New pharmacologic treatments for idiopathic chronic constipation: a financial strain for strainers

KEYWORDS:

• Bile acid transport inhibitors
• chronic constipation
• 5-HT4 agonists
• new drugs
• prosecretory agents
• treatment
• costs
• medical therapy

There’s three things in this world that you need:

respect for all kinds of life, a nice bowel movement

on a regular basis, and a navy blazer

Robin Williams

1. Introduction

Chronic idiopathic constipation (CIC) is a frequent gastrointestinal complaint among the general population, mostly affects women with impairment of the quality of life, and it is associated with potentially life-threatening diseases and increased mortality [1]. CIC it is often treated in an empirical manner in real-life conditions [2,3]. Despite laxative having a long history of use for CIC treatment, it is surprising that in 2002 a meta-analysis concluded that, due to poorly published studies, there was no objective evidence of their use for this indication [4]. Since then, however, things have changed and more solid scientific evidence appeared in literature, allowing the formulation of treatment guidelines from both Western and Eastern countries [5,6].

2. Current evidence

Lifestyle modifications and the use of bulking agents (fibers) are often employed as first-line remedies. However, although fiber supplementation with preference for soluble fibers [5] is often used to treat constipation, this approach often worsen symptoms in patients with slow transit constipation. Therefore, the mainstay of CIC treatment relies on the use of laxatives. Among these, osmotic laxatives represent at present the therapeutic cornerstone, and are the agents more frequently used and recommended as first-line approach, even in the long-term and in elderly patients [5,6]. However, it is worth noting that patients’ dissatisfaction with this approach is reported in about 20% of patients, and may rise up to more than 40% when assessed by rigorous means [7]. In recent years, there had been a renewed research interest in the treatment of CIC, and several new drugs with proven efficacy have been developed and released on the market. These agents belong to different chemical families, such as 5-HT4 agonists (prucalopride, velusetrag), prosecretory agents (lubiprostone, linaclotide, plecanatide, tenapanor), and bile acid transport inhibitors (elobixibat), and have been evaluated according to strict efficacy criteria [8]. Unfortunately, these drugs are not available in all countries. Concerning Western countries, for instance, only prucalopride is currently available in Europe to treat CIC patients, whereas other drugs are commercialized in the USA (lubiprostone, linaclotide, plecanatide, tenapanor) or not yet approved by the regulatory authorities (velusetrag, elobixibat) [9]. Some points merit to be discussed.

First, it must be considered that, overall, there are relatively few randomized controlled trials (RCT) available concerning drug treatment of CIC patients.

Second, an important issue to be taken into consideration when using the new drugs against CIC is their cost, at least in Europe and in the US. For instance, in Europe the cost of 1-month treatment with prucalopride is about 100 euros, and in some countries (e.g. Italy) there is no reimbursement from the National Health Systems. However, there is some evidence that the use of prucalopride in CIC patients refractory to conventional laxative treatment might potentially decrease the use of secondary care resources and yield cost savings [10]. Concerning the other agents, available at present only in the US, these are considerably more expensive, and 1 month of treatment costs to the patients approximately 450 US dollars (USD) [11]. This fact raised some critical issue, and prompted some author to calculate a potential cost of 850 USD per bowel movement for each constipated patient, also questioning the affordability of these treatments for a non-lethal condition [12].

Third, a recent systematic review and network meta-analysis on RCT showed that all the above new drugs have similar efficacy to treat CIC patients [13], but might not be more effective than older therapies. Briefly, although all drugs included in this thorough analysis proved to be superior to placebo, the stimulant laxatives sodium picosulfate and bisacodyl (even though frequently causing abdominal cramps and diarrhea) were those most effective at 4 weeks, compared to prucalopride, linaclotide, and elobixibat. Prucalopride was the most effective drug at 12 weeks. However, an important point to consider is that no head-to-head comparisons of drugs investigated to treat CIC is available at present.

These results are quite interesting concerning costs. In fact, the cost of one-month treatment with bisacodyl or polyethylene glycol is about 10 USD, and it is slightly higher (about 15 UDS) for lactulose [14]; this cost is almost equivalent in euros. The treatment with bisacodyl or polyethylene glycol, in addition, seems to have a more favorable number needed to treat compared with the newer drugs [14]. On the other hand, as seen for prucalopride and although no such data are presently available, the use of the new drugs could decrease the use/dosage of conventional laxatives (often employed in association and in high doses) and led to cost savings. Another point to consider is the fact that the trials with newer drugs may appear less effective than those with older drugs because the former might have recruited patients with more severe symptoms [11].

Fourth, there is a paucity of data on cost-effectiveness of CIC treatments. The cost-effectiveness literature on available treatments for CIC has been systematically reviewed in only one study [15]. Lifestyle advice, dietary approaches, and abdominal massage were compared with standard laxatives; macrogol and combination of senna-fibers were compared with lactulose; prucalopride was compared with continuing laxatives; linaclotide was compared with lubiprostone. All these interventions, except abdominal massage, were reported to be cost-effective to treat CIC [15].

3. Expert opinion

Can we find at present a right equilibrium in the use of the newer drugs to treat CIC? Indeed, there is a quite wide consensus that, given the proven efficacy and the lesser cost of several conventional laxatives, these should be used as second-line weapons [5,6], and their indication should be possibly given by physician experts in this field. However, there are data suggesting that, at least in patients refractory to conventional treatments, i.e., those failing to respond to lifestyle modifications with adequate dosage of osmotic and/or stimulant laxatives used for an appropriate period of time, the use of these new drugs could decrease the costs of further investigations and the use of secondary care resources [10]. In addition, it is important to keep in mind that the pharmacologic interactions of these drugs are scarce [11]. Therefore, these agents can be used in combination with conventional laxatives or between them, especially in patients refractory to treatment and that sometimes are very difficult to manage [16]. This may be important to limit or decrease the repeated accesses of these patients to emergency settings, and reduce the expenses of multiple unnecessary reevaluations. Of course, some subtypes of constipation (e.g. opioid-induced constipation, fecal impaction, pelvic floor dysfunction, constipation due to collagenopathies or other diseases) may require different and focused treatment approaches, such as the use of specific antagonists, biofeedback techniques, and enemas. However, some of the new drugs may be effective also in this setting (e.g. lubiprostone for patients with opioid-induced constipation or prucalopride for constipation secondary to scleroderma).

As recently demonstrated [13], today we have several new drugs effective for the treatment of CIC, in addition to the proven efficacy of conventional treatments. In fact, the use (even combined) of osmotic and stimulant laxatives seems a reasonable first-line option, especially in patients with moderate-severe symptoms, even though the side effects associated with their use may limit the patients’ compliance. Thus, the recently approved new drugs (where available) should increase the possibility to treat in an effective manner more patients and, hopefully, also those not responding to more conventional approaches. The relative paucity of side effects and the possibility to combine drugs with different mechanisms of action is therefore very appealing in this setting. The use of the newer drugs, however, due to the lack of long-term data and the relatively high cost, requires a good dose of judgment and expertise by the physicians involved in the care of CIC patients. For instance, the use of prucalopride (due to the effects on colonic propulsive activity) could benefit patients with slow transit constipation, whereas linaclotide could be more useful in CIC patients with associated abdominal pain. Of interest, the prokinetic effects of these drugs also on more proximal gut segments could benefit patients with associated dyspeptic symptoms, as suggested by anecdotal reports.

The above considerations seem quite reasonable, in order to provide the better therapeutic options for CIC patients, and avoid to further straining financially patients that are often psychologically strained in addition to have to strain to empty their bowels. Such a judicious approach will likely yield better clinical results avoiding an additional strain to these strainers.

Declaration of interests

The author 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

Acknowledgments

This paper is dedicated to the memory of Corrado Blandizzi, friend and colleague.

Additional information

Funding

This paper was not funded.