Quality of Life in Patients with Irritable Bowel Syndrome (IBS), Assessed Using the IBS–Quality of Life (IBS-QOL) Measure After 4 and 8 Weeks of Treatment with Mebeverine Hydrochloride or Pinaverium Bromide: Results of an International Prospective Observational Cohort Study in Poland, Egypt, Mexico and China

Irritable Bowel Syndrome (IBS) has a substantial impact on health-related quality of life (HR-QoL) [1, 2]. The impact of IBS on quality of life (QOL) is often underestimated in patients as they do not appear to be disabled in any obvious way and there is no apparent impact on life expectancy [3]. QoL in IBS patients has been documented to be even lower than QoL of diabetes mellitus, dialysis-dependent end-stage renal disease or gastroesophageal reflux patients [4]. As there are limited data available pre- and post-treatment and specifically with mebeverine hydrochloride and pinaverium bromide [5, 6], this study was initiated to obtain QoL data in different regions of the world, using these treatments within a single study and using the IBS–Quality of Life (IBS-QOL) measure [7].

Mebeverine hydrochloride (Duspatal^®, Duspatalin^®, Colofac^®, Colotal^®, Mebeverin(e-i-a)^®, Colospa^®, Rudakol^®, Boots IBS relief^®, Fomac^®, Mebecon^®) is a musculotropic antispasmodic with a direct effect on the smooth muscle of the gastrointestinal tract, relieving spasm without affecting normal gut motility. Pinaverium bromide (Dicetel^®, Eldicet^®) is an antispasmodic that selectively acts on the gastrointestinal tract, by inhibiting the influx of calcium into intestinal smooth muscle cells. Both antispasmodics are indicated for the treatment of IBS. Mebeverine hydrochloride is a sodium channel antagonist and pinaverium bromide is a gastrointestinal-selective calcium channel antagonist. Both antispasmodics are available in different dosages. In a pharmacokinetic study, the Duspatalin^® 200 mg twice-daily formulation has been compared with the 135 mg tablet three times daily and has demonstrated optimal relative bioavailability (103 % for single and 97 % for multiple doses) [8].

The IBS-QOL measure is a specific tool developed and validated to assess impairment of QoL in IBS [7, 9]. The IBS-QOL measure consists of 34 IBS-specific items and a 5-point Likert scale (1 = not at all, 2 = slightly, 3 = moderately, 4 = quite a bit, 5 = extremely or a great deal). The sum of the items is transformed into a score (potential range 34–100; 100 = maximum QoL). The IBS-QOL measure contains eight IBS-QOL subscales: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual concerns and relationships. With regards to interpretation of results, apart from reaching statistical significance, a minimal important response (MIR) for the IBS-QOL measure is an increase of 10.2 and meaningful clinical response (MCR) is an increase of at least 14 [10].

The IBS-QOL [7] questionnaire was developed by Patrick and Drossman [7] in the 1990s and further validation has confirmed the responsiveness of the scale [1, 10, 2]. A systematic review has appraised the IBS-QOL measure as the best of five IBS-specific QoL scores available and assessed to establish changes in HR-QoL [12].

This study (596 IBS patients, 59.6 % females, assessed using the Rome III criteria) shows a mean, overall IBS-QOL total score at baseline of 56.4, indicative of moderate/severe disease and is consistent with an international survey of patients with IBS published by Drossman et al. in 2009, where patients also met Rome III criteria for IBS in 90.8 % of the cases (1,966 patients; 83 % female, 91 % Caucasian, 78 % USA/Canada) [2] and where the overall mean at baseline was 51.1.

In this study, the impairment at baseline was similar in Egypt, Mexico and Poland (mean IBS-QOL total scores of 48.9–52.0), but lower in China at 76.4 (indicative of mild/moderate disease). Of note, there are no general practitioners in China and patients consult specialist care immediately, which potentially explains severity of disease being less in China at baseline; thereby leaving a smaller relative room for improvement. Previous studies have shown different mean baseline IBS-QOL total scores, using different diagnostic criteria, a different male/female ratio, different IBS subtyping distribution and different geographical locations: 70.3 (30 Japanese patients, percentage females/males not stated, Rome II diagnosis) [3]; 66.3 (1,555 patients in Canada, 85.1 % females, physician diagnosed) [13]; and 64.3 (value adjusted for age, education, race, marital status) (317 patients in Canada, 100 % females, Rome I diagnosis) [10]. These differences may reflect known cross-cultural differences across countries (e.g. race, food or lifestyle) and variation in diagnosis and sex of patients. In this study, all patients were diagnosed according to the Rome III criteria, so the diagnosis of IBS (Rome III) is not a contributory factor to the higher baseline seen in China.

For the IBS-QOL, Drossman et al. [10] reported an MIR to be an increase of 10.2 and an MCR to be an increase ≥14. In this study, the overall change from baseline in IBS-QOL total score at Week 4 of 11.8 achieved the MIR and by Week 8 the improvement of 24.3 greatly exceeded the MCR.

In this study, the greatest impairment at baseline (determined as scores <55) was observed for the subscale of food avoidance (43.7), health worry (51.8), dysphoria (53.0) and interference with activity (54.4). These findings were similar to the previously mentioned international survey results [2], where the greatest impairments of similar magnitude were shown for food avoidance, dysphoria and interference with activity, but not health worry. In Japanese patients [3], food avoidance, dysphoria and interference with activity also showed the greatest impairment. Studies in Canada showed the greatest baseline impairment in food avoidance, health worry and body image [13], and for food avoidance, interference with activities and dysphoria [10].

The greatest improvements in IBS-QOL in this study, after 8 weeks of treatment, were observed for the subscales of food avoidance, health worry, dysphoria and interference with activity; with these subscales having the lowest pre-treatment scores, they have a greater potential for improvement. Similar findings to this study have been previously reported [2], with the exception of social reaction also having a greater improvement and replacing food avoidance. The remaining subscales of body image, social reaction, sexual concerns and relationships in this study all showed clinically meaningful responses at 8 weeks (range 17.4–28.9).

Randomised placebo-controlled trials conducted in patients with IBS tend to be characterised by a relatively high placebo response. Considering the fact that a placebo effect generally tends to occur early in treatment and is less likely to persist, and the IBS-QOL scores increasing up to Week 8, this does not appear to have significantly impacted the outcome of the study; albeit a certain degree of placebo response cannot be completely excluded. Patel et al. [14] have demonstrated that fulfilment of the Rome criteria for study entry and an increased number of office visits are significantly associated with a lower placebo response rate. By requiring patients to fulfil the Rome III criteria, and by having three visits within the 8-week treatment period, a proactive effort was made to contribute to a lower placebo response rate.

Abdominal pain is one of the main symptoms associated with IBS and a responder has been defined in several studies in IBS patients [15] as demonstrating a 50 % decrease in symptom severity. For the IBS symptoms of abdominal pain and discomfort in this study, a mean decrease of >50 % in symptom severity was seen in all countries, and overall, at Week 8.

This study provides further relevant information on the IBS-QOL measure as a means to determine adequate treatment response. For the clinician, the study attests to the value of the IBS-QOL as a ‘barometer’ of the patient’s clinical course, more than any biological measure. It provides information on the patient’s perception of ill health, and how it is modified for better or worse in response to treatment, and can therefore be used as a yardstick of treatment progress, including when a particular intervention would be considered optimal.

The limitations of this study are in regard to both the study being observational in design and also to how the findings can be related to other populations. An observational study represents a ‘less perfect’ experiment than an efficacy trial and there can be issues relating to data quality and completeness, as well as the non-randomised design. The aim of this study, however, was to provide high-quality data by gathering it electronically, and statistical analysis showed significant increases from baseline in IBS-QOL total score at Weeks 4 and 8 for all countries and overall, which could be quantified in terms of a high MCR at Week 8. The findings, however, may not be applicable to men or women with milder or more severe disease, or with other functional gastrointestinal symptoms. The study does provide new information regarding the impact of IBS on HR-QoL and the magnitude of improvement in response to treatment with mebeverine hydrochloride or pinaverium bromide, showing the effectiveness of these treatments in a real-life setting. Many patients in this observational study received treatment for IBS and then in addition received mebeverine hydrochloride or pinaverium bromide, reflective of the real-life setting (where often a combination of medications is given to address the symptoms of the individual patient and IBS subtype) and showing the added value of additional treatment.

Treatment of patients with IBS with mebeverine hydrochloride in Poland, Egypt and Mexico and pinaverium bromide in China confirmed the effectiveness of the study medication in terms of the improvement in IBS-QOL total scores and subscales. Results were statistically significant and exceeded the MIR (≥10.2) for the IBS-QOL measure, from baseline, with the changes being greater at Week 8 than Week 4. At Week 8, the increase in the IBS-QOL total score was 24.3, greatly exceeding the MCR (considered to be an increase of at least 14) [10].

An improvement in IBS and gastrointestinal symptoms was also shown for the patients overall and for each subgroup (IBS-C, IBS-D and IBS-M). There was also an improvement in the health economic data for the patients, with a reduction during the treatment period in both the number of days spent in hospital and the number of days missed from work. Furthermore, the favourable safety profile of these treatments was confirmed in this study.