Treatment strategies for chronic constipation invoving dietary modification and laxatives often do not provide satisfactory results but newer agents, such as lubiprostone and prucalopride offer significant advances in the management of this prevalent condition
Omer F Ahmad BSc MBBS MRCP
Gastroenterology Registrar,
North Middlesex University Hospital,
London, UK
Ayesha Akbar MBChB Hons MRCP PhD
Consultant Gastroenterologist,
St Mark’s Hospital; Honorary Senior Lecturer, Imperial College, London, UK
Support for the editorial and financial development of this review has been provided by Sucampo Pharma Europe Ltd
Chronic constipation is a common disorder associated with a significant reduction in quality of life. Estimates of prevalence vary depending on defining criteria with most studies suggesting a range of 12 to 19%.1,2
Currently, the most widely accepted definition of functional constipation is that established by the Rome III diagnostic criteria,3 which are shown in Box 1.
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Box 1: Rome III diagnostic criteria for chronic idiopathic constipation*
Must include two or more of the following:
a) Straining during at least 25% of defecations;
b) Lumpy or hard stools in at least 25% of defecations;
c) Sensation of incomplete evacuation for at least 25% of defecations;
d) Sensation of anorectal obstruction/blockage for at least 25% of defecations;
e) Manual manoeuvres to facilitate in at least 25% of defecations (for example. digital evacuation, support of the pelvic floor);
f) Fewer than three defecations per week.
Loose stools are rarely present without the use of laxatives.
Insufficient criteria for a diagnosis of irritable bowel syndrome.
* Criteria fulfilled for the last three months with symptom onset at least six months prior to diagnosis.
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Abdominal pain or discomfort is a key feature that helps to distinguish constipation-predominant irritable bowel syndrome (IBS-C) from functional chronic constipation. Although pain can occur in both conditions its predominance is more characteristic of IBS-C particularly when it is relieved by defecation or associated with a change in frequency and/or form of stool.
Pathophysiology
Chronic constipation may be primary (idiopathic) or secondary to other causes including medications, intrinsic GI causes, for example, colorectal cancer, metabolic, for example, hypercalcaemia, endocrine disease such as hypothyroidism, neurological and psychiatric, for example, anorexia nervosa.
Chronic idiopathic constipation (CIC) is categorised into three broad, non-mutually exclusive subtypes: normal transit constipation, slow transit constipation (prolonged delay of passage of stool through the colon), and disorders of rectal evacuation (which may be due to structural disorders or lack of co-ordination/dyssynergia of the muscles involved in defecation).
Diagnostic evaluation
A thorough history is essential particularly to identify any secondary causes including a detailed drug history. Alarm features such as rectal bleeding, anaemia, a change in bowel habit after the age of 50 years, unexplained weight loss, a family history of colorectal cancer or inflammatory bowel disease warrant urgent investigation.
A physical examination including a digital rectal examination may aid in diagnosing an underlying disorder of rectal evacuation. Further physiological tests can be helpful which include colonic transit studies with radio-opaque markers while disorders of rectal evacuation may be revealed with a balloon expulsion test, anorectal manometry and defaecography imaging.
Management
There is no consensus pathway for the management of CIC, although a number exist. Several pathways, however, have been proposed,4–6 which have common themes, although differing in some aspects depending upon when they were drafted as newer therapies may have been excluded.
The evidence for a number of interventions (including modifications to diet and lifestyle) is weak or contradictory; however the majority of guidelines recommend these be tried before pharmacological intervention. In general, where treatment pathways are recommended, the sequence is:5
(1) Exclude other pathologies and secondary causes
(2) Begin treatment with dietary and lifestyle adjustments
(3) Move to osmotic laxatives, stool softeners and bulk-forming agents – there is no consensus on the order in which these should be tried
(4) Move to stimulant laxatives, suppositories and/or enemas
(5) Surgery as a last resort to treat identified disorders that require surgical correction.
Biofeedback therapy has been shown to be effective in those whom pelvic floor dysfunction is contributing to chronic constipation and there is dyssynergic defecation. It is a behavioural approach, but expensive and only available in certain centres.
Dietary fibre
Traditionally, individuals with CIC are told to increase dietary fibre intake in order to alleviate symptoms, but there is little evidence from randomised controlled trials (RCTs) that this approach has any benefit even in the short-term treatment of the condition.7 Fibre supplements tend to be relatively mild and safe products hence their recommendation initially in management pathways; however, they are not always effective for relieving constipation symptoms.8,9
Laxatives
In the UK, laxatives can be sub-divided into four main classes:
(1) Bulking agents (fibre supplements), for example, ispaghula, methylcellulose. These increase faecal mass which then stimulates peristalsis. They should be taken with plenty of fluids and avoided in intestinal obstruction
(2) Stool softeners, for example, docusate sodium. Side effects can include faecal incontinence and malabsorption of fat-soluble vitamins
(3) Osmotic laxatives, for example, magnesium citrate, sodium citrate, polyethylene glycol (PEG) 3350. These cause fluid retention within the bowel. Lactulose, a disaccharide, produces osmotic diarrhoea of low pH that discourages the growth of ammonia-producing organisms. It is useful for chronic constipation and hepatic encephalopathy. Magnesium salts are useful for rapid bowel emptying.
(4) Stimulant agents, for example, bisacodyl, senna. These stimulate intestinal motility and are contra-indicated in intestinal obstruction. Docusate sodium has stimulant and softening actions.
Relative costs
Senna, bisocodyl – cheap
Magnesium hydroxide, methylcellulose, ispaghula – moderate
Lactulose – expensive.
Osmotic and stimulant agents are generally most used for the relief of constipation symptoms, but the onset of that relief can be unpredictable, and these agents can have a variety of abdominal and gastrointestinal side effects.7,10 There remain high levels of dissatisfaction with laxatives, primarily due to concerns about efficacy and safety.
About 40% of patients will fail to respond to laxatives.7 They are, however, readily available over the counter or by prescription, and not costly, with a number of patients receiving relief from this modality of therapy. They should therefore be recommended before newer therapies and, if not effective, most guidelines suggest a trial with a different class of laxatives before an escalation in the management pathway.
Newer agents
Prucalopride
Prucalopride is a selective serotonin 5-HT4 receptor agonist with prokinetic properties for chronic constipation. Prucalopride is recommended in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least six months, has failed to provide adequate relief and invasive treatment for constipation is being considered. If treatment with prucalopride is not effective after four weeks, the women should be re examined and the benefit of continuing treatment reconsidered. Prucalopride should only be prescribed by a clinician with experience of treating chronic constipation, who has carefully reviewed the patient’s previous course of laxative treatments.
Three large Phase III studies in CIC have been performed, employing identical patient inclusion criteria, in the US and Europe.11–13 In these mostly laxative-refractory patients (80% had fewer than one complete spontaneous bowel movement per week), there was a prucalopride-associated increase in bowel frequency to more than three per week in 24% of patients (compared with 11% with placebo).
A recently reported meta-analysis7 included data from seven RCTs comparing prucalopride with placebo in 2639 CIC patients. A total of 1288 (71.7%) of 1796 patients receiving prucalopride failed to respond to therapy, compared with 731 (86.7%) of 843 allocated to placebo (relative risk (RR) of failure to respond to therapy=0.82; 95% CI 0.76 to 0.88), with significant heterogeneity between studies (I2=60%, p=0.02), and a number-needed-to-treat (NNT) of 6 (95% CI 5 to 9). Six trials reported total numbers of adverse events (AEs), which were more common with prucalopride than with placebo (RR=1.14; 95% CI 1.05 to 1.24, number-needed-to-harm (NNH)=10; 95% CI 6 to 29). Individual AEs including headache (RR=1.70; 95% CI 1.25 to 2.31), nausea (RR=1.98; 95% CI 1.39 to 2.82), and diarrhoea (RR=2.72; 95% CI 1.80 to 4.13) were all more common with prucalopride. There was no significant increase in serious AE rates detected with prucalopride (RR=0.88; 95% CI 0.58 to 1.34), and there was only one cardiovascular event reported with the drug, an episode of supraventricular tachycardia.
Lubiprostone
Lubiprostone, a prostone, is a locally acting chloride channel activator that acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of intestinal epithelial cells, in a protein kinase A-independent fashion. Lubiprostone is not systemically absorbed. By increasing intestinal fluid secretion, lubiprostone facilitates the passage of stools and alleviates the symptoms associated with CIC.
Three double-blind, placebo-controlled studies of similar design were conducted in patients with CIC; studies SC013114 and SC023215 were identically designed multicentre, parallel-group, double-blind, placebo-controlled, Phase III studies conducted in the US. The third study, CC0831,16 was conducted in Japan. The primary endpoint of the two US studies was spontaneous bowel movement (SBM) frequency at Week 1; in the Japanese study, the primary endpoint was the change from baseline in SBM frequency at Week 1.
All studies demonstrated that patients treated with lubiprostone had a higher frequency of SBMs and significantly increased post-treatment changes from baseline in SBM frequencies. Discontinuation of therapy in the studies did not result in a rebound effect. The most common AE associated with lubiprostone was nausea, which was at least 3.5-times as common in the lubiprostone groups (17.7–34.2% of patients) as in the placebo groups (1.6–6.8%) in the pivotal trials. Nausea was generally a mild to moderate and transient event, with resulting therapy discontinuation rates of 5%.
Ford’s meta-analysis7 included data from three RCTs comparing lubiprostone with placebo in 610 patients with CIC. There were 151 (45.1%) of 335 patients receiving lubiprostone who failed to respond to therapy, compared with 184 (66.9%) of 275 placebo patients (RR of failure to respond to therapy=0.67; 95% CI 0.56 to 0.80), with no significant heterogeneity between studies (p=0.24). The NNT was 4 (95% CI 3 to 7). Total numbers of AEs were significantly higher with lubiprostone (RR=1.79; 95% CI 1.21 to 2.65, NNH=4; 95% CI 3 to 6). Diarrhoea (RR=4.46; 95% CI 1.28 to 15.48) and nausea (RR=7.27; 95% CI 3.76 to 14.06) both occurred significantly more frequently with lubiprostone, but no significant difference in rates of abdominal pain or headache were detected.
Lubiprostone is recommended as an option for the treatment of CIC, for adults in whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least six months, has failed to provide adequate relief and for whom invasive treatment for constipation is being considered. Treatment should be assessed at two weeks and if there is a failure to respond (about 30% from studies), the benefit of continuing treatment reconsidered.
A proposed treatment pathway for chronic constipation is shown in Figure 1.
Conclusions
CIC is a prevalent condition that has a significant impact on quality of life and healthcare resources. Current treatment strategies involving dietary modification and laxatives often do not provide satisfactory results. Newer agents such as lubiprostone and prucalopride offer significant advances and should be considered in the management pathway for CIC.
Key points
- Chronic idiopathic constipation (CIC) is a common condition with an impact on quality of life comparable to that seen in conditions such as chronic obstructive pulmonary disease, diabetes or depression.
- Traditionally, people with CIC are first advised to increase dietary fibre intake to help alleviate symptoms and, if these measures are unsuccessful, laxatives are the first line of medication.
- Between 16% and 40% of people with CIC are reported to use laxatives, but levels of dissatisfaction with this treatment are high, primarily due to concerns about efficacy and safety.
- About 40% of patients with CIC do not respond to laxative treatment. Further options were limited and invasive; however, two newer therapies (lubiprostone and prucalopride) offer therapy options to those with refractory chronic constipation.
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