Clinical trial: predictive factors for response to gut‐directed hypnotherapy for refractory irritable bowel syndrome, a post hoc analysis

Gut‐directed hypnotherapy is effective for patients with irritable bowel syndrome (IBS). Despite its considerable evidence base, gut‐directed hypnotherapy is not widely available and remains a limited resource. This emphasises the need to select patients who are most likely to benefit.


| INTRODUC TI ON
Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction, 1 with an estimated global prevalence of 4.1%, 2 and is associated with considerable healthcare utilisation and financial costs. 3fortunately, conventional treatment approaches have limited efficacy particularly in those with severe, refractory symptoms, 4 which affect approximately 25% of patients. 5This often results in a reduction of health-related quality of life (QOL), [6][7][8][9][10][11][12] increased healthcare costs 6,11,[13][14][15] and absenteeism at work. 6,11t-directed hypnotherapy, a gut-specific behavioural treatment, is one of the few treatments with an evidence base for refractory IBS 16 and is recommended in clinical guidelines when patients have not responded to medical treatments for at least 12 months. 17,18Gut-directed hypnotherapy aims to induce a state of relaxation and suggestibility, which allows the patient to take control of their gut by making physiological and psychological changes. 4,195][26][27][28] Studies have also shown that the beneficial effects of individualised therapist delivered gut-directed hypnotherapy are long-lasting in both adult 29,30 and paediatric populations. 26,31wever, despite the growing evidence base, gut-directed hypnotherapy is not widely available outside highly specialised centres.
Therefore, there is increasing interest in initiatives to widen access.Data from a recently published randomised study have shown that outcomes from six sessions of individualised gut-directed hypnotherapy are non-inferior, with better completion rates than 12 sessions. 27ese findings have implications for improving access by doubling the throughput of services, thereby reducing the costs of provision and waiting times. 4Other recent initiatives to widen hypnotherapy access have included group delivery, [20][21][22][23]32 remote delivery of individualised therapy via video platforms 33,34 and self-directed digital gut-directed hypnotherapy delivery via Smartphone applications. 35However, despite these developments, outcomes from patient satisfaction surveys, 36 and data from self-directed gut-directed hypnotherapy via digital applications where compliance is low, 37 suggest that there remains a strong need for face-to-face individualised treatment for many patients, particularly those with severe refractory IBS who may require a more personalised approach to treatment.
9][40][41] However, they have not focused on factors such as symptom burden which, if predictive, would be relatively easy to document before treatment.
In this context, the aim of this post hoc analysis of outcomes from a large, randomised study of individualised therapist delivered gut-directed hypnotherapy was to determine which baseline patient characteristics might predict either a clinical response to this form of treatment or a tendency to dropout.If any characteristics are identified, this may help to concentrate services on those patients most likely to respond to hypnotherapy.

| Materials
This post hoc analysis was conducted at the Neurogastroenterology Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust using data from an RCT ISRCTN61738583 comparing 6 versus 12 sessions of gut-directed hypnotherapy. 27In the original randomised study, patient demographic data and questionnaires were collected from 448 participants with Rome III IBS prior to starting GDH delivered according to the Manchester Protocol 4 and at the completion of treatment (6 or 12 weeks).

| Gut-directed hypnotherapy
Individualised gut-directed hypnotherapy was delivered face-toface by a therapist using the Manchester Protocol. 4This consists of weekly sessions of 1 h delivered by a suitably qualified hypnotherapist and adapted to the patient's symptoms. 4A detailed description of gut-directed hypnotherapy is available elsewhere 4 but briefly involves trance induction followed by suggestions of symptom and physiological control utilising imagery, metaphors and tactile techniques.

| IBS-Symptom Severity Scale
The IBS-Symptom Severity Scale (IBS-SSS) is a self-reported questionnaire used to assess the severity of IBS symptoms in the previous 10 days.It scores pain severity, pain frequency, abdominal distension or bloating, satisfaction with bowel habit and quality of life.Each component is scored out of 100 on a numerical scale, with a maximum score of 500.The total score is used to classify IBS severity with a score of <75 indicating remission, 75 to <175 mild, 175 to ≤300 moderate and >300 severe IBS. 43

| Extraintestinal symptoms
Before and after treatment, patients completed the non-colonic symptom questionnaire consisting of 10 items (nausea/vomiting, early satiety, headaches, backache, lethargy, excess wind, heartburn, urinary symptoms, thigh pain and pains in muscles and joints).Each symptom is scored out of 100, with all the symptom scores divided by 2 to give a maximum score out of 500. 44

| Quality-of-life score
Patients completed a quality-of-life questionnaire before and after gut-directed hypnotherapy consisting of 15 items (coping with problems, confidence and security, quality of sleep, feelings of irritability, frequency of worrying, enjoyment of life, feelings of hopefulness, physical well-being, relationships with others, maintaining friendships, feelings of inferiority, feeling wanted, feelings of helplessness, difficulty making decisions and enjoyment of leisure time), Each domain is scored on a 0-100 scale with higher scores indicating a better quality of life. 44The sum of these 15 components was divided by 3 to give a maximum quality-of-life score out of 500.

| Hospital Anxiety Depression Questionnaire
Participants completed the Hospital Anxiety Depression (HAD) scale before and after treatment to assess anxiety and depression levels.The maximum score for both anxiety and depression is 21. 48For the purposes of this study, a HAD score of >8 for either domain was used as a threshold for abnormal levels of anxiety or depression.

| EQ-5D questionnaire
The EQ-5D questionnaire, an instrument comprising five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) which results in a score calculated in such a way that a score of 1 equals full health.In addition, it also includes a visual analogue scale to record a self-rated health state from worst imaginable to best imaginable. 46

| Outcome measures and statistical analysis
For this post hoc analysis, comparisons were made between patients who achieved a clinically meaningful response to gut-directed hypnotherapy, and non-responders, as defined by the primary and secondary endpoints.
The primary endpoint was a ≥50-point improvement in IBS-SSS, which has been shown to represent a clinically meaningful improvement in IBS symptoms. 43e secondary endpoint was a ≥30% improvement in abdominal pain score, taken from the pain severity section of the IBS-SSS, which has been recommended by the Food and Drug Administration (FDA) to represent a clinically meaningful reduction. 47mparisons were also made between those who completed treatment and those dropped out of the study, defined as a failure to complete the prescribed course of GDH such that follow-up data at the end of treatment was not available.
Statistical analysis was conducted using SPSS Statistics V23, using the conventional 5% significance level (p < 0.05).For analysis of the association between individual non-colonic symptoms and treatment response, a 1% significance level was used (p < 0.01) as this is considered indicative of a true difference when conducting multiple comparisons.General linear regression models with a binary response variable incorporating multiple imputations with the iterative Markov chain Monte Carlo procedure (in order to take account of missing data) were used to determine which baseline patient characteristics had a statistically significant relationship with the achievement of the primary outcome measure (≥50-point reduction in the IBS-Symptom Severity Scale [IBS-SSS]) and secondary outcome measure (≥30% reduction in the pain severity section of the IBS-SSS).Multivariable regression models were used to determine the significant independent predictors of the two outcome measures.
The primary modified intention-to-treat analysis (ITT) was conducted on the aggregated data set (i.e.combined group) including all 448 participants in the primary RCT, as similar response rates were achieved in the six-session and 12-session groups.Analysis was also conducted independently on the six-and 12-session groups.
Additional analysis, using chi-squared tests and two-sample ttests, was performed on the 6-session, 12-session, and combined groups, to determine whether any baseline patient characteristic had a statistically significant relationship with treatment dropout.
Multiple logistic regression analysis was used to determine the significant independent predictors of dropout.
Mean data are presented ± SD, unless stated otherwise.
There was a large improvement in mean baseline IBS-SSS after gut-directed hypnotherapy in both the 12-(baseline 325.9 ± 86.0 to 205.1 ± 100.9, mean reduction −120.8 ± 104.6) and six-session groups (baseline 309.1 ± 85.9 to 178.8 ± 95.9, mean reduction −130.3 ± 97.0).249/416 (59.8%) achieved the secondary endpoint of ≥30% reduction in abdominal pain score.Thirty-two patients with Rome III IBS and a baseline abdominal pain score of zero were omitted from the analyses for this secondary endpoint.

| Predictors of response to gut-directed hypnotherapy defined by a ≥50-point reduction in IBS-SSS
Patients who met the primary endpoint, defined by a ≥50-point reduction in IBS-SSS, had a higher baseline non-colonic symptom score than non-responders p = 0.005, Table 1, Figure 1).There were no differences in response rates by gender (female No other baseline patient characteristic was found to be associated with response to treatment in the 6-session, 12-session, or combined groups, Table 1. Out of the individual components of the non-colonic symptom score, responders had higher baseline scores for backache (p = 0.010) and excessive wind (p = 0.005), Table 2.

| Predictors of response to hypnotherapy as defined by a ≥30% reduction in abdominal pain scores
Compared to non-responders, abdominal pain responders had lower baseline HAD-depression scores (p = 0.012, Table 3).
When comparing abdominal pain response rates to gut-directed hypnotherapy, patients with baseline HAD-depression score ≤8 (n = 267) had a greater pain response to hypnotherapy than those with HAD-depression score >8 (n = 149; 64% vs 53%, p = 0.028).
Abdominal pain response rates did not differ between those with TA B L E 1 Baseline characteristics of responders and non-responders to gut-directed hypnotherapy (response defined as ≥50-point reduction in IBS-SSS).and without HAD-anxiety scores >8 (abdominal pain response rates:

| Baseline QOL as a predictor of abdominal pain response
Baseline QOL scores were higher in abdominal pain responders than non-responders (265.3 vs 245.5, difference 19.9 [95% CI: 1.8, 38.0], p = 0.032).Multiple regression analysis concluded that the difference found between responders and non-responders was heavily influenced by baseline depression score.When QOL score was adjusted for baseline depression score, the statistical effect was found to be non-significant.
In the 12-session subgroup, baseline IBS severity was found to be associated with abdominal pain response to treatment, with the severe subgroup having a greater response rate (mild IBS 50%, moderate IBS 46%, severe IBS 61%, p = 0.048).By contrast, IBS severity was not found to be predictive of abdominal pain response in the six-session subgroup (response rates: mild IBS 57%, moderate 62%, severe 64%, p = 0.65).

Responders
Multiple logistic regression analyses showed that age and baseline EQ-5D were the leading predictors of dropout in the 12-session and combined groups, whereas age and baseline QOL were found to be the leading predictors in the six-session subgroup.

| D ISCUSS I ON
This study of outcomes from a large, randomised trial suggests that certain baseline patient characteristics may be predictive of clinical response to therapist delivered gut-directed hypnotherapy.The response rates to individualised, face-to-face gutdirected hypnotherapy reported in this study are in line with previous studies in refractory IBS populations. 25,26,28Moreover, gut-directed hypnotherapy improved non-colonic symptoms by a similar magnitude to previous studies. 25Importantly, when comparing baseline characteristics of responders and non-responders to hypnotherapy, our data suggest that patients with greater physical symptom burden at baseline were most likely to achieve the primary and secondary endpoints.Overall response, defined by a ≥ 50-point reduction in IBS-Symptom Severity Scale, was associated with a higher burden of somatic extraintestinal symptoms at baseline.The pathophysiology of extraintestinal symptoms in IBS is complex and multifactorial, but it is likely that central sensitisation is contributary. 48Consistent with this, the prevalence of extraintestinal symptoms in IBS has often been found to be associated with greater IBS severity. 49vere abdominal pain is one of the most debilitating symptoms of IBS and is considered by some to be one of the most important therapeutic targets.Patients who achieved the secondary endpoint of ≥30% reduction in abdominal pain scores were more likely to do so if they had a HAD-depression score ≤8 and had a higher baseline IBS symptom severity.Abdominal pain response was more likely in those with severe IBS (baseline IBS-SSS >300), particularly in those who had received 12 rather than six sessions.patient motivation is likely to be a contributory factor.Consequently, it is possible that those who have higher baseline IBS symptom severity may be most likely to engage with therapy.Furthermore, a face-to-face treatment offers the opportunity for treatment to be flexible and tailored to specific symptom patterns.Whilst we have previously shown that the outcomes of six sessions of gut-directed hypnotherapy are similar to that from 12 sessions, this post hoc analysis suggests that some patients with greater baseline severity may require 12 sessions.The implications are that a personalised approach to gut-directed hypnotherapy may be necessary, whereas a 'one-size-fits-all', generic approach to treatment may not suit all patients and highlight the importance of baseline symptom severity assessments in guiding treatments.
Aside from gastrointestinal and extraintestinal symptoms, psychological symptoms were also found to affect outcomes to gut-directed hypnotherapy.Recent recommendations from a Rome Foundation Working Party suggested which patients may be appropriate candidates for this type of intervention. 50According to this report, those with significant mental health pathologies may not be the best candidates for this type of treatment.However, the report acknowledged the lack of data and highlighted the need for future research to identify psychological or clinical characteristics to predict treatment response.In the past, we have shown that IBS patients with a positive mood are more like to respond to gut-directed hypnotherapy 40 and the present study supports this Working Party's empirical recommendation.Firstly, those HAD-depression scores >8 were less likely to achieve the FDA-recommended endpoint of a ≥ 30% improvement in abdominal pain scores.Secondly, those who dropped out of the study had much higher anxiety levels compared to those that completed the hypnotherapy programme.Overlapping anxiety and depression symptoms are common in IBS 51 ; however, the current study suggests that patients with high levels of anxiety and depression may be better served by a broader psychological approach rather than a gut-specific behavioural treatment such as gut-directed hypnotherapy.Without psychological treatment to stabilise the underlying mental health condition, it is unlikely that the patient will be able to receive the full benefit from gut-specific be- The current study suggests that high gastrointestinal symptom and extraintestinal symptom severity and low psychological symptom severity at baseline may be predictive of good outcomes to therapist delivered individualised gut-directed hypnotherapy using the Manchester protocol. 4Better clinical phenotyping of patients with IBS to guide treatments has recently been voted as the top research priority for patients living with IBS. 52Whilst the current study has provided an insight into factors which may influence the response to gut-directed hypnotherapy, recent evidence suggests that the situation may be more complex.A seminal study by Black et al. 53 using latent class analysis suggests that there may be seven distinct clinical phenotypes of IBS with different extents of gastrointestinal, extraintestinal and psychological symptoms.These phenotypes were found to be predictive of long-term IBS prognosis and outcomes at follow-up. 54,55Following on from the present study, future studies should explore whether this type of clinical phenotyping can be used to predict outcomes to gut-directed hypnotherapy.In the meantime, consistent with current clinical guidelines, 18 our study suggests that response to individualised, face-to-face GDH, may be better in severe, refractory IBS.
There were several limitations to our study.Firstly, as this was a post hoc analysis of a large randomised controlled trial, the study was not powered to detect differences in some of the potential predictive factors such as gender response to gut-directed hypnotherapy.Secondly, the non-colonic and QOL questionnaires used in the study have not been formally validated but have been widely used in gut-directed hypnotherapy studies over the years and shown to be robust.Moreover, the questionnaire on non-colonic symptoms was based on the original description of their association with IBS, 24 which has been confirmed in several subsequent studies. 48,56,57rthermore, back pain, headaches, lethargy, musculoskeletal pains listed in the non-colonic questionnaire have also been shown to be associated with IBS in somatic symptom validation studies. 58Finally, as this is a tertiary refractory IBS population with severe IBS with a mean IBS-SSS greater than 300, it is unclear if the findings would be generalisable to primary or secondary care patients with IBS with lower IBS severity.

4
The findings of this study have important clinical implications for patient selection for gut-brain behavioural interventions such as gut-directed hypnotherapy.Traditionally, gut-directed hypnotherapy has been reserved for severe or refractory IBS, mainly due to limited access outside of specialist centres.To the authors' knowledge, this is the first study that has confirmed our previous clinical impression that response rates to individualised, therapist delivered, hypnotherapy is higher in those with higher baseline severity.The exact reasons for this are unclear, but as gut-directed hypnotherapy is a time-consuming intervention, which requires considerable patience, engagement, practice and 6-12 1-h treatment sessions, F I G U R E 2 Baseline IBS symptom severity of abdominal pain responders (≥30% reduction in abdominal pain scores) and non-responders following gut-Baseline characteristics of dropouts and completers during gutdirected hypnotherapy.
havioural interventions.This highlights the importance of screening for psychological symptoms as part of the baseline clinical assessment and patient selection process.Previously, gut-directed hypnotherapy had traditionally been regarded as a 'psychological' treatment for IBS.However, the positive change in terminology to the less stigmatising term brain-gut behavioural therapies is aligned with modern understanding of the brain-gut axis and the pathophysiology and biopsychosocial basis of IBS.The current data build on this by emphasising the importance of patient selection in personalisation and customisation of the number of GDH sessions according to baseline severity.The data also suggest that clinicians may be able to reduce dropout rates by recognising those who may need broader psychological support rather than gut-directed hypnotherapy from the outset.
help to predict response rates to individualised, therapist delivered gut-directed hypnotherapy in patients with refractory IBS in tertiary care.Those with higher gastrointestinal and extraintestinal symptom severity at baseline were most likely to benefit from gut-directed hypnotherapy.Conversely, high baseline psychological symptom severity was associated with a lack of response in terms of abdominal pain and a high dropout rate.When selecting candidates for gutdirected hypnotherapy, clinicians should conduct a thorough and careful biopsychosocial assessment of gastrointestinal, somatic and psychological symptom severity profiles.Identification of patient characteristics at baseline predictive of a good or poor response to treatment may help streamline services, allocate individualised Baseline characteristics of abdominal pain responders and non-responders to gut-directed hypnotherapy (response defined as ≥30% reduction in abdominal pain score).
TA B L E 3Abbreviations: HAD, hospital depression and anxiety; QOL, quality of life.*p < 0.05.