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IntroductionDrotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon.MethodsColon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1 µM tetrodotoxin) and (2) contractility induced by 10–5 M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin.ResultsCompared with the vehicle, drotaverine and paracetamol (10−9–10−5 M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10−7–10−5 M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10−4 M) and hyoscine butylbromide (10−7–10−5 M) was not different from hyoscine butylbromide alone (10−7–10−5 M). At higher concentrations (10−3M–3*10−3 M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10–7 M was concentration-dependently enhanced by drotaverine (10−6M–10−5M).DiscussionPeppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties.

Background Irritable bowel syndrome with diarrhoea is characterised by frequent, loose or watery stools with associated urgency, resulting in marked reduction of quality of life. Ondansetron, a 5-hydroxytryptamine-3 receptor antagonist, has been shown to benefit patients with irritable bowel syndrome with diarrhoea. Objective To evaluate the effect of ondansetron in irritable bowel syndrome with diarrhoea. Design Phase III, parallel-group, randomised, double-blind, multicentre, placebo-controlled trial in 400 patients, with embedded mechanistic studies. Setting Hospital, primary care and community. Participants Eighty participants meeting Rome IV criteria for irritable bowel syndrome with diarrhoea. Intervention Ondansetron 4 mg (dose titrated up to two tablets three times a day) or matched placebo for 12 weeks. Main outcome measures Clinical – Primary patient-reported end point was % ‘Food and Drug Administration-defined responders’ over 12 weeks. Secondary end points were worst abdominal pain intensity, worst urgency, stool consistency, stool frequency, anxiety, depression and dyspepsia at 12 and 16 weeks. Main outcome measures Mechanistic – Whole gut transit time, faecal water, protease (FP), bile acids and assessment of rectal sensitivity using a barostat. Results Clinical – The study closed early due to slow recruitment. Between 1 January 2018 and 11 May 2020, 80 patients were recruited and randomised (20% of target), 37 to ondansetron, 43 to placebo. Discontinuations (4 ondansetron; 2 placebo) meant 75 completed the 12-week trial treatment. There were four protocol violations. In the intention-to-treat analysis, 15 (40.5%) on ondansetron were primary end-point responders (95% CI 24.7% to 56.4%), and 12 (27.9%) on placebo (95% CI 14.5% to 41.3%), p = 0.19, adjusted OR 1.93 (0.73, 5.11). Pain intensity reduction occurred in 17 (46.0%) on ondansetron (95% CI 29.9% to 62.0%) and 16 (37.2%) on placebo (95% CI 22.8% to 51.7%), p = 0.32. Improvement in stool consistency occurred in 25 (67.6%) on ondansetron (95% CI 52.5% to 82.7%) and 22 (51.2%) on placebo (95% CI 36.2% to 66.1%), p = 0.07. Use of rescue medication, loperamide, was lower on ondansetron [7 (18.9%) vs. 17 (39.5%)]. Average stool consistency in the final month of treatment reduced significantly more on ondansetron, adjusted mean difference –0.5 [standard error (SE) 0.25, 95% CI (–1.0 to –0.02), p = 0.042]. Ondansetron improved dyspepsia score (SFLDQ), adjusted mean difference –3.2 points [SE 1.43, 95% CI (–6.1 to –0.4), p = 0.028]. There were no serious adverse events. Mechanistic – mean (SD). Ondansetron increased whole gut transit time between baseline and week 12 by 3.8 (9.1) hours on ondansetron, significantly more than on placebo –2.2 (10.3), p = 0.01. Mean volume to reach urgency threshold using the barostat increased on ondansetron by 84 (61) ml and 38 (48) ml on placebo, n = 8, p = 0.26. Ondansetron did not significantly alter protease, faecal water or bile acids. Changes in referral pathways substantially reduced referrals, impairing recruitment, which meant the study was underpowered. Conclusion Our results are consistent with previous studies and confirmed ondansetron improves stool consistency and urgency but showed minor effect on pain. We plan to undertake a simplified version of this trial overcoming the changed referral pathways by recruiting in primary care, using software linked to primary care records to identify and randomise patients with irritable bowel syndrome with diarrhoea to ondansetron or placebo and remotely follow their progress; thus minimising barriers to recruitment. Trial registration This trial is registered as ISRCTN17508514. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 9. See the NIHR Journals Library website for further project information. Plain language summary Background Irritable bowel syndrome with diarrhoea is characterised by frequent, loose, or watery bowel movements with marked reduction of quality of life. A previous small study suggested ondansetron benefits patients with irritable bowel syndrome with diarrhoea. Methods A clinical trial aiming to recruit 400 patients meeting established criteria for irritable bowel syndrome with diarrhoea from 18 centres throughout the UK. Patients received either ondansetron or placebo for 12 weeks but neither the investigator and nor patient could tell which they were receiving. They recorded their worst abdominal pain, stool frequency and consistency daily. The main end point was the proportion of patients meeting a standard recommended by the U.S. Food and Drug Administration (FDA). Being called a “FDA responder” meant they showed reductions to both pain and days with loose bowel movements. Other less important end points included pain intensity, stool consistency and frequency. We also measured the time for content to pass through the gut (whole gut transit time). Results The study closed early due to slow recruitment with 80 patients randomised. There were 40.5% of responders in the ondansetron group and 27.9% in the placebo group; however, due to low numbers these differences could be due to chance. Ondansetron produced a significant improvement in average stool consistency in the final month of treatment. Ondansetron slowed whole gut transit time which increased from baseline to 12 weeks by a mean of 3.8 hours, while it fell 2.2 hours on placebo, a difference unlikely to be due to chance. Conclusion These results are consistent with previous studies showing that ondansetron improves stool consistency and slows transit. However, because the numbers recruited were smaller than planned, the apparent improvement in “FDA responder” rate could have been due to chance. A further larger trial is needed to confirm the benefit of ondansetron which should be done in primary care where most patients are to be found. Scientific summary Background Irritable bowel syndrome (IBS), which affects around 10% of the population, accounts for 1.8 million consultations/year in primary care in England and Wales (0.6 million patients). Symptoms of IBS with diarrhoea (IBS-D) include frequent, loose or watery stools with associated urgency, which can severely limit socialising, travelling and eating out, with resulting marked reduction in quality of life and loss of work productivity. Around one-third of all IBS patients meet Rome criteria for IBS-D. When patients are asked to rank symptoms in order of importance, the erratic bowel habit is rated first, followed by abdominal pain and, for those with diarrhoea, urgency. Ondansetron, a 5-hydroxytryptamine-3 (5HT3) receptor antagonist, has an excellent safety record for over 20 years as an antiemetic, but is only exceptionally used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, crossover pilot study, benefited patients with IBS-D. While the current trial was ongoing, a separate trial in the USA using a fixed dose bimodal release formulation (3 mg ondansetron +9 mg delayed release formulation) also reported improvement in stool consistency but not pain. Objectives Our primary aim was to determine the efficacy of generic ondansetron compared to placebo in controlling the symptoms of IBS-D using the US FDA-recommended combined end point in which a responder is defined as a patient who met the response criteria for both pain and bowel habit for 6 out of 12 weeks of the trial. Secondary end points included its effect on the characteristic abnormalities of stool consistency, frequency and urgency as well as abdominal pain, satisfactory relief of IBS symptoms, mood and use of rescue medication and to determine the effect of 12 weeks ondansetron over the 1 month after discontinuation, as well as safety. The study also included mechanistic studies to examine the correlation of rectal sensitivity and compliance, faecal bile acids (FBAs) and proteases and postprandial sigmoid motility with the baseline symptoms of our IBS-D patients. We also attempted to determine whether ondansetron significantly altered these biomarkers compared to placebo. Methods Treatment of irritable bowel syndrome using titrated ondansetron trial (TRITON) was a multisite, parallel-group, randomised, double-blinded, placebo-controlled trial, with embedded mechanistic studies within selected sites. Our aim was to determine the superiority of ondansetron compared with placebo. We aimed to randomise 400 patients with IBS-D on a 1 : 1 basis to receive either ondansetron or placebo. Both treatments were administered for 12 weeks in oral doses ranging from 4 mg every third day to 24 mg daily. Dose titration was undertaken in the first 2 weeks of the study to avoid constipation, which at a standard dose occurs in one-quarter of patients. This was achieved by frequent consultation with the research nurse, starting with 1 × 4 mg tablet per day and increasing in increments every 2 days to a maximum of 2 tablets thrice daily. If constipation developed, the treatment was stopped to allow the return of bowel movements and then restarted at a lower dose, typically one every alternate day or one every second day. Rescue medication of loperamide was discouraged but allowed exceptionally for uncontrolled diarrhoea and was documented in the daily diary. The primary outcome of response for both reduction in pain intensity and improvement in stool consistency was assessed over the 12 weeks post randomisation. Secondary and safety outcomes were measured up to 16 weeks post randomisation. Symptoms that were recorded daily included (1) stool consistency and abdominal pain (measured by both paper diary and daily text message); (2) stool frequency, urgency of defaecation, use of rescue medication (defined as the use of loperamide) over 12 weeks of treatment and the answer to the question in the diary ‘Overall, have you had satisfactory relief from your IBS symptoms in the past week?’. Irritable bowel syndrome symptom severity [measured by the IBS Severity Scoring System (IBS-SSS)], dyspepsia [using the Short Form Leeds Dyspepsia Questionnaire (SFLDQ)], quality of life and mood [using the IBS Quality of Life (IBS-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires], and somatic symptoms [using the Patient Health Questionnaire 12 Somatic Symptoms (PHQ-12) questionnaire] were assessed by patient-reported questionnaires at the baseline and 12 weeks post randomisation. The trial also assessed possible underlying mechanisms of any effect of ondansetron on changes in the primary and secondary end points. Whole gut transit was measured at baseline and 12 weeks using radio-opaque markers and an abdominal X-ray. High-resolution manometry was performed at baseline and after 8–11 weeks of treatment at two centres to assess whether ondansetron decreased the number of high-amplitude propagating contractions (HAPCs) or increased the percentage time occupied by cyclical retrograde propagated contractions. Barostat assessment was performed at baseline and after 8–11 weeks of treatment at two centres in order to assess if ondansetron increases rectal compliance or decreases sensitivity (manifested as increased pressure thresholds for pain and urgency). Stool samples were assessed for faecal water % (FW), faecal protease (FP) and FBAs. Clinical results The study closed early due to slow recruitment with just 80 patients randomised; 37 to ondansetron and 43 to placebo. Four patients discontinued ondansetron and one placebo during 12-week randomised treatment. Four were excluded from the per-protocol population due to major protocol violations. In the intention to treat (ITT) analysis, 15 patients (40.5%) on ondansetron achieved the primary end point response [95% confidence interval (CI) 24.7% to 56.4%], compared to 12 (27.9%) patients on placebo (95% CI 14.5% to 41.3%), p = 0.19, adjusted OR 1.93 (0.73, 5.11). Response for pain intensity reduction was achieved by 17 (46.0%) on ondansetron (95% CI 29.9% to 62.0%) and 16 (37.2%) on placebo (95% CI 22.8% to 51.7%), p = 0.32, adjusted OR 1.61 (0.63 to 4.12). Response for stool consistency improvement was reported by 25 (67.6%) on ondansetron (95% CI 52.5% to 82.7%) and 22 (51.2%) on placebo (95% CI 36.2% to 66.1%), p = 0.07, adjusted OR 2.45 (0.92, 6.52). Overall use of the rescue medication, loperamide, was 39.5% (n = 17) on placebo compared with 18.9% (n = 7) on ondansetron. However, by week 12, loperamide use fell to 13.5% on ondansetron versus 25.6% on placebo. Average stool consistency in the final month of treatment fell significantly more on ondansetron than placebo, adjusted mean difference –0.5 [standard error (SE) 0.25, 95% CI (–1.0 to –0.02), p = 0.042]. Ondansetron improved the dyspepsia score (SFLDQ) significantly more than placebo; the largest reduction being in symptoms of indigestion and nausea. The adjusted mean difference in the total score compared to placebo was –3.2 points [SE 1.43, 95% CI (–6.1, to –0.4), p = 0.028]. Ondansetron was well tolerated with most adverse reactions being mild or moderate and not significantly greater than on placebo. The commonest was constipation, reported in 32% on ondansetron and 23% on placebo, of which 75% and 80%, respectively, were rated as mild. Just two patients withdrew citing constipation as the cause. Mechanistic results Results are expressed as mean (SD). Comparing baseline and week 12 showed ondansetron increased average whole gut transit 3.78 (9.1) hours on ondansetron significantly more than placebo –2.2 (10.3), p = 0.01. Mean volume to reach urgency threshold using the barostat increased on ondansetron by 84 (61) ml and 38 (48) ml on placebo, n = 8; the difference was not significant, p = 0.26. Too few underwent manometry to allow meaningful assessment of the effect of ondansetron but anecdotally one patient who had a dramatic clinical improvement showed a loss of HAPCs and an increase in retrograde contractions, but this could have been due to chance. Ondansetron appeared not to significantly alter FP, though overall the increase in whole gut transit time from baseline to week 12 was correlated with a decrease in FP. There were no significant changes in FBAs and no evidence that ondansetron altered these though we did confirm that we had effectively excluded those with bile acid diarrhoea (BAD). The ratio of secondary to primary bile acids, a measure of bacterial metabolism of bile acids, increased substantially on ondansetron from 9.7 (7.08) to 21.4 (32.9) and less so on placebo from 22.84 (58.23) to 28.61 (31.42). However, owing to small numbers and wide variability these differences were not significant. Limitations Two previous studies in Nottingham had recruited 120 and 136 IBS-D patients within 2 years so we did not anticipate problems with recruitment. However, changes in referral pathways from primary to secondary care substantially reduced referrals to our coinvestigators who were all in secondary care, thus impairing recruitment. The power calculations required 400 to achieve 90% power to detect a 15% difference in primary end point, so the study is substantially underpowered. Use of loperamide did somewhat complicate interpretation since those on placebo used more rescue medication reducing the size of the effect on transit and stool consistency. Conclusion Despite being underpowered for our primary end point, our results are consistent with previous studies and confirmed ondansetron improves stool consistency but showed little effect on pain. Ondansetron significantly slowed whole gut transit time. Ondansetron reduced sensitivity to rectal distension more than placebo without altering compliance, but numbers were too small to achieve statistical significance. This could plausibly contribute to the reduction in urgency and stool frequency but needs repeating with larger numbers to be sure it was not due to chance. We found no evidence that rectal sensitivity was related to either faecal protease or bile acids. The manometry studies were underpowered but anecdotally ondansetron appeared to alter rectosigmoid motor patterns in a way that could reduce inflow of stool to the rectum. Future work We plan to do a simplified version of this trial, using an efficient and remote process, to overcome the changed referral pathways by recruiting in primary care. We will search for patients who have had a diagnosis of chronic diarrhoea and the recommended screening including a normal full blood count, a negative tissue transglutaminase (excluding coeliac disease) and a normal faecal calprotectin using software linked to primary care records. This will allow rapid screening of large numbers of patients to identify and approach patients with IBS-D who meet criteria to take part in a randomised trial of ondansetron or placebo, thus minimising barriers to recruitment. We would remove the pain threshold, which would increase the number of eligible patients and facilitate recruitment. Not allowing loperamide as rescue medication would simplify interpretation and dropouts would be treated as treatment failures. Further streamlining by removing all additional tests that were included in the current trial, as well as efficient trial processes, including e-consent, remote blood and stool samples (if required), and online questionnaires would also optimise recruitment. Study registration This trial is registered as ISRCTN17508514. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 9. See the NIHR Journals Library website for further project information.

Abstract Background Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond. Trial registration ISRCTN, ISRCTN17508514, Registered on 2 October 2017.

Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on “Understanding Gastrointestinal Absorption-related Processes (UNGAP)” was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.

ObjectiveThe gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method.Material and methodsEighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later.ResultsData from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence.ConclusionNon-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes.Clinical trialThis trial was registered at ClinicalTrials.gov as NCT03191045.

Opioids have recently received much attention because of the epidemic in their use in some countries such as the USA and the UK. Concerns have been raised about the possibility that they can increase mortality in patients when used on a long-term basis. Moreover, they are known to induce paradoxical hyperalgesia as well as alterations of gut function. The analgesic properties of opioids are mediated by receptors located in the brain, but as opioid receptors are also expressed in the gastrointestinal tract, new drugs acting on these receptors have recently been developed to treat two functional disorders, namely irritable bowel syndrome with diarrhoea and opioid-induced constipation. The aim of this article is to highlight some interesting observations resulting from the development of these drugs in the field of functional gastrointestinal disorders.

Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the different assimilations of two µ-receptors agonists, eluxadoline and loperamide, with a peculiar pharmacokinetic profile. Compared to loperamide, eluxadoline is absorbed less after the intake of a fatty meal, and the LogP values do not explain this event. Firstly, keeping in mind the different pH in the intestinal tract, the protonation states of both compounds were calculated. Then, all structures were subjected to a conformational search by using MonteCarlo and Molecular Dynamics methods, with solvation terms mimicking the water and weak polar solvent (octanol). Both computational results showed that eluxadoline has less conformational freedom in octanol, unlike loperamide, which exhibits constant behavior in both solvents. Therefore, we hypothesize that fatty meal causes the “closure” of the eluxadoline molecule to prevent the exposure of the polar groups and their interaction with water, necessary for the drug absorption. Based on our results, this work could be a reasonable “case study”, useful for future investigation of the drug pharmacokinetic profile.

Functional dyspepsia is a prevalent functional gastrointestinal disorder that can significantly erode the quality of life of sufferers and places a major cost burden on healthcare services. In this article, we review the recent literature, selecting the information we consider relevant since it has changed our clinical management of patients with functional dyspepsia.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal (GI) disorder that can significantly erode the quality of life (QoL) of sufferers and places a major cost burden on healthcare services. This paper reviews the literature on the impact of IBS on healthcare services and society, including a recent report on the subject, in order to formulate a plan for the future. A completely different model of care for these patients is recommended based on this review and the experience of the two authors who have been treating patients with functional GI disorders for 20 and 35 years, respectively.