Glucocorticoid‐enhanced extinction‐based exposure therapy in irritable bowel syndrome – a proof of concept study

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Örebro University

School of Medical Science Degree project, 30 ECTS 2016-‐01-‐07

Glucocorticoid-‐enhanced extinction-‐based

exposure therapy in irritable bowel syndrome

– a proof of concept study

Version 1

Author: Malin Hoglert, bachelor of medicine, Örebro University,

malin.hoglert@gmail.com

Supervisor: Michiel van Nieuwenhoven, MD, PhD, Associate Professor,

Dept. of Gastroenterology, Örebro University Hospital,

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ABSTRACT

Introduction

IBS is associated with a decreased serotonergic activity in amygdala, which increases activity in the emotional arousal network, resulting in an increased perception of visceral pain. This pattern is also seen in phobic disorders, resulting in enhanced fear response. Recent studies demonstrated that a combination of exposure therapy and acute cortisone administration is highly effective in the treatment of acrophobia. We hypothesize that IBS-patients demonstrate a phobic response following visceral stimulation, and that visceral stimulation with a rectal balloon (barostat) combined with i.v. cortisol administration will lead to a decreased visceral pain perception and improvement of abdominal symptoms.

Aim

To establish whether Glucocorticoid-enhanced Extinction-based Exposure Therapy (GEET) is able to improve visceral hypersensitivity, abdominal complaints and anxiety in IBS patients.

Methods

A pilot study based on a semi-blinded placebo-controlled parallel design. Six IBS-patients were randomized into two groups receiving GEET or placebo. GEET was applied 3 times within 1 week and consisted of a 30 min barostat protocol combined with 40 mg cortisol i.v. Visceral perception data, and symptom- and psychometric questionnaires, were evaluated at baseline, 1 week and 5-6 weeks after treatment.

Results

In treatment-group median pressure at baseline was: key4 24mmHg, key5 40mmhg. At first follow up: key4 24mmHg, key5 32mmHg. In placebo-group: key4 12mmHg, key5 24mmHg at baseline. At first follow up: key4 16mmHg, key5 20mmHg. Treatment-group median value for IBS-SSS was 100,7 at baseline and 71,2 at first follow up, IBS-QoL 30,1 and 52,2, VSI 65 and 61 respectively. In placebo-group the median value for IBS-SSS was 48,2 and 34,7, IBS-QoL 82,4 and 93,4, VSI 52 and 17 respectively.

Conclusions

Until now we have included 6 patients, this number does not allow non-parametric statistics. Descriptive statistics show no differences in visceral sensitivity, GI-symptoms and anxiety between placebo and treatment group. Further inclusion of subjects is needed for a final conclusion.

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ABBREVIATIONS

IBS Irritable Bowel Syndrome

GEET Glucocorticoid-enhanced Extinction-based Exposure Therapy

GI Gastrointestinal

SOP Standard Operation Procedure

IBS-SSS IBS Symptom Severity Scale

GSRS-IBS Gastrointestinal Symptom Rating Scale IBS

SF-NDI NEPEAN Dyspepsia Index

IBS-QoL IBS Quality of Life

VSI Visceral Sensitivity Index

GAD-7 Generalized Anxiety Disorder 7

HADS Hospital Anxiety and Depression Scale

PHQ Patient Health Questionnaire

B Baseline

F1 First follow up

F2 Second follow up

T Treatment-patient

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INTRODUCTION

IBS is a functional bowel disorder characterized by pain or discomfort with changes in stool pattern [1]. The pathophysiology of IBS is multifactorial and not completely understood, increased visceral perception (hypersensitivity) and disturbed

bidirectional brain-gut signalling are considered key factors [2,3]. The disturbed brain-gut signalling is might be associated with serotonergic dysregulation [4], which is also associated with a high prevalence of mood/anxiety disorders in IBS patients [5].

Experimental lowering of serotonergic activity in healthy controls, by means of a nutritional intervention called Acute Trypthophan Depletion, results in a loss of negative feedback inhibition of the amygdala, which leads to increased activity in the emotional arousal network [6]. The alteration in the activity of the emotional arousal circuits in healthy controls leads to increased visceral pain perception when exposed to a rectal stimulus [7]. IBS patients show similar pattern in the emotional arousal network when exposed to a rectal stimulus, which may provide an explanation for the visceral hypersensitivity in IBS-patients [6,7].

The amygdala plays an important part in consolidation of memory, activation of amygdala, and its efferent projections, enforces the storage of information [8]. Stress hormones and stress-activated neurotransmitters affect the activity of the amygdala and enhance the consolidation of memory in situations which are emotionally arousing [8]. Glucocorticoids are one of these stress hormones which improve memory and learning [8,9], but they can also facilitate extinction processes and inhibit retrieval of fear memories [10,11]. When people are exposed to chronic stress, or intensely emotional events, memory consolidation via the amygdala can produce traumatic memories and induce an enhanced fear response, thus leading to anxiety disorders like phobia or affective disorders [8].

In anxiety disorders conditioning and associative learning leads to formation of a fear memory [12-14]. Individuals with a phobic disorder demonstrate, when exposed to their phobic stimuli, a major fear response, due to retrieval of the stimulus-associated fear memory [15]. During a phobic response to a stimulus the activity in the

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amygdala increases and the activity in the emotional arousal network increases as well [16-18]. This pattern of increased activation in the emotional arousal network with a central role for the amygdala is similar to the pattern showed in IBS patients during a rectal stimulus [6,7,16-18].

Phobic disorders are often treated with exposure-based behavioural therapy, which is thought to eradicate the exaggerated fear response when exposed to stimulus [14]. Recently, de Quervain et al. demonstrated that a combination of exposure therapy and acute corticosteroid administration is highly effective in the treatment of acrophobia [14]. Other studies exploring cortisol-augmented cognitive behavioural therapy in phobic disorders have also shown beneficial result [11,19,20].

We hypothesize that visceral sensations should be considered as phobic stimuli in IBS patients, resulting in increased activity within the emotional arousal network, leading to central pain amplification. Hence, we hypothesize that Glucocorticoid-enhanced Extinction-based Exposure Therapy (GEET) results in a decreased visceral pain perception and improvement of abdominal complaints. This approach is completely new; no other studies have been carried out with respect to this topic.

The treatment offered to IBS patients is very limited. Lifestyle-alterations and diets can be difficult to maintain. Selective smooth muscle relaxants andprobiotic administration have limited effects [21,22],and antidepressants have side effects [23,24].Hence the findings of a new alternative and effective IBS-treatment would be significant for the healthcare and IBS patients.

Aim

The aim of this study is to establish whether GEET is able to improve (i.e. decrease) visceral hypersensitivity, abdominal complaints and anxiety in IBS patients.

Research Questions

• Is GEET able to improve (i.e. decrease) visceral perception in IBS patients? • Does GEET affect (i.e. decrease) abdominal symptoms and parameters of

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MATERIAL and METHODS

Study Design

This is a proof-of-concept pilot study; the design is a semi-blind placebo-controlled parallel design. The data described in this paper are part of a larger study; in which 24 IBS-patients are to be included.So far 6 subjects have been randomized into two groups receiving GEET or placebo. Randomization was conducted using 6 envelopes, 3 envelopes contained the word treatment and 3 envelopes contained the word control. For each subject an envelope was drawn at random. The subjects were not told if the were to receive treatment or placebo, hence the study was semi-blinded.

Material

Recruitment of subjects was performed at the gastroenterology outpatient clinic at Örebro University Hospital during Sept-November 2015. The inclusion criteria were: 1. Subjects fulfil Rome III diagnostic criteria for IBS (see appendix A) and

pain/discomfort frequency is at least 2 days a week in the last 12 weeks. 2. Visual Analogue Scale score of subject’s global assessment of abdominal pain and

discomfort equals ≥ 35mm at the randomisation visit.3. Males or females aged 18-65 years. 4. Signed informed consent. Exclusion criteria were: 1. Concurrent or recent treatment with drugs affecting intestinal function or mood, e.g. antidepressants. 2. Concurrent or recent (< 2 weeks) use of nutritional supplements or herb products affecting intestinal function or mood (e.g. aloe vera, St John’s Worth and probiotics). 3. Diagnosis of major psychiatric or somatic disease other than part of IBS. 4.

Pregnancy or breastfeeding. 5. Abuse of alcohol or drugs. 6. A recent history of systemic or oral steroid therapy.

8 patients met the criteria and were asked to participate, 6 patients chose to

participate. The 2 patients who chose not to participate did so because of lack of time for participation. The study group consisted of 1 male and 5 female, age ranging from 22 to 55, median age 28. Placebo-group consisted of 3 females, median age 24. Treatment-group consisted of 1 male and 2 female, median age 34. One treatment-patient chose to end the study before second follow up because of lack of treatment

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for IBS-symptoms. One patient in each group did not go through second follow up before the study ended. Therefore two patients from the treatment-group and one patient from placebo-group did not participate in second follow up.

Barostat

The barostat is a device that allows examinations of pressure-volume relations and visceral sensitivity in a hollow organ, such as the bowel or stomach. It can also be used as a tool to apply visceral stimuli to the rectum. It comprises of a computer-controlled pump, which is connected via a catheter to a polyethylene rectal probe.

In this study, visceral sensitivity measurements as well as treatment, by means of repeated rectal stimuli, were conducted using a barostat (Dual Drive Barostat Distender II Series, G&J Electronics Inc., Toronto, Ontario, Canada). Protocol Plus Deluxe Software (G&J Electronics Inc.) was used.One hour before every barostat procedure, a 750ml water enema was administrated for bowel preparation.

Method

The baseline barostat protocol was conducted according to SOP Rectal Barostat, see appendix B. Visceral sensations are scored on a scale; 1 first sensation, 2 first desire to defecate, 3 urgency, 4 discomfort, 5 maximal tolerable pressure/pain. The baseline examination also included several symptom questionnaires (appendix C); Visceral Sensitivity Index (VSI), IBS Symptom Severity Scale (IBS-SSS), Gastrointestinal Symptom Rating Scale IBS (GSRS-IBS), Nepean Dyspepsia Index (SF-NDI), Patient Health Questionnaire 15 (PHQ-15). And psychometric questionnaires (appendix D); IBS Quality of Life (IBS-QoL), Generalized Anxiety Disorder 7 (GAD-7), Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire 9 (PHQ-9).

One week later patients received treatment with GEET or placebo 3 times within a week (Mon-Wed-Fri). GEET comprised a combination of a 40 mg hydrocortisone (Solu-Cortef, Pfizer, see appendix E) i.v. a one hour before barostat exposure, and a 30 min barostat protocol based on the baseline measurements. Treatment protocol

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starts at 4mmHg, increase in steps of 4 mmHg for 15 seconds each, until the pressure reaches 85% of the maximal tolerable pressure of baseline, thereafter the pressure alternates between the pressure corresponding key 2 (first desire to defecate) and 85% of the corresponding pressure of key 5 (maximal tolerable pressure) measured at baseline, for 20 seconds in each step for a total of 30 minutes. The control group received 1 ml 0.9% NaCl solution i.v. one hour before barostat exposure, combined with rectal placement of the barostat probe, which was not inflated, i.e a “sham-procedure”.

The SOP Rectal Barostat was conducted again 1 week and 5-6 weeks after treatment for evaluation of visceral perception. During these examinations, the patients filled in the same symptom- and psychometric questionnaires as previous. For flow-chart of the process, see appendix F.

Data

Primary outcome parameter comprises evaluation of visceral sensitivity, measured with the barostat method. Secondary outcome parameters comprise evaluation of abdominal complaints and parameters ofanxiety and stress, using questionnaires. Data presented are from SOP Rectal Barostat and questionnaires at baseline (B), 1 week after treatment (F1) and 6-7 weeks after treatment (F2).

Visceral perception data and questionnaires are presented as individually results. Baseline and first follow up data are also presented as median for each group.For visceral perception and questionnaires the between subjects factor is treatment (two levels: GEET, placebo), and the within subjects factor were time (baseline, after 3 weeks and after 9 weeks) for questionnaires and time and pressure for visceral perception.

Descriptive statistics were used for analysis of the barostat data and questionnaires, as the patient number does not allow non-parametric comparisons. Data are presented in charts and tables. After completion of the whole study, the data will be statistically analysed using the non-parametric Wilcoxon signed-rank test for within subject factors, and Mann-Whitney U-test for between subject factors.

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Ethics

The study was approved by the Ethical Committee in Uppsala, EPN 2013/292. Patients signed an informed consent after been given oral and written information. The barostat method is a widely used technique and well established, it does not cause severe pain or discomfort for the patients.Intravenous administration of

hydrocortisone or placebo was not considered harmful for the patients. Performance of the study was justifiable as treatment for IBS is limited and often ineffective. Subjects received reimbursement for participation.

Study finance

The study was conducted with contribution from Nyckelfonden Foundation for Medical Research at Örebro University Hospital.

RESULTS

Barostat

For individual results se table 1.

In treatment-group median pressure at baseline was: key1 12mmHg, key2 16mmHg, key3 24mmHg, key4 24mmHg, key5 40mmhg. Ranging from 4mmHg to 40mmHg. At first follow up: key1 12mmHg, key2 20mmHg, key3 24mmHg, key4 24mmHg, key5 32mmHg. Ranging from 4mmHg to 52mmHg.

In placebo-group median pressure at baseline was: key1 8mmHg, key2 8mmHg, key3 16mmHg, key4 12mmHg, key5 24mmHg. Pressure ranging between 4mmHg and 24mmHg. At first follow up: key1 8mmHg, key2 12mmHg, key3 20mmHg, key4 16mmHg, key5 20mmHg. Ranging from 4mmHg to 32mmHg.

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Table 1. Individual Barostat Data.

Baseline First Follow Up Second Follow Up

Patient Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5

T1 4 12 16 16 40 4 4 12 8 32 4 12 12 16 24 T2 12 18 24 24 28 12 20 24 24 28 8 12 16 16 20 T3 16 16 24 28 40 20 20 28 36 52 P1 4 8 12 8 24 4 8 12 12 20 P2 8 8 20 16 24 12 16 20 16 20 8 12 16 16 20 P3 8 12 16 12 20 8 12 24 24 32

Table 1. Barostat data in unit mmHg. T and P stand for Treatment-patient and Placebo-patient respectively. Individual data from barostat examinations at baseline, first follow up and second follow up.

Chart 1. Barostat Data in Treatment Group

Chart 1. Barostat data, treatment group. T stands for Treatment-patient. Shows the corresponding pressure for the sensation: 1 First sensation, 2 First desire to defecate, 3 Urgency, 4 Discomfort, 5 Pain. At baseline, first and second follow up.

0 10 20 30 40 50 60

Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5

Patient T1 Patient T2 Patient T3

Treatment

Pressure mmHg

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Chart 2. Barostat Data in Placebo Group

Chart 2. Barostat data, placebo group. P stands for Placebo-patient. Shows the corresponding pressure for the sensations: 1 First sensation, 2 First desire to defecate, 3 Urgency, 4 Discomfort, 5 Pain. At baseline, first and second follow up.

Questionnaires

Patients filled in several GI-‐symptomatic questionnaires, for individual results se table 2, and questionnaires of anxiety and GI-‐specific anxiety, for individual results se table 3.

In treatment group median value for IBS-‐SSS was 100,7 at baseline and 71,2 at first follow up. GSRS scoring was 51 and 33 respectively. SF-‐NDI was 125 and 71 respectively. PHQ-‐15 was 16 and 8 respectively.

In placebo group the median value for IBS-‐SSS was 48,2 at baseline and 34,7 at first follow up. GSRS scoring was 41 and 33 respectively. SF-‐NDI was 88 and 40 respectively. PHQ-‐15 was 8 and 5 respectively.

In treatment group median value for IBS-QoL was 30,1 at baseline and 52,2 at first follow up. VSI scoring was 65 and 61 respectively. GAD-7 was 14 and 14

respectively. HADS anxiety score was 16 and 12 respectively; HADS depression score was 12 and 8 respectively. PHQ-9 was 12 and 6 respectively.

0 5 10 15 20 25 30 35

Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5 Key1 Key2 Key3 Key4 Key5

Patient P1 Patient P2 Patient P3

Placebo

Pressure mmHg

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In placebo group median value for IBS-QoL was 82,4 at baseline and 93,4 at first

follow up. VSI scoring was 52 and 17 respectively. GAD-7 was 3 and 0 respectively. HADS anxiety score was 3 and 5 respectively; HADS depression score was 0 and 1 respectively. PHQ-9 was 4 and 3 respectively.

Table 2. Individual Results in GI-‐symptomatic Questionnaires.

Patient IBS-SSS B IBS-SSS F1 IBS-SSS F2 GSRS B GSRS F1 GSRS F2 SF-NDI B SF-NDI F1 SF-NDI F2 PHQ-15 B PHQ-15 F1 PHQ-15 F2 T1 100,7 80,1 91,3 51 60 59 154 138 143 21 18 21 T2 110,7 71,2 133,2 56 33 61 125 71 105 16 7 14 T3 50,1 36,1 - 39 32 - 46 53 - 10 8 - P1 101,6 78,9 - 50 45 - 135 111 - 21 22 - P2 48,2 29,9 40,2 39 27 37 88 40 40 6 5 4 P3 37,4 34,7 - 41 33 - 35 34 - 8 5 -

Table 2. Results for GI-symptomatic questionnaires. T and P stand for Treatment-patient and Placebo-patient respectively. Baseline (B), first follow up (F1) and second follow up (F2). IBS-SSS score ranging between 0-140, GSRS score ranging between 0-91, SF-NDI score ranging between 0-245. A higher score represents more severe GI-symptoms. PHQ-15 ranging between 0-30, a higher score indicates more severe somatic symptoms.

Table 3. Individual Results in Anxiety and GI-Specific Anxiety Questionnaires.

Patient IBS-QoL B IBS-QoL F1 IBS-QoL F2 VS I B VSI F1 VSI F2 GAD-7 B GAD-7 F1 GAD-7 F2 HADS B HADS F1 HAD S F2 PHQ-9 B PHQ-9 F1 PHQ-9 F2 T1 30,1 27,2 45,6 65 66 63 16 14 10 A18 D13 A12 D12 A13 D8 22 22 15

T2 13,2 52,2 27,9 73 61 65 14 15 10 A16 D12 A14 D8 A13 D8 12 6 8 T3 75 79,4 - 26 27 - 3 6 - A9 D3 A5 D1 - 5 4 - P1 58,8 58,8 - 52 56 - 11 15 - A11 D5 A16 D7 - 14 23 - P2 86 94,9 96,3 53 17 17 3 0 2 A3 D0 A5 D0 A3 D0 1 0 0 P3 82,4 93,4 - 19 6 - 0 0 - A1 D0 A0 D1 - 4 3 -

Table 3. Results for anxiety and GI-specific anxiety questionnaires. T and P stand for Treatment-patient and Placebo-patient respectively. Baseline (B), first follow up (F1) and second follow up (F2). GI-specific questionnaires: IBS-QoL ranging between 0-100, a higher score indicates higher life quality, VSI ranging between 0-75, a higher score indicates more severe GI-specific anxiety. Questionnaires of anxiety and depression: GAD-7 ranging between 0-21, HADS ranging between 0-21 in both anxiety (A) and depression (D) scores, PHQ-9 ranging between 0-27, a higher score indicates poorer mental health.

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DISCUSSION

Median values in both groups show similar trends. Median value in the placebo-group shows improvement in discomfort but worsening in pain from baseline to first follow up. There is an improvement in GI-symptoms and an improvement in anxiety; only HADS showed a small worsening. In treatment-group median values reports no difference in discomfort and a worsening in pain from baseline till first follow up, but there is an improvement in both GI-symptoms and anxiety. However the low number of patients, with only 3 patients in each group, does not allow preliminary

conclusions.

In treatment-group patient 1 (T1) showed worsening in visceral sensitivity at each follow up, but reported fewer GI-symptoms at first, at second follow up the symptoms had increased but were still lower or the same as in baseline. The questionnaires of anxiety and GI-specific anxiety showed no clear trend. Patient T2 showed no

difference in visceral sensitivity at first but reported an improvement in GI-symptoms and mental health. This patient reported a worsening in visceral sensitivity and GI-symptoms till the second follow up, with mixed result in the psychometric data. Patient T3 showed improvement in discomfort and pain at first follow up, but did not demonstrate a big improvement in GI-symptoms or in the psychometric data.

The results in the placebo-group were very similar; Patient 1 (P1) had an improvement in discomfort but worsening in pain, and reported a worsening in psychometric data, but a small decrease in GI-symptoms. Patient P2 showed no difference in discomfort and a worsening in pain, but reported fewer GI-symptoms and improvement in the psychometric data. Patient P3 showed improvement in visceral sensitivity, but no direct or little improvement in GI-symptoms and in the psychometric data.

Until now, the results do not show differences in descriptive data between groups, and the low number of patients does not allow non-parametric statistics.

The limitations of this study are dominated by the low number of patients included. This is a mechanistic pilot study and no other study has been made on the subject. Because of lack of data, it is not possible to perform an exact and formal sample size

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calculation. Based on earlier IBS-barostat studies, a power calculation has been

performed and it was estimated that a minimum of 24 patients have to be included. Hence, 6 patients are not sufficient for an accurate conclusion.

As the study takes 9 weeks for each patient, including several hospital visits,

completion of the whole study is time-consuming, and was also limited by the amount of barostat-equipment and personnel operating it. The duration and amount of time for each examination may be a reason for patients not to participate or to withdraw from the study. Two of the 8 patients asked to participate chose not to because of lack of time, and two patients, one treatment and one placebo, did not go through the second follow before the study ended.

The study is semi blinded. Patients were told that they would receive treatment or placebo; that they would receive NaCl or Solu-Cortef, and either an inflation or a flat barostat protocol, but not in which combination. One weakness in this is that the treatment protocol compared to the “sham-procedure” differs a lot in sensation, and patients could figure out and it could affect the results.

A well-known problem is that IBS-patients often show fluctuating symptoms, some periods worse than others. Fluctuation in anxiety and mood can also influence the results. In some of the patients in this study there occurred troublesome life events during the study period, which could influence GI- and anxiety-symptoms.

The study is a mechanistic pilot study and there is yet no other data on the magnitude and variation of GEET on visceral perception using the barostat protocol. It can, however, not be excluded that another design would be more effective and show different results.

However, this study explores a new territory and lays a good foundation for further research. Inclusion of more patients, and further exploration of variation in treatment, could answer if GEET is a possible treatment for IBS. A continuation could also investigate if there is a difference in treatment result between sexes. Or if any

personality type benefits more from treatment than others, considering the great result in studies of GEET in treating anxiety disorders like acrophobia.

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Conclusion

Until now we have included 6 patients, this number does not allow non-parametric statistics. Descriptive statistics do not show differences in visceral sensitivity, GI-symptoms and anxiety between placebo and treatment group. Further inclusion of subjects is needed for a final conclusion.

Acknowledgements

I would like to give a special thanks to my supervisor Michiel van Nieuwenhoven for introducing me to this interesting project, for the help with forming this study, and for all the guidance in with the result and paper. I would also like to give my warmest thanks to the Endoscopy Unit at Örebro University Hospital for all the help with the Barostat, and for making room to perform the examinations. My final thanks goes to all the personnel at the gastroenterology outpatient clinic at Örebro University Hospital for the helping hand and warm welcome.

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Appendix A: ROME III

FRÅGOR OM BESVÄR

RELATERADE TILL

MAGEN/BUKEN

ROME III

ROME III – Svensk vers 1.0: Magnus Simrén och Anna Rydén, Sahlgrenska Universitetssjukhus, Göteborg Originalvers: D A Drossman, E Corazziari, M Delvaux, R C Spiller, N J Talley, W G Thompson, W E Whitehead.

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1. Under de 3 senaste månaderna, hur ofta har Du haft obehag eller ont i magen/buken?

0=avsluta

2. För kvinnor: Kände Du det här obehaget eller smärtan i samband med menstruationen men inte annars?

3. Har Du känt det här obehaget eller smärtan 6 månader eller längre?

4. Hur ofta blev obehaget/smärtan bättre eller upphörde helt när Du tömt tarmen?

5. När den här obehaget/smärtan började, fick Du då tömma tarmen oftare?

6. När den här obehaget/smärtan började, fick Du då tömma tarmen mer sällan?

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TACK FÖR DIN MEDVERKAN!

7. När den här obehaget/smärtan började, var Din avföring lösare än vanligt?

8. När den här obehaget/smärtan började, hur ofta var Din avföring hårdare än vanligt?

9. Under de 3 senaste månaderna, hur ofta har Din avföring varit hård eller klumpig?

10. Under de 3 senaste månaderna, hur ofta har Din avföring varit lös, grötig eller vattning?

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Appendix B: SOP Rectal Barostat

SOP: Rectal barostat

After an overnight fast, the subjects present to the laboratory at 7.30 a.m. They receive a cleansing tap water enema (750mL) and after bowel emptying, they are placed in a left lateral decubitus position in a hospital bed tilted by 15°. Put a pillow between legs and offer several pillows to go under the head to make patients more comfortable. A rectal barostat catheter with a polyethylene bag attached will be inserted into the rectum so that the middle of the bag is located approximately 10 cm from the anal verge, and the barostat catheter will be taped to the buttocks. The catheter is to be inserted following lubrication of the catheter and barostat bag with KY jelly (or similar non-‐anesthetic lubricant). Digital examination may be performed for catheter

insertion, but is not strictly required. No endoscopic insertion aids are to be used for catheter placement. The barostat bag is then unfolded by transiently inflating it with75 mL of air and subsequently deflating it completely but leaving it in situ. Flow rate for barostat inflations 32 ml/s.

After a 20–30 min recovery period, the catheter is connected to a barostat and the pressure in the bag increased from 4 mmHg in steps of 1 mmHg for 1 min per step until respiratory excursions are observed. The baseline operating pressure (BOP) is defined as 2 mmHg above the minimal distension pressure at which respiratory excursions are clearly recorded from the barostat tracing. If respiratory variations are not seen by 18 mmHg, BOP is set at 12 mmHg. Next, an initial “conditioning“ distension of the rectum will be performed in which the pressure is increased from 0 mmHg to 20 mmHg in steps of 4 mmHg for 15 sec per step. Subsequently, the bag is deflated to 0 mmHg but left in situ, and the patients are allowed to rest for 10 min before proceeding to the ascending method of limits (AML) protocol.

Ascending Method of Limits (AML) protocol

Sensory pressure thresholds and colorectal compliance will be measured by ramp inflation, starting at 0 mmHg and increasing in steps of 4 mmHg for 1 min per step to a maximum of 60 mmHg. Thresholds for first sensation, first desire to defecate, urgency, discomfort and pain will be indicated by the patients by pressing a button at the distension pressure at which sensations are perceived. Ramp inflation is terminated as soon as the patients report the first sensation of pain. Following this procedure, the bag is deflated to BOP and left in situ, and the patients are allowed to rest for 10 min, then the random phasic distensions (RPD) protocol will be conducted.

Random Order Phasic Distensions (RPD) protocol

Phasic distensions of 12, 24, 36 and 48 mmHg above BOP will be each applied once in a random order. The maximum pressure to be used for RPD is limited by the pain

threshold from the previous AML, so that only the next higher pressure should be applied for RPD (e.g. if pressure threshold in AML is 30 mmHg above BOP, use 12, 24 and 36 mmHg above BOP,but not 48 mmHg above BOP). Each distension will be maintained for 60 sec with an interstimulus interval of 2 min during which the bag is deflated to BOP. The subjects will rate the intensity of four different sensations during the last 30 sec of each distension (gas, urgency, discomfort and pain).

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Outcome variables:

• The sensory thresholds for first sensation, first desire to defecate, urgency, discomfort and pain during AML; i.e., the barostat pressures [mmHg] at which the patients press the button to signal perception of the corresponding

sensation, and the corresponding balloon volumes (ml).

• The aggregate sensation intensity scores for gas, urgency, discomfort and pain in response to the four random phasic distensions during RPD (12, 24, 36 and 48 mmHg above baseline operating pressure (BOP)); i.e., the visual analogue scale (VAS) scores [mm] marked by the patients at each distension.

• Colorectal compliance, summarized as the distension pressure Pr1/2 [mmHg] at half of the maximum observed volume of the barostat bag during AML. A

pressure-‐volume curve will also be created during the AML distension (balloon volume during the last 10 sec of each pressure step).

Definition of sensations to be recorded during AML and RPD

Patients will be given instructions separately before AML and RPD. During the AML there should be no interaction between operator and patient, i.e. just let the patient select the AML sensation via the keypad as indicated in the script.

NOTE: For AML, sensations are to be reported if they occur immediately after balloon inflation. The 5 sensation pressure thresholds do not have to occur according to their numerical order. If any sensation buttons are not hit during AML, report sensation as greater than 60 mmHg.

For RPD, a prompt should be given approximately 30 seconds into the distension indicating that the subject should now complete the 4 VAS supplied by the operator for each distension.

If on the pain VAS the subject scores greater than 80mm, the distension is to be immediately aborted and no higher pressures are to be applied.

NOTE: Due to the AML-‐based cap to applied pressures, patients may not receive all 4 distension pressures. Please briefly instruct patients prior to each RPD session how many distensions to expect (may vary). Distensions are to be numbered consecutively, even if you skip distension(s) from the applicable randomization scheme (i.e. if you use 3 distensions, you will have distensions #1, 2 and 3; if you use 2 distensions, you will have distensions #1 and 2 only. Please cross out any omitted distensions on the randomization list to be part of the source documents).

Definition of volumes for compliance calculations to be recorded during AML Volumes recorded for compliance should reflect average volume during the 2nd 30 sec period of each AML step reached during the procedure.

NOTE: This applies only for non-‐painful balloon distensions. For the last (painful) pressure exerted during AML, the following rules apply:

a. If pressure applied for > 30 sec, average last 30 sec; b. If pressure ≤ 30 sec, average last 15 sec;

c. If pressure < 15 sec, average last 5 sec if/where the volume has stabilized (<10% volume change)

d. If none of the above applies, skip value and make a note

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Suggested patient script

On arrival outline the procedure to the patient

• Today we will ask you some questions about your IBS and your bowel habits. • We will then give you a saline enema to clean out the lower part of your bowel. • One hour after this we will put the barostat catheter in place.

• You will be asked to lie on your left hand side with your legs bent. After a brief rectal examination the catheter will be eased gently into place.

• The catheter consists of a thin flexible tube with a polythene bag attached at the end. The bag will be inflated slowly with a little air and then deflated to ensure that it is lying correctly.

• After about 20 minutes we will start the barostat procedure. First of all only small amounts of air will be put into the bag till we have established the baseline. Then a “conditioning” step will follow, when the pressure in the bag will increase stepwise for 15 seconds per step.

• The bag is then deflated and there is a 10 minute rest period.

Ascending Method of Limits

General guidance

• During the next part of the test I will not be able to talk to you but I will give you full instructions beforehand.

• Increasing amounts of air will be put into the bag and you will be given a keypad to register the sensations that you feel. The air will then be removed and you will have a 10 minute rest.

Instructions given before AML

• This part of the study must be done with a minimum of interaction between you and me, so I will not be able to speak to you unless there is a problem.

• The bag will now be inflated with increasing amounts of air for 1 minute before going on to the next inflation. Here is a keypad with labelled buttons.

• We ask that you press these buttons when you first feel a particular sensation. o First Sensation – press the first time you feel something different.

o First Desire to Defecate (pass a bowel movement) -‐ press the first time you feel this desire.

o Urgency – press when you feel that you would have to stop what you are doing to have a bowel movement immediately.

o Discomfort – press if you feel discomfort. o Pain – press if you feel pain.

• As soon as you press the pain button the inflations will stop and the bag will be deflated.

• You may not feel all of these sensations and you won’t necessarily feel them in the order of the buttons. You will be given a card with the explanation for each button on to remind you of the sensations that we are asking about.

• It is important for you to know that although during this procedure/test you will feel that you need to have a bowel movement, you will not, as it is only the inflation of the bag that makes you feel the sensation.

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Random Phasic Distension (RPD)

General guidance

• During this final part, the bag will be inflated to four different pressures in a random order with a short rest between each inflation.

• You will be given a score sheet to record your rating of what you feel. • The tube will then be removed and you will be finished for this visit.

Instructions given before RPD

• During this section the bag will be inflated to four different levels in a random order. • 30 seconds after the bag has been inflated I will hand you a sheet of paper.

• On the sheet there will be 4 lines: one for gas, one for urgency, one for discomfort and one for pain.

• We want you to mark on each line your sensation score for each of the different sensations, with no sensation on the left, going up to unbearable on the right.

• For instance if it felt like you had a lot of gas that needed to be passed you would put a vertical mark on the line far over towards the right hand side, corresponding to the level of gas you felt.

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Appendix C: Questionnaires of GI-symptoms

IBS-SSS

IBS symptom Severity Scale

Namn _________________________________________________ Datum ______________ Endast för

Ålder _________ Kön (ringa in): M F Annat __________________________

summa:

Det här formuläret är utformat för att mäta och utvärdera graden av din IBS. Det är rimligt att dina symptom varierar över tid, besvara därför frågorna utifrån hur du för tillfället känner dig (dvs. under de senaste 10 dagarna ungefär). All information behandlas strikt konfidentiellt.

1. a) Lider du för tillfället av magsmärtor? b) Om ja, hur kraftiga är dina magsmärtor?

0 % 100 %

Ingen smärta Inte så kraftig Ganska kraftig Kraftig Mycket kraftig

c) Vänligen fyll i antalet dagar som du har smärta under en 10-dagars period. Om du till exempel skriver 4 betyder det att du har smärta under 4 av 10 dagar. Om du har smärta varje dag så skriver du 10.

X 10 Antalet dagar med smärta:

2. a) Är du för tillfället uppblåst i magen?

(till exempel uppsvälld, svullen eller spänd i magen.

För kvinnor- ignorera eventuell uppblåsthet under menstruationen)

b) Om ja, hur allvarlig är uppblåstheten/spändheten i magen?

0 % 100 %

Ingen uppblåsthet Inte så kraftig Ganska kraftig Kraftig Mycket kraftig

3. Hur nöjd är du med dina avföringsmönster?

0 % 100 %

Mycket nöjd Ganska nöjd Missnöjd Mycket missnöjd

4. Vänligen indikera på linjen nedan med ett kryss hur mycket IBS generellt sett påverkar eller stör ditt liv.

0 % 100 %

Inte alls Inte mycket Ganska mycket Helt och hållet

Ja Nej

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GSRS-IBS

THE GASTROINTESTINAL SYMPTOM RATING SCALE (GSRS)

Undersökningen innehåller frågor om hur Du mår och hur Du har haft det DEN SENASTE VECKAN. Markera med ett kryss X det alternativ som bäst passar in på Dig och Din situation.

Inga besvär alls Obetyd-liga besvär Milda besvär Måttliga besvär Ganska svåra besvär Svåra besvär Mycket svåra besvär

1. Har du under den senaste veckan besvärats av ont i magen?

2. Har du under den senaste veckan besvärats av smärta eller obehag i magen som blir bättre när du tömmer tarmen?

3. Har du under den senaste veckan besvärats av en känsla av uppkördhet i magen? 4. Har du under den senaste veckan besvärats

av att du släpper ut gaser?

5. Har du under den senaste veckan besvärats av förstoppning? (problem med att tömma tarmen.)

6. Har du under den senaste veckan besvärats av många tarmtömningar per dag?

7. Har du under den senaste veckan besvärats av lös avföring?

8. Har du under den senaste veckan besvärats av hård avföring?

9. Har du under den senaste veckan besvärats av trängande avföringsbehov? (bråttom till toaletten.)

10. Har du under den senaste veckan besvärats av en känsla av att du inte riktigt kan tömma tarmen?

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11. Har du under den senaste veckan besvärats av att du känt dig mätt innan du har ätit färdigt? (blir fort mätt.)

12. Har du under den senaste veckan besvärats av att du känt dig mätt länge efter att du ätit (färdigt)?

13. Har du under den senaste veckan besvärats av att magen svullnar så att det syns?

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SF-NDI

NEPEAN DYSPEPSI FRÅGEFORMULÄR

- KORTVERSION

SF-NDI

®

Tack för att du hjälper oss med den här undersökningen. Det här frågeformuläret innehåller detaljerade frågor om dina magbesvär och hur de påverkar dig och ditt liv.

En del av frågorna är ganska personliga, men informationen som du lämnar kommer att behandlas med sekretess och känslighet.

SF-NDI© Nicholas J Talley, 1998

Detta är den ÖVRE DELEN AV BUKEN (magen)

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Nepean dyspepsi frågeformulär - kortversion (SF-NDI)©

Var vänlig SKRIV SIFFROR i tabellen nedan för att ange hur ofta du har haft magbesvär under de senaste 14 DAGARNA och hur intensiva och besvärande de har varit. Illustrationen på framsidan visar den ”ÖVRE DELEN AV BUKEN” – var vänlig titta på illustrationen när du svarar på frågor om besvär i den ”ÖVRE DELEN AV BUKEN”.

Under de senaste 14 dagarna, hade du något av

följande MAGBESVÄR?

Hur MÅNGA DAGAR hade du

det? 0 = Inga alls 1 = En till fyra dagar 2 = Fem till åtta dagar 3 = Nio till tolv dagar 4 = Varje dag/nästan

varje dag

Om du upplevde detta symptom, hur INTENSIVT var

det vanligtvis? 0 = Inte alls 1 = Väldig svagt 2 = Svagt 3 = Måttligt 4 = Kraftigt 5 = Väldigt kraftigt Om du upplevde detta symptom, hur BESVÄRANDE var det? 0 = Inte alls 1 = Lite grann 2 = Måttligt 3 = Mycket 4 = Extremt mycket

Smärta eller värk i den övre delen av

buken (magen)

Obehag i den övre delen av buken

(magen)

Brännande känsla i den övre delen av

buken (magen)

Brännande känsla i bröstet (halsbränna) Kramper i den övre delen av buken

(magen)

Smärta eller värk i bröstet, ovanför

magen

Oförmåga att avsluta en vanlig måltid Bitter/sur vätska som kommer upp i din

mun eller hals

Tidig mättnadskänsla vid måltid eller

långsam matsmältning

Tryck i den övre delen av buken (magen)

Känsla av uppsvälldhet i magen

Illamående

Rapningar

Kräkningar

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Spänningar

1. Har ditt ALLMÄNNA KÄNSLOMÄSSIGA VÄLBEFINNANDE blivit stört av dina

magbesvär under de senaste 14 dagarna? 1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

2. Har du varit LÄTTRETLIG, SPÄND eller FRUSTRERAD under de senaste 14 dagarna på grund av dina magbesvär?

1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

Störning av dagliga aktiviteter

3. Har din FÖRMÅGA att engagera dig i saker som du vanligtvis gör som

FRITIDSAKTIVITET (som rekreation, uteliv, hobbies, sport mm) blivit störd av dina magbesvär under de senaste 14 dagarna?

4. Har din GLÄDJE av det du vanligtvis gör som FRITIDSAKTIVITET (som rekreation, uteliv, hobbies, sport mm) blivit störd av dina magbesvär under de senaste 14 dagarna? 1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

6 Ej tillämpligt (Jag har inte kunnat göra någon av dessa saker under de senaste 14 dagarna, på grund av mina magbesvär)

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Att äta/dricka

5. Har din FÖRMÅGA att ÄTA eller DRICKA (inklusive när, vad och hur mycket) blivit störd av dina magbesvär under de senaste 14 dagarna?

6. Har din GLÄDJE av att ÄTA och/eller DRICKA störts av dina magbesvär under de senaste 14 dagarna? (Inkludera din aptit och hur du mår efter mat eller dryck). 1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

Kunskap om/kontroll över magbesvären

7. Under de senaste 14 dagarna, har du UNDRAT om du ALLTID kommer att ha de här magbesvären? 1 Nästan aldrig 2 Ibland 3 Ofta 4 Väldigt ofta 5 Ständigt

8. Under de senaste 14 dagarna, har du UNDRAT om dina magbesvär kan bero på en mycket ALLVARLIG sjukdom (såsom cancer eller hjärtproblem)? 1 Nästan aldrig 2 Ibland 3 Ofta 4 Väldigt ofta 5 Ständigt

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Arbete/hushållsarbete/studier

9. Har din FÖRMÅGA att ARBETA, STUDERA eller göra HUSHÅLLSARBETE

störts av dina magbesvär under de senaste 14 dagarna? 1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

6 Ej tillämpligt (Jag har inte arbetat, studerat eller gjort

hushållsarbete under de senaste 14 dagarna, på grund av mina magbesvär)

10. Har din GLÄDJE av att ARBETA, STUDERA eller göra HUSHÅLLSARBETE

störts av dina magbesvär under de senaste 14 dagarna? 1 Inte alls 2 Lite grann 3 Måttligt 4 Mycket 5 Extremt mycket

6 Ej tillämpligt (Jag har inte arbetat, studerat eller gjort

hushållsarbete under de senaste 14 dagarna, på grund av mina magbesvär)

Poängräkning: Summera poängen för vart och ett av de fem områdena (varje område kan få 2-‐10 poäng).

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PHQ-15

FYSISKA SYMTOM

(PHQ-15)

Hur mycket har du besvärats av något av följande symptom under de senaste fyra veckorna?

Inte alls

(0) Något (1) Mycket (2)

a. Ont i magen b. Ryggsmärta

c. Smärta i armar, ben eller leder (knän, höfter o.s.v.) d. Kramp eller andra problem vid menstruation

ENDAST KVINNOR

e. Huvudvärk

f. Smärta i bröstkorgen g. Yrsel

h. Svimningsanfall

i. Känning av hjärtklappning eller att hjärtat slår häftigt j. Andfåddhet

k. Smärta eller problem vid samlag l. Förstoppning, lös avföring eller diarré m. Illamående, gas- eller matsmältningsbesvär n. Trötthetskänsla eller brist på energi

o. Svårt att sova

(For office coding: Total Score T_____ = _____ + _____ )

Utvecklat av Dr. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke och kolleger, med ett utbildningsbidrag från Pfizer Inc. Ingen behörighet att reproducera, översätta, visa eller distribuera.

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Appendix D: Questionnaires of anxiety

IBS-‐Quality of Life

Om hur du känner dig

Tänk på ditt liv under den senaste månaden (senaste 30 dagarna), och titta på påståendena nedan. Varje påstående har fem olika svar. För varje påstående, ringa in det svar som bäst beskriver dina känslor.

Inte alls

Lite Måttligt Mycket Väldigt mycket

1 2 3 4 5

1. Jag känner mig hjälplös på grund av mina tarmproblem.



2. Jag är generad över lukten orsakad av mina tarmproblem.



3. Jag är besvärad av hur mycket tid som jag spenderar på toaletten.



4. Jag känner mig sårbar för andra sjukdomar på grund av mina tarmproblem.



5. Jag känner mig tjock/uppsvälld på grund av mina tarmproblem.



6. Jag känner att jag håller på att tappa kontrollen över mitt liv på grund av mina tarmproblem.



7. Jag känner att mitt liv känns mindre njutbart på grund av mina tarmproblem.



8. Jag känner mig obehaglig till mods när jag talar om mina tarmproblem.



9. Jag känner mig nedstämd på grund av mina tarmproblem.



10. Jag känner mig isolerad från andra på grund av mina tarmproblem.



11. Jag måste se upp med den mängd mat jag äter på grund av mina tarmproblem.



12. Sexuella aktiviteter/intimitet är besvärligt för mig på grund av mina tarmproblem. (Om ej tillämplig,

markera in "INTE ALLS").



13. Jag känner mig arg för att jag har tarmproblem.



1. Jag känner att jag irriterar andra på grund av mina tarmproblem.



2. Jag oroar mig för att mina tarmproblem skall förvärras.

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3. Jag känner mig lättretlig på grund av mina tarmproblem.



Inte

alls

Lite Måttligt Mycket Väldigt mycket 1 2 3 4 5

4. Jag oroar mig för att folk tycker att jag överdriver mina tarmproblem.



5. Jag känner att jag får mindre gjort på grund av mina tarmproblem.



6. Jag måste undvika stressande situationer på grund av mina tarmproblem.



7. Mina tarmproblem minskar sexlusten.



8. Mina tarmproblem begränsar vad jag kan ha på mig.



9. Jag måste undvika fysiskt ansträngande aktiviteter på grund av mina tarmproblem.



10. Jag måste se upp med vilken sorts mat som jag äter på grund av mina tarmproblem.



11. På grund av mina tarmproblem har jag svårt för att vara bland folk jag inte känner väl.



12. Jag känner mig slö på grund av mina tarmproblem.



13. Jag känner mig inte riktigt fräsch på grund av mina tarmproblem.



14. Långa resor är svåra för mig på grund av mina tarmproblem.



15. Jag känner mig frustrerad över att jag inte kan äta när jag vill på grund av mina tarmproblem.

Glucocorticoid‐enhanced extinction‐based exposure therapy in irritable bowel syndrome – a proof of concept study