Irritable bowel syndrome (IBS) is characterized by abdominal

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1 Treatment With Hypnotherapy Reduces the Sensory and Motor Component of the Gastrocolonic Response in Irritable Bowel Syndrome MAGNUS SIMRÉN, MD, PHD, GISELA RINGSTRÖM, RN, EINAR S. BJÖRNSSON, MD, PHD, AND HASSE ABRAHAMSSON, MD, PHD Objective: Postprandial symptoms in irritable bowel syndrome are common and relate to an exaggerated motor and sensory component of the gastrocolonic response. We investigated whether this response can be affected by hypnotherapy. Methods: We included 28 patients with irritable bowel syndrome refractory to other treatments. They were randomized to receive gut-directed hypnotherapy 1 hour per week for 12 weeks (N 14) or were provided with supportive therapy (control group; N 14). Before randomization and after 3 months, all patients underwent a colonic distension trial before and after a 1-hour duodenal lipid infusion. Colonic sensory thresholds and tonic and phasic motor activity were assessed. Results: Before randomization, reduced thresholds after vs. before lipid infusion were seen in both groups for all studied sensations. At 3 months, the colonic sensitivity before duodenal lipids did not differ between groups. Controls reduced their thresholds after duodenal lipids for gas ( mm Hg vs mm Hg, p.01), discomfort ( mm Hg vs mm Hg, p.01), and pain ( mm Hg vs mm Hg, p.01), whereas the hypnotherapy group reduced their thresholds after lipids only for pain ( mm Hg vs mm Hg, p.01). The colonic balloon volumes and tone response at randomization were similar in both groups. At 3 months, baseline balloon volumes were lower in the hypnotherapy group than in controls (83 14 ml vs ml, p.01). In the control group, reduced balloon volumes during lipid infusion were seen ( ml vs ml, p.05), but not after hypnotherapy (83 14 ml vs ml, p.20). Conclusion: Hypnotherapy reduces the sensory and motor component of the gastrocolonic response in patients with irritable bowel syndrome. These effects may be involved in the clinical efficacy of hypnotherapy in IBS. Key words: hypnotherapy, irritable bowel syndrome, visceral sensitivity, gastrocolonic response, colonic tone. IBS irritable bowel syndrome; 5-HT 5-hydroxytryptamine; IOP intraoperative pressure; PVE phasic volume event; IBS- D diarrhea-predominant irritable bowel syndrome; IBS-C constipation-predominant irritable bowel syndrome; IBS-A alternating-type irritable bowel syndrome. INTRODUCTION Irritable bowel syndrome (IBS) is characterized by abdominal pain, discomfort, or both related to abnormal bowel habits (1). It is probably the most common disorder encountered by gastroenterologists (2) and also the most common gastrointestinal disorder seen in primary care (3). This disorder may be viewed as a benign disorder from a strictly medical point of view, but in many patients, there is a chronic, relapsing course that severely affects quality of life (4). Therefore, there is a quest for efficient therapy, but pharmacological treatment is of limited value in many cases (5). There is convincing evidence that psychosocial factors are of major importance in IBS (6, 7). However, rather than being a cause of the disease, they are viewed as factors that contribute to the predisposition, precipitation, and perpetuation of IBS symptoms and affect the clinical outcome (8). There is some evidence that treatment modalities affecting psychological factors, such as dynamic psychotherapy (9), cognitive-behavioral treatment (10), and hypnotherapy (11), are effective in IBS. Hypnotherapy especially has From the Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden. Address correspondence and reprint requests to Magnus Simrén, MD, PhD, Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, S-41345, Göteborg, Sweden. magnus.simren@medicine.gu.se Received for publication March 17, 2003; revision received September 26, This study was supported by the Swedish Medical Research Council (grant 13409), the Health and Medical Care Executive Board of the Västra Götaland Region, the County Council and the Social Insurance Office in the Västra Götaland Region, and the Faculty of Medicine, University of Göteborg. DOI: /01.psy e Psychosomatic Medicine 66: (2004) /04/ Copyright 2004 by the American Psychosomatic Society proven efficacious in IBS, as demonstrated by several groups (12 15). The mechanisms responsible for the therapeutic success of hypnotherapy are largely unknown, but there are suggestions that it may act by affecting visceral sensitivity (16, 17), gastrointestinal motor function (18, 19), and psychological distress (20). In patients with IBS, postprandial worsening of symptoms is common (21, 22). The mechanism behind this has largely been attributed to an exaggerated motor response of the colon after a meal the gastrocolonic response in IBS compared with healthy people (23, 24). There also appears to be a sensory component of the gastrocolonic response, demonstrated by increased colorectal sensitivity in healthy volunteers after meal intake (25). Lipids appear to be the major stimulant for both the motor component and the sensory component of the gastrocolonic response (26 28). We recently demonstrated that patients with IBS have an exaggerated sensory component of the gastrocolonic response, as shown by marked reduction of colonic sensory thresholds and an alteration of the viscerosomatic referral pattern after lipid administration in the upper gut (29), which in part may explain their postprandial symptoms. This response was partly inhibited by alosetron, a 5-hydroxytryptamine (5-HT) 3 receptor antagonist, indicating that 5-HT 3 receptors, possibly located within the gastrointestinal tract, may be a cofactor for the exaggerated sensory component of the gastrocolonic response in IBS (30). There are also indications that central factors may be involved in this response (29). In the present study, we aimed to investigate the effects of hypnotherapy on the sensory and motor components of the gastrocolonic response in patients with IBS. We hypothesized that reduction of the gastrocolonic response, both in terms of reduced sensitivity and reductions in the colonic tonic and phasic motor response, in IBS patients with hypnotherapy might prove to be one explanation behind its clinical efficacy. 233

2 M. SIMRÉN etal. METHODS Subjects Thirty-five patients with IBS were invited to participate in the study from December 2000 to September 2001, and of these, 28 patients with IBS (mean age, years; range, 19 to 67 years; 19 females) according to the Rome II criteria (1) accepted participation and were enrolled in the study. Organic gastrointestinal disorder had been excluded with reasonable certainty, preferably by demonstrating normal routine laboratory tests and stool samples and, if indicated, colonoscopy with biopsies and a 75 Se-labelled homocholic acid-taurine examination. The patients were all refractory to standard medical treatment, and no continuous drug treatment was allowed during the study. They were referred to our research unit for hypnotherapy treatment partly from our own outpatient clinic and partly from other gastroenterologists in the area surrounding Göteborg. All subjects provided informed consent before inclusion, and the study was approved by the ethics committee of the University of Göteborg. Study Design The patients were randomized by the study nurse (G.R.) in blocks of 4 using numbered containers to receive gut-directed hypnotherapy 1 hour per week for 12 weeks or to serve as controls. Three experienced clinical psychologists, specially trained in hypnotherapy, conducted the hypnotherapy. Specifically, the hypnotherapy included hypnotic induction using progressive relaxation to deepen the hypnotic state. Thereafter, suggestions directed toward normalizing the gastrointestinal function were used, such as a river flowing smoothly, or a blocked river flow that was cleared by the patient. The patients were also told to practice their hypnotic skills at home between the sessions as often as possible, ideally on a daily basis. The patients randomized to the control group were provided with supportive therapy. They met with a dietitian once for 1 hour to receive general food advice with emphasis on good and bad food items in IBS, and with a physiotherapist for 1 hour, who provided information about relaxation training. Furthermore, a gastroenterologist specializing in functional gastrointestinal disorders met the patients in the control group for 1 hour and informed them about gastrointestinal physiology and especially about the pathophysiology of IBS. Moreover, a study nurse telephoned the subjects in the control group regularly during the treatment period for extra support. They were also assured that they would receive hypnotherapy after 6 months. Before randomization and after 12 1 week (3 months), ie, after the treatment period, all patients underwent a colonic distension trial with a barostat before and after a duodenal lipid infusion. The staff members performing the barostat trial were not blinded to the group assignment (Figure 1). Barostat Procedure The barostat procedure is reported in detail elsewhere (29, 30). After an overnight fast, the subjects took a tap water enema (1000 ml), after which an enteral feeding tube (Meda Polyuretansond; Fresenius AG, Bad Homburg, Germany) was placed with its tip in the descending part of the duodenum under fluoroscopic guidance. A balloon catheter consisting of a highly compliant polyethylene balloon was placed in the midsigmoid colon using a flexible sigmoidoscope. The balloon catheter was connected to a computerdriven electronic barostat (Dual Drive Barostat, Distender Series II; G&J Electronics, Toronto, Canada). The subjects were instructed to stay awake and to be alert during the entire investigation. A small number of distensions as large as 25 mm Hg were made to unfold the balloon properly. The intraoperative pressure (IOP) was then set to 2 mm Hg above the minimal distending pressure necessary to record respiratory variations in the balloon volume. An initial conditioning distension sequence was performed, inflating the balloon by 5 mm Hg stepwise increments every 30 seconds until the subjects reported discomfort. This step was performed because a previous study showed that measurement of compliance and sensation are different between the first and second distension sequence but not between the second and subsequent distension sequences (31). A 30-minute equilibrium period was allowed with the balloon pressure at IOP, during which fasting colonic tone was assessed. In addition to the conditioning distension sequence, 2 distension sequences were performed each day 1 before and 1 immediately after the administration of lipid solution (Calogen, 1.5 kcal/ml; Nutricia Nordica, Stockholm, Sweden) via the enteral feeding tube. The infusion rate was 2 ml/min for 1 hour. When the subjects received the infusions, the balloon pressure was set at IOP. The subjects were told to report if they perceived any symptoms during the infusions. Distensions We used phasic distensions with a duration of 30 seconds starting at IOP and increasing stepwise by 3 mm Hg until the subject reported pain or a pressure of 50 mm Hg was reached. Resting periods of 30 seconds with balloon pressure set to the IOP separated the distensions. The subjects were instructed to grade their sensations during the distensions using a keypad linked to the main barostat. A grading scale consisting of 5 parameters was used: 1 represented no sensation, 2 fullness, 3 gas, 4 discomfort, and 5 pain. A tracking technique (single random staircase) (32) was used, with tracking beginning when pain (score of 5) was first reported, after which 10 more distensions were performed, provided the subject reported pain for at least 3 of them. The subjects were also instructed to mark the location of their respective sensation on a body map to evaluate the viscerosomatic referral pattern. This step was performed separately for each distension sequence. Barostat Data Collection The Protocol Plus software package (G&J Electronics) was used for barostat data collection. The thresholds for first sensation, gas, discomfort, and pain were determined during each distension sequence. The pain threshold was the average pressure of the distensions at which pain was reported. If pain was not experienced, the pain threshold was set to the maximum pressure of 50 mm Hg. First sensation was the balloon pressure at which the subject first could perceive the balloon, and the thresholds for gas and discomfort were the lowest pressure during the distensions at which these sensations were reported. Colonic balloon volumes, reflecting tone, were assessed with the pressure at IOP. Increasing balloon volumes reflected reduced colonic tone, whereas decreased balloon volumes indicated higher tone. Barostat balloon volumes were averaged over periods of 10 minutes for 30 minutes before the distensions (fasting tone) and during the infusions, respectively. Mean volumes were calculated for the 30-minute period before the distensions representing fasting tone. Furthermore, as a measure of phasic contractility, the number of phasic volume events (PVEs), defined as changes of 10% or greater compared with the baseline volume, and occurring at a rate of 1 to 4 per minute (33), were calculated during the lipid infusion. Compliance curves, ie, pressure-volume relationships, were also created for each distension sequence by plotting the volume increase ( V) against the corresponding pressure level above the IOP ( P). To evaluate the viscerosomatic referral pattern, the relative area of referred discomfort and pain was recorded by the subjects on a body map. By using a simple geometric formula, this information was measured (for instance, r 2 if a circle was drawn by the patient). Figure 1. A schematic drawing of the study design. Statistical Analysis Results are expressed as means SEM in this study. The thresholds for first sensation, gas, discomfort, and pain before vs. after the lipid infusion 234 Psychosomatic Medicine 66: (2004)

3 IRRITABLE BOWEL SYNDROME were compared within both the hypnotherapy and control group before randomization and after the treatment period, respectively. The baseline thresholds that is, before the enteral administration of lipids; the percent reduction in the thresholds after lipids; the colonic tone response (reduction in balloon volumes during lipid infusion relative to baseline); and the number of PVEs were compared between the groups, both before randomization and after the treatment period. For these within-group and between-group comparisons, t test statistics were used. The compliance curves and the balloon volumes, reflecting tone, before vs. during the infusions were compared using 1-way and 2-way analysis of variance. Significance was accepted at the.05 level. RESULTS Patients The hypnotherapy group consisted of 14 patients with IBS (mean age, years; range, 25 to 67 years; 9 females), of whom 3 had diarrhea-predominant IBS (IBS-D), 2 constipation-predominant IBS (IBS-C), and 9 alternating diarrhea and constipation (IBS-A), according to Rome II criteria (1). In the control group, there were also 14 patients with IBS (mean age, years; range, 19 to 66 years; 10 females), and 5 of these had IBS-D, 3 IBS-C, and 6 IBS-A. All patients completed the hypnotherapy and the supportive therapy (control group). In the hypnotherapy group, 10 of 14 patients reported improvement of their gastrointestinal complaints after the treatment period compared with baseline, whereas this was the case for 5 of 14 patients in the control group ( , p.06). More details about the effects of the hypnotherapy on symptoms will be reported elsewhere. One patient in each group withdrew after the treatment phase because of unwillingness to undergo the second barostat study, leaving patients with fully evaluable data from both barostat trials. The barostat trials were generally well tolerated, as were the lipid infusions, and this was similar in both groups. Thresholds The sensory thresholds in the fasting state, ie, before the lipid infusions, did not differ between the control group and the hypnotherapy group at baseline or after the treatment period (3 months). The thresholds in the fasting state were similar at baseline and after the treatment period (3 months) in both groups (Table 1). At baseline, both groups demonstrated significantly reduced thresholds for all sensations first sensation, gas, discomfort, and pain after the lipid infusion compared with the fasting state, except for first sensation in the control group, which did not reach statistical significance (p.13; Figure 2). This reduction in thresholds did not differ between the groups for any of the sensations (data not shown). After the treatment period, the sensory thresholds were significantly reduced after lipid infusion vs. the fasting state in the control group for gas ( mm Hg vs mm Hg, p.003), discomfort ( mm Hg vs mm Hg, p.006), and pain ( mm Hg vs mm Hg, p.005; Figure 3, A). After hypnotherapy, only the pain threshold was significantly reduced after lipid infusion ( mm Hg vs mm Hg, p.006), whereas the other sensations were unaffected by the infusion (Figure 3, B). Comparisons between the groups (percent reduction in thresholds) revealed that the control group reduced their threshold for gas significantly more than the hypnotherapy group (25 5.8% vs %, p.04), and a trend was noted in the same direction for the discomfort threshold (24 6.3% vs %, p.15). The thresholds after the infusions did not differ significantly between the groups. Increased referral areas for discomfort and pain were seen after lipid infusion compared with the fasting state at baseline and after the treatment period in both groups. Although there were numerically greater increments in the referral areas at baseline in the hypnotherapy group than in the control group, no significant group differences were observed in the increment in the relative area of discomfort at baseline ( cm 2 vs cm 2, NS) or after the treatment period ( cm 2 vs cm 2, NS), or for pain at baseline ( cm 2 vs cm 2, NS) or after the treatment period ( cm 2 vs cm 2, NS). Comparisons within each group between baseline and after the treatment period did not reveal any significant changes. Colonic Tone and Compliance The minimal distending pressure did not differ between the groups at baseline ( mm Hg vs mm Hg, NS) or after the treatment period ( mm Hg vs mm Hg, NS). At baseline, both groups had similar fasting balloon volumes in the colon and demonstrated reduced balloon volumes, indicating increased tone during the lipid infusion, without significant group differences (Figure 4, A). How- TABLE 1. Sensory Thresholds in the Fasting State a Baseline 3 Months Controls (N 14) Hypnotherapy (N 14) Controls (N 13) Hypnotherapy (N 13) First sensation Gas Discomfort Pain a Sensory thresholds (mm Hg) in the fasting state in both groups at baseline, ie, before the treatment, and at 3 months, ie, after the treatment period. Both within-group and between-group comparisons are nonsignificant. Psychosomatic Medicine 66: (2004) 235

4 M. SIMRÉN etal. Figure 2. Colonic sensory thresholds at baseline (mean SEM), ie, before the treatment period in the control group (N 14, black bars) and hypnotherapy group (N 14, white bars). The thresholds for the sensations are shown before and after duodenal lipid infusion. *p.05, **p.01, ***p.001 vs. before lipid infusion for the same sensation. Figure 4. Colonic balloon volumes (mean SEM) in the fasting state (before lipids) and during the first (0 to 30 minutes) and second (30 to 60 minutes) half-hour of duodenal lipid infusion before the treatment period (baseline; A) and after treatment (B). The balloon volumes reflect colonic tone, and significant reductions in the balloon volumes during the lipid infusion compared with before are seen in both groups, as an indicator of increased tone at baseline (A). However, after the treatment period (B), significant reductions in the balloon volumes during the lipid infusion compared with before are seen only in the control group, indicating increased tone, whereas no colonic tone response to the duodenal lipids is seen in the hypnotherapy group. Moreover, the balloon volumes before lipids are significantly lower in the hypnotherapy group than in the control group after treatment (p.05; B), whereas no differences are seen at baseline (A). Figure 3. Colonic sensory thresholds before and after duodenal lipid infusion (mean SEM) in the control group (A; N 13) and the hypnotherapy group (B; N 13) after the treatment period. Significant reductions of the sensory thresholds after vs. before the lipid infusion are seen for gas, discomfort and pain in the control group (A), but only for pain in the hypnotherapy group (B). **p.01 vs. before lipid infusion ever, after the treatment period, the balloon volumes in the fasting state were significantly lower in the hypnotherapy group compared with the controls (83 14 ml vs ml, p.009). The patients in the hypnotherapy group failed to demonstrate a colonic tone response during the lipid infusion, but the controls demonstrated reduced balloon volumes during the lipid infusion, similar to baseline (Figure 4B). The colonic tone response (reduction in balloon volumes) after the treatment period was greater in the control group than in the hypnotherapy group during the first half-hour of the lipid infusion (17 6mlvs. 1 3 ml, p.01), with a trend in the same direction during the second half-hour (30 12 ml vs. 4 7 ml; p.08). Colonic compliance was not affected by the lipid infusion in any of the groups and did not differ between the groups (data not shown). The number of PVEs, as a measure of phasic contractility, was similar at baseline and after the treatment period, both in the hypnotherapy group (28 4.8/60 min vs /60 min, NS) and the control group (27 6.6/60 min vs /60 min, NS), and did not differ between the groups. DISCUSSION In the present study, we have demonstrated that hypnotherapy reduces some variables in both the sensory and motor component of the gastrocolonic response in patients with IBS refractory to other treatments. Because these patients often complain of postprandial symptoms (22), this may be an important explanation behind the clinical efficacy of hypnotherapy in IBS, at least in patients with severe IBS. It now has been almost 20 years since hypnotherapy was 236 Psychosomatic Medicine 66: (2004)

5 IRRITABLE BOWEL SYNDROME introduced as an effective treatment alternative for patients with IBS (11). Despite this, it is still not quite clear why it is effective. When proposing this treatment to patients, which is looked on with a certain degree of skepticism by some, it would be helpful to be able to explain the way it works more clearly. Some studies have suggested that hypnotherapy alters sensory and motor function within the gastrointestinal tract, and that this is related to symptom improvement (17, 19). Another possibility is that hypnotherapy affects the way information from the gastrointestinal tract is interpreted in the brain in a favorable way (34). However, a recent study demonstrated that improvement after hypnotherapy was unrelated to changes in physiological parameters, such as rectal sensitivity, rectal smooth muscle tone, and autonomic functioning, but instead was explained by reductions in psychological distress and somatization (20). Possibly a mixture of central and peripheral effects of hypnotherapy may be active in reducing symptoms in our patients with IBS; however, at this stage, it is fair to say that the mechanisms behind the positive results of hypnotherapy in functional bowel disease are somewhat unclear. Visceral hypersensitivity has been proposed to be one of the key factors behind symptoms in patients with IBS (35). Therefore, the search after effective pharmacological treatment alternatives for these patients has largely focused on reducing this hypersensitivity within the gastrointestinal tract (36, 37). Also, hypnotherapy has been proposed to reduce visceral sensitivity (16, 17). However, a recent trial failed to detect an effect of hypnotherapy on visceral sensitivity (20). This is in agreement with our findings, with the absence of an effect of hypnotherapy on fasting colonic sensitivity. However, the enhanced colonic sensitivity after nutrients in the upper gut seen in these patients (29, 38) was reduced after hypnotherapy for some of the sensations assessed in the present study. This effect may be of importance for reducing the postprandial symptoms that are so common in this patient group (21, 22). We propose that this can be one of several mechanisms through which this treatment modality exerts its positive effects. However, in the present study, we did not specifically ask for postprandial symptoms, making it impossible to correlate this to the experimental results. The mechanisms behind the reduction in postprandial colonic sensitivity after hypnotherapy are not covered in the present study. A recent study from our group indicated that 5-HT 3 receptors are involved in the sensory component of the gastrocolonic response, even though they do not appear to be the major mediator (30). Moreover, a pilot study in IBS-D proposed an enhanced postprandial release of 5-HT in these patients (39). Therefore, reduced postprandial 5-HT release after the hypnotherapy is one plausible explanation behind the less pronounced sensory component of the gastrocolonic response after hypnosis compared with the control group, but this remains to be proven. Another possibility is that reductions in psychological distress could be involved in the reduction of the lipid-induced colonic hypersensitivity. Palsson et al. (20) recently demonstrated that improvement in IBS symptoms Psychosomatic Medicine 66: (2004) after hypnosis is related to reductions in psychological distress and somatization. Moreover, patients with IBS appear to have altered brain responses to gastrointestinal stimuli (40, 41), and psychological improvement for instance, after hypnotherapy (12) may therefore positively affect how gastrointestinal stimuli are perceived. In our previous study, we found an effect of duodenal lipids on the viscerosomatic referral pattern of colonic balloon distensions, indicating involvement of factors at the spinal or a more central level (29). In the present study, however, we did not find a significant effect of hypnotherapy on the viscerosomatic referral pattern, even though the enhancement of the referral area for perceived discomfort and pain was numerically less pronounced after hypnosis. However, a type II error cannot be ruled out altogether, because we studied only 13 patients in each group, making it fair to state that the involvement of psychological factors behind the reduction in the sensory component of the gastrocolonic response cannot be excluded. This risk of a type II error is, of course, present for all the comparisons made in the present study. Cholecystokinin is another possible mediator of the sensory component of the gastrocolonic response, and patients with IBS appear to have an increased sensitivity to cholecystokinin (42, 43). However, whether the release profile of cholecystokinin and the sensitivity to this peptide are affected by hypnotherapy is, to the best of our knowledge, not known. Effects of hypnosis on gastrointestinal motor function have been described previously both a retarding effect on orocecal transit time (18) and a reduction in colonic motility (19). We also demonstrated an abolished motor component of the gastrocolonic response in terms of the postprandial colonic tone response after hypnotherapy. Even though the tonic gastrocolonic response is not significantly altered in patients with IBS as a group (44, 45), a number of patients with IBS suffer from urgency after meal intake, and in these patients, a reduction in the gastrocolonic response may certainly be beneficial. Somewhat surprising, however, was the increased basal tone (lower balloon volumes) in the hypnotherapy group compared with the control group. The control of muscle tone in humans is complex, and there is evidence that cholinergic, adrenergic and nonadrenergic noncholinergic factors are involved (46, 47). There are indicators of sympathetic nervous system activation in some patients with IBS (48), and this may be related to enhanced stress reactivity. From a theoretical point of view, hypnotherapy could result in reduced stress levels and thereby reduced sympathetic nervous activity. Based on existing knowledge, this would increase the fasting tone (46) and reduce the gastrointestinal sensitivity (49), which is in line with our findings. However, this hypothesis needs to be tested in future studies. In conclusion, we have demonstrated that hypnotherapy results in reduction of the sensory and motor component of the gastrocolonic response in patients with IBS refractory to other treatments. This could be one of perhaps several factors re- 237

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