Interactions between Symptoms and Motor and Visceral Sensory Responses of Irritable Bowel Syndrome Patients to Spasmolytics (Antispasmodics)

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1 Interactions between Symtoms and Motor and Visceral Sensory Resonses of Irritable Bowel Syndrome Patients to Sasmolytics (Antisasmodics) Igor L.Khalif 1, Eamonn M.M.Quigley 2, P.A.Makarchuk 1, O.V.Golovenko 1, L.F.Podmarenkova 1, Y.A.Dzhanayev 1 1) State Scientific Centre for Coloroctology, Moscow, Russia; 2) Alimentary Pharmabiotic Center, Deartment of Medicine, National University of Ireland, Cork, Ireland Abstract Aim: to evaluate and correlate the symtomatic, motor and sensory resonses to two widely used categories of sasmolytic agents in irritable bowel syndrome (IBS). Methods: 118 atients with IBS, diagnosed by Rome II criteria and 45 healthy individuals were studied. In the IBS subjects, ain severity, as well as the sensory resonse to rectal balloon distention and rectal and sigmoid motility, were studied at baseline and after two weeks theray with either oral buscoan (20 mg three times a day, n=37), a buscoan suository (30 mg once daily, n=21), oral drotaverine (80 mg three times a day, n=30), calcium gluconate tablets (one three times a day, n=16) as a control for oral agents, or calendula suository (once daily, n=14) as a control for those who received a suository. Results: Buscoan, whether administered as a tablet or a suository, roduced a significant reduction in ain scores among IBS atients with redominant diarrhea. No significant differences were evident among other IBS subgrous or in resonse to drotaverine. None of the interventions had any effect on any of the arameters of rectal or sigmoid motility studied. However, both buscoan and drotaverine led to a significant augmentation of the rectal threshold for discomfort/ain among IBS subjects with redominant diarrhea [21.78±2.8 vs 39.60±2.4 (<0.05), 20.5±2,8 vs 36.84±3.8 (<0.05) and 22.18±2.8 vs 36.9±2.42 (<0.05) for oral buscoan, rectal buscoan and oral drotaverine, resectively]. Conclusion: We conclude that the clinical benefits of suosed sasmolytic (anti-sasmodic) agents may relate more to effects on visceral sensation than motility. Key words Irritable bowel syndrome sasmolytics symtoms Received: Acceted: J Gastrointestin Liver Dis March 2009 Vol.18 No 1, Address for corresondence: Eamonn M M Quigley MD FRCP Det of Medicine, Clinical Sciences Building, Cork University Hosital Cork, Ireland e.quigley@ucc.ie motility visceral sensation. Introduction Irritable bowel syndrome (IBS) is one of the most imortant clinical roblems in modern gastroenterology. The recise etiology of IBS is not known. Both sychological and emotional factors and chronic stress have been regarded as imortant initiators of IBS [1]. While, more recently, enteric infection, food intolerance, immune activation and disturbances in the colonic and small intestinal microflora have been roosed as laying a role in the athohysiology of IBS [2-4], disordered intestinal motility and visceral hyersensitivity have long been regarded of rimary imortance [5-7]. However, the recise nature of the relationshi between any one of these factors and the clinical resentation and/or natural history of IBS has yet to be elucidated [7, 8]. The diagnosis of IBS currently rests, therefore, on symtoms alone or, more recisely, on an aggregation of clinical symtoms. For examle, in one of the most commonly used clinical definitions, the Rome II and III criteria [9, 10], IBS is defined by the resence of abdominal ain or discomfort for not less than 12 weeks during the last 3-12 months, which is related to, or imroved by, defecation and which may be accomanied by changes in the frequency and/or consistency of the stool. In Rome II, ain is central to the definition of IBS; considerable effort has been exended, therefore, on attemting to understand the genesis of ain in IBS. Visceral hyersensitivity (VHS) which refers to an increased sensitivity to eriheral stimuli (mechanical, thermal, chemical and other) and which is manifested through the develoment of ain, motor and/or secretory disturbances in resonse to a sub-threshold stimulus [6,11-13] is widely regarded as laying a key role. Visceral hyeralgesia (the henomenon whereby usually non-ainful stimuli are areciated as being ainful) is one manifestation of VHS. At resent, VHS is considered as the rimary mechanism originating and influencing the intensity of the ain syndrome and motility disorder in IBS [6].

2 18 Khalif et al The athogenesis of VHS in IBS is not comletely understood. Neuromodulatory etides, such as serotonin, are now thought to lay a most imortant role [14]. As intraluminal ressure in the large intestine rises, the enterochromaffin cells which line the eithelium roduce and release serotonin, which by activating 5-HT 3 - recetors, located on afferent (sensory) neurons, results in the generation of ascending sensory imulses from the erihery [15]. In the cerebral cortex, these sensory imulses induce different sensations, including ain. Meanwhile, the activation of 5-HT 4 and 5-HT 1 recetors located on neurons in the submucosal nerve lexus, intensifies eristalsis and romotes intestinal secretion [14, 16]. Other factors may also lay a role in the athogenesis of VHS, including an imbalance in the system which controls ascending ain imulses at the level of sinal interneurons, and a reduction in descending anti-nocicetive inut from the cerebral cortex [15, 17]. This focus on VHS has led to a search for agents that could decrease VHS and thus ain. Currently, the agents most widely used in an attemt to reduce ain in IBS are antisasmodics, also termed sasmolytics, directed at intestinal smooth muscle. In the ast, it was assumed that these agents acted through an inhibition of muscle sasm ; their effects on what is thought to be a fundamental abnormality in IBS, VHS, has not, as yet, been studied. The aim of this study was to examine, in a dynamic fashion, relationshis between ain, motility and visceral sensation, among IBS atients being treated with myogenic sasmolytics. Methods Patient characteristics The study was carried out on 118 consecutive atients with IBS, diagnosed in accordance with Rome II criteria [9]. The age of the atients was 33.8±10.4 years; 85 (67.4%) were females. In terms of IBS redominant symtom, 43 had constiation, 25 diarrhea, and in 50 atients ain and bloating dominated the clinical icture. None had consumed antisasmodic medications rior to study. The control grou comrised 45 healthy individuals free of gastrointestinal symtoms. The age of the control subjects was 32.6± 6.2 years; 20 were male and 25 female. Method Pain intensity at baseline and following was estimated with the aid of a visual analog scale. Patients were asked to mark their ain intensity along a 20 cm graduated line where 0 corresonded to an absence of ain and 20 to unbearable ain. Visceral sensation was assessed in both IBS atients and controls by assessing the resonse to balloon inflation. Following an overnight fast and the administration of a one liter cleansing enema on the revious evening, a latex balloon connected to a catheter syringe was introduced into the rectum and inflated in a ste-wise fashion in 10 ml increments at 1 minute intervals. The subjective symtomatic resonse of the atient to balloon inflation was assessed throughout. The minimum ressure, at which discomfort or ain was exerienced, was defined for each atient as their threshold for sensation. Colonic motility was assessed at baseline in all atients using the multile balloon manometry technique. Prior to testing, rectal evacuation was achieved with an enema; all medications that could affect colorectal motility had been discontinued for at least two days. A multi-channel robe incororating five 2 ml balloons arrayed at a distance of 5 cm from each other was then introduced into the colon under sigmoidoscoic guidance. During the examination the atient lay on their left side with their knees drawn u to the chest. Recordings commenced 15 to 20 minutes after the introduction of the robe and were continued for 2 hours. All data from sensory and motility studies was dislayed on a monitor and subsequently analyzed using the Polygraf gastrointestinal motility recording system (Medtronic, USA-Denmark). Control data for the colonic motility studies was derived from rior studies of the large intestine of healthy volunteers at the State Scientific Centre of Coloroctology (Moscow, Russia) [18]. Study rotocol On comletion of the baseline measurements, 96 of the original 118 atients agreed to articiate in the rest of the rotocol and were consecutively assigned (in a manner that ensured equal distribution of IBS subgrous to each theraeutic grou) to one of five grous and received one of the following medications over the next two weeks: 1. Oral buscoan 60 mg daily (20 mg three times a day) (n=37); 2. Buscoan suository, 30 mg once daily (n=21); 3. Oral drotaverine 240 mg er day (80 mg three times a day) (n=30); 4. Calcium gluconate tablets (0.5g one three times a day) (n=16), as a control for oral agents; 5. Calendula (Calendula Officinalis L., or marigold, a herbal rearation) suository once daily (n=14), as a control for those who received a suository. Given the differences in formulation and method of administration of the various medications, subjects were not blinded to their theraeutic agent. Those erforming the objective measurements (manometry and sensory testing) as well as those recording symtomatic resonses were blinded to the atient s theray. All sensory and motility tests were reeated in each of these grous at the end of the eriod. As at baseline, all studies were erformed in the morning on an emty stomach, the last dose of medication having been taken on the evening before. Data analysis Motor activity of the large bowel was reresented by recognizable atterns of wave forms which could be classified as segmenting, eristaltic and roulsive. Their differentiation was based on amlitude, roagation and

3 Irritable bowel syndrome and sasmolytics 19 temoral occurrence as well as the very secific features of the roulsive waves. Segmenting contractions featured low amlitude waves and were non-roagating. Secific features of eristaltic waves included their distal roagation, high amlitude and intermediate duration. Proulsive waves were rare, related, erhas to the rior cleansing of the rectum but were very distinctive being of high amlitude, long duration (arox 30 sec) and distinctly roagative. These waves corresond to the high amlitude roagating contractions or ower contractions described by others. In evaluating motor activity, the following values were defined: a. The magnitude of the tone of intestinal wall, calculated using the formula Tone = 1/ A, where A is amlitude of resiration waves, exressed in mmhg; b. The median amlitude and duration of individual waves of motor activity; c. Longitudinal relationshis between wave forms (i.e. whether segmenting, eristaltic or roulsive); d. The index of motor activity calculated using the formula: Index = A x t / T, where A = amlitude of wave, t = duration of the wave, T = the duration of the eriod of recording registering and = sum of A x t e. Timing and intensity of the 1 st and 2 nd hases of the gastro-colonic reflex. Statistics For comarisons re- and ost-, within a given grou Student s t-test or Wilcoxon and Mann-Whitney U tests were used, for arametric and non-arametric data, resectively. Where multile comarisons were erformed, the Bonferroni correction was used. Results All 96 subjects who entered the randomization hase comleted the two-week study (Table 1); there were no dro-outs relating to adverse events or otherwise and, indeed, no side effects were reorted in relation to any of the theraies. 1. Baseline symtoms and resonse to (Table I) As exected, the highest ain scores were recorded at baseline by those IBS atients with redominant ain and bloating. On the visual analog scale, the average intensity of ain at baseline was estimated by IBS atients with redominant ain and bloating at 13 (on a scale whose maximum was 20 oints), by IBS atients with redominant diarrhea at 10 oints and by IBS atients with redominant constiation at 8 oints. Significant reductions in ain score were achieved only among IBS atients with redominant diarrhea and in resonse to either oral or er suository buscoan. 2. Rectal sensation a. Baseline studies In the control grou, the threshold for the develoment of discomfort/ain was 43.6±3.2 mm Hg which corresonds closely to revious reorts [6]. In the IBS atients, the threshold for the develoment of discomfort/ain was significantly lower at mmhg. Differences in discomfort/ain threshold were also evident between the IBS subgrous, being significantly (<0.05) lower among those with redominant diarrhea in comarison to those with constiation or ain and bloating: 19.66±4.2 mm Hg vs 33.82±4.78 mm Hg vs 28.17±6.7 mm Hg, resectively. b. Resonse to with oral buscoan (Table II) in the grou of IBS atients with redominant ain and bloating, their discomfort/ain sensitivity threshold increased to 34.64±4.8 mmhg (ns) and 32% of atients reached the normal sensitivity threshold ( 40 mmhg). In the grou of atients with redominant constiation the discomfort/ain sensitivity threshold increased to 35.4±2.6mmHg (ns); normal values were not achieved by any atient in this grou. The most striking results of this were in the grou of IBS atients with redominant diarrhea: in 58%, their ain Table II. Discomfort/ain thresholds in IBS atients in resonse to oral buscoan. ain and bloating (n=17) constiation (n=13) diarrhea (n=7) Discomfort/ain threshold (mmhg) 29.12± ±4.8 > ± ±2.6 > ± ±2.4 <0.05 Table I. Pain scores at baseline in IBS atients and in resonse to Prearation constiation (n= 36) diarrhea (n= 21) ain and bloating (n= 39) Oral buscoan 8.2± ± ± ±1.1 (<0.05) 13.5± ±2.6 Buscoan suository 7.8± ± ± ±1.6 (<0.05) 13.6± ±2.2 Oral drotaverine 8.1± ± ± ± ± ±2.1 Oral calcium gluconate Calendula suository 8.4± ± ± ± ± ± ± ± ± ± ± ±2.4

4 20 Khalif et al sensitivity threshold reaching the normal value (<0.05). with drotaverine (Table III) in the grou of atients with redominant ain and bloating the discomfort/ ain threshold after increased to 34.22±4.1mmHg (ns). In the grou of atients with redominant constiation the discomfort/ain sensitivity threshold did not increase significantly. For IBS atients with redominant diarrhea, the discomfort/ain sensitivity threshold increased to 36.9±2.42 (<0.005).. None of the other changes were statistically significant and normal values of discomfort/ain sensitivity threshold were not reached in any of the grous. Table III. Discomfort/ain thresholds in IBS atients in resonse to oral drotaverine IBS with revailing ain and bloating (n=11) IBS with revailing constiation (n=12) IBS with revailing diarrhea (n=7) Discomfort/ain threshold (mmhg) 30.06± ±4.1 > ± ±2.1 > ± ±2.42 <0.05 The use of the lacebo rearation (calcium gluconate) roduced a minor increase in the discomfort/ain threshold in two IBS atients with redominant ain and bloating, and in one atient from the IBS grou with redominant diarrhea (Table IV). Table IV. Discomfort/ain thresholds in IBS atients in resonse to oral lacebo (calcium gluconate) ain and bloating (n=6) constiation (n=6) diarrhea (n=4) Discomfort/ain threshold (mmhg) 31.02± ±3.1 > ± ±.6 > ± ±2.33 >0.05 Following with buscoan as a suository (Table V), IBS atients with redominant ain and bloating showed an increase of their discomfort/ain sensitivity threshold to 33.96±4.6 (ns) and 23% reached normal values ( 40mm.Hg). The grou with redominant constiation showed only a slight and non-significant increase of their discomfort/ain sensitivity threshold to 34.22±3.64mm.Hg. In the grou of IBS atients with redominant diarrhea, a significant increase of the discomfort/ain sensitivity threshold was observed, to 36.84± 3.8 mm.hg. However, a normal discomfort/ain threshold was not reached by any atient among these grous. No significant changes or even trends in discomfort/ ain threshold were identified in any IBS grou following with the lacebo calendula suository (Table VI). Table V. Discomfort/ain thresholds in IBS atients in resonse to buscoan as a suository ain and bloating (n=11) constiation (n=6) diarrhea (n=4) 3. Colonic motility In the IBS atients, the balloon kymograhic data revealed hyersegmentary hyokinesia in 67%, hyotonic hyokinesia was observed in 24% and antieristaltic comlexes in 9%. We did not identify any differences in motility arameters either between IBS subtyes or before and after with any of the rearations tested (Tables VII, VIII). Discussion Discomfort/ain threshold (mmhg) 28.32± ±4.6 > ± ±3.64 > ± ±3.8 <0.05 Table VI. Discomfort/ain thresholds in the control subjects in resonse to rectal lacebo (calendula suository) ain and bloating (n=5) constiation (n=6) diarrhea (n=3) Discomfort/ain threshold (mmhg) 30.18± ±2.9 > ± ±3.2 > ± ±3.24 >0.05 This lacebo-controlled study investigated relationshis between symtomatic, motility and visceral sensory effects of two harmacological agents (buscoan and drotaverine) which have been develoed and are used on the basis of their antisasmodic roerties. Buscoan hydrochloride has been shown, in a large lacebo-controlled study to relieve IBStye ain and is widely used for this indication world-wide [19] while drotaverine, a aaverine derivative, and related comonds, such as alverine, have been widely used as a sasmolytic agent in obstetrics, urology and gastroenterology [20]. The main finding of this study was that while neither agent had any effect on motor arameters in the rectum and sigmoid colon, the agent that had a symtomatic benefit, buscoan, exerted its rincial hysiological effects not on arameters of motor activity, but on visceral sensation. Indeed, indices of motor function of the large intestine changed very little following ; while a few instances of recovery of intraluminal ressure to normal values were observed, these atients remaining symtomatic. Therefore, balloon kymograhy, the methodology emloyed in this study, while roducing interretable recordings of colorectal motor activity, did not rove of value in redicting the likely efficacy of a given theray.

5 Irritable bowel syndrome and sasmolytics 21 Table VII. Rectal motility arameters in IBS atients Motility Parameters Motor Activity (as a % of total time) (normal: 75.6±4.7) Motor Quiescence (as a % of total time) (normal: 24.46±4.7) Intraluminal ressure (cm H 2 O) (normal: 25-30) Motility index (normal: 8,5) Tye of IBS constiation (n= 36) 75.3± ± ± ± ± ± ± ±2.8 diarrhea (n= 21) 70.5± ± ± ± ± ± ± ±2.2 ain and bloating (n= 39) 75.4± ± ± ± ± ± ± ±2.6 Table VIII. Sigmoid motility arameters in IBS atients Motility arameters Time of activity (%) normal: (85.8±2.2) Time of rest (%) (normal: 14.2±2.2) Intraluminal ressure (cm H 2 O) (normal: 30-40) Activity index normal: 12,5) Tye of IBS constiation (n= 36) 67.3± ± ± ± ± ± ± ±2.2 diarrhea (n= 21) 65.5± ± ± ± ± ± ± ±1.8 ain and bloating (n= 39) 64.4± ± ± ± ± ± ± ±2.8 Visceral hyersensitivity testing, in contrast, roved more useful; increases in the threshold for ain coinciding with a decrease in the atients exerience of ain as a symtom. Furthermore, it is worth noting that the lower the level of the ain threshold at baseline, the more ronounced the effect, which might exlain the low effectiveness of the various rearations among IBS atients with redominant constiation. Indeed, the athogenesis of VHS in different tyes of IBS may vary to some extent as may the imact of various harmacological agents. Values for visceral sensitivity are considerably influenced by the method emloyed. It aears that not only the material emloyed in the manufacture of the balloon, but also the technique of inflation can significantly influence the study outcome. Slow constant inflation results in accommodation of the rectum, while stewise inflation does not and hyersensitivity has been observed far more often in studies emloying ste-wise inflation methods. Accordingly, the threshold for ain sensitivity with the more traditional method of slow continuous balloon inflation was significantly lower than with the use of the tracked ste technique [21, 22]. Indeed, Lembo et al could not differentiate between IBS subjects and controls when using the constant inflation technique [7]. Aart from methodological issues, it is also evident that variations in ercetion by individual atients, rior conditioning [23] and sychological factors will also influence the outcome of such tests and resent considerable challenges in develoing the ideal test for VHS as well as in understanding the athogenesis of ain in IBS [12]. Pending the develoment of the ideal technique, balloon inflation emloying the ste-wise technique remains the most accessible method for assessing VHS in clinical ractice. However, it is noteworthy that the threshold for discomfort/sensation documented in this study is remarkably similar to that of Bouin et al, who reorted, in their large series of IBS and control subjects that a cut off threshold of 40 mmhg was highly sensitive (90.7%) and secific (71.8%) in differentiating IBS atients from healthy controls [6]. We acknowledge the limitations of the study. It was not formally randomized; however, the demograhics of the various grous illustrate that each was reresentative of the overall oulation and of IBS in the community. Furthermore, the investigators were blinded to the s and as results of objective tests from the bulk of the recorded data, this should have minimized the effects of a failure to randomize. It is also ossible that drug effects could have unblinded the atients; we feel that this is unlikely as the one drug that had an effect on symtoms, buscoan, is oorly bio-available when taken orally with associated lasma levels being below levels of detection [24]. In conclusion, in this study, while we observed the resence of visceral hyersensitivity in all IBS atients studied, the lowest threshold for ain sensitivity was noted among those with redominant diarrhea. Among the theraeutic agents studied, the most ronounced effect on the ain sensitivity threshold was reached with buscoan when given orally, and had its greatest imact among those with redominant diarrhea. In contrast, none of the theraies had a major effect on any of the arameters of colorectal motility studied. We roose, therefore, that visceral hyersensitivity and not motor dysfunction may be a more aroriate target for assessing the imact of roosed antisasmodics/ sasmolytics in IBS. Conflicts of interest Nothing to declare. References 1. Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE. Psychosocial asects of the functional gastrointestinal disorders. Gut 1999; 45 (Sul 2): II McKendrick MW, Read NW. Irritable bowel syndrome-ost salmonella infection. J Infect 1994; 29: Neal KR, Hebden J, Siller RC. Prevalence of gastrointestinal symtoms six months after bacterial gastroenteritis and risk factors

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