Prevalence and management of abdominal cramping and pain: a multinational survey

Alimentary Pharmacology & Therapeutics Prevalence and management of abdominal cramping and pain: a multinational survey E.M.M.QUIGLEY*,G.R.LOCKE, S. MUELLER-LISSNERà, L.G.PAULO,G.N.TYTGAT, I. HELFRICH** & E. SCHAEFER** *Alimentary Pharmabiotic Centre, National University of Ireland, Cork, Ireland; Mayo Clinic, Rochester, MN, USA; àpark-klinik Weißensee, Humboldt University, Berlin, ; Academia de Medicina do Rio de Janeiro, Rio de Janeiro, ; Academisch Medisch Centrum, Amsterdam, the Netherlands; **Boehringer Ingelheim, Ingelheim, Correspondence to: Dr E. M. M. Quigley, Department of Medicine, Alimentary Pharmabiotic Centre, Clinical Sciences Building, Cork University Hospital, Cork, Ireland. E-mail: e.quigley@ucc.ie Publication data Submitted 20 March 2006 First decision 24 March 2006 Resubmitted 9 May 2006 Accepted 10 May 2006 SUMMARY Background Though functional gastrointestinal complaints are recognised as being common throughout the world, there have been few comparative studies of prevalence. Aim To compare the prevalence and management of abdominal cramping/ pain in nine countries. Methods In a two-stage community survey, approximately 1000 subjects were interviewed in each of nine countries to establish the demographics of individuals with abdominal cramping/pain (stage 1) followed by market research-driven interviews with 200 sufferers per country (stage 2). Results 9042 subjects were interviewed in stage 1. (46%) and (43%) had the highest prevalence of abdominal cramping/pain; Japan the lowest (10%). cramping/pain was more common in women (12 55%) than in men (7 38%).About 1717 subjects participated in stage 2; 65% were women and the average age at symptom onset was 29 years. The frequency of episodes differed between countries, being highest in the US (61% suffered at least once in a week). Sufferers in the US and Latin America reported a higher usage of medications (around 90%) than those in Europe (around 72%). In most countries over-the-counter drugs were principally used. Antispasmodic drugs were most popular in Latin America and, antacids in and the. Drug therapy decreased the duration of episodes (by up to 81% in ). Conclusions The community prevalence, severity, healthcare seeking and medication usage related to abdominal cramping/pain are high overall, but vary considerably between countries. Aliment Pharmacol Ther 24, 411 419 ª 2006 Blackwell Publishing Ltd 411 doi:10.1111/j.1365-2036.2006.02989.x

412 E. M. M. QUIGLEY et al. INTRODUCTION While functional disorders of the gastrointestinal tract, which have been estimated to occur in up to 30% of the adult population in western countries, 1, 2 are recognized as a frequent cause of painful abdominal cramps, it is also evident that only 20 50% of these same symptoms can be formally attributed to irritable bowel syndrome (IBS), 3, 4 the best characterized and most relevant of the functional disorders. 5 Recent surveys have, however, provided estimates of IBS prevalence which have ranged from as low as 3% to as high as 22%. 4 6 IBS is an intestinal symptom complex of which abdominal cramping and pain is the central symptom, but which features other digestive symptoms, such as constipation, diarrhoea, bloating, or flatulence. 3, 7 In an effort to simplify IBS definition and diagnosis three sets of symptom-based diagnostic criteria have been proposed: Manning, Rome I and Rome II. 8 10 The application of these criteria, both in prevalence studies and in clinical practice, is not without inherent problems, 3, 7, 11 as indicated by the observation that the actual prevalence of IBS varies considerably depending on the criteria used for diagnosis. 1 Moreover, the use of the term IBS appears to be largely limited to the Anglo-Saxon world whereas in other countries similar complaints are usually referred to as abdominal cramping and pain, abdominal discomfort or abdominal disorder, unspecified. This may result in an underestimation of the prevalence of functional gastrointestinal disorders in surveys of IBS prevalence. For these reasons we set out to focus directly, in this multinational survey, on complaints of abdominal cramping and pain, rather than employ one of the IBS criteria. The goal was to compare the prevalence, demographics, clinical features and management of abdominal cramping and pain in the United States of America, Latin American countries, Japan and European countries. A community survey was performed utilizing well-established market research techniques, in two stages. In the first stage, we established the prevalence of abdominal cramping and pain and concomitant digestive symptoms in the general community. In the second stage, which was performed independent of stage 1, more extensive interviews were performed among subjects who suffered from abdominal cramping and pain in order to obtain insights into the nature of the abdominal complaints, the characteristics of individual episodes and the role of drug therapy in dealing with these symptoms. METHODS Study design The survey was based on face-to-face interviews carried out by a professional third party market research organization (Ipsos; Hamburg, ) in nine countries (,,,,, Japan,, the United Kingdom and the US) between June and September 2004. The master questionnaire was developed in English by market research experts and medical advisors and distributed to local market research institutes for review and translation; local input was sought on the appropriateness of terminology before individual questionnaires were finalized. As deemed appropriate for market research purposes and because the head office of the market research organization was based in, the German version questionnaire was then piloted and tested in full in five subjects to assess feasibility of completion and the subjects understanding of the questions. The prevalence of abdominal cramping and pain was assessed by asking the survey participants whether they had experienced on a regular basis, i.e. more than just occasionally, abdominal cramping and pain over the past 2 years. The study was carried out in two phases (stage 1 and stage 2; for details see Appendix 1). The results of stage 1 were used to define the selection criteria for participants in stage 2 of the survey. Study population There were no a priori selection criteria for the participants in stage 1 as this was an epidemiological survey. The use of a multi-client Omnibus approach utilizing multi-stratified sampling techniques ensured the selection of a random sample of approximately 1000 subjects from the general population in each country. Respondents for stage 2 of the survey, which was performed independent of stage 1, had to meet the following selection criteria defined by market researchers and medical advisors according to best medical knowledge in this area: (i) suffered from abdominal cramping and pain on a regular basis for at least 2 years, (ii) acid-related problems-like heartburn should not be the dominant symptom and (iii) for females, abdominal cramping and pain should not be exclusively linked to menstruation. Respondents in each country were stratified to provide a 35%/65% male/female gender split

ABDOMINAL PAIN AND CRAMPS: A MULTINATIONAL SURVEY 413 and an equal representation over the age groups of 16 29, 30 49 and 50+ years. Data collection Respondents in stage 2 of the survey were classified according to their own assessment of the severity of their abdominal cramping and pain on a scale of 1 (low) to 10 (high). Scores were grouped as follows: 1 4 as mild, 5 7 as moderate and 8 10 as severe. Other symptoms were assessed according to presence, frequency (always or occasionally) and associated distress (on a visual analogue scale). Statistical methods and sample size Data were analysed using descriptive statistics and logistic regression. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated where appropriate. cramping and pain. In all countries the great majority of such subjects also suffered from other digestive symptoms. The average number of associated digestive symptoms varied from 1.2 () to 2.4 (, ). Sufferers from the US and Latin American countries reported more digestive symptoms (2.1 2.4) than sufferers in European countries (1.2 1.5) and Japan (1.5). Regional differences in the occurrence rates of individual symptoms were evident, with constipation and flatulence being most common in, diarrhoea in the US and and bloating in and. Acid-related problems played an important but regionally variable role (data not shown). Among sufferers in, 53% reported acid-related problems as a predominant symptom; in Japan only 16% reported acid-related problems as predominant. Sufferers with predominant acid-related problems were excluded from stage 2 of the survey. RESULTS Stage 1 interviews: general population In the first stage of the survey, a total of 9042 interviews from nine countries were included in the analysis. Prevalence of abdominal cramping and pain The survey results for stage 1 are illustrated in Figure 1. The prevalence of abdominal cramping and pain in the general population varied considerably between countries, from 10% in Japan to 46% in (Figure 1a). In general, the prevalence of abdominal cramping and pain was highest in Latin American countries ( 46%, OR: 6.8, CI 5.5 8.5; 43%, OR: 5.2, CI: 4.1 6.5) and lowest in Japan (10%). In all countries studied, with the exception of, the prevalence in females was higher than in males (Figure 1b, OR: 1.7, CI: 1.6 1.9). Overall, there was no difference in prevalence between the different age groups (Figure 1c), though the prevalence of abdominal cramping and pain was higher in younger subjects in and in and lower in younger subjects in and the. Concomitant digestive and acid-related problems Table 1 lists the occurrence rates for various other digestive symptoms among sufferers from abdominal Stage 2 interviews: sufferers from abdominal cramping and pain The target sample size of 210 respondents was reached in all eight countries (Appendix 2). The recruitment took place mainly in urban areas. The stratification for gender (two-thirds of females) and for the three age groups (one-third each) was achieved with only minor deviations (Appendix 2). Complaints profile The participants were interviewed with respect to their complaints profile during the 12 months preceding the interview. These questions referred to the frequency of suffering, as well as the severity and distress associated with episodes. These data are illustrated in Figure 2a. The frequency of suffering from abdominal cramping and pain was highly variable between countries. It was the highest in the US, followed by, and the and lowest in. The severity of abdominal cramping and pain was rated as high in all countries. The mean score ranged from 6.6 to 7.8 (out of a total score of 10) in all countries. Sufferers in (mean score 7.8) and (mean score 7.5) perceived their symptoms to be most severe and were most concerned by the symptoms. The frequency of drug usage and the duration of episodes in the presence or the absence of

414 E. M. M. QUIGLEY et al. (a) 50 45 43 46 40 % Of subjects 35 30 25 20 15 10 19 12 27 31 10 24 31 5 0 Japan USA (b) 60 Female Male scbxfbv 55 50 46 % Of subjects (c) % Of subjects 40 30 20 10 0 60 50 40 30 20 10 0 23 16 29 1514 37 36 38 37 31 29 28 23 24 16 12 12 13 7 Japan <34 years 35 54 years >55 years 36 30 30 31 27 21 242324 121312 12 12 9 Japan USA USA 49 4344 44 40 32 3031 32 Figure 1. Prevalence of abdominal cramping and pain in the general population in nine countries. The numbers indicate the proportion of regular sufferers and include those who were suffering from predominant acid-related problems: (a) provides the overall prevalence, (b) the prevalence by gender and (c) the prevalence by age group. Number of respondents included were 1400 in, 1250 in Japan, 1000 in,, US, and, 715 in and 677 in the. medication were also evaluated (Figure 2b). Approximately one episode per week in each country required drug treatment. Drug use correlated well with frequency of attacks being highest in the US and lowest in and. Similar trends were evident for the average duration of episodes without medication, which was again highest in the US and lowest in and. As perceived by sufferers, medication shortened the duration of episodes considerably: for instance from 65 to 18 h in the US and from 25 to 5 h in. In all countries, approximately one-third of all sufferers experienced some premonitory symptoms preceding an acute episode, such as discomfort related to abdominal gas/air, abdominal distension, or a rumbling stomach (data not shown). The total number of symptoms experienced in an acute episode was highest in and the 7 and lowest in 4 and 3 (Table 2). Nevertheless, the results were quite consistent across countries with abdominal pain and digestive symptoms being mentioned most often, and with abdominal pain and cramps being identified as the most bothersome symptoms. Argentinean sufferers differed as they reported headache in addition to abdominal pain as the most bothersome symptom. pressure and feeling of tightness was especially bothersome in the, and.

ABDOMINAL PAIN AND CRAMPS: A MULTINATIONAL SURVEY 415 Table 1. Survey stage 1: Digestive symptoms in sufferers from abdominal cramping and pain in nine countries Proportion of sufferers with digestive symptoms (%) Average number of digestive symptoms with other with flatulence with bloating/fullness with diarrhoea with constipation with other symptoms (total) (solely) Country (sufferers) (n ¼ 192) 49 64 20 28 24 20 10 1.5 (n ¼ 124) 25 76 21 24 31 16 6 1.2 (n ¼ 191) 20 90 25 29 30 16 17 1.4 (n ¼ 213) 20 90 26 32 30 20 26 1.5 Japan (n ¼ 131) 19 90 40 36 17 31 8 1.5 US (n ¼ 237) 39 88 36 38 31 42 27 2.1 (n ¼ 311) 26 87 40 33 55 36 17 2.1 (n ¼ 428) 29 97 63 21 46 67 19 2.4 (n ¼ 646) 56 92 42 38 55 24 26 2.4 The number of sufferers per country includes those who suffered from predominant acid-related problems. The role of medication The importance of medications in the management of abdominal cramping and pain is apparent from Figure 2b. Sufferers of abdominal cramping and pain perceived a considerable shortening of the duration of the attack when they used medication. A more detailed analysis of medication use is provided in Table 3. In all countries the majority of sufferers of abdominal cramping and pain used medication (67 92%). This usage was clearly higher in the US and Latin America (89 92%) than in European countries (67 77%). In all countries, except, the use of over-the-counter (OTC) medicines exceeded that of prescription drugs. The ratio of OTC to prescription use varied from 0.9 () to 4.6 (). The average number of drugs concomitantly taken varied from 1.6 () to 2.4 (). Antispasmodic drugs were most popular in Latin America and ; 45 73% of sufferers used these. In, the use of antacids dominated (46%), in the analgesics (25%) and antacids (32%). DISCUSSION This study extends our understanding of the prevalence, nature and implications of common digestive symptoms in nine different countries. We have confirmed the usefulness of community surveys performed using well-established market research techniques, as demonstrated earlier by Hungin et al. 11 While our survey did not include any diagnostic testing and we cannot, therefore, exclude organic diagnoses, we feel that given the duration of complaints that it is reasonable to assume that most were functional in origin. One of the most important findings in this study is related to our ability to detect common, important and, presumably, functional symptoms which would not have been detected by survey techniques which involved one of the diagnostic paradigms used to define IBS. While the prevalence and severity of the various abdominal symptoms showed considerable variation in the general population of the different countries, the overall prevalence of abdominal cramping and pain (10 40%) exceeded the prevalence of IBS, as described in the literature. 4 6 This confirms the observation of others that the application of stringent criteria for IBS, such as Rome II, leads to lower estimates for the prevalence of IBS. 1, 11 14 However, the prevalence of complaints of abdominal cramping and pain in the present study is at the lower end of the

416 E. M. M. QUIGLEY et al. Figure 2. Profile of complaints, perceived severity and stress intensity and drug usage associated with abdominal cramping and pain. (a) Percentage of subjects who suffered from symptoms of abdominal cramping and pain at least once in a week, who had severe abdominal symptoms (score 8, 9 or 10 for Suffering) and in whom the abdominal symptoms caused major distress (score 8, 9 or 10 for Concern). (b) Percentage of subjects who used drugs at least once in a week and the duration of episodes without or with drug medication. Table 2. Symptoms experienced during episodes of abdominal cramping and pain US (N ¼ 214) (N ¼ 211) (N ¼ 209) (N ¼ 212) (N ¼ 218) (N ¼ 213) (N ¼ 211) (N ¼ 229) Average number of 6 5 7 6 6 4 3 7 complaints pain 71 65 84 66 74 59 57 78 Bloating, distension, 66 46 78 72 61 37 37 74 flatulence, other gas-related complaints cramps 65 59 69 31 66 61 50 71 Nausea 51 54 49 42 53 21 22 59 Diarrhoea 49 35 16 31 46 25 27 56 Pressure, feeling of 48 52 73 57 73 39 37 64 tightness Heartburn 43 27 42 56 39 30 27 39 Constipation 37 40 45 19 30 18 19 51 Headache, other non-gi symptoms 34 49 61 74 33 35 22 51 Respondents were asked which symptoms from a list provided were experienced during episodes. GI, gastrointestinal.

ABDOMINAL PAIN AND CRAMPS: A MULTINATIONAL SURVEY 417 Table 3. Usage of medications in the management of abdominal cramping and pain US (N ¼ 214) (N ¼ 211) (N ¼ 209) (N ¼ 212) (N ¼ 218) (N ¼ 213) (N ¼ 211) (N ¼ 229) Usage of medication (%) 92 89 92 91 77 67 74 68 Prescription drug only (%) 10 33 8 2 5 8 12 5 OTC drug only (%) 53 30 62 67 62 51 46 42 Prescription + OTC (%) 26 19 15 22 11 8 12 14 Ratio OTC/prescription use 2.2 0.9 3.3 3.7 4.6 3.9 2.4 3.0 Number of concomitant drugs 2.2 1.6 1.8 2.4 1.7 1.7 1.7 2.0 Main drug categories Analgesics 21 7 5 14 23 15 25 Antacids 19 9 12 46 20 18 32 Antidiarrhoeals 11 9 11 3 Antiemetics 1 14 Antispasmodics 4 73 51 72 23 33 45 18 Antigas 1 22 3 5 Gastrointestinal 15 Others 44 7 7 2 4 5 OTC, over-the-counter. prevalence of IBS defined using less stringent criteria. 11, 15 Among 4807 adults living in the community in the, the prevalence of IBS, estimated by means of a postal questionnaire and defined using the Manning criteria, was 11% 15 and a similar prevalence (12%) was found by Hungin et al. in a telephonic survey performed on 40 000 adults from eight European countries using a combination of a history of a diagnosis of IBS in the past and Manning, Rome I and II criteria. 11 In this study, we further noted that, whether because of a lack of awareness of the concept or differences in diagnostic criteria, a diagnosis of IBS was, with the exception of the and the US, rarely applied to our sufferers. A survey based purely on the concept of IBS would, therefore, have missed most of these symptoms. These findings reinforce the limitations of current diagnostic approaches to functional gastrointestinal complaints and also emphasize the tremendous differences that exist between cultures in the appreciation of the concept of IBS. Most patients and their doctors focus on symptoms, not syndromes. This consideration led to the symptom approach in the present market research surveys. The first stage of the survey described a prevalence of abdominal cramping and pain between approximately 10% and 46% of the general population. These findings are in agreement with previously published data. 2, 4 6, 13 We also confirmed a higher prevalence in women (two-thirds of subjects were females; OR: 1.7) 13, 16 and a similar prevalence across the different age groups studied. Based on these findings the selection criteria for stage 2 of the research survey were modified to include stratification for gender and age group. International variations were noted with respect to the impact of symptoms, with sufferers in Latin American countries and the US being more concerned about their condition than sufferers in European countries. Another major finding was the tremendous international variation in the terms used to describe the symptoms that occurred in an attack or episode. While abdominal pain and cramps, and to a lesser extent bloating, diarrhoea and constipation, were, overall, the most bothersome symptoms, there were significant between-country variations in the occurrence rates for these symptoms. These findings must be interpreted with caution; while they could be taken to imply a true difference in the prevalence of various symptoms between countries, they could also reflect differences in culture, language or expression that render interpretation problematic. While this was a market research exercise and not a true epidemiological survey, it must also be borne in mind that market research methods have been developed and validated to reach the man in the street rather than patients and were thus appropriate to our goals. This study

418 E. M. M. QUIGLEY et al. provides a crude snapshot of symptom prevalence; concise diagnostic categorization would require other instruments and medical evaluation. However, the information gleaned does provide insights into what patients actually complain of in various countries and what steps they take to deal with these problems. While respondents, in general, considered drug therapy to be quite effective, there were significant variations in the rate and nature of drug use, being higher in the US compared with Europe. We conclude that the prevalence of abdominal cramping and pain, as well as related medication usage, and especially OTC products and antispasmodics, are consistently high in the general population in different countries. On the other hand, there are significant differences between these same countries in the nomenclature employed to describe symptoms, as well as in the frequency, severity, sufferer impact and sufferer response to these same symptoms. A diagnostic approach based on the concept of IBS would have missed most of these sufferers. These findings have major implications for international studies of prevalence, pathophysiology and therapy of these common functional gastrointestinal symptoms. ACKNOWLEDGEMENTS This study was sponsored by Boehringer Ingelheim, Ingelheim,. The authors are grateful to Ipsos, Hamburg, for the execution and analysis of the interviews and to Ismar Healthcare NV for their assistance in editing of the manuscript. REFERENCES 1 Bommelaer G, Poynard T, Le Pen C, et al. Prevalence of irritable bowel syndrome (IBS) and variability of diagnostic criteria. Gastroenterol Clin Biol 2004; 28: 554 61. 2 Sandler RS, Stewart WF, Liberman JN, Ricci JA, Zorich NL. pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci 2000; 45: 1166 71. 3 Kruis W, Thieme C, Weinzierl M, et al. A diagnostic score for the irritable bowel syndrome. Gastroenterology 1984; 87: 1 7. 4 Drossman DA, Li Z, Andruzzi E, et al. US householder survey of functional gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis Sci 1993; 38: 1569 80. 5 Talley NJ. Irritable bowel syndrome: definition, diagnosis and epidemiology. Clin Gastroenterol 1999; 13: 371 84. 6 Jones R, Lydeard S. Irritable bowel syndrome in the general population. Br Med J 1991; 304: 87 90. 7 Weber FH, McCallum RW. Clinical approaches to irritable bowel syndrome. Lancet 1992; 340: 1447 52. 8 Manning AP, Thompson WG, Heaton KE, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978; 2: 653 4. 9 Drossman DA, Richter JE, Talley NJ, et al. The Functional Gastrointestinal Disorders, Pathophysiology and Treatment a Multinational Consensus. Boston, USA: Little Brown and Co., 1994. 10 Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller- Lisner SA. Functional bowel disorders and functional abdominal pain. Gut 1999; 45: 1143 7. 11 Hungin APS, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40 000 subjects. Aliment Pharmacol Ther 2003; 17: 643 50. 12 Cash BD, Chey WD. Review article: Irritable bowel syndrome an evidencebased approach to diagnosis. Aliment Pharmacol Ther 2004; 19: 1235 45. 13 Mearin F, Badia X, Balboa A, et al. Irritable bowel syndrome prevalence varies enormously depending on the employed diagnostic criteria: comparison of Rome II versus previous criteria in the general population. Scand J Gastroenterol 2001; 36: 1155 61. 14 Hillilä MT, Färkkilä MA. Prevalence of irritable bowel syndrome according to different diagnostic criteria in a nonselected adult population. Aliment Pharmacol Ther 2004; 20: 339 45. 15 Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel syndrome: a community survey. Br J Clin Pract 2004; 54: 495 502. 16 Chang L. Review article: Epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004; 20 (Suppl. 7): 31 9.

ABDOMINAL PAIN AND CRAMPS: A MULTINATIONAL SURVEY 419 APPENDICES Appendix 1. Methods used in the two stages of the survey Sample Stage 1 Stage 2 Random, community-based, representative sample of approximately 1000 subjects per country Non-random sample of at least 200 regular sufferers from abdominal cramping and pain since at least 2 years per country, for whom the ailment was not primary linked to acid/heartburn and not exclusively linked to menstruation Sample size 9042 respondents 1717 respondents, stratified to yield 35% males and 65% females, equal distribution (approximately 33%) in age groups of 16 29, 30 49, 50 years and above Countries and number of subjects interviewed per country Tools Questions N ¼ 9: US (N ¼ 1000); (N ¼ 1400); (N ¼ 1000); (N ¼ 1000); (N ¼ 677); (N ¼ 1000); (N ¼ 715); (N ¼ 1000); Japan (N ¼ 1250) Structured interviews based on a core questionnaire, slightly adapted for each country; face-to-face at subject s home (US: telephonic interviews); paper and pencil or computer-aided Four close-ended multiple choice questions: prevalence of abdominal cramping and pain with and without other abdominal symptoms (constipation, diarrhoea, bloating and/or fullness, gas, other digestive disorders); relevance (primary symptom, secondary symptom or no issue at all) of acid-related problems, such as indigestion or heartburn; use of OTC drugs; use of prescription drugs N ¼ 8: US (N ¼ 214); (N ¼ 211); (N ¼ 212); (N ¼ 209); (N ¼ 229); (N ¼ 213); (N ¼ 211); (N ¼ 218) Structured interviews based on a core questionnaire, slightly adapted for each country; face-to-face at subject s home (US: at shopping malls); paper and pencil or computer-aided Main interview (63 questions) preceded by a screening interview to identify sufferers from abdominal cramping and pain (10 questions): characteristics of ailment; usage and attitudes; treatment options Period June 2004 August 2004 July 2004 September 2004 Appendix 2. Stage 2: The aim was to select 65% female sufferers with an equal distribution over the three age groups Country Subjects (n) Female (%) 16 29 years (%) 30 49 years (%) 50+ years (%) Location of recruitment 213 67 28 41 31 Dutch-speaking Flemings and French-speaking Walloons from 10 larger towns in both regions 218 64 32 36 32 National distribution 211 66 31 37 32 12 large cities spread over 5 Nielsen areas 229 65 32 35 33 8 towns all over the country US 214 66 33 34 33 8 major towns covering east, west, north and south 212 65 33 34 33 Greater Buenos Aires 209 65 33 35 32 Greater Sao Paulo and Greater Rio de Janeiro 211 64 32 37 31 3 major Mexican urban areas Sufferers of acid- or menstruation-related abdominal cramping and pain were excluded.