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Current and future therapies for chronic constipation
Best Practice & Research Clinical Gastroenterology 25 (2011) 151–158
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Best Practice & Research Clinical Gastroenterology
12
Current and future therapies for chronic constipation J. Tack, MD, PhD, Professor of medicine * Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
In this article, traditional and novel therapies for chronic constipation are reviewed. Traditional laxatives are effective at inducing bowel movements, but efficacy in long-term management and efficacy on constipation-associated abdominal symptoms are less well established, with the exception of polyethylene glycol, for which long-term studies confirm sustained efficacy. Recently approved drugs include the colonic secretagogue lubiprostone and the 5-HT4 agonist prucalopride. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, with a favourable safety record. Methylnaltrexone, a subcutaneously administered peripherally acting mu opioid receptor antagonist, has recently been approved for opioid-induced constipation in terminally ill patients. New agents under evaluation include the 5-HT4 agonists velusetrag and naronapride, the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan. Ó 2011 Published by Elsevier Ltd.
Introduction Chronic constipation is a common disorder on a worldwide scale. Estimates of population prevalence range from 8.75% in the Asian Pacific region to 27% in Western countries [1,2]. Typical symptoms of constipation include infrequent bowel movements, hard stools and straining when passing stool. In addition abdominal discomfort, bloating, cramps and pain are often associated and complications like hemorrhoids and anal fissures may occur [1,2]. A variety of treatment options are available for patients with chronic constipation, ranging from older over-the-counter laxatives to more recently developed prescription drugs [1–6]. In spite of these * TARGID, Department of Pathophysiology, University of Leuven, Herestraat 49, 0&N 1, bus 701, B-3000 Leuven, Belgium. Tel.: þ32 16344225; fax: þ32 16344419. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.bpg.2011.01.005
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different treatment approaches, there remains a substantial unmet need in the treatment of chronic constipation [7]. This article reviews the pharmacological therapies currently indicated for chronic constipation and looks ahead to future developments that may offer benefits. Current medical therapies Current laxatives aid defecation by decreasing stool consistency and/or by stimulating colon motility (Table 1). Different classes of laxative drugs include bulking agents, stool softeners, osmotic laxatives and stimulant laxatives, and they can enhance defecation by binding luminal water, by altering mucosal absorption or secretion, by increasing bacterial mass and by stimulating contractile activity. The available efficacy and safety data for traditional laxatives have been summarised before [5,6]. Bulk (fibre) laxatives Undigestible fibres attract water which leads to a larger and softer fecal mass. Systematic reviews of studies with bulking agents indicate that they induce an average increase of 1.4 bowel movements per week [5,6]. However, the quality of the studies is highly variable and the treatment duration was usually short (maximum 4 weeks) [1]. Fibre has no major adverse effects and is usually well tolerated, although they may worsen symptoms of bloating. Osmotic laxatives Osmotic laxatives include poorly absorbed sugars (lactulose, sorbitol,.), polyethylene glycol (PEG) preparations or magnesium salts (magnesium hydroxide, magnesium citrate, magnesium sulphate, ..). Through their osmotic actions, these agents retain water in the intestinal lumen, which leads to softer
Table 1 Classes of traditional laxatives. Laxative class
Laxative agents
Mechanism of action
Potential limitations
Bulk laxatives
Natural fibre (e.g. psyllium seed husk) Semisynthetic fibre (e.g. methylcellulose) Synthetic fibre (e.g. polycarbophil, polyethylene glycol (macrogol) Magnesium hydroxide, Magnesium citrate, Magnesium sulphate, Sodium phosphate Lactulose Sorbitol
Luminal water binding increases stool bulk and reduces consistency.
Abdominal distention
Osmotic water binding
May cause electrolyte abnormalities; to be used with caution in patients with renal or cardiac failure Bacterial fermentation with bloating, flatulence Less effective in slow transit due to bacterial degradation Abdominal discomfort and creamps
Osmotic salts,
Disaccharides and sugar alcohols Stool softeners
Paraffin oil Docusate
Stimulant laxatives
Diphenylmethane derivatives (bisacodyl, sodium picosulphate) Anthraquinone derivatives (senna, aloe, cascara)
Osmotic water binding
Luminal water binding increases stool bulk and reduces consistency Induce colonic contractions by acting on enteric nerves Decrease colonic absorption of water and electrolytes
Abdominal discomfort and cramps
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stools with a larger volume and improved propulsion. Controlled studies demonstrate increased stool frequency, softer consistency and decreased straining compared to placebo. Except for the more recent PEG studies, the available trials are usually of short duration and inconsistent quality. Only few studies have directly compared osmotic laxatives with other agents. Non-absorbable sugars induce a limited improvement of stool frequency and consistency, but may also lead to symptoms like bloating and abdominal distention due to colonic fermentation. In a randomised controlled trial in the elderly, both treatments were equally effective but lactulose caused more nausea as a side effect [8]. In a systematic review of controlled trials, lactulose was less effective than PEG [9]. PEG is well tolerated and provides short-term relief of constipation compared to placebo [9,10]. Recent long-term retrospective series confirm that PEG maintains its efficacy for up to 24 months of treatment [11,12]. PEG was compared to tegaserod in an open-label study, where PEG induced a higher number of bowel movements [13]. PEG preparations are available both with or without electrolyte supplements, and in different dosages [1]. Patients prefer the electrolyte-free preparations, and the electrolyte containing preparations are mainly indicated when high volumes are given, such as for colon cleansing prior to colonoscopy or surgery [14,15]. Magnesium hydroxide and other magnesium salts improve stool frequency and consistency. Absorption of magnesium is limited, but may induce problems in patients with impaired renal function [16]. In a randomised 12-month trial with magnesium hydroxide or PEG in children with chronic constipation and fecal incontinence, both treatments were equally effective and well tolerated [17]. Stool softeners Laxatives which mainly soften or lubricate stools (e.g. sodium dioctyl sulfosuccinate and liquid paraffin) appear to be more effective than placebo in increasing the frequency of bowel movements and in overall symptom improvement, but data are limited [30]. Liquid paraffin may interfere with absorption of fat-soluble vitamins, and should be avoided in patients with oropharyngeal dysphagia as aspiration of this mineral oil causes a lipoid pneumonia [1–6,18]. Stimulant laxatives (phenyl methanes and anthraquinones) Stimulant laxatives act on the enteric nervous system to increase intestinal motility and secretion, thereby inducing passage of stools [1,3–6,19]. Bisacodyl and picosulfate are both phenylmethane prodrugs, which are hydrolysed by colonic bacteria or brush border enzymes to their active metabolite bis-(p-hydroxyphenyl)- pyridyl-2-methane (BHPM) which causes peristalsis. Placebo-controlled trials show that these drugs are more effective than placebo, but most of the trials are of short duration and the quality is variable [1,3–6]. In a recent 4-week placebo-controlled trial, picosulfate improved bowel function, symptoms, and quality of life [20]. Stimulant laxatives are generally well tolerated, do not cause electrolyte abnormalities, but may induce abdominal pain [1,3–6,21]. The latter can often be managed by dose titration [20]. It has been suggested that stimulant laxatives may induce damage to enteric nerves or colonic epithelium, but this has not been confirmed in experimental studies and in clinical practice [19]. New therapies for chronic constipation Several new pharmacological classes have been evaluated or are under evaluation for the treatment of chronic constipation, including 5-HT4 receptor agonists, colonic secretagogues and opioid antagonists (Table 2). 5-HT4 receptor agonists Serotonin (5-hydroxytryptamine, 5-HT) is a key regulator of gastrointestinal motility, sensitivity and secretion. Through 5-HT4 receptors, which are mainly expressed mainly by enteric neurons, 5-HT triggers and coordinates intestinal peristalsis [22]. Cisapride, a benzamide compound, is a 5-HT4
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Table 2 New and emerging drugs for chronic constipation. Drug class
Individual agents
Mechanism of action
Status
5-HT4 receptor agonists
Prucalopride
Stimulation of colonic and intestinal peristalsis
5-HT4 receptor agonists Colonic secretagogue
Velusetrag Naronapride Lubiprostone
Stimulation of colonic and intestinal peristalsis CCl2 channel activation
Prucalopride approved in Europe and Switzerland. Studies in Asian-Pacific region ongoing Phase 3 testing
Colonic secretagogue
Linaclotide
Opioid receptor antagonists
Methylnaltrexone
CFTR channel activation through agonism for the guanylin C-receptor Peripheral inhibition of mu opioid receptor, reversing gastrointestinal side effects of opioid analgesics
Opioid receptor antagonists
Alvimopan
Peripheral inhibition of mu opioid receptor, reversing gastrointestinal side effects of opioid analgesics
Approved in the U.S. and Switzerland Phase 3 studies finalised Approved in U.S. and Europe for the treatment of opioid-induced constipation in patients with advanced illness Phase 3 studies for the treatment of opioid-induced constipation
receptor agonist that was mainly used for the stimulation of upper gastrointestinal tract motility in patients with gastro-esophageal reflux disease, gastroparesis and functional dyspepsia [23]. Effects of cisapride in chronic constipation were not well studied. In 2000, the drug was withdrawn from the market because of the occurrence of fatal arrhythmia’s through QT interval prolongation in patients with predisposing conditions [23]. This effect was unrelated to the 5-HT4 receptor stimulating properties of cisapride, and is attributed to blockade of hERG (human ether-a-go-go) potassium channels in ventricular muscle and Purkinje fibres [23,24]. Tegaserod, a 5-HT4 receptor agonist from another chemical class (an aminoguanidine indole), was shown to be effective for the treatment of chronic constipation and the irritable bowel syndrome with constipation [25]. Tegaserod was withdrawn from the market in 2007 because of an increased risk of cardiovascular adverse events including rare cases of myocardial infarction, unstable angina and stroke. While the underlying mechanism is incompletely elucidated, it has been suggested that affinity of tegaserod for other receptors, including 5-HT1 receptors on blood vessels, may have contributed to these events [23,26]. Prucalopride, a 5-HT4 receptor agonist from yet another chemical class (a benzofuran carboxamide), is a highly selective compound, with affinity for other receptors that is at least 2 log scales below its affinity for 5-HT4 receptors [26]. Prucalopride dose-dependently enhances colonic transit in healthy controls and in patients with chronic constipation [27,28]. In three identical pivotal trials, patients with chronic constipation (predominantly women) were treated for 12 weeks with placebo, prucalopride 2 mg or prucalopride 4 mg once daily [29–31]. Both doses of prucalopride resulted in an average of three spontaneous, complete bowel movements (SCBM) per week in approximately 20% of patients, compared with 10% of patients receiving placebo. In addition, improvements of at least one SCBM per week, and clinically relevant improvements in constipation-associated abdominal symptoms (using the validated PAC-SYM questionnaire) and in constipation-associated quality of life (using the validated PAC-QOL questionnaire) were seen in significantly more patients in the prucalopride groups compared to placebo [29–31]. Both active doses of prucalopride generated similar response rates, with an excellent safety and tolerance profile. Extensive cardiovascular safety assessments, including a study in elderly institutionalised patients, showed no arhytmogenic potential for prucalopride [32]. Prucalopride 2 mg has been approved in Europe for the treatment of chronic constipation in women who failed to respond to laxatives. In elderly patients, 1 mg is the recommended dose, and this is potentially attributable to a larger bio-availability with increasing age, as the drug is mainly excreted unchanged in the urine [33]. A number of other 5-HT4 agonists are under development, including the highly selective agents velusetrag (TD-5108) and naronapride (ATI-7505) which enhance colonic transit times and which were studied in phase 2 trials for chronic constipation [23,34–36]. Based on their selectivity for 5-HT4
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receptors over other receptors and channels such as the hERG channel, these agents are expected to have favourable safety profiles and a low potential for cardiovascular side effects [23,26]. Colonic secretagogues A recent novel approach to treating chronic constipation is the stimulation of colonic fluid secretion. Lubiprostone is a poorly absorbed lipophylic prostanoid component which stimulates colonic water and electrolyte secretion through the activation of type-2 chloride channels on enterocytes from the luminal side [37]. Lubiprostone dose-dependently enhances colonic transit, and this was hypothesised to be an indirect consequence of increased colonic water content [38]. In two phase 3 studies of 4 weeks duration, lubiprostone 24 mg twice daily significantly enhanced bowel movement frequency (5.69 and 5.89 spontaneous bowel movement per week with lubiprostone vs. 3.46 and 3.99 with placebo, p ¼ 0.0001) and relieved other constipation-related symptoms compared to placebo [39,40]. The main side effect was nausea (up to 32% compared with 3% for placebo), leading to withdrawal in up to 5% of patients [39]. Lubiprostone was approved by the US FDA in 2006 for the treatment of chronic idiopathic constipation and for the treatment of IBS with constipation [41] in 2008 but, apart from Switzerland, has not been approved in Europe at this time. Linaclotide is a 14-amino acid peptide analog of guanylin and of heat-stable Escherichia coli enterotoxin. Linaclotide acts as an agonist at the luminal guanylin receptor on enterocytes, the guanylate cyclase-C receptor, which induces intestinal chloride and fluid secretion through cyclic GMP production [42]. In a mechanistic study, linaclotide enhanced colonic transit in IBS with constipation [43] and dose-dependently increased bowel movement frequency and loosened stool consistency in phase 2 clinical trials in chronic constipation, with few side effects [44]. The increase in weekly spontaneous bowel movements ranged between 2.6 and 4.3 for linaclotide doses that ranged between 75 and 600 mg daily. Recently, favourable outcomes of two phase 3 studies were presented in abstract form, where more than 1200 patients were randomised to a 12-week treatment with placebo and 133 or 266 mg of linaclotide [45]. In both trials, significantly higher percentages of patients met the primary endpoint with linaclotide 133 mg (respectively 16% and 21.2%) and 266 mg (respectively 21.4% and 19.3%) compared to placebo (respectively 6% and 3.3%, all p-values <0.001). The onset of efficacy occurred in the first week and was maintained for 12 weeks. Symptoms of abdominal discomfort, bloating and straining were also significantly improved [45]. Linaclotide is also under evaluation for IBS with constipation, and an application for marketing approval of linaclotide will probably be filed to regulatory agencies in the near future. Opioid antagonists A number of peripherally acting mu opiate antagonists are currently being investigated for the treatment of opiate-induced constipation and postoperative ileus. As they do not cross the bloodbrain-barrier, they are used for diminishing peripheral side effects of opioids such as constipation, nausea and vomiting, while maintaining analgesic efficacy. A meta-analysis supports the efficacy of methylnaltrexone and alvimopan, while there is insufficient evidence for other antagonists such as naloxone and nalbuphine [46]. Methylnaltrexone bromide, a peripheral mu opioid receptor antagonist, has already been approved for the treatment of opiate-induced constipation in patients with advanced illness. After subcutaneous administration, the onset of the effect is rapid (bowel movement within 4 h in 48% of patients on methylnaltrexone, as compared with 15% after placebo) and improvement is maintained for at least 3 months during treatment with methylnaltrexone subcutaneously administered every other day [47,48]. Patients with potential mechanical gastrointestinal obstruction should not receive methylnaltrexone, as a number of cases of intestinal perforation shortly after administration of methylnaltrexone have been reported [49]. Alvimopan is an orally administered peripherally acting opioid antagonist which is being developed for opioid-induced bowel dysfunction and postoperative ileus. In a controlled study in 522 patients on opioids for chronic non-cancer pain, alvimopan in doses of 0.5 mg–2 mg b.i.d. was superior to placebo in inducing spontaneous bowel movements and reducing constipation-associated symptoms, while there was no evidence of opioid analgesia antagonism [50,51].
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The use of opioid antagonists in the treatment of non-opiate-induced constipation has not yet been fully assessed. In transit studies in healthy volunteers, alvimopan not only reversed codeine-induced delay in gut transit, but alvimopan monotherapy also accelerated colonic transit in monotherapy.[53] Similar effects were not seen with methylnaltrexone, possibly due to the shorter half-life of this compound [53]. Other agents Neurotrophins stimulate the development, growth and function of the nervous system, and enhance colonic transit when administered subcutaneously in health and in chronic constipation [54]. In a phase 2 randomised, double-blind, placebo-controlled trial, subcutaneous injection of neurotrophin3, three times per week, significantly increased the frequency of complete spontaneous bowel movements and improved other measures of constipation [55]. This class of drug is currently not being further developed for treatment of chronic constipation. Colchicine, an alkaloid substance used in the treatment of acute gout, induces diarrhea through an unknown mechanism when taken in higher doses. In an 8-week controlled trial in patients with slow transit constipation, colchicine 1 mg daily was superior to placebo in improving a combined constipation symptom severity score [56]. Conclusion A variety of traditional and novel treatment options are available for patients with chronic constipation. Traditional laxatives are effective at inducing bowel movements, but data for their role in long-term management and on efficacy on constipation-associated abdominal symptoms are limited. Long-term studies are available for polyethylene glycol, confirming sustained efficacy. Recently, the colonic secretagogue lubiprostone and the 5-HT4 agonist prucalopride became available for the treatment of chronic constipation. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, and both seem to have a favourable safety record, although a high incidence of nausea was reported with lubiprostone. For opioid-induced constipation in terminally ill patients, subcutaneously administered methylnaltrexone, a peripherally acting mu opioid receptor antagonist, was shown to be effective in inducing laxation. A number of new agents is currently under evaluation for the treatment of (opioid-induced) chronic constipation, including the 5-HT4 agonists velusetrag and naronapride, the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan.
Practice points Five different classes of traditional laxatives can be distinguished. Traditional laxatives are effective at inducing bowel movements; their efficacy on constipation-associated abdominal symptoms has not been convincingly demonstrated. With the exception of polyethylene glycol, efficacy in long-term management has not been well established. Recent studies show the short- and long-term efficacy of lubiprostone, a chloride channel activator, and prucalopride, a 5-HT4 agonist in improving bowel movements and symptoms in chronic constipation. Methylnaltrexone, a peripherally acting opioid receptor antagonist, is effective in opioidinduced constipation but does not interfere with the analgesic opioid action. New agents under evaluation include other 5-HT4 agonists (velusetrag and naronapride), the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan.
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Research agenda The place of newer agents in the management of chronic constipation, relative to laxatives, biofeedback therapy needs to be established. Studies need to address whether the presence of disordered defecation hampers responsiveness to traditional laxatives and to newer drugs for chronic constipation. Combination therapy of traditional and newer drugs for chronic constipation, as well as combinations of newer drugs with different modes of action, need to be studied. Conflict of interest statement None. References [1] Tack J, Müller-Lissner S. Treatment of chronic constipation: current pharmacologic approaches and future directions. Clin Gastroenterol Hepatol 2009 May;7(5):502–8. [2] Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006 Apr;130(5):1480–91. [3] Motola G, Mazzeo F, Rinaldi B, Capuano A, Rossi S, Russo F, et al. Self-prescribed laxative use: a drug-utilization review. 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Pain 2008 Jul 15;137(2):428–40. [51] Paulson DM, Kennedy DT, Donovick RA, Carpenter RL, Cherubini M, Techner L, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction – a 21-day treatmentrandomized clinical trial. J Pain 2005 Mar;6(3):184–92. [52] Gonenne J, Camilleri M, Ferber I, Burton D, Baxter K, Keyashian K, et al. Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study. Clin Gastroenterol Hepatol 2005;3(8):784–91. [53] Wong BS, Rao AS, Camilleri M, Manabe N, McKinzie S, Busciglio I, et al. The effects of methylnaltrexone alone and in combination with acutely administered codeine on gastrointestinal and colonic transit in health. Aliment Pharmacol Ther 2010 Oct;32(7):884–93. [54] Coulie B, Szarka LA, Camilleri M, Burton DD, McKinzie S, Stambler N, et al. Recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans. Gastroenterology 2000 Jul;119(1):41–50. [55] Parkman HP, Rao SS, Reynolds JC, Schiller LR, Wald A, Miner PB, et alFunctional Constipation Study Investigators. Neurotrophin-3 improves functional constipation. Am J Gastroenterol 2003 Jun;98(6):1338–47. [56] Taghavi SA, Shabani S, Mehramiri A, Eshraghian A, Kazemi SM, Moeini M, et al. Colchicine is effective for short-term treatment of slow transit constipation: a double-blind placebo-controlled clinical trial. Int J Colorectal Dis 2010 Mar;25(3): 389–94.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
12
Current and future therapies for chronic constipation J. Tack, MD, PhD, Professor of medicine * Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
In this article, traditional and novel therapies for chronic constipation are reviewed. Traditional laxatives are effective at inducing bowel movements, but efficacy in long-term management and efficacy on constipation-associated abdominal symptoms are less well established, with the exception of polyethylene glycol, for which long-term studies confirm sustained efficacy. Recently approved drugs include the colonic secretagogue lubiprostone and the 5-HT4 agonist prucalopride. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, with a favourable safety record. Methylnaltrexone, a subcutaneously administered peripherally acting mu opioid receptor antagonist, has recently been approved for opioid-induced constipation in terminally ill patients. New agents under evaluation include the 5-HT4 agonists velusetrag and naronapride, the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan. Ó 2011 Published by Elsevier Ltd.
Introduction Chronic constipation is a common disorder on a worldwide scale. Estimates of population prevalence range from 8.75% in the Asian Pacific region to 27% in Western countries [1,2]. Typical symptoms of constipation include infrequent bowel movements, hard stools and straining when passing stool. In addition abdominal discomfort, bloating, cramps and pain are often associated and complications like hemorrhoids and anal fissures may occur [1,2]. A variety of treatment options are available for patients with chronic constipation, ranging from older over-the-counter laxatives to more recently developed prescription drugs [1–6]. In spite of these * TARGID, Department of Pathophysiology, University of Leuven, Herestraat 49, 0&N 1, bus 701, B-3000 Leuven, Belgium. Tel.: þ32 16344225; fax: þ32 16344419. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.bpg.2011.01.005
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different treatment approaches, there remains a substantial unmet need in the treatment of chronic constipation [7]. This article reviews the pharmacological therapies currently indicated for chronic constipation and looks ahead to future developments that may offer benefits. Current medical therapies Current laxatives aid defecation by decreasing stool consistency and/or by stimulating colon motility (Table 1). Different classes of laxative drugs include bulking agents, stool softeners, osmotic laxatives and stimulant laxatives, and they can enhance defecation by binding luminal water, by altering mucosal absorption or secretion, by increasing bacterial mass and by stimulating contractile activity. The available efficacy and safety data for traditional laxatives have been summarised before [5,6]. Bulk (fibre) laxatives Undigestible fibres attract water which leads to a larger and softer fecal mass. Systematic reviews of studies with bulking agents indicate that they induce an average increase of 1.4 bowel movements per week [5,6]. However, the quality of the studies is highly variable and the treatment duration was usually short (maximum 4 weeks) [1]. Fibre has no major adverse effects and is usually well tolerated, although they may worsen symptoms of bloating. Osmotic laxatives Osmotic laxatives include poorly absorbed sugars (lactulose, sorbitol,.), polyethylene glycol (PEG) preparations or magnesium salts (magnesium hydroxide, magnesium citrate, magnesium sulphate, ..). Through their osmotic actions, these agents retain water in the intestinal lumen, which leads to softer
Table 1 Classes of traditional laxatives. Laxative class
Laxative agents
Mechanism of action
Potential limitations
Bulk laxatives
Natural fibre (e.g. psyllium seed husk) Semisynthetic fibre (e.g. methylcellulose) Synthetic fibre (e.g. polycarbophil, polyethylene glycol (macrogol) Magnesium hydroxide, Magnesium citrate, Magnesium sulphate, Sodium phosphate Lactulose Sorbitol
Luminal water binding increases stool bulk and reduces consistency.
Abdominal distention
Osmotic water binding
May cause electrolyte abnormalities; to be used with caution in patients with renal or cardiac failure Bacterial fermentation with bloating, flatulence Less effective in slow transit due to bacterial degradation Abdominal discomfort and creamps
Osmotic salts,
Disaccharides and sugar alcohols Stool softeners
Paraffin oil Docusate
Stimulant laxatives
Diphenylmethane derivatives (bisacodyl, sodium picosulphate) Anthraquinone derivatives (senna, aloe, cascara)
Osmotic water binding
Luminal water binding increases stool bulk and reduces consistency Induce colonic contractions by acting on enteric nerves Decrease colonic absorption of water and electrolytes
Abdominal discomfort and cramps
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stools with a larger volume and improved propulsion. Controlled studies demonstrate increased stool frequency, softer consistency and decreased straining compared to placebo. Except for the more recent PEG studies, the available trials are usually of short duration and inconsistent quality. Only few studies have directly compared osmotic laxatives with other agents. Non-absorbable sugars induce a limited improvement of stool frequency and consistency, but may also lead to symptoms like bloating and abdominal distention due to colonic fermentation. In a randomised controlled trial in the elderly, both treatments were equally effective but lactulose caused more nausea as a side effect [8]. In a systematic review of controlled trials, lactulose was less effective than PEG [9]. PEG is well tolerated and provides short-term relief of constipation compared to placebo [9,10]. Recent long-term retrospective series confirm that PEG maintains its efficacy for up to 24 months of treatment [11,12]. PEG was compared to tegaserod in an open-label study, where PEG induced a higher number of bowel movements [13]. PEG preparations are available both with or without electrolyte supplements, and in different dosages [1]. Patients prefer the electrolyte-free preparations, and the electrolyte containing preparations are mainly indicated when high volumes are given, such as for colon cleansing prior to colonoscopy or surgery [14,15]. Magnesium hydroxide and other magnesium salts improve stool frequency and consistency. Absorption of magnesium is limited, but may induce problems in patients with impaired renal function [16]. In a randomised 12-month trial with magnesium hydroxide or PEG in children with chronic constipation and fecal incontinence, both treatments were equally effective and well tolerated [17]. Stool softeners Laxatives which mainly soften or lubricate stools (e.g. sodium dioctyl sulfosuccinate and liquid paraffin) appear to be more effective than placebo in increasing the frequency of bowel movements and in overall symptom improvement, but data are limited [30]. Liquid paraffin may interfere with absorption of fat-soluble vitamins, and should be avoided in patients with oropharyngeal dysphagia as aspiration of this mineral oil causes a lipoid pneumonia [1–6,18]. Stimulant laxatives (phenyl methanes and anthraquinones) Stimulant laxatives act on the enteric nervous system to increase intestinal motility and secretion, thereby inducing passage of stools [1,3–6,19]. Bisacodyl and picosulfate are both phenylmethane prodrugs, which are hydrolysed by colonic bacteria or brush border enzymes to their active metabolite bis-(p-hydroxyphenyl)- pyridyl-2-methane (BHPM) which causes peristalsis. Placebo-controlled trials show that these drugs are more effective than placebo, but most of the trials are of short duration and the quality is variable [1,3–6]. In a recent 4-week placebo-controlled trial, picosulfate improved bowel function, symptoms, and quality of life [20]. Stimulant laxatives are generally well tolerated, do not cause electrolyte abnormalities, but may induce abdominal pain [1,3–6,21]. The latter can often be managed by dose titration [20]. It has been suggested that stimulant laxatives may induce damage to enteric nerves or colonic epithelium, but this has not been confirmed in experimental studies and in clinical practice [19]. New therapies for chronic constipation Several new pharmacological classes have been evaluated or are under evaluation for the treatment of chronic constipation, including 5-HT4 receptor agonists, colonic secretagogues and opioid antagonists (Table 2). 5-HT4 receptor agonists Serotonin (5-hydroxytryptamine, 5-HT) is a key regulator of gastrointestinal motility, sensitivity and secretion. Through 5-HT4 receptors, which are mainly expressed mainly by enteric neurons, 5-HT triggers and coordinates intestinal peristalsis [22]. Cisapride, a benzamide compound, is a 5-HT4
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Table 2 New and emerging drugs for chronic constipation. Drug class
Individual agents
Mechanism of action
Status
5-HT4 receptor agonists
Prucalopride
Stimulation of colonic and intestinal peristalsis
5-HT4 receptor agonists Colonic secretagogue
Velusetrag Naronapride Lubiprostone
Stimulation of colonic and intestinal peristalsis CCl2 channel activation
Prucalopride approved in Europe and Switzerland. Studies in Asian-Pacific region ongoing Phase 3 testing
Colonic secretagogue
Linaclotide
Opioid receptor antagonists
Methylnaltrexone
CFTR channel activation through agonism for the guanylin C-receptor Peripheral inhibition of mu opioid receptor, reversing gastrointestinal side effects of opioid analgesics
Opioid receptor antagonists
Alvimopan
Peripheral inhibition of mu opioid receptor, reversing gastrointestinal side effects of opioid analgesics
Approved in the U.S. and Switzerland Phase 3 studies finalised Approved in U.S. and Europe for the treatment of opioid-induced constipation in patients with advanced illness Phase 3 studies for the treatment of opioid-induced constipation
receptor agonist that was mainly used for the stimulation of upper gastrointestinal tract motility in patients with gastro-esophageal reflux disease, gastroparesis and functional dyspepsia [23]. Effects of cisapride in chronic constipation were not well studied. In 2000, the drug was withdrawn from the market because of the occurrence of fatal arrhythmia’s through QT interval prolongation in patients with predisposing conditions [23]. This effect was unrelated to the 5-HT4 receptor stimulating properties of cisapride, and is attributed to blockade of hERG (human ether-a-go-go) potassium channels in ventricular muscle and Purkinje fibres [23,24]. Tegaserod, a 5-HT4 receptor agonist from another chemical class (an aminoguanidine indole), was shown to be effective for the treatment of chronic constipation and the irritable bowel syndrome with constipation [25]. Tegaserod was withdrawn from the market in 2007 because of an increased risk of cardiovascular adverse events including rare cases of myocardial infarction, unstable angina and stroke. While the underlying mechanism is incompletely elucidated, it has been suggested that affinity of tegaserod for other receptors, including 5-HT1 receptors on blood vessels, may have contributed to these events [23,26]. Prucalopride, a 5-HT4 receptor agonist from yet another chemical class (a benzofuran carboxamide), is a highly selective compound, with affinity for other receptors that is at least 2 log scales below its affinity for 5-HT4 receptors [26]. Prucalopride dose-dependently enhances colonic transit in healthy controls and in patients with chronic constipation [27,28]. In three identical pivotal trials, patients with chronic constipation (predominantly women) were treated for 12 weeks with placebo, prucalopride 2 mg or prucalopride 4 mg once daily [29–31]. Both doses of prucalopride resulted in an average of three spontaneous, complete bowel movements (SCBM) per week in approximately 20% of patients, compared with 10% of patients receiving placebo. In addition, improvements of at least one SCBM per week, and clinically relevant improvements in constipation-associated abdominal symptoms (using the validated PAC-SYM questionnaire) and in constipation-associated quality of life (using the validated PAC-QOL questionnaire) were seen in significantly more patients in the prucalopride groups compared to placebo [29–31]. Both active doses of prucalopride generated similar response rates, with an excellent safety and tolerance profile. Extensive cardiovascular safety assessments, including a study in elderly institutionalised patients, showed no arhytmogenic potential for prucalopride [32]. Prucalopride 2 mg has been approved in Europe for the treatment of chronic constipation in women who failed to respond to laxatives. In elderly patients, 1 mg is the recommended dose, and this is potentially attributable to a larger bio-availability with increasing age, as the drug is mainly excreted unchanged in the urine [33]. A number of other 5-HT4 agonists are under development, including the highly selective agents velusetrag (TD-5108) and naronapride (ATI-7505) which enhance colonic transit times and which were studied in phase 2 trials for chronic constipation [23,34–36]. Based on their selectivity for 5-HT4
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receptors over other receptors and channels such as the hERG channel, these agents are expected to have favourable safety profiles and a low potential for cardiovascular side effects [23,26]. Colonic secretagogues A recent novel approach to treating chronic constipation is the stimulation of colonic fluid secretion. Lubiprostone is a poorly absorbed lipophylic prostanoid component which stimulates colonic water and electrolyte secretion through the activation of type-2 chloride channels on enterocytes from the luminal side [37]. Lubiprostone dose-dependently enhances colonic transit, and this was hypothesised to be an indirect consequence of increased colonic water content [38]. In two phase 3 studies of 4 weeks duration, lubiprostone 24 mg twice daily significantly enhanced bowel movement frequency (5.69 and 5.89 spontaneous bowel movement per week with lubiprostone vs. 3.46 and 3.99 with placebo, p ¼ 0.0001) and relieved other constipation-related symptoms compared to placebo [39,40]. The main side effect was nausea (up to 32% compared with 3% for placebo), leading to withdrawal in up to 5% of patients [39]. Lubiprostone was approved by the US FDA in 2006 for the treatment of chronic idiopathic constipation and for the treatment of IBS with constipation [41] in 2008 but, apart from Switzerland, has not been approved in Europe at this time. Linaclotide is a 14-amino acid peptide analog of guanylin and of heat-stable Escherichia coli enterotoxin. Linaclotide acts as an agonist at the luminal guanylin receptor on enterocytes, the guanylate cyclase-C receptor, which induces intestinal chloride and fluid secretion through cyclic GMP production [42]. In a mechanistic study, linaclotide enhanced colonic transit in IBS with constipation [43] and dose-dependently increased bowel movement frequency and loosened stool consistency in phase 2 clinical trials in chronic constipation, with few side effects [44]. The increase in weekly spontaneous bowel movements ranged between 2.6 and 4.3 for linaclotide doses that ranged between 75 and 600 mg daily. Recently, favourable outcomes of two phase 3 studies were presented in abstract form, where more than 1200 patients were randomised to a 12-week treatment with placebo and 133 or 266 mg of linaclotide [45]. In both trials, significantly higher percentages of patients met the primary endpoint with linaclotide 133 mg (respectively 16% and 21.2%) and 266 mg (respectively 21.4% and 19.3%) compared to placebo (respectively 6% and 3.3%, all p-values <0.001). The onset of efficacy occurred in the first week and was maintained for 12 weeks. Symptoms of abdominal discomfort, bloating and straining were also significantly improved [45]. Linaclotide is also under evaluation for IBS with constipation, and an application for marketing approval of linaclotide will probably be filed to regulatory agencies in the near future. Opioid antagonists A number of peripherally acting mu opiate antagonists are currently being investigated for the treatment of opiate-induced constipation and postoperative ileus. As they do not cross the bloodbrain-barrier, they are used for diminishing peripheral side effects of opioids such as constipation, nausea and vomiting, while maintaining analgesic efficacy. A meta-analysis supports the efficacy of methylnaltrexone and alvimopan, while there is insufficient evidence for other antagonists such as naloxone and nalbuphine [46]. Methylnaltrexone bromide, a peripheral mu opioid receptor antagonist, has already been approved for the treatment of opiate-induced constipation in patients with advanced illness. After subcutaneous administration, the onset of the effect is rapid (bowel movement within 4 h in 48% of patients on methylnaltrexone, as compared with 15% after placebo) and improvement is maintained for at least 3 months during treatment with methylnaltrexone subcutaneously administered every other day [47,48]. Patients with potential mechanical gastrointestinal obstruction should not receive methylnaltrexone, as a number of cases of intestinal perforation shortly after administration of methylnaltrexone have been reported [49]. Alvimopan is an orally administered peripherally acting opioid antagonist which is being developed for opioid-induced bowel dysfunction and postoperative ileus. In a controlled study in 522 patients on opioids for chronic non-cancer pain, alvimopan in doses of 0.5 mg–2 mg b.i.d. was superior to placebo in inducing spontaneous bowel movements and reducing constipation-associated symptoms, while there was no evidence of opioid analgesia antagonism [50,51].
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The use of opioid antagonists in the treatment of non-opiate-induced constipation has not yet been fully assessed. In transit studies in healthy volunteers, alvimopan not only reversed codeine-induced delay in gut transit, but alvimopan monotherapy also accelerated colonic transit in monotherapy.[53] Similar effects were not seen with methylnaltrexone, possibly due to the shorter half-life of this compound [53]. Other agents Neurotrophins stimulate the development, growth and function of the nervous system, and enhance colonic transit when administered subcutaneously in health and in chronic constipation [54]. In a phase 2 randomised, double-blind, placebo-controlled trial, subcutaneous injection of neurotrophin3, three times per week, significantly increased the frequency of complete spontaneous bowel movements and improved other measures of constipation [55]. This class of drug is currently not being further developed for treatment of chronic constipation. Colchicine, an alkaloid substance used in the treatment of acute gout, induces diarrhea through an unknown mechanism when taken in higher doses. In an 8-week controlled trial in patients with slow transit constipation, colchicine 1 mg daily was superior to placebo in improving a combined constipation symptom severity score [56]. Conclusion A variety of traditional and novel treatment options are available for patients with chronic constipation. Traditional laxatives are effective at inducing bowel movements, but data for their role in long-term management and on efficacy on constipation-associated abdominal symptoms are limited. Long-term studies are available for polyethylene glycol, confirming sustained efficacy. Recently, the colonic secretagogue lubiprostone and the 5-HT4 agonist prucalopride became available for the treatment of chronic constipation. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, and both seem to have a favourable safety record, although a high incidence of nausea was reported with lubiprostone. For opioid-induced constipation in terminally ill patients, subcutaneously administered methylnaltrexone, a peripherally acting mu opioid receptor antagonist, was shown to be effective in inducing laxation. A number of new agents is currently under evaluation for the treatment of (opioid-induced) chronic constipation, including the 5-HT4 agonists velusetrag and naronapride, the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan.
Practice points Five different classes of traditional laxatives can be distinguished. Traditional laxatives are effective at inducing bowel movements; their efficacy on constipation-associated abdominal symptoms has not been convincingly demonstrated. With the exception of polyethylene glycol, efficacy in long-term management has not been well established. Recent studies show the short- and long-term efficacy of lubiprostone, a chloride channel activator, and prucalopride, a 5-HT4 agonist in improving bowel movements and symptoms in chronic constipation. Methylnaltrexone, a peripherally acting opioid receptor antagonist, is effective in opioidinduced constipation but does not interfere with the analgesic opioid action. New agents under evaluation include other 5-HT4 agonists (velusetrag and naronapride), the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan.
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Research agenda The place of newer agents in the management of chronic constipation, relative to laxatives, biofeedback therapy needs to be established. Studies need to address whether the presence of disordered defecation hampers responsiveness to traditional laxatives and to newer drugs for chronic constipation. Combination therapy of traditional and newer drugs for chronic constipation, as well as combinations of newer drugs with different modes of action, need to be studied. Conflict of interest statement None. References [1] Tack J, Müller-Lissner S. Treatment of chronic constipation: current pharmacologic approaches and future directions. Clin Gastroenterol Hepatol 2009 May;7(5):502–8. [2] Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006 Apr;130(5):1480–91. [3] Motola G, Mazzeo F, Rinaldi B, Capuano A, Rossi S, Russo F, et al. Self-prescribed laxative use: a drug-utilization review. 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