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The treatment – constipation in adults

Gastroenterologists Dr Giles Major and Professor Robin Spiller discuss the treatment options for adult cases of constipation.

Constipation affects one in five of the adult population in the UK but, when surveyed, one in two sufferers are dissatisfied with their current treatment.1 The complaint of ‘constipation’ may mean hard stool, difficult evacuation, abdominal discomfort or bloating, as well as infrequent motions. It is important to distinguish the patient’s predominant complaint – pain and discomfort (constipation-predominant irritable bowel syndrome/IBS-C) and those for whom discomfort is of secondary importance (functional constipation), as they require different treatments.

Few tests are necessary in this condition, although a one-to-two-week stool diary can help greatly in objective assessment and doctor-patient communication. It may be helpful to reassure patients consulting with constipation that they are no more likely to have colorectal cancer than patients without constipation.2

 

Standard current treatment

Lifestyle and dietary intervention

Low levels of exercise and a low-fibre diet have been associated with increased incidence of constipation, so it is reasonable to encourage more exercise and more fibre, recognising that these changes may be difficult to achieve. It is worth noting that bran may aggravate both bloating and flatulence. Evidence
of any benefit from drinking more water is limited unless overt dehydration is present.

The colonic motility follows a circadian rhythm, being depressed during sleep. Waking, combined with eating breakfast, provides a powerful colonic stimulus, as does the usually larger evening meal. These stimuli are often followed by powerful propulsive contractions, which cause mass movements. Patients should make time to respond to the feelings associated with these mass movements, as this is the time when complete bowel evacuations are easiest to achieve.

Bulk forming and osmotic laxatives

Ispaghula bean husk forms a gel with water, softening the stool and distending the colon, and encouraging propulsion. But raw ispaghula is unpleasant to drink and patients may dislike the need for daily dosing, as opposed to occasional ‘rescue therapy’. Polyethylene glycol formulations also act by osmotically trapping water in the bowel lumen. Increasing the dose can provide the occasional bowel clearance that some patients want, but this may result in discomfort from the resulting colonic distension. Combining with a stimulant may reduce this.

Lactulose is a synthetic fructose-galactose disaccharide that cannot be digested until it reaches the colonic bacteria. Being a small molecule, it is osmotically active and increases small bowel water, which enters the colon and stimulates motility. Its bacterial metabolism to short-chain fatty acids and gas may also stimulate motility, but the increased gas can cause bloating and discomfort, which limits tolerability.

Docusate 200mg twice daily increases intestinal secretion in animals, but shows weak or no efficacy in clinical trials.

Stimulants

These are all pro-drugs, requiring bacterial metabolism to be effective. Senna, a plant product, has been successfully used as a stimulant for a long time, but lacks good quality trial data and often causes excessive cramps and loose stools. Bisacodyl 5-10mg tds as a tablet or suppository has good trial evidence of efficacy and provides a good option for a prn treatment of functional constipation. Sodium picosulphate and bisacodyl are both metabolised by bacteria to a common active agent and have similar efficacy.

 

What to avoid

Opiates are well known to induce constipation and they should not be used for the pain of IBS, since they may paradoxically exacerbate visceral pain, causing ‘narcotic bowel syndrome’.3 Tapentadol, a new µ-opioid receptor agonist and noradrenaline uptake inhibitor, causes significantly less constipation than traditional opiates. The anti-emetic ondansetron is well known to cause constipation, and calcium channel antagonists may also contribute to symptoms, along with the wide range of drugs with anticholinergic effects, including tricyclic antidepressants.

 

What’s newly available

A number of new locally-acting agents that are poorly absorbed from the GI tract have become available in the last few years. All have good quality data from large trials supporting their use, although it should be borne in mind that polyethylene glycol (NNT 3) compares favourably with all in the assessment of efficacy of achieving laxation, but not necessarily relief of associated symptoms like abdominal pain.4

These newer agents are more expensive and so their use should be restricted to those who have not responded to an adequate trial of standard laxatives, or for whom side-effects are intolerable. NICE defines this as using two laxatives from different classes at the highest tolerated doses for at least six months. Response should be assessed after four weeks and the drug discontinued in non-responders. Novel agents are usually initiated under specialist supervision, but if successful, prescriptions should be continued in primary care.

Prucalopride

Prucalopride was appraised by NICE in 2010 and recommended for use in women only (trials entered insufficient males to prove efficacy), although gender does not alter the pharmacology. As a 5-HT4 receptor agonist, it acts as a stimulant and shows efficacy, and may complement the use of bulk-forming agents described earlier.5,6 Some patients report headaches for the first few days, while others may experience tachyphylaxis and need to dose intermittently to maintain efficacy.

Linaclotide

A Guanylate-cyclase-C receptor agonist, linaclotide is designed to stimulate the same secretory mechanism as the Escherichia coli heat-stable enterotoxin, which mimics the endogenous ligand guanylin. It was authorised in the EU in 2012 and assessed by NICE in April 2013. Trials have demonstrated some superiority over placebo in both IBS-C7 and functional constipation.8 A NICE update to the IBS guidelines in February 2015 featured the inclusion of linaclotide in the treatment pathway.9 It advised that linaclotide should be considered only in patients who have had constipation for at least 12 months, and where maximum tolerated doses of previous laxatives from different classes has failed to help. 

Lubiprostone

Lubiprostone is also a secretagogue. NICE published its appraisal in July 2014 (TA318) on the basis of three large randomised controlled trials in different continents, all of which showed benefit (NNT 5). On that basis, lubiprostone was recommended as an option for the treatment of chronic idiopathic constipation (analogous to functional constipation). It is also licensed for IBS-C, but the NNT is larger at 12,10 although safety appears good. Nausea and headaches are common side-effects, but lead to discontinuation in 5%.11

 

What has fallen out of fashion and why

Paraffin oil is little used now as it has been associated with inhalation pneumonia and anal leakage of oil. Magnesium salts, such as Epsom salts, are less used, possibly because of difficulty in getting the right dose, causing either excessive or inadequate effect. The efficacy of high-dose macrogols for treating impaction has thankfully led to much less need for extreme measures such as manual disimpaction, evacuation under anaesthesia or arachis oil enemas.

 

Special/atypical cases and their treatment, including non-drug options

In cases where proximal gut function or co-ordinated peristalsis cannot be relied upon, it may be necessary to use phosphate enemas as a stimulant. Where faecal impaction limits the effectiveness of other agents, controlled irrigation of the colon may be of benefit. In highly selected patients with visceral neuropathy, anticholinesterase inhibitors such as pyridostigmine or prucalopride can be used, but only under specialists.

A more common scenario is that of defaecation disorders, sometimes referred to as obstructive or dyssynergic defaecation. Specific difficulty in the act of defaecation of even loose stool, or vaginal splinting or the use of digitation to extract stool, may suggest disordered defaecation, which requires specialist evaluation as such cases generally fail to respond to standard laxatives. In one unit, defaecation disorder was the cause of constipation in 25% of referrals.12

Identification of such cases is important, as the best approach to treatment may be behavioural and not pharmacological. Biofeedback therapy, training the patient to relax the puborectalis and exert adequate propulsive force, has been shown to increase frequency of bowel motions in those with defaecation disorder, but not to slow colonic transit.13 Such services may be available through gastroenterology or urology as part of a continence service.

 

Professor Robin Spiller is professor of gastroenterology, and Dr Giles Major a clinical research fellow, both at Nottingham University Hospitals NHS Trust.

Competing interests: Professor Spiller has received research funding from LeSaffre and Ironwood, free drug for a clinical trial from Norgine and has been on advisory boards for Almirall, Alberio, Ironwood, Shire and Prometheus

 

References

1 Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther, 2007;25:599-608

2 Power AM, Talley NJ, Ford AC. Association between constipation and colorectal cancer: systematic review and meta-analysis of observational studies. Am J Gastroenterol, 2013;108:894-903

3 Kurlander JE, Drossman DA. Diagnosis and treatment of narcotic bowel syndrome. Nat Rev Gastroenterol Hepatol, 2014;11:410-18

4 Chapman RW, Stanghellini V, Geraint M et al. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol, 2013;108:1508-15

5 Camilleri M, Kerstens R, Rykx A et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med, 2008;358:2344-54

6 Muller-Lissner S, Rykx A, Kerstens R et al. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil, 2010;22:991-8

7 Quigley EM, Tack J, Chey WD et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C – a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther, 2013;37:49-61

8 Lembo AJ, Schneier HA, Shiff SJ et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med, 2011;365:527-36

9 Drossman DA, Chey WD, Johanson JF et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome – results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther, 2009;29:329-41

10 Johanson JF, Morton D, Geenen J et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol, 2008;103:170-7

11 Nullens S, Nelsen T, Camilleri M et al. Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation. Gut, 2012;61:1132-9

12 Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology, 2005;129:86-97

13 Kamm MA, Dudding TC, Melenhorst J et al. Sacral nerve stimulation for intractable constipation. Gut, 2010;59:333-40

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