SEPTEMBER 2001 VOLUME 7 NUMBER 1 ISSN: 0965-0288 Effective

Bulletin on the effectiveness Health Care of health service interventions forfor decisiondecision makersmakers Effectiveness of This bulletin summarises the research evidence laxatives in adults on the effectiveness of laxatives in the treatment of Laxative treatments are There is no good constipation in adults. associated with evidence that laxatives increases in bowel prevent constipation in movement frequency older patients and improvements in the symptoms of A stepped approach to constipation laxative treatment would seem justified, Bulk (fibre-based) involving initial laxatives and osmotic treatment with cheaper laxatives are associated laxatives, before with increases in proceeding to the more frequency, and expensive alternatives improvements in stool consistency and There is a need for symptoms large comparative trials of different Little evidence is strategies for the available as to the management of comparative constipation in adults effectiveness of bulk including comparisons and non-bulk laxatives of the effectiveness of in the treatment of different classes of constipation laxatives.

NHS CENTRE FOR REVIEWS AND DISSEMINATION more criteria to be present for at Fluid intake A. Background least 12 weeks in the last 12 Low fluid intake has also been cited months in the absence of a 25,26 Constipation is a common reason as a risk factor for constipation. structural or biochemical for GP consultations in adults. The 14 Older people in particular may be explanation (Box 1). UK National Survey of Morbidity at risk as they may drink less in an in General Practice in England and attempt to control incontinence.25 Wales found consultations for A.2 Risk factors for constipation There have been few studies that constipation were particularly Diet have examined the effects of low common among the very young fluid intake on constipation while and the very old.1 The prevalence The prevalence of constipation controlling adequately for other is less than 10% in the UK general may be increasing because factors. However, studies have population,2 about 20% among modern food processing methods shown low fluid intake to be older people living in the have produced a refined related to slow colonic transit23 and 15,16 community,3 and higher still roughage-free diet. Dietary fibre low stool output in healthy adults.27 among those living in nursing intake is positively associated with A large USA survey also reported homes.4 About half of all patients increases in bowel movement lower consumption of beverages admitted to specialist palliative frequency and faecal mass and (sweetened, carbonated and non- care units report constipation, but reductions in bowel transit time carbonated) in constipated adults.21 about 75% will require laxatives.5 and symptoms. (For overviews see A community survey in New 17 Laxatives are required by 87% of Spiller, 1994 ; Bennett & Cerda Zealand, however, found no 18 terminally ill patients taking strong 1996. ) Studies also show a lower association between reduced fluid oral opioids, 74% of those on weak incidence of constipation in intake and constipation.28 19,20 opioids and 64% of those not vegetarians. One large receiving opioid analgesia.6 There population survey carried out in No trials have systematically also appear to be socio-economic, the USA has found that assessed the impact of fluid intake gender, regional and national constipated adults report lower as a treatment, though one small differences in the prevalence of consumption of beans, peas, fruit trial has included 400ml/day of 21 constipation.3,7 Constipation and vegetables. Frequency of water as a control intervention, adversely affects the quality of life consumption of fruit, vegetables and found it to be less effective of the sufferer8 and accounts for a and bread declines significantly than fibre plus the same amount 22 29 significant proportion of the NHS with age in UK adults. Low of water. The authors of another drug bill.9 At over £46 million per calorie intake in older people, small laxative trial also suggested year in England, expenditure on (adjusted for fibre consumption), that the dose-response effect the four main types of laxative has also been implicated in the which they observed may have 23 (bulk, osmotic, stimulant and aetiology of constipation. been partly due to the associated 30 softener) is higher than on increased intake of fluid. A meta-analysis of the effects of hypnotics and anxiolytics However the effectiveness of wheat bran which incorporated (e.g. benzodiazepines).10 increased fluid intake as a twenty comparative studies (non- treatment for constipation remains randomised controlled trials) of largely unknown at present. A.1 Defining constipation the association between stool A frequency of defecation of less weight and gastrointestinal transit Mobility than three times a week has been time found that bran widely used as an objective supplementation resulted in Constipation has been found to be criterion for defining increased stool weight and more prevalent in those who take constipation,11,12 though patients’ decreased transit time in both little exercise or are relatively 21 definitions emphasise symptoms healthy and constipated adults.24 inactive, and this association such as pain and straining rather However, in constipated patients persists after controlling for age. than frequency.13 The ‘Rome II’ receiving bran, stool weight The highest risks are associated diagnostic criteria for remained lower than in controls, with being chairbound or 31 constipation, which tend to be suggesting that low dietary fibre bedbound. Several studies have used as inclusion criteria for intake may not be the only factor described bowel management laxative trials, require two or influencing constipation. programmes in institutionalised patients which have recommended exercise in the treatment of 14 Box 1 Rome II Criteria for functional constipation, updated 1999 constipation.32,33 Other studies 1. Straining at defecation at least a quarter of the time; have also recommended 13,34 2. Lumpy and/or hard stools at least a quarter of the time; exercise on the basis that there 3. Sensation of incomplete evacuation at least a quarter of the time; is an association between physical 4. Three or fewer bowel movements per week. inactivity and the prevalence of constipation in older people.3 Two or more of the above should be present for at least 12 weeks out of the preceding 12 months

2 EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults SEPTEMBER 2001 However these interventions Table 1 Systematic reviews of effectiveness of laxatives in adult patients appear not to have been formally Author (year) Inclusion criteria Main results evaluated in constipated patients.35 NHS HTA review (1997)3 RCTs in any language were Laxatives improve bowel movement included if all participants were frequency, consistency and Drug treatments 55 years or older, and were symptoms in older adults. There is treated for chronic constipation little evidence of differences in Use of drugs that can cause with any oral laxative effectiveness between laxatives, and constipation is also important, in no good research evidence to support current NHS trends towards particular anticholinergic anti- prescribing the more expensive depressants, opioid analgesics and stimulant laxatives NSAIDs including aspirin.36-38 Tramonte et al. (1997)43 English language RCTs of Laxatives and fibre increased laxative or fibre therapies in frequency by overall weighted Other risk factors constipated adults (all ages) average of 1.4 (95% CI: 1.1-1.8) bowel movements per week, and Other factors which have been decreased abdominal pain and implicated in the development of improved consistency. No clear constipation include anxiety, evidence found as to superiority of various treatments depression and impaired cognitive function. For a more extensive list of risk factors associated with and liquid in the diet, and/or by small minority with intractable constipation see the 1997 NHS HTA 3 fermentation in the colon. Other constipation will require referral review. The validity of many non-pharmacological treatments for further investigations.41 suspected risk factors for for constipation include abdominal constipation has been questioned by massage, biofeedback, hypnosis some researchers as they have not 39 and yogic breathing. None of these been systematically investigated. interventions are evaluated in this B. Nature of bulletin. A.3 Treatment of constipation the evidence A number of different Laxatives are the most commonly interventions have been used in prescribed pharmacological This bulletin is based largely on the treatment of constipation. interventions, of which there are two systematic reviews3,43 (Table 1) Non-pharmacological four main types (see Box 2). and on the additional randomised interventions include guar gum, Prescribing of bulk-forming controlled trials (RCTs) identified bread, bran, lentils, aloe vera, and laxatives is decreasing yearly, since the publication (1997) of fruit. Some of these treatments while that of stimulant and these reviews (Tables 2 and 3). may act by increasing dietary fibre, osmotic laxatives is increasing.10 (See appendix for further details of while others have a stimulant review methods.) The first of these action. Aloe is a folk remedy, A.4 Who should be treated with reviews was commissioned by the which like senna and rhubarb laxatives? NHS HTA programme and was published in 1997.3 This review contains anthraquinone In general, there is much included 10 RCTs (involving 367 derivatives with a stimulant effect. uncertainty over what constitutes participants) that had evaluated Fruit may work by increasing bulk effective management of the effectiveness of laxatives used constipation and laxatives may not Box 2 Main categories of laxatives in older patients with constipation. be appropriate in all constipated Bulking agents (eg bran, ispaghula) which The second systematic review patients. For mobile people increase the amount of fibre in the diet, included adults of any age and increasing the weight and water-absorbent (including older patients), it has again focused on the effectiveness properties of the stool. been suggested that lifestyle of laxatives.43 Only RCTs which Stimulant laxatives (eg senna, bisacodyl) changes involving changes in diet, involved patients with a minimum which increase intestinal motility by increasing fluid intake and stimulation of colonic nerves. duration of constipation of two increasing physical activity may be 41 weeks, evaluated treatment for at Faecal softeners such as liquid paraffin soften sufficient, though treatment will the stool. It has been recommended that the least one week and assessed use of these faecal softeners should be ultimately depend on the clinical outcomes such as bowel discouraged altogether on the grounds of underlying causes and severity of their adverse effects including anal seepage movement frequency, consistency 40 the constipation. It has also been and irritation. or symptoms were included. suggested that mild constipation Osmotic laxatives (such as magnesium Thirty-six trials were identified for can be managed with increasing hydroxide, lactulose) also act by softening inclusion in this review, involving and increasing water absorption in the stool. fibre in the diet, whilst more 1815 participants of which 70% The most commonly used of these in Britain is severe constipation may require lactulose, which may also have some were women, in a variety of treatment with pharmacological stimulant effect. Lactitol is a similar agent and settings including clinics, hospitals may also work by improving stool laxatives, after exclusion of characteristics through encouraging the 42 and nursing homes. fermentation of anaerobic bacteria. underlying pathology. Only a

2001 SEPTEMBER EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults 3 Because the definitions of laxatives are associated with an consistency, straining and pain constipation adopted by the increase in frequency of 1-2 bowel compared to placebo, based on the original systematic reviews movements per week compared to results of the two systematic exclude underlying pathology, the placebo and may be better reviews3,43 and the additional small use of laxatives in the treatment of tolerated than other laxative trials identified for this bulletin. 51-54 terminally ill patients is not products. covered in this bulletin. There is little evidence for Most trials that have evaluated differences in effectiveness One other recently published fibre or bulk laxatives have found between osmotic laxatives and systematic review was identified an improvement in abdominal other treatments. Two small which included RCTs of docusate pain with treatment, though no hospital-based RCTs compared for constipation in chronically ill comparisons were significant.43 polyethylene glycol ‘3350’ (PEG patients.44 All studies showed a Consistency of the stool was ‘3350’) with lactulose55 and trend in favour of increased bowel improved in laxatives compared to Konsyl® (ispaghula)56 respectively. movement frequency with placebo. A recent unblinded RCT Both trials suggest that PEG ‘3350’ docusate. However, it was compared ispaghula (Fybogel®) may produce a greater increase in concluded that treatment of with lactulose in 473 patients frequency than either constipation in chronically ill recruited by 65 GPs in the UK. comparators, with no significant patients is based on inadequate This study found that ispaghula difference in the incidence of experimental evidence. was more effective overall than adverse effects. In addition the lactulose, with greater tolerability use of PEG ‘3350’ may result in a and fewer adverse effects, though greater reduction in straining than frequency data are not reported.49 lactulose.55 Another small trial has C. Effectiveness reported lactitol and lactulose to There is little comparative be equally effective.57 of laxative evidence that there are differences between bulk and other laxatives C.4 Other classes of laxatives treatments in terms of frequency or symptoms. Laxatives with a softening action appear to be more effective than C.1 Bulk laxatives placebo in terms of increasing C.2 Stimulant laxatives The average weighted mean frequency and overall symptom increase in bowel frequency No consistent evidence was found improvement,3,43 but again there is associated with treatment with that stimulant laxatives are more little evidence available as to their bulk laxatives is around 1.4 bowel effective than non-stimulant comparative effectiveness. One movements per week in adults.43 laxatives. In trials conducted additional trial was identified The increase associated with among older adults (>55 years) which supports this conclusion.58 treatment with other laxative there is also little evidence of A crossover trial combined a agents is approximately 1.5 bowel differences in effectiveness softener with a stimulant and movements per week, with no between categories of laxatives, found that this was associated significant differences between and no trial evidence to suggest with an increase in frequency bulk and non-bulk laxatives.43 Four that the more expensive stimulant compared to placebo.59 Both these additional RCTs carried out in dantron (danthron) based laxatives trials are very small. populations of ambulant and are more effective than cheaper 3 institutionalised patients that were alternatives. (Note: the BNF now identified for this bulletin (Table 2) states that dantron should only be suggest an increase in frequency of prescribed for constipation in D. Adverse 50 up to 1 bowel movement per week terminally ill patients.) with bulk laxatives compared to A combination of a bulk plus effects and placebo. However these trials are stimulant laxative (Agiolax® – very small, and/or have available as Manevac® in the UK) quality of life methodological problems.29,45-47 has been reported in two good quality trials of older adults to be Few studies have used A double-blinded comparative more effective in improving standardised outcome measures to study involving bulk laxatives consistency and frequency than an assess adverse effects and/or found a significantly greater osmotic laxative (lactulose).3 quality of life, though most studies increase in frequency and feelings did not report an increase in pain of complete evacuation with fibre C.3 Osmotic laxatives with fibre or non-bulk laxatives. compared to docusate sodium.48 Only two trials have examined Laxatives with an osmotic effect Overall, the evidence from these improvements in general well- appear to be consistently new RCTs and previous systematic being, neither of which showed associated with significant reviews suggests that bulk any difference between fibre and improvements in frequency,

4 EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults SEPTEMBER 2001 Table 2 Additional trials evaluating single laxative treatments in adults

Author Population Intervention Results Comments (Country,Year) Funding Details Parallel RCTs Ashraf et al Ambulant patients Bulk vs placebo Frequency: I: increase in BM/week from 2.9 (0.1) to 3.8 Quality score: 3 (USA, 1995)45 I: Metamucil (n=11) (0.4) (p<0.05). C: No data given, estimated from graph: Randomisation: stated Mean age: 51 yrs 5g/day 2.7 vs 2.9 Double blind 64% female C: Placebo (n=11) Pain score (range 1-7): I: Decreased from 2.6 (0.5) to 2.0 Description of dropouts (0.4), p<0.05. C: Slight increase (from Fig 3c): 2.7 vs 2.8 Funding: Proctor and 8 weeks No significant group differences in consistency, straining, Gamble evacuation, or side effects. Howard et al Institutionalised men Bulk vs usual care Frequency (BM/week): End of treatment: I=2.3 (0.39), Quality score: 1 (USA, 2000)46 from a single care I: Bran mixture: (n=6) C=2.7 (0.79), (ns) Randomisation: not centre 3 cups apple sauce, Number of bowel medications/week: End of treatment: stated 2 cups coarse wheat bran, I=1.39 (1.08), C=13.28 (5.68) (p=0.03). Reduction of bowel Open study Mean age 1.5 cups prune juice medication with bran at maximum dose (p=0.03) Funding: not stated intervention: 73 yrs C: Usual care (n=6) Mean age normal diet, laxatives and comparator: 74 yrs enemas as needed

4 months Sculatti & Ambulant patients Bulk vs water Overall effectiveness: % non-constipated at 15 days: I=30%, Quality score: 2 Giampiccoli I: Fibraform (n=20) C=5% p=0.09. At 30 days: I=74%, C=15% p=0.001. Randomisation: (Italy, 1984)29 Mean age: 67.4 yrs 7g/day+400ml water Consistency: % with soft faeces at 15 days: I=25%, C=20% not stated 83% female C: Water (n=20) 400ml p=0.9. At 30 days:I=84%, C=25% p=0.0001 Not blind Painful defecation: % Pain-free at 15 days: I=73%, C=64% Description of dropouts 30 days p=0.5. At 30 days: I=90%, C=67% p=0.13. Funding: not stated Corazziari et al Outpatients Osmotic vs placebo Frequency (BM/week): End of 4 week run in: I=2.2 (0.5), Quality score: 4 (Italy, 1996)51 I: PMF-100 (Normopeg) C=1.9 (0.8) Randomisation: stated Mean age: 41.8 yrs (n=25) 14.6g PEG 4000, End of 8 week treatment period: I=4.8 (2.3), C=2.8 (1.6). Double-blind 77% female 1.42g anhydrous sodium Bowel frequency normalised: I= 64%, C= 22% (p<0.008; per Description of dropouts sulphate, 0.42g sodium ITTanalysis p<0.04) ITT bicarbonate, 0.18g Consistency: % with hard stools : I=12%, C=50% (per ITT Funding: not stated potassium chloride, 0.01 analysis p<0.07) simethicone, flavoured Use of laxatives: I=16%, C=48% (p<0.03; per ITT analysis C: Placebo (flavoured p<0.1) maltodextrine)(n=23) Straining: I=8%, C= 41% (p<0.03). No group differences in occurrence or severity of other symptoms. 4 week run-in, then 8 weeks PMF-100 or placebo twice daily in 250 ml of water. Corazziari et al Outpatients Osmotic vs placebo Frequency (BM/week): Week 4 (end of run-in): I=8.3 (4.0), Quality score: 4 (Italy, 2000)52 I: PMF-100 (Normopeg) C=7.7 (4.3). Week 12: I=7.4 (3.1) C=4.3 (2.5). Week 24: Randomisation: stated Mean age (n=33), as in Corazziari I=7.4 (3.2), C=5.4 (2.1) Double-blind intervention: 42.4 yrs (1996) trial, above Mean consumption of non-study laxatives, previous 4 weeks: Description of dropouts Mean age C: Placebo (flavoured Week 4: I=1.1 (2.8), C=0.31 (0.74). Week 12: I=0.7 (2.7), Funding: not stated comparator: 43.2 yrs maltodextrine) (n=37) C=2.2 (3.3). Week 24: I=0.2 (0.8), C=1.4 (2) 82.9% female Mean number of drug sachets, previous 4 weeks: Week 4: 4 week run-in, then I=38 (12) C=38 (15). Week 12: I=33 (13), C=43 (12). 20 weeks of PMF or Week 24: I=33 (13), C=44 (12) placebo as above Number of adverse events: I=57, C=41 DiPalma et al Participants recruited Osmotic vs placebo Frequency (BM/week): Week 1: I=4.2 (2.8), C=2.9 (1.9). Quality score: 3 (USA, 2000)53 from gastroenterology I: Braintree PEG 3350 Week 2: I=4.5 (3.0) C=2.7 (1.8) Randomisation: stated practices and local (Miralax) (n=80). Treatment success (>3 BM/week): Weeks 1 and 2 I=72.2%, Single blind advertising 17g/day in approx 8 oz C=49.6% (p<0.001; p<0.05 on ITT analysis). Description of dropouts water or juice Patient-rated effectiveness: I=68%, C=40% (p<0.001) ITT Mean age C: Dextrose powder Investigator-rated effectiveness: I=71.4%, C=47.1% Funding: Braintree intervention: 46.7 yrs placebo (n=71) same size (p<0.005) Laboratories Mean age scoop/day as I in 8oz Other: Significant improvements in self-reported consistency, comparator: 45.8 yrs water or juice straining passage, cramping and flatus (all p=0.001) Overall mean age: 45 yrs 14 days 87% female Huys & Van Hospital in-patients Softener/stimulant vs Frequency: % patients with daily stools: I: pre: 32%; post: Quality score: 2 Vaerenbergh placebo 72%. C: pre: 33%; post: 47%. Significant group difference, Randomisation: (Belgium, 1975)58 Mean age: not stated I: Softener (n=15) 60mg no alpha stated. No difference in diarrhoea incidence not stated Ratio male:female not DSS, 50mg of 1.8- Double-blind stated dioxyanthraquinone Description of dropouts C: Placebo (n=15) Funding: not stated

10 days ‘preparation’ then 20 days treatment

2001 SEPTEMBER EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults 5 Table 2 (cont...) Additional trials evaluating single laxative treatments in adults

Author Population Intervention Results Comments (Country,Year) Funding Details Crossover RCTs Marsicano Hospital cardiology Bulk vs placebo Frequency: I: 3g: Increase of 0.47 bm/day, compared with Quality score: 3 (Venezuela, 1995)47 patients I: Glucomannan fibre. 4g: increase of 0.83 bm/day Randomisation: stated 3g/day and 4g/day C: Change of - 0.2 to 0.1 Double-blind Mean age: 40.1 yrs, C: Placebo (n=60) Straining: 9 cases with placebo (15%), 5 (8.3%) with 3g and Description of dropouts all female 6 (10%) with 4g Glucomannan Funding: not stated 5 weeks Diarrhoea: I: Glucomannan 3g 6 (10%), 4g: 5 (8.3%), (2 weeks washout) Placebo: 1 (2%). Flatulence: Glucomannan 3g: 10 (17%), Glucmannan 4g: 13 (22%), Placebo: 11 (18%) Andorsky Outpatients Osmotic vs placebo Frequency (BM/5 day period): I (8oz)=5.81 (3.92), C=4.36 Quality score: 2 (USA, 1990)30 I: PEG, 8 or 16 oz daily (2.8) I (16oz): 9.56 (4.41), C=5.38 (2.44). Overall, PEG Randomisation: stated Mean age: 62yrs C: Placebo significantly more effective than placebo, and 2 glasses more Double-blind 76% female (N=37) effective than 1. No ITT Consistency score (range 1-4): PEG significantly more Authors note that 5 days (2 day washout) effective than placebo (2.6 vs 1.2; p<0.05), and 2 glasses greater effect of 16oz more effective than 1 (2.7 vs 0.8; p<0.05). may be due to fluid Side effects: Problems with cramps, gas, nausea, loose stools intake and taste with PEG but none resulted in termination of trial. Funding: drugs donated 9/37 (24%) had transient gas/cramps. by Reed and Carnrick Pharmaceuticals Castillo Ambulant patients Osmotic vs placebo Overall effectiveness: Number of satisfactory or partially Quality score: 1 (Argentina, 1995)66 I: Lactulose, 30ml/day satisfactory treatments at 1 week: I=23, C=17 (p<0.01) at 1 Randomisation: not Mean age: not stated C: Placebo week. I=22, C=8 (p<0.01) at 4 weeks stated Ratio male:female Adverse effects: Number of patients with meteorism: I=3, Double blind unclear 4 weeks (2 weeks C=6, p not stated. Flatulence: I=5, C=3, p not stated No ITT analysis washout) Funding: not stated Lemann et al Patients with chronic Osmotic vs placebo Frequency (BM/week): I: 9.4 (4.3) C:4.7 (3.4) (p<0.001) Quality score:2 (France, 1994)54 constipation I: PEG 3350 13-39 g/day Straining score (range not stated): Lower with PEG (0.7 (0.7) Randomisation: not C: Placebo vs 1.6 (0.7), p<0.001). stated Mean age: 48 yr (N=32) Overall improvement: Greater with PEG (score 6.4 vs 1.6, Double blind 85% female P<0.001; score range not stated) No dropouts reported Funding: Norgine Pharma

Table 3 Additional trials comparing laxative treatments in adults

Author Population Intervention Results Comments (Country,Year) Funding Details Parallel RCTs Attar Recruited from Osmotic vs osmotic Frequency (BM/day): I=1.3 (0.7), C=0.9 (0.6), p=0.005. Quality score: 2 France & Scotland, general and geriatric I: PEG 3350 low dose Proportion passing <3 BM/week: I=10%, C=14% Randomisation: stated 1999)55 hospitals (n=60) Mean=1.6 x 13g Straining (Median score; range 0 (absence)-3 (severe)): I=0.5 Single blind sachets/day (0.7), C=1.2 (0.9), p=0.0001 No ITT analysis Mean age: 55 yrs C: Lactulose (n=55) Overall improvement: (VAS, range 0 (no change) -10 Funding not stated 82% female Mean=2.1 sachets x (excellent)): I=7.4 (2.5), C=5.2 (3.3), p<0.001 10g/day Adverse events: 2 in PEG group, 1 in lactulose group Use of suppositories/enemas: I=16%, C=34%, p=0.04 4 weeks Symptoms No difference in % with liquid stools, pain, bloating, flatus, rumbling. More days with flatus with lactulose (I=9.2 (10.1), C=3.8 (6.8)). Mean number of liquid stools higher with PEG (I=2.4 (3.5), C=0.6 (1.2), p=0.001) Bobbio Patients with chronic Osmotic+bulk vs osmotic Frequency (BM/week): I: 5.75 (0.29); C: 6.55 (0.18), p<0.05 Quality score: 2 (Italy, 1995)67 constipation I: Lactulose+glucomannan Flatulence: Mean change in score; range 0 (symptom absent) Randomisation: not (n=20). 12g/day (24% -2 (intense): I=-0.2, C=+0.7, p<0.01 stated Mean age: 63.5yrs glucomannan, 70% Meteorism score: I=-0.1, C=0.8, p<0.001 Double blind 63% female lactulose) Pain score: No difference between groups. No dropouts reported C: Lactulose (n=20). Tolerance score (range 0 (low tolerability)-3 (optimimum Funding not stated 8.4g/day tolerability)): I=2.2, C=1.9, p<0.05

4 weeks Norgine Ltd Hospital population Osmotic vs bulk Frequency (BM/week): Increase in BM at 1 week vs baseline: Quality score: 3 unpublished data I: PEG 3350 plus I=6.95 (3.46), p=0.0001, C=3.98 (2.68), p<0.0001. At 2 Randomisation: stated (China, 2001)56 Mean age electrolytes (n=60) weeks vs baseline: I=7.48 (3.54), C=4.33 (2.40), p<0.0001. Unclear whether intervention: 51yrs 13.7g/bag twice/day Consistency: % normal stools: Week 1: I:84%, C: 52%, blinded 64% female C: Konsyl (ispaghula) p=0.001. Similar results for 2nd week Description of Mean age (n=60) 3.5g/bag Overall efficacy: I:Overall effectiveness rate = 92.07%, dropouts comparator: 50 yrs twice/day C: 73%, p=0.005 Funding: Norgine Ltd 56% female Adverse events: I: 12%, C: 8%, p=0.5 (ns) 14 days

6 EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults SEPTEMBER 2001 Table 3 (cont...) Additional trials comparing laxative treatments in adults

Author Population Intervention Results Comments (Country,Year) Funding Details Dettmar & Sykes Participants recruited Osmotic vs bulk vs other Overall effectiveness:Self-reported overall effectiveness (77% Quality score: 2 (UK, 1998)49 by 65 GPs I: Ispaghula husk (Fybogel) excellent or good with ispaghula versus 61% lactulose, 49% Randomisation: not (n=224) 3.5g twice/day other), palatability (62%, 49%, 50%) , acceptability (73%, stated Mean age: unclear with water 49%, 50%), all higher with ispaghula with fewer adverse Open study 63.4% female C1: Lactulose (n=91) effects (all p<0.01). Description of dropouts 35.3% male C2: Other prescribed Consistency (% normal): 55% vs 43% vs 39% (p<0.05) Funding: Reckitt and 1.3% not recorded laxatives (n=79): Speed of action: No difference in onset time of first bowel Colman (bisacodyl (n=24), softener movement. (n=21), senna (n=18), Other symptoms: Lower incidence of pain and diarrhoea with docusate sodium (n=13), ispaghula husk magnesium sulphate (n=3))

4 weeks Gordin Ambulant patients Osmotic+stimulant vs Frequency: Patients with 1 or 2 BM/day: I=88%, C=81% (ns) Quality score: 1 (France, 1997)68 osmotic Overall effectiveness: % patients self-reporting good or very Randomisation: not Mean age: not stated I: Lactulose and paraffin good improvement: I=76%, C=54%, p=0.05 stated Ratio male:female not (n=36) 15ml/day Tolerability: % patients reporting good or very good: I=70%, No blinding stated C: Lactulose 50% (n=36) C=40% (p=0.01) No ITT analysis 15ml/day Consistency: % "Soft" I=61%, C=55% Funding not stated

2 weeks Hammer & Ravelli Ambulant patients Osmotic vs osmotic Frequency (BM/week): I=6.7 (4.39) C=7.4 (4.48) Quality score: 2 (Germany, 1992)57 I: Lactitol (Importal) % patients with ≥3.5 BM/week at end of study: I=82%, Randomisation: not Mean age: 54 yrs (n=31). 20g/day for 3 C=81% stated 81% female days, then 10g/day for 25 Consistency: % patients reporting 'normal' or 'soft' at end of Open study days (maintenance dose) trial: I=19/25 (76%), C=16/24 (67%) p=0.50 Description of dropouts C: Lactulose (Dulphalac) Overall effectiveness and tolerability: No significant difference Funding not stated (n=26). Initial dose 20.1g between in I and C in terms of patients’, or physicians’ ratings for 3 days, then 13.4g for Adverse effects: % reporting adverse effects: I=10/32 25 days C=16/26 p=0.02

4 weeks Heitland & Participants were Osmotic vs osmotic Frequency (BM/day): After 2 weeks treatment: I=0.87 Quality score: 0 Mauersberger laxative users I: Lacitol (Importal) (n=30) C=0.79 (0.05

7 days (with 1 week washout) Michetti Unclear Softener+stimulant vs Frequency (BM/day): I=1.05, C1=1.26, C2=0.83 (Both Quality score: 2 (Italy, 1975)59 softener+stimulant vs treatments significantly different from placebo at p<0.05) Randomisation: stated Mean age: 52.4 yrs placebo Use of laxatives (mean number of days): I=1.76, C1=1.73, Not blinded 66% female I: Droctil (50mg DSS C2=1.68 (ns) No dropouts reported softener + 25mg Mean number of days with liquid stools: Highest with C1 Funding: not stated danthron). 100mg x 2 (DSS+cascara): 0.29 vs 1.88 vs 0.59 (p<0.05) caps/day Pain: Mean number of days with abdominal pain highest with C1: DSS (.075g)+Cascara C1(DSS+cascara): 0.59 vs 1.88 vs 0.77 (p<0.05) (.05g) + herbal ingredients Meteorism: Most common with I (Droctil): 1.94 vs 3.06 vs C2: Placebo 2.39 (p<0.05) (N=35)

Key: I=Intervention, C=Comparator. BM=Bowel movements. DSS=dioctyl sodium sulfosuccinate. ITT=intention to treat. ns=not significant.

2001 SEPTEMBER EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults 7 other laxatives.43 Stimulant per stool associated with treatment primarily rests on reduction in the laxatives have previously been with a senna-fibre combination or use of unnecessary laxatives by reported to cause abdominal with lactulose, giving a cost of promoting increased fibre intake cramping and diarrhoea with 39.7p for lactulose and 10.3p per in older people.34 However there is excessive use.40 Adverse effects stool for a senna-fibre no formal assessment of the cost- previously noted with the use of combination.62,63 The senna-fibre effectiveness of this lactulose include cramping and combination was concluded to be recommendation. A comparison of nausea.60,61 significantly more effective in cost per dose for laxatives listed in older people than lactulose, at a the BNF is given in Table 4.50 lower cost. Another RCT compared two osmotic agents, E. Cost- lactulose and sorbitol, and found them to be equally effective and F. Prevention effectiveness of similar in terms of adverse effects in the treatment of older patients.64 Three RCTs of the prevention of laxatives The authors concluded that constipation in older people were sorbitol is a cost-effective also reviewed.3 Two of the trials Two UK RCTs have examined the alternative to lactulose. A review evaluated the effectiveness of bran cost-effectiveness of laxative of cost-containment strategies has in preventing constipation and the treatment. One calculated the cost noted that cost-containment third evaluated the bulking agent

Table 4: Cost of laxatives50 * usually taken as single treatments

Classification Preparation Recommended dose Cost range/day range/day Bulk-forming laxatives Bran Trifyba® 7-10.5g £0.12-£0.18 Ispaghula Husk Fybogel® 7g £0.07 Konsyl® 3.4-10.2g £0.07-£0.21 Isogel® 4-8g £0.05-£0.10 Regulan® 5.85-17.6g £0.05-£0.15 Methylcellulose Celevac® 3-6g £0.14-£0.28 Sterculia Normacol® 7-28g £0.07-£0.31 Normacol Plus® 7-28g £0.08-£0.32 Stimulant laxatives Bisacodyl Bisacodyl - tablet 5-10mg £0.04-£0.08 - suppository 10mg* £0.06* Dantron (danthron) Co-danthramer 1-2 capsules £0.21-£0.42 Co-danthrusate 1-3 capsules £0.21-£0.63 Docusate Sodium Dioctyl® 100-500mg £0.05-£0.25 Docusol® 100-500mg £0.08-£0.41 Fletchers’ Enemette® 5mL* £0.31* Norgalax Micro-enema® 10g* £0.64* Glycerol Glycerol Suppositories, BP 1 suppository* £0.06* Senna Senna 15-30mg £0.03-£0.06 Manevac® 4-8g* £0.07-£0.14* Sodium Picosulfate Sodium Picosulfate 5-10mL £0.09-£0.18 (Sodium Picosulphate) Dulco-lax® 5-10mg £0.11-£0.22 Faecal softeners Arachis Oil Fletchers’ Arachis Oil Retention 130mL* £1.02* Enema® Liquid Paraffin Liquid Paraffin Oral Emulsion, BP 10-30mL £0.05-£0.15 Osmotic laxatives Lactitol Lactitol 20g £0.20 Lactulose Lactulose 30mL £0.15 Macrogols Movicol® 2-3 sachets £0.74-£1.11 Magnesium Salts Magnesium Hydroxide Mixture, BP 25-50mL £0.11-£0.22 Liquid Paraffin and Magnesium 5-20mL £0.02-£0.08 Hydroxide Oral Emulsion, BP Magnesium Sulphate 5-10g £0.01-£0.02 Phosphates (Rectal) Carbalax® 1 suppository* £0.18* Fleet® Ready-to-use Enema 118mL* £0.46* Fletchers’ Phosphate Enema® 128mL* £0.44* Sodium Citrate (Rectal) Micolette Micro-enema® 5-10mL* £0.32-£0.64* Micralax Micro-enema® 5mL* £0.33* Relaxit Micro-enema® 5mL* £0.32*

8 EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults SEPTEMBER 2001 sterculia. None of the three RCTs extended (up to May 2001). The palliative medicine. Zeitschrift found any significant benefit for following databases were searched: fur Arztliche Fortbildung und the prevention of constipation. No MEDLINE, EMBASE, PsycINFO, Qualitatssicherung new trials of prevention were Cochrane Library, CINAHL, 2000;94:563–7. found for this bulletin. International Pharmaceutical Abstracts and AMED, and the NHS 6. Sykes N. The relationship Economic Evaluation Database. between opioid use and Other studies were obtained laxative use in terminally ill G. Implications through contacts with laxative cancer patients. Palliat Med manufacturers and relevant 1998;12:375–82. experts. Individual search Bulk (fibre-based) laxatives and strategies are available on request 7. Ehrenpreis ED. Definitions and osmotic laxatives (including from NHS CRD. Additional trials epidemiology of constipation. lactulose and (PEG ‘3350’) are (originally excluded because they In: Wexler SD, Bartolo DC, associated with increases in were in a foreign language) were editors. Constipation: etiology, frequency and improvements also included. Two reviewers evaluation, and management. in stool consistency and independently screened each Oxford: Butterworth- symptoms of constipation. study for inclusion. Data Heinemann, 1995:3–8. extraction and validity assessment Little evidence is available at were carried out by one reviewer present as to the comparative 8. O’Keefe EA, Talley NJ, and checked by a second. Quality effectiveness of bulk and non- Zinsmeister AR, et al. Bowel assessment was based on the Jadad bulk laxatives. disorders impair functional scale.65 RCTs with quality scores status and quality of life in the There is no good evidence that less than 2 are tabulated but not elderly: a population-based laxatives prevent constipation discussed further in the text. In study. J Gerontol A Biol Sci in older patients. crossover trials, interim data were Med Sci 1995;50:M184–9. extracted where available and are A stepped approach to laxative reported as for a parallel RCT. 9. Department of Health. treatment would seem justified, Statistical Bulletin 2000/20 - involving initial intervention Prescriptions dispensed in the with cheaper laxatives, before community, statistics for 1989 proceeding to the more References to 1999: England: Department expensive alternatives. of Health, 2000. 1. McCormick A, Fleming D, There is a pressing need for Charlton J. Morbidity statistics 10. Department of Health. large comparative trials of from general practice: fourth Prescription cost analysis: different strategies for the national study 1991-1992. England 2000. Department of management of constipation in London: HMSO, 1995. Health; 2000. [cited 2001 adults. This should include 10/8]. Available from: comparisons of the 2. Probert CS, Emmett PM, http://www.doh.gov.uk/stats/ effectiveness of different Heaton KW. Some pca2000.htm classes of laxatives. determinants of whole-gut transit time: a population Research is also required into 11. Wolfsen CR, Barker JC, based study. QJM Mon J Assoc Mitteness LS. Constipation in the effectiveness of overall Phys 1995;88:311–5. dietary change (including the daily lives of frail elderly increased fluid intake) in the people. Arch Fam Med 3. Petticrew M, Watt I, Sheldon T. treatment of constipation. 1993;2:853–8. Systematic review of the effectiveness of laxatives in 12. Whitehead WE, Drinkwater D, the elderly. Health Technol Cheskin LJ, et al. Constipation Appendix – Assess 1997;1:1–52. in the elderly living at home. Definition, prevalence and review methods 4. Read NW, Celik AF, Katsinelos relationship to lifestyle and P. Constipation and health status. J Am Geriatr Soc This bulletin is based on an incontinence in the elderly. 1989;37:423–9. updated systematic review Clin Gastroenterol originally commissioned by the 1995;20:61–70. 13. Romero Y, Evans JM, Fleming NHS HTA programme,3 and on a KC, et al. Constipation and review of the effectiveness of 5. Beck D, Kettler D. Treatment faecal incontinence in the laxatives in adults.43 The original of constipation and different elderly population. Mayo Clin searches were updated and laxative requirements in Proc 1996;71:81–92.

2001 SEPTEMBER EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults 9 14. Thompson WG, Longstreth GF, 26. Maestri-Banks A, Burns D. 36. Monane M, Avorn J, Beers MH, Drossman DA, et al. Functional Assessing constipation. et al. Anticholinergic drug use bowel disorders and functional Nursing Times 1996;92:28–30. and bowel function in nursing abdominal pain. Gut home patients. Arch Intern 1999;45:II43–7. 27. Klauser AG, Beck A, Med 1993;153:633–8. Schindlbeck NE, et al. Low 15. Taylor R. Management of fluid intake lowers stool output 37. Canty SL. Constipation as a constipation: high fibre diets in healthy male volunteers. Z side effect of opiods. Oncol work. BMJ 1990;300:1063–4. Gastroenterol 1990;28:606–9. Nurs Forum 1994;21:739–45.

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10 EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults SEPTEMBER 2001 Journal of Care for the Aging 3350 a faible dose (Movicol) lactulose in elderly patients 2000;21:78–83. dans la constipation with chronic constipation. idiopathique: essai en double Pharmacology 1993;47:249–52. 47. Marsicano LJ, Berrizbeitia ML, inso, croise, contre un placebo. Mondelo AM. Uso de la fibra Gastroenterol Clin Biol 64. Lederle FA, Busch DL, Mattox dietetica de glucomannan en 1994;18:B256. KM, et al. Cost-effective la modificacion del habito treatment of constipation in intestinal. GEN 1995;49:7–14. 55. Attar A, Lemann M, Ferguson the elderly: a randomized A, et al. Comparison of a low double-blind comparison of 48. McRorie JW, Daggy BP, Morel dose polyethylene glycol sorbitol and lactulose. Am J JG, et al. Psyllium is superior to electrolyte solution with Med 1990;89:597–601. docusate sodium for treatment lactulose for treatment of of chronic constipation. chronic constipation. Gut 65. Jadad A, Moore R, Carroll D, et Aliment Pharmacol Ther 1999;44:226–30. al. Assessing the quality of 1998;12:491–7. reports of randomised clinical 56. Norgine Ltd. Unpublished trials: is blinding necessary? 49. Dettmar PW, Sykes J. A multi- manuscript. 2001. Control Clin Trials centre, general practice 1996;17:1–12. comparison of ispaghula husk 57. Hammer B, Ravelli GP. with lactulose and other Chronische funktionelle 66. Castillo R, Nardi G, Simhan D. laxatives in the treatment of obstipation. Ther Schweiz La lactulosa en el tratamiento simple constipation. Curr Med 1992;8:328–5. de la constipacion cronica Res Opin 1998;14:227–33. idiopatica. Pren Med Argent 58. Huys J, Van Vaerenbergh PM. 1995;82:173–76. 50. Joint Formulary Committee. Behandeling van chronische British National Formulary. obstipatie: Dubbelblindestudie 67. Bobbio F, Guissani E, Zaccala (Issue 42) London: BMA, met een combinatie van G. Studio comparativo di un RPSGB, 2001. natrium-dioctylsulfosuccinaat preparato di associazione di met dioxyanthraquinone en lattulosio e glucomannano 51. Corazziari E, Badiali D, Habib een placebo. Acta Therapeutica (Dimalosio) con lattulosio nel FI, et al. Small volume 1975;1:67–74. trattamento stipsi abituale. isosmotic polyethylene glycol Rass Int Clin Ter electrolyte balanced solution 59. Micheti P, De Conca V, Giunta 1995;75:313–22. (PMF-100) in treatment of P. Sull’effetto terapeutico di un chronic nonorganic prodotto ad azione lassativa 68. Gordin J, Berger M, Blatrix C, constipation. Dig Dis Sci polivalente. Cl Therap et al. The treatment of 1996;41:1636–42. 1974;75:17–29. constipation in adults with lactulose + paraffin 52. Corazziari E, Badiali D, 60. Sykes NP. Current approaches (Transulose registered ) versus Bazzocchi G, et al. Long term to the treatment of lactulose solution 50%. Med efficacy, safety, and tolerability constipation. Cancer Surv Chir Dig 1997;26:91–5. of low daily doses of isosmotic 1994;21:137–46. polyethylene glycol electrolyte 69. Heitland W, Mauersberger H. balanced solution (PMF-100) 61. Kot TV, Pettit-Young NA. Untersuchung der laxativen in the treatment of functional Lactulose in the management Wirkung von Lactitol gegen chronic constipation. Gut of constipation: a current Lactulose in einer offenen, 2000;46:522–6. review. Ann Pharmacother randomisierten 1992;26:1277–82. Vergleichsstudie. 53. DiPalma JA, DeRidder PH, Schweizerische Rundschau fur Orlando RC, et al. A 62. Passmore AP, Wilson-Davies K, Medizin/Praxis 1988;77:493–5. randomized, placebo- Stoker C, et al. Chronic controlled, multicenter study constipation in long stay 70. Lugli R, Briunetti G, Salvioli G. of the safety and efficacy of a elderly patients: a comparison Stipsi cronica: Favorevoli new polyethylene glycol of lactulose and a senna-fibre modificazioni dell’alvo indotte laxative. Am J Gastroenterol combination. BMJ da tre diversi agenti formanti 2000;95:446–50. 1993;307:769–71. massa in pazienti can stipsi chronica. Basi Raz Ter 1990;20. 54. Lémann M, Chaussade S, 63. Passmore AP, Davies KW, Flourié B, et al. Efficacite du Flanagan PG, et al. A polyethylene glycol (PEG) comparison of Agiolax and

2001 SEPTEMBER EFFECTIVE HEALTH CARE Effectiveness of laxatives in adults 11 provided information for this Peter Clappison, Effective bulletin: Department of Health Galen Ltd Alison Corlett, Health Care York Health Services NHS Madaus AG Trust This bulletin was written and Norgine Ltd Alison Evans, produced by staff at the NHS University of Leeds Centre for Reviews and Procter and Gamble Dissemination, University of Schwarz Pharma Susie Jollie, York and Mark Petticrew at the Bradford South and West PTC The assistance of the following MRC Social and Public Health Dinesh Mehta, British who commented on the text is Sciences Unit, University of National Formulary Glasgow. gratefully acknowledged: Colin Pollock, Mark Baker, Wakefield HA North Yorkshire HA Acknowledgements Stephen Singleton, Effective Health Care would like Simon Balmer, Leeds HA Northumberland HA to thank the following Roger Barton, Colin Waine, pharmaceutical companies who University of Newcastle Sunderland HA Effective Health Care Bulletins The Effective Health Care bulletins are Vol. 2 2. The prevention and treatment 2. Dental restoration: what type based on systematic review and of obesity of filling? synthesis of research on the clinical 1. The prevention and treatment 3. Mental health promotion in 3. Management of of pressure sores high risk groups gynaeological cancers effectiveness, cost-effectiveness and 2. Benign prostatic hyperplasia 4. Compression therapy for 4. Complications of diabetes I acceptability of health service 3. Management of cataract venous leg ulcers 5. Preventing the uptake of 4. Preventing falls and 5. Management of stable angina smoking in young people interventions. This is carried out subsequent injury 6. The management of 6. Drug treatment for by a research team using established in older people colorectal cancer schizophrenia. 5. Preventing unintentional methodological guidelines, with injuries in children and Vol. 4 Vol. 6 advice from expert consultants for young adolescents 1. Cholesterol and CHD: 1. Complications of diabetes II 6. The management of breast screening and treatment 2. Promoting the initiation of each topic. Great care is taken cancer 2. Pre-school hearing, speech, breast feeding to ensure that the work, and 7. Total hip replacement language and vision screening 3. Psychosocial interventions for 8. Hospital volume and health 3. Management of lung cancer schizophrenia the conclusions reached, fairly care outcomes, costs and 4. Cardiac rehabilitation 4. Management of upper patient access 5. Antimicrobial prophylaxis in and accurately summarise the gastro-intestinal cancer Vol. 3 colorectal surgery research findings. The University of 6. Deliberate self-harm 5. Acute and chronic low back York accepts no responsibility for any 1. Preventing and reducing the pain adverse effects of unintended Vol. 5 6. Informing, communicating consequent damage arising from the teenage pregnancies 1. Getting evidence into and sharing decisions with use of Effective Health Care. practice people who have cancer Full text of previous bulletins available on our web site: www.york.ac.uk/inst/crd

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