Pharmacological management of constipation management of constipation A. V. EMMANUEL,* J. TACK, E. M. QUIGLEY & N. J. TALLEY *Physiology Unit, University College Hospital, London,

Pharmacological management of constipation

A. V. EMMANUEL,* J. TACK,� E. M. QUIGLEY� & N. J. TALLEY§

*Physiology Unit, University College Hospital, London, UK

�University Hospital Gasthuisberg, Leuven, Belgium

�Department of Medicine, National University of Ireland, Cork, Ireland

§Mayo Clinic, Jacksonville, FL, USA

Abstract The approach of this review is to give a

pragmatic approach to using laxatives, based on a

combination of what is known about mechanism of

action and the available literature on evidence.

Keywords laxatives, prokinetics, probiotics, sero-

tonin, opioids.

INTRODUCTION

In constipated patients, laxatives are the most com-

monly prescribed pharmacological agents, and they are

classically classified as belonging to four main types:

bulking agents, stool softeners, stimulant laxatives and

osmotically active compounds. Robust clinical trial

evidence is difficult to determine with a condition as

chronic and subjective as constipation.

However, meta-analyses and reviews over the last

few years have highlighted that there are some proven

agents.1–3 The corollary of this is that there are a

number of older agents whose efficacy has never been

demonstrated to the standards of modern clinical trial

design, and we would be ill-advised to ignore the

potential role of these drugs.4,5

Laxatives

Bulking agents According to their FDA approval, these

agents are mostly indicated for patients with episodic

constipation when stools are lacking in water content.

They are primarily organic polysaccharides that act by

encouraging water retention in the stool. A number of

them (methylcellulose, psyllium) also undergo bacte-

rial fermentation which may enhance this effect;

unfortunately this also predisposes to the frequent side

effect of bloating and flatulence. Much rarer side-

effects of bolus obstruction of the oesophagus or colon

have been reported.1,6 Reflecting the poverty of the

literature and the modest effect of these agents, two

systematic reviews1,6 have yielded conflicting conclu-

sions. The Tramonte et al. review1 compared only

bulking agents with placebo, showing an increase in

stool frequency. By contrast, the Jones et al. meta-

analysis6 compared stimulants, osmotic and bulking

agents, showing no efficacy for the latter over placebo.

Psyllium. Psyllium is the husk of the seed of

Plantago ovata. Two7,8 of three placebo-controlled

trials7–9 have shown that stool frequency, consistency

and ease of evacuation are improved by the agent. Two

other studies have compared psyllium with lactu-

lose,10,11 showing that compared to baseline, the

bulking agent results in fewer hard stools10 and greater

stool frequency;11 the magnitude of effect of psyllium

and lactulose was similar.10,11 However, all but one

study8 was of less than 4 weeks duration, a significant

factor given that it is suggested that it takes 14 days for

these drugs to exert an effect.

Bran. A placebo-controlled trial of bran12 failed to

show an improvement over placebo in a cross-over

design. Two other low-quality randomized studies

showed a minimal13 or absent14 effect on stool fre-

quency and moisture.

Methylcellulose. One study15 comparing various

doses of methylcellulose with psyllium showed that

whilst both agents exerted a modest effect in terms

of stool frequency and consistency, there was no

difference between agents. The effect of the drug was

more marked in healthy controls than those with

chronic constipation (CC).

Calcium polycarbophil. One, nursing home-based

cross-over study (compared with psyllium) showed that

whilst these patients preferred the calcium salt to

psyllium, there was no effect on stool frequency or ease

of defecation.16

Address for correspondence

Dr Anton V Emmanuel BSc, MD, FRCP, Senior Lecturer inGastroenterology, Physiology Unit, University CollegeHospital, 235 Euston Road, London NW1 2BU, UK.Tel: 0207 380 9311; fax: 0207 380 9239;e-mail: [email protected]: 4 August 2009Accepted for publication: 10 August 2009

Neurogastroenterol Motil (2009) 21 (Suppl. 2), 41–54 doi: 10.1111/j.1365-2982.2009.01403.x

� 2009 The AuthorsJournal compilation � 2009 Blackwell Publishing Ltd 41

Stool softeners These are indicated for occasional

constipation, and often as an adjuvant to a bulking or

stimulant agent. They are anionic surfactants, with an

emulsifying and wetting action. Their effect depends

on the strength of their action on the surface of the

stool with a generally modest effect. Stool softeners are

well-tolerated.

Docusate. Two placebo-controlled,17,18 and one psyl-

lium-controlled19 randomized studies have addressed

the effect of docusate in patients with CC. The 1968

study of sodium docusate17 showed significant

improvements in stool frequency and overall subjec-

tive assessment, whilst the later study of calcium

docusate18 showed no advantages over placebo. The

comparison of sodium docusate with psyllium19

showed that the bulking agent had a greater effect on

stool frequency, although this study was limited by

only looking at a 14-day treatment window. One

further single-blind study20 underlined the modest

effect of stool softeners: neither of two doses of sodium

docusate improved stool frequency, whilst calcium

docusate was shown to have a slight increase in stool

frequency compared to the placebo run-in period.

Stimulant laxatives Although widely used, as over-

the-counter and prescribed agents, there is an

extremely limited evidence base supporting the use of

stimulants in CC. They are either naturally occurring

agents (such as senna and cascara) or phenolphthalein

analogues (such as bisacodyl). They are hydrolysed in

the gut (by either enterocyte enzymes or colonic flora)

and act by stimulating peristalsis, sensory nerve end-

ings (hence the frequent side effect of colic) and pos-

sibly interfering with electrolyte flux to inhibit water

absorption. Stimulant agents are taken up by entero-

cytes and hence cause melanosis coli. Whilst classical

thinking was that they caused a �cathartic colon�,21

there is no evidence that currently available stimulants

do this.22 There are no placebo-controlled studies of

efficacy.

Nevertheless, stimulants tend to be used for

occasional constipation as a night-time dose prior to

a morning bowel action, and have a particular (if

unproven) place in neurogenic bowel dysfunction.23

Senna. Two non-placebo controlled studies are

found in the literature.24,25 The earlier one compared

senna with sodium picosulfate (an osmotic agent),

and found that whilst there was no difference in stool

frequency between the two agents, the osmotic agent

was more likely to cause loose stools.24 The second

trial compared senna liquid with bran, showing equal

effect of both in terms of stool frequency and

consistency.25

Bisacodyl. A cross-over trial of bisacodyl and bisox-

atin (a stool softener) represents the only available

randomized clinical trial and that showed no difference

between the agents.26

Osmotic laxatives This class of laxatives comprises

both inorganic salts (magnesium compounds) and

organic alcohols or sugars [such as lactulose, polyeth-

ylene glycol (PEG)]. They act by generating an osmotic

gradient which encourages water retention in the

lumen. As such they have the potential to be dose

titrated according to the stool output, and are usually

used for both chronic and occasional constipation. The

nature of their mechanism of action means that a

number of electrolyte abnormalities may occur, but the

commonest adverse effect relates to difficulty getting

titration correct (namely diarrhoea). Abdominal bloat-

ing, nausea and flatulence are common, but these drugs

are often used in slow transit, and have a particular

place in megacolon.27

Magnesium salts. A cross-over study of magnesium

hydroxide vs laxamucil (a bulking agent) showed a

benefit with the osmotic agent, such that as required

use of extra laxative doses were reduced and sponta-

neous stool frequency was increased with magnesium

hydroxide.28 No trials are available for magnesium

sulphate (Epsom salts).

Lactulose. Two placebo-controlled trials have shown

that although both placebo and lactulose improved

stool frequency and consistency compared to baseline,

this was significantly greater with lactulose.29,30 This

efficacy was seen across a range of doses from 15 to

60 mL per day.

Polyethylene glycol. Recently, PEG has been subject

to a larger number of clinical trials than other agents:

there are five placebo-controlled studies31–35 and two

lactulose-controlled ones.36,37 Of the five placebo-

controlled studies, three are parallel design and two

crossover. Stool frequency – and when assessed, stool

consistency – was improved by PEG compared to

placebo in all these studies.31–35 In the lactulose-

controlled studies, one showed improved stool

frequency and ease of defecation with PEG over

lactulose37 whilst the other showed equal effect with

both agents.36 Diarrhoea was the commonest adverse

effect, occurring in as many as 40% in one of the trials.

Electrolyte abnormalities, again, may occur – but tend

to be rare except in the elderly.

CRITICAL APPRAISAL OF RCTS

Despite the fact that constipation can be a chronic

disabling disorder accompanied, as we now realize, in

A. V. Emmanuel et al. Neurogastroenterology and Motility

� 2009 The AuthorsJournal compilation � 2009 Blackwell Publishing Ltd42

the most severely affected individuals, by very marked

impairments in quality of life (QOL) and social func-

tioning,38 relatively few well-conducted clinical trials

have been performed. Indeed, until very recently, when

the pharmaceutical industry became aware of both the

high prevalence of these conditions and of the glaring

unmet therapeutic needs that existed throughout the

functional gastrointestinal disorders, including CC,

few trials of any quality were performed in CC. This

drought of new compounds is vividly illustrated by the

fact that over the past 17 years only four pharmaceu-

ticals have been approved in the US by the FDA for

constipation, and one, tegaserod, has already been

withdrawn because of safety concerns. The reasons

for this paucity of research are explained by the range

of problems that confront the clinical trialist who sets

out to study this disorder and the clinician or clinical

scientist who attempts to interpret the results of their

research and translate them into clinical practice. Each

of these issues will now be dealt with in the following

sections.

Constipation is a symptom which means different

things to different individuals; to some it refers to stool

frequency, for others, to stool form and consistency,

difficulty with defecation or a sense of incomplete

evacuation. How are these symptoms norm referenced

by the patient? To their own prior experience or to

what they expect the norm to be? Furthermore, as is

the case with any purely symptom-based disorder,

there are the vagaries of recall bias which may be

refuted by prospective stool diaries.39 Up until fairly

recently and reflecting the physician�s perspective,

constipation was viewed, for the purposes of patient

selection in clinical trials, as simply an issue of stool

frequency; we now realize that frequency of defecation

is not the most bothersome symptom from the consti-

pated patient�s perspective.40,41 Patients are usually

more concerned about straining, hard stools and diffi-

cult defecation. Appreciative of these patient concerns

and seeking to design trials around end points which

have real clinical meaning, investigators have, more

recently turned to definitions that are more encom-

passing of these variable expressions of constipation.

Modifications of the Rome II or III definitions of

functional constipation have been especially popular.42

Although moving in the right direction, this approach

still does not satisfy the rigors of the standards for a

patient-reported outcome measure recently promul-

gated by the FDA for use in functional gastrointestinal

disorders.43

Constipation is not a single homogenous entity but

includes those with idiopathic slow transit constipa-

tion, others with an evacuation disorder (ED) which

itself comprises a number of sub-types, a further group

where these two pathophysiological entities co-exist or

overlap, and a final group in whom constipation is a

component of the irritable bowel syndrome (IBS). As it is

assumed that the therapeutic approach to these groups

will vary, it would appear desirable to study these

separately or, at the very least, to stratify for these

groups in designing a trial. This is not an easy task, not

only because of the frequency of overlap between the

groups, but also because of the difficulty of predicting

pathophysiology on the basis of symptoms44 or tests.45

It should come as no surprise, therefore, that inclusion

criteria for clinical trials have adopted �looser� and more

inclusive symptom-based criteria such as that described

above; this approach not only simplifies life for the

investigator but avoids the spectre (from the perspective

of the pharmaceutical industry) of a label which limits

the use of particular medication to those patients who

have a particular pathophysiology underlying their

constipation. The down side of this approach is that

the patient population in most trials is inevitably

heterogeneous, a factor which, no doubt, contributes

to lower than expected success rates for an agent.

The overlap with IBS raises a further challenge; in

clinical practice, differentiating IBS-C from CC is often

one of semantics, representing parts of the same

spectrum. It is interesting to note that a number of

recently approved drugs for CC have also been

approved for IBS-C. While it may seem churlish to

criticize studies from some decades ago, it needs to be

stressed that most of the older literature (which forms

the �scientific� basis for our continued use of laxatives,

as described above) is, quite simply, bad, in terms of

trial design. Several basic principles of trial design, now

regarded as de rigeur, were absent: randomization,

blinding, placebo control, adequate description of entry

criteria and outcomes, to name but a few. Even recent

studies are not above criticism. For example, some

have employed a cross-over design, a feature regarded

as inappropriate for use in functional disorders, while

other studies vary considerably in overall duration

(commonly somewhere from 2 to 12 weeks) and in the

length and conduct of run-in and wash-out periods.

A major lacuna in the CC literature is the dearth of

long-term studies; CC is a chronic condition yet there

are few controlled studies beyond 12 weeks!

There is, then the issue of comparator. In general, it

is clinically relevant to compare the efficacy of novel

agents to a well-chosen active comparator drug. How-

ever, most recent high quality studies of putative

enterokinetics in CC have been placebo controlled and

have not compared the new agent with �standard

therapy� (i.e. a laxative), although it needs to be

Volume 21, Supplement 2, December 2009 Drug treatment of constipation


conceded that, in some instances, only those who had

failed laxative therapy were included.

Given the considerable gulf in cost that exists

between these remedies and the more recently devel-

oped prescription drugs, it seems inevitable that regu-

latory agencies, mindful of potential costs to

governments and the individual patient, will soon

demand that new chemical entities be compared to a

laxative. However, comparator controlled trials in CC

are specifically problematic for a number of reasons:

currently available laxatives, at least in Europe, are

generally limited in their indication and established

duration of use. In addition, many patients with CC do

not have an adequate long-term response to existing

laxatives. Enrolling such patients in a trial comparing a

novel agent against such a laxative may thus be

considered inappropriate. PEG could be considered as

an active comparator in constipation trials, as its

efficacy in the short-term relief of constipation has

been well documented, and some long-term studies are

now also available. Indeed, two studies comparing PEG

with lactulose37 and tegaserod46 are among the few

attempts to make clinically relevant comparisons.

However, using PEG as a comparator is difficult with

regards to blinding. Use of PEG requires the consump-

tion of large volumes of fluid. Matching this fluid

consumption with the investigational drug could also

potentially impact on its pharmacokinetic and phar-

macodynamic properties as compared with its normal

clinical use without a large fluid load. Furthermore, the

taste and appearance of PEG are distinctive, such that

it may not be feasible to make appropriate as placebo.

Two other issues in trial design deserve consideration:

the use of rescue medication and the timing of invasive

investigations prior to trial commencement. There is no

standardization of approach to rescue medications in

CC. Again, given its demonstrated efficacy in good

quality trials, and the fact that it is, in general, well-

tolerated and widely available, a PEG-based laxative

appears a reasonable option. Furthermore, and regard-

less of the choice of rescue laxative, its use should be an

important secondary outcome variable in CC trials. It is

well known to clinicians that the performance of a

colonoscopy or any procedure that requires bowel

cleansing often leads to prolonged periods of remission

among CC patients, it is critical that this �honeymoon�be accounted for at the time of randomization.

OPTIMIZATION OF STUDY DESIGN ANDVALID OUTCOME MEASURES

It follows from the discussions above of the very

definition of constipation and patient selection, that

the definition and validation of clinically meaningful

outcome measures and thus study end points repre-

sents a major challenge. End points such as bowel

frequency, laxative use, patient-reported changes in

stool consistency and �overall� symptom improvement

were variably recorded. Considerable efforts have been

exerted of late to produce outcome measures that are

more meaningful, and which encompass the totality of

the patient experience with constipation.

Some progress has been made: from bowel move-

ments per week we have advanced through spontaneous

bowel movements47 to spontaneous complete bowel

movements (SCBM).48,49 To account for the range of CC

symptoms, composite outcome measures such as the

Patient Assessment of Constipation Assessment Ques-

tionnaire (PAC-SYM) have been developed.50 The PAC-

SYM contains 12 items assigned to three subscales

(stool symptoms, rectal symptoms and abdominal

symptoms) and has been shown to be internally

consistent, valid, and responsive to change.51

Given the appropriate preoccupation in the func-

tional bowel world with impact on QOL, a variety of

measures of QOL have been included as secondary

outcomes in more recent studies the ability of a

particular intervention to improve QOL, especially

when measured by a CC-specific instrument such as

the Patient Assessment of Constipation Quality of Life

Questionnaire (PAC-QOL),52 being regarded as adding

additional credibility to the reported outcome. The

PAC-QOL was designed to provide a comprehensive

assessment of the burden of constipation on patients�everyday functioning and well-being, and has been

shown in a multinational study to be internally

consistent, reproducible, valid, and responsive to

improvements over time.52

It is obvious, but essential, to recognize that a

composite score or a measure of QOL should be given

in the context of results being clinically meaningful.

For example, the frequently used achievement of three

or more SCBM/week as a clinically valid endpoint, still

only represents the lower end of the normal range. In

designing new standards of outcome measures and

study endpoints, there is a great and urgent need to

clearly define the magnitude of an effect that is truly

meaningful to a patient.

Despite its impact on social functioning and per-

sonal life, as expressed on any number of QOL scales,

CC is a benign disorder and, as such, is one in which

regulatory agencies retain a very low threshold for

acceptance of risk. This poses another major hurdle for

drug development, especially given the recent case of

tegaserod,53 where the more rare events only came to

light in post-marketing surveillance. More rigorous



pre-clinical testing, especially in relation to cardiovas-

cular toxicity is now required, and clinical trials in

more diverse patient groups and, not just the ultra-fit,

may soon be mandated.

EVOLVING AND FUTURE MEDICALTREATMENTS

Pharmabiotics

The normal gut flora (microbiota): an essential factor

in digestive health The human gastrointestinal

microflora is a complex ecosystem of approximately

300–500 bacterial species comprising nearly two

million genes (the �microbiome�). When disturbed, the

flora has a remarkable capacity to restore itself and to

return to exactly the same state as it was before.54

Because of the normal peristaltic motility of the

intestine and the antimicrobial effects of gastric acid,

the stomach and proximal small intestine contain

relatively small numbers of bacteria in healthy

subjects; on crossing into the colon, the bacterial

concentration and variety of the enteric flora changes

dramatically. Here, concentrations as high as

1012 CFU mL)1 may be found; comprised mainly of

anaerobes, such as bacteroides, porphyromonas,

bifidobacterium, lactobacillus and clostridium, with

anaerobic bacteria outnumbering aerobic bacteria by a

factor of 100–1000 : 1.55 However, conventional

culture-based approaches to the enumeration and

identification of the bacterial species greatly under-

estimate both the number and diversity of the flora,

and the full definition of the normal human micro-

biota and its variations in health must await detailed

and painstaking molecular studies. The normal

enteric bacterial flora influences a variety of intestinal

functions directly relevant to motor function and the

pathogenesis of constipation.56 Firstly, unabsorbed

dietary sugars are salvaged by bacterial disaccharid-

ases, converted into short-chain fatty acids (SCFAs)

and used as an energy source by the colonic mucosa.

Secondly, the colonic flora is essential to the

deconjugation of primary bile acids which could

significantly influence stool form and consistency.

Finally, certain members of the commensal flora have

been shown to stimulate gut motility, and the

production of neuropeptides and gases, capable of

modulating gut nerve and muscle function, has been

identified. However, data are scant as to whether

constipation is associated with an alteration in the

colonic flora, although there is a limited literature to

suggest some disturbances in the flora in both

children57 and adults.58

Mining the microbiota The concept of a pharmabiotic

was introduced to attempt to embrace the various ways

in which the microbiota could be manipulated to

confer a clinical benefit to the host.59 A therapeutic

benefit could be conferred through supplementation

with commensal organisms (the probiotic approach),

through selectively stimulating the growth of certain

commensal species (the prebiotic approach) or by

extracting and purifying components or products of

commensal flora which are biologically active.

Probiotics are defined as live organisms that, when

ingested in adequate amounts, exert a health benefit to

the host.60 The most commonly used probiotics are

lactic acid bacteria and non-pathogenic yeasts. The

many products that are found in health food stores and

supermarket shelves which include the term probiotic

in their label often fail to fulfil the definition provided

above:

1 they may not contain live organisms or have not been

adequately tested to ensure that the organisms will

survive in the conditions (e.g. room temperature) or

for the length of time (days, weeks, or months) that

is claimed;

2 they may not confer health benefit because, either

they have never been tested in man, or because what

tests have been preformed have been inadequate or

even negative;

3 they may contain organisms (including pathogens)

that they are not supposed to contain.61

Although probiotics have been proposed for use in

inflammatory, infectious, neoplastic and allergic dis-

orders, the ideal probiotic strain for many of these

indications has yet to be defined, although progress

continues in this area. While probiotic �cocktails� have

also been advocated to maximize effect, it needs to be

noted that some probiotic combinations have been

shown to prove antagonistic, rather than synergistic, in

certain situations.

Prebiotics are defined as non-digestible, but ferment-

able, foods that beneficially affect the host by selec-

tively stimulating the growth and activity of one species

or a limited number of species of bacteria in the colon.62

Compared with probiotics, which introduce exogenous

bacteria into the human colon, prebiotics stimulate the

preferential growth of a limited number of health-

promoting commensal flora already residing in the

colon, especially lactobacilli and bifidobacteria. Their

relative efficacies will depend, in part, on the initial

concentrations of the probiotic component of the flora

and on luminal pH. The only prebiotics for which

sufficient data have been generated to allow an evalu-

ation of their possible classification as functional food

ingredients are the inulin-type fructans [which are



linked by b (2-1)bonds that limit their digestion by

upper intestinal enzymes] and fructooligosaccharides.

Both are present in significant amounts in many

edible fruits and vegetables, including wheat, onion,

chicory, garlic, leeks, artichokes and bananas. Because

of their chemical structure, prebiotics are not absorbed

in the small intestine but are fermented, in the colon,

by endogenous bacteria to energy and metabolic sub-

strates, with lactic and short-chain carboxylic acids as

end products of the fermentation. Most of the evidence

regarding the potential health benefits of prebiotics is

derived from experimental animal studies and human

trials in small numbers of subjects; there are insuffi-

cient, prospective, adequately powered studies in gas-

trointestinal disease to permit definitive conclusions

to be drawn.

Synbiotics, defined as a combination of a probiotic

and a prebiotic, aim to increase the survival and

activity of proven probiotics in vivo and stimulating

indigenous bifidobacteria and lactobacilli. Again, data

for efficacy in human disease is scanty.

The potential importance of bacterial metabolic

products, such as SCFAs and deconjugated bile salt

salts to the pathogenesis or alleviation of diarrhoea has

already been mentioned. One can also envision how

changes in bacterial fermentation rates or in the

relative production of gases, such as hydrogen, meth-

ane or sulphide could affect symptomatology.

The identification of the elaboration of a number of

neuropeptides and the important inhibitory neuro-

transmitter nitric oxide by certain commensal bacte-

ria63 suggests new mechanisms whereby the flora

could influence colonic motor function.

Prebiotics and probiotics in constipation While pro-

biotics and, to a lesser extent, prebiotics have been

extensively studied in IBS,64,65 data on the impact of

probiotics on constipation is lacking. A number of

studies have demonstrated the ability of Bifidobacte-

rium animalis (also referred to as Bifidobacterium

lactis DN) to shorten colonic transit in healthy

women,66 the elderly67 and in subjects with IBS.68

These effects were observed only if live organisms were

used and were most obvious if colon transit time was

slower at baseline. Of note, when studied, these effects

on (particularly right colon) transit were noted to be

independent of changes in faecal mass or bile acid

content, suggesting a direct effect on colonic motil-

ity.68 A symbiotic combination of Lactobacillus

rhamnosus, B. lactis and inulin prebiotic has been

shown to stimulate small bowel motility.69

While few, if any studies, have examined the effect

of one of the classical prebiotics (e.g. inulin, fructose

oligosaccharides) in constipation, it must be remem-

bered that the main contributor to the increase in stool

bulk that accompanies the ingestion of bran or fibre

supplements comes from bacteria; i.e. these agents are

acting like prebiotics to promote bacterial prolifera-

tion. Furthermore, lactulose, a very commonly used

laxative, has been shown to exert a truly prebiotic

effect by promoting the growth of a number of strains

of bifidobacteria in human subjects.70

Very few double-blind placebo controlled trials of

probiotics in acute or CC per se (i.e. other that in

association with IBS) is available. Among the few

positive randomized controlled trials (RCT) are those

of Koebnick and colleagues which documented a

positive benefit for a probiotic beverage containing

Lactobacillus casei Shirota and of Yang and colleagues

which reported benefits from B. lactis DN-173010, in

patients with CC.71,72 In their study using lactobacillus

GG as an adjunct to lactulose, Banaszkiewicz and

Szajewska found no additional benefit from the

probiotic.73 Other studies which were uncontrolled, or

in which the probiotic was combined with some other

form of therapy, reported variable benefits for

bifidobacteria, lactobacilli and proprionibacteria and

infusions of faecal suspensions.74–80

Some support for the use of probiotics in constipation

comes from IBS studies and, especially those that

provided results for constipated IBS subjects.64,65,81–83

In accordance with the aforementioned effects on

colonic transit, Bifidobacterium animalis has been

shown to significantly increase stool frequency among

IBS subjects with baseline constipation (as defined by

stool frequency of less than 3 per week).84 Another strain

Bifidobacterium infantis 35624 was shown to normalize

stool consistency (as assessed by the Bristol stool scale)

and reduce straining among constipated IBS subjects,

without an apparent effect on stool frequency.85,86

5 HT4 agonists

The 5-HT4 receptor is considered to have a particularly

important role, both physiologically and pathophysio-

logically, in the regulation of GI function.87–89 Activa-

tion of neuronal 5-HT4 receptors results in prokinetic

activity throughout the GI tract,90 and triggers the

release of neurotransmitters from the enteric nerves

resulting in increased contractility and stimulation of

the peristaltic reflex.88,91–93 Pro-secretory effects occur

with release of chloride and bicarbonate being observed

from duodenal, colonic or jejunal epithelial cells.94–96

Notably, the precise role of the 5-HT4 receptor in

visceral sensitivity remains unclear. A number of 5-HT4

receptor agonists are currently under investigation with



the goal to avoid the cardiac side effects seen with

tegaserod and cisapride.

Tegaserod Tegaserod, an aminoguanidine indole com-

pound, is a partial 5-HT4 agonist. In animal models,

tegaserod acts as a motility-enhancing agent, exerting

activity throughout the gastrointestinal tract.97,98

Tegaserod has also been shown to significantly accel-

erate colonic transit in healthy volunteers and in

patients with constipation-predominant IBS-C.99,100 In

addition, tegaserod may attenuate the visceromotor

response evoked by colorectal distension in control

animals,101 and this may occur in healthy human

subjects.102 Several large randomized, double-blind,

placebo-controlled trials of oral tegaserod performed in

patients with IBS-C103–106 have shown superiority for

tegaserod over placebo, as evaluated by the subjects�global assessment of overall relief, and secondary end

points (i.e., abdominal pain, bowel frequency and con-

sistency). In a recent Cochrane review on tegaserod,107

the relative risk (RR) of being a responder in terms of

global relief of GI symptoms during the last 4 weeks of

treatment was significantly higher with tegaserod

compared with placebo in patients with C-IBS; the RR of

being a responder in terms of SCBM/week with

tegaserod 12 mg was 1.54 (95% CI 1.35–1.75), compared

with placebo where it was 0.6 (95% CI 0.42–0.78). Two

large randomized clinical trials108,109 have been

performed to evaluate the efficacy of tegaserod in the

management of CC. They showed that constipated

patients younger than 65 years randomized to tegaserod

had 16–19% greater SCBMs compared to placebo.

Following these two large studies, several other

relatively small studies46,110–112 have been performed.

On Chan et al.110 evaluated the effect of tegaserod in

216 patients with CC from a Chinese population, and

showed that the tegaserod group induced a significantly

higher response rate in terms of the mean increase of

SCBM >1/week (48%) compared with placebo group

(29%). In another Chinese study, Lin et al.111 reported

that tegaserod (48%) was more effective vs placebo

(35%) as measured by the mean increase of more than

one SCBM/week. Fred et al. evaluated the effect of

tegaserod in 322 male patients with CC, and also

reported that increases of at least one SCBM/week

occurred more often on tegaserod (41%) compared with

placebo (29%). Finally, Di Palma et al.46 performed a

randomized, open-labelled, parallel, multicenter study

comparing tegaserod and PEG laxative in 237 patients

with CC. In this study, treatment success was defined

differently; the primary end point was no longer fulfill-

ing modified ROME criteria for constipation for 50% or

more of their treatment weeks. This study demon-

strated that PEG was more efficacious than tegaserod in

treating constipation over a 4-week period; the primary

end point was reached significantly more often with

PEG (50%) vs tegaserod (31%). However this study has

some limitations, including its open label design and

lack of a baseline observation period. Tegaserod was

more commonly associated with an increase in diar-

rhoea compared with placebo (6.6% vs 3.0%); more

concerning was a possible association with the devel-

opment of ischemic colitis.93,107,113 However, the most

clinically important possible adverse events with

tegaserod have been reported to be coronary and cere-

brovascular events (with a 0.01% incidence). For these

reasons, tegaserod was suspended in the US.53

Prucalopride Prucalopride, a dihydrobenzofurancarb-

oxamide, is a highly selective, high-affinity 5-HT4

receptor agonist with enterokinetic properties.114 It

differs from other 5-HT3 receptor agonists, such as

cisapride, tegaserod, mosapride, and renzapride, which

interact in part with one or more other receptors

[5-HT3, 5-HT1B, and the human ether-a-go-go-related

protein (hERG) channel]. In vivo studies have shown

that prucalopride increases the velocity of coordinated

colonic propulsion115 and triggers the peristaltic reflex

in animal models.98 Prucalopride has also been shown

to enhance colonic motility and transit.116–119

With regard to clinical trials of prucalopride in CC,

Sloots et al.119 studied 28 patients, and showed that

prucalopride enhanced colonic transit time, and in-

creased the number of SCBM and SBM per week, and

improving individual constipation symptoms. Core-

mans et al.120 evaluated the efficacy of prucalopride in

53 patients with CC, and showed that prucalopride was

significantly more effective than placebo in softening

stools, and decreasing straining and time to first bowel

movement. After these early studies, three multicenter

phase III studies121–123 were performed simultaneously

between 1998 and 1999.

Camilleri et al.121 in the United States reported that

prucalopride increased the number of the SCBM per

week (47% in prucalopride vs 29% in placebo groups),

and reduced the severity of symptoms in patients with

CC. In another international multicenter, placebo-

controlled, phase III trial, Tack et al.122 showed that

prucalopride also significantly and consistently

improved bowel function including SCBMs/wk, strain-

ing, stool consistency, laxative use, time to first bowel

movement, and constipation severity, and satisfaction

in chronically constipated patients. Finally Quigley

et al.123 also reported the similar efficacy of prucalo-

pride in 641 patients with CC compared to placebo.

They showed that significantly more patients taking



prucalopride 2 or 4 mg (24%) than placebo (12%)

achieved the primary efficacy end point (3 or more

SCBMs per week), or an increase of more than one

SCBMs per week (43% and 47% vs 28% respectively).

The most frequently reported adverse events of pru-

calopride were headache, nausea, abdominal pain and

diarrhoea, which were mainly reported on the first day

of treatment. There were no clinically relevant adverse

events reported on prucalopride. However, there is still

a theoretical concern about the potential cardiac risks

associated with this drug.

Renzapride and other 5-HT4 agonists Renzapride is a

mixed 5-HT4 agonist and 5-HT3 antagonist that has a

stimulatory effect on gastrointestinal motility and

transit.124 Renzapride has shown promising effects on

gastrointestinal transit and relief of symptoms of

constipation in patients with constipation-predomi-

nant IBS.125–128 Camilleri et al.126 reported that ren-

zapride induces a clinically significant dose-related

acceleration of colonic transit which was associated

with improvement of bowel function in female IBS-C.

Tack et al.125 also reported similar effects of renza-

pride on enhancing gut transit and improvement of

symptoms (reducing abdominal pain, increasing the

number of pain-free days, and improving stool con-

sistency) in patients with IBS-C. In a multicenter,

randomized, placebo-controlled, double-blind study in

a primary healthcare setting, George et al.127 reported

among 510 patients with IBS-C that renzapride 4 mg

improved the frequency of bowel movements, and

provided a positive effect on abdominal pain and/or

discomfort in the post hoc analysis in women,

although the primary endpoint did not show statisti-

cal significance and overall the results were disap-

pointing.

Other 5HT4 agonists, such as mosapride,129

TD-5108,130,131 and ATI-7505132 are currently under

development in CC.88 In addition, MKC-733 is a 5-HT3

receptor partial agonist which was shown to stimulate

motility in the upper gastrointestinal tract.133 In a

single-blind dose-escalation study (placebo, 0.2 and

0.5 mg b.i.d.) in 14 patients with CC, MKC-733

improved stool frequency, sensation of incomplete

evacuation and gastrointestinal symptoms. This was

associated with enhanced transit as evaluated by

radio-opaque marker technique.134

Opioid antagonists

Opioid antagonists such as methylnaltrexone and

alvimopan have been investigated for opiate-induced

constipation and postsurgical ileus.135,136 Alvimopan, a

peripherally acting mu-opioid antagonist that does not

cross the blood–brain barrier, has been investigated in

patients with opiate-induced constipation.136 In a

healthy volunteer study, alvimopan reversed the pro-

longation of orocaecal transit time produced by oral

loperamide,137 morphine138 and codeine.139 In a recent

randomized, double-blind, placebo-controlled study in

522 patients with opioid induced constipation, Webster

et al.136 showed that alvimopan increased the mean

spontaneous bowel movement frequency compared to

placebo, and improved symptoms such as straining,

stool consistency, incomplete evacuation, abdominal

bloating/discomfort and decreased appetite.

Few studies have tested the efficacy of alvimopan in

patients with idiopathic CC. Gonenne et al.139 showed

that alvimopan significantly accelerated colonic transit

compared to placebo in healthy volunteers. In addition

Garnett et al.140 evaluated the effect of alvimopan in 23

patients with CC. They showed that alvimopan

decreased colonic transit time, and improved bowel

movement frequency, stool hardness, straining, dis-

comfort and satisfaction with bowel movements in

patients with CC vs placebo. In another study of 217

patients with chronic idiopathic constipation, however,

Kelleher et al.141 failed to show any differences in mean

weekly SCBM frequency between alvimopan and pla-

cebo. Furthermore, alvimopan did not benefit other

bowel symptoms including the degree of straining or

stool consistency, although alvimopan was generally

well-tolerated, with a safety profile similar to placebo.

Overall, further studies are needed to establish the place

of alvimopan in chronic non-opioid induced constipa-

tion. Methylnaltrexone is the first quaternary ammo-

nium opioid receptor antagonist that does not cross the

blood–brain barrier in human,142,143 and has been intro-

duced for the treatment of opiate-induced constipa-

tion.144,145 In healthy volunteers, methylnaltrexone

reversed the morphine-induced delay in both gastric

emptying and orocaecal transit time without affecting

analgesia.146–148 Yuan et al.145 evaluated the effect of

methylnaltrexone in 22 patients with constipation due

to chronic methadone use. In this small pilot study, they

showed that all 11 subjects after intravenous methyln-

altrexone administration defecated, compared to no one

after placebo administration. Recently, a relatively large

phase III study was performed evaluating the treatment

effect of methylnaltrexone in 133 patients with opiate-

induced constipation.144 Given as a subcutaneous

injection, they observed that 48% of patients in the

methylnaltrexone group had defecation within 4 h after

the first dose, as compared with 15% in the placebo

group. Further, 52% defecated without the use of a

rescue laxative within 4 h after two or more of the first



four doses, compared with 8% in the placebo group.

There are no studies that have tested the efficacy of

methylnaltrexone in patients with idiopathic CC.

Finally, in the latest Cochrane review on mu-opioid

antagonists for opioid-induced bowel dysfunction,149

alvimopan and methylnaltrexone both appear to show

promise in treating in OBD. However, they concluded

further data will be required to fully assess their place

in therapy.

Lubiprostone

Lubiprostone, a bicyclic fatty acid derived from pros-

taglandin E1, is a chloride channel activator which

stimulates intestinal fluid secretion, was approved by

the U.S. FDA in 2006 for the treatment of chronic

idiopathic constipation in adults. Lubiprostone acts on

the enterocytes from the luminal side and is not

systemically absorbed, which is an attractive mode of

action from a safety perspective. This is associated

with faster colonic transit and softer stool consis-

tency.150,151 The drug is not currently approved in

Europe. In RCTs, lubiprostone was superior to placebo

in improving the frequency of spontaneous bowel

movements, stool consistency and straining. The most

frequently reported side-effects with lubiprostone are

diarrhoea and especially nausea, usually transient,

which was reported in up to 30% of patients.47,48

Linaclotide

Linaclotide is a 14-amino acid oligopeptide that

activates the luminal receptor guanylate cyclase-C

on enterocytes, and leads to increased chloride and

bicarbonate secretion into the intestinal lumen

through a rise in cyclic guanosine monophosphate.

Linaclotide was shown to accelerate ascending colon

transit and to improve stool pattern and consistency

in women with IBS-C.152 In CC, linaclotide was

shown to improve the frequency of SCBM, straining

and stool consistency.49,153

Neurotrophins

Neurotrophin-3 stimulates the development, growth

and function of the nervous system and enhances

colonic transit.154 In a phase II randomized, double-

blind, placebo-controlled trial, subcutaneous injection

of neurotrophin-3, three times per week, significantly

increased the frequency of SCBMs and improved other

measures of constipation.155 To date, no further devel-

opment of neurotrophins for the treatment of CC

seems to have occurred.

ISSUES IN FUTURE DRUG DEVELOPMENT

As discussed above, a long-standing area of controversy

is the need for comparator drugs in CC trials. Another

issue is that many recent studies with novel agents for

the treatment of CC instructed physicians to exclude

patients with a known ED. On the one hand, this is a

group of patients that may respond well to biofeedback

therapy,40 and on the other hand it seems logical that

these patients may be less responsive to agents that act

on colonic motility or secretion. Both concerns,

whether this is a population that is less responsive to

agents targeting the colon, and whether there are more

suitable ways to recognize these patients using for

instance a simple questionnaire, will need to be

addressed for future studies.

A final unresolved issue is the overlap between CC

and IBS-C. It is clear that a large grey area of overlap

between both conditions exists, and that agents that

are effective in one condition are often also efficacious

in the other indication. How to handle IBS-C overlap

when recruiting patients for clinical trials in CC is

unclear. It might be useful to investigate whether CC

patients who also fulfil Rome IBS criteria have a

different symptomatic response than those without a

concomitant IBS diagnosis.

AREAS FOR FUTURE RESEARCH

1 Improve clinical trial design.

2 Improve symptom measures as efficacy outcomes.

3 Include quality of life measures as efficacy outcomes.

4 Include comparator laxative (such as PEG) rather

than placebo in new drug studies.

5 Undertake more studies of probiotics – looking at

specific probiotic classes and probiotic mixtures.

6 Undertake longer trials of medication for this chronic

condition.

ACKNOWLEDGEMENTS

Dr Talley wishes to acknowledge the input provided by Rok SeonChoung MD for his contribution to this chapter.

CONFLICTS OF INTEREST

EQ has worked as a consultant for, Procter and Gamble, Salix,Sucampao/Takeda, Movetis, Boehringer Ingleheim, ScheringPlough, McNeil and Ironwood. He has been a speaker/teacherfor and received Honoraria from, Norgine, Danone andYakult. He has also received research support from Procterand Gamble.

AE has received consulting/speaker fees from the followingcompanies in the last 2 years: Abbott Laboratories, Astra-Zeneca,Coloplast, Ferring, Pfizer and Reckitt-Benckiser.



NT has been a consultant for the following companies:AccreditEd, Addex Pharma, Annanberg Center, AryX, AstellasPharma, AstraZeneca, Callisto PharmY, Centocor, Conexus,Dynogen, Eisai/MGI Pharma, Elsevier, F-Network, Ferring Phar-maceuticals, Gilead, Interactive Forum, In2Med, Ironwood,Johnson & Johnson, Lexicon, McNeil, Medscape, MeritagePharma, Metabolic Pharma, Microbia, NicOx, Novartis, OakstonePublishing, Pharma Frontiers, Proctor & Gamble, Optum HC,

Salix, Sanofi-Aventis, SK Life Sciences, Spire, Steigerwald,Theravance, The Journal of Medicine, XenoPort, and Wyeth. Hehas also received financial support from Novartis, GlaxoSmithK-line, Dynogen and Tioga.

JT has been an advisor for AGI Therapeutics, Movetis,Sucampo, Pfizer, Procter and Gamble and Theravance, and hasbeen a speaker for Movetis.

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Pharmacological management of constipation management of constipation A. V. EMMANUEL,* J. TACK, E. M. QUIGLEY & N. J. TALLEY *Physiology Unit, University College Hospital, London,