Dieetaanpassing is een belangrijke initiële behandelstap bij patiënten met PDS. Er zijn verschillende soorten dieetinterventies en er is veel publieke en wetenschappelijke interesse voor de verschillende diëten. Deze toegenomen aandacht heeft ervoor gezorgd dat meer mensen zich zijn gaan verdiepen in voeding en darmklachten. Het gevaar daarbij is dat er vaak (digitale) bronnen geraadpleegd worden die niet noodzakelijkerwijs de meest accurate informatie weergeven. Veel patiënten volgen een bepaald dieet, vaak op eigen initiatief, zonder adequate (medische of diëtistische) begeleiding. Dit kan leiden tot nadelige gezondheidsuitkomsten, zoals deficiënties of ongewenste gewichtsverandering.

In deze module worden 4 dieetinterventies vergeleken met de Richtlijnen goede voeding 2015 van de Gezondheidsraad. Deze 4 dieetinterventies zijn uitgekozen omdat ze op dit moment populair zijn bij PDS-patiënten en er vragen zijn over de effectiviteit.

Glutenvrij dieet

Gluten is een mengsel van eiwitten dat van nature voorkomt in bepaalde granen, zoals tarwe (waaronder spelt), rogge en gerst. Bij een glutenvrij dieet worden producten die gluten bevatten vermeden. Een gedeelte van de PDS-patiënten geeft aan te denken dat ze overgevoelig of intolerant zijn voor gluten, zonder dat ze coeliakie hebben.

Laag FODMAP-dieet

FODMAP is de verzamelnaam voor een aantal koolhydraten die slecht of niet opgenomen worden in de dunne darm: fermenteerbare oligosacchariden, disacchariden, monosacchariden en polyolen. FODMAP’s trekken door hun osmotische werking vocht aan in het darmlumen en dit kan zorgen voor dunne ontlasting. De fermentatie van deze koolhydraten in het colon leidt bovendien tot overmatige gasvorming.

Het laag-FODMAP-dieet is een eliminatiedieet dat berust op het tijdelijk (bij voorkeur zo kort mogelijk) vermijden van de FODMAP-koolhydraten. Na 2-6 weken worden de verschillende groepen koolhydraten weer langzaam een voor een getest. Na meerdere keren testen weet de patiënt welke groepen FODMAP’s klachten geven. Daarna kan de patiënt weer ‘normaal’ eten, zij het met minder of geen van de koolhydraten die tot de FODMAP’s behoren die klachten geven.

NICE-PDS

Het NICE-IBS-dieet maakt deel uit van het voedings- en leefstijladvies in de Britse NICE-Guideline Irritable bowel syndrome. Het dieet beschrijft onder andere regelmatig en rustig eten, met aandacht voor voldoende inname van (oplosbare) voedingsvezels en vocht bij beperkte inname van voedingsmiddelen die klachten geven zoals gasvormers, cafeïne, alcohol en frisdranken.

Psyllium

Psylliumvezels zijn oplosbare viskeuze vezels die maar beperkt fermenteerbaar zijn en die veel water kunnen opnemen. Psylliumvezels kunnen zowel bij obstipatie als bij diarreeklachten worden gebruikt om de ontlasting te verbeteren.

Bij obstipatie is het van belang om de psylliumvezels met ruim voldoende vocht in te nemen. De ontlasting wordt dan zachter en zwelt wat op, wat de stoelgang stimuleert. Bij te weinig vochtinname kan hinderlijke coprostase ontstaan.

Bij diarree moeten de psylliumvezels met zo min mogelijk vocht ingenomen worden. Dan kunnen ze in de darm het teveel aan vocht binden en zo de ontlasting juist vaster maken.

Doordat psylliumvezels beperkt fermenteerbaar zijn in het colon geven ze minder gasvormingsklachten dan andere typen vezels (So 2021).

Since four different dietary interventions were included in the clinical question, we divided this summary into four parts, each part describing one of the dietary interventions.

1. Gluten free diet

Description of studies

Dionne (2018) conducted a systematic review and meta-analysis of randomized controlled trials examining the efficacy of exclusion diets (low FODMAP and gluten-free

diets) in IBS. A search of the literature was conducted in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews until November 2017. RCTs that evaluated an FODMAP exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were included. Data were synthesized as relative risk of symptoms remaining using a random effects model. A total of nine studies were eligible for inclusion. There were two RCTs describing a gluten free diet (111 participants) and seven RCTs comparing a low FODMAP diet with various control interventions (397 participants). Below the two RCT included in this review on a gluten free diet (Biesiekierski and Shahbazkhani) are described in detail.

• Biesiekierski (2011) performed a double-blind, randomized, placebo-controlled trial undertaken in patients with IBS who were symptomatically controlled on a gluten-free diet. After a two-week run-in period, participants continued the gluten free diet. After the two-week run-in period, all participants continued the gluten free diet and received in addition two bread slices and one muffin per day for six weeks. In the gluten group the bread and muffin contained gluten (total intake of 16 g / day). In the for the placebo group the bread and muffin were gluten free.  with a gluten-free diet for up to six weeks. A total of 34 patients (aged 29 – 59 years, 12% men) completed the study. Nineteen patients were included in the gluten group and fifteen in the gluten free group. The primary outcome was the proportion of patients answering “ no ” on more than half of the symptom assessments to the question. “ Over the last week were your symptoms adequately controlled? ” was asked at the end of each study week or at withdrawal if premature. Secondary outcomes were change in overall and individual gastrointestinal symptoms as assessed by the visual analog scale.
• Shahbazkhani (2015) studied the effect of a gluten-free diet on gastrointestinal symptoms in patients with IBS. In a double-blind RCT, 148 IBS patients fulfilling the Rome III criteria were enrolled. The gluten free diet was started in 102 IBS patients; 22 patients found it hard and difficult to continue with the gluten-free diet and subsequently were withdrawn from study. Eighty patients responded to the diet and achieved significant improvement. From this group 8/80 did not follow a strict gluten free diet and were unwilling to continue the diet any further, and the remaining 72 patients commenced on a gluten-free diet for up to six weeks and completed the study. From this group, 35 out of 72 were randomized in the gluten group and 37 out of 72 were in the placebo group for six weeks. The mean age in the gluten group was 44.5 ± 10 years and 43.2 ± 17 years in the placebo group. Six patients (17.1%) in the gluten group and 13 in the placebo group (35.1%) were male. In the second stage after six weeks, patients whose symptoms improved to an acceptable level were randomly divided into two groups; patients either received packages containing powdered gluten (35 cases) or patients received placebo (gluten free powder) (37 cases). Both groups still continued their gluten free diet. Outcomes were assessed using a symptom questionnaire containing the question for the primary outcomes including bloating, abdominal pain, defecation satisfaction, nausea, fatigue and overall symptoms, and scored with visual analogue scale (VAS), with 0 representing no symptoms and 10 indicating severe clinical signs and symptoms.

Zanwar (2016) aimed to evaluate the effects of gluten on IBS symptoms. A double-blind randomized placebo-controlled rechallenge trial was performed in a tertiary care hospital with IBS patients who fulfilled the Rome III criteria. The participants were administered a gluten-free diet for 4 weeks and were asked to complete a symptom-based questionnaire to assess their overall symptoms, abdominal pain, bloating, wind, and tiredness on the visual analog scale (0−100) at the baseline and every week thereafter. The participants who showed improvement were randomly assigned to one of two groups to receive either a placebo (gluten-free breads) or gluten (whole cereal breads) as a rechallenge for the next 4 weeks. Sixty-five patients underwent randomization; 34 received gluten and 31 received placebo. Sixty patient completed the study.

Table 2: Description of study characteristics

Results

Summary of Findings Table 3.

^1. Risk of bias: Serious. Incomplete data and / or a lot of drop-out of participants (loss to follow up); Indirectness: Serious. Only patients who showed improvement on a gluten-free diet were enrolled in some of the studies; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300);

^2. Risk of bias: Serious. Incomplete data and / or a lot of drop-out of participants (loss to follow up); Indirectness: Serious. Only patients who showed improvement on a gluten-free diet were enrolled in the studies; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300);

^3. Risk of bias: Serious. Incomplete data and / or a lot of drop-out of participants (loss to follow up); Indirectness: Serious. Only patients who showed improvement on a gluten-free diet were enrolled in the studies; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300);

Abdominal pain

Biesiekierski (2011) found that, over the entire study period, the severity score for pain was statistically significantly higher for those consuming the gluten diet compared to the gluten free diet. Absolute numbers were not reported in the paper but estimated from the included graph. After 6 weeks, the score for pain was 38 in the gluten group and 18 in the gluten free group (approximation). 

Shahbazkhani (2015) found that in the gluten-containing group, abdominal pain increased (from mean 3.1 ± 2.3 to 5.1 ± 2.2 measured on a VAS) one week after starting the gluten diet. No absolute number were reported for any of the other weeks. A graph was included in the result section of the paper but it was not possible to read the absolute values from it. However, after six weeks, no statistically significant difference between the two groups was observed. 

Zanwar (2016) found that after four weeks of gluten free diet, the median value for abdominal pain (measured on a VAS scale) was 15. After four weeks rechallenge, patients in the gluten group reported a median VAS of 30, while patients in the gluten free group reported a mean VAS of 10. Patients in the gluten group showed statistically significantly higher changes in the abdominal pain VAS scores from the fourth week of GFD to each of the 4 rechallenge weeks, compared to the patients in the placebo group (P<0.05).

Global improvement

Dionne (2018) performed a meta-analysis with primary outcome global improvement in IBS symptoms. If global improvement was not reported, abdominal pain was used as the outcome of interest. If different definitions of symptom improvement were provided in the same study, the most stringent outcome reported was used that minimized placebo response rate (e.g., an improvement in IBS symptoms of >50% would be chosen ahead of an improvement in symptoms of >25%).

A greater proportion of participants had an exacerbation of their IBS symptoms among

those allocated to have their diet spiked with gluten, compared with those remaining on a gluten free diet. The pooled RR was 0.42; 95% CI 0.11 to 1.55; I^{2 =} 88%.

Quality of life

None of the included studies reported the outcome measure quality of life.

Relief of symptoms (likertscale; number of days without symptoms)

Biesiekierski (2011) found that significantly more patients in the gluten group (68 %; n = 13 / 19) reported no adequate control of symptoms on more than half of the symptom assessments compared to those using no gluten (40 % ; n = 6 / 15) ( P = 0.001; generalized estimating equation). Changes in symptoms from baseline to end of week 1 as scored on the visual analog scale after 1 week ’s therapy were significantly greater in those patients who consumed the gluten diet for overall symptoms, pain, bloating, satisfaction with stool consistency, and tiredness, but not for wind or nausea. Over the entire study period, the severity scores of pain, satisfaction with stool consistency, and tiredness were significantly higher for those consuming the gluten diet. Absolute numbers were not reported in the paper but were read from the graph included in the study. After 6 weeks, the VAS score for overall symptoms was 38 in the gluten group compared to 24 in the gluten free group.  

Shahbazkhani (2015) found after six weeks of the diet, that symptoms were controlled in nine patients (25.7%) in the gluten-containing group, compared to 31 patients (83.8%) in the gluten free group, indicating that 26 out of 35 patients in the gluten group became symptomatic on a gluten containing diet (p < 0.001). In the gluten-containing group, all symptoms significantly increased one week after starting the gluten. Mean bloating VAS before starting the gluten-free diet in the gluten group was 8.4 ± 1.5, and after the six-week diet was decreased to 3.1 ± 2.3. Overall time trend analysis revealed statistically significant satisfaction with stool consistency (p = 0.01) and bloating (p = 0.05) (but no statistically significant difference between the two groups). After a one-week gluten challenge, the mean score was increased to 4 ± 2.1, which was not statistically significant compared with the gluten free group. But this symptom continued to increase to 5.1 ± 2.2 in the fifth week.

Zanwar (2016) found that out of the initial group of 180 patients on a gluten free diet, overall symptom VAS improved for 65 patients after a gluten free diet. These 65 were subsequently randomized to a gluten free diet or gluten containing diet. After four weeks of food rechallenge, patients in the gluten-containing group exhibited worsening of symptoms, with significantly higher weekly median overall symptom VAS, compared to those in the gluten free group (P <0.05). The mean VAS in the gluten group was 25 and in the gluten free group 10 for overall symptoms. During the entire rechallenge period, the median VAS scores for abdominal pain, bloating, and tiredness were significantly higher in the gluten group compared to the placebo. Patients in the gluten group showed significantly higher changes in the abdominal pain, bloating, and tiredness VAS scores from the fourth week of GFD to each of the four rechallenge weeks, compared to the patients in the placebo group (P <0.05). However, VAS score for wind was not significantly different in both groups following the rechallenge (P >0.05). Within the gluten group, the VAS scores for abdominal pain, bloating, wind, tiredness, and overall symptoms, differed significantly over the entire study period. The placebo group also showed similar changes in the VAS symptom scores over the study period; however, only the changes in abdominal pain and wind VAS scores after rechallenge remained significantly different following post hoc analysis (P <0.05).

Conclusions gluten free diet

• We are uncertain about the effect of a gluten free diet on abdominal pain in IBS patients.
• We are uncertain about the effect of a gluten free diet on global improvement in IBS patient
• The outcome measure ‘Quality of live’ was not reported in the included studies
• We are uncertain about the effect of a gluten free diet on reducing gastrointestinal symptoms in IBS patients.

2. Low FODMAP diet

Description of studies

One systematic review and five RCTs were identified. To enhance readability the studies are described briefly and the information per study is displayed in table 3.

The systematic review of Dionne (2018) is described on page 41. Table 2.1.4 describes the individual study characteristics. Seven RCTs were included that compared a low FODMAP diet with various control interventions in 397 participants (Staudacher, 2012, Eswaran, 2016; McIntosh, 2017; Böhn, 2015; Halmos, 2014; Hustoft, 2017; Staudacher, 2017).

Zahedie (2017) compared a low FODMAP diet with a standard diet according to the British Dietetic Association’s guidelines in patients with IBS-D. Participants were randomly assigned to the low FODMAP diet (n=55) or general dietary advice group N=55). All participants met with the specialized dietitians to educate and receive dietary plan in a 45-min one-to one appointment. The low FODMAP diet was supplied less than 0.5 gr per meal fermentable oligosaccharides, monosaccharides, disaccharides, and polyols. The general dietary advice group received recommendations such as limitation of caffeine, alcohol, spicy food, fatty food, and carbonated drinks; to eat small frequency meals; to eat slowly and in peace; and avoidance of chewing gums and sweeteners containing polyols. Participants had to follow the diet for six weeks. One-hundred-and-one participants completed the study.

Eswaran (2016/2017) compared a low FODMAP diet with a modified diet recommended by the National Institute for Health and Care Excellence (mNICE) in patients with IBS-D. Eswaran conducted two studies using the same patient population. One study (Eswaran 2016, included in the review of Dionne) included the outcome measures adequate relief. The other study (Eswaran 2017) included the outcome measure quality of life. Participants were randomly assigned to the low FODMAP diet (n=50) or the mNICE diet (n=42). Specially trained research dieticians gave standardized instructions about the diet interventions. The mNICE group was instructed to eat small frequent meals, avoid trigger foods, and avoid excess alcohol and caffeine. Foods containing FODMAPs were not specifically excluded as part of the mNICE instructions provided to study participants. Participants had to follow the diet for four weeks. Eighty-four participants completed the study

Harvie (2017) compared a low FODMAP diet with no dietary advices in patients with IBS. Patients were randomly assigned to the low FODMAP diet (n=23) or to the control group (n=27). At three months, the comparator group crossed over to a low FODMAP diet and the initial low FODMAP group started re-challenging foods. Dietary advice was provided to individual participants in a standardized manner by an experienced registered dietitian. At the initial consultation all participants were advised to significantly reduce their intake of excess fructose, lactose, sorbitol, mannitol, Fructooligosaccharide (FOS) and Galactooligosaccharide (GOS). At follow-up (after 3 months) participants were taught to systematically try to reintroduce FODMAP molecules individually, one follow-up appointment was scheduled and then additional appointments were provided on demand. Fifty patients completed the study.

Patcharatrakul (2019) compared a structural individual low FODMAP diet with a commonly recommended diet in patients with IBS. Patients with moderate-to-severe IBS were randomized to a low FODMAP diet (n=33) or a brief advice on a commonly recommended diet (n=33). Patients randomized to the low FODMAP diet received a maximum of 30 minutes of advice. High-FODMAP items that might aggravate the patient’s symptoms were identified from an individual 7-day food diary. Then, the investigator discussed with the patients to avoid high-FODMAP items and modify recipe/menu with the commonly available low-FODMAP items. The control group received brief advice on a commonly recommended diet, which included reducing certain foods that have been traditionally recognized as triggers for gas, bloating, or abdominal pain, including fruits, vegetables, nuts, beans, and garlic, and avoidance of large meals. Patients followed the diet for four weeks. Sixty-four patients completed the study.

Pedersen (2014) compared a low FODMAP diet to a normal Danish/Western Diet in patients with IBS. Patients were randomized to a low FODMAP diet (n=42) or a normal Danish/Western diet (n=40). Each patient allocated to the low FODMAP diet was instructed

during a one hour session by nutritionists or dietitians. Patients allocated to the normal diet were requested to follow an unchanged normal (Danish/Western) diet during the 6-wk study. Seventy-one patients completed the study.

Table 4: Description of study characteristics – low FODMAP

Results

Table 5 shows the summary of findings for the various outcome measures. Below the table, more detailed information on the outcomes can be found. Forest plots can be found in the attachment 5.

Table 5 Summary of Findings table low FODMAP diet

^1. Risk of bias: Serious. Insufficient blinding / lack of blinding of the participants and researchers, which may cause bias; Indirectness: Serious. Wrong control group, follow-up duration insufficient; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300);

^2. Risk of bias: Serious. Insufficient blinding / lack of blinding of the participants and researchers, which may cause bias; ; Indirectness: Serious. Wrong control group, follow-up duration insufficient

^3. Risk of bias: Serious. Insufficient blinding / lack of outcome assessors, possibly causing detection bias; ; Indirectness: Serious. Wrong control group, follow-up duration insufficient; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300);

^4. Risk of bias: Serious. Insufficient blinding / lack of outcome assessors, possibly causing detection bias; Inconsistency: Serious. Unexplained variability of the data; Indirectness: Serious. Wrong control group, follow-up duration insufficient; Imprecision: Serious. Low number of patients (<100) / Average number of patients (100-300)

Abdominal pain

Zahedi (2017), Harvie (2017), Pederson (2014) and Patcharatrakul (2019) reported the outcome measure abdominal pain. A meta-analysis was not possible because different measurement instruments were used to measure abdominal pain and not all studies reported the absolute values. A summary of the results is presented in table 2.1.6. All studies showed a reduction in abdominal pain for the low FODMAP group compared to the control group. This difference is in some cases a clinically relevant difference. 

Table 6: Results of a low FODMAP diet on abdominal pain measures

*: Not reported in the study but calculated by Kennisinstituut van de Federatie Medisch Specialisten

Global improvement

Global improvement was measured in different ways across the studies, which made it not possible to pool the results of all studies. We used the meta-analysis of Dionne as a measure for global improvement and performed a meta-analysis on the results of the RCTs that reported the IBS-SSS. We describe the results of Patcharatrakul separately since they could not be combined with any of the meta-analysis.

Dionne (2018) included 7 RCTs in the meta-analysis (figure 1 –Attachment 5). The primary outcome was global improvement in IBS symptoms. If global improvement was not reported, abdominal pain was used as the outcome of interest. If different definitions of symptom improvement were provided in the same study an improvement in IBS symptoms of >50% would be chosen ahead of an improvement in symptoms of >25%. This approach may lead to an underestimation of the effect of a low FODMAP diet. The relative risk of symptoms not improving in IBS compared with control was 0.69 (95%CI 0.54 – 0.88).

Three studies used the IBS-SSS as an outcome measure (Zehedi, Harvie, Pedersen). We performed a meta-analysis by extracting the mean difference in IBS-SSS score between the endpoint and baseline for the low FODMAP group and the control group for all studies. If this information was not available, we calculated it ourselves by using the data from the papers. Pooled mean difference was -83.6 (-118.3, -49.0) meaning that patients in the low FODMAP group scored 83.6 points lower on the IBS-SSS compared to the control group (Figure 2 – Attachment 5).

Patcharatrakul (2019) measured global IBS symptom severity using a VAS scale (0-100). The group on the low FODMAP diet started at 61.2±21 at baseline and improved to 38.5 ± 20 at 4 weeks. The control group started at 56.3± 17.8 at baseline and improved to 53.5 ±19.2 at 4 weeks.

Quality of life

Five studies assessed quality of life (QoL) by the OBS-QoL (0= worst quality of life, 100=best quality of life). (Eswaran, Harvie, Zahedi, Pederson, Staudacher 2017). The results of four of these studies could be pooled in a meta-analysis (figure 3 – Attachment 5). From each study, we extracted the mean difference in QoL score between the endpoint and baseline for the low FODMAP group and the control group. If this information was not available in the studies we calculated it ourselves by using the data from the papers. We calculated a pooled mean difference of 7.29 (-1.1, 15.7) meaning that patients in the low FODMAP group scored 7.3 points higher on the IBS-QoL compared to the control group.

Relief of symptoms

The systematic review of Dionne (2018) did not report on relief of symptoms. Patcharatrakul (2019) assessed abdominal discomfort, bloating, belching and stool urgency.

In the low FODMAP group, abdominal discomfort and bloating improved statistically significant after four weeks. In the control group, none of the symptoms improved statistically significant. When comparing the improvement in the low FODMAP group with the improvement in the control group there was no clinically relevant differences between both group and no statistically significant difference.

Table 7 Results of a low FODMAP diet on abdominal pain measures

Conclusions

• The evidence is very uncertain about the effect of a low FODMAP diet on abdominal pain.
• A low FODMAP diet may increase global improvement.
• The evidence is very uncertain about the effect of a low FODMAP diet on quality of life.
• The evidence is very uncertain about the effect of a low FODMAP diet on relief of symptoms

3. NICE diet

There were no studies identified that met the PICO.

4. Psyllium fibre

Description of studies

One systematic review was identified on psyllium fibre.

Ford (2018) aimed to assess the efficacy of psyllium fibre compared to placebo on global improvement in IBS symptoms and quality of life in a systematic review. MEDLINE, EMBASE, EMBASE classic, PsychINFO and the Cochrane central register of controlled trials were searched until July 2017. Fifteen RCTs were identified on fibre, of which seven described ispaghula husk (psyllium) in 499 patients. A meta-analysis was performed on global improvement, defined as symptoms or abdominal pain persisting with intervention compared with control. This was expressed as a relative risk (RR) with 95 % confidence intervals (CIs).

Table 8: Description of study characteristics

Results

Table X shows the summary of findings for the various outcome measures. Below the table, more detailed information on the outcomes can be found. Forest plots can be found in the attachment 5.

Table 9. Summary of Findings table Psyllium fibre

^1.symptoms not improving

^2.Risk of bias: Serious. Inadequate or unclear randomization; Imprecision: Serious. Wide confidence interval, not a minimal clinically important difference;

Abdominal pain

Not reported.

Global improvement

Ford (2018) conducted a meta-analysis for the outcome measure global improvement, including 7 RCTs and 499 patients. If this was not available then improvement in abdominal pain was taken as the primary outcome. When more than one definition was provided for improvement in the primary outcome, the most stringent definition with the lowest placebo response rate was taken. The pooled risk ratio of global symptoms not improving of Ispaghula (psyllium) versus placebo was 0.83 95%CI: 0.73, 0.94, meaning that Ispaghula (psyllium) is beneficial in treating IBS symptoms. The number needed to treat (NNT) was 7 (95% 4-25).

Quality of live

Not reported.

Relief of symptoms

Not reported.

Conclusions

• Use of psyllium fibre may result in an increase in global improvement
• The outcome abdominal pain was not reported in the included studies.
• The outcome quality of life was not reported in the included studies.
• The outcome relief of symptoms was not reported in the included studies.

A systematic review of the literature was performed to answer the PICO:

Relevant outcome measures

The guideline development group considered abdominal pain, global improvement / IBS-symptom severity score, quality of life, relief of symptoms (Likert scale; number of days without symptoms) as critical outcome measures for decision making.

The working group defined 20% as a minimal clinically (patient) important difference for all outcome measures, except the IBS-SSS. That means a Standardized Mean Difference (SMD) > 0.50, OR or RR < 0.75 or > 1.25 and a change of (10-)20% of the total score on a questionnaire.  A 10% (50 points) improvement on the IBS-SSS is considered a minimal clinically (patient) important difference (based on literature).

The working group defined the outcome measures as follows:

• Abdominal pain: abdominal pain can be measured on different scales, for example VAS-scale or the IBS-SSS subscale
• Global improvement / IBS symptom severity scale (IBS-SSS): global improvement or global relief is usually measured by asking patients if their symptoms were adequately controlled in the past 7 days. The IBS-SSS is in this literature summary  used as a measure for global improvement.
• Quality of life: measured with a general questionnaire, such as the SF 36, or disease-specific (IBS-QOL) 
• Relief of symptoms: there are many different symptoms of irritable bowel syndrome, for example bloating, nausea, stool consistency. All symptoms described in the included papers are used.

Search and select (Methods)

The databases [Medline (via OVID) and Embase (via Embase.com)] were searched with relevant search terms from 2000 until November 2020. The detailed search strategy is depicted in the Annex (Totstandkoming)/ under the tab Methods. Studies were selected based on the following criteria as described in the PICO. Attachment 1 contains the PRISMA flowchart showing the number of hits, and Attachment 2 contains the reasons of exclusion. 

Results

Two systematic reviews (SR) and eight RCTs were included in the analysis of the literature, see Table 2.1.1 Important study characteristics and results are summarized in the evidence tables (Attachment 3). The assessment of the risk of bias is summarized in the risk of bias tables (Attachment 4).

Table 1. Results of systematic literature search