What can be done pharmacologically for a subject with severe refractory constipation-predominant irritable bowel syndrome?

KEYWORDS:

• Constipation-predominant IBS
• irritable bowel syndrome
• pharmacological treatment
• secretagogues
• treatment refractoriness

1. Introduction

Irritable bowel syndrome (IBS) is a complex gut disorder characterized by an interplay of psychosocial, motility, perceptive, and microbiota abnormalities [1]. This complexity extends to its management, and the treatment of IBS symptoms is frequently a great challenge for physicians. The latter is due to a series of problems: for instance, notwithstanding an abundant literature, to date no validated therapeutic algorithm is available for IBS. Moreover, the huge variation in symptoms complained by these patients accounts for the great variability reported in the responses to identical therapeutic approaches; this leads to various recommended treatments for the same symptoms [2]. It should be also taken into account the fact that the various treatments employed for IBS patients may be limited by the appearance of adverse events, in turn leading to safety concerns [3]. Thus, the patients’ willingness to take risks linked to their treatment is widely variable [4]. The above considerations, and the wide placebo effect observed in IBS patients [5], make therefore quite challenging the pharmacologic (but also other) treatment of these patients.

2. State of the art

In the time course, numerous pharmacologic therapeutic approaches have been tried in constipation-predominant IBS (IBS-C) patients [6]; however, it is sadly depressing that only a few of these drugs resisted to scientific scrutiny. Even more worrisome is the fact that a high strength of evidence for therapeutic efficacy has been demonstrated – except the tryciclic antidepressants – only for a handful, recent new drugs [7]. Traditionally, the cornerstone of pharmacological treatment for IBS-C patients relies on management of constipation (laxatives, featuring polyethylene glycol in pole position) and of abdominal pain (antispasmodics, peppermint oil), followed/associated to tryciclic antidepressants [8]. The latter are presently strongly recommended, and with high quality of evidence, for overall symptom improvement in all IBS patients [7]. Other drugs (rifaximin, selective serotonin reuptake inhibitors) are often used alone or in combination with the above to treat associated symptoms such as bloating and mood disorders and modulate abdominal pain. The number needed to treat (NNT) for the above drugs ranges from 3 to 16 [7]. Until recently patients not responding to these treatments, most of which had scarce to moderate strength of scientific evidence of effectiveness, were labeled as unresponsive or pharmacologically intractable. Fortunately, the last years have seen a remarkable research interest in this field, and new drugs with high strength of evidence to treat IBS-C patients (i.e. lubiprostone, linaclotide, and plecanatide) have been approved [7]. These new prosecretory drugs act as potent peptide agonists of the guanylate cyclase C receptor (linaclotide, in a pH-independent manner, and plecanatide, in a pH-dependent manner) or by activation of the intestinal chloride channel type 2 on the apical surface of small intestinal enterocytes (lubiprostone). Of interest, these three drugs are recommended (recommendation: strong; quality of evidence: moderate) for overall symptom improvement in IBS-C patients by the recent expert panel of American College of Gastroenterologists [7]. Another drug recently approved (September 2019) by the Food and Drug Administration (FDA) for this purpose is tenapanor, a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger 3, that in recent trials (at the dose of 50 mg b.i.d) significantly increased stool frequency and reduced abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) in patients with IBS-C [9].

Concerning the specific efficacy of these secretagogues in IBS-C patients, a recent systematic review with network meta-analysis [10] showed that the above drugs were all superior to placebo. Moreover, based on the recommended primary FDA endpoints (abdominal pain, complete spontaneous bowel movements), linaclotide had the higher rank. Tenapanor scored first for decreasing bloating and plecanatide for safety [10].

However, although effective in a sizable portion of IBS-C patients (NNT 5 to 25) [7], the use of these secretagogues has unfortunately some limitations, since at present the new treatments are not available worldwide: for instance, only linaclotide has been approved in Europe for this purpose. Another important issue is the cost: in absence of Health Services reimbursement the monthly cost of treatment is above 400 USD, and some critical observations on this point have been raised [11].

Costs and drug availability apart, it remains the fact that the secretagogues are not ‘magical bulletts’ useful for all subjects, and there is a subgroup of patients unaffected also by these treatments.

Thus, the old question still remains: what can be done pharmacologically for a subject with severe refractory IBS-C? An important consideration is that the new secretagogues, in addition to their efficacy, are also remarkably safe (at least in the short-term period) [10] and have few pharmacological interactions [12]. Therefore, they can be often used in combination with older drugs and/or with drugs having different mechanisms of action, to increase the therapeutic efficacy. In addition, a few new interesting drugs seemingly effective in IBS-C patients are in the pipeline around the corner, and will be hopefully available in the very near future. Among these elobixibat, a locally acting ileal bile acid transporter inhibitor has been successfully tested in patients with severe constipation, and could hopefully be also used in IBS-C [13]. Other drugs with several different mechanisms of action are being developed (itopride hydrochloride, pumosetrag, sodium deoxycholate, and clinical trials are in the recruiting phase), and the results of their effects will be likely available soon.

3. Expert opinion

Treating pharmacologically IBS-C patients may be a challenging task, due to both the complex pathophysiological grounds and the frequent clinical heterogeneity of this condition. Although many of these subjects may be more or less successfully managed by means of traditional approaches [6,8,14], there is a consistent subgroup of patients that is still labeled as resistant to those therapies. The recent introduction of secretagogues in the clinical practice has been a tremendous improvement, since these drugs are usually both effective on constipation symptoms and abdominal pain, the latter being often the Cinderella concerning symptoms’ treatment of these patients. The added bonus to the efficacy of secretagogues is the relatively low percentage of side effects (mainly diarrhea) leading to treatment discontinuation, and the fact that their scarce pharmacologic interactions allow them to be used in combination therapies without increasing the toxicity. This often increases the percentage of therapeutic success, at least in many daily instances, although solid scientific data on this issue are not available. However, the use of secretagogues may also encounter therapeutic resistance or ineffectiveness, and even adopting poly-drug combinations (costs apart) may not invariably result in a therapeutic success.

The -hopefully near- future availability of drugs such as elobixibat and tenapanor (and some others still in the developing phase), with further different mechanism of action that act on several pathophysiological variables will surely add more weapons for better therapeutic targeting these often difficult patients. In fact, if these drugs will also prove as effective in improving the main symptoms complained by IBS-C patients, i.e. constipation and abdominal pain, and without significant adverse events or drug interactions, we will be able to act on more than one pathophysiological mechanism with single or multiple drugs and tackle the patients’ discomfort by improving symptoms and the quality of life.

Declaration of interest

G Bassotti has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.