This study published in the NEJM seems to have tackled the really dicey issue of unearthing a pharmacotherapeutic agent to deal with the rather ubiquitous, though poorly understood, and more often than not, even less poorly managed problem of irritable bowel syndrome. The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurring symptoms of abdominal pain, bloating, and altered bowel function in the absence of structural, inflammatory, or biochemical abnormalities. (1) Now, the pathophysiology of this disease being very poorly understood, it was only natural that the modalities of therapy were also not forthcoming. This study is definitely not the first of its kind in suggesting that Rifaximin maybe a useful modality of treatment of IBS without constipation. There have been predecessors which have dwelled on this idea (2,3). There have been a lot of criticisms of those studies, which I do not want to get into now, but maybe some time later, in a related post! For now, the focus is on the NEJM paper.

So let us crunch the numbers awhile:

1260 patients were randomized in two identically designed, large, placebo-controlled, randomized trials, to either receive rifaximin (550 mg TDS) or placebo for a period of 2 weeks and they were then followed up for a period of 10 weeks, post-treatment. The primary end point was, as is always the case with elegant studies, bewitchingly simple:

…the proportion of patients who reported adequate relief of IBS symptoms, as assessed by responses (yes or no) to a question about relief of symptoms that was asked weekly during the first 4 weeks after treatment. The key secondary end point was the proportion of patients reporting adequate relief of bloating during the same period.

In the rifaximin groups, as compared with the placebo groups, a significantly higher proportion of patients reported adequate relief of IBS symptoms (41% vs. 32% in the two trials combined, P<0.001) or bloating (40% vs. 30%, P<0.001) for at least 2 of the first 4 weeks. Similarly significant results were obtained in an analysis of relief of symptoms during the 10-week period after the end of the double-blind treatment phase.

Now, the benefits that have been thrown up by the study are self evident. A relatively sustained period of relief following a 2 week course is a very attractive finding. The fact that Rifaximin helps in relieving almost all the symptoms of IBS, including bloating, is also a factor which would promote its usage. The studies are well-designed, have compelling number of patients, and the fact that there were two identical studies, which reproduced almost parallel results is also proof of the fact that the numbers are reproducible. Although this may not be a consideration in the developed world, cost of therapy is also an added factor in India. With Rifaximin, this is also adequately addressed, especially since it is to be administered for a relatively short period of time. Compared to the benefits, and the fact that the other modalities of treatment are nowhere as effective or cost-effective, the cost considerations of this therapy is heavily favorable.

Also, rifaximin, a poorly absorbed antibiotic which has broad spectrum coverage against gram negative, gram positive and anaerobic bacteria, is a relatively safe drug. It has previously been used in treatment of traveler’s diarrhea with much clinical success. The adverse effect profile of the drug and its therapeutic index are also substantially wide to favor 2-week administrations, on multiple ocassions, if needed!

However, as is the case with every finding, there is another side to the coin. By the admission of the authors, the results, although significant and look healthy numerically, fall in the lower range of clinically significant findings. (4) Another thing is that, there is a reduction in efficacy over the 10 week period studied. How the efficacy of rifaximin wears off with time is also an important consideration, especially keeping in mind the chronic nature of the disease. Until more compelling data supporting longitudinal benefits of a 2-week rifaximin course are forthcoming, there will hang a shadow of doubt over the long term implication of the benefits. What follows as a natural corollary of this is the need of future re-administrations as well as their efficacy in comparison to past usages. The burning question in this regard is whether the reuse of rifaximin will be accompanied with a fall in efficacy. If it is, and if with consequent repetitions the effect keeps getting weaker, it will seriously hamper the practical use of the drug for this condition.

The data also shows that a particular sub-group of patients are more benefited than the rest. Although no demographic or investigational parameters have been defined with regards to identifying this sub group, it may be a great research question to pursue in further future studies of the drug! With reference to this fact, one may add the much criticized lactulose breath test and its validity in such a setting. Prone to false positives, and poorly reproducible, this was one of the mainstays of diagnosing small intestinal bacterial overgrowth in patients of IBS.

And finally, keeping the best for the last, the issue of using an antibiotic to treat a chronic condition, which may therefore, raise questions regarding the issues of antibiotic resistance is also a pertinent threat. One has to keep in mind the fact that it is still early days and although resistance profiles of bacteria against rifaximin is favorable, it may rapidly change with over use, and worse, abuse!

Another consideration, which, hopefully, does not have any bearing on the results are the significant industrial ties which are involved with this study. It goes without saying that a joournal of the status of NEJM is probably immune to the fiscal machinations of “big pharma”, yet, one cannot but be skeptical of such an association (especially seeing the case of MMR-Autism and big money case rolling around).

So, in conclusion, although these results are heartening, there is still some distance to go before one can approve this drug for treating the pesky problem of IBS. Most importantly, long term follow up data have to show that the treatment affords relief not over a period of weeks, but years. Given the chronic nature of the disease, this is an important consideration. Also, the necessity of repetition of therapy and the efficiency thereof needs to be investigated. Finally, one needs to identify the disease/demography parameters which identify the best responders to rifaximin therapy. Only then can we move to institute it as an approved means of treating IBS.

Till then what are you going to do? Will you prescribe it for your patients? Do let me know!

References:

1. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based systematic review on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104:Suppl 1:S1-S35

2. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial.Ann Intern Med 2006;145:557-563

3. Drossman DA. Treatment for bacterial overgrowth in the irritable bowel syndrome. Ann Intern Med 2006;145:626-628

4. Corazziari E, Bytzer P, Delvaux M, et al. Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2003;18:569-580

Study in Focus:

Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP, & TARGET Study Group (2011). Rifaximin therapy for patients with irritable bowel syndrome without constipation. The New England journal of medicine, 364 (1), 22-32 PMID: 21208106