COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care

In this issue: Glossary Page Chronic Constipation lasting longer than 3 months Introduction and background 1 constipation Drugs used in the management of Functional Chronic constipation without a known cause. Also known as primary 3 chronic constipation constipation constipation or idiopathic constipation Bulk-forming laxatives 4 Gastrocolic The occurrence of peristalsis following the entrance of food into the Osmotic laxatives 5 response empty stomach Stimulant laxatives 6 IBS Irritable Bowel Syndrome IBS-C Irritable Bowel Syndrome with Constipation Faecal softeners 7 Melanosis Dark brownish black pigmentation of the mucous membrane of the colon Peripheral opioid-receptor 7 coli due to the deposition of pigment in macrophages antagonists Myenteric Part of the enteric nervous system with an important role in regulating 5HT4 – receptor agonists 7 plexus gut motility Managing constipation in 8 NNT Number Needed to Treat pregnancy and breastfeeding OTC Over The Counter RCT Randomised Controlled Trial Secondary Constipation caused by a drug or medical condition. Secondary constipation constipation is also known as organic constipation SmPC Summary of Product Characteristics A twisting or looping of the bowel resulting in obstruction; can be life- Volvulus threatening

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Introduction and background

Constipation means different things to different people and Definitions used for constipation there is little shared understanding between patients and The diagnosis of constipation is often arbitrary and is largely professionals about “normal” bowel function.1 There is a lack dependent on the patient’s perception of “normal” bowel of consensus in general practice regarding the optimum function. Doctors often define constipation based on stool management strategies for chronic constipation.1 frequency,8 but patients define constipation as a multi- symptom disorder that includes infrequent bowel What is meant by constipation? movements, hard/lumpy stool, straining, bloating, feeling of Constipation can broadly be defined as the passage of 2 incomplete evacuation after a bowel movement and stools less frequently than the patient’s own normal pattern. abdominal discomfort.9 Stools are often dry and hard, and may be abnormally large 3 The Rome III criteria were developed to provide a working or small. In the clinical consultation, if a person continues to 10 complain about constipation after a discussion of what is definition of chronic constipation. The criteria highlight the normal and what is abnormal (especially with respect to difference between stool frequency and stool form and frequency), they are asking for help in managing their emphasise that infrequent bowel movements alone do not problem. necessarily define constipation (See Box ONE). Although symptoms of constipation are assessed over the prior 3 In children, the signs and symptoms of constipation may be months, patients must be symptomatic for at least 6 months different and may be poorly recognised. They can include prior to diagnosis.10 While these criteria stand as a guideline infrequent bowel activity, foul smelling wind and stools, excessive flatulence, irregular stool texture, passing Box ONE: Rome III criteria10* occasional enormous stools or frequent small pellets, withholding or straining to stop passage of stools, soiling or Presence of two or more of the following symptoms: overflow, abdominal pain, distension or discomfort, poor • Straining during at least 25% of defaecations appetite, lack of energy, an unhappy, angry or irritable mood • Lumpy or hard stools in at least 25% of defaecations 4 and general malaise. •Sensation of incomplete evacuations for at least 25% of

What is meant by “normal”? defaecations Establishing what is ‘normal’ for a particular person, and • Sensation of anorectal obstruction/blockage for at least 25% whether or not the person has constipation, can be difficult. of defaecations Bowel habits vary widely.5 The commonest reported • Manual manoeuvres to facilitate at least 25% of defaecations frequency of bowel movements is once per day,6,7 but a (such as digital evacuation, support of the pelvic floor) Swedish survey found that this was reported by only 20% of • Fewer than three bowel movements a week 7 respondents. A UK survey identified that a frequency of less Loose stools are rarely present without the use of laxatives than three bowel movements per week was more common in women than men.6 *Criteria have to have been met for the previous three months, with the onset of symptoms six months prior to diagnosis

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 1 for diagnosis, it should be acknowledged that bowel habits is important (particularly with a high fibre diet or fibre Box THREE: Causes of constipation Table ONE: Number and cost of prescriptions for laxatives supplements), but can be difficult for some people (e.g. frail differ across individuals; one person may feel distraught and Dietary in Northern Ireland for the 12 months to September 2011 uncomfortable having only 2 bowel movements a week, • Low fibre, dieting, dementia, depression, anorexia, fluid or elderly). Fruits high in fibre and sorbitol, and fruit juices while another may find this frequency to be normal. Number of high in sorbitol can help prevent and treat constipation. depletion Class of laxative Cost prescriptions It is useful to note the difference between chronic Metabolic Fruits (and their juices) that have a high sorbitol content Bulk-forming laxatives 55,552 £205,363 constipation and irritable bowel syndrome with constipation • Diabetes mellitus, hypercalcaemia, hypokalaemia, include apples, apricots, gooseberries, grapes (and raisins), Stimulant laxatives 167,756 £779,195 (IBS-C). Whereas the hallmark symptom of IBS-C is hypothyroidism, porphyria peaches, pears, plums (and prunes), raspberries, and Faecal softeners 741 £983 abdominal pain in association with constipation, patients with Neurological strawberries. The concentration of sorbitol is about 5–10 Osmotic laxatives 394,118 £2,279578 times higher in dried fruit. chronic constipation do not report pain as a predominant • Parkinson’s disease, spinal cord pathology, multiple sclerosis 10,11 Peripheral opioid-receptor feature. Practically, however, many patients do not Iatrogenic 7 £189 In addition, exercise and increasing fluid intake are often antagonists comply with this tidy dichotomy. It is common to encounter • Aluminium antacids recommended to treat constipation, but again, there is 5HT -receptor agonists 387 £22,786 patients who have mild or moderate abdominal discomfort in • Antimuscarinic (e.g. procyclidiine, oxybutynin) 4 insufficient evidence that these interventions help in chronic Total 618,561 £3,288,093 chronic constipation but who do not report discomfort as a • Antidepressants (most commonly tricyclic antidepressants) constipation.27 predominant symptom. Similarly, patients with IBS-C may • Antiepileptics (e.g. carbamazepine, gabapentin, Assessing frequency, amount and consistency of stools Despite limited data supporting their use in clinical practice, have abdominal pain on some occasions but not oxcarbazepine, pregabalin, phenytoin) Because most patients understandably lack a working the suggested lifestyle changes promote general health and consistently. These variations in patient assessment of • Sedating antihistamines knowledge of normative stool consistency, it is instructive to may improve bowel symptoms in some patients.29-32 Another abdominal discomfort make it difficult to clearly distinguish • Antipsychotics use the Bristol Stool Scale: behavioural modification to consider includes ensuring that IBS-C from chronic constipation. If in doubt, ask the patient • Antispasmodics (e.g. Dicycloverine, hyoscine) ( www.nursingtimes.net/Journals/1/Files/2009/3/31/Stool patients spend an adequate amount of time on the toilet for whether pain or discomfort is a predominant feature or • Calcium supplements Chart O4.pdf ) when asking patients to classify their bowel bowel movements, preferably at a regularly scheduled time 10,23,24 whether the "main problem" is limited to the constipation • Diuretics movements. The scale provides 7 prototypical stool (typically in the morning to coincide with the body’s natural itself. Patients who acknowledge that abdominal pain is a • Iron supplements forms. Patients with constipation typically point to type 1 and gastrocolic response). • Opioids major factor are more likely to have IBS-C than chronic type 2 bowel movements as their predominant stool form. In children, NICE4 indicate that dietary interventions alone constipation. Those principally concerned with improving • Verapamil Painful anorectal conditions What should be advised about the role of lifestyle in should NOT be used as first-line treatment for idiopathic stool frequency or form independent of abdominal pain constipation. Constipation in children should be treated with probably have chronic constipation.11 • Anal fissure, haemorrhoids, abbscess, fistula, levator ani preventing and treating constipation? syndrome, proctalgia fugax Many guidelines recommend general lifestyle modifications laxatives and a combination of: How common is constipation? before considering drug treatment. Traditionally, individuals • Negotiated and non-punitive behavioural interventions Constipation is a common, often chronic, disorder estimated with chronic constipation are told to increase dietary fibre suited to the child or young person’s stage of 12,13 appropriate. In addition, if dietary intervention, laxatives and to affect 10-15% of adults in developed countries. The intake in order to alleviate symptoms, but there is little development. These could include scheduled toileting 14 other approaches fail, referral to a specialist may be condition occurs twice as frequently in women as in men 18 evidence from randomised controlled trials (RCTs) that this and support to establish a regular bowel habit, 15 indicated. and is highly prevalent in the elderly, with up to 20% of approach is of any benefit.25,26 However, observational maintenance and discussion of a bowel diary, information those living in the community and 50% of those living in an What causes constipation? studies suggest a beneficial effect of dietary fibre in on constipation, and use of encouragement and rewards 9,13 institution reporting symptoms. Box THREE summarises the causes of chronic constipation. 27,28 systems constipated patients. Constipation may be primary or secondary to other medical Constipation is also common in childhood. It is prevalent in • Dietary modifications to ensure a balanced diet and conditions, including metabolic, neurological or endocrine In general, the diet should be balanced and contain whole around 5–30% of the child population, depending on the grains, fruits, and vegetables. This is recommended as part sufficient fluids are consumed 4 diseases. Furthermore, medication used in the treatment of criteria used for diagnosis. of the treatment for constipation. It is also recommended for Advise parents, children and young people that a balanced other conditions may cause secondary constipation. The diet should include: Complications general health and promoted by the 'five-a-day' policy. Fibre BNF lists over 900 drugs that report constipation as a side- • Adequate fluid intake Chronic constipation may lead to additional health problems. effect, and where possible this should be addressed first as intake should be increased gradually (to minimise flatulence • Adequate fibre. Recommend including foods with high The following complications are sometimes associated with the likely aetiology. and bloating) and maintained for life. Adults should aim to 10,16,17 fibre content. Do not recommend unprocessed bran, chronic constipation: consume 18–30g fibre per day. (As a guide, a medium-sized The impact and economic burden of constipation which can cause bloating and flatulence and reduce the • Haemorrhoids bowl of porridge contains around 2g of fibre; 2 slices of Constipation may often be regarded as a trivial medical brown bread contain 2.5g of fibre). absorption of micronutrients • Faecal impaction problem, but for people with chronic constipation the impact • Volvulus Although the effects of a high fibre diet may be seen in a few on their quality of life is considerable and the burden on days, it may take as long as 4 weeks. Adequate fluid intake • Ulcers of the colon or rectum healthcare resources, in terms of medical care visits, GI- • Rectal prolapse related procedures, investigations and medications, can be Drugs used in the management of chronic constipation • Anal fissures substantial.1 • Faecal incontinence Quality of life A variety of treatment options are available for patients with efficacy of individual laxatives. Therefore management of Features requiring further referral In the most severely affected individuals, chronic chronic constipation, ranging from older over-the-counter chronic constipation in adults is largely based on expert (OTC) laxatives to more recently developed prescription opinion.3 It is vital to screen for “alarm features” when evaluating any constipation is accompanied by very marked impairment in 19 patient with chronic constipation, regardless of age. Any quality of life and social functioning. Chronic constipation- drugs. A majority (96%) of patients who seek consultation for Begin by relieving faecal loading/impaction, if present. Set associated GI symptoms significantly interfere with many constipation will have already attempted self-medication with patient reporting the signs or symptoms listed in Box TWO 33 realistic expectations for the results of treatment of chronic should be referred for further investigation.11 Although the aspects of sufferers’ daily lives, including mood (44%), OTC products. In spite of these different treatment constipation. Advise people about lifestyle measures and mobility (37%), normal work (42%), recreation (47%), and approaches, there remains a substantial unmet need in the predictive validity of these features for malignancy is 34 adjust any constipating medication, if possible. Exclude enjoyment of life (58%).20 The impact of chronic constipation treatment of chronic constipation. somewhat unreliable, their presence should never be underlying causes (e.g. hypothyroidism, metabolic disease, ignored. on quality of life for patients is comparable with that for anal fissure, haemorrhoids). Laxatives are divided into the following main groups: conditions such as COPD, diabetes and depression.21 When does a patient with constipation require referral to • Bulk-forming laxatives Laxatives are recommended: a specialist? Burden on healthcare resources • Stimulant laxatives • if lifestyle measures are insufficient, or whilst waiting for The ‘alarm’ symptoms shown in Box TWO might indicate a Costs associated with constipation, including direct costs • Faecal softeners them to take effect serious underlying condition, and specialist referral would be such as evaluation and treatment and indirect costs such as • Osmotic laxatives • for people taking a constipating drug that cannot be work absenteeism are high.22 • Bowel cleansing preparations (not covered in this review) stopped In Northern Ireland in the 12 months to September 2011 There are also newer agents for managing constipation that • for people with other secondary causes of constipation Box TWO: Signs and symptoms that might indicate almost 620,000 prescriptions were filled for laxatives, at a do not fit into any of these traditional groups: • as 'rescue' medicines for episodes of faecal loading a serious underlying condition:3 cost of over £3million - see Table ONE. • Peripheral opioid-receptor antagonists The aim of treatment with laxative agents is to adjust the

• Unexplained change in bowel habits lasting longer than 6 weeks • 5HT4-receptor agonists dose, choice, and combination of laxative to produce • Palpable mass in the lower right abdomen or the pelvis This simple classification disguises the fact that some comfortable defaecation with soft, formed stools once or • Persistent rectal bleeding without anal symptoms laxatives have a complex action. twice a day.

• Narrowing of stool calibre Expert consensus opinion35 tends to favour starting Guidance about which laxative(s) to use in adults • Family history of colon cancer, or inflammatory bowel disease treatment with a bulk-forming laxative. It is important to With the exception of relatively recent evidence comparing • Unexplained weight loss, iron deficiency anaemia, fever, or the efficacy of macrogols with lactulose (see later), there is maintain good hydration when taking bulk-forming laxatives. nocturnal symptoms limited clinical evidence on which to judge the comparative This may be difficult for some people (e.g. the frail or • Severe, persistent constipation that is unresponsive to treatment elderly). If stools remain hard, add or switch to an osmotic

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 2 COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 3 is important (particularly with a high fibre diet or fibre Table ONE: Number and cost of prescriptions for laxatives in Northern Ireland for the 12 months to September 2011 supplements), but can be difficult for some people (e.g. frail or elderly). Fruits high in fibre and sorbitol, and fruit juices Number of Class of laxative Cost high in sorbitol can help prevent and treat constipation. prescriptions Fruits (and their juices) that have a high sorbitol content Bulk-forming laxatives 55,552 £205,363 include apples, apricots, gooseberries, grapes (and raisins), Stimulant laxatives 167,756 £779,195 peaches, pears, plums (and prunes), raspberries, and Faecal softeners 741 £983 strawberries. The concentration of sorbitol is about 5–10 Osmotic laxatives 394,118 £2,279578 times higher in dried fruit. Peripheral opioid-receptor 7 £189 In addition, exercise and increasing fluid intake are often antagonists recommended to treat constipation, but again, there is 5HT -receptor agonists 387 £22,786 4 insufficient evidence that these interventions help in chronic Total 618,561 £3,288,093 constipation.27

Assessing frequency, amount and consistency of stools Despite limited data supporting their use in clinical practice, Because most patients understandably lack a working the suggested lifestyle changes promote general health and knowledge of normative stool consistency, it is instructive to may improve bowel symptoms in some patients.29-32 Another use the Bristol Stool Scale: behavioural modification to consider includes ensuring that ( www.nursingtimes.net/Journals/1/Files/2009/3/31/Stool patients spend an adequate amount of time on the toilet for Chart O4.pdf ) when asking patients to classify their bowel bowel movements, preferably at a regularly scheduled time 10,23,24 movements. The scale provides 7 prototypical stool (typically in the morning to coincide with the body’s natural forms. Patients with constipation typically point to type 1 and gastrocolic response). type 2 bowel movements as their predominant stool form. 4 In children, NICE indicate that dietary interventions alone What should be advised about the role of lifestyle in should NOT be used as first-line treatment for idiopathic preventing and treating constipation? constipation. Constipation in children should be treated with Many guidelines recommend general lifestyle modifications laxatives and a combination of: before considering drug treatment. Traditionally, individuals • Negotiated and non-punitive behavioural interventions with chronic constipation are told to increase dietary fibre suited to the child or young person’s stage of intake in order to alleviate symptoms, but there is little development. These could include scheduled toileting evidence from randomised controlled trials (RCTs) that this and support to establish a regular bowel habit, approach is of any benefit.25,26 However, observational maintenance and discussion of a bowel diary, information studies suggest a beneficial effect of dietary fibre in on constipation, and use of encouragement and rewards constipated patients.27,28 systems

In general, the diet should be balanced and contain whole • Dietary modifications to ensure a balanced diet and grains, fruits, and vegetables. This is recommended as part sufficient fluids are consumed of the treatment for constipation. It is also recommended for Advise parents, children and young people that a balanced general health and promoted by the 'five-a-day' policy. Fibre diet should include: intake should be increased gradually (to minimise flatulence • Adequate fluid intake and bloating) and maintained for life. Adults should aim to • Adequate fibre. Recommend including foods with high consume 18–30g fibre per day. (As a guide, a medium-sized fibre content. Do not recommend unprocessed bran, bowl of porridge contains around 2g of fibre; 2 slices of which can cause bloating and flatulence and reduce the brown bread contain 2.5g of fibre). absorption of micronutrients

Although the effects of a high fibre diet may be seen in a few days, it may take as long as 4 weeks. Adequate fluid intake Drugs used in the management of chronic constipation A variety of treatment options are available for patients with efficacy of individual laxatives. Therefore management of chronic constipation, ranging from older over-the-counter chronic constipation in adults is largely based on expert (OTC) laxatives to more recently developed prescription opinion.3 drugs. A majority (96%) of patients who seek consultation for Begin by relieving faecal loading/impaction, if present. Set constipation will have already attempted self-medication with 33 realistic expectations for the results of treatment of chronic OTC products. In spite of these different treatment constipation. Advise people about lifestyle measures and approaches, there remains a substantial unmet need in the adjust any constipating medication, if possible. Exclude treatment of chronic constipation.34 underlying causes (e.g. hypothyroidism, metabolic disease, anal fissure, haemorrhoids). Laxatives are divided into the following main groups: • Bulk-forming laxatives Laxatives are recommended: • Stimulant laxatives • if lifestyle measures are insufficient, or whilst waiting for • Faecal softeners them to take effect • Osmotic laxatives • for people taking a constipating drug that cannot be • Bowel cleansing preparations (not covered in this review) stopped There are also newer agents for managing constipation that • for people with other secondary causes of constipation do not fit into any of these traditional groups: • as 'rescue' medicines for episodes of faecal loading

• Peripheral opioid-receptor antagonists The aim of treatment with laxative agents is to adjust the • 5HT4-receptor agonists dose, choice, and combination of laxative to produce This simple classification disguises the fact that some comfortable defaecation with soft, formed stools once or laxatives have a complex action. twice a day.

35 Guidance about which laxative(s) to use in adults Expert consensus opinion tends to favour starting With the exception of relatively recent evidence comparing treatment with a bulk-forming laxative. It is important to the efficacy of macrogols with lactulose (see later), there is maintain good hydration when taking bulk-forming laxatives. limited clinical evidence on which to judge the comparative This may be difficult for some people (e.g. the frail or elderly). If stools remain hard, add or switch to an osmotic

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 3 laxative. If stools are soft but the person still finds them difficult to pass or complains of inadequate emptying, add a Prescribing Notes: Laxatives2 stimulant laxative. Adjust the dose, choice, and ► Before prescribing laxatives it is important to be sure that combination of laxative according to symptoms, speed with the patient is constipated and that the constipation is not which relief is required, response to treatment, and individual secondary to an underlying undiagnosed complaint preference. The dose of laxative should be gradually titrated ► It is important for those who complain of constipation to upwards (or downwards) to produce one or two soft, formed understand that bowel habits can vary considerably in stools per day. frequency without doing harm. Some people tend to Guidance on managing constipation in children consider themselves constipated if they do not have a bowel All children and young people with idiopathic constipation movement each day. A useful definition of constipation is the should be assessed for faecal impaction.4 Use a passage of hard stools less frequently than the patient’s own combination of history-taking and physical examination to normal pattern and this can be explained to the patient diagnose faecal impaction – look for overflow soiling and/or ► Misconceptions about bowel habits have led to excessive faecal mass palpable abdominally and/or rectally if indicated. laxative use. Abuse may lead to hypokalaemia If impaction is present, see the section on disimpaction if ► The BNF recommends that laxatives should generally be needed. If impaction is not present or has been treated, treat avoided except where straining will exacerbate a condition the child promptly with a laxative (even if the history of (such as angina) or increase the risk of rectal bleeding as in constipation is very short). Delays of greater than 3 days haemorrhoids between stools may increase the likelihood of pain on ► Laxatives are of value in drug-induced constipation, for passing hard stools leading to anal fissure, anal spasm and the expulsion of parasites after anthelmintic treatment, and eventually to a learned response to avoid defaecation.36 to clear the alimentary tract before surgery and radiological

NICE recommend polyethylene glycol 3350 (Movicol® procedures Paediatric Plain) as the preferred first-line agent for the ► Prolonged treatment of constipation is sometimes 4 necessary management of constipation in children. Ensure that an effective dose is used, by adjusting the dose according to contact to contact every few weeks). Where possible, response to treatment. (If the child has needed disimpaction, reassessment should be provided by the same person/team. the usual dose is half the disimpaction dose). Please note: At the time of publication (January 2012), If this approach does not work, add in a stimulant laxative; or ® if this approach is not tolerated, substitute a stimulant Movicol Paediatric Plain does not have UK marketing laxative. If stools are hard, consider adding in lactulose or authorisation for use in faecal impaction in children under 5 another laxative with softening effects, such as docusate. years, or for chronic constipation in children less than 2 years. Informed consent should be obtained and Do not use suppositories or enemas in primary care documented. unless all oral medications have failed and preferably following specialist advice. Doses above the licensed Stopping laxatives maximum dose may be needed, so informed consent should Laxatives should not be stopped abruptly. Laxatives should be verbally obtained and documented.4 be gradually withdrawn when regular bowel movements

Continue medication at maintenance dose for several weeks occur without difficulty (e.g. 2 - 4 weeks after defaecation after regular bowel habit is established – this may take has become comfortable and a regular bowel pattern with several months.4 Children who are toilet training should soft, formed stools has been established). The rate at which remain on laxatives until toilet training is well established. doses are reduced should be guided by the frequency and Some children may require laxative therapy for several consistency of the stools. Doses should be reduced in a years. A minority may require ongoing laxative therapy.4 gradual manner in order to minimise the risk of requiring ‘rescue therapy’ for recurrent faecal loading. If a combination Disimpaction in children of laxatives has been used, reduce and stop one laxative at Offer the following oral medication regimen for disimpaction 4 a time. Stimulant laxatives doses should be reduced first, if if indicated: possible. However, it may be necessary to also adjust the • polyethylene glycol, using an escalating dose regimen as dose of the osmotic laxative to compensate. The patient the first-line treatment should be advised that it can take several months to be • add a stimulant laxative if polyethylene glycol does not successfully weaned off all laxatives. It is common to get work relapses and these should be treated early with increased • substitute a stimulant laxative if polyethylene glycol is not doses of laxatives. tolerated by the child or young person. Add another laxative such as lactulose or docusate if stools are hard Bulk-forming laxatives

Please note: (ispaghula, methylcellulose and sterculia) • use rectal medications for disimpaction unless all do not How do bulk-forming laxatives work? oral medications have failed and only if the child or young Bulk-forming laxatives relieve constipation by increasing person and their family consent faecal mass which stimulates peristalsis. During treatment • administer sodium citrate enemas only if all oral with bulk-forming laxatives, adequate fluid intake must be medications for disimpaction have failed maintained to avoid intestinal obstruction.2,36 Proprietary • do not administer phosphate enemas for disimpaction preparations containing a bulking agent are often difficult to unless under specialist supervision in hospital/health administer to children.36 centre/clinic, and only if all oral medications and sodium citrate enemas have failed Is there any evidence for the use of bulk-forming laxatives? Review children and young people undergoing disimpaction There is a lack of high-quality data demonstrating the within 1 week. Start maintenance therapy as soon as the efficacy of bulk-forming laxatives. A systematic review found child or young person’s bowel is disimpacted. Reassess that ispaghula husk increased stool frequency; however, children frequently during maintenance treatment to ensure there were insufficient data on methylcellulose to provide they do not become re-impacted and assess issues in evidence-based recommendations for its use in chronic maintaining treatment such as taking medicine and toileting. 11 constipation. Despite the lack of data, substantial clinical Tailor the frequency of assessment to the individual needs of experience supports the use of these agents as a first-line the child and their families (this could range from daily intervention.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 4 laxative. If stools are soft but the person still finds them How quickly do bulk-forming laxatives work? 2 difficult to pass or complains of inadequate emptying, add a Prescribing Notes: Laxatives2 Patients and/or carers should be advised that the full effect Prescribing Notes: Bulk-forming laxatives stimulant laxative. Adjust the dose, choice, and of bulk-forming laxatives may take some 2-3 days to ► Adequate fluid intake must be maintained to avoid ► Before prescribing laxatives it is important to be sure that 2,36 combination of laxative according to symptoms, speed with the patient is constipated and that the constipation is not develop. If after 2-3 days the patient reports no relief of intestinal obstruction which relief is required, response to treatment, and individual secondary to an underlying undiagnosed complaint their constipation, the dosage and frequency should be ► Preparations that swell in contact with liquid should preference. The dose of laxative should be gradually titrated increased to the maximum recommended before adding always be carefully swallowed with water and should not be ► It is important for those who complain of constipation to 16 upwards (or downwards) to produce one or two soft, formed understand that bowel habits can vary considerably in in/switching to another laxative. taken immediately before going to bed stools per day. frequency without doing harm. Some people tend to In which patients are bulk-forming laxatives particularly Guidance on managing constipation in children consider themselves constipated if they do not have a bowel useful? Osmotic laxatives All children and young people with idiopathic constipation movement each day. A useful definition of constipation is the Bulk-forming laxatives are of particular value in those with (lactulose, macrogols) should be assessed for faecal impaction.4 Use a passage of hard stools less frequently than the patient’s own small hard stools. Bulk-forming laxatives are also useful in normal pattern and this can be explained to the patient Action combination of history-taking and physical examination to the management of patients with colostomy, ileostomy, 40 diagnose faecal impaction – look for overflow soiling and/or ► Misconceptions about bowel habits have led to excessive haemorrhoids, anal fissure, chronic diarrhoea associated Osmotic laxatives include: faecal mass palpable abdominally and/or rectally if indicated. laxative use. Abuse may lead to hypokalaemia with diverticular disease, irritable bowel syndrome, and as • poorly absorbed sugars (lactulose, sorbitol) If impaction is present, see the section on disimpaction if ► The BNF recommends that laxatives should generally be adjuncts in ulcerative colitis.2 • macrogols (also known as polyethylene glycol needed. If impaction is not present or has been treated, treat avoided except where straining will exacerbate a condition Bulk-forming laxatives are not appropriate for rapid relief of preparations (PEG)) the child promptly with a laxative (even if the history of (such as angina) or increase the risk of rectal bleeding as in constipation, but are a good option for long-term control.3 • magnesium salts constipation is very short). Delays of greater than 3 days haemorrhoids Through their osmotic actions,, these agents retain water in between stools may increase the likelihood of pain on ► Laxatives are of value in drug-induced constipation, for Are there any situations in which prescribing a bulk- the intestinal lumen, which leaads to softer stools with a larger 40 passing hard stools leading to anal fissure, anal spasm and the expulsion of parasites after anthelmintic treatment, and forming laxative would be contra-indicated? volume and improved propulsion. eventually to a learned response to avoid defaecation.36 to clear the alimentary tract before surgery and radiological Bulk-forming laxatives are contra-indicated in patients with How long do osmotic laxatives take to hava e their effect? ® difficulty in swallowing, intestinal obstruction, colonic atony, NICE recommend polyethylene glycol 3350 ( procedures 2 Movicol faecal impaction. Osmotic laxatives may take a few days to take effect and are ► Prolonged treatment of constipation is sometimes Paediatric Plain) as the preferred first-line agent for the not suitable for rapid relief of constipation. They may be 4 necessary Maintaining an adequate intake of fluids is important to avoid management of constipation in children. Ensure that an given in divided doses throughout the day. Adequate fluid effective dose is used, by adjusting the dose according to the possibility of intestinal obstruction. However, this may be 3 contact to contact every few weeks). Where possible, 3 intake should be encouraged. response to treatment. (If the child has needed disimpaction, difficult for some people (e.g. the frail or elderly). reassessment should be provided by the same person/team. Adverse effects the usual dose is half the disimpaction dose). What are the sidde-effects of bulk-forming laxatives? Osmotic laxatives may cause flatulence, bloating, abdominal If this approach does not work, add in a stimulant laxative; or Please note: At the time of publication (January 2012), There is often initial discomfort and abdominal distension 16,41 ® 37 cramping, nausea and diarrhoea with higher doses. if this approach is not tolerated, substitute a stimulant Movicol Paediatric Plain does not have UK marketing upon initiation of therapy with a bulk-forming laxative. With laxative. If stools are hard, consider adding in lactulose or authorisation for use in faecal impaction in children under 5 continued use, these effects usually decrease, particularly if Lactulose is degraded by colonnic bacteria to low-molecular another laxative with softening effects, such as docusate. years, or for chronic constipation in children less than 2 the agent is started at a low dose and gradually increased. weight acids that increase stool acidity and osmolarity and years. Informed consent should be obtained and lead to the accumulation of fluid in the colon. Macrogols are Do not use suppositories or enemas in primary care Alternatively, patients with substantial bloating might benefit documented. from using methylcellulose, an inorganic bulking agent that less likely than lactulose to produce bloating and flatulence, unless all oral medications have failed and preferably 11 as macrogols are inert and not degraded by colonic is not fermentable. 42 following specialist advice. Doses above the licensed Stopping laxatives bacteria. maximum dose may be needed, so informed consent should Laxatives should not be stopped abruptly. Laxatives should Rarely, side-effects including obstruction of the oesophagus 38,39 be verbally obtained and documented.4 be gradually withdrawn when regular bowel movements or colon have been reported. Are there any patient groups in which osmotic laxatives

® ® ® may be inappropriate? Continue medication at maintenance dose for several weeks occur without difficulty (e.g. 2 - 4 weeks after defaecation Ispaghula husk (Fibrelief , Fybogel , Isogel , Ispagel ® ® • Osmotic laxatives may lead to electrolyte disturbance and after regular bowel habit is established – this may take has become comfortable and a regular bowel pattern with Orange , Regulan ) 4 soft, formed stools has been established). The rate at which fluid overload, they should be used with caution in several months. Children who are toilet training should Ispaghula husk is a commonly used bulking agent in the UK. 43 patients with renal impairment or cardiac failure remain on laxatives until toilet training is well established. doses are reduced should be guided by the frequency and There is published evidence of its effectiveness in the short- • Some children may require laxative therapy for several consistency of the stools. Doses should be reduced in a term treatment of constipation (up to eight weeks), but Osmotic laxatives may be counterproductive in patients 4 gradual manner in order to minimise the risk of requiring 28 with constipation associated with irritable bowel syndrome years. A minority may require ongoing laxative therapy. limited evidence of its role in the long-term. Nevertheless, 42 ‘rescue therapy’ for recurrent faecal loading. If a combination and in patients with severe bloating and fullness clinical experience suggests that it remains effective even Disimpaction in children of laxatives has been used, reduce and stop one laxative at 28 with long-term use. Evidence Offer the following oral medication regimen for disimpaction a time. Stimulant laxatives doses should be reduced first, if 4 ® The best-studied osmotic laxattives are the macrogols and if indicated: possible. However, it may be necessary to also adjust the Methylcellulose (Celevac 500mg tablets) • polyethylene glycol, using an escalating dose regimen as In adults and children over the age of 12 years, 3-6 tablets lactulose, and there are well-designed RCTs supporting their dose of the osmotic laxative to compensate. The patient effectiveness in treating chronic constipation.44,45 While both the first-line treatment should be advised that it can take several months to be should be taken twice daily. Tablets should be taken with at • add a stimulant laxative if polyethylene glycol does not least 300 ml of liquid. The dose may be reduced as normal have been found to be effective, macrogols have been found successfully weaned off all laxatives. It is common to get to be superior to lactulose for increasing stool frequency and work relapses and these should be treated early with increased bowel function is restored. In children aged 7-12 years, 2 45 2,36 reducing straining. • substitute a stimulant laxative if polyethylene glycol is not doses of laxatives. tablets should be taken twice daily. tolerated by the child or young person. Add another Lactulose ® laxative such as lactulose or docusate if stools are hard Bulk-forming laxatives Caution: It is recommended that Celevac tablets Lactulose has been used for over 30 years and is one of the should be broken in the mouth before swallowing. Please note: (ispaghula, methylcellulose and sterculia) most commonly used laxatives. Lactulose is a semi- Celevac® tablets swell in contact with water and • do not use rectal medications for disimpaction unless all synthetic disaccharide which is not absorbed from the How do bulk-forming laxatives work? should therefore be swallowed carefully. It is not gastro-intestinal tract. Lactulose can cause nausea, but this oral medications have failed and only if the child or young Bulk-forming laxatives relieve constipation by increasing recommended that these tablets be taken before going to bed. person and their family consent can be minimised by administering lactulose with water, fruit faecal mass which stimulates peristalsis. During treatment juice or a meal. Long term use of lactulose possibly • administer sodium citrate enemas only if all oral with bulk-forming laxatives, adequate fluid intake must be Sterculia 2 ® ® enhances anticoagulant effect of coumarins. medications for disimpaction have failed maintained to avoid intestinal obstruction.2,36 Proprietary Normacol (sterculia) and Normacol Plus (sterculia plus • Trials have demonstrated that lactulose is safe and is more do not administer phosphate enemas for disimpaction preparations containing a bulking agent are often difficult to frangula*) are in the form of granules. In adults, 1 or 2 11,46 36 effective than placebo but less effective than unless under specialist supervision in hospital/health administer to children. sachets or 1-2 heaped 5ml spoonfuls, once or twice daily 47 macrogols. centre/clinic, and only if all oral medications and sodium after meals. In children aged 6-12 years, give half this citrate enemas have failed Is there any evidence for the use of bulk-forming amount. The granules should be placed dry on the tongue Macrogols (also called polyethylene glycols)Table TWO laxatives? Review children and young people undergoing disimpaction and without chewing or crushing, swallowed immediately Macrogols are inert, non-absorbable, non-metabolisable There is a lack of high-quality data demonstrating the 2,36,48 within 1 week. Start maintenance therapy as soon as the with plenty of water or a cool drink. The granules may also polymers of ethylene glycol. Daily doses of macrogols efficacy of bulk-forming laxatives. A systematic review found child or young person’s bowel is disimpacted. Reassess be sprinkled onto soft food such as yoghurt, followed by are effective in chronic constipation by: that ispaghula husk increased stool frequency; however, 2,36 children frequently during maintenance treatment to ensure plenty of liquid. • there were insufficient data on methylcellulose to provide normalising frequency of bowel movements (NNT=2.4) they do not become re-impacted and assess issues in evidence-based recommendations for its use in chronic (* Frangula acts as a mild peristaltic stimulant and aids the • decreasing straining (NNT=3.2) maintaining treatment such as taking medicine and toileting. 11 constipation. Despite the lack of data, substantial clinical evacuation of the softened faecal mass). • improving stool consistency (NNT=3 to 4) Tailor the frequency of assessment to the individual needs of experience supports the use of these agents as a first-line In addition, daily macrogols facilitate discontinuing other the child and their families (this could range from daily laxatives (NNT=3.1).49 intervention.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 4 COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 5 Compared with lactulose, macrogols are more effective in Rectal preparations (suppositories/enemas containing improving symptoms of chronic constipation; they have a phosphates or sodium citrate) can be used effectively to better tolerability profile (due to reduced electrolyte produce rapid evacuation (within 30 minutes) but should be disturbance) and are associated with a reduced need for used with caution in the elderly and debilitated.2 45,47 rescue medication. In patients with refractory Glycerol suppositories act as a rectal stimulant by virtue of constipation taking macrogols daily, a stimulant laxative may the mildly irritant action of glycerol.2,36 Both bisacodyl and be added every second or third day to improve treatment sodium picosulfate are prodrugs that are converted in the efficacy.50 gut into the same active metabolite, which causes the Macrogols have been suggested to be more cost-effective desired laxative effect. than lactulose.51 Is there an evidence-base for the use of stimulant

laxatives? Prescribing Notes: Macrogols Although widely used, there is a limited evidence base ► Movicol® Liquid must not be taken undiluted and may supporting the use of stimulants in chronic constipation. The only be diluted in water – see SmPC for further details clinical data supporting the use of stimulant laxatives in ► Multi-ingredient products, such as macrogols, should be chronic constipation are derived from studies which were prescribed by brand52 often done in specific subsets of patient populations and had ill-defined endpoints.54-61 Placebo-controlled trials show that Stimulant laxatives bisacodyl and picosulfate are more effective than placebo, but most trials are of short duration and quality is (bisacodyl, dantron, docusate sodium, glycerol, senna, 17,39,46 sodium picosulfate) variable. In a recent 4-week placebo-controlled trial, picosulfate improved bowel function, symptoms and quality Stimulant laxatives include bisacodyl, sodium picosulfate, of life.62 Practically speaking, however, many patients report and members of the anthraquinone group, senna and clinically relevant benefits from these agents and symptom dantron. Docusate sodium probably acts both as a stimulant recurrence upon discontinuation. and as a softening agent. This group also includes glycerol What adverse effects are associated with using suppositories. stimulant laxatives? How do stimulant laxatives work? Gastrointestinal adverse effects Stimulant laxatives increase intestinal motility by stimulating Stimulant laxatives are generally well tolerated, but may the colonic myenteric plexus on their contact with the colonic induce abdominal pain.17,39,46,63 This can often be managed mucosa, and by inhibiting water absorption, thereby inducing by dose titration.62 Stools should be softened by increasing passage of stools.17,39,46,48,53 These agents usually produce dietary fibre and liquid or with an osmotic laxative before an effect within 6 to 12 hours of ingestion and so are giving a stimulant laxative.2,36 Stimulant laxatives should be commonly administered at bedtime to produce an effect in avoided in intestinal obstruction.2,36 16 the morning.

Table TWO: Macrogol laxatives as listed in the BNF2

Licensed? Agent Formulation, dosage and administration Cost Adult Child Macrogol Oral Powder, Compound Sachets of powder to be dissolved Not licensed £6.68 for 30 (Non-proprietary). YES under 12 sachets Brands include Each sachet should be dissolved in 125ml water (approx half a ® years (£0.22 per dose) Laxido Orange, glass) Molaxole® Sachets of powder to be dissolved

1-3 sachets daily in divided doses, according to individual response Not licensed £6.68 for 30 ® Movicol For extended use, the dose can be adjusted down to 1 or 2 YES under 12 sachets sachets daily years (£0.22 per dose)

Each sachet should be dissolved in 125ml water (approx half a glass) Concentrate for oral solution Not licensed ® £4.45 for 500ml Movicol Liquid YES under 12 25 ml diluted in 100 ml of water 1-3 times daily in divided doses, (£0.22 per dose) according to individual response years Sachets of powder to be dissolved

2 - 6 sachets daily in divided doses, according to individual Not licensed £4.01 for 30 ® response Movicol -Half YES under 12 sachets For extended use, the dose can be adjusted down to 2 - 4 sachets years (£0.13 per dose) daily

Each sachet should be dissolved in 62.5ml water Sachets of powder to be dissolved

Usual starting dose is 1 sachet daily for children aged 2 - 6 years £4.45 for 30 ® and 2 sachets daily for children aged 7 – 11 years. The dose YES – see Movicol Paediatric sachets should be adjusted up or down as required to produce regular soft NO BNF or Plain (£0.15 - £0.30 per stools SmPC dose) Each sachet should be dissolved in 62.5 ml (quarter of a glass) of water In adults, a course of treatment for constipation does not normally exceed two weeks, although this can be repeated if required

Treatment of children with chronic constipation needs to be for a prolonged period (at least 6 – 12 months). However, safety and efficacy of Movicol® Paediatric Plain has only been proved for a period of up to three months. Treatment should be stopped gradually and resumed if constipation recurs.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 6 Melanosis coli The most common adverse effects are abdominal cramping Senna products may discolour the urine, and chronic use (~28%), flatulence (~13%), nausea (~11%), and dizziness may cause melanosis coli, a brown-black pigmentation of (~7%). Long-term use of methylnaltrexone has not been the colonic mucosa. This condition does not lead to colon evaluated.48 cancer and is reversible over time after discontinuation of use. 5HT4-receptor agonists (prucalopride▼) Tolerance/ intestinal atony 3 Stimulant laxatives are only licensed for short-term use, but Serotonin (also known as 5-hydroxytryptamine or 5-HT) is a long-term use is common and is justifiable in some key regulator of GI motility, sensitivity and secretion. circumstances. For example, in children with chronic Through 5-HT4 receptors, 5-HT triggers and co-ordinates constipation, especially where withholding of stool occurs, intestinal peristalsis.72,73 Prucalopride (Resolor®▼) is the additional doses of a stimulant laxative may be required and first selective, high affinity 5-HT4 receptor agonist to undergo long-term use of stimulant laxatives is sometimes necessary. clinical development.74 Prucalopride has been shown to

Historically, there have been concerns that long-term use of enhance colonic transit in healthy controls and in patients 75,76 stimulant laxatives may cause a “cathartic colon” marked by with chronic constipation. 64,65 diminished motility from a “burned out” myenteric plexus. In which patients is prucalopride licensed? However, this has not been confirmed in experimental 53,64,66,67 Prucalopride is licensed for the treatment of chronic studies nor in clinical practice. When used constipation in women, when other laxatives have failed to appropriately, stimulant laxatives are not harmful and are provide an adequate response.2 often both efficacious and cost-effective in many patients with occasional or chronic constipation.42 Dosage and administration The recommended dosage in female adults is 2mg Why are the indications for using dantron limited? administered orally once daily; exceeding this dosage is not The indications for dantron are limited by its potential expected to increase efficacy.77 The recommended starting carcinogenicity (based on rodent carcinogenicity studies) dosage of prucalopride in females aged > 65 years is 1mg and evidence of genotoxicity. Dantron should only be used once daily; thereafter, the dosage can be increased to 2mg to manage constipation in terminally ill patients (of all 2,36 once daily, if needed. Prucalopride does not require dosage ages). adjustment in women with mild or moderate renal or hepatic Faecal softeners impairment. However, the recommended dosage in women with severe renal or hepatic impairment is 1mg once daily. (arachis oil, liquid paraffin) Importantly, most women who will benefit from treatment Action with prucalopride respond within four weeks. If the intake Faecal softeners are surface-acting agents that function of once-daily prucalopride is not effective after four weeks of primarily as detergents, that is, they allow water to interact treatment, the woman should be re-examined and the more effectively with solid stool, thereby softening the benefit of continuing treatment reconsidered.77,78 stool.48 The evidence-base for prucalopride Evidence In three identical pivotal trials, 1974 patients with chronic Laxatives which mainly soften or lubricate stools appear to constipation (predominantly women) were treated for 12 be more effective than placebo in increasing the frequency weeks with placebo, prucalopride 2mg or prucalopride 4mg of bowel movements and in overall symptoms improvement, once daily (NB: 4mg daily is not a licensed dose).68,79,80 Both 68 but data are limited. doses of prucalopride resulted in an average of three

Problems spontaneous complete bowel mmovements per week in Although faecal softeners are relatively inexpensive and well approximately 20% of patients, compared with 10% of tolerated, in patients with severe symptoms, or in patients in patients receiving placebo. Booth active doses of prucalopride generated similar response rates. whom other forms of therapy have failed, it is unlikely that 35 stool softeners alone will be adequate. Of note regarding these trials:

Prolonged use of liquid paraffin should be avoided because • trials were short (lasting up to 12 weeks) compared with of anal seepage of paraffin and consequent anal irritation the chronic nature of constipation after prolonged use. Prolonged use has also been • trials did not compare the drug with existing treatments associated with granulomatous reactions caused by • trials did not specify previous laxative-use as an inclusion criterion absorption of small quantities of liquid paraffin (especially from the emulsion), lipoid pneumonia,69 and interference Long-term open-label follow-up studies involving patients with the absorption of fat-soluble vitamins. Liquid paraffin is who had previously participated in the original trials have contra-indicated in children under 3 years. shown that satisfaction with bowel movement was

maintained for up to 18 months of treatment. A total of 20% Caution: Arachis oil of patients discontinued treatment during the course of the Do not use arachis oil in a patient with a peanut studies due to insufficient response.81 allergy. Why is prucalopride only licensed in women? The drug company’s initial prooposed therapeutic indication Peripheral opioid-receptor antagonists for prucalopride was for the treatment of adults (both women (methylnaltrexone bromide) and men) with chronic constipation in whom laxatives fail to 35 Methylnaltrexone bromide (Relistor®▼) provide adequate relief. However, most of the participants Methylnaltrexone is one of a new class of medications; it is a in the key trials were women, and subgroup analysis showed peripherally acting opioid-receptor antagonist that is licensed that the drug might not have a statistically significant effect in for the treatment of opioid-induced constipation in male participants. The Committtee for Medicinal Products for patients receiving palliative care, when response to other Human Use noted that the efficacy had not been laxatives is inadequate; it should be used as an adjunct to demonstrated sufficiently in men and therefore existing laxative therapy.2 Methylnaltrexone does not alter recommended that it should be licensed for use only in the central analgesic effect of opioids.70,71 Methylnaltrexone women. is given by subcutaneous injection.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 7 Contra-indications Prucalopride is NOT licensed in:82 Figure ONE: Cost comparison chart for laxatives (28 days treatment) (Prices taken from BNF 62) • men • children and adolescents under 18 Senna tablets 15mg daily £1.34 years of age • renal impairment requiring dialysis Bisacodyl 10mg daily £1.83

• intestinal perforation or obstruction Lactulose 20ml daily £2.55 due to structural or functional disorders of the gut Glycerol suppositories 4gm, 1 daily £3.27 • severe inflammatory conditions of Docusate 200mg daily £3.58 the intestinal tract, such as Crohn’s disease and ulcerative colitis Ispaghula (Ispagel® sachets, 2 daily) £3.92 • pregnancy Sodium picosulfate oral solution 10ml daily £5.29 • breast-feeding Sodium citrate enema (Relaxit Micro-enema®, 1 daily) £8.96 Patient groups requiring dosage Macrogols (Movicol®, 2 sachets daily) £12.47 modification82 • women >65 years – 1mg daily Prucalopride 2mg daily £59.52 initially, may be increased to 2mg daily if needed £0 £20 £40 £60 £80 • severe renal impairment – 1mg once daily (no dose adjustment necessary for patients In contrast, in 2011, the Scottish Medicines Consortium with mild to moderate renal impairment) (SMC) has recommended against the use of prucalopride for • severe hepatic impairment – 1mg once daily (no dose the second time. The SMC states that in the key trials, most adjustment necessary for patients with mild to moderate patients did not achieve the primary or the key secondary hepatic impairment) outcome measures and that the outcomes most relevant to

What are the adverse effects of prucalopride? the licensed indication are derived from post-hoc subgroup In initial clinical trials, the adverse effects which were analyses in women. The SMC stated that the company did experienced more frequently by patients treated with not present a sufficiently robust clinical and economic analysis. prucalopride versus placebo include: • headache How much does prucalopride cost? • nausea See Figure ONE. The cost of 28 days treatment with • diarrhoea prucalopride 1-2mg daily is £39 to £60 per patient compared • abdominal pain with, for example, These effects resolved within a few days of continued • around £4 for a typical formulation of ispaghula husk, treatment. Other unwanted effects included abnormal bowel • around £12 for macrogols sounds, anorexia, dizziness, dyspepsia, fatigue, fever, • around £2 for a typical stimulant laxative flatulence, frequent urination, malaise, palpitations, rectal haemorrhage, tremors and vomiting. Key points from the NICE guidance on 84 During long-term follow-up studies, the most frequent prucalopride▼ adverse effects which resulted in study discontinuation were ► Prucalopride is an option for the treatment of chronic abdominal pain, diarrhoea, headache and nausea.81 constipation only in women for whom treatment with at least two Cisapride, a drug in the same class, was withdrawn from the laxatives from different classes, at the highest tolerated UK market in July 2000 because it prolonged the Q-TC recommended doses for at least six months, has failed to interval. However, prucalopride has been reported to be provide adequate relief and invasive treatment for constipation is being considered. more selective than cisapride; clinical trials on prucalopride found the incidence of QT interval prolongation to be low ► If treatment with prucalopride is not effective after four weeks, 68,79,80 and similar to that with placebo. Additionally, extensive the woman should be re-examined and the benefit of continuing cardiovascular safety assessments, including a study in treatment reconsidered. elderly institutionalised patients, showed no arrhythmogenic ► Prucalopride should only be prescribed by a clinician with potential for prucalopride.83 experience of treating chronic constipation, who has carefully The SmPC advises prucalopride should be used with reviewed the woman’s previous courses of laxative treatments. caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.82 Constipation in pregnancy and breastfeeding What do national or regional guidelines say? In its 2010 Technology Appraisal of prucalopride, NICE How should constipation in a pregnant or breastfeeding recommends:84 woman be managed? • prucalopride is an option for symptomatic treatment for Constipation is quite common during pregnancy. For chronic constipation in women who have had inadequate pregnant and breastfeeding women the emphasis lies in relief with at least two laxatives (from different classes, first-line use of dietary and lifestyle measures. The use of laxatives should only be considered if these measures fail.3 at the highest tolerated recommended doses for at least 6 months) and for whom invasive treatment for Using laxatives in pregnancy constipation is being considered If dietary and lifestyle changes fail to control constipation in • prucalopride should be prescribed only by a “clinician pregnancy or breastfeeding, moderate doses of poorly with experience of treating chronic constipation”, and absorbed laxatives may be used. Consider a bulk-forming only after the clinician has carefully reviewed the laxative first. If stools remain hard, add or switch to lactulose woman’s previous laxative treatments or a macrogol. If stools are soft but the woman still finds • if treatment with prucalopride is not effective after 4 them difficult to pass or complains of inadequate emptying, weeks, the woman should be re-examined and the consider a short course of bisacodyl or senna.4 Occasional benefit of continuing treatment reconsidered use of glycerol or bisacodyl suppositories is also an option.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 8 • Bulk-forming laxatives, lactulose and macrogols are 17. Tack, J. and Muller-Lissner, S. Treatment of chronic not absorbed from the gastrointestinal tract and are constipation: current pharmacologic approaches and future therefore suitable for use during pregnancy directions. Clin.Gastroenterol.Hepatol. 2009; 7: 502-508. 18. McCallum, I. J., Ong, S. and Mercer-Jones, M. Chronic • Bisacodyl is poorly absorbed from the gastrointestinal constipation in adults. BMJ 2009; 338: b831. tract (only about 5%). It has not been reported to cause 19. Rao, S. S., Seaton, K., Miller, M. J., et al. Psychological profiles teratogenic or fetotoxic effects and is therefore suitable and quality of life differ between patients with dyssynergia and for use during pregnancy. those with slow transit constipation. J.Psychosom.Res. 2007; • Senna is partially absorbed from the gastrointestinal tract 63: 441-449. but does not appear to be teratogenic. Concerns have 20. Johanson, J. F. Review of the treatment options for chronic been raised that senna should be avoided in the third constipation. MedGenMed. 2007; 9: 25. 21. Wald, A., Scarpignato, C., Kamm, M. A., et al. The burden of trimester because a stimulating effect on uterine constipation on quality of life: results of a multinational survey. contractions has been reported with other anthraquinone Aliment.Pharmacol.Ther. 2007; 26: 227-236. derivatives. However, this has not been reported with 22. Dennison, C., Prasad, M., Lloyd, A., et al. The health-related senna. quality of life and economic burden of constipation. • Glycerol suppositories are also suitable for use during Pharmacoeconomics. 2005; 23: 461-476. pregnancy 23. Heaton, K. W. and O'Donnell, L. J. An office guide to whole-gut transit time. Patients' recollection of their stool form. Laxatives that are not recommended: J.Clin.Gastroenterol. 1994; 19: 28-30. • Docusate is less preferred because there is a single case 24. Lewis, S. J. and Heaton, K. W. Stool form scale as a useful report of neonatal hypomagnesaemia after maternal guide to intestinal transit time. Scand.J.Gastroenterol. 1997; 32: overuse of oral docusate sodium. However, docusate 920-924. could be considered in low doses if the recommended 25. Badiali, D., Corazziari, E., Habib, F. I., et al. Effect of wheat bran in treatment of chronic nonorganic constipation. A double- laxatives (above) are unsuccessful blind controlled trial. Dig.Dis.Sci. 1995; 40: 349-356. • Sodium picosulfate: there is less experience with its use 26. Ashraf, W., Park, F., Lof, J., et al. 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V., McGowan, J., et al. A 15. Gallagher, P. F., O'Mahony, D. and Quigley, E. M. Management randomized, multicenter, placebo-controlled trial of polyethylene of chronic constipation in the elderly. Drugs Aging 2008; 25: glycol laxative for chronic treatment of chronic constipation. 807-821. Am.J.Gastroenterol. 2007; 102: 1436-1441. 16. Eoff, J. C. Optimal treatment of chronic constipation in managed 45. Attar, A., Lemann, M., Ferguson, A., et al. Comparison of a low care: review and roundtable discussion. J.Manag.Care Pharm. dose polyethylene glycol electrolyte solution with lactulose for 2008; 14: 1-15. treatment of chronic constipation. Gut 1999; 44: 226-230.

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 9 46. Ramkumar, D. and Rao, S. S. Efficacy and safety of traditional 71. McNicol, E. D., Boyce, D., Schumann, R., et al. Mu-opioid medical therapies for chronic constipation: systematic review. antagonists for opioid-induced bowel dysfunction. Am.J.Gastroenterol. 2005; 100: 936-971. Cochrane.Database.Syst.Rev. 2008; CD006332. 47. Lee-Robichaud, H., Thomas, K., Morgan, J., et al. Lactulose 72. Gershon, M. D. and Tack, J. The serotonin signaling system: versus Polyethylene Glycol for Chronic Constipation. from basic understanding to drug development for functional GI Cochrane.Database.Syst.Rev. 2010; CD007570. disorders. Gastroenterology 2007; 132: 397-414. 48. Singh, S. and Rao, S. S. Pharmacologic management of 73. Cash, B. D. and Chey, W. D. Review article: The role of chronic constipation. Gastroenterol.Clin.North Am. 2010; 39: serotonergic agents in the treatment of patients with primary 509-527. chronic constipation. Aliment.Pharmacol.Ther. 2005; 22: 1047- 49. Corazziari, E., Badiali, D., Habib, F. I., et al. Small volume 1060. isosmotic polyethylene glycol electrolyte balanced solution 74. De Maeyer, J. H., Lefebvre, R. A. and Schuurkes, J. A. 5-HT4 (PMF-100) in treatment of chronic nonorganic constipation. receptor agonists: similar but not the same. Dig.Dis.Sci. 1996; 41: 1636-1642. Neurogastroenterol.Motil. 2008; 20: 99-112. 50. Blaker P and Wilkinson M. Chronic constipation: diagnosis and 75. Bouras, E. P., Camilleri, M., Burton, D. D., et al. Selective current treatment options. Prescriber 2010; 21: 30-45. stimulation of colonic transit by the benzofuran 5HT4 agonist, 51. Guest, J. F., Clegg, J. P. and Helter, M. T. Cost-effectiveness of prucalopride, in healthy humans. Gut 1999; 44: 682-686. macrogol 4000 compared to lactulose in the treatment of chronic 76. Bouras, E. P., Camilleri, M., Burton, D. D., et al. Prucalopride functional constipation in the UK. Curr.Med.Res.Opin. 2008; 24: accelerates gastrointestinal and colonic transit in patients with 1841-1852. constipation without a rectal evacuation disorder. 52. NI Health and Social Care Board. Items Unsuitable for Generic Gastroenterology 2001; 120: 354-360. Prescribing. 77. Frampton, J. E. Prucalopride. Drugs 2009; 69: 2463-2476. http://primarycare.hscni.net/pdf/Generic_Exception_List_Nov20 78. Emmanuel, A. and Kerr, S. Prucalopride. Prescriber 11.pdf 2011; (Supplement) 2011; 53. Geboes, K., Nijs, G., Mengs, U., et al. Effects of 'contact 79. Camilleri, M., Kerstens, R., Rykx, A., et al. A placebo-controlled laxatives' on intestinal and colonic epithelial cell proliferation. trial of prucalopride for severe chronic constipation. Pharmacology 1993; 47 Suppl 1: 187-195. N.Engl.J.Med. 2008; 358: 2344-2354. 54. Stern, F. H. Constipation--an omnipresent symptom: effect of a 80. Tack, J., van, Outryve M., Beyens, G., et al. Prucalopride preparation containing prune concentrate and cascarin. (Resolor) in the treatment of severe chronic constipation in J.Am.Geriatr.Soc. 1966; 14: 1153-1155. patients dissatisfied with laxatives. Gut 2009; 58: 357-365. 55. Kinnunen, O., Winblad, I., Koistinen, P., et al. Safety and 81. Camilleri, M., Van Outryve, M. J., Beyens, G., et al. Clinical trial: efficacy of a bulk laxative containing senna versus lactulose in the efficacy of open-label prucalopride treatment in patients with the treatment of chronic constipation in geriatric patients. chronic constipation - follow-up of patients from the pivotal Pharmacology 1993; 47 Suppl 1: 253-255. studies. Aliment.Pharmacol.Ther. 2010; 32: 1113-1123. 56. Williamson, J., Coll, M. and Connolly, M. A comparative trial of 82. Shire Pharmaceuticals Ltd. Resolor. Summary of Product a new laxative. Nurs.Times 1975; 71: 1705-1707. Characteristics 2011; 57. Odes, H. S. and Madar, Z. A double-blind trial of a celandin, 83. Camilleri, M., Beyens, G., Kerstens, R., et al. Safety aloevera and psyllium laxative preparation in adult patients with assessment of prucalopride in elderly patients with constipation: constipation. Digestion 1991; 49: 65-71. a double-blind, placebo-controlled study. 58. KASDON, S. C. and MORENTIN, B. O. The management of Neurogastroenterol.Motil. 2009; 21: 1256-e117. puerperal constipation with a senna preparation. J.Int.Coll.Surg. 84. NICE. Prucalopride for the treatment of chronic constipation in 1959; 31: 455-458. women. NICE Technology Appraisal 211 2010; 59. Corman, M. L. Management of postoperative constipation in anorectal surgery. Dis.Colon Rectum 1979; 22: 149-151. © Queen’s Printer and Controller of HMSO 2012

60. Connolly, P., Hughes, I. W. and Ryan, G. Comparison of This material was prepared on behalf of the Northern Ireland Health "Duphalac" and "irritant" laxatives during and after treatment of and Social Care Board by: chronic constipation: a preliminary study. Curr.Med.Res.Opin. Lynn Keenan BSc (Hons) MSc MPS 1974; 2: 620-625. Medicines Management Information Pharmacist 61. MacLennan, W. J. and Pooler, A. F. W. M. A comparison of COMPASS Unit sodium picosulphate ("Laxoberal") with standardised senna Pharmaceutical Department ("Senokot") in geriatric patients. Curr.Med.Res.Opin. 1974; 2: NI Health and Social Care Board 641-647. 2 Franklin Street, Belfast 62. Mueller-Lissner, S., Kamm, M. A., Wald, A., et al. Multicenter, 4- BT2 8DQ. week, double-blind, randomized, placebo-controlled trial of sodium picosulfate in patients with chronic constipation. You may re-use this material free of charge in any format or medium Am.J.Gastroenterol. 2010; 105: 897-903. for private research/study, or for circulation within an organisation, 63. Kienzle-Horn, S., Vix, J. M., Schuijt, C., et al. Comparison of provided that the source is appropriately acknowledged. The bisacodyl and sodium picosulphate in the treatment of chronic material must be re-used accurately in time and context, and must constipation. Curr.Med.Res.Opin. 2007; 23: 691-699. NOT be used for the purpose of advertising or promoting a particular product or service for personal or corporate gain. 64. Wald, A. Is chronic use of stimulant laxatives harmful to the colon? J.Clin.Gastroenterol. 2003; 36: 386-389. Any queries on re-use should be directed to Lynn Keenan (e-mail 65. Joo, J. S., Ehrenpreis, E. D., Gonzalez, L., et al. Alterations in [email protected], telephone 02890 535629) colonic anatomy induced by chronic stimulant laxatives: the With thanks to the following for kindly reviewing this document: cathartic colon revisited. J.Clin.Gastroenterol. 1998; 26: 283- 286. • Professor BT Johnston. Consultant Gastroenterologist, 66. Muller-Lissner, S. A., Kamm, M. A., Scarpignato, C., et al. Belfast Health and Social Care Trust. Myths and misconceptions about chronic constipation. Am.J.Gastroenterol. 2005; 100: 232-242. • Dr TCK Tham. Consultant Gastroenterologist, South Eastern Health and Social Care Trust. 67. Xing, J. H. and Soffer, E. E. Adverse effects of laxatives. Dis.Colon Rectum 2001; 44: 1201-1209. The editorial panel for this edition of COMPASS Therapeutic Notes: 68. Quigley, E. M., Vandeplassche, L., Kerstens, R., et al. Clinical trial: the efficacy, impact on quality of life, and safety and Ms Kathryn Turner (Medicines Management Lead, Health and tolerability of prucalopride in severe chronic constipation--a 12- Social Care Board).

week, randomized, double-blind, placebo-controlled study. Dr Bryan Burke (General Practitioner) Aliment.Pharmacol.Ther. 2009; 29: 315-328. Miss Veranne Lynch (Medicines Management Advisor, Belfast LCG) 69. Laurent, F., Philippe, J. C., Vergier, B., et al. Exogenous lipoid pneumonia: HRCT, MR, and pathologic findings. Eur.Radiol. Dr Ursula Mason (General Practitioner) 1999; 9: 1190-1196. Mrs Stephanie Sloan (Community Pharmacist) 70. Becker, G. and Blum, H. E. Novel opioid antagonists for opioid- induced bowel dysfunction and postoperative ileus. Lancet Dr Thérèse Rafferty (Medicines Management Information Analyst, 2009; 373: 1198-1206. HSCBSO).

COMPASS Therapeutic Notes on the Management of Chronic Constipation in Primary Care ● January 2012 Page 10 COMPASS THERAPEUTIC NOTES ASSESSMENT Management of Chronic Constipation in Primary Care

COMPASS Therapeutic Notes are circulated to GPs, nurses, pharmacists and others in Northern Ireland. Each issue is compiled following the review of approximately 250 papers, journal articles, guidelines and standards documents. They are written in question and answer format, with summary points and recommendations on each topic. They reflect local, national and international guidelines and standards on current best clinical practice. Each issue is reviewed and updated every three years. Each issue of the Therapeutic Notes is accompanied by a set of assessment questions. These can contribute 2 hours towards your CPD/CME requirements. Submit your completed MCQs to the appropriate address (shown below) or complete online (see below). Assessment forms for each topic can be submitted in any order and at any time.

If you would like extra copies of Therapeutic Notes and MCQ forms for this and any other topic you can: Visit the COMPASS Web site: www.medicinesni.com or www.hscbusiness.hscni.net/services/2163.htm or Email your requests to: [email protected] or Phone the COMPASS Team on: 028 9053 5661

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Pharmacists: Complete the form overleaf and return to: Northern Ireland Centre for Pharmacy Learning & Development FREEPOST NICPLD Belfast BT9 7BL COMPASS THERAPEUTIC NOTES ASSESSMENT Management of Chronic Constipation in Primary Care

For copies of the Therapeutic Notes and assessment forms for this and any other topic please visit: www.medicinesni.com or www.hscbusiness.hscni.net/services/2163.htm

Successful completion of these assessment questions equates with 2 hours Continuing Professional Development time. Circle your answer TRUE (T) or FALSE (F) for each question. When completed please post this form to the relevant address shown overleaf. Alternatively, you can submit your answers online: • Doctors and nurses should submit their answers at: www.medicinesni.com • Pharmacists should submit their answers at: www.nicpld.org

1 Constipation: There is robust evidence that individuals with chronic constipation should be a T F advised to increase dietary fibre intake in order to alleviate symptoms b Tricyclic antidepressants can cause constipation T F c Constipation can occur in up to 20% of elderly patients who live in an institution T F The diagnosis of constipation is often arbitrary and is largely dependent on the d T F patient’s perception of “normal” bowel function

2 Laxatives in general: There is a wealth of robust evidence that underpins the use of laxatives in a T F chronic constipation The aim of treatment with laxative agents is to produce comfortable defaecation b T F with soft, formed stools once or twice a day Consider gradually withdrawing laxatives when regular bowel movements occur c without difficulty (2–4 weeks after defaecation has become comfortable and a T F regular bowel pattern with soft, formed stools has been established) d Prolonged treatment with laxatives is sometimes necessary T F

3 Osmotic laxatives: a Osmotic laxatives take around 12 hours to produce an effect T F b Macrogols are less likely than lactulose to cause bloating and flatulence T F c Lactulose is less effective than macrogols T F d Movicol® liquid should always be diluted with water before taking T F

4 Stimulant laxatives: Stimulant laxatives usually produce an effect within 6 to 12 hours of ingestion a and so are commonly administered at bedtime to produce an effect in the T F morning Stools should be softened by increasing dietary fibre and liquid or with an b T F osmotic laxative before giving a stimulant laxative c Long term use of stimulant laxatives should be avoided T F d Dantron should only be used to manage constipation in terminally ill patients T F

5 In regard to the newer agents used in the management of chronic constipation: Methylnaltrexone is a new oral agent licensed for the treatment of opioid- a T F induced constipation in patients receiving palliative care b Prucalopride is licensed in women only T F Prucalopride is an option for the treatment of chronic constipation only in women for whom treatment with at least two laxatives from different classes, at the c highest tolerated recommended doses for at least six months, has failed to T F provide adequate relief and invasive treatment for constipation is being considered Prucalopride should be continued for 12 weeks before a decision is made on d T F efficacy