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REVIEW

CME LEARNING OBJECTIVE: Readers will differentiate the types of chronic constipation and apply traditional
CREDIT and newer treatments to best advantage
UMAR HAYAT, MD MOHANNAD DUGUM, MD SAMITA GARG, MD
Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Department of Gastroenterology and Hepatol-
Medicine Institute, Cleveland Clinic Nutrition, Department of Medicine, University of ogy, Digestive Disease Institute, Cleveland Clinic;
Pittsburgh, PA Assistant Professor, Cleveland Clinic Lerner College
of Medicine of Case Western Reserve University,
Cleveland, OH

Chronic constipation:
Update on management
ABSTRACT
Managing chronic constipation involves identifying and
C hronic constipation has a variety of pos-
sible causes and mechanisms. Although
traditional conservative treatments are still
treating secondary causes, instituting lifestyle changes, valid and first-line, if these fail, clinicians can
prescribing pharmacologic and nonpharmacologic thera- choose from a growing list of new treatments,
pies, and, occasionally, referring for surgery. Several new tailored to the cause in the individual patient.
drugs have been approved, and others are in the pipeline. This article discusses how defecation works
(or doesnt), the types of chronic constipation,
KEY POINTS the available diagnostic tools, and traditional
Although newer drugs are available, lifestyle modifica- and newer treatments, including some still in
tions and laxatives continue to be the treatments of development.
choice for chronic constipation, as they have high re-
THE EPIDEMIOLOGY OF CONSTIPATION
sponse rates and few adverse effects and are relatively
affordable. Chronic constipation is one of the most com-
mon gastrointestinal disorders, affecting about
15% of all adults and 30% of those over the
Chronic constipation requires different management age of 60.1 It can be a primary disorder or sec-
approaches depending on whether colonic transit time ondary to other factors.
is normal or prolonged and whether outlet function is Constipation is more prevalent in wom-
abnormal. en and in institutionalized elderly people.2
It is associated with lower socioeconomic
Surgical treatments for constipation are reserved for pa- status, depression, less self-reported physical
tients whose symptoms persist despite maximal medical activity, certain medications, and stressful
therapy. life events.3 Given its high prevalence and
its impact on quality of life, it is also asso-
ciated with significant utilization of health-
care resources.4
Constipation defined by Rome IV criteria
Physicians and patients may disagree about what
constitutes constipation. Physicians primarily
regard it as infrequent bowel movements, while
patients tend to have a broader definition. Ac-
cording to the Rome IV criteria,5 chronic consti-
pation is defined by the presence of the follow-
ing for at least 3 months (with symptom onset at
least 6 months prior to diagnosis):
(1) Two or more of the following for more
doi:10.3949/ccjm.84a.15141 than 25% of defecations:
CL EVE L AND CL I NI C J O URNAL O F M E DI CI NE V O L UM E 84 NUM BE R 5 M AY 2017 397
CHRONIC CONSTIPATION

Straining Normal-transit constipation is the most


Lumpy or hard stools common type of constipation. The term is
Sensation of incomplete evacuation sometimes used interchangeably with consti-
Sensation of anorectal obstruction or pation-predominant irritable bowel syndrome,
blockage but the latter is a distinct entity characterized
Manual maneuvers to facilitate evacuation by abdominal pain relieved by defecation as
Fewer than 3 spontaneous bowel move- the primary symptom, as well as having occa-
ments per week. sional loose stools. These 2 conditions can be
(2) Loose stools are rarely present without hard to tell apart, especially if the patient can-
the use of laxatives. not describe the symptoms precisely.
(3) The patient does not meet the criteria Slow-transit constipation
for diagnosis of irritable bowel syndrome. Slow-transit constipationalso called de-
layed-transit constipation, colonoparesis, co-
DEFECATION IS COMPLEX lonic inertia, and pseudo-obstructionis de-
Defecation begins when the rectum fills with fined as prolonged stool transit in the colon,
stool, causing relaxation of the internal anal ie, for more than 5 days.9 It can be the result
sphincter and the urge to defecate. The external of colonic smooth muscle dysfunction, com-
anal sphincter, which is under voluntary con- promised colonic neural pathways, or both,
trol, can then either contract to delay defeca- leading to slow colon peristalsis.
tion or relax to allow the stool to be expelled.6 Factors that can affect colonic motility
Colonic muscles propel stool toward the such as opioid use and hypothyroidism should
rectum in repetitive localized contractions that be carefully considered in these patients. Opi-
help mix and promote absorption of the content, oids are notorious for causing constipation by
and larger coordinated (high-amplitude propa- decreasing bowel tone and contractility and
gating) contractions that, in healthy individu- thereby increasing colonic transit time. They
als, move the stool forward from the proximal also tighten up the anal sphincters, resulting
to the distal colon multiple times daily. These in decreased rectal evacuation.10
Chronic
contractions usually occur in the morning and Outlet dysfunction
constipation are accentuated by gastric distention from food Outlet dysfunction, also called pelvic floor
is linked to and the resulting gastrocolic reflex. dysfunction or defecatory disorder, is associ-
lower Serotonin (5-HT) is released by entero- ated with incomplete rectal evacuation. It
chromaffin cells in response to distention of can be a consequence of weak rectal expulsion
socioeconomic the gut wall. It mediates peristaltic move- forces (slow colonic transit, rectal hyposensi-
status, ments of the gastrointestinal tract by binding tivity), functional resistance to rectal evacu-
to receptors (especially 5-HT4), stimulating ation (high anal resting pressure, anismus,
depression, release of neurotransmitters such as acetyl- incomplete relaxation of the anal sphincter,
lack of physical choline, causing smooth-muscle contraction dyssynergic defecation), or structural outlet
activity, certain behind the luminal contents and propelling obstruction (excessive perineal descent, rec-
them forward. toceles, rectal intussusception). About 50% of
medications, patients with outlet dysfunction have concur-
and stressful PRIMARY CONSTIPATION DISORDERS rent slow-transit constipation.
life events The American Gastroenterological Associa- Dyssynergic defecation is the most com-
tion7 classifies constipation into 3 groups on mon outlet dysfunction disorder, accounting
the basis of colonic transit time and anorectal for about half of the cases referred to tertiary
function: centers. It is defined as a paradoxical eleva-
tion in anal sphincter tone or less than 20%
Normal-transit constipation relaxation of the resting anal sphincter pres-
Stool normally takes 20 to 72 hours to pass sure with weak abdominal and pelvic propul-
through the colon, with transit time affected sive forces.11 Anorectal biofeedback is a thera-
by diet, drugs, level of physical activity, and peutic option for dyssynergic defecation, as we
emotional status.8 discuss later in this article.
398 CLEV ELA N D C LI N I C JOURNAL OF MEDICINE VOL UME 84 N UM BE R 5 M AY 2017
HAYAT AND COLLEAGUES

SECONDARY CONSTIPATION TABLE 1


Constipation can be secondary to several con-
ditions and factors (Table 1), including: Causes of secondary constipation
Neurologic disorders that affect gastroin- Neurologic and motility disorders
testinal motility (eg, Hirschsprung disease, Amyloidosis
Parkinson disease, multiple sclerosis, spi- Diabetes
nal cord injury, stroke, spinal or ganglionic Hirschsprung disease
tumor, hypothyroidism, amyloidosis, dia- Hypothyroidism
betes mellitus, hypercalcemia) Multiple sclerosis
Drugs used to treat neurologic disorders Parkinson disease
Spinal cord injury
Mechanical obstruction Spinal or ganglionic tumors
Diet (eg, low fiber, decreased fluid intake). Stroke

EVALUATION OF CONSTIPATION Diseases in which treatment can cause constipation


Bipolar disorder
It is crucial for physicians to efficiently use the Chronic pain
available diagnostic tools for constipation to Depression
tailor the treatment to the patient. Parkinson disease
Evaluation of chronic constipation be- Schizophrenia
gins with a thorough history and physical ex- Medications
amination to rule out secondary constipation Anticholinergics
(Figure 1). Red flags such as unintentional Anticonvulsants
weight loss, blood in the stool, rectal pain, Antidepressants
fever, and iron-deficiency anemia should Antipsychotics
prompt referral for colonoscopy to evaluate Antispasmodics
for malignancy, colitis, or other potential co- Calcium channel blockers
Opioids
lonic abnormalities.12
A detailed perineal and rectal examina- Other causes Red flags:
tion can help diagnose defecatory disorders Chagas disease
Conversion disorder unintentional
and should include evaluation of the resting
anal tone and the sphincter during simulated Decreased fluid intake weight loss,
Hypercalcemia
evacuation. Hyperparathyroidism blood in
Laboratory tests of thyroid function, elec-
trolytes, and a complete blood cell count
Low-fiber diet the stool,
Mechanical obstruction
should be ordered if clinically indicated.13 rectal pain,
Further tests anorectal manometry and the balloon expul- fever,
Further diagnostic tests can be considered if sion test are normal. The study uses radiopaque iron-deficiency
symptoms persist despite conservative treatment markers, radioisotopes, or wireless motility cap- anemia
or if a defecatory disorder is suspected. These sules to confirm slow-transit constipation and to
include anorectal manometry, colonic transit identify areas of delayed transit in the colon.16
studies, defecography, and colonic manometry. Defecography is usually the next step in
Anorectal manometry and the rectal bal- diagnosis if anorectal manometry and bal-
loon expulsion test are usually done first because loon expulsion tests are inconclusive or if
of their high sensitivity (88%) and specificity an anatomic abnormality of the pelvic floor
(89%) for defecatory disorders.14 These tests mea- is suspected. It can be done with a variety of
sure the function of the internal and external techniques. Barium defecography can identify
anal sphincters at rest and with straining and as- anatomic defects, scintigraphy can quantify
sess rectal sensitivity and compliance. Anorectal evacuation of artificial stools, and magnetic
manometry is also used in biofeedback therapy in resonance defecography visualizes anatomic
patients with dyssynergic defecation.15 landmarks to assess pelvic floor motion with-
Colonic transit time can be measured if out exposing the patient to radiation.17,18
CL EVE L AND CL I NI C J O URNAL O F M E DI CI NE V O L UM E 84 NUM BE R 5 M AY 2017 399
CHRONIC CONSTIPATION

History and physical examination

If secondary constipation is ruled out If secondary constipation is possible

Trial of lifestyle modifications, Blood tests, as indicated:


eg, physical activity, diet, toilet training Complete blood cell count
(Table 2), with or without laxatives Thyroid-stimulating hormone
Electrolytes, including calcium

If symptoms do not If symptoms improve


improve

Refer to a specialist Continue same Refer for colonoscopy if there is:


for special testing therapy Weight loss
Unexplained anemia
Fever
Blood in stool

Defecatory disorder, Slow colonic transit time Normal colonic transit time
pelvic outflow dysfunction

Pelvic floor retraining Trial of novel drugs, Trial of novel drugs,


exercises, nutrition, eg, lubiprostone, eg, lubiprostone,
psychiatric evaluation linaclotide linaclotide

If symptoms improve If symptoms do not If symptoms do not If symptoms improve


improve improve

Continue same Consider colonic Repeat colonic transit Continue same


therapy manometry and study on medications therapy
surgical evaluation

If colonic transit study If colonic transit study


is abnormal is normal

Treat as slow-transit Adjust medications


constipation

FIGURE 1. Diagnosis and management of chronic constipation.

Colonic manometry is most useful in pa- TRADITIONAL TREATMENTS


tients with refractory slow-transit constipa- STILL THE MAINSTAY
tion and can identify patients with isolated Nonpharmacologic treatments are the first-
colonic motor dysfunction with no pelvic line options for patients with normal-transit
floor dysfunction who may benefit from subto- and slow-transit constipation and should pre-
tal colectomy and end-ileostomy.7 cede diagnostic testing. Lifestyle modifications
400 CLEV ELA N D C LI N I C JOURNAL OF MEDICINE VOL UME 84 N UM BE R 5 M AY 2017
HAYAT AND COLLEAGUES

and dietary changes (Table 2) aim to augment TABLE 2


the known factors that stimulate the gastro-
colic reflex and increase intestinal motility by Nonpharmacologic management
high-amplitude propagated contractions. of chronic constipation
Increasing physical activity increases in-
testinal gas clearance, decreases bloating, and Increase physical activity (most beneficial in early morning)
lessens constipation.19,20 Toilet training. Instruct patients to:
Toilet training is an integral part of life- Not ignore urges to defecate
style modifications.21 Use correct posture, ie, brace-pump technique: sit on the toilet and
Diet. Drinking hot caffeinated beverages, lean forward, with knees higher than hips and with feet supported
eating breakfast within an hour of waking up, on a step to straighten the anorectal angle
and consuming fiber in the morning (2530 g of Do deep-relaxation techniques while defecating
fiber daily) have traditionally been recommend- Avoid straining when passing stool
ed as the first-line measures for chronic consti- Not stay on the toilet for more than 510 minutes
pation. Dehydrated patients with constipation
also benefit from increasing their fluid intake.22 Dietary changes
Drink a hot caffeinated beverage after waking up
LAXATIVES Eat breakfast within 1 hour of waking up
Increase fluid intake to 1.52 L daily
Fiber (bulk-forming laxatives) Increase dietary fiber to 2530 g daily; do this slowly
for normal-transit constipation to avoid abdominal cramps and bloating
Fiber remains a key part of the initial manage-
ment of chronic constipation, as it is cheap,
available, and safe. Increasing fiber intake is with constipation. They draw water into the
effective for normal-transit constipation, but lumen by osmosis, helping to soften stool and
patients with slow-transit constipation or re- speed intestinal transit. They include macro-
fractory outlet dysfunction are less likely to gols (inert polymers of ethylene glycol), non-
benefit.23 Other laxatives are incorporated absorbable carbohydrates (lactulose, sorbitol),
into the regimen if first-line nonpharmaco-
Increasing
magnesium products, and sodium phosphate
logic interventions fail (Table 3). products. dietary fiber
Bulk-forming laxatives include insoluble Polyethylene glycol, the most studied os- is less likely
fiber (wheat bran) and soluble fiber (psyllium, motic laxative, has been shown to maintain
methylcellulose, inulin, calcium polycarbo therapeutic efficacy for up to 2 years, though
to benefit
phil). Insoluble fiber, though often used, has it is not generally used this long.26 A meta- patients with
little impact on symptoms of chronic consti- analysis of 10 randomized clinical trials found
pation after 1 month of use, and up to 60% slow-transit
it to be superior to lactulose in improving
of patients report adverse effects from it.24 On stool consistency and frequency, and rates of constipation
the other hand, clinical trials have shown that adverse effects were similar to those with pla- or refractory
soluble fiber such as psyllium facilitates defeca- cebo.27
tion and improves functional bowel symptoms outlet
Lactulose and sorbitol are semisynthetic
in patients with normal-transit constipation.25 disaccharides that are not absorbed from the dysfunction
Patients should be instructed to increase gastrointestinal tract. Apart from the osmot-
their dietary fiber intake gradually to avoid ic effect of the disaccharide, these sugars are
adverse effects and should be told to expect metabolized by colonic bacteria to acetic acid
significant symptomatic improvement only af-
and other short-chain fatty acids, resulting in
ter a few weeks. They should also be informed
acidification of the stool, which exerts an os-
that increasing dietary fiber intake can cause
motic effect in the colonic lumen.
bloating but that the bloating is temporary. If
Lactulose and sorbitol were shown to have
it continues, a different fiber can be tried.
similar efficacy in increasing the frequency of
Osmotic laxatives bowel movements in a small study, though
Osmotic laxatives are often employed as a first- patients taking lactulose had a higher rate of
line laxative treatment option for patients nausea.28
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CHRONIC CONSTIPATION

TABLE 3 Stimulant laxatives for short-term use only


Stimulant laxatives include glycerin, bisacodyl,
Agents for treating chronic constipation senna, and sodium picosulfate. Sodium piosulfate
and bisacodyl have been validated for treatment
Bulk-forming laxatives
of chronic constipation for up to 4 weeks.3133
Insoluble fiber (bran)
Soluble fiber (psyllium, methylcellulose, calcium polycarbophil) Stimulant laxative suppositories should be
used 30 minutes after meals to augment the
Osmotic laxatives physiologic gastrocolic reflex.
Polyethylene glycol, lactulose, sorbitol, magnesium hydroxide, As more evidence is available for osmotic
magnesium citrate, sodium phosphate enemas
laxatives such as polyethylene glycol, they
Stool softeners tend to be preferred over stimulant agents,
Docusate especially for long-term use. Clinicians have
Stimulant laxatives traditionally hesitated to prescribe stimu-
Bisacodyl, anthraquinones, glycerin suppository lant laxatives for long-term use, as they were
thought to damage the enteric nervous sys-
Intestinal secretagogues tem.34 Although more recent studies have not
Linaclotide, lubiprostone
shown this potential effect,35 more research is
Opioid receptor antagonists warranted on the use of stimulant laxatives for
Methylnaltrexone, neloxegol longer than 4 weeks.
AGENTS IN DEVELOPMENT
STOOL SOFTENERS: LITTLE EVIDENCE
Selective serotonin (5-HT4) agonists
Naronapride, prucalopride, velusetrag Stool softeners enhance the interaction of
Ileal bile acid transporter inhibitors
stool and water, leading to softer stool and eas-
Elboxibat ier evacuation. Docusate sodium and docusate
calcium are thought to facilitate the mixing of
Intestinal secretagogues aqueous and fatty substances, thereby soften-
Plecanatide ing the stool.
NHE3 sodium transporter inhibitors However, there is little evidence to support
Tenapanor the use of docusate for constipation in hospital-
ized adults or in ambulatory care. A recent review
reported that docusate was no better than place-
The usual recommended dose is 15 to 30 bo in diminishing symptoms of constipation.36
mL once or twice daily.
Adverse effects include gas, bloating, and INTESTINAL SECRETAGOGUES
abdominal distention (due to fermentation by The secretagogues include lubiprostone, lina-
colonic bacteria) and can limit long-term use. clotide, and plecanatide. These medications
Magnesium citrate and magnesium hy- are preferred therapy for patients with normal-
droxide are strong osmotic laxatives, but so far or slow-transit constipation once conservative
no clinical trial has been done to assess their therapies have failed. Even though there is no
efficacy in constipation. Although the risk current consensus, lifestyle measures and con-
of hypermagnesemia is low with magnesium- servative treatment options should be tried for
based products, this group of laxatives is gen- about 8 weeks.
erally avoided in patients with renal or cardiac Lubiprostone and linaclotide are approved
disease.29 by the US Food and Drug Administration
Sodium phosphate enemas (Fleet enemas) (FDA) for both constipation and constipation-
are used for bowel cleansing before certain predominant irritable bowel syndrome. They
procedures but have only limited use in con- activate chloride channels on the apical sur-
stipation because of potential adverse effects face of enterocytes, increasing intestinal secre-
such as hyperphosphatemia, hypocalcemia, tion of chloride, which in turn increases lumi-
and the rarer but more serious complication of nal sodium efflux to maintain electroneutrality,
acute phosphate nephropathy.30 leading to secretion of water into the intestinal
402 CLEV ELA N D C LI N I C JOURNAL OF MEDICINE VOL UME 84 N UM BE R 5 M AY 2017
HAYAT AND COLLEAGUES

lumen. This eventually facilitates intestinal activating submucosal neurons and increasing
transit and increases the passage of stool. gut motility.47
Two 5-HT4 receptor agonists were with-
Lubiprostone drawn from the market (cisapride in 2000 and
Lubiprostone, a prostaglandin E1 derivative, tegaserod in 2007) due to serious cardiovascu-
is approved for treating chronic constipation, lar adverse events (fatal arrhythmias, heart at-
constipation-predominant irritable bowel syn- tacks, and strokes) resulting from their affinity
drome in women, and opioid-induced constipa- for hERG-K+ cardiac channels.
tion in patients with chronic noncancer pain. The newer agents prucalopride,48 velusetrag,
Adverse effects in clinical trials were nau- and naronapride are highly selective 5-HT4
sea (up to 30%) and headache.37,38 agonists with low affinity for hERG-K+ recep-
Linaclotide tors and do not have proarrhythmic properties,
Linaclotide, a minimally absorbed 14-amino based on extensive assessment in clinical trials.
acid peptide, increases intestinal secretion of Prucalopride
chloride and bicarbonate, increasing intestinal Prucalopride has been shown to accelerate
fluid and promoting intestinal transit.39 It also gastrointestinal and colonic transit in patients
decreases the firing rate of the visceral afferent with chronic constipation, with improvement
pain fibers and helps reduce visceral pain, es- in bowel movements, symptoms of chronic
pecially in patients with constipation-predom- constipation, and quality of life.4952
inant irritable bowel syndrome.40 It is approved Adverse effects reported with its use have
for chronic constipation and constipation-pre- been headache, nausea, abdominal pain, and
dominant irritable bowel syndrome.4143 cramps.
Dosage starts at 145 g/day for chronic Prucalopride is approved in Europe and
constipation, and can be titrated up to 290 Canada for chronic constipation in women
g if there is no response or if a diagnosis of but is not yet approved in the United States.
constipation-predominant irritable bowel Dosage is 2 mg orally once daily. Caution
syndrome is under consideration. Linaclotide is advised in elderly patients, in whom the
should be taken 30 to 60 minutes before break- preferred maximum dose is 1 mg daily, as there
The newer,
fast to reduce the likelihood of diarrhea.44 are only limited data available on the safety of highly selective
Adverse effects. Diarrhea led to treatment this medication in the elderly.
discontinuation in 4.5% of patients in one study.42 5-HT4 agonists
Plecanatide
Velusetrag have a low
Velusetrag has been shown to increase colonic
Plecanatide is a guanylate cyclase-c agonist motility and improve symptoms of chronic
affinity for
with a mode of action similar to that of lina- constipation. In a phase 2 trial,53 the most hERG-K+
clotide. It was recently approved by the FDA effective dose was 15 mg once daily. Higher
for chronic idiopathic constipation in adults. receptors and
doses were associated with a higher incidence
The recommended dose is 3 mg once daily. of adverse effects such as diarrhea, headache, do not have
Data from phase 2 trials in chronic consti- nausea, and vomiting.
pation showed improvement in straining, ab-
proarrhythmic
dominal discomfort, and stool frequency after Naronapride properties
14 days of treatment.45 Naronapride (ATI-7505) is in phase 2 trials for
A phase 3 trial showed that plecanatide chronic constipation. Reported adverse effects
was more effective than placebo when used were headache, diarrhea, nausea, and vomiting.54
for 12 weeks in 951 patients with chronic
constipation (P = .009).46 The most common BILE SALT ABSORPTION INHIBITORS
adverse effect reported was diarrhea. Bile acids exert prosecretory and prokinetic
effects by increasing colonic secretion of wa-
SEROTONIN RECEPTOR AGONISTS ter and electrolytes through the activation of
Activation of serotonin 5-HT4 receptors adenylate cyclase. This happens as a result of
in the gut leads to release of acetylcholine, their deconjugation after passage into the co-
which in turn induces mucosal secretion by lon.
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CHRONIC CONSTIPATION

Elobixibat is an ileal bile acid transporter Adverse effects. Although the mu receptor
inhibitor that prevents absorption of noncon- antagonist alvimopan had been shown to be
jugated bile salts in the distal ileum. It has few associated with cardiovascular events hypothe-
side effects because its systemic absorption is sized to be a consequence of opioid withdrawal,
minimal. Phase 3 trials are under way. Dosage methylnaltrexone has been deemed to have a
is 5 to 20 mg daily. Adverse effects are few be- safe cardiovascular profile without any poten-
cause systemic absorption is minimal, but in- tial effects on platelets, corrected QT interval,
clude abdominal pain and diarrhea.55,56 metabolism, heart rate, or blood pressure.61
Side effects include abdominal pain, nausea,
MANAGING OPIOID-INDUCED diarrhea, hot flashes, tremor, and chills.
CONSTIPATION Contraindications. Methylnaltrexone is
Opioids cause constipation by binding to mu contraindicated in patients with structural
receptors in the enteric nervous system. Acti- diseases of the gastrointestinal tract, ie, pep-
vation of these receptors decreases bowel tone tic ulcer disease, inflammatory bowel disease,
and contractility, which increases transit time. diverticulitis, stomach or intestinal cancer)
Stimulation of these receptors also increases since it can increase the risk of perforation.
anal sphincter tone, resulting in decreased Dosing is 1 dose subcutaneously every
rectal evacuation.57 other day, as needed, and no more than 1
Though underrecognized, opioid-induced dose in a 24-hour period. Dosage is based on
constipation affects 40% of patients who take weight: 0.15 mg/kg/dose for patients weigh-
these drugs for nonmalignant pain and 90% ing less than 38 kg or more than 114 kg; 8 mg
of those taking them for cancer pain. Patients for those weighing 38 to 62 kg; and 12 mg for
with this condition were found to take more those weighing 62 to 114 kg.62
time off work and feel more impaired in their Naloxegol
domestic and work-related obligations than Naloxegol, FDA-approved for treating opioid-
patients who did not develop constipation induced constipation in 2014, consists of nal-
with use of opioids.58 oxone conjugated with polyethylene glycol,
For Initial management of opioid-induced which prevents it from crossing the blood-
constipation- constipation includes increasing intake of flu- brain barrier and diminishing the central
predominant ids and dietary fiber (fiber alone can worsen effects of opioid-induced analgesia. Unlike
abdominal pain in this condition by increasing methylnaltrexone, which is given by subcuta-
IBS, adjunctive stool bulk without a concomitant improve- neous injection, naloxegol is taken orally.
therapies such ment in peristalsis) and increasing physical Adverse effects reported in clinical trials63,64
activity. It is common clinical practice to use a were abdominal pain, diarrhea, nausea, head-
as peppermint stool softener along with a stimulant laxative
ache, and flatulence. No clinically relevant asso-
oil, probiotics, if lifestyle modifications are inadequate.59 If ciation with QT and corrected QT interval pro-
and acupuncture these measures are ineffective, osmotic agents longation or cardiac repolarization was noted.64
can be added. Dosing is 25 mg by mouth once daily,
have shown If these conventional measures fail, a pe- which can be decreased to 12.5 mg if the ini-
promise, ripherally acting mu-opioid receptor antago- tial dose is difficult to tolerate. It should be
nist such as methylnaltrexone or naloxegol taken on an empty stomach at least 1 hour
but more data should be considered.
before the first meal of the day or 2 hours after
are needed the meal. In patients with renal impairment
Methylnaltrexone
Methylnaltrexone60,61 is a peripherally acting (creatinine clearance < 60 mL/min), the dose
mu receptor antagonist with a rapid onset of is 12.5 mg once daily.65
action. It does not cross the blood-brain bar-
rier, as it contains a methyl group. It was ap- CONSTIPATION-PREDOMINANT
proved by the FDA in 2008 to treat opioid- IRRITABLE BOWEL SYNDROME
induced constipation in adults with advanced Irritable bowel syndrome is the reason for 3.1
illnesses when other approaches are ineffec- million office visits and 59 million prescrip-
tive. tions in the United States every year, with
404 CLEV ELA N D C LI N I C JOURNAL OF MEDICINE VOL UME 84 N UM BE R 5 M AY 2017
HAYAT AND COLLEAGUES

patients equally distributed between diarrhea- Peppermint oil is an antispasmodic that


predominant, constipation-predominant, and inhibits calcium channels, leading to relax-
mixed subtypes.66 ation of smooth muscles in the gastrointes-
To be diagnosed with constipation-predom- tinal tract. Different dosages and treatment
inant irritable bowel syndrome, patients must durations have been studied450 to 900
meet the Rome IV criteria, more than 25% of mg daily in 2 to 3 divided doses over 1 to 3
bowel movements should have Bristol stool months.71,72 The most common adverse effect
form types 1 or 2, and less than 25% of bow- reported was gastroesophageal reflux, related
el movements should have Bristol stool form in part to the oils relaxing effect on the lower
types 6 or 7. In practice, patients reporting that esophageal sphincter. Observation of this led
their bowel movements are usually constipated to the development of enteric-coated prepa-
often suffices to make the diagnosis.5 rations that have the potential to bypass the
Osmotic laxatives are often tried first, but upper gastrointestinal tract.73
despite improving stool frequency and con- Tenapanor inhibits the sodium-hydrogen
sistency, they have little efficacy in satisfying exchanger 3 channel (a regulator of sodium
complaints of bloating or abdominal pain in and water uptake in intestinal lumen), which
patients with constipation-predominant ir- in turn leads to a higher sodium level in the
ritable syndrome.67 Stimulant laxatives have entire gastrointestinal tract (whereas lina-
not yet been tested in clinical trials. Lubipro- clotides action is limited to the duodenum
stone and linaclotide are FDA-approved for and jejunem), resulting in more fluid volume
this condition; in women, lubiprostone is ap- and increased luminal transit.74 It was found
proved only for those over age 18. effective in a phase 2 clinical trial,75 and the
Antidepressant therapy most effective dose was 50 mg twice daily.
Patients often derive additional benefit from Since tenapanor is minimally absorbed, it has
treatment with antidepressants. A meta-anal- few side effects, the major ones being diarrhea
ysis demonstrated a number needed to treat of (11.2% vs 0% with placebo) and urinary tract
4 for selective serotonin reuptake inhibitors infection (5.6% vs 4.4% with placebo).75 Further
and tricyclic antidepressants in managing ab- study is needed to confirm these findings. Biofeedback
dominal pain associated with irritable bowel Tenapanor also has the advantage of in- has been
syndrome.68 The major limiting factor is usu- hibiting luminal phosphorus absorption. This controversial,
ally adverse effects of these drugs. has led to exploration of its use as a phosphate
For constipation-predominant irritable bow- binder in patients with end-stage renal disease.but trials found
el syndrome, selective serotonin reuptake in- it better than
hibitors are preferred over tricyclics because of DYSSYNERGIC DEFECATION
their additional prokinetic properties. Start- AND ANORECTAL BIOFEEDBACK placebo,
ing at a low dose and titrating upward slowly According to the Rome IV criteria,5 dyssyn- laxatives,
avoids potential adverse effects. ergic defecation is present if the criteria for and muscle
Cognitive behavioral therapy has also chronic constipation are met, if a dyssynergic relaxants
been beneficial in treating irritable bowel syn- pattern of defecation is confirmed by manom-
drome.69 etry, imaging, or electromyography, and if 1 or
Adjunctive therapies more of the following are present: inability to
Adjunctive therapies including peppermint expel an artificial stool (a 50-mL water-filled
oil, probiotics (eg, Lactobacillus, Bifidobacteri- balloon) within 1 minute, prolonged colonic
um), and acupuncture have also shown prom- transit time, inability to evacuate, or 50% or
ise in managing irritable bowel syndrome, more retention of barium during defecography.5
but more data are needed on the use of these Even though biofeedback has been contro-
therapies for constipation-predominant ir- versial as a treatment for dyssynergic defecation
ritable bowel syndrome before any definite because of conflicting results in older studies,76
conclusions can be drawn.70 Other emerging 3 trials have shown it to be better than placebo,
pharmacologic therapies are plecanatide (dis- laxatives, and muscle relaxants, with symptom-
cussed earlier) and tenapanor. atic improvement in 70% of patients.7779
CL EVE L AND CL I NI C J O URNAL O F M E DI CI NE V O L UM E 84 NUM BE R 5 M AY 2017 405
CHRONIC CONSTIPATION

Biofeedback therapy involves an instrument- intractable slow-transit constipation. Before


based auditory or visual tool (using electromyo- considering surgery, complete diagnostic test-
graphic sensors or anorectal manometry) to help ing should be done, including colonic ma-
patients coordinate abdominal, rectal, puborec- nometry and documentation of whether the
talis, and anal sphincter muscles and produce a patient also has outlet dysfunction.
propulsive force using their abdominal muscles Even though it has shown excellent out-
to achieve complete evacuation. Important comes and satisfaction rates as high as 100%
components of this therapy include: in patients with pure slow-transit constipa-
Proper evacuation positioning (brace- tion,8183 results in older studies in patients
pump technique, which involves sitting on with mixed disorders (eg, slow-transit con-
the toilet leaning forward with forearms stipation with features of outlet dysfunction)
resting on thighs, shoulders relaxed, and were less predictable.84 More recent studies
feet placed on a small footstool have reported comparable long-term morbidi-
Breathing relaxation and training exercises ty and postoperative satisfaction rates in those
during defecation (no straining, keeping a with pure slow-transit constipation and those
normal pattern of breathing, and avoiding with a mixed disorder, indicating that careful
holding the breath while defecating) patient selection is likely the key to a favor-
Use of the abdominal muscles by pushing able outcome.85
the abdomen forward, along with relax- Partial colectomies based on segmental
ation of the anal sphincter.80 colon transit time measurements can also be
The anorectal feedback program usually considered in some patients.86
consists of 6 weekly sessions of 45 to 60 min-
utes each. Limitations of this therapy include Stapled transanal resection
unavailability, lack of trained therapists, lack Stapled transanal resection involves circum-
of insurance coverage, and inapplicability to ferential transanal stapling of the redundant
certain patient groups, such as those with de- rectal mucosa. It is an option for patients with
mentia or learning disabilities. defecatory disorders, specifically large recto-
celes and rectal intussusception not amenable
SURGERY FOR CHRONIC CONSTIPATION to therapy with pelvic floor retraining exer-
cises.87
Surgery for constipation is reserved for pa-
tients who continue to have symptoms despite The efficacy of this procedure in control-
optimal medical therapy. ling symptoms and improving quality of life
is around 77% to 81% at 12 months, though
Total abdominal colectomy complication rates as high as 46% and disap-
and ileorectal anastomosis pointing long-term outcomes have been a
Total abdominal colectomy with ileorectal deterrent to its widespread acceptance in the
anastomosis is a surgical option for medically United States.8891

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