Irritable bowel syndrome (IBS) is a chronic and frequent condition characterized by abdominal discomfort or pain associated with defecation and/or changes in bowel habit (diarrhea, constipation or alternating of both), more evident during acute pain episodes 1. These symptoms fluctuate over time, typically with exacerbations associated with life stress events. During exacerbations, patient’s expectation is a fast and significant improvement of abdominal pain, the main factor affecting health-related quality of life ².

The most recent theories regarding the pathogenesis of IBS have emphasized the role of visceral hypersensitivity as the source of pain ³. Nevertheless, an increased or disorganized motor activity in the small bowel and/or the colon remains relevant to the generation of abdominal pain or discomfort. Manometric studies have shown that patients with diarrhea-predominant IBS have more jejunal contractions during phase II of the migrating motor complex and postprandial than healthy subjects. In addition, there is a relationship between the occurrence of pain episodes and the onset of clusters of jejunal motor activity ^4–7. Pain episodes have been also related to altered colonic phasic contractions and some studies have provided evidence of increased responsiveness of the IBS colon, both to the effects of eating and to stress ⁸. It must be also pointed out that visceral pain and altered gut motility may depend upon altered motility reflexes resulting from increased sensitivity of the digestive tract ⁹. Taken together, all these data provide rationale for the usefulness of antispasmodic agents in the short-term treatment of acute painful episodes.

Phloroglucinol (P) and its methylated derivative (TMP) are both antispasmodic agents acting on smooth muscle and devoted to treat abdominal pain. Based on glycerol-induced visceral pain model, animal studies suggested that P/TMP may modulate the release of prostaglandins and/or other inflammatory mediators such as nitric oxide (Bueno L et al, unpublished data). In IBS patients, P has been shown to reduce glycerol-induced abdominal pain and to inhibit colonic phasic contractions without affecting colonic tone ¹⁰. P/TMP is also characterized by a rapid and potent spasmolytic activity, suggesting that it may have some efficacy to relieve pain particularly during acute pain episodes.

The aim of this randomised, double-blinded, placebo-controlled study was to test the efficacy of P-TMP in the treatment of an acute exacerbation of pain in IBS patients seen in a primary care practice.

The study aimed to test the efficacy of P/TMP as a symptomatic treatment for the relief of abdominal pain intensity during an acute exacerbation of IBS over a one-week period of treatment. Our objective differs of previously published trials devoted to IBS, in which the primary endpoint was the possible modification on the medium term of the natural history of IBS by a treatment given daily for at least four weeks in order to decrease not only the intensity but also the frequency of abdominal pain episodes. Indeed, IBS is a chronic syndrome characterized by recurrent abdominal pain episodes. Therefore, short term clinical trials, lasting only few days are considered of limited clinical relevance to conclude that the treatment is effective to improve IBS 15 and one to three months is the recommended trial duration to achieve a good compromise between the time needed to assess efficacy and the time to reach the recession of a placebo effect ¹¹. IBS is characterized during its cyclic evolution by abdominal pain/discomfort exacerbations lasting for less than a week ^{16, 17}. It was also suggested that antispasmodics are better used on an as-needed basis for pain, distension or bloating exacerbation ¹⁸. A design of treatment trials committee recently recommended innovative trial design to evaluate short-course treatment after symptom recurrence ¹⁹.

During such exacerbations, IBS patients seek medical advice to receive a treatment able to provide a quick and significant improvement of abdominal pain. This study was carried out to assess if P/TMP, an antispasmodic agent, was able to provide such a fast significant relief. To achieve this goal, the symptomatic efficacy of P/TMP was compared to that of placebo over a one-week period of treatment with study conditions as closed as possible to real-life management of IBS patients in a primary care practice. To our knowledge, this is the first study with such a design, focusing on the relief of exacerbation of painful symptoms.

Several meta-analysis or reviews have already reviewed the symptomatic efficacy of antispasmodics in IBS ^20–22. These trials are characterized by a low methodological quality and the heterogeneity of the populations recruited in these trials, leading to contradictory conclusions ²³. Antispasmodic efficacy to improve abdominal pain in IBS remains a matter of debate. To avoid these methodological criticisms, our study was designed in accordance with the “Points to consider” on the evaluation of drugs for the treatment of IBS and followed the recommended criteria for methodological good quality ^11–13. Our study was designed a randomised, double-blinded, placebo-controlled parallel trial and patients were enrolled both if they fulfilled Rome II IBS criteria ¹ and if they suffered from an exacerbation of their abdominal pain when entering into the trial. The primary endpoint was abdominal pain intensity reduction using a well-established scale. Obviously, in this condition the patient is the best expert to judge the relief of his/her symptoms ^{12, 24}.

The definition of responder was based on a 50% reduction in pain intensity ¹¹. Moreover, a sufficient sample size calculated on a priori hypotheses, the low number of patients lost to follow-up (1% of treated patients) and the comparability of the two treatment groups for all baseline characteristics were also important points to consider for the quality of this trial.

When analyzing the results of a trial, one needs to consider not only the statistical significance of the results but also the clinical relevance of the study. This must be assessed in considering the effect of the treatment on the primary endpoint, i.e. the reduction of pain intensity. We have shown a greater reduction of abdominal pain intensity in patients treated with P/TMP with a relative reduction of pain intensity between baseline and day 7 of 57.8 ± 31.7% in P/TMP group. In the placebo group, the reduction was significantly lower, 46.3 ± 34.7% (p=0.0029). This led to a difference of 11.5 ± 3.8% [CI_95%: 4.0; 19.1] between the two treatment groups while at least a 10% difference is usually considered as clinically relevant ^{11, 25}. Moreover, consistent results were obtained for all secondary endpoints, therefore contributing to the robustness of the conclusions. Per-protocol analysis showed also similar level of differences between treatment groups.

The placebo effect is known to be maximal during the first four weeks of treatment and reflects to a large part the spontaneous improvement of symptoms ^{11, 26}. Despite the high placebo response observed in this study, similar to that observed in previous published studies ²⁷, P/TMP was still able to be significantly superior over placebo on all primary and secondary endpoints, e.g. by a 15.3 ± 5.7% [CI_95%: 4.1; 26.5] difference in rate of responders.

We have pointed out that the effect of P/TMP occurs within the first few days of treatment as a more significant improvement was already observed in the P/TMP group after the third day according to the daily diary filled by the patients. But, P/TMP had also an efficacy which is maintained since the daily improvement was persistent until the 7^th day in the P/TMP versus placebo group. Indeed, more patients who achieved at least a 50% of decrease of pain intensity remained responders until day 7, when treated with P/TMP rather than with placebo, respectively 47.3% versus 33.3% (p=0.015).

Patients were included according to the strict Rome II criteria, which are conservative and underestimate the number of patients having functional intestinal disorders in general practice, e.g. when using Manning or Rome I criteria ²⁸. On the other hand, patients included in this study were likely to have a diagnosis of IBS and their characteristics at baseline were very similar to that reported in previous French epidemiological studies ^{28, 29}.

In this trial, to be as closed as possible of the usual conditions in primary care, patients previously treated with other antispasmodics before exacerbation of their abdominal pain were included when the daily dose of antispasmodics was stable prior to the inclusion. This choice might have altered our ability to show a significant difference between P/TMP treatment and placebo. This was not the case and a subgroup analysis carried out on the 77 patients receiving concomitant treatment even showed the superiority of P/TMP over placebo with about the same level of difference than that observed on the whole population (although not reaching the significance, p=0.078, probably due to the small sample size).

In conclusion, this placebo-controlled trial demonstrated that P/TMP is effective to provide a fast and significant relief of abdominal pain, during an acute exacerbation of pain, in IBS patients fulfilling Rome II criteria. Our results confirm that antispasmodics can be used on an as-needed basis. Although the population included in this study corresponds to the majority of IBS patients managed in primary care, results may not be applicable to long standing sufferers and patients having a high level of anxiety. Further studies are warranted to demonstrate the sustained efficacy of repeated on-demand treatment during long-term disease management.

Contributed by 1. Authors’ declaration of personal interests:

(i) O. Chassany, B. Bonaz, S. Bruley des Varannes, L. Bueno, G. Cargill, B. Coffin, P. Ducrotté have served as advisory board members for Céphalon France.