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Abstract

  1. Top of page
  2. Abstract
  3. Diagnosis: Do Not Miss Pelvic Floor Dysfunction
  4. Treatment: When Should Prucalopride Be Used?
  5. Conclusions
  6. Acknowledgment
  7. References

Chronic constipation (CC) is widely prevalent in the Western world, with a significant negative impact on quality of life, yet new and effective pharmacological and non-pharmacological treatment options have only recently emerged. The article by Tack and colleagues in the current issue of NGM is timely with the recent introduction of the serotonin type 4 receptor agonist prucalopride in Europe and wider acceptance of anorectal biofeedback for patients with pelvic floor dyssynergia. This Editorial (i) highlights the importance of identifying patients with pelvic floor dysfunction who are candidates for pelvic floor retraining programs and (ii) discusses the potential limitations of the 5-HT4 agonist, prucalopride, as an early option in the treatment algorithm for CC.

Chronic constipation (CC) is widely common in the United states, Europe and Oceania1,2 can adversely affect a person’s quality of life3 and work productivity, and is also associated with significant direct and indirect costs.4 CC can be divided into three subtypes (normal transit, slow transit, and pelvic floor dysfunction).

Identifying patients with pelvic floor dysfunction, which is most frequently secondary to paradoxical contraction, or inability to relax, pelvic floor muscles during defecation, is clinically relevant as treatment with anorectal biofeedback appears to be more effective than laxatives.5

Treatments for constipation have been available for millennia. The Romans included chicory and beet root in the menu of their endless banquets to facilitate digestion. At the Medical School at Salerno, Italy, whose origins date back to the 10th century, infusions of mauve and other herbs to help lazy bowels were used.6 Doctors in Moliere’s play Le Malade Imaginaire, which was first produced in 1673, insist on the constant need of purging, traditionally done with ricin, castor oil, for general health.7

Modern treatment options for CC, although somewhat more evidence-based than those used in the ancient times, are still centered on laxatives. In a multi-national survey that included almost 14 000 individuals with self-reported constipation, up to 40% of adults reported laxatives use at least monthly.8

Only recently have non-laxative agents emerged.9 Prokinetics such as cisapride, tegaserod, mosapride, prucalopride, and the chloride channel activator lubiprostone 10 have shown efficacy for the treatment of motility disorders of the gut, including CC. Unfortunately, none of these therapies have attained world-wide acceptance and availability. For example, lubiprostone is currently available only in the US and Switzerland, while prucalopride is currently available in the 27 countries of the European Economic Area.

In this issue of NGM, an authoritative board of European experts presents their view of modern diagnostic and therapeutic approaches to CC in the ‘Old Continent’, proposing diagnostic and therapeutic algorithms.11 One might argue that potential differences between Europe and elsewhere in the world in terms of patients’ culture and expectations, physician referral patterns, logistics of access to care, and availability of resources may present a challenge to generalization of diagnostic and therapeutic algorhythms from one continent to another.

However, epidemiological studies of CC suggest similar prevalence rates in Europe, Oceania, North America, and in developed countries in Asia.2 The use of laxatives also appears to be similar between Europe and North America.8 Despite differences in the health care systems, constipation is likely to remain the same affliction throughout the world. Therefore, with the exception of medications that are not yet available, the recommendations put forth by Tack and colleagues should be applicable throughout the world. There are, however, issues pertaining to the diagnostic algorithm and to the early use of non-laxative agents in CC which are valid everywhere and which should be further discussed.

Diagnosis: Do Not Miss Pelvic Floor Dysfunction

  1. Top of page
  2. Abstract
  3. Diagnosis: Do Not Miss Pelvic Floor Dysfunction
  4. Treatment: When Should Prucalopride Be Used?
  5. Conclusions
  6. Acknowledgment
  7. References

Up to one-third of patients referred to a gastroenterologist with CC may have features of pelvic floor dysfunction.12 While physiological testing of the pelvic floor (e.g., anorectal manometry, defecography) are available predominantly at specialized tertiary centers, simpler and cheaper alternatives might be also be effective. A study of 209 patients with CC diagnosed by Rome III criteria who underwent anorectal manometry, balloon expulsion test and a transit study found that a standardized rectal exam performed by specifically trained personnel blindly of test results could correctly identify pelvic floor dysfunction with 75% sensitivity, 87% specificity and a positive predictive value of 93%.13

Identifying pelvic floor dysfunction in patients with CC is relevant as demonstrated by a recent study conducted in Italy, that found patients with pelvic floor dyssynergia to have a superior response to biofeedback than to an osmotic laxative, and that this response persists 24 months after biofeedback5,14,15.

Despite these data, our personal experience is that biofeedback is more commonly used in patients with urinary and fecal incontinence than in patients with constipation. The greater diffusion of surgical options such as the stapled transanal rectal resection in Europe (the STARR procedure, also available in the US),16 and the availability in Europe of sacral neuromodulation,17 which is approved by the FDA only for fecal incontinence, also limit the use of biofeedback there. Nonetheless, there can be difficulty obtaining reimbursement for biofeedback programs, and this modality needs the patient’s cooperation and understanding of the retraining exercises. In a study of 102 patients, greater patient willingness to participate was a significant predictor of biofeedback success.18

Recognizing these limitations, physicians should still be cautious about ‘giving up’ on patients with pelvic floor dysfunction who might benefit from biofeedback.

Treatment: When Should Prucalopride Be Used?

  1. Top of page
  2. Abstract
  3. Diagnosis: Do Not Miss Pelvic Floor Dysfunction
  4. Treatment: When Should Prucalopride Be Used?
  5. Conclusions
  6. Acknowledgment
  7. References

Prucalopride is a highly selective full 5HT4 agonist, which was recently approved for the treatment of CC in Europe and represents a promising novel treatment option for CC. In patients ‘refractory’ to laxatives, prucalopride improves symptoms of CC over placebo in approximately 18–24% of patients.19,20 Likewise, meta-analysis pooling of results from seven trials of prucalopride reports a number needed to treat (NNT) of 6.21 While this effect size is comparable or better to that seen with tegaserod,22 if only focusing on efficacy, osmotic laxatives and lubiprostone could provide a better margin over placebo, with a NNT of 3 and 4, respectively, according to the same meta-analysis.21 An important limitation of this calculation, however, is the much smaller size and significant heterogeneity of clinical trials of laxatives as opposed to those of prucalopride and tegaserod.21

The algorithm proposed by a distinguished group of European experts in this issue of the journal11 supports switching to prucalopride as soon as an attempt at treatment with a laxative fails to provide relief of CC. These Authors deserve to be commended for disclosing their relationships with Movetis. Among the studies reported by Tack et al. to support their argument in favor of early use of Prucalopride, one trial included a large subgroup (83% of the overall sample) of patients dissatisfied with previous laxative use. These patients reported similar outcomes to the rest of the sample. Despite the emphasis on dissatisfaction with laxatives, this study presented no formal evaluation of the type, dose, duration of use, category of laxative(s) previously administered. This evidence of prucalopride efficacy is not a direct comparison to laxatives and should not prompt the bypassing of these agents in the therapeutic algorithm of CC. Clinical experience also shows that patients who ‘search’ for a more effective and better tolerated laxative sometimes achieve satisfactory results.

Close examination of the prucalopride efficacy data in CC suggests that the effect of this drug is less effective on anorectal symptoms and on straining,20,23 clinical presentations that are more common in patients with pelvic floor dysfunction.

These considerations suggest that prucalopride is not a one-size-fits-all option, and that switching too soon to prucalopride in the course of CC limits other options.

Importantly, there have been significant efforts to explore the safety of prucalopride. Available studies in various patient populations, including the elderly, show no effects on ECG tracings of this 5HT4 agonist, no incidence of arrhythmias, and no changes on Holter monitorings.21,24,25 Nevertheless, when a novel agent becomes available for condition as prevalent as CC, it is likely that this drug will become widely prescribed. In the case of tegaserod, potential cardiovascular side effects prompted withdrawal from the market in the United States, Switzerland, and other countries. Despite the compelling data on prucalopride safety, the possibility of rare, yet significant post-marketing events remain of concern to physicians and regulatory agencies. Even the remote potential for severe unwanted side effects in the treatment of a chronic, yet benign condition is an unacceptable tradeoff.

Cost is also significant issue when introducing a novel therapeutic. Lubiprostone costs approximately $178 for 1 month supply in the US, comparable to the cost of Tegaserod when this drug was available $194. The monthly cost of prucalopride in Germany is 61 Euros for the 1 mg, 90 Euros for the 2 mg dose. Polyethylene glycol, an over-the-counter laxative, costs approximately $43 a month at 17 g daily dose.26

Given the pricing differences and constraints to the resources of health care systems worldwide, cost effectiveness data are needed to determine if incorporating prucalopride as an early option in the management algorithm of CC is appropriate.

Conclusions

  1. Top of page
  2. Abstract
  3. Diagnosis: Do Not Miss Pelvic Floor Dysfunction
  4. Treatment: When Should Prucalopride Be Used?
  5. Conclusions
  6. Acknowledgment
  7. References

The review by Tack and colleagues describes the diagnostic approach to CC in Europe and proposes early use of the novel 5-HT4 agonist, prucalopride, in the management of this prevalent condition. We welcome and support the availability and use of novel non-laxative agents for the treatment of CC. We believe, however, that an accurate selection of patients who could benefit from non-pharmacologic approaches needs to be performed in the diagnostic algorithm of CC. We also argue that prucalopride, and other novel agents which potentially will become available for CC, should be used after an adequate trial of laxatives.

References

  1. Top of page
  2. Abstract
  3. Diagnosis: Do Not Miss Pelvic Floor Dysfunction
  4. Treatment: When Should Prucalopride Be Used?
  5. Conclusions
  6. Acknowledgment
  7. References