Advanced Studies in Medicine n S965

ABSTRACT

This is an exciting time in the treatment offunctional gastrointestinal (GI) disorders becauseof our rapidly evolving understanding of themechanism of action of these illnesses and theirtreatment. In this article, chronic constipation(CC), which is one of the most common function-al disorders of the gut, is discussed. Although notlife-threatening, CC can profoundly and nega-tively affect quality of life and is associated witha significant economic burden of direct andindirect annual healthcare costs. In the UnitedStates alone, estimates from several years agoplaced the annual cost of laxatives to treat con-stipation at $800 million. Possible causes of CCrange from psychologic disorders to dysfunc-tions of GI motility, though most patients do nothave an identifiable explanation for their consti-pation. Recent research indicates that constipa-tion most likely results from abnormalities ofmyenteric neurons or pacemaker function,defects in neurotransmitters, or incoordinationof the muscles of the pelvic floor or anorectum,and may be influenced by environmental factorsor chronic stress. In this article, the symptoms ofCC are reviewed and the safety and efficacy oftraditional, novel, and emerging therapies areexamined. Because of the overlap in symptoms,many of the treatments discussed in this reviewalso apply to patients with constipation-predom-inant irritable bowel syndrome.(Adv Stud Med. 2005;5(10B):S965-S976)

The definition of constipation differsamong individuals affected with the dis-order, their physicians, and the profes-sional medical organizations that provideguidelines for treatment. Research reveals

that 50% of patients define constipation by the symp-toms reported most often: infrequent, difficult, orincomplete evacuation; the passage of hard stool; orthe unproductive urge to defecate.1-3 Most cliniciansdefine constipation simply as fewer than 3 bowelmovements per week,1-3 but both the Rome IIFunctional Gastrointestinal Disorders CoordinatingCommittee4 and the American College ofGastroenterology (ACG) Chronic Constipation (CC)Task Force5 have published current guidelines for diag-nosis and treatment that are more specific.

Rome II criteria for CC specify that during the pre-ceding 12 months symptoms must have occurred for atleast 12 (not necessarily consecutive) weeks. In addition,more than 25% of defecations must be characterized by2 or more of the following symptoms: lumpy or hardstools, straining, a sensation of incomplete evacuation oranorectal obstruction, the need for a manual maneuverto evacuate the rectum, and/or fewer than 3 defecationsper week. It is essential that no organic disease, irritablebowel syndrome (IBS), or loose stools be present.4

However the ACG CC Task Force members concludedthat this definition was rather onerous for primary careclinicians because many patients who self-report CC donot meet these criteria.6 The Task Force proposed abroader definition of the disorder that includes the mostcommon symptoms of self-reported constipation (infre-quent stools, difficult defecation [straining, incompleteevacuation, hard or lumpy stools, prolonged time fordefecation], or both)5 and states that a combination ofthose symptoms should have been present for at least 3of the prior 12 months.7 The ACG CC Task Force rec-

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CHRONIC CONSTIPATION: MECHANISMS OF ACTION AND EFFECTIVE TREATMENT

—

Lucinda A. Harris, MS, MD*

*Senior Associate Attending, Division of Gastroenterology,Department of Medicine, Mayo Clinic, Scottsdale, Arizona.

Address correspondence to: Lucinda A. Harris, MD,Division of Gastroenterology, Mayo Clinic, Scottsdale,13400 East Shea Blvd, Scottsdale, AZ 85259. E-mail:Harris.Lucinda@mayo.edu.

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ognized that CC is associated with a significant decreasein quality of life8 and that, because there are no symp-tom-based criteria that identify subtypes of CC such ascolonic inertia or defecatory disorders, those subtypesmay occur concomitantly in individual patients. In itsdefinition of CC, the Task Force also recognized thatabdominal discomfort or bloating usually is minimallypresent in patients with CC and that the symptoms ofCC often are difficult to differentiate from those of IBS.

PATHOGENESIS AND PATHOPHYSIOLOGY

In his article in this monograph, Dr Camilleriaddresses the pathogenesis and pathophysiology of CCand IBS. In summary, the clinical causes of CC can bedivided into 3 primary categories: extracolonic constipa-tion, mechanical constipation, and functional constipa-tion.9 In patients with extracolonic constipation thefunction of the colon and/or rectum is affected by exoge-nous factors such as dietary habits (eg, low fiber intake,anorexia); medications (eg, antidepressants, anticholiner-gics, antihypertensives, opioids, iron supplements, alu-minum- or calcium-based antacids); metabolic,endocrine, neurologic, or connective-tissue disorders; ortrauma such as spinal cord injury.9 Mechanical constipa-tion is caused by a physical anomaly of the colon and/orrectum (ie, anal stenosis, rectal prolapse, rectocele, thecolonic effects of diverticular disease). Functional consti-pation is classified as 1 of 3 entities: constipation-pre-dominant IBS (C-IBS) characterized by abdominaldiscomfort and bloating10; slow-transit constipation, inwhich fewer than 3 bowel movements per week are pro-duced without either the urge to defecate or abdmomi-nal pain; or a defecatory disorder of the pelvic floor oranal sphincter, in which patients must strain excessivelyand may rely on manual maneuver to defecate.9 Withinany one person slow-transit constipation, defecatory dis-order, and C-IBS may coexist.5

CHRONIC CONSTIPATION: FALLACIES AND FOLKLORE

CC is a widespread disorder of the gut that hasbeen long misunderstood.11 Before various treatmentsare presented, it is important to briefly review themyths about constipation, which influence prescribingpractices, patients’ perceptions of CC, and compliancewith therapy. Misconceptions about the benefits offiber consumption and fluid intake will be discussed inthe treatment section of this article.

THE TOXIC GUT

Many patients (and even some healthcare providers)believe that toxins produced by undigested food in thegut are systemically absorbed and produce a wide varietyof adverse health-related symptoms, from lassitude tohypertension to various cancers.12,13 The need for a “dailybowel movement” is a widespread myth to which theregular use by many individuals of laxatives or cleansingtechniques ranging from herbal teas to enemas can beattributed. To date, however, no single such toxin hasbeen identified, and the prompt relief of many nonspe-cific symptoms of idiopathic constipation probablyresults from a mechanical rather than systemic effect.Another common myth states that in some individuals,CC is caused by a colon that is too long or “kinked” andthat surgical intervention might be helpful. Other thanfor the treatment of volvulus or severe refractory colonicinertia, surgery does not play a role in the treatment ofconstipation, and no valid studies correlate coloniclength with transit.11

THE EFFECT OF HORMONES

Sex hormones and GI hormones have been longhypothesized to influence intestinal transit. Sex hor-mones do not appear to exert a major effect on bowelfunction during the menstrual cycle, although the looserstools often seen on the first day of menses may be relat-ed to the local action of prostaglandins produced on thefirst day of menstruation.14 However, progesterone maybe responsible for the slower colonic transit that occursduring pregnancy.15 Xiao et al have suggested the possi-bility that down-regulation of contractile G proteins andup-regulation of inhibitory G proteins, likely caused byoverexpression of progesterone receptors, may be a causeof slow-transit CC in women.16 Women with severe idio-pathic constipation seem to exhibit a reduction in steroidhormones, which may result from alterations in thehepatic circulation of those hormones and/or theirbreakdown by the intestine.17 The role of GI hormonessuch as motilin, glucagon, and pancreatic polypeptide isless clear. Alterations in hormone levels have been foundin people with severe idiopathic constipation, but thedifferences in primary and secondary changes in thoselevels must be further elucidated.11 In individuals with-out the clinical features of hypothyroidism, the role ofthyroid dysfunction in CC is minimal.11

THE HAZARDS OF LONG-TERM LAXATIVE USE

The myth that the long-term use of laxatives caus-

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es enteric neuronal damage, impairs the function ofthe colon, and creates laxative dependency often leadspatients to fear treatment with a laxative medicationwhen it is required. Recent reviews11,18 examining thismisconception and the literature that created it showthat such concern is unfounded. However, laxativescan cause electrolyte disturbances and abdominal dis-comfort and must therefore be appropriately selectedand prescribed in correct doses.

THE INCREASED RISK OF COLORECTAL CANCER

FROM ANTHRAQUINONE USE

Also common is the misperception thatanthraquinone cathartic use increases the risk of colo-rectal cancer. That impression results from a meta-analy-sis by Sonnenberg and Muller,19 who examined thecolorectal cancer risk associated with cathartic use andconstipation in 14 case-controlled studies. The analysisof those investigators revealed a statistically significantpooled odds ratio of 1.46 for cathartics and 1.48 for con-stipation, and their review of the data on dietary factorssuch as the consumption of fat, alcohol, meat, and low-residue foods revealed relative risks ranging from 2 to 4.19

It thus appears much more likely that the risk associatedwith anthraquinone laxatives reflects the effect of diet. Asubsequent population-based, case-controlled investiga-tion confirmed that constipation and not laxative usewas the significant risk factor for colorectal cancer.20

TREATMENT

Before treatment for constipation is initiated, the clin-ician must obtain the patient’s complete medical historyand perform a thorough physical examination (especiallyimportant is a rectal examination to assist in excludingpatients with defecatory disorders). When patients withCC present without alarm symptoms (Table 1), the rec-ommendation from the ACG CC Task Force is to initi-ate empiric treatment without diagnostic testing (GradeC recommendation).5 The ACG CC Task Force6 alsorecently reviewed many available laxative treatments andclassified those therapies as Grade A, B, or C according tothe quality of the studies supporting their use. The ACGgrades of laxative treatment are similar to those developedby the American College of Gastroenterology FunctionalGastrointestinal Disorders Task Force on the manage-ment of IBS in North America.10

ACG Grade A recommendations for the treatmentof CC are based on Level I evidence, which represents

data obtained from high-quality randomized controlledtrials (RCTs). Grade B recommendations are based onintermediate-quality RCTs (Level II evidence), andGrade C recommendations are based on Level III-V evi-dence (primarily observational studies). Where applica-ble, the ACG grades are discussed in this article, but it isimportant to note that only North American literature(United States and Canada) was reviewed in determiningthe levels of evidence. Those grades should be used asguidelines to assist the clinician in choosing therapies forthe treatment of CC but are not meant to prohibit treat-ment with any of the agents graded.

The goals of treatment for patients with CC, then,are to restore normal bowel function and relieve symp-toms by accelerating colonic transit time, stimulatinggut motility, facilitating defecation, and/or promotingsecretion by the intestinal mucosa. Discussed beloware treatments commonly used to do so, such as tradi-tional therapies including lifestyle changes, laxativesand enemas, pelvic floor retraining, and surgery; noveltherapies including tegaserod; and emerging therapies.Traditional and novel pharmacotherapeutic agents forthe treatment of CC are listed in Table 2, and emerg-ing therapies are featured in Table 3.

LIFESTYLE CHANGES

Although public perception holds that diet, fluid,and exercise influence constipation, most studiesdemonstrate only limited support of that view.21-24

Analysis of available data indicates that a low-fiber diet isa contributing factor to CC in only a select group ofindividuals.25 Because increasing natural fiber intakeincreases bloating and flatulence,26 patients’ acceptanceof this recommendation is limited. Clinicians often rec-

Table 1. Alarm Signs and Symptoms in PatientsWith Chronic Constipation*

Acute onset of constipation in older individuals

Overt or occult blood in stool

Weight loss ≥10 lb

Anemia

Family history of colon cancer or inflammatory bowel disease

*The list above is not all-inclusive; the suggested signs and symptoms arebased on guidelines from the American College of GastroenterologyChronic Constipation Task Force.5

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ommend that individuals with constipa-tion increase their fluid intake, but stud-ies do not demonstrate that thisincreases stool bulk or colon transittime,23 even if the fluids consumed arehyperosmolar.27 Only in the setting ofclinical dehydration is increasing fluidintake helpful in treating CC.11 With theexception of especially vigorous activitysuch as marathon running,28 exerciseexerts no proven benefit in amelioratingCC in young, healthy patients.21,22,24,29,30

In older adults, the cause of constipationmay be multifactorial; etiologic factorsinclude medication, diet, and inactivity.However, evidence for physical inactivi-ty as a risk factor for CC in older personsdoes exist.31,32 Despite the fact thatchanges in lifestyle and diet have notbeen validated in controlled trials, thosemeasures often are recommended astreatment for both CC and IBS beforepharmacologic therapy is considered.6,33

LAXATIVES

Bulking agents: Initial treatment forthe patient with CC who seeks clinicalassessment often involves the use of abulk-forming supplement such as psylli-um (ispaghula husk, Metamucil®,Konsyl®), calcium polycarbophil(Perdiem® Fiber Therapy, FiberCon®),methylcellulose (Citrucel®), car-boxymethylcellulose, or bran. Thoseagents have been approved by the USFood and Drug Administration (FDA)for the treatment of occasional constipa-tion6; however, only psyllium has beenshown to increase stool frequency.34,35

Bulking agents retain water in andincrease the solid content of the stoolbut, like high-fiber foods, they may pro-duce gas and bloating. The ACG CCTask Force, citing the fact that studiesoften were of short duration or subopti-mal design or revealed conflictingresults, applied a Grade B recommenda-tion to bulking agents for the treatmentof constipation.6,36,37 These agents also

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Table 2. Agents for the Treatment of Chronic Constipation andConstipation-Predominant Irritable Bowel Syndrome*

Class Generic Name Brand Name ACG Grade†

LaxativesBulking agents Psyllium Metamucil, Konsyl B

Methylcellulose Citrucel BCalcium polycarbophil FiberCon, Equalactin, B

Perdiem Fiber TherapyStool softeners(emollients) Docusate sodium Colace B

Docusate calcium Surfak BMineral oil No brand name B

Osmotics Magnesium hydroxide Milk of Magnesia BMagnesium citrate Citroma ‡

Sodium phosphate Fleet Phospho-Soda ‡

Lactulose Cephulac, Kristalose, AEnulose

Polyethelene glycol (PEG) MiraLax ASorbitol No brand name ‡

Mannitol No brand name ‡

Stimulants (irritants) Cascara sagrada Nature’s Remedy B

Senna Perdiem, Senokot BRicinoleic acid Castor oil BDiphenylmethane Dulcolax, Correctol B

derivatives

Enemas and suppositories ‡

Innovative-use agents Sodium phosphate Visicol ‡

monobasic monohydrate + sodium phosphate dibasic anhydrous

Misoprostol Various brand names Off-label useBethanechol Various brand names Off-label useColchicine Various brand names Off-label use

Prokinetic agents(5-HT4 agonists ) Tegaserod Zelnorm A

Alternativetreatments Herbal supplements Various commercial C§

Combination laxatives brandslubricants (in adults)

ACG = American College of Gastroenterology; 5-HT4 = 5-hydroxytryptoamine4.*Adapted from: Harris L, Chang L. The functional bowel spectrum. In: Wallace DJ, Clauw DJ, eds.Textbook of Fibromyalgia and Other Non-Neuropathic Pain Syndromes. Philadelphia, Pa: Lippincott,Williams & Wilkins; 2005.†Grade A, recommendations supported by 2 or more Level 1 trials without conflicting evidence from otherLevel 1 trials; Grade B, recommendations based on evidence from a single Level I trial or recommendationsbased on evidence from 2 or more Level I trials with conflicting evidence from other Level I trials or sup-ported by evidence from 2 or more Level II trials; Grade C, recommendations based on Level III-V evidence.‡Insufficient studies available to judge safety and effectiveness.§Applies only to herbal laxatives; other alternative therapies have not yet been evaluated.

Advanced Studies in Medicine n S969

received a Grade B designation from the AmericanCollege of Gastroenterology Functional GastrointestinalDisorders Task Force as treatment for IBS.10

Because of flaws in study design, an accurate assess-ment of the efficacy of bulking agents cannot be made.In addition, adverse effects such as an increased risk ofmechanical obstruction of the esophagus or colon oran anaphylactic reaction have been associated with theuse of those agents.26 When bulking agents fail, stoolsofteners may be added or other laxatives may be used.

Stool softeners (emollients): Stool softeners (emol-lients), which are thought to be inferior to psyllium inmanaging the symptoms of CC,6 act primarily as deter-gents to soften stools. The most common agents avail-able as stool softeners in the United States are docusatecalcium (Surfak) and docusate sodium (Colace). Thosemedications, which are FDA approved for the treatmentof occasional constipation, received a Grade B recom-mendation from the ACG CC Task Force.6

Mineral oil, which also exerts an emollient effect, wasnot evaluated by the ACG Task Force because no RCTs ofthat agent have been conducted in adults. RCTs in thepediatric population demonstrate that mineral oil is moreeffective than senna-based laxatives and less effective thanosmotic laxatives in producing more frequent and softerstools as treatment for CC.5 Adverse effects of mineral oilinclude lipoid pneumonia, anal seepage, malabsorption offat-soluble vitamins, and foreign-body reactions in tissue.38

The ACG CC Task Force has designated a Grade Crecommendation for the use of herbal supplements (eg,

aloe), lubricants (eg, mineral oil) in adult patients, orcombination laxatives (eg, psyllium plus senna) becauseno published RCTs on the efficacy of those therapiesexist in the United States in patients with CC.5

Osmotic laxatives: Osmotic laxatives, whichincrease stool bulk and the volume of water in thesmall and large intestine, often require 1 to 2 days toproduce a full result. Osmotics are of 3 types: saline lax-atives (magnesium hydroxide [milk of magnesia], mag-nesium citrate, magnesium sulfate, sodium phosphate,etc), nonabsorbed sugars (solutions of lactulose[Cephulac, Kristalose®, Enulose], sorbitol, or manni-tol),38 or polyethylene glycol (PEG, MiraLax), which is alarge polymer with osmotic activity. FDA approval ofthose agents for the treatment of CC is variable.Lactulose is approved for the treatment of constipation,but magnesium hydroxide is approved for only occa-sional use. PEG can be used for 2 weeks or fewer in thetreatment of CC. Both PEG and lactulose received aGrade A recommendation from the ACG CC TaskForce, but a Grade B recommendation was applied tomagnesium hydroxide because of insufficient data on theeffect of that agent in patients with CC.6

Lactulose and sorbitol have been shown to be simi-larly effective, but in 1 trial that compared those agents,lactulose was more likely to produce nausea.33,39 As atreatment for constipation, PEG has been shown to besomewhat more effective than lactulose and to causefewer adverse effects, although both agents have beenreported to cause abdominal bloating, flatulence, andabdominal cramps.9,29 Osmotic laxatives also have beenassociated with multiple electrolyte abnormalities(hypermagnesemia, hyperphosphatemia, hypercalcemia,hyponatremia, hypokalemia), hypovolemia, and diar-rhea,6,26 and for those reasons may be contraindicated inpatients with renal insufficiency or cardiac dysfunc-tion.29,40 In addition, magnesium toxicity has been asso-ciated with the use of magnesium hydroxide.38 Whenoverused, osmotic laxatives can cause dehydration.41

Stimulant (irritant) laxatives: Stimulant (irritant)laxatives, which increase the frequency of intestinalcontractions, include over-the-counter remediessuch as cascara sagrada (Nature’s Remedy), senna(Perdiem, Senokot), ricinoleic acid (castor oil,Castor), and derivatives of diphenylmethane(Correctol, Dulcolax).42 Those agents, which arebelieved to exert a direct effect on mucosal transportand motility, have been approved by the FDA for thetreatment of occasional constipation,6 but insuffi-

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Table 3. Emerging Therapies* for the Treatment ofChronic Constipation and Constipation-Predominant Irritable Bowel Syndrome

Class Generic Name Brand Name

Prokinetic agents(5-HT4 agonists ) Prucalopride No brand name

Combination Mosapride No brand name

5-HT4 agonist- Renzapride No brand name5-HT3 antagonists

Chloride-channelactivators Lubiprostone No brand name

Nonspecific opioidantagonists Methylnaltrexone No brand name

Mu-opioid antagonists Alvimopan Entereg

*All agents are not yet FDA approved and await further study.

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cient evidence exists about their effectiveness in the man-agement of CC. As a result, stimulant laxatives havereceived a Grade B recommendation from the ACG TaskForce.6 Diphenylmethane derivatives include bisacodyl,picosulfate, and phenolphthalein (which has been with-drawn from the US market). Bisacodyl is a diacetic acidester, picosulfate is a disulfuric acid semiester, and phe-nolphthalein consists of free diphenolic groups. Themechanism of all stimulant laxatives involves conversionto free diphenolic groups.

Phenolphthalein is no longer available in the UnitedStates because it was associated with an increased risk ofcarcinogenesis (an assumption that remains unprovenand probably is incorrect). Bisacodyl, which is morepotent than phenolphthalein, is thought to inhibit waterabsorption in the colon and small bowel by exerting aneffect on kinases, prostaglandins, and (possibly) adeno-sine triphosphatase. Picosulfate, which seems to exert adirect effect on colonic bacteria, is transformed to thesame active molecule as that of bisacodyl.42

Stimulant laxatives exert their effect within hours afteringestion but should be taken infrequently9 because theycan cause flatulence, abdominal pain, and metabolic dis-turbances and may be overused.43 Other adverse effectsassociated with stimulant-laxative use abound.Diphenylmethane derivatives can cause abdominalcramping, Stevens-Johnson syndrome, fixed drug erup-tions, protein-losing enteropathy, hepatotoxicity, andreactions similar to those produced by lupus erythemato-sus.29,40,42 Long-term use of any stimulant laxative cancause diarrhea and resultant hypokalemia, hyponatremia,and dehydration,41 and some investigators associate radio-graphic changes in the colon with the use of thoseagents.40,43 As discussed previously, however, neurologicdamage is unlikely to be caused by this class of drug.

ENEMAS AND SUPPOSITORIES

Enemas are of different types: phosphate, mineraloil, tap water, and soap suds. The mechanism of actionvaries with the type of enema used. Suppositories canbe osmotic (bisacodyl) or more lubricating (glycerine).Glycerine suppositories are thought to exert an osmot-ic effect and also may act as a local irritant. This groupof agents, which was not evaluated or even mentionedby the ACG CC Task Force, is thought to be useful inthe management of patients with fecal impaction ofthe rectosigmoid colon.44 Adverse effects includemechanical trauma from placement and (with phos-phate enemas) hyperphosphatemia. Soap suds enemas

can be severely irritating to the lining of the intestineand generally are not recommended.

INNOVATIVE-USE AGENTS

A variety of other agents (sodium phosphate com-pounds, misoprostol, bethanechol, colchicine) have beenprescribed as innovative treatments for CC in certainpopulations. Those therapies often are limited in theirapplication because of their unfavorable adverse effectprofile. At the time of this writing, only sodium phos-phate compounds remain the focus of ongoing investi-gation for the treatment of constipation.

Sodium phosphate monobasic monohydrate + sodiumphosphate dibasic anhydrous: A combination of low-dose sodium phosphate monobasic monohydrate plussodium phosphate dibasic anhydrous (Visicol) wasshown in an open-label, multicenter, 4-week, phase 4study to provide relief of constipation in patients withC-IBS and CC. Benefit was achieved in subjectsreceiving the 4- or 8-tablet regimen of sodium phos-phate as opposed to those receiving placebo. The treat-ment was well tolerated in general (particularly in thelow-dose group) and promptly relieved constipation(usually within the first week of treatment), a benefitthat persisted during the 28-day period of therapy.45

This combination drug currently is approved by theFDA for bowel cleansing before colonoscopy. Sodiumphosphate laxatives, like osmotic laxatives, can causeelectrolyte disturbances. Because of this and the factthat phosphate may be more readily absorbed thanmagnesium, this laxative is contraindicated in patientswith renal insufficiency and cardiac dysfunction.

Misoprostol: Because misoprostol often causes diar-rhea when prescribed to treat acid peptic disorders, it hasbeen used to treat severe constipation that is refractory toother therapy.38 Adverse effects (nausea, diarrhea,abdominal pain, increased risk of spontaneous abortion)have limited the use of this drug. Some studies haveshown, however, that 50% of patients with severe CCbenefit from treatment with misoprostol.38,42,46

Bethanechol: The cholinergic agent bethanecholincreases gastric motility and tone and can improvediminished rhythmic peristalsis. Older research indi-cates that bethanechol 25 mg to 50 mg, when admin-istered 3 or 4 times daily, ameliorates constipationcaused by tricyclic antidepressant use.38,47 However, italso is associated with hypersalivation, nausea, vomit-ing, and dizziness, and those adverse effects have lim-ited the usefulness of bethanechol.

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Colchicine: Although the exact mechanism of actionof colchicine is unknown, this agent seems to act as amucosal toxin. It is used primarily in the treatment ofacute gout and may produce diarrhea as an adverseeffect. A double-blind, placebo-controlled, randomized,crossover study of colchicine was performed in a smallgroup of patients with CC.48 A dose of 0.6 mg 3 timesdaily was used for a 4-week treatment period. Patientsreported reduced transit time, an increased number ofbowel movements, and no particularly adverse effects.However, colchicine can cause neutropenia, aplastic ane-mia, and neuromyopathy. Less severe side effects includealopecia, rash, nausea, vomiting, and abdominal pain.The use of colchicine or misoprostol usually is reservedfor patients with severe constipation that is refractory toother therapy because the desired result of treatmentwith those agents is, in essence, an adverse reaction to thedrug. Both drugs are contraindicated in pregnancy.

PROKINETIC AGENTS (5-HT4 AGONISTS) Tegaserod: Tegaserod (Zelnorm®) currently is the

only 5-hydroxytryptamine4 (5-HT4) agonist approvedby the FDA for the treatment of CC. A partial agonistof the 5-HT4 (serotonin) presynaptic receptors in theenteric nervous system (Figure 1), tegaserod exerts sev-eral beneficial effects in those who suffer from CC. Itmay decrease visceral hypersensitivity, stimulates theperistaltic reflex, increases colonic motility, and acts onintestinal chloride secretion, thus facilitating the trans-port of fluid into the lumen of the colon and improv-ing stool consistency and frequency.6,49-51 Studies haveshown that this agent also is effective in improving thefrequency of complete spontaneous defecation and thatit decreases straining.6 Approved by the FDA to treatCC in men and women younger than 65 years,tegaserod received a Grade A recommendation from theACG CC Task Force.6 The American College ofGastroenterology Functional GastrointestinalDisorders Task Force applied a Grade A recommenda-tion to tegaserod for the treatment of C-IBS, but its useis restricted to women with that disorder.10

The mechanism of action of tegaserod is limited tothe periphery by a unique design: Its molecular struc-ture replicates that of the serotonin molecule but hasbeen altered by the addition of a hydrophilic “tail”that restricts passage across the blood-brain barrier. Asan aminoguanidine indole, tegaserod does notobstruct cardiac potassium channels and is thusthought not to potentiate cardiac arrhythmia.52

In a recent review of therapies for CC, Ramkumarand Rao found that Grade A evidence similar but notequivalent to that of the ACG CC Task Force gradingsystem supported the use of tegaserod for the treat-ment of constipation.33 The grades those authors citedwere based on 2 large, multinational, randomized,double-blind, placebo-controlled studies53,54 indicatingthat tegaserod was a safe, effective, and tolerable ther-apy that was superior to placebo for the treatment ofCC in those under age 65. Treated subjects experi-enced significant improvement in the frequency ofcomplete spontaneous bowel movements, total spon-taneous bowel movements, global satisfaction withbowel habits, and straining to defecate. Mild, transientdiarrhea occurred significantly more often in thetegaserod-treated group but usually resolved withoutadditional therapy.53,54 Other reported adverse effectsof treatment include headache and nausea, but in gen-eral, the safety profile of that agent is favorable.According to the results of several studies, serioussequelae were no more likely to occur with tegaserodtreatment than with placebo, and tegaserod inducedneither clinically relevant drug interactions nor elec-trocardiographic abnormalities.55-57 New prescribingrecommendations from the FDA include a “precau-tion” stating that ischemic colitis has occurred inpatients treated with this drug, but according to infor-mation gathered from clinical trials and postmarketing

Figure 1. Role of Serotonin in Gastrointestinal Function

CNS = central nervous system; ENS = enteric nervous system.Data from Grider, et al. Gastroenterology. 1998;115:370 and Gershon M. RevGastroenterol Dis. 2003;3:S25.

Signals to CNS(visceral sensation)

Motor neurons(contraction)

Signals to ENS Motor neurons(relaxation)

5-HT (serotonin)

Myentericplexus

Submucosa

Mucosa

5-HT4 receptor5-HT1p receptor5-HT3 receptor

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surveillance, the likelihood that tegaserod producesthat adverse effect is minimal.6,58

EMERGING TREATMENTS

Although safe and effective therapies do exist for thetreatment of occasional constipation, the need forimprovement in the treatment of CC is evident.Pharmacologic agents that increase peristalsis by theireffect on serotonergic receptors are under investigation.Other receptor sites targeted pharmacologically in indi-viduals with CC include opioid receptors and chloridechannels, which work via different mechanisms. Newerpharmacotherapeutic agents effective at those receptorsand the combination 5-HT4 agonist-5-HT3 antagonistsrenzapride and mosapride are reviewed below.

5-HT4 agonists—prucalopride: The drug prucalo-pride, a benzofurancarboxamide and a full agonist at 5-HT4 receptors,52 once was thought to be a promisingagent in the treatment of CC. The results of 2 largeRCTs revealed that when compared with placebo, dailydoses of prucalopride 2 mg or 4 mg produced a modestbenefit in patients who had characterized themselves ashaving “severe” or “very severe” CC. Over 12 weeks oftherapy, treatment with prucalopride increased the num-ber of complete spontaneous bowel movements from amedian of 0 per week to 3 per week in 29% of studypatients.52,59 However, studies of prucalopride were sus-pended because of concern about the development ofcardiac arrhythmias in treated patients.52 It is unlikelythat this drug will be marketed in the United States, butits development underscores the importance of the 5-HT4 receptor as a target for drug therapy.

Combination 5-HT4 agonist–5-HT3 antagonists—mosapride, renzapride: Mosapride citrate, a novel selec-tive 5-HT4 receptor agonist–5-HT3 receptor antago-nist, enables acetylcholine release from entericcholinergic neurons but does not block potassiumchannels or D2 dopaminergic receptors.60 In a smalltrial of patients with Parkinson’s disease, 10 men and 4women (mean age, 67 years) with constipation (abowel movement fewer than 3 times per week or diffi-cult defecation) were treated with 15 mg daily ofmosapride citrate for 3 months. Treatment was well tol-erated by all but 1 patient, who terminated participationin the study because of epigastric discomfort. Theremaining 13 patients reported a subjective improve-ment in the frequency of bowel movements and difficultdefecation. The investigators concluded that mosapridealleviated several symptoms of constipation in subjects

with Parkinson’s disease without inducing serious adverseeffects. This agent awaits further study.

Renzapride is another promising therapy that may beused for the treatment of CC and C-IBS. This agent,which functions as both a 5-HT3 antagonist and a 5-HT4 agonist, has been tested in clinical trials in men andwomen with C-IBS. Its presumed mechanism of actionis the activation of 5-HT4 receptors in cholinergic neu-rons that stimulate contractions, and the 5-HT3 antago-nist activity of this agent also may decrease visceralsensation. In a recent trial of its effects in patients withC-IBS, renzapride improved stool consistency andincreased the frequency of bowel movements but pro-vided no overall relief of abdominal pain and discom-fort.61 In a randomized, double-blind, parallel-group,2-week study of 48 patients with C-IBS and normal orslow baseline colonic transit but without pelvic outletobstruction, renzapride was associated with an improve-ment in bowel function scores and accelerated colonictransit, although small-bowel transit and gastric empty-ing were not affected.62,63 In that study, the renzapride-treated subjects exhibited an acceleration of colonictransit and an improvement in bowel function scores,although gastric emptying and small-bowel transit werenot affected. Like many evolving agents for the treat-ment of CC, renzapride also awaits further study.

Chloride-channel activators—lubiprostone: Lubipros-tone (RU 0211) is an orally administered novelbicyclic fatty acid64,65 undergoing development for thetreatment of CC, postoperative ileus, and C-IBS.64 Byactivating a chloride channel on the apical side ofepithelial cells lining the gut (the driver of intestinalfluid secretion), lubiprostone increases fluid to thesmall intestine, which in turn increases overall fluidcontent in the colon (Figure 2). The greater amount offluid in the intestine promotes spontaneous bowelmovements; reduces abdominal discomfort, pain, andbloating; and softens the stool.64 In addition, chloride-channel activators show promise in the ability to repairmucosal barrier function following ischemic injury, aneffect that appears to result from reduction in paracel-lular permeability via changes to the tight junction fol-lowing CIC-2 channel activation.66,67

Two phase 3, multicenter, double-blind, placebo-controlled studies have shown that lubiprostone, whencompared with placebo, was significantly more effectivein providing relief from the symptoms of CC (Figure3).56,57 Both male and female patients meeting Rome IIcriteria for CC were included in the study. At a dose of

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24 mg twice daily highly significant statistical improve-ments were seen, not only in the global assessments oftreatment effectiveness and constipation severity but alsoin that patients experienced an increase in spontaneousbowel movements. Secondary measures of frequency andconsistency of spontaneous bowel movements were alsosignificantly improved. The most common adverseeffects of treatment were headache, diarrhea, and nau-sea.67 Nausea occurred in approximately 30% of patients.Although more common in the treatment than the con-trol group, the number of patients in either group whowithdrew from the study because of nausea was limited.The new drug application for the use of lubiprostone inthe treatment of CC, under review at the FDA at thetime of this writing, includes the results of 3 long-termsafety studies, 2 of which are 12-month assessments.68-70

Peripheral opioid antagonists—methylnaltrexone andalvimopan: Opioids administered as long-term analgesicsfor patients with cancer or during and after surgery cancause constipation or postoperative ileus.69 Althoughblocking peripheral opioid receptors in the bowel is theideal mechanism for ameliorating opioid-induced con-stipation, most opioid antagonists (eg, naloxone) crossthe blood-brain barrier, reverse analgesia, and result inopioid withdrawal.71 N-methylnaltrexone bromide(methylnaltrexone), the first peripheral opioid receptorantagonist, is a quaternary derivative of naltrexone,which is a pure opioid antagonist.72,73 Because methylnal-trexone does not cross the blood-brain barrier,72-74 it mayblock the adverse effects of opioids that are primarilymediated by peripherally located receptors73,75,76 and pre-serve centrally mediated analgesia. It is presumed to actas an antinociceptive and to disrupt the antimotilityeffects of opioids.77 Research indicates that in healthyindividuals, intravenous or oral methylnaltrexonereversed opioid-induced inhibition of bowel motilitywithout affecting analgesia and, in patients receivinglong-term opioid therapy, reduced (with minimaladverse effects) the delay in oral-cecal transit and evokedlaxation in all subjects without evoking withdrawalsymptoms.78 Other investigators suggest that subcuta-neous methylnaltrexone may also be useful in treatingopioid-induced constipation.73

Alvimopan, a novel peripherally acting mu-opioidantagonist, is currently being evaluated for the treat-ment of acute postoperative ileus and reversal of thedelayed gastrointestinal and colonic transit caused byopioid therapy.79 Mu-opioid receptors are located inthe enteric nervous system and on nociceptive path-

ways that transmit pain to the central nervous system.A study by Paulson and colleagues indicated that alvi-mopan reversed the opioid-induced inhibition of gas-trointestinal transit without affecting analgesia.80 Mildto moderate adverse events, which were bowel-related,occurred during the first week of treatment, but ther-apy with alvimopan generally was well tolerated.

Figure 3. Effect of Lubiprostone on ChronicConstipation*

0

1

2

3

4

5

6

7

Baseline Week 1 Week 2 Week 3 Week 4

Bo

wel

Mo

vem

ents

/wk

PlaceboLubiprostone 48µg 24µg x 2/day)

P=.0001

P=.0017 P=.0002 P=.0002

Multi-center, parallel-group, double-blind,placebo-controlled study

[ITT population]

*Reprinted with permission from Johanson JF, Gargano MA, Holland PC,Patchen ML, Ueno R. Phase III efficacy and safety of RU-0211, a novel chlo-ride channel activator, for the treatment of constipation. Gastroenterology.2003;124(4, suppl 1):A48.

Figure 2. The Role of Chloride Channels inIntestinal Transport

Ion Transport

Chloride channels located onthe apical surface of theepithelial cells are a drivingforce for intestinal fluidsecretion.

1. As negatively charged chlo-ride ions actively enter thelumen via chloride chan-nels,

2. positively charged sodiumions passively diffusethrough the intracellularspaces to balance chloride,

3. allowing water to followpassively into the lumen.

Entry

<3 BM/wk

+

Rome II

N = 242

• Onset of action was within 24 hours in the majority of subjects• Most common adverse events were nausea (31%), diarrhea, and headache• 9 subjects taking lubiprostone withdrew due to adverse events

Chloride

Sodium

Intestinallumen

Water

Tightjunction

Epithelial

Chloride-channel

K+ channelNa+ pump

Na+-K+-2CIcotransporter

CI-

H20

Na+

CI-

K+

K+Na+

Na+

K+

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NONPHARMACOLOGIC TREATMENTS

Pelvic floor retraining (biofeedback): For patients withevidence of pelvic floor dysfunction (PFD), biofeedbackis a behavioral approach of varying effectiveness in thetreatment of CC. Via manometry or electromyography,patients with PFD learn techniques for the relaxation ofthe pelvic floor muscles and the anal sphincter, whichenables the expulsion of stool. Although good results areobtained from biofeedback in many medical centers, theeffectiveness of the training depends on the availability ofqualified personnel. Success rates have varied from 48%to 75%.9,38 Anal disorders, such as fissures or a tenderpuborectalis muscle, also may limit participation, andpatients must exhibit some degree of rectal perception tobenefit from biofeedback training. The cost of the tech-nique may also be prohibitive.52,44

Surgery: Surgery is rarely required and should bereserved only for the most refractory cases of CC. Theprocedure of choice is subtotal colectomy with ileorec-tal anastomosis (in patients with megarectum, the rec-tum also is removed). In some individuals, ileostomy isperformed. Ten percent of patients who undergosurgery for CC experience postoperative ileus andmechanical small- bowel obstruction. Postsurgicaldiarrhea is common but tends to resolve over time inmost cases.38,44 A limited number of patients with out-let obstruction also may require surgery to correct alarge rectocele or repair rectal prolapse.38 Patients witha high rate of postoperative bowel obstruction in addi-tion to PFD, small-bowel dysmotility, or severeabdominal pain are not candidates for the surgicaltreatment of CC.

Colonic electrical stimulation: Three types of colonicelectrical stimulation, a nondrug treatment for CC, arecurrently under development. The electric stimulationof sacral nerve function is used as therapy for urinaryand fecal incontinence, and patients so treated exhib-ited an increase in the sensory threshold for desire todefecate as well as an increase in the frequency of thesensation of the need to defecate.81 Another approach,which has been tested only in a canine model, involvesusing microprocessor-controlled sequential electricstimulation to induce peristalsis.82 This techniqueappears to be successful but awaits further study.Fajardo and colleagues demonstrated that in patientswith spinal cord injury, electric stimulation of theabdominal wall muscles reduced (by half ) the timenecessary for a bowel movement and also decreased thetime required for bowel care.83

CONCLUSION

CC and C-IBS are among the most prevalent andenduring GI diagnoses in North America. Most oftenidentified by primary care physicians and gastroen-terologists, these common disorders of the gut imposea substantial burden of healthcare costs and can nega-tively affect quality of life and productivity. Research hasshown that nonpharmacologic and pharmacologic ther-apies designed to address each patient’s specific symp-toms are most effective in the management of CC, thecauses of which may range from abnormalities in myen-teric neuron function, defects in neurotransmitters, andincoordination of pelvic-floor or anorectal muscles toenvironmental factors and chronic stress. A more com-plete understanding of those etiologic mechanisms willenable the development of a new generation of superiortherapeutic agents, which even now are the subject ofongoing analysis and research.

ACKNOWLEDGEMENT

Dr Harris would like to thank Jane Vail for her assis-tance in the development of this manuscript.

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