Characteristics of Acute Pain Attacks in Patients With Irritable Bowel Syndrome Meeting Rome III Criteria

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1 nature publishing group ORIGINAL CONTRIBUTIONS 1299 Characteristics of Acute Pain Attacks in Patients With Irritable Bowel Syndrome Meeting Rome III Criteria Per M. Hellstr ö m, MD, PhD 1, Yuri A. Saito, MD, MPH 2, Peter Bytzer, MD, PhD 3, Jan Tack, MD, PhD 4, Stefan Mueller-Lissner, MD 5 and Lin Chang, MD 6 OBJECTIVES: METHODS: RESULTS: An international multicenter, prospective, non-interventional, 2-month study characterized acute pain attacks in patients with irritable bowel syndrome (IBS). Adult patients meeting the Rome III IBS diagnostic criteria with a history of 3 pain attacks per month participated in a survey that captured daily and episodic information regarding IBS symptoms and pain attacks for 2 months. Acute pain attacks were defined as a sudden onset or increase in the intensity of IBS abdominal pain with a minimum intensity of 4 ( 1 scale). The majority (84 % ) of the 158 patients taking the survey were women with a mean age of 41 years and time since IBS diagnosis of 5 years. The median pain attack frequency was 5.4 attacks per month and was significantly higher in the IBS with diarrhea (IBS-D, 6.4 per month) group vs. the IBS with constipation (4.4 per month) and the IBS with mixed pattern (5.5 per month) groups ( P =.19). The median pain attack duration was 2.8 h and the median intensity score was 7. The majority of pain attacks resulted in defecation (78 % ), and occurred more often in IBS-D patients than in other subgroups. The majority of pain attacks (63 % ) interfered with work and / or daily activities. Medication to manage pain attacks was used by 44 % of patients during 29 % of attacks. Although used by less than half of all patients, medication helped 66 % of attacks treated. CONCLUSIONS: The frequency of severe pain attacks was 1.4 per week and the majority affected daily activities. However, most of the pain attacks were untreated in IBS patients. Pain attack management is an unmet need of IBS treatment. Am J Gastroenterol 211; 16: ; doi:1.138/ajg ; published online 29 March 211 INTRODUCTION Irritable bowel syndrome (IBS) is characterized by abdominal pain and discomfort with altered bowel habits (such as diarrhea (IBS-D), constipation (IBS-C), or both (IBS-M)) occurring in the absence of consistently demonstrable structural or biochemical causes ( 1 ). Abdominal pain is the hallmark symptom of IBS, which is believed to be a brain gut disorder associated with disordered smooth muscle activity coupled with sensory dysregulation resulting in enhanced visceral perception ( 2,3 ). Patients for whom abdominal pain is the predominant complaint are most affected by their IBS ( 4 ). Moreover, abdominal pain is a key predictor of IBS severity and health-care utilization ( 5 7 ). In a recent study of 755 patients with IBS in a university setting, abdominal pain was the most powerful predictor of patient- perceived severity among 25 clinical factors ( 7 ). Abdominal pain also negatively affects health-related quality of life independently of other IBS symptoms and characteristics ( 8 ). Recognizing that abdominal pain is a key diagnostic symptom in IBS, the Food and Drug Administration has recently suggested that abdominal pain intensity should serve as a co-primary interim end point in IBS clinical trials ( 9 ). An 11-point (i.e., 1) numeric rating scale that asks patients daily to rate their worst abdominal pain over the past 24 h was recommended to measure pain intensity ( 1,11 ). Population-based studies suggest that IBS pain is episodic ( 12,13 ), but the natural history of acute pain attacks is poorly understood. The characteristics of pain attacks over time and across IBS 1 Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Uppsala, Sweden ; 2 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA ; 3 Department of Medicine, K ø ge Hospital, K ø ge, Denmark ; 4 Department of Gastroenterology, University Hospital, Leuven, Belgium ; 5 Park-Klinik Weissensee, Berlin, Germany ; 6 Division of Digestive Diseases, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA. Correspondence: Lin Chang, MD, Division of Digestive Diseases, Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, 1945 Le Conte Avenue, PVUB 2114, Los Angeles, California 995, USA. linchang@ucla.edu Received 23 August 21; accepted 1 February by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 13 Hellstr ö m et al. subtypes need defining. Therefore, we conducted an international multicenter, prospective, non-interventional, 2-month longitudinal study to characterize acute pain attacks experienced by patients with IBS. In particular, we aimed to characterize the frequency, duration, and intensity of acute pain attacks, to determine patient behaviors during pain attacks, to assess how attacks interfere with daily activities in patients from Western countries, and to compare characteristics across IBS subtypes. METHODS Study sites Six urban hospital centers (Departments of Gastroenterology and / or Medicine) in Sweden, Belgium, Germany, Denmark, and the United States ( n = 2) enrolled patients. Principal investigators were gastroenterologists with expertise in IBS. This study was conducted in compliance with the guidelines for Good Epidemiology Practice. Each participating study site was responsible for obtaining approval of the study protocol from applicable Institutional Review Board / Independent Ethics Committee, in compliance with applicable local regulations. Patients Patients presenting at a hospital for either a new diagnosis of IBS or ongoing IBS treatment / investigation were enrolled in a patient registry and screened for the survey. Consecutive outpatients (men or women 18 years of age) consulting for IBS as a self-reported diagnosis or previously diagnosed by a physician were screened after providing informed consent. Screened patients who met the Rome III criteria for IBS ( 1 ) participated in a survey designed to capture daily and episodic information regarding their IBS symptoms and pain attacks for up to 2 months. Inclusion criteria for the survey were the presence of the Rome III diagnostic criteria for IBS ( 1 ) and a history of at least three pain attacks per month during the previous 3 months. Acute pain attacks were defined as a sudden onset of pain or increase in the intensity of IBS abdominal pain (minimum intensity of 4 on an 11- point numeric rating scale in which = no pain and 1 = maximum tolerated pain). Exclusion criteria were consultations for gastrointestinal (GI) problems other than IBS, evidence of organic GI conditions that could explain IBS symptoms, and participation in any other clinical trial at the time of recruitment. IBS subtypes were determined using the Rome III subclassification criteria ( 1 ). No study treatments were administered in the study, but there were no restrictions regarding therapies used during the study. Patient questionnaires (paper) were translated by the investigators and site coordinators who were all native speakers and fluent in English. Efforts were made to ensure that correct patient idioms were used in the translation, and were consistent with local practice in the hospital for patient data reporting. Study end points The primary end points were the frequency of pain attacks (calculated as number per month) during the survey, the duration of pain attacks, and the intensity of pain attacks at the beginning of the attack and every hour for 24 h using the 11-point numeric rating scale described above. Secondary assessments included the number of pain attacks interfering with work and social life activities and behaviors occurring during pain attacks (such as going to bed, going to the toilet, defecation, nausea / vomiting episodes, and treatment), time between pain attacks and the last meal, patient s perception that treatment taken during pain attacks was helpful, and self-ratings of IBS severity at the end of the study. IBS severity was rated using an 11-point scale in which = best possible and 1 = worst possible. Physicians also assessed IBS severity at visit 1. Study visits Patients eligible for the survey completed a clinic visit (visit 1) in which demographic and medical history information was recorded. Physicians rated their patients IBS severity at the beginning of the study using the 11-point numeric rating scale. Patients were given paper diaries for daily assessments and pain questionnaires for recording pain attack characteristics. On a daily basis, patients recorded the occurrence and location of abdominal pain, and occurrence of abdominal discomfort and bloating. For each pain attack, patients recorded the date and time of the onset and end of the attack and the pain intensity at the beginning of the attack and for the next 1, 2, 4, 6, 8, 12, and 24 h. They also recorded the times of the last meal and whether the attack interfered with the ability to work or perform normal activities (yes / no responses), and their behavior (yes / no responses) during the attack (such as going to bed, going to the toilet, defecation, nausea /vomiting episodes, treatment). After visit 1, patients had up to two additional clinic visits (at 1 and / or 2 months for visits 2 and 3, respectively) in which diary and pain questionnaires were collected and reviewed. Statistical analysis Data are presented for all patients with a survey visit 1 (included population). Statistical analyses were conducted using SAS v8.2 or higher software (SAS Institute, Cary, NC). Quantitative data were summarized using descriptive statistics (means, s.d., medians, 25th and 75th percentiles, and minimums / maximums). Qualitative data were summarized using counts and percentages. Significant differences among subgroups were determined using χ 2 tests for analyses of proportions and ANOVA (analysis of variance) type III for analyses of other variables. P values for differences among subgroups needed to be <.5 to conclude that there is a significant difference. When a significant difference was determined among subgroups, pairwise comparisons of subgroups were performed using χ 2 tests for analyses of proportions and Tukey s test for analyses of other variables. To adjust for multiplicity issues in χ 2 tests, P values for pairwise comparisons needed to be <.167 (.5 /3) to conclude significant differences between two subgroups. As characteristics of pain attacks in relation to patients behaviors vary considerably between individuals, statistical evaluation of pain attacks and the consequent behaviors were based on the actual occurrence of pain attacks. The American Journal of GASTROENTEROLOGY VOLUME 16 JULY 211

3 Characteristics of Acute Pain Attacks in IBS Patients 131 RESULTS Baseline characteristics A total of 374 patients were screened and 158 (42 % ) of these patients were eligible for the survey (included population). The number of screened patients ( % ) by country was: 19 (51), 111 (3), 35 (9), 23 (6), and 15 (4) for the United States, Denmark, Germany, Sweden, and Belgium, respectively. The number of surveyeligible patients by country is included in Table 1. The majority of patients completed the optional visit 2 (132 / 158, 84 % ) and / or visit 3 (129 / 158, 82 % ); the median duration of the period with diary recordings was 62 days (range 1 74 days). Overall, 53 patients (34 % ) were excluded from the per-protocol analyses because of major protocol deviations, including > 6 days between the first and final visits ( n = 27), no pain attack data at visit 2 or 3 ( n = 26), less than three pain attacks per month during the last 3 months before enrollment ( n = 1), and pain intensity score < 4 ( n = 1). The single patient with less than three pain attacks per month was included in the survey by the investigator, even though the patient did not fulfill the inclusion criteria. Therefore, this patient was excluded from the per-protocol analysis. Baseline and demographic data for all eligible survey patients are shown in Table 1. The majority (84 % ) of patients were women and mean age was 41. ± 13.3 years. The mean time since IBS diagnosis was 5.1 ± 6.4 years. Overall, 28 % of patients were classified as having IBS-C, 34 % had IBS-M, and 42 % had IBS-D. Investigators rated the baseline severity of patients IBS as 5.8 ± 1.7 on a scale of 1. Investigators ratings of IBS severity at visit 1 were not significantly different across the IBS subgroups. Patients retrospectively reported frequent pain attacks of moderate intensity at the start of the study: the median number of pain attacks was eight per month with a median pain intensity score of 7.. Bloating during pain attacks occurred in 82 % of patients. Although all patients included in the survey fulfilled the Rome III criteria, ( 1 ) most but not all met each of the three individual pain-related symptom criteria as shown in Table 2. Each of the three symptom criteria was endorsed by > 8 % of IBS patients. The use of any IBS medication was reported at baseline by 68 (43 % ) of the survey patients. The medication groups most frequently represented (used by > 5 % of patients) were natural and synthetic tertiary anti-cholinergics (13 /68 (8.2 % ) and 12 of 68 (7.6 % ), respectively), osmotic laxatives (13 /68, 8.2 % ), and antidiarrheals (1 /68, 6.3 % ). Pain attack characteristics The duration, frequency, and intensity of pain attacks for the overall study population and by the IBS subgroups over the 2-month observational period are shown in Table 3. The 158 IBS patients collectively reported 1,247 pain attacks for a median frequency of 5.4 (range of 64.3) attacks per month. The majority of pain attacks (81 % ) started during daytime / evening hours (between 6 hours and 23 hours). The frequency of pain attacks was significantly different among the three IBS subgroups ( P =.19) with the highest median frequency in the IBS-D (6.3 per month; range 64.3) group compared with the IBS-C (4.4 per month; range 33.6) and IBS-M (5.5 per month; range 17.) groups. Table 1. Demographic and baseline characteristics of survey patients Characteristics N =158 Country of origin n ( % ) United States 13 (65) Sweden 17 (11) Denmark 16 (1) Germany 12 (8) Belgium 1 (6) Age, years Mean ± s.d. 41. ± 13.3 Median 4 Sex no. ( % ) Female 127 (84) Male 24 (16) Missing information 7 (4) BMI, kg / m 2 Mean ± s.d. 25. ± 5.2 Median 24.3 Time since IBS diagnosis, years Mean ± s.d. 5.1 ± 6.4 Median (range) 2.4 (., 28.8) Pain attack frequency, no. per month Mean ± s.d ± 15.1 Median (range) 8 (2, 12) Baseline pain attack intensity 1 point scale Mean ± s.d. 7. ± 1.7 Median 7 IBS severity, physician rating 1 point scale Mean ± s.d. 5.8 ± 1.7 Median 6 Bloating during pain attacks, no. ( % ) Yes 13 (82) IBS subgroup, no. ( % ) a IBS-C 44 (28) IBS-D 66 (42) IBS-M 53 (34) IBS treatments, no. ( % ) Any treatment 68 (43) Belladona alkaloids 13 (8) Osmotic laxatives 13 (8) Synthetic anti-cholinergics 12 (8) Anti-diarrheals 1 (6) BMI, body mass index; IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. a Five patients were classifi ed into more than one subgroup. 211 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 132 Hellstr ö m et al. Table 2. Proportion of survey patients meeting individual Rome III pain-related symptom criteria Rome III criteria for IBS N ( % ) Recurrent abdominal pain or discomfort Yes 158 (1) Associated with two or more of the following: Improvement with defecation Yes 139 (88) No 18 (11) Onset associated with a change in frequency of stool Yes 142 (9) No 16 (1) Onset associated with a change in form / appearance of stool Yes 129 (82) No 29 (18) IBS, irritable bowel syndrome. Pairwise comparison between the IBS-D and IBS-M groups demonstrated a significant difference ( P =.27). The median duration of all pain attacks was 2.8 h. Of the 1,247 pain attacks reported, 77 % of attacks lasted 3 min. The proportion of pain attacks with a duration of < 3 min was significantly higher in IBS-D (35 % ) vs. IBS-C (4 % ) and IBS-M (5 % ) patients (both P <.1). However, the median duration for pain attacks lasting at least 3 min (2.9 h for all patients; range.5 724) was similar across all IBS subgroups as shown in Table 3, although the range was very broad in IBS-D. No correlations between age and pain attack frequency ( P =.57), duration ( P =.15), or intensity (P =.26) were found. Median intensity scores at the start of pain attacks were 7 (range 5 1) in the overall IBS and subgroup populations and remained 4 through the initial 6-h assessment. Figure 1 shows the time course of intensity scores over 24 h by the IBS subgroup. The intensity scores over time remained higher in the IBS-D subgroup than in the IBS-C and IBS-M subgroups ( P <.1). Although the intensity of pain diminishes over time, pain remains for some patients at 24 h. Pain attack frequency, duration, and intensity over time were compared for patients in the United States and Europe. Table 4 shows the frequency and duration of pain attacks. The mean pain attack frequency ± s.d. was numerically higher but not statistically different among European patients (9.88 ± 11.89; median 5.8) as compared with US patients (7.3 ± 7.68; median 4.8, P =.1). A significantly higher proportion of pain attacks reported by US patients lasted at least 3 min compared with European patients (8 vs. 73 %, P =.39), although the median durations in US vs. European patients were similar (3. and 2.8 h, respectively P =.64). US patients also showed a greater decline in pain intensity of pain attacks over the ensuing 24 h than did European patients. Both US and European patients reported similar mean intensities of 6.89 ±1.42 and 6.96 ±1.49, respectively, at the beginning of the attack. However, the pain intensity in US patients decreased at 4 h and continued to decline over the 24-h period (4.3 ± 2.42 at 4 h and 2.85 ± 2.84 at 24 h), whereas European patients had a relatively stable mean intensity during the 24-h period (5.46 ± 3.4 at 24 h). The mean decrease in intensity was 3.96 for US patients and 3.2 for European patients, and this difference was statistically significant ( P <.1). Other GI symptoms were associated with pain attacks in IBS. Bloating and / or discomfort occurred frequently (21. ± 8.1 events per month), but frequency was not significantly different across subgroups (2.9 ±8.7, 22.7 ±6.8, and 19.8 ±8.4 events per month in the IBS-D, IBS-C, and IBS-M groups, respectively). Nausea was common, occurring in 58.9 % of all pain attacks, but the occurrences were not significantly different across subgroups. Vomiting occurred in only 2.6 % of pain attacks for the total survey population, but occurred more frequently in the IBS-C group (7.7 % of attacks) than in the IBS-D (1.1 %, P <.1) and IBS-M (2.1 %, P =.4) groups. Patients self-rating of overall IBS severity at the end of study is shown in Table 3 and was similar to physician rating of severity at the beginning of the study (mean patient rating 5.5 ± 2.4 vs. physician rating 5.8 ± 1.7). Patient or physician ratings of IBS severity were not significantly different across the IBS subgroups. Correlations between patient-rated IBS severity and pain attack frequency and intensity were assessed. Patients estimating their IBS severity as low ( < 5) had significantly fewer pain attacks than did patients with a high severity score ( 5, P =.26). No correlation was detected between IBS severity score as assessed by the patient and pain attack intensity ( P =.12). The median time from last meal to start of a pain attack was 2.9 h, ranging from.2 to 29 h for all patients. Given the broad range in times, a plot of all pain attacks by time intervals for duration since the last meal of 1, 1 3, 3 5, 5 1, and > 1 h is shown in Figure 2a for the IBS-D, IBS-C, and IBS-M populations. The same information is also presented as the proportion of pain attacks for each group in Figure 2b. The data show that approximately half of the pain attacks occur within 3 h of eating a meal. Information about subsequent meal intake during the pain attack was not collected. Patient behaviors during pain attacks The behaviors of patients during pain attacks are summarized in Figure 3. The majority of pain attacks resulted in IBS patients going to the toilet (86 % ) and defecating (78 % ). Behaviors during pain attacks differed among the IBS subgroups. IBS-D patients reported more pain attacks (91 % ) that resulted in going to the toilet than did IBS-M (86 % ) and IBS-C (74 % ) patients ( P =.56 and P <.1, respectively). IBS-M patients also had significantly more pain attacks resulting in going to the toilet than did IBS-C patients ( P =.5). A greater percentage of pain attacks induced defecation in the IBS-D (87 % ) and IBS-M (81 % ) groups vs. the IBS-C (51 % ) group (both P <.1). The proportion of pain attacks associated with defecation was not significantly different for the IBS-D and IBS-M groups ( P =.183). A greater proportion of pain attacks in the IBS-C (44 % ) group resulted in patients going to bed at the time of the pain attack compared with IBS-D The American Journal of GASTROENTEROLOGY VOLUME 16 JULY 211

5 Characteristics of Acute Pain Attacks in IBS Patients 133 Table 3. Characteristics of pain attacks in overall survey population and by IBS subgroup Group Number All attacks No. attacks < 3 min ( % ) No. attacks > 3 min ( % ) Unknown duration Total 1,247 Duration a h Median (range) Mean ± s.d. Frequency Attacks / mo Median (range) Mean ± s.d. Intensity b 1 scale Median (range) Mean ± s.d. Patient rating of overall IBS severity c 1 scale Median (range) Mean ± s.d. n = (23) 2.9 (.5, 724.) 5.4 (, 64.3) 7 (5, 1) 6 (, 1) 769 (77) 7.1 ± ± ± ± IBS-D 762 n = (35) 2.8 (.5, 724.) 6.3 (, 64.3) 7 (5, 1) 5 (, 1) 399 (65) 7.9 ± ± 12.5* 6.8 ± ± IBS-C 25 n = 44 8 (4) 2.6 (.5, 85.8) 4.4 (, 33.6) 7 (5, 1) 6 (, 1) 191 (96) 6. ± ± ± ± IBS-M 251 n = 53 1 (5) 3. (.5, 66.) 5.5 (, 17.) 7 (5, 1) 6 (, 1) 192 (95) 6.8 ± ± 4.1* 6.9 ± ± IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. *Signifi cant difference between IBS-D and IBS-M groups, P =.27. a Duration for pain attacks lasting 3 min is shown. b Intensity at beginning of pain attack measured on a 1 scale, where was no pain and 1 was the maximum tolerated, is shown. c Patient rating of overall IBS severity is measured at the end of the study by the patient on a 1 point scale, where was the best possible and 1 was the worst possible. Table 4. Pain attack characteristics in patients from the United States vs. European centers End point Attacks / month US patients, N =13 European patients, N =55 P value Mean (s.d.) 7. (7.7) 9.9 (11.9).1 Median Number of attacks All < 3 min 12 (2 % ) 132 (27 % ) 3 min 418 (8 % ) 351 (73 % ).39 Unknown duration Duration of attacks (h) 3 min Mean (s.d.) 7.9 (36.6) 6.1 (8.7) Median (26 % ) and IBS-M (33 % ) patients ( P <.1 and P =.141, respectively). Patients went to bed more often during pain attacks that occurred 5 h after the last meal (41 % of the attacks) as compared with those that occurred within 5 h (22 % ) ( P <.1). Influence of pain attacks on daily activities The influence of pain attacks on patients work and daily activities is shown in Figure 4. Of the 1,247 pain attacks reported over the 2-month period, the majority interfered with work and / or normal daily activities (63 % in all patients, and 74, 59, and 62 % in IBS-C, IBS-D, and IBS-M groups, respectively). The proportion of pain attacks interfering with activities in the IBS-C group was significantly higher than that in the IBS-D ( P =.6) and IBS-M ( P =.163) groups. Use of medication Medication to manage pain attacks was taken by 7 of 158 (44 % ) patients during 337 of 1,247 (27 % ) pain attacks. There was a statistically significant difference across the three subgroups: 29, 26, and 32 % of pain attacks were treated in the IBS-C, IBS-D, and IBS-M groups, respectively ( P =.38). Information regarding whether medication was perceived to be helpful was available for 211 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

6 134 Hellstr ö m et al. Median pain intensity score IBS-D IBS-C IBS-M Time (h) Figure 1. Median pain attack intensity over 24 h by IBS subgroup. Intensity over time in the IBS-D group was signifi cantly different from that in the IBS-C and IBS-M groups ( P <.1). Intensity was measured on a 1 scale, where was no pain and 1 was the maximum tolerated pain. IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. Proportion of pain attacks with behavior Goes to the toilet 2 Defecates All IBS-D IBS-C IBS-M 3 Goes to bed Takes medication Figure 3. Behaviors during pain attacks for total population and by IBS subgroup. Statistical signifi cance for pairwise comparisons: 1 = IBS-D vs. IBS-M ( P =.6). 2 = IBS-C vs. IBS-D and IBS-C vs. IBS-M (all P <.1). 3 = IBS-C vs. IBS-D ( P <.1), and IBS-C vs. IBS-M ( P =.14). IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. a Number of pain attacks b Percentage of pain attacks Time (h) IBS-D IBS-C IBS-M Time (h) Figure 2. Pain attacks as a function of time after eating a meal in the IBS subgroups. ( a ) The number of pain attacks as a function of the time intervals from last meal, and ( b ) the percentage of pain attacks occurring during the intervals within the IBS subgroups. IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. Proportion of pain attacks All IBS-D Interfered with activities Did not interfere IBS-C IBS-M Figure 4. Effect of pain attacks on work and daily activities. Of the 1,247 pain attacks reported over the 2-month period, the majority interfered with work and / or normal daily activities. The difference between the three groups was signifi cant ( P =.3), as was the pairwise comparison of the IBS-C group vs. the IBS-D and IBS-M groups ( P <.1 and P =.16, respectively). IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. 298 of 337 pain attacks: medication was helpful in 66 % of cases (196 / 298). Numerically, medications reportedly helped more pain attacks in the IBS-C (83 %, 52 / 63) and IBS-M (78 %, 49 / 63) groups than in the IBS-D group (53 %, 87 / 164) as shown in Figure 5, but these differences were not statistically significant. With regard to pain attacks for which medication was used, 35 % of attacks (119 / 337) were treated with opioids, alone or in combination with other drugs. Anti-spasmodics were used in 24 % (82 / 337) of attacks, and paracetamol / acetaminophen was used in 15 % (49 / 337) of attacks. Analgesic medication use was similar across the IBS subgroups: 4, 45, and 44 % of pain attacks were treated The American Journal of GASTROENTEROLOGY VOLUME 16 JULY 211

7 Characteristics of Acute Pain Attacks in IBS Patients 135 Proportion of pain attacks All IBS-D IBS-C Helped by medication Not helped IBS-M Figure 5. Treatment effects. There were 337 pain attacks for which medication was used. Patients recorded whether the pain attacks were helped or not helped by medication. IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS with mixed pattern. with analgesics in the IBS-C, IBS-D, and IBS-M subgroups, respectively. However, IBS-D patients were more likely to use opioids during pain attacks (32 % of attacks) than were IBS-C patients (2 % of attacks) or IBS-M patients (19 % of attacks). DISCUSSION This 2-month observational study of IBS patients demonstrates that acute pain attacks are highly prevalent in IBS patients regardless of the bowel habit subtype (i.e., IBS-C, IBS-D, or IBS-M). Although some differences emerged between subgroups regarding pain attack characteristics and associated behaviors, pain intensities of attacks and overall physician and patient ratings of IBS severity were similar across the subgroups. Pain attacks had a significant impact on work capability and other daily activities in all the IBS subgroups. To our knowledge, this is the first longitudinal study that has assessed characteristics of pain attacks in IBS patients. In addition, another unique aspect of our study is the enrollment of patients from the United States and Europe. We found that pain attacks reported by US patients were more often at least 3 min in duration and had a greater decline over 24 h than those in European patients. IBS patients in the survey had a median of 5.4 pain attacks per month. Although the comparison of results across studies is difficult because of the lack of uniformity in capturing frequency and duration of IBS pain episodes, our results are consistent with IBS pain episode patterns previously reported in community studies or in clinical trials. In a cross-sectional study, Si et al. ( 14 ) reported that 68 % of 616 Chinese patients with IBS meeting the Rome II criteria reported having two or more episodes of abdominal pain per week, with a duration of at least an hour in 58 % of patients. This frequency and duration differed slightly between subgroups, with the highest frequency and durations reported by IBS patients with an alternating bowel pattern, and the lowest by IBS-C patients. Chassany et al. (15 ) reported that among 3 patients enrolled in a clinical trial to treat acute pain episodes, 4 % had pain episodes 1 3 times per week by a recall assessment and 34 % had daily episodes. In our study, ~ 5 % of pain attacks occurred within 3 h of eating a meal. These results are similar to those reported by Ragnarsson and Bodemar ( 16 ) who prospectively assessed the relationship of pain to eating and defecation in 8 patients with IBS. Postprandial worsening of pain periods was reported by 5 % of patients in the study who recorded daily symptoms ( 16 ). Information about the patients diets is potentially relevant as certain foods are associated with pain attacks. This analysis was beyond the scope of our study, and no information on patients diets was collected. Recruitment in all study centers was primarily from urban centers, and it is assumed that regardless of US or European origins, patients were consuming Western diets. Patients in the survey reported a higher median number of pain attacks (8 per month) for the pre-study period as compared with the number of attacks occurring during the 2-month study period (5.4 per month). This discrepancy may have resulted for several reasons. One is that the recall of pain experienced beyond the past several days may be an inaccurate reflection of current pain ( 17 ). Somatic pain studies have demonstrated that recall ratings were consistently inflated relative to averaged momentary ratings ( 17 ) and could be affected by the variability of real-time pain ( 18 ). Another possible reason is that an initially higher health-seeking behavior among IBS patients was addressed once patients were enrolled in the study and had ongoing contact with study personnel. Furthermore, based on overall symptom assessment in a prospective naturalistic IBS study by Bond et al. ( 19 ), the severity of self-assessed symptom burden is related to all symptoms recorded, not just to abdominal pain or individual aberrations in bowel habits, which may contribute to the higher number of estimated pain attacks before inclusion into the study than when assessed using the more stringent study criteria. Patients may experience a symptom burden that involves an affective component that was eliminated once the strict symptom protocol was introduced to focus on pain attacks as the main end point. Furthermore, many patients were recruited during visits to their gastroenterologist, and it is conceivable that an intervention was made that may have resulted in fewer pain attacks during the study observation period. The findings from this study support the association of abdominal pain with defecation as defined by the Rome criteria ( 1 ), although these findings were likely influenced by the requirement that participants meet the Rome criteria. Most pain attacks were associated with going to the toilet and defecating, particularly in the IBS-D group. The frequency of pain attacks was higher in IBS-D, but a greater proportion lasted < 3 min compared with the IBS-M and IBS-C groups. It is possible that a higher proportion of pain attacks in the IBS-D group are closely associated with bowel movements and relieved with defecation. Therefore, it seems as if bowel emptying, which occurs more frequently in diarrhea, is a symptom-relieving process in the course of an IBS pain attack, at least for attacks of shorter duration. However, the intensity of pain attacks over 24 h was elevated in the IBS-D group relative to patients in the IBS-C and IBS-M groups. It suggests that a subset of longer-duration pain attacks in IBS-D is not relieved after having a bowel movement. The higher and prolonged intensity of pain 211 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

8 136 Hellstr ö m et al. attacks in IBS-D may in part be because significantly more IBS-C and IBS-M patients took medication to relieve their pain attacks. It is not clear whether these two patient subgroups took medication because their pain attacks typically were prolonged in duration and not relieved by defecation. Patient behaviors captured during pain attacks show a significant impact of the attacks on daily activities regardless of the IBS subgroup. Almost two-thirds of pain attacks affected work and other daily activities in IBS patients and a third of attacks resulted in bed rest. These results are consistent with studies demonstrating that the chronic or recurrent symptoms of IBS result in lower social and physical functioning scores for IBS patients relative to patients with diabetes, gastroesophageal reflux, and depression ( 2 ). Pain symptoms are key predictors of the physical component of health-related quality of life ( 8 ). Productivity loss in IBS patients participating in a prospective natural history study was equivalent to 13.8 h of lost productivity per 4-h work week ( 12 ). Estimated total direct and indirect (i.e., absenteeism, lost productivity) costs are up to six times higher for IBS patients than for non-ibs subjects ( 21,22 ). The proportion of pain attacks interfering with work and daily activities was highest in the IBS-C group. Consistent with this finding, patients in the IBS-C group were more likely to need bed rest and to experience vomiting during their pain attacks. Previous studies support this observation because they have shown that IBS-C patients report more upper GI symptoms consistent with functional dyspepsia ( 23 ), more frequent lower abdominal pain and bloating ( 23 ), and more non-gi-related symptoms ( 24 ) than do IBS-D patients. Although characteristics of pain attacks and behaviors differed somewhat across subgroups, they did not substantially affect patients perception of the severity of their illness, as severity ratings did not significantly differ across the IBS subgroups. Patient-rated severity correlated with pain attack frequency but not intensity, implying that specific pain characteristics impact a patient s perceived severity of their IBS. However, there is increasing evidence that IBS severity is a multidimensional concept ( 6 ). Although Spiegel et al. ( 8 ), found that abdominal pain was a strong predictor of illness severity in IBS; straining with defecation and urgency with defecation were other significant predictors of IBS severity. IBS-C and IBS-D patients, respectively, commonly report these symptoms and both are reported by IBS patients with alternating or mixed pattern ( 25 ). This finding is also consistent with the role that subjective theories of illness, regardless of IBS subtype, can have in self-reported symptom severity ( 26 ). Medication to treat IBS at the start of the study was used by less than half of the patients, and medication was used to treat < 3 % of pain attacks during the study. When medication was used to treat pain attacks, the IBS-C and IBS-M groups reported that close to 8 % of attacks were helped by medication compared with 5 % in the IBS-D groups. However, a relatively small number of pain attacks overall were effectively treated with medication. This may explain why the duration of pain attacks was prolonged in some patients, with pain still reported 24 h after the onset of the attack. Given that medication seemed to help manage pain attacks when used, it is unclear why so few attacks were treated with medication. It may be because most medications used during a pain attack have not been shown to relieve abdominal pain in IBS significantly. The frequency of medication use by patients in this study is very similar to that reported by Faresjo et al. ( 27 ) who examined self-reported medication use among IBS patients. Among 347 IBS patients, 13 % used acid suppressants, and fewer than 5 % used laxatives, antidiarrheals, anti-spasmodics / motility agents, or anti-flatulants (27 ). In the results of a recent international survey of IBS patients, Drossman et al. ( 13 ) reported that the most common medication groups were non-narcotic analgesics (31 % of patients), whereas 2 % of patients were taking opioids, consistent with their observation that pain was the predominant symptom reported by the participants and the proportion of medications taken for pain increase based on severity. Our finding that 35 % of pain attacks were treated with opioids during the survey period confirms the high frequency of opioid use specifically taken for an IBS pain attack rather than a comorbid condition, such as general somatic pain or menstrual pain. IBS-D patients used opioids for more pain attacks than did IBS-C patients, perhaps because of the higher frequency of pain attacks and pain intensity over time occurring in the IBS-D group than in the other two subgroups. Another explanation could be that patients with IBS-C do not tolerate the side effects of constipation associated with opioid use. The high frequency of opioid use in certain IBS patients underlines the need for effective and safe alternate pain treatments. In another population survey, IBS patients reported a significant IBS symptom burden, with approximately half of patients reporting that abdominal pain was distressing and bothersome quite a bit or extremely despite multiple treatments used (12 ). These data highlight that pharmacological management of pain attacks in patients with moderate-to-severe IBS remains unsatisfactory. Limitations of this study include uncertainty as to whether the results can be extrapolated to IBS patients in primary care as enrollment criteria for the survey restricted IBS patients to those with a minimum of three pain attacks per month. Complete data are missing for ~ 2 % of patients, and the use of paper diaries is known to be associated with poorer compliance compared with electronic recording systems ( 28 ). Mean and median data were presented as in some cases, there was a wide range around the median. For example, in the IBS-D group, the duration of pain attacks ranged from.5 to 724 h. We acknowledge that the higher value is not indicative of acute pain, but limitations of the survey question capturing the start and finish dates of each attack reported in the patient diary allowed prolonged pain to be recorded. Finally, although we found some differences in characteristics of pain attacks between US and European patients, we had a relatively higher proportion of US vs. European patients (65 vs. 35 % ). Thus, differences between these regions need to be confirmed in larger patient populations. In summary, this observational study supports that pain attacks are frequently reported by patients and are a significant cause of disruption of daily activities. It seems that the currently available treatments for IBS pain are not effective in treating acute pain attacks as so few patients in the study manage their pain attacks with medication despite the prolonged duration of these attacks. Given the incidence, duration, and intensity of acute pain attacks regardless of IBS subtype, and lack of effective medication use, pain attack treatment is an unmet need and should be a major focus of IBS management. The American Journal of GASTROENTEROLOGY VOLUME 16 JULY 211

9 Characteristics of Acute Pain Attacks in IBS Patients 137 CONFLICT OF INTEREST Guarantor of the article: Lin Chang, MD. Specific author contributions: Per M. Hellstr ö m conceived and initiated the study and scrutinized eligible patients who were included in the survey and Registry. Drs Lin Chang, Yuri A. Saito, Peter Bytzer, Jan Tack, and Stefan Muller-Lissner screened and enrolled IBS patients into the study. All authors participated in writing, reviewing, and editing manuscript drafts and approving the final draft of the manuscript for submission. Financial support: Support for the study was provided by Rose Pharma A/S. Editorial support, funded by Rose, for preparation of the manuscript was provided by Patrice Ferriola, PhD. All authors received standard and economical support for patient recruitment and clinical work in the study. Potential competing interests: Lin Chang has served as a consultant for Albireo, Ironwood, Prometheus, Takeda, Ocera, GlaxoSmith- Kline, Salix, and Movetis. Per M. Hellstr ö m had no competing financial interest during the study. Peter Bytzer had no competing financial interest during the study. Stefan Mueller-Lissner is an advisor for ARYx Therapeutics, AstraZeneca, Axcan, Boehringer Ingelheim, Movetis, and Mundipharma. Jan Tack has served as a consultant to Addex Pharma, AstraZeneca, Menarini, Movetis, Novartis, Nycomed, Pfizer, Theravance, Tranzyme, and Zeria. Study Highlights WHAT IS CURRENT KNOWLEDGE 3 Irritable bowel syndrome (IBS) is a heterogeneous condition manifested by multiple gastrointestinal symptoms. 3 Abdominal pain is a hallmark feature of IBS and a key indicator of patient-assessed overall IBS severity. 3 Information on the natural history of IBS pain attacks is lacking. 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BMJ 22 ; 324 : by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY