Irritable bowel syndrome (IBS) is a common functional. Self-Management for Women With Irritable Bowel Syndrome

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2: Self-Management for Women With Irritable Bowel Syndrome MARGARET M. HEITKEMPER,* MONICA E. JARRETT,* RONA L. LEVY, KEVIN C. CAIN, ROBERT L. BURR,* ANDREW FELD, PAM BARNEY,* and PAM WEISMAN* *Department of Biobehavioral Nursing and Health Systems; School of Social Work; Department of Biostatistics and Office of Nursing Research; and Division of Gastroenterology, University of Washington, Seattle, Washington Background & Aims: A randomized clinical trial was used to test the effectiveness of an 8-session multicomponent program (Comprehensive) compared to a Brief (single session) version and Usual Care for women with irritable bowel syndrome. Methods: Menstruating women, ages years, were recruited from a health maintenance organization as well as community advertisements. Psychiatric nurse practitioners delivered both programs. The primary outcomes were improved symptoms, psychological distress, health-related quality of life, and indicators of stress-related hormones. Outcome indicators were measured at 3 points: (1) immediately after the Comprehensive program or 9 weeks after entry into the Usual Care and Brief Self-Management groups, (2) at 6 months, and (3) at 12 months. Results: Compared to Usual Care, women in the Comprehensive program had reduced gastrointestinal symptoms, psychological distress indicators, interruptions in activities because of symptoms, and enhanced quality of life that persisted at the 12-month follow-up evaluation. Women in the Brief group also demonstrated statistically significant improvements in quality of life and smaller nonsignificant improvements in other outcome variables than observed in the Comprehensive group. There were no group differences in urine catecholamines and cortisol levels. Conclusions: A comprehensive self-management program is an important therapy approach for women with irritable bowel syndrome. The Brief 1-session version is also moderately helpful for some women with IBS. Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder that affects 10% 17% of women in industrialized nations. 1,2 The costs of IBS are high, and in 2000, the direct and indirect costs of diagnosis and symptom management of IBS were estimated to be $1.66 billion, making it not only costly to the individual but also to the health care system. 3 9 Leong et al. 9 found that the total health care expenditures per year for the individual with IBS were $4527 compared with $3276 dollars for an age- and gendermatched control subject in Excess surgeries are among the health care events related to an IBS diagnosis. 10 Although the exact etiology of IBS remains to be determined, several triggering factors have been associated with the onset of symptoms in patients with IBS. These factors include infection/inflammation, diet, and stress (e.g., stressful events, psychological distress). Such events might contribute to the waxing and waning of symptoms over many years. Social learning, stress, and distress are likely contributors to the development and maintenance of IBS symptoms A number of nonpharmacologic interventions involving changes in cognition and/or behavior have been tested for persons with IBS during the last 20 years These interventions are aimed at decreasing the severity and frequency of distressing symptoms, increasing role function, and enhancing quality of life, while decreasing health care utilization costs. Examples of these interventions include providing education and reassurance, supportive psychotherapy, 20,21 assertiveness training, relaxation training, 15,22,23 cognitive behavior therapy, 16,17,19 hypnotherapy, 24 meditation, and dietary restrictions. 25 A limited number of studies have also used multicomponent approaches to the management of IBS. 16,17 Measurements of physiologic indicators such as catecholamines and cortisol levels have been measured in descriptive studies of patients with IBS There is limited evidence from other subject populations (e.g., athletes, human immunodeficiency virus positive men) that cognitive behavioral therapy reduces both hypothalamic-pituitary-adrenal activity and sympathetic nervous system activation as exemplified by reductions in cortisol and catecholamine levels, respectively It has been suggested that stress activation of the hypothalamicpituitary-adrenal axis might play a role in the pathogen- Abbreviations used in this paper: BDQ, Bowel Disease Questionnaire; CSFBD, Cognitive Scale for Functional Bowel Disorders; GI, gastrointestinal; GSI, Global Severity Index of the Symptom Checklist- 90R; IBS, irritable bowel syndrome; IBSQOL, Irritable Bowel Syndrome Quality of Life questionnaire; SD, standard deviation; UC, Usual Care by the American Gastroenterological Association /04/$30.00 PII: /S (04)

2 586 HEITKEMPER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 esis and/or perpetuation of IBS symptoms. 34 To date, no studies have examined whether non-drug therapies reduce physiologic arousal in conjunction with GI symptoms and quality of life (QOL) measures. This 3-arm randomized clinical trial tested the efficacy of a multicomponent, nonpharmacologic treatment approach for IBS and included indicators of physiologic arousal. The 4 key components of the approach were education and reassurance, diet, relaxation, and cognitive behavior therapy. One group received the treatment over 8 sessions (Comprehensive), and a second group received a condensed version of the therapy in 1 session (Brief), whereas the control group received usual care (UC). We hypothesized that those in the Comprehensive program would exhibit decreased GI symptoms and psychological distress, enhanced QOL, and reduced urine catecholamine and cortisol levels as compared to those in the Brief and UC groups, and subjects in the Brief program would show some improvement but not as much as those in the Comprehensive program. Materials and Methods Recruitment and Baseline Assessment Phase Table 1. Major Themes of the Treatment Sessions Comprehensive treatment Session 1: Introduction and review baseline assessment Session 2: Physiologic arousal and abdominal breathing Session 3: Diet and automatic thoughts Session 4: Automatic thoughts and active progressive muscle relaxation Session 5: Cognitive restructuring and mini-relaxation Session 6: Targeted problem-solving skills and passive relaxation Session 7: Consolidate strategies and review goals, plan, and obstacles Session 8: Maintenance and termination Brief treatment Session included review baseline data and orientation to diet, relaxation, and cognitive-behavioral strategies in the workbook. Examples of strategies for each topic were provided. Women with IBS were recruited through community advertisements and a local health maintenance organization (Group Health Cooperative of Puget Sound). All women who were enrolled were years of age, were menstruating, had a prior diagnosis of IBS by a health care professional, and reported current symptoms during the prior month consistent with the Rome I criteria. 35 No additional diagnostic procedures were conducted by study personnel. Women were excluded if they had a history of GI pathology (e.g., inflammatory bowel disease), major GI surgery (e.g., bowel resection but not appendectomy), renal or gynecologic pathology (e.g., endometriosis) that might result in IBS-like symptoms, taking specific medications for IBS 3 or more times a week (e.g., laxatives other than fiber), tricyclic antidepressants, or lithium. Women taking oral contraceptives and selective serotonin reuptake inhibitors were not excluded. Before recruitment, approval was obtained from the human subjects institutional review board. At the beginning of the baseline assessment phase women gave informed written consent, completed questionnaires, and were oriented to the study procedures during an in-person interview. The women completed a symptom diary each evening for approximately 5 weeks to capture 1 menstrual cycle. They also collected urine samples from the first void of the morning at 5 occasions across the menstrual cycle, which were assayed for norepinephrine, epinephrine, and cortisol levels. To match the collection of urine samples to the menstrual cycle, ovulation was determined by measuring luteinizing hormone surge by using ClearPlan home testing kits (Unipath Diagnostics, Inc., Waltham, MA). Study Design This 3-arm randomized controlled trial compared women receiving the multicomponent intervention during a period of 8 weeks (Comprehensive) to women receiving a condensed 1-session version (Brief) to women receiving Usual Care (UC). The treatment phase was followed by 3 posttreatment assessments. The first assessment was at 1 week after treatment in the Comprehensive group or a comparable time interval for the Brief and UC groups and again at 6 and 12 months after baseline. All 3 groups completed questionnaires, kept a symptom diary, and also collected urine samples across 1 menstrual cycle or a comparable period. After completion of the baseline assessment, women were randomized to the Comprehensive, Brief, or UC group. A randomized block design with block size randomly varying from 3 to 9 was used for equal allocation to groups. Comprehensive Protocol Women in the Comprehensive group received 8 weekly 1-hour individual sessions (Table 1) with a research nurse (trained psychiatric nurse practitioner). Each session included a review of homework assignments from the previous session, new strategies were presented, and homework based on the content of the session was assigned. Adherence strategies 36 were integrated throughout the sessions (e.g., breaking tasks into small pieces, beginning with assignments that allow participants to succeed, reinforcement, rehearsal of assignments). Assignments included symptom monitoring and other homework specific to the intervention. At the last session, each woman made a plan specific for her symptom management needs that included selected effective components of the program. The intervention had the following 4 components. Education and reassurance. In addition to defining IBS and providing reassurance that IBS is not life-threatening,

3 July 2004 SELF-MANAGEMENT FOR WOMEN WITH IBS 587 this content also included a discussion of signs and symptoms for which it is important to consult a health care provider. Dietary counseling. The participants were first instructed on healthy eating strategies; for example, participants were encouraged to eat small frequent meals/snacks and slowly increase their fiber intake to g/day. In addition, participants were taught to recognize foods that were associated with their symptoms (e.g., coffee, fatty foods, raw vegetables) as well as situations when select foods were not tolerated (e.g., a time of high work stress). 37,38 Homework included keeping a food diary to identify when they ate, what they ate, and what was happening in their environment. Relaxation training. Abdominal breathing, progressive muscle relaxation, 39 and mini-relaxation 40 were taught. Homework included abdominal breathing at least 3 times a day (e.g., before each meal), use of the relaxation audiotape 3 times a week, and daily mini-relaxation with tension as a cue. Cognitive-behavioral strategies. Specific cognitivebehavioral strategies were selected on the basis of individualized assessment. These included anger management, cognitive restructuring, assertiveness and social skills training, and social support. Homework included writing down their automatic thoughts and identifying and using alternative thoughts. 41,42 Brief Protocol The Brief program attempted to cover the same material as the Comprehensive program, but it was condensed into one 90-minute session. Each participant was given the same workbook and relaxation tape; the research nurse discussed how dietary changes, relaxation exercises, and cognitive strategies could be integrated into her lifestyle. The women in the Brief group were not contacted again until the first follow-up assessment 9 weeks later. Usual Care Protocol Women in the UC group were notified that they would not receive either of the active treatments, but they should continue with whatever treatment was recommended or provided by their usual health care provider. They were told that they would be contacted at the post-treatment follow-up visits. At the end of the study they were offered the Brief session. Primary Outcomes Quality of life. The Irritable Bowel Syndrome Quality of Life questionnaire (IBSQOL) is composed of 30 items measuring 9 dimensions of health: emotional, mental health, sleep, energy, physical functioning, eating/diet, social role, role physical, and sexual relationships. 43 The questionnaire uses a 4-week recall period; items are rated on 5- or 6-point Likert scale. For example, questions such as How often did your IBS make you feel fed up or frustrated or feel uncomfortable during social or family activities are rated 1 for always, 2 for often, 3 for sometimes, 4 for seldom, and 5 for never. The dimensions are transformed to a standard scale. Acceptable content and construct validity and reliability have been reported for the IBSQOL. 44 Internal consistency (Cronbach alpha) of the total scale score in this sample was 0.94, and for the subscale scores ranged from except for the eating/diet subscale, which was only A higher dimension score means better quality of life. A total IBSQOL score, computed by averaging all but 2 of the dimensions, was used as a primary outcome variable, and the individual dimensions were considered secondary outcomes. The dimension of eating/diet was omitted from the total score because as part of Comprehensive and Brief programs, subjects are encouraged to avoid foods that cause problems for them, and 1 of the 3 items in the eating/diet dimension is avoiding foods. The dimension of sexual relations was left out of the total score because it was missing for a large fraction of the sample because of lack of sexual activity. However, these 2 subscales were presented as secondary outcomes, even though they were left out of the total score. Psychological distress. The Symptom Checklist- 90R is a 90-item checklist that includes symptoms in 9 areas: somatization, interpersonal sensitivity, obsessive-compulsive, hostility, depression, anxiety, paranoid ideation, psychoticism, and phobic anxiety. 45,46 The respondent is asked to consider how distressed or bothered she felt by the items during the past 7 days and rate them as 0, not at all; 1, a little bit; 2, moderately; 3, quite a bit; and 4, extremely. For reliability and validity information see Derogatis. 46 For the purposes of analysis the Global Severity Index (GSI), computed as the mean of all 90 items, is used as a primary outcome variable. The internal consistency of the GSI in this sample was The published value of the mean for a large normative sample of women (N 480) is 0.26, and the mean plus 1 standard deviation (SD) is Cognitive Scale for Functional Bowel Disorders (CSFBD). This scale is composed of 25 statements (e.g., I cannot function normally when I get bowel symptoms; Feeling guilty if I nurture myself) that are rated as 1 for strongly disagree to 4 for neutral to 7 for strongly agree. 47 Findings indicate that the scale has high content, concurrent and convergent validity, reliability, and minimal social desirability contamination. Internal consistency of the scale for this sample was The higher the mean score was, the greater was the agreement with negative cognitions. Daily GI symptoms. GI symptoms recorded on the daily diary included the 5 lower GI symptoms of abdominal pain, bloating, intestinal gas, constipation, and diarrhea, which were rated from 0, not present; 1, minimal; 2, mild; 3, moderate; to 4, extreme. In a prior study the mean reliability of symptom items across 2 menstrual cycles and 3 phases was Symptom severity was summarized across all days for each person as the percent of days on which symptoms were at least 3, moderate. Secondary Outcomes Additional symptoms. The Bowel Disease Questionnaire (BDQ) is a 97-item questionnaire developed by Talley et al. 49,50 that covers GI symptoms, health habits, psychosomatic

4 588 HEITKEMPER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 symptoms, and GI screening tests. BDQ has acceptable discriminant validity and test-retest reliability. Several categorical items from the BDQ are used as outcome variables in the current analysis: usual bowel pattern (normal, constipation, diarrhea), and alternating constipation and diarrhea, activities interrupted by pain (yes, no), activities interrupted by bowel problems (yes, no), abdominal pain that is severe or very severe, diarrhea/constipation that is severe or very severe, bloating with visible abdominal swelling (yes, no), and days missed from work (none, 1 2 times, 3 5 times, 6 10 times, more than 10 times). In the daily diary, stools were rated for consistency from 0 9 by using words and images (i.e., no bowel movement, hard defined as hard or hard and dry and loose as loose, very loose-semiliquid, mushy, liquid-creamy, and watery). Physiologic arousal measures. Urine catecholamine levels (norepinephrine and epinephrine) were measured by high-performance liquid chromatography. The intra-assay variation is 3.9%, and the inter-assay variation is 6.7%. Urine cortisol levels were assayed as per directions of Coat-A-Count Cortisol Kit (Diagnostic Products Corporation, Los Angeles, CA). The intra-assay variation is 4.6%, and the inter-assay variation is 8.4%. Details of the assay procedures have been reported previously. 51 Demographic Characteristics All participants were asked about their age, marital status, formal educational achievements, ethnicity, occupation, and personal and family income levels. Data Analysis 2 and t tests were used to test whether the 12 subjects who were lost to follow-up before the first outcome time point differed from the subjects who did provide at least some follow-up data. Continuous outcome variables were tested with repeated measures analysis of covariance, with 3 outcome time points and by using the baseline value of that outcome variable plus baseline GSI and abdominal pain as covariates. Baseline GSI was used as a covariate in all analyses because it is significantly correlated with most outcome variables, and baseline abdominal pain was used as a covariate because it differed significantly across the 3 groups. A significant P value from the repeated measures analysis of covariance indicates that the 3 groups differed somehow at least at 1 time point. To further elucidate how the groups differ, analysis of covariance controlling for the covariates described above was used at each time point, and contrasts within this analysis were tested within this model to determine which of the 3 treatment groups differed from which. A Bonferroni adjustment was used to account for the 3 pair-wise comparisons. Binary outcome variables from all 3 outcome time points were analyzed by using logistic regression and generalized estimating equations to account for the correlation among the 3 time points. The same covariates described above were used as control variables. Logistic regression was then used to test for pair-wise differences between groups at each time point by using a Bonferroni adjustment. An intent-to-treat approach was followed in the conduct of the study and analysis. Every effort was made to get follow-up data on all subjects once they were randomized, even those who did not complete the intervention to which they were assigned. Subjects were not excluded from analysis because of failure to attend all therapy sessions. However, despite these efforts, some subjects were lost to follow-up and did not provide data after a certain point. In addition, some subjects provided only partial data at some time points. The analysis results presented in this article were based on a complete-case analysis using only subjects with no missing data on any of the variables used in an analysis. This approach might be biased unless data are missing at random, meaning the probability of being missing is unrelated to the value the variable would have had if it were not missing. Three approaches were used to address this possible bias. First, all analyses controlled for the baseline value of the outcome variable being analyzed as well as baseline GSI and abdominal pain. This weakened the requirement for unbiasedness to being missing at random conditional on these baseline values, which might be a more reasonable assumption. In addition to the analyses presented, additional analyses were done in which missing values were imputed on the basis of a regression model, and the results were compared to those presented. The regression model did not include treatment group as a predictor, so these imputations are conservative in that they were done under the null hypothesis of no treatment effects. Finally, a sensitivity analysis was done to see how bad the bias in subjects lost to follow-up would have to be before the results became nonsignificant. This was done in a very conservative way, assuming that if the missing data had been observed, all of the subjects in the 2 intervention groups who were lost to follow-up would have had outcomes X points worse than predicted by the regression model, and those in the UC group who were lost to follow-up would have had outcomes X points better than predicted, where the value X was varied to see how large it had to be before the P value became nonsignificant. Results Baseline Characteristics Of the 144 women randomized to the 3 study arms, 12 women (3 UC, 1 Brief, 8 Comprehensive) were lost to follow-up before the 9-week assessment, and 132 provided at least some follow-up data. Four of the women in the Comprehensive group were lost to follow-up before attending any treatment sessions; 2 were lost after attending a few sessions, and 2 were lost after completing all treatment sessions. Reasons for loss to follow-up were: moved out of state (3 subjects in UC, 1 in Brief, and 2 in Comprehensive); too busy or refused (3 in Comprehensive); and unable to contact or did not return calls (3 in Comprehensive). When demographic

5 July 2004 SELF-MANAGEMENT FOR WOMEN WITH IBS 589 Table 2. Baseline Characteristics of Sample Variable UC (N 44) Brief (N 48) Comprehensive (N 40) P value a Demographics Age, mean (yr) (SD) 33 (8) 33 (7) 33 (8) Race, white 91% 92% 82% Married 52% 67% 60% Education, bachelors degree or above 64% 54% 55% Income, $40,000/yr 48% 52% 52% Professional job 43% 27% 42% Predominant bowel pattern Normal 21% 6% 18% Constipation 14% 15% 18% Diarrhea 7% 31% 10% Alternating 57% 48% 55% History of mental health disorders Somatization 7% 6% 3% Depression 40% 59% 42% Generalized anxiety 26% 24% 19% NOTE. The results are presented as column percents. a P value for one-way analysis of variance (age) or Pearson 2. characteristics were compared, those without follow-up data were less likely (P 0.12) to be married or partnered (33%) as compared to those with follow-up data (60%) and less likely to have family income $40,000 per year (25% compared to 51%; P 0.13). Demographics, bowel patterns, and mental health disorders of those who provided follow-up data are shown in Table 2. There were no significant group differences in demographic characteristics. At baseline, about half of women reported alternating stool characteristics, and about a third believed they were either constipationprone (UC, 14%; Brief, 15%; Comprehensive, 18%) or diarrhea-prone (UC, 7%; Brief, 31%; Comprehensive, 10%) on the BDQ. Note that as a result of chance, more diarrhea-prone women were randomized to the Brief group than to the other 2 groups. This discrepancy was further exacerbated by the fact that among the 27 women with diarrhea-predominant IBS, none of the 15 women who were randomized to Brief dropped out before the 9-week follow-up, whereas 1 of 4 women randomized to UC and 4 of 8 randomized to Comprehensive dropped out before providing any follow-up data. This difference in predominant bowel pattern among the 3 treatment groups is statistically significant (P.03). Nearly half of the subjects had a history of depression, and nearly a quarter had a history of general anxiety. Baseline means or percents of outcome variables are shown in Tables 3 through 7. None of these differed significantly across the 3 groups, with the exception of the percents with severe abdominal pain (30% in UC, 25% in Brief, 50% in Comprehensive). Because of baseline differences, group differences on all variables at 6 and 12 months were tested controlling for baseline value of abdominal pain. Primary Outcomes Baseline and change scores for the primary outcome variables are shown in Table 3. The P values in the right-hand column are based on repeated measures analyses of covariance to test the null hypothesis that there are no differences among the 3 treatment groups at any of the 3 outcome time points. Six of the 8 primary outcome variables showed statistically significant treatment effects, with Comprehensive being significantly better than UC for 5 outcomes. The remaining 2 outcome variables showed a trend in the same direction that was not quite statistically significant. In the Comprehensive group, 4 of the 5 symptoms from the daily diary were reduced to below 50% of baseline at 6 and 12 months; the exception was diarrhea, which started out very low at baseline and only showed a reduction at 12 months. Taken as a whole, these results provided strong evidence for the efficacy of the Comprehensive intervention. The results for the Brief group were mixed. For most outcome variables, means in the Brief group were between the Comprehensive or UC groups and were not significantly different from either the Comprehensive or UC groups. The exceptions were QOL, for which the Brief group was significantly better than UC and almost as good as Comprehensive, and CSFBD and constipation, in which the Brief group was not much better than UC and was significantly worse than Comprehensive. Thus, the Brief group showed some treatment effect, although not as strong as in the Comprehensive group. Analyses in which missing values were replaced with imputed values gave results very similar to the completecase results shown in Table 3. P values were generally a

6 590 HEITKEMPER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 Table 3. Baseline and Change Scores on the Primary Outcome Variables by Treatment Group Variable (range of possible values) Mean (SD) at baseline Mean (SD) change from baseline 9 wk 6 mo 12 mo P value a QOL-total score (0% 100%) UC 74.5 (18.3) 1.7 (13.2) 2.7 (16.0) 4.6 (14.8) b,c Brief 73.3 (15.3) 5.8 (13.4) 8.5 (11.8) 11.7 (14.1) d Comprehensive 74.6 (14.8) 10.6 (12.4) c 12.8 (11.7) c 12.2 (11.1) e SCL-90R, GSI (0 4) UC 0.56 (0.40) 0.06 (0.28) 0.00 (0.21) 0.08 (0.28) e Brief 0.66 (0.47) 0.06 (0.28) 0.11 (0.29) 0.13 (0.28) Comprehensive 0.56 (0.47) 0.14 (0.30) e 0.14 (0.29) e 0.15 (0.33) CSFBD (1 7) UC 4.18 (1.17) 0.00 (0.69) 0.31 (0.86) 0.50 (0.91) c,f Brief 4.19 (1.05) 0.47 (0.67) b 0.55 (0.67) 0.58 (0.73) Comprehensive 4.23 (1.17) 1.00 (0.87) c,f 0.95 (1.05) c 1.14 (0.79) c,f Diary: abdominal pain (0% 100%) UC 14.9 (18.3) 5.4 (12.9) 2.3 (14.1) 4.9 (11.9) Brief 15.8 (13.3) 5.9 (13.5) 8.1 (11.6) d 8.6 (13.1) Comprehensive 20.5 (20.8) 10.4 (18.2) 12.7 (17.9) c 14.8 (17.4) Diary: bloating (0% 100%) UC 15.0 (23.4) 1.0 (12.6) 2.9 (9.1) 2.2 (12.4) c Brief 15.4 (18.4) 4.3 (21.1) 4.1 (17.7) 1.6 (15.1) Comprehensive 22.7 (26.3) 15.6 (22.1) e 15.9 (26.2) 20.7 (25.7) e,f Diary: intestinal gas (0% 100%) UC 28.4 (30.6) 6.8 (19.7) 6.2 (19.5) 9.0 (16.7) e Brief 26.2 (24.2) 15.5 (22.0) 12.1 (21.7) 9.7 (26.1) Comprehensive 32.5 (30.8) 20.3 (26.1) c 19.2 (30.1) e 25.1 (26.7) Diary: constipation (0% 100%) UC 13.0 (22.0) 2.5 (18.1) 5.7 (19.7) 7.0 (20.7) f Brief 10.2 (15.9) 4.2 (15.0) 3.9 (15.4) 1.8 (26.3) Comprehensive 19.9 (25.6) 14.9 (22.7) c 14.5 (21.1) 15.4 (19.0) Diary: diarrhea (0% 100%) UC 6.4 (8.0) 0.6 (6.5) 0.9 (8.5) 0.4 (5.7) Brief 8.4 (9.8) 1.8 (6.1) 2.3 (7.0) 3.4 (7.7) Comprehensive 6.6 (7.9) 0.1 (10.0) 0.7 (9.3) 3.8 (6.6) NOTE. Sample sizes for UC, Brief, Comprehensive, respectively, are 44, 48, 40 at baseline; 42, 41, 38 at 9 weeks; 40, 44, 36 at 6 months; 39, 43, 35 at 12 months. a P value from repeated measures analysis of variance for testing the null hypothesis that the mean is the same in all 3 treatment groups at all 3 time points, adjusting for the baseline value of the variable and for GSI and abdominal pain severity at baseline. b Brief significantly better than UC, P c Comprehensive significantly better than UC, P d Brief significantly better than UC, P e Comprehensive significantly better than UC, P f Comprehensive significantly better than Brief, P little more significant, but the means were not very different from those in Table 3. Sensitivity analyses on the magnitude of differential bias because of loss to follow-up showed that the bias needs to be fairly large before it cancels out the treatment effect. For example, if the imputed values of QOL for all subjects lost to follow-up in the treatment groups are reduced by 11 units and the imputed values for all subjects lost to follow-up in the UC group are increased by 11 units, the P value for testing treatment effectiveness is still significant. However, if the assumed bias for QOL is 12 units, then the P value becomes nonsignificant. An assumed bias for QOL of 24 units makes the effect size go to 0. The assumed biases needed to make P values nonsignificant are.08, 1.0, 4, 5, and 4 for GSI, CSFBD, abdominal pain, bloating, and intestinal gas, respectively. Secondary Outcomes Table 4 shows results for the 9 subscales of IBS- QOL. Six of the subscales showed Comprehensive better than UC, but only Energy and Social Role showed evidence of Brief being better than UC. Brief appears to be better than UC on Physical Function, but this was not significant after controlling for baseline, because the baseline mean was much lower in the Brief than in the UC or Comprehensive group. Table 5 shows changes over time in categorical outcome variables from the BDQ. All of these showed substantial improvement in

7 July 2004 SELF-MANAGEMENT FOR WOMEN WITH IBS 591 Table 4. Baseline and Change Scores on Subscales of Quality of Life by Treatment Group Variable Mean (SD) at baseline Mean (SD) change from baseline 9 wk 6 mo 12 mo P value a QOL-Emotional UC 61.8 (25.1) 0.7 (20.7) 4.5 (21.2) 7.0 (22.9) b Brief 63.2 (21.2) 1.2 (17.3) 6.2 (14.7) 10.9 (18.4) Comprehensive 57.2 (20.9) 15.6 (20.4) c 20.5 (18.4) b 21.6 (19.6) c QOL-Mental UC 78.8 (22.6) 1.3 (21.2) 4.9 (20.0) 5.9 (22.8) b Brief 79.8 (14.2) 2.9 (15.7) 7.0 (13.4) 8.4 (15.9) Comprehensive 80.2 (15.1) 5.8 (15.4) 13.3 (13.6) b 10.3 (14.9) QOL-Sleep UC 85.1 (18.1) 0.8 (14.3) 0.4 (16.6) 0.7 (15.4) c Brief 82.2 (19.9) 4.4 (17.6) 7.1 (20.3) 7.9 (19.5) Comprehensive 86.8 (15.0) 5.1 (10.8) 3.3 (12.8) 5.1 (10.6) QOL-Energy UC 73.0 (23.0) 2.1 (20.3) 0.3 (24.9) 2.9 (19.5) b,d Brief 69.1 (21.8) 10.1 (19.6) 10.3 (18.7) 17.6 (19.5) e Comprehensive 69.2 (22.9) 13.9 (26.5) 17.6 (19.0) b 16.4 (18.4) b QOL-Physical function UC 87.2 (17.2) 0.4 (14.2) 0.5 (20.2) 0.1 (13.5) c Brief 81.9 (21.2) 6.0 (18.5) 8.3 (22.7) 12.2 (24.8) e Comprehensive 87.0 (14.9) 7.5 (13.7) b 6.9 (12.3) 8.3 (15.3) c QOL-Food/diet UC 67.4 (16.6) 1.1 (13.8) 0.5 (18.1) 2.1 (21.3) Brief 66.4 (16.4) 0.5 (17.1) 6.2 (19.6) 6.7 (19.0) Comprehensive 63.8 (18.6) 7.2 (13.8) 14.7 (14.9) b 7.6 (15.4) QOL-Social role UC 70.2 (26.2) 1.8 (19.4) 2.6 (26.6) 4.8 (17.5) c,d Brief 71.4 (21.0) 7.6 (15.7) d 7.6 (14.3) 11.4 (19.3) d Comprehensive 74.7 (22.8) 10.3 (16.8) b 12.1 (15.7) b 9.2 (19.4) QOL-Physical role UC 66.3 (25.8) 5.8 (22.4) 7.9 (23.8) 11.9 (27.4) Brief 65.7 (24.7) 8.2 (23.4) 11.9 (19.5) 13.3 (23.8) Comprehensive 67.3 (26.2) 17.7 (23.4) c 16.8 (23.2) 16.4 (26.0) QOL-Sex UC 65.8 (25.8) 6.5 (22.7) 7.6 (21.4) 10.1 (24.9) Brief 72.0 (20.5) 4.6 (22.1) 5.1 (17.7) 8.0 (16.6) Comprehensive 73.9 (26.7) 5.9 (14.2) 8.7 (18.7) 9.0 (19.6) NOTE. Sample sizes for UC, Brief, Comprehensive, respectively, are 44, 47, 40 at baseline; 42, 41, 38 at 9 weeks; 40, 41, 35 at 6 months; 39, 39, 35 at 12 months. a P value from repeated measures analysis of variance for testing the null hypothesis that the mean is the same in all 3 treatment groups at all 3 time points, adjusting for the baseline value of the variable and for GSI and abdominal pain severity at baseline. b Comprehensive significantly better than UC, P c Comprehensive significantly better than UC, P d Brief significantly better than UC, P e Brief significantly better than UC, P the Comprehensive group at 6 and 12 months, compared to baseline. For example, the fraction of subjects with activities interrupted by pain or bowel problems dropped from about two thirds at baseline to about one third at 12 months, and the prevalence of severe pain dropped from 50% 11% at 12 months. However, not all of these outcome variables showed a statistically significant treatment effect, because the UC group improved as well for several of them, although not as much as in the Comprehensive group. Table 6 shows baseline values and changes in stool characteristics derived from the daily diary. There was not much evidence of a treatment effect on stool characteristics. Percent of days with hard stools improved more in the Comprehensive group than in the Brief group, and percent of days with loose stools improved somewhat more in the Brief group than in the other 2 groups, although not significantly. This pattern might be due to there being more diarrhea-predominant subjects in the Brief group than in the other 2 groups. There was no evidence that the intervention affected stool frequency. Table 7 shows concentrations of norepinephrine, epinephrine, and cortisol in urine from the first morning void. Values shown are the means at baseline and mean

8 592 HEITKEMPER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 Table 5. Percent of Women With Bowel and Symptom Characteristics Over Time Variable Baseline 6 mo 12 mo P value a Severe pain UC Brief Comprehensive Severe diarrhea/constipation UC Brief Comprehensive Bloating, see belly swell up UC b Brief Comprehensive b 64 Normal stools UC b Brief Comprehensive c Often hard stools UC b Brief Comprehensive b 28 Often loose stools UC Brief Comprehensive Often 3 bowel movements/wk UC Brief Comprehensive Often 3 bowel movements/day UC Brief Comprehensive Often straining UC Brief Comprehensive Often incomplete evacuation UC b Brief Comprehensive b 58 Often urgency UC Brief Comprehensive Activities interrupted by pain UC c Brief Comprehensive Activities interrupted by bowel problems UC c Brief Comprehensive b 33 b Missed work 5 times UC Brief Comprehensive NOTE. Sample sizes for UC, Brief, Comprehensive, respectively, are 43, 48, 40 at baseline; 40, 43, 36 at 6 months; 40, 43, 36 at 12 months. a Logistic regression was used to test for pairwise differences between groups at each time point, adjusting for the baseline value of the variable and for GSI and abdominal pain severity at baseline. The overall P value is based on logistic regression with generalized estimating equations to account for the fact that each person contributes 2 data points at 6 and 12 months. b Comprehensive significantly better than UC, P c Comprehensive significantly better than UC, P 0.01.

9 July 2004 SELF-MANAGEMENT FOR WOMEN WITH IBS 593 Table 6. Baseline and Change Scores on the Secondary Outcome Variables by Treatment Group Variable Mean (SD) at baseline Mean (SD) change from baseline 9 wk 6 mo 12 mo P value a Diary: hard stools UC 23.8 (26.1) 2.8 (17.5) 2.7 (23.0) 6.2 (19.5) b Brief 22.6 (22.6) 0.3 (15.6) 5.0 (16.9) 1.7 (24.0) Comprehensive 19.5 (21.0) 7.5 (16.5) b 7.3 (18.6) 8.6 (20.2) Diary: loose stools UC 29.0 (24.9) 1.1 (23.3) 0.3 (20.3) 0.9 (20.4) Brief 33.0 (25.2) 10.4 (19.6) 10.7 (19.0) 11.2 (26.6) Comprehensive 33.5 (26.8) 3.3 (20.2) 2.5 (22.1) b 9.0 (23.9) Diary: zero stools UC 4.5 (7.0) 1.2 (5.3) 0.9 (5.0) 2.3 (7.1) Brief 2.6 (5.3) 0.3 (2.5) 1.4 (3.8) 2.2 (5.5) Comprehensive 3.6 (6.8) 1.6 (6.8) 1.7 (6.0) 2.2 (6.9) Diary: 2 stools UC 21.6 (24.0) 1.4 (26.4) 4.7 (18.9) 1.3 (18.0) Brief 18.0 (14.5) 2.1 (10.5) 0.2 (17.8) 1.5 (23.4) Comprehensive 15.9 (19.8) 4.2 (23.6) 1.3 (12.9) 4.2 (11.7) NOTE. Sample sizes for UC, Brief, Comprehensive, respectively, are 44, 48, 40 at baseline; 42, 41, 38 at 9 weeks; 40, 44, 36 at 6 months; 39, 43, 35 at 12 months. a P value from repeated measures analysis of variance for testing the null hypothesis that the mean is the same in all 3 treatment groups at all 3 time points, adjusting for the baseline value of the variable and for GSI and abdominal pain severity at baseline. b Comprehensive significantly better than Brief, P change from baseline. At baseline, mean norepinephrine level differed across the 3 groups (P.027). Controlling for baseline levels, none of the 3 measures of physiologic arousal showed evidence of a significant treatment effect, although there was a slight trend for cortisol level to decrease more in the Comprehensive group than in the other 2 groups. Discussion This study demonstrated the efficacy of a comprehensive self-management program delivered by a psychiatric nurse practitioner in reducing GI symptoms, reducing lifestyle disruption produced by GI symptoms, and enhancing QOL in women with IBS. These improvements were not just short-term, but they persisted up to 12 months after the multicomponent intervention. As such, the results of this study support and extend the results in studies with shorter follow-up ,37 In a recent report Drossman et al. 19 reported significantly greater improvements after a 12-week cognitive-behavioral treatment group as compared to education alone in women with moderate to severe functional bowel dis- Table 7. Baseline and Change Scores on the Physiologic Arousal Variables by Treatment Group Variable Mean (SD) at baseline Mean (SD) change from baseline 9 wk 6 mo 12 mo P value a Norepinephrine (ng/mg creatinine) UC 17.6 (6.6) 3.5 (8.9) 4.8 (11.7) 3.7 (9.2) 0.36 Brief 21.0 (7.8) 2.3 (11.7) 0.5 (7.9) 6.3 (8.8) Comprehensive 20.2 (10.9) 1.1 (11.6) 0.5 (9.2) 3.0 (12.5) Epinephrine (ng/mg creatinine) UC 1.22 (0.77) 0.39 (1.42) 0.52 (1.60) 0.63 (1.49) 0.87 Brief 1.53 (0.85) 0.45 (2.53) 0.16 (1.50) 0.62 (1.78) Comprehensive 1.31 (1.14) 0.49 (1.88) 0.41 (1.40) 0.30 (1.86) Cortisol ( g/mg creatinine) UC 31.4 (17.2) 1.2 (26.7) 0.6 (15.2) 6.3 (17.1) 0.42 Brief 33.6 (33.7) 0.6 (16.6) 0.9 (19.0) 7.3 (21.7) Comprehensive 33.5 (24.5) 7.8 (26.7) 9.9 (27.4) 3.1 (34.2) NOTE. Sample sizes for UC, Brief, Comprehensive, respectively, are 43, 48, 40 at baseline; 39, 43, 36 at 6 months; 39, 43, 36 at 12 months. a P value from repeated measures analysis of variance for testing the null hypothesis that the mean is the same in all 3 treatment groups at all 3 time points, adjusting for the baseline value of the variable and for GSI and abdominal pain severity at baseline.

10 594 HEITKEMPER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 tress. However, no long-term follow-up has been reported yet. Unlike some other studies, this study used a usual care control group rather than an attention-placebo control group. Thus, this study answered the clinical question of whether the Comprehensive self-management program is better than UC for women with IBS, considering the weekly attention received by the subjects to be a component of the intervention rather than a confounding factor to be controlled for. In addition, the study also included the Brief group as the third arm of the study design to evaluate the efficacy of a less timeconsuming, 1-session version of the intervention. Cognitive-behavior therapy is based on the hypothesis that IBS symptoms are due, at least in part, to inappropriate cognitions about visceral sensations. 14,16 Heymann-Monnikes et al. 16 found improvement in symptoms and QOL after a 14-week intervention as compared to usual care, but there were no differences in visceral algesia as measured by the barostat technique. Their results suggest that symptom improvement might not be correlated directly with physiologic changes in bowel sensitivity. We had hypothesized that our self-management cognitive-behavioral therapy might reduce physiologic arousal as reflected in first morning voided urine cortisol and catecholamine levels. However, our results showed no evidence of treatment effects on these physiologic arousal indicators. Catecholamine and cortisol levels, similar to bowel sensitivity, might represent trait measures that are not amendable to change with this intervention. Alternatively, first voided urine cortisol and catecholamines levels might not be sensitive measures of physiologic arousal in this population. Given that the levels of catecholamines and cortisol noted in this sample of women were lower than those observed in a prior study of IBS and control subjects, 52 it might be that further decreases in these parameters were not possible (i.e., a floor effect). The Brief version of the intervention showed improvement relative to UC in QOL, especially the subscales of Energy, Physical Function, and Social Role, although this improvement was somewhat less than in the Comprehensive group. Improvement in the Brief group, although not statistically significant, was also seen in psychological distress (GSI) and in the secondary outcomes of Normal Stools, Activities Interrupted by Bowel Problems, and Bloating. However, the Brief intervention did not appear to reduce symptoms as measured by the daily diary and only showed a temporary improvement in cognitions (CSFBD), which did not persist beyond 9 weeks. The lack of improvement on CSFBD is not surprising, because other research that has used cognitive behavior therapy and shown significant cognitive change has typically been for more sessions than our brief intervention (for example, Drossman et al. 19 used 12 sessions), and no research in this area to date has demonstrated cognitive change in this short a time. It is not clear why the Brief intervention showed greater improvement on bowel pattern and symptoms as measured retrospectively (Table 5) than it did on these symptoms measured by daily diary (Table 3). It is also not clear why the Brief intervention had an impact on QOL in spite of its minimal impact on symptoms and the CSFBD. Although not statistically significant, the UC group also exhibited an overall trend of decreasing symptoms and improving QOL over time. It should be pointed out that this group completed 4-week daily diaries on 4 occasions during the study. Such record keeping might have helped women to identify symptom triggers and thus reduce symptom provocation over time. It is also possible that women in the UC group might have received additional care through their own care providers, although a post hoc analysis showed no differences from baseline in terms of health care utilization. Because this intervention was multicomponent, it is not possible to determine which components were most beneficial to the women who participated. Furthermore, it remains to be determined whether this intervention is as effective in men or perimenopausal or postmenopausal women. There has been limited discussion of the role of gender or age in behavioral management of IBS. Toner and Akman 53 recommended that attention to genderspecific themes of possible sexual and physical abuse, gender role socialization, gender role conflict, public embarrassment and humiliation (related to GI symptoms such as belching, gas, frequent trips to the bathroom, and soiling), perfectionist views of bodily function, and balancing personal versus supportive roles be included in cognitive-behavioral interventions. Such issues, in particular, social role, sexual function issues, and family responsibilities, were integrated into this intervention. Indeed, women in the Comprehensive program self-reported increases in social role functioning after the intervention. This intervention was delivered by 2 masters degree prepared, advanced practice nurses with backgrounds in mental health. Whether these results could be duplicated by clinic registered nurses experienced in working with gastroenterology patients remains to be determined. The delivery of content was also performed one-on-one rather than in a group setting. Additional modes of delivery including telephone- or Web-based programs as well as group sessions also remain to be tested.

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