on thefunctioning of the GI system. In addition, psychological treatments and antidepressants are of particular value to patients withmore moderate to severe symptoms. Both physician and patient can work together to define the clinical needs for treatmentand then choose the best treatment strategy.References1) Drossman DA, Whitehead WE, Toner BB, Diamant NE, Hu YJB, Bangdiwala SI et al. What determines severity among patientswith 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 Bowel Disorders: A multicentercomparison of health status, and development of illness severity index. Dig Dis Sci. 1995;40:986-95.(3) Shapiro MS, Olden KW. Symptom expression in pain-predominant functional bowel syndrome: Is visceral hyperalgesia thewhole truth? AJG. 2000;95:862-63.(4) Sperber AD, Carmel S, Atzmon Y, Weisberg I, Shalit Y, Neumann L et al. Use of the Functional Bowel Disorder Severity Index(FBDSI) in a study of patients with the Irritable bowel syndrome and fibromyalgia. Am J Gastroenterol. 2000;95:995-98.(5) Drossman DA. Diagnosing and treating patients with refractory functional gastrointestinal disorders.Ann Intern Med. 1995;123:688-97.(6) Drossman DA, Thompson WG. The irritable bowel syndrome: Review and a graduated, multicomponent treatment approach.Ann Intern Med. 1992;116:1009-16.(7) Owens DM, Nelson DK, Talley NJ. The irritable bowel syndrome: Long term prognosis and the physician-patient interaction.Ann Intern Med. 1995;122:107-12.(8) Oï¿½Sullivan MA, Mahmud N, Kelleher DP, Lovett E, Oï¿½Morain CA. Patient knowledge and educational needs in irritable bowelsyndrome [see comments]. Eur J Gastroenterol Hepatol. 2000;12:39-43.(9) Jackson JL, Kroenke K. The effect of unmet expectations among adults presenting with physical symptoms.Ann Intern Med. 2001;134 (2):889-97.(10) Shimberg EF. Relief from IBS. 1 ed. New York: M. Evans and Company, Inc.; 1988.(11) Drossman DA, Li Z, Leserman J, Keefe FJ, Hu YJ, Toomey TC. Effects of coping on health outcome among female patients withgastrointestinal disorders. Psychosom Med. 2000;62:309-17.(12) Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S et al. Cognitive-Behavioral Therapy vs. educationand Desipramine vs. Placebo for Moderate to Severe Functional Bowel Disorders. Gastroenterol. 2003;125:19-31.(13) Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: A systematic review ofrandomized, controlled trials. Ann Intern Med. 2000;133:136-47.Continued from page 5TREATMENTS OF IBS, CONT.Digest Page 7(14) Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.Aliment Pharmacol Ther. 2001;15:355-61.(15) Akehurst R, Kaltenthaler E. Treatment of irritable bowel syndrome: a review of randomized controlled trials.Gut. 2001;48:272-82.(16) Veldhuyzen van Zanten SJO, Talley NJ, Bytzer P, Klein K, Whorwell PJ, Zinsmeister AR. Design of treatment trials for thefunctional gastrointestinal disorders. In: Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, eds. Rome II.Functional gastrointestinal disorders: Diagnosis, pathophysiology, and treatment-A multinational consensus. 2nd ed. McLean,VA: Degnon Associates; 2000: 577-622.(17) Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis of smooth muscle relaxers in the treatment of irritable bowelsyndrome. Aliment Pharmacol Ther. 1994;8:499-510.(18) Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: A critical review and metaanalysis.Am J Gastroenterol. 1998;93:1131-35.(19) Camilleri M, Mayer EA, Drossman DA, Heath AT, Dukes GE, McSorley D et al. Improvement in pain and bowel function infemale irritable bowel patients with Alosetron, a 5HT3-receptor antagonist. Aliment Pharmacol Ther. 1999;13:1149-59.(20) Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mill JG et al. A double-blind, randomized, placebo-controlleddose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome.Aliment Pharmacol Ther. 2000;14:23-34.(21) Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritablebowel syndrome: A randomised, placebo-controlled trial. The Lancet. 2000;355:1035-40.(22) Mangel, A. W., Camilleri, M., Chey, W. Y., Mayer, E. A., Northcutt, A. R., Heath, A. T., Dukes, G. E., and McSorley, D. Alosetron, a5-HT3 receptor antagonist, in the treatment of non-constipated female IBS patients. AJG 94(x), 2677. 1999.(23) Caras, S., Krause, G., Biesheuvel, E., and Steinborn, C. Cilansetron shows efficacy in male and female non-constipated patientswith irritable bowel syndrome in a United States study. Gastroenterology 120(5 (1)), A217. 2001.(24) Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E, Nault B et al. Tegaserod, a 5-HT4 receptor partial agonist,relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation.Aliment Pharmacol Ther. 2001;15:1655-66.(25) Bharucha AE, Camilleri M, Zinsmeister AR, Hanson RB. Adrenergic modulation of human colonic motor and sensory function.Am J Physiol. 1997;273:G997-G1006.(26) Tack, J., Piessevaux, H., Coulie, B., Fischler, B., De Gucht, V., and Janssens, J. A placebo-controlled trial of buspirone, afundus-relaxing drug, in functional dyspepsia: Effect on symptoms and gastric sensory and motor function.Gastroenterology 116, A325. 1999.(27) Tack, J. F., Vos, R., Broekaert, D., Fischler, B., and Janssens, J. Influence of citalopram, a selective serotonin reuptake inhibitor,on colonic tone and sensitivity in man. Gastroenterology 118(4), A175. 2000.(28) Broekaert, D., Vos, R., Gevers, A. M., Janssens, J., Vandenberghe, J., Fischler, B., and Tack, J. A double-blind randomisedplacebo-controled crossover trial of citalopram, a selective 5-hydroxytryptamine reuptake inhibitor, in irritable bowelsyndrome. Gastroenterology 120(5 (1)), A641. 2001.(29) Smart HL, Mayberry JF, Atkinson M. Alternative medicine consultations and remedies in patients with the irritable bowelsyndrome. Gut. 1986;27:826-28.(30) Sloth H, Mortensen NH, Bisgard C. Irritable colon and ulcerative colitis. Alternative treatment is used frequently.Ugeskr Laeger. 1991;153:3304-6.(31) Verhoef MJ, Sutherland LR, Brkich L. Use of alternative medicine by patients attending a gastroenterology clinic.Can Med Assoc J. 1990;142:121-25.(32) Sutherland LR, Verhoef MJ. Why do patients seek a second opinion or alternative medicine?J Clin Gastroenterol.1994;19:194-97.(33) Bittinger M, Barnert J, Wienbeck M. Alternative therapy methods in functional disorders of the gastrointestinal system.Zeitschrift fur Gastroenterologie. 1998;36:519-24.(34) Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel syndrome with chinese herbalmedicine: A randomized controlled trial. JAMA. 1998;280:1585-89.(35) Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA Technical Review on Irritable Bowel Syndrome.Gastroenterol. 2002;123:2108-31.(36) Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE. Psychosocial aspects of the functionalgastrointestinal disorders. In: Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, eds. Rome II. Thefunctional gastrointestinal disorders: Diagnosis, pathophysiology and treatment;A multinational consensus. 2 ed. Degnon and Associates; 2000: 157-245.Continued on page 8TREATMENTS OF IBS, CONT.Page 8 Digest(37) Creed F, Fernandes L, Guthrie E, Palmer S, Ratcliffe J, Read N et al. The cost-effectiveness of psychotherapy and paroxetinefor severe irritable bowel syndrome. Gastroenterol. 2003;124 :303-17.(38) Toner BB, Segal ZV, Emmott SD, Myran D. Cognitive-behavioral treatment of irritable bowel syndrome: The brain-gutconnection. London/New York: Guilford Press; 2000.(39) Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable bowelsyndrome. Lancet. 1984;2:1232-33.(40) Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel syndrome: A large-scale audit of a clinicalservice with examination of factors influencing responsiveness. The American Journal of Gastroenterology. 2002;97:954-61.(41) Calvert EL, Houghton LA, Cooper P, Morris J, Whorwell PJ. Long-term improvement in functional dyspepsia usinghypnotherapy. Gastroenterol. 2002;123:1778-85.(42) Blanchard EB, Schwartz SP, Neff DF, Gerardi MA. Prediction of outcome from the self-regulatory treatment of irritable bowelsyndrome. Behav Res Ther. 1988;26:187-90.(43) Guthrie E, Creed F, Dawson D, Tomenson B. A controlled trial of psychological treatment for the irritable bowel syndrome.Gastroenterol. 1991;100:450-457.(44) Jackson JL, Oï¿½Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders withanti- depressants: A meta-analysis. Am J Med. 2000;108:65-72.(45) Drossman DA. Review Article: An Integrated Approach to the Irritable Bowel Syndrome.Aliment Pharmacol Ther. 1999;13 (Suppl. 2):3-14.Continued from page 7TREATMENTS OF IBS, CONT.ANNOUNCING: A SYMPOSIUM FOR PATIENTSUnderstanding Irritable Bowel Syndrome and Other Gastrointestinal DisordersSaturday, June 12th , 2004This is a symposium for patients and the general public, will be held on Saturday,June 12th. It will provide an opportunity to learn about diagnosis, tests, and treatmentoptions of the disorder, explore the role of diet, nutrition, gender, and hormones onIBS , and understand the pain of IBS through cutting edge research on brain imaging.Attendees will acquire a set of tools for symptom management and explore thebenefits of alternative treatments, as well as learn about other available resources.Participants will also have the opportunity to select a break out session most relatedto their symptoms, which will be facilitated by Center faculty.The Symposia will be held at the William and Ida Friday Center at UNC, ChapelHill, North Carolina. The agenda and further information can be found our the web site at www.med.unc.edu/ibs.Registrations forms can be printed from the web site or mailed in with the symposium brochure. Either way the deadlinefor registration is June 1, 2004.Enter the chatroom from ourCenter web page: http://www.med.unc.edu/ibs We ask that all questions be related tothe topic under discussionrather than on personal medical conditions.CHAT WITH THE EXPERTS FROM HOME!NICHOLAS SHAHEEN, MDGERD AND HEARTBURNAPRIL 13TH FROM 8-10 PMDigest Page 9Continued on page 10DOES DESIPRAMINE DOSE MATTERIN THE TREATMENT OF FUNCTIONAL BOWEL DISORDERSAlbena Halpert, MDINTRODUCTIONTricyclic antidepressants (TCA) are commonly used outside of psychiatry practice inthe treatment of various chronic pain syndromes including post herpetic and otherneuralgias, fibromyalgia, headaches, and functional bowel disorders (FBD)(1-7). Whentreating major depression, blood levels of TCA are used to adjust dosage and monitorfor potential toxicity. The efficacy of TCA in the treatment of FBD has been shown byseveral studies in the past(7-9), but all of which have had design limitations. Recently, awell-designed, multi-center placebo-controlled study (University of North Carolina,Chapel Hill, N.C. & University of Toronto, Canada) using 50-150 mg. day of thetricyclic antidepressant (TCA) Desipramine( DES,) , was conducted among womenwith moderate to severe FBD(10). This study demonstrated that Desipramine wasstatistically and clinically effective in patients included in the per protocol analysis (i.e.subjects who completed the treatment). The presence of detectable Desipramine bloodlevels was associated with a good clinical response(10-11). These findings providefurther supportive evidence that Desipramine (DES) may be effective for patients with FBD provided they stay on themedication.When Desipramine is used in higher ï¿½psychiatricï¿½ dose ranges (150-300 mg day) there is a linear relationship between theplasma concentration and therapeutic response in the majority of patients and the lower limit of response is at a plasma levelof 116 ng ml(12). However, for the treatment of FBD, Desipramine is used in much lower doses, usually ranging between 25-150 mg day. It is not known whether Desipramine blood levels are helpful in predicting the clinical response in FBD whentypically lower dosages are used.AIMThe aim of this study was to determine, when treating women with moderate to severe FBD with DES, whether there is acorrelation between:1) Desipramine dose and blood level,2) Desipramine dose and response to treatment and3) Desipramine blood levels and response to treatment.A significant association would mean that clinicians can use Desipramine blood levels to adjust Desipramine dose to atherapeutic plasma level range when treating FBD. This will be similar to psychiatry practice. However, no correlationbetween dose of DES and clinical response would support the clinical experience that lower dosages can still be effective intreating FBD.METHODSThis study was a per protocol sub analysis of a study on Cognitive Behavioral Therapy and Desipramine vs. Placebo forModerate to Severe Functional Bowel Disorders. Females , 18-70 years old , with a diagnosis of FBD (IBS, painful constipation,CFAP (chronic functional abdominal pain), unspecified FBD with moderate (Functional Bowel Disease Severity index (FBDI)37-110) to severe symptoms ( FBDSI 110) present for more than 2 days week for more than 6 months, and at least a 7thgrade reading level were included.In the pretreatment period, subjectï¿½s symptoms were assessed via multiple questionnaires - Rome II Criteria( FBDSI(13)McGill Pain Questionnaire(14) Stool Frequency and consistency(15), Global Well-Being(16), IBS- Quality of life (IBS-QOL)(17-18) and other psychosocial and physiological assessment questionnaires .Page 10 DigestDESIPRAMINE DOSAGE IN FUNCTIONAL GI TREATMENTS, CONT. Continued from page 9Desipramine or placebo were started at 1 pill day (50 mg Desipramine) and increased by one pill per week, up to 3 pills dayfor weeks 2-12 and if tolerated (up to 150 mg day for Desipramine and 3 placebo pills for placebo). Subjects were assessedweekly by the study coordinator and number of pills adjusted for side effects and counted to assess compliance. Desipramineplasma levels were taken at week 6 and outcome assessment was done at week 12. The primary outcome was a compositeScore consisting of four components: Satisfaction Scale, Global Well-Being, IBS-QOL (IBS related quality of life), andMcGill Pain Questionnaire.ANALYSISThe DES average daily dose from weeks 5 and 6 were correlated with the DES blood levels (drawn at week 6) Blood levelvalues were standardized between sites and then readjusted to Chapel Hill values so both sides could be combined for theanalysis. Spearman correlations were used to correlate DES blood levels and dose to the composite score and DES bloodlevels to dose.RESULTS97 subjects were included in the per protocol analysis of the medication arm (Desipramine vs. 55 of Placebo of the originalstudy(10). The majority of the participants were Caucasian women in their late 30ï¿½s, with an average of 15 years formaleducation, and married or cohabiting. Their clinical diagnosis was predominantly IBS (80%) with 2/3 of the sample havingmoderate disease severity with moderate abdominal pain (38.5 on VAS) and an average of 2 bowel movements per day. Ahistory of physical or sexual abuse was reported by 57% of the participants.The mean number of pills taken over the 12 week treatment period for DES was 2.2 + 0.60 and PLA 2.4 + 0.35 over the 12-week treatment period. There was a correlation between DES blood levels at week 6 and Desipramine dose during weeks1-12 (r=0.28, p 0.05) ( Figure 1 ). There was no association between DES dose for weeks 1-12 and the composite scoreat week 12 (Figure 2a). There was also no correlation between Desipramine blood levels at week 6 and the compositeoutcome score (Figure 2b). These findings held for the DES group after those with non-detectable blood levels were excluded.There was no correlation between number of placebo pills taken with the composite score or blood levels (non-detectable).FIGURE 1: Scatter Plot of Log of Desipramine Blood Levels (Week 6) and Dose (Week 5 & 6 Mean)Blood level was standardized between sites and then re-transformed to US levels so that a natural log could be calculated.Negative re-transformed values were assigned a value of 1. Spearman Correlation coefficient r=0.20, p=.07Digest Page 11DESIPRAMINE DOSAGE IN FUNCTIONAL GI TREATMENTS, CONT.FIGURE 2a: Scatter Plot of Mean Dose (12 week) and Composite ScoreSpearman Correlation coefficient r=-0.04, p=0.7FIGURE 2b: Scatter Plot of Log of Desipramine Blood Levels (Week 6) and Composite ScoreContinued on page 12Blood level was standardized between sites and then re-transformed to US levels. Negative re-tranformed values wereassigned a value of 1 so that a natural log could be calculated. Spearman Correlation coefficient r=0, p=0.13DISCUSSIONTCAï¿½s have been widely used in the treatment of Functional Bowel Disorders (FBD), and clinical experience suggests thatdoses smaller than those used in psychiatry are effective when treating FBD. Within the psychiatry literature, a dose responserelationship for the TCA has been established and TCA levels are used to adjust dosages and monitor for side effects(19-21).Page 12 DigestThere have been no studies examining the doseï¿½response relationship of TCA in FBD where lower dosages are traditionallyused. However, , it is not known whether high doses of TCA are more effective than low doses, or if monitoring TCA bloodlevels is useful in assessing clinical response.To address this question, we did a sub analysis of the medication arm (Desipramine vs. placebo) of our multi-center study offemale subjects with moderate to severe FBD. We found, that there is a modest correlation between DES plasma levels anddose. However, we found no correlation between DES dose or plasma levels and the composite score clinical response. Thisfinding indicates that higher dosages or higher blood levels are not predictive of a better clinical response, and supports theclinical experience that lower doses of TCA may be sufficient to treat FBD. Themain study also demonstrated that detectable blood levels were associatedwith improved response to treatment(10). Thus it seems that patientï¿½s adherenceto treatment is a major factor in determining treatment response.Therefore, it is very important that the patient attitudes towards taking DES areassessed prior to initiating the therapy (understanding of the role ofantidepressants, including past experiences, misconceptions or perceivedstigma) so proper education to increase compliance is provided if necessary.Compliance with TCAï¿½s may be enhanced by providing an explanation ofthe mechanisms of action of antidepressants in FBD (e.g., as differentfrom mood alteration), an explanation of delayed onset of action and recovery from possible side effects in 1-2 weeks. In ourclinical experience, an early follow up (with a phone call in the first week of treatment done by the physician or physicianextender) is vital in improving adherence. Notably a detectable Desipramine blood level regardless of the value may helpassess adherence to treatment in selected cases and when present, increases the likelihood of a clinical response. Finding anon-detectable blood level, signifying nonadherence, provides an opportunity to address the reasons for it, provide educationand modify treatment if needed.Our study has several limitations. It is a post hoc sub-analysis, the results of which can only provide preliminary information tobe later confirmed by prospective testing apply specifically to females with moderate to severe FBD and cannot be generalizedfor males or patients with milder symptom severity. Both study centers were academic institutions comprised of study subjectswho may be potentially different from those seen in private practices. The dose of DES was limited to a maximum 150 mgday; therefore, the design of the study does not allow us to determine if there is a dose ï¿½ response relationship when DES isused for the treatment of FBD in higher ï¿½psychiatricï¿½ or lower doses. Lastly, the correlation between DES blood levels (week6) and outcome composite score (week 12) could have been potentially different if DES blood levels were obtained at thetime of the outcome score assessment (week 12).CONCLUSIONFor female patients with moderate to severe FBD treated with Desipramine, there is a modest correlation between DES doseand plasma level. However, the clinical response is not determined by the DES dose or plasma level. This supports the existingwisdom that patients with FBD may respond even to low doses (e.g., 50 mg or less) of DES. The response to treatment islargely dependent upon adherence to treatment. This project was supported by NIH Grant R01DK49334.References:1. Maxton, D. G. and Whorwell, P. J. Use of Medical Resources and Attitudes to Health Care of Patients With ï¿½Chronic AbdominalPainï¿½. Br J Med Econ 1992;2:75-9.2. Onghena, P. and Houdenhove, B. V. Antidepressant-Induced Analgesia in Chronic Non-Malignant Pain: A Meta-Analysis of 39Placebo-Controlled Studies. Pain 1992;49:205-19.3. Magni, G. The Use of Antidepressants in the Treatment of Chronic Pain: A Review of the Current Evidence. Drugs 1991;42(5):730-48.4. Pilowsky, I. and Barrow, C. G. A Controlled Study of Psychotherapy and Amitriptyline Used Individually and in Combinationin the Treatment of Chronic Intractable, ï¿½Psychogenicï¿½ Pain. Pain 1990;40:3-19.5. Egbunike, I. G. and Chaffee, B. J. Antidepressants in the Management of Chronic Pain Syndromes


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