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This paper summarises the research evidence presented in a recent issue of Effective Health Care on the effectiveness of the four main types of laxatives used in the treatment of constipation in adults.1 The bulletin was based on two systematic reviews2,3 (table 1) and on the additional randomised controlled trials (RCTs) identified since the publication (1997) of these reviews (tables 2 and 3).
Constipation is a common reason for GP consultations in adults. The UK National Survey of Morbidity in General Practice in England and Wales found consultations for constipation were particularly common among the very young and the very old.4 The prevalence is less than 10% in the UK general population,5 about 20% among older people living in the community,2 and higher still among those living in nursing homes.6 About half of all patients admitted to specialist palliative care units report constipation, but about 75% of such patients will require laxatives.7 Laxatives are required by about 87% of terminally ill patients taking strong oral opioids, 74% of those on weak opioids, and 64% of those not receiving opioid analgesia.8 There also appear to be socioeconomic, sex, regional, and national differences in the prevalence of constipation.2,9 Constipation adversely affects the quality of life of the sufferer10 and accounts for a significant proportion of the NHS drug bill.11 At over £46 million per year in England, expenditure on the four main types of laxative (bulk, osmotic, stimulant, and softener) is higher than on hypnotics and anxiolytics such as benzodiazepines.12
A frequency of defaecation of less than three times a week has been widely used as an objective criterion for defining constipation,13,14 although patients' definitions emphasise symptoms such as pain and straining rather than frequency.15 The “Rome II” diagnostic criteria for constipation, which tend to be used as inclusion criteria for laxative trials, require two or more criteria to be present for at least 12 weeks in the last 12 months in the absence of a structural or biochemical explanation.16
Risk factors for constipation
The prevalence of constipation may be increasing because modern food processing methods have produced a refined roughage-free diet.17,18 Dietary fibre intake is positively associated with increases in bowel movement frequency and faecal mass and reductions in bowel transit time and symptoms (for overviews see Spiller,19 Bennett and Cerda20). Studies also show a lower incidence of constipation in vegetarians.21,22 One large population survey carried out in the USA has found that constipated adults report lower consumption of beans, peas, fruit and vegetables.23 Frequency of consumption of fruit, vegetables, and bread declines significantly with age in UK adults.24 Low calorie intake in older people (adjusted for fibre consumption) has also been implicated in the aetiology of constipation.25
A meta-analysis of the effects of wheat bran which incorporated 20 comparative studies (non-randomised controlled trials) of the association between stool weight and gastrointestinal transit time found that bran supplementation resulted in increased stool weight and decreased transit time in both healthy and constipated adults.26 However, in constipated patients receiving bran, stool weight remained lower than in controls, suggesting that low dietary fibre intake may not be the only factor influencing constipation.
Low fluid intake has also been cited as a risk factor for constipation.27,28 The elderly, in particular, may be at risk as they may drink less in an attempt to control incontinence.27 There have been few studies that have examined the effects of low fluid intake on constipation while controlling adequately for other factors. However, studies have shown low fluid intake to be related to slow colonic transit25 and low stool output in healthy adults.29 A large USA survey also reported lower consumption of beverages (sweetened, carbonated and non-carbonated) in constipated adults.23 A community survey in New Zealand, however, found no association with constipation.30
No trials have systematically assessed the impact of fluid intake as a treatment, although one small trial included 400 ml/day water as a control intervention and found it to be less effective than fibre plus the same amount of water.31 The authors of another small laxative trial also suggested that the dose-response effect which they observed may have been partly due to the associated increased intake of fluid.32 However, the effectiveness of increased fluid intake as a treatment for constipation remains largely unknown at present.
Constipation has been found to be more prevalent in those who take little exercise or are relatively inactive,23 and this association persists after controlling for age. The highest risks are associated with being chairbound or bedbound.33 Several studies have described bowel management programmes in institutionalised patients which have recommended exercise in the treatment of constipation.34,35 Several reviews have also recommended exercise.15,36 However, these interventions appear not to have been formally evaluated in constipated patients.37
Other factors which have been implicated in the development of constipation include anxiety, depression, and impaired cognitive function. For a more extensive list of other risk factors associated with constipation the reader is referred to the 1997 NHS HTA review.2 The validity of many suspected risk factors for constipation has been questioned by some researchers as they have not been systematically investigated.38
Treatment of constipation
A number of different interventions have been used in the treatment of constipation. Non-pharmacological interventions include guar gum, bread, bran, lentils, aloe vera, and fruit. Some of these treatments may act by increasing dietary fibre, while others have a stimulant action. Aloe is a folk remedy which, like senna and rhubarb, contains anthraquinone derivatives with a stimulant effect. Fruit may work by increasing bulk and liquid in the diet and/or by fermentation in the colon. Other non-pharmacological treatments for constipation include abdominal massage, biofeedback, hypnosis, and yogic breathing. None of these interventions are evaluated in this bulletin.
Laxatives are the most commonly prescribed pharmacological interventions, of which there are four main types (bulk, osmotic, stimulant, and softener). Prescribing of bulk-forming laxatives is decreasing yearly, while that of stimulant and osmotic laxatives is increasing.12
WHO SHOULD BE TREATED WITH LAXATIVES?
In general, there is much uncertainty over what constitutes effective management of constipation and laxatives may not be appropriate in all constipated patients. For mobile people (including older patients) it has been suggested that lifestyle changes involving changes in diet, increasing fluid intake, and increasing physical activity may be sufficient,39 although treatment will ultimately depend on the underlying causes and severity of the constipation. It has also been suggested that mild constipation can be managed with increasing fibre in the diet, while more severe constipation may require treatment with pharmacological laxatives after exclusion of underlying pathology.40 Only a small minority with intractable constipation will require referral for further investigations.39
EFFECTIVENESS OF LAXATIVE TREATMENTS
The average weighted mean increase in bowel frequency associated with treatment with bulk laxatives is around 1.4 bowel movements per week in adults.3 The increase associated with treatment with other laxative agents is approximately 1.5 bowel movements per week, with no apparent differences between bulk and non-bulk laxatives.3 Four additional RCTs carried out in populations of ambulant and institutionalised patients that were identified (table 2) suggest an increase in frequency of up to one bowel movement per week with bulk laxatives compared with placebo. However, these trials are very small and/or have methodological problems.31,41–43
A double blind comparative study of bulk laxatives found a significantly greater increase in frequency and feelings of complete evacuation with fibre than with docusate sodium.44 Overall, the evidence from these new RCTs and previous systematic reviews suggests that bulk laxatives are associated with an increase in frequency of 1–2 bowel movements per week compared with placebo and may be better tolerated than other laxative products.
Most trials that have evaluated fibre or bulk laxatives have found an improvement in abdominal pain with treatment, although no comparisons were significant.3 Consistency of the stool was improved in laxatives compared with placebo. A recent unblinded RCT compared ispaghula (Fybogel) with lactulose in 473 patients recruited by 65 GPs in the UK. Ispaghula was found to be more effective overall than lactulose with greater tolerability and fewer adverse effects, although frequency data are not reported.45
There is little comparative evidence of differences between bulk and other laxatives in terms of frequency or symptoms.
No consistent evidence was found that stimulant laxatives are more effective than non-stimulant laxatives. In trials conducted in older adults (>55 years) there is also little evidence of differences in effectiveness between categories of laxatives, and no trial evidence to suggest that the more expensive stimulant dantron (danthron) based laxatives are more effective than cheaper alternatives.2 (Note: the BNF now states that dantron should only be prescribed for constipation in terminally ill patients.46) A combination of a bulk plus stimulant laxative (agiolax, available as Manevac in the UK) has been reported in two good quality trials of older adults to be more effective in improving consistency and frequency than an osmotic laxative (lactulose).2
Laxatives with an osmotic effect appear to be consistently associated with significant improvements in frequency, consistency, straining, and pain compared with placebo based on the results of two systematic reviews2,3 and additional small trials.47–50 There is little evidence for differences in effectiveness between osmotic laxatives and other treatments. Two small hospital based RCTs compared polyethylene glycol (PEG) 3350 with lactulose51 and ispaghula (Konsyl),52 respectively. Both of these trials suggest that PEG 3350 may produce a greater increase in frequency than either comparator, with no significant difference in the incidence of adverse effects. In addition, the use of PEG 3350 may result in a greater reduction in straining than lactulose (Norgine Ltd, unpublished data, 2001). Another small trial has reported lactitol and lactulose to be equally effective.52
Laxatives with a softening action appear to be more effective than placebo in terms of increasing frequency and overall symptom improvement,2,3 but again there is little evidence available as to their comparative effectiveness. One additional parallel trial was identified which supports this conclusion.53 A crossover trial combined a softener with a stimulant and found that this was associated with an increase in frequency compared with placebo.54 Both these trials are very small.
Adverse effects and quality of life
Few studies have used standardised outcome measures to assess adverse effects and/or quality of life, although most studies did not report an increase in pain with fibre or non-bulk laxatives. Only two trials have examined improvements in general well being, neither of which showed any difference between fibre and other laxatives.3 Stimulant laxatives have previously been reported to cause abdominal cramping and diarrhoea with excessive use.55 Adverse effects previously noted with the use of lactulose include cramping and nausea.56,57
Cost effectiveness of laxatives
Two UK RCTs have examined the cost effectiveness of laxative treatment. One calculated the cost per stool associated with treatment with a senna fibre combination or with lactulose, giving a cost of 10.3p and 39.7p, respectively.58,59 The senna fibre combination was concluded to be significantly more effective in older subjects than lactulose at a lower cost. Another RCT compared two osmotic agents—lactulose and sorbitol—and found them to be equally effective and similar in terms of adverse effects in the treatment of older patients.60 The authors concluded that sorbitol is a cost effective alternative to lactulose. A review of cost containment strategies has noted that cost containment primarily rests on reduction in the use of unnecessary laxatives by promoting increased fibre intake in older people.36 However, there has been no formal assessment of the cost effectiveness of this recommendation.
Three RCTs of the prevention of constipation in older people were also reviewed.2 Two of the trials evaluated the effectiveness of bran in preventing constipation and the third assessed the use of a bulking agent (sterculia). None of the three RCTs found any significant benefit for the prevention of constipation.
Bulk (fibre based) laxatives and osmotic laxatives (including lactulose and PEG) are associated with increases in frequency and improvements in stool consistency and symptoms of constipation.
Little evidence is available at present as to the comparative effectiveness of bulk and non-bulk laxatives.
There is no good evidence that laxatives prevent constipation in older patients.
A stepped approach to laxative treatment would seem justified, involving initial intervention with cheaper laxatives, before proceeding to the more expensive alternatives.
There is a pressing need for large comparative trials of different strategies for the management of constipation in adults. This should include comparisons of the effectiveness of different classes of laxative.
Research is also required into the effectiveness of overall dietary change (including increased fluid intake) in the treatment of constipation.