Supplement November 2008 Optimal Treatment of Chronic Constipation in Managed Care:

Transcription

Optimal Treatment of Chronic
Constipation in Managed Care:
Review and Roundtable Discussion
James C. Eoff III, PharmD
Anthony J. Lembo, MD
Supplement
November 2008
Vol. 14, No. 9-a
Continuing Education Activity
F a c u lt y
Editor-in-Chief
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Publisher
Judith A. Cahill, CEBS
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Academy of Managed Care Pharmacy
This supplement to the Journal of Managed Care Pharmacy
(ISSN 1083–4087) is a publication of the Academy of Managed
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James C. Eoff III, PharmD, is Executive Associate Dean and Professor of Clinical
Pharmacy at the University of Tennessee (UT) College of Pharmacy in Memphis,
Tennessee. He is responsible for recruitment, admissions, and student affairs in
the College. Dr. Eoff received both his bachelor and doctorate degrees in pharmacy
from the UT College of Pharmacy. He served on the faculty full time from 1970 to
1978, at which time he purchased Balmoral Pharmacy in Memphis. He rejoined
the College in 1984 and served as interim Dean of the College in 1989. He also
holds the position of Director of the UT College of Pharmacy’s Minority Center of
Excellence and is the principal investigator of a $2,800,000 grant for the Center’s
funding.
Dr. Eoff was appointed to the Tennessee Board of Pharmacy in 1978 and served
as President of the Board of Pharmacy in 1982. He has served as President of the
UT College of Pharmacy Alumni Association on 2 occasions, and he was the recipient of the Outstanding Alumni Award of the College of Pharmacy in 1987. He was
awarded the UT National Alumni Association’s Outstanding Teacher Award for 4
years and received the Distinguished Community Service Award in 1990. Dr. Eoff
has taught numerous courses over his career including orientation to pharmacy,
nonprescription drugs, drug abuse, clinical pharmacy, and therapeutics. He also
taught a review course for the pharmacy licensure examination for more than
30 years and is Co-Editor of the American Pharmacists Association’s Complete
Pharmacy Review.
Dr. Eoff is active in many professional organizations including the American
Pharmaceutical Association, the National Community Pharmacists Association,
the American Society of Health-System Pharmacists, the American Association of
Colleges of Pharmacy, and the Tennessee Pharmacist’s Association, who honored
him as their 1989 recipient of the A. H. Robbins “Bowl of Hygeia” Award for outstanding community service. Dr. Eoff served as President of the Tennessee Society
of Independent Pharmacists from 1989-1990 and as President of the Tennessee
Pharmacist’s Association from 1996-1997.
Anthony J. Lembo, MD, is currently Instructor in Medicine, Harvard Medical
School, Director of the Gastrointestinal Motility Center and Co-Director of the
Inflammatory Bowel Disease Center at Beth Israel Deaconess Medical Center
(BIDMC) in Boston, Massachusetts. Dr. Lembo earned his undergraduate degree
in Mathematics at Amherst College in Amherst, Massachusetts, and then received
his MD from Tufts Medical School in Boston. His Internal Medicine internship and
residency, as well as Gastroenterology fellowship, were completed at the University
of California − Los Angeles (UCLA) Medical Center in Los Angeles, California. After
completing his fellowship, he joined the faculty at UCLA Medical Center, where he
was Co-Director of the Functional Bowel Disorders and Gastrointestinal Motility
Center. In 1997, he joined the faculty at BIDMC. His research interests include
irritable bowel syndrome, constipation, and the role of placebo in functional bowel
disorders.
Table of Contents
Optimal Treatment of Chronic Constipation in Managed Care:
James C. Eoff III, PharmD, and Anthony J. Lembo, MD
S3 Impact of Chronic Constipation
S4 Etiopathogenesis and Other Risk Factors
S5 Diagnosis
S6 Management Strategies
S9 Peripheral Opioid Antagonists for Opioid-Induced Constipation
S9 Tegaserod: Removed From the Market
S9 Future Therapy Options
S9 Cost of Treatment
S10 Conclusions
S11 Roundtable Discussion
S16 Continuing Education: CE/CME Submission Instructions and Posttest Questions
Target Audience and Activity Purpose
Pharmacy and medical directors as well as managed care pharmacists and physicians interested in the diagnosis and treatment of chronic constipation.
Learning Objectives
Upon completion of this educational activity, the participant should be able to:
1. Describe management strategies for the various etiologies of constipation, including drug-related causes.
2. Evaluate the clinical impact and cost-effectiveness of traditional and newer treatment options for chronic constipation.
3. Recommend appropriate treatments based on efficacy, safety, and the potential for drug interactions while accounting
for comorbid conditions.
4. Summarize the impact of constipation on health-related quality of life.
Source of Funding and Joint Sponsorship Statement
This educational activity was supported by an educational grant from Sucampo Pharmaceuticals, Inc. and Takeda
Pharmaceuticals North America, Inc.
and produced jointly by AKH Inc. and Medical
Communications Media, Incorporated.
Continuing Education Credit
Physicians
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation
Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. and Medical Communications
Media. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this
educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate
with the extent of their participation in the activity.
Pharmacists
AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy
education. This program has been assigned the Universal Program Number 077-999-08-035-H01-P and is approved
for 1 contact hour (0.10 CEU). Initial release date: November 1, 2008; Expiration date: November 1, 2009.
www.amcp.org
Vol. 14, No. 9, S-a
November 2008
JMCP
Supplement to Journal of Managed Care Pharmacy S1
Optimal Treatment of Chronic Constipation in Managed Care: Review and Roundtable Discussion
Author Disclosures, Acknowledgement, and AKH Conflict of Interest Statement
It is the policy of AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities.
The faculty must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned
in the activity or with the commercial supporter of this continuing education activity. Identified conflict of interest is resolved by AKH prior
to accreditation of the activity. In meeting the requirements of full disclosure as required by the Accreditation Council for Continuing Medical
Education and Accreditation Council of Pharmacy Education, the faculty has provided the following information regarding potential conflicts
of interest.
Dr. Eoff has no conflicts to disclose.
Dr. Lembo discloses participation on the speakers’ bureaus of Prometheus; Salix Pharmaceuticals, Inc.; and Takeda Pharmaceuticals North
America, Inc., and as a consultant for Prometheus; Salix Pharmaceuticals, Inc.; Takeda Pharmaceuticals North America, Inc.; Ironwood
Pharmaceutical; and Wyeth Pharmaceuticals.
This supplement was written by Sara L. Thier, MPH, a professional medical writer who has the recommendations, review, and approval of the
authors. Ms. Thier discloses that her father is a member of the board of directors at Merck and Co., Inc. The authors would like to acknowledge
Dea Belazi, PharmD, for his review of the manuscript and insightful comments. Dr. Belazi discloses no conflicts related to the subject of this
supplement.
This is a self-study journal supplement, “Optimal Treatment of Chronic Constipation in Managed Care: Review and Roundtable Discussion.” The
opinions expressed in this publication are those of the authors and do not necessarily reflect the opinions or recommendations of their affiliated
institutions: Medical Commutations Media, Inc.; AKH Inc.; Sucampo Pharmaceuticals, Inc.; or Takeda Pharmaceuticals North America, Inc. Any
medications, diagnostic procedures, or treatments discussed in the program activity should not be used by clinicians or other health care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s
product information, and comparing any therapeutic approach with the recommendations of other authorities.
Disclosure of Off-Label Use
This educational activity contains discussion of unapproved (investigational) use of linaclotide and prucalopride for constipation as well as alvimopan and intravenous methylnaltrexone for opioid-induced constipation. Please refer to the official prescribing information for each product for
description of approved indications, contraindications, and warnings.
Method of Participation
There are no fees to participate in and receive credit for this activity. Credit is awarded to participants scoring 70% or better on the online posttest and completing the course evaluation. Two opportunities to pass the posttest are allowed. A CE statement can be printed upon successful
completion.
S2 Supplement to Journal of Managed Care Pharmacy
JMCP
November 2008
Vol. 14, No. 9, S-a
www.amcp.org
James C. Eoff III, PharmD, and Anthony J. Lembo, MD
Abstract
BACKGROUND: Prevalence studies estimate that chronic constipation
affects 12%-19% of Americans. This prevalence rate exceeds that of
many highly publicized chronic conditions, including diabetes and asthma.
Identifying the etiology of each patient’s constipation is essential for
determining treatment and management plans. The etiology of chronic
constipation falls into 2 broad categories: primary or idiopathic constipation
caused by physical and functional problems, and secondary constipation
resulting from a variety of organic conditions as well as the use of certain
medications. Patients may have more than one cause of their constipation.
Treatment options may be based not only on the cause but may be dictated
by a patient’s health care coverage and the inclusion criteria of different
health care plans.
OBJECTIVES: To (a) present key information on the causes, diagnosis, and
treatment recommendations for patients with chronic constipation; (b)
describe how chronic constipation impacts quality of life; and (c) describe
how all providers can work to improve the quality of care and health outcomes for patients with chronic constipation.
SUMMARY: Chronic constipation is a prevalent condition that disproportionately affects women and the elderly. Most agents are available over-thecounter, although their efficacy has not been extensively tested. Few prescription agents are currently available, and they are more costly; therefore,
managed care plans may restrict these products for patients who fail traditional treatments. A lack of evidence-based algorithms leaves many providers to treat patients empirically. Practitioners can assist patients seeking
recommendations and provide information on treatment options.
J Manag Care Pharm. 2008;14(9)(Suppl S-a):S1-S17
Copyright © 2008, Academy of Managed Care Pharmacy. All rights reserved.
Authors
JAMES C. EOFF III, PharmD, is Executive Associate Dean, University
of Tennessee College of Pharmacy, Memphis, Tennessee. ANTHONY
J. LEMBO, MD, is Instructor in Medicine and Assistant Professor of
Medicine, Harvard Medical School, and Director, Gastrointestinal
Motility Center, Beth Israel Deaconess Medical Center, Boston,
Massachusetts.
AUTHOR CORRESPONDENCE: James C. Eoff III, PharmD,
Executive Associate Dean, University of Tennessee College of Pharmacy,
847 Monroe Ave., Ste. 226, Memphis, TN 38163. Tel.: 901.448.6120;
Fax: 901.448.7053; E-mail: [email protected]
Anthony J. Lembo, MD, Director, GI Motility Center, Beth Israel
Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215.
Tel: 617.667.2138; Fax: 617.667.2767; E-mail: [email protected]
www.amcp.org
Vol. 14, No. 9, S-a
D
espite a widespread misconception that constipation is
uncommon, in reality it affects an estimated 12%-19%
of Americans, with estimates varying based on differences in diagnostic assessments, methods of data collection, and
the definition of constipation.1 Constipation may be perceived
as being less prevalent and burdensome than other conditions,
such as asthma and diabetes. In spite of this impression, estimated prevalence rates of constipation exceed many of the more
commonly discussed conditions (Figure 1).1,2 While health care
providers use the frequency of bowel movements (i.e., <3 bowel
movements per week) to define constipation, patients report
that they consider straining (81%) and hard stools (72%), among
other symptoms, to define constipation.3,4 Constipation is classified as chronic if it occurred for 12 weeks during the previous
year, although these weeks need not be consecutive. A consensus
definition of chronic constipation, known as the Rome III Criteria
(Table 1)5 requires a patient to have experienced at least 2 of the
following symptoms of constipation over the past 3 months: <3
bowel movements per week, straining, lumpy/hard stools, sensation of anorectal obstruction, sensation of incomplete defecation,
or manual maneuvering required to defecate. In addition, the
Rome III Criteria note that a patient should not meet the suggested criteria for irritable bowel syndrome (IBS) and that loose
stools are rarely present without the use of laxatives. Although
symptoms of constipation are assessed over the prior 3 months,
patients must be symptomatic for at least 6 months prior to diagnosis.5 While these criteria stand as guidelines for diagnosis, it
should be acknowledged that bowel habits differ across individuals; one person may feel distraught and uncomfortable having
only 2 bowel movements a week, while another may find this
frequency to be normal. Even though this factor is often stressed,
the number of bowel movements should not be used as the sole
indicator of chronic constipation.
In terms of demographics, women are twice as likely to
report constipation than men (18.3% vs. 9.2%) and are much
more likely to receive care for constipation (35.6% vs. 19.5%),
although the gap between women and men decreases with age.3,6
Constipation is more common in older adults, with a prevalence
rate approximating 30%-40% in those over the age of 65 years.7
Compared with whites, the prevalence of constipation is 30%
higher among nonwhite populations.7
■■ Impact of Chronic Constipation
Health Care and Health Care Costs
The scale of the economic costs associated with constipation (both direct and indirect) is becoming evident. In the
United States, the number of constipation-related physician visits
reached 5.7 million in 2006; of these, 2.7 million visits had constipation as the primary diagnosis.8 Because patients who suffer
from constipation may be embarrassed and reluctant to discuss
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FIGURE 1
TABLE 1
Prevalence of Constipation Compared
With Other Common Diseasesa
Rome III Definition of
Functional Constipationa
– Two or more of the following for the last 3 months:
Prevalence of Selected Disease in U.S. Adults
• Straining during at least 25% of defecations
6%
Coronary Heart Disease
Diabetes
• Hard or lumpy stools in at least 25% of defecations
• Sensation of incomplete evacuation in at least 25% of defecations
8%
• Sense of anorectal obstruction in at least 25% of defecations
• Manual maneuvers to facilitate in at least 25% of defecations
11%
Asthma
Migraines
• Less than 3 bowel movements per week
15%
Constipation
– Loose stools are rarely present without the use of laxatives.
– Criteria for irritable bowel syndrome are not fulfilled.
12%-19%b
a
23%
Hypertension
0
5
10
15
20
25
30
Percent
Derived from Higgins andbJohanson
(2004)1 and
Pleis andrate
Lethbridge-Cejky
Average reported
prevalence
of
(2007).2
constipation is estimated between 12% and 19%
b
(*Total
Range fromis2%
to 27%)between 12% and
Average reported prevalence rate
of constipation
estimated
19% (total range from 2% to 27%)
a
or seek care for their bowel issues, these numbers may underestimate the potential impact of constipation on health care.9 The
mean annual health care cost per patient with constipation is an
estimated $7,522, and the average annual out-of-pocket cost per
patient is estimated at $390, primarily due to purchase of overthe-counter (OTC) treatments.10 In 2004, it was reported that
Americans spent an estimated $800 million annually on laxatives alone.11 Therefore, calculations that go beyond direct medical costs to include out-of-pocket costs, even using conservative
prevalence measures, estimate that the total annual cost of care
for patients with chronic constipation in the United States is in
the billions of dollars.12
Based on 2001 national data, direct costs for constipation have
been estimated to be at least $235 million a year, which does
not include estimated OTC medication expenses.8 In addition to
these significant direct costs, the indirect costs of chronic constipation are an even greater burden. In one study, 12% of constipated participants reported missing an average of 2.4 days of
work per month due to constipation, and 60% reported impairment while at work (presenteeism) resulting in a 21% decrease in
productivity.13 Further, chronic constipation results in nearly 14
million restricted activity days per year and 3.4 million days of
bed disability.14
Health-Related Quality of Life
Along with absenteeism and daily life restrictions, chronic constipation has a significant negative impact on individuals’ healthrelated quality of life (QOL). In a recent study of 2,870 subjects
from 7 countries, constipation was associated with impairment
JMCP
Derived from Choung et al. (2003).5
in health-related QOL. The impairment seen in chronic constipation is similar to that observed in patients with longstanding
illnesses such as gastroesophageal reflux disease, diabetes, heart
disease, or depression.15 The study also noted that women with
constipation report more health-related QOL impairment than
constipated men.15 Patients with chronic constipation secondary
to pelvic floor dysfunction (i.e., pelvic dyssynergia) have an even
greater impairment in health-related QOL (and psychological distress) than patients with chronic constipation due to slow-transit
constipation (STC).16
■■ Etiopathogenesis and Other Risk Factors
The first step in managing patients with chronic constipation is
to determine whether the symptoms of constipation are due to
primary constipation (i.e., idiopathic, functional) or secondary
constipation (i.e., due to an organic disease, such as hypothyroidism or colorectal cancer).17
Primary (Idiopathic, Functional) Constipation
Primary constipation can be divided into 3 pathophysiological
groups.
1.Normal-transit constipation is the most common subtype of
primary constipation. Despite stool passing through the colon
at a normal rate, patients perceive difficulty in evacuating their
bowels. This group frequently overlaps with patients experiencing irritable bowel syndrome with constipation (IBS-C).
The primary distinction between chronic constipation and
IBS-C is the prominence of abdominal pain or discomfort in
IBS.
2.Slow-transit constipation occurs most commonly in women
and is characterized by infrequent bowel movements, limited
urgency, or straining to defecate. Most patients with STC have
impaired phasic colonic motor activity from a decrease in highamplitude propagated contractions, abnormal rectosigmoid
contractile activity, and reduced release of neurotransmitters or
altered contractile response.
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3.Pelvic floor dysfunction (i.e., pelvic floor dyssynergia) is characterized by dysfunction of the pelvic floor or anal sphincter,
with patients having poor ability to coordinate these muscles
during defecation. Patients with pelvic floor dysfunction frequently report straining at stools and feelings of incomplete
evacuation. At times, patients with pelvic floor dysfunction
will require perineal or vaginal pressure during defecation to
allow stools to pass. There is considerable overlap of patients
with pelvic floor dysfunction and STC.17 Because pelvic floor
dysfunction can cause slow colon transit, patients with STC
should be evaluated for pelvic floor dysfunction.
Secondary Constipation
A variety of medical conditions and medications may lead to
chronic constipation. The following list contains some of the
more common causes of secondary constipation.
• Medications: Many medications may cause or contribute to constipation (Table 2).9,18 Reducing the dosage of the constipationcausing medication, finding an alternative agent, or stopping
use of the constipation-causing medication may assist in relieving symptoms. Studies have shown that analgesics are significantly associated with constipation.19,20 Narcotic use is a common cause of chronic constipation and can significantly reduce
QOL. When starting narcotics, concurrent laxative use should
be considered in an attempt to prevent constipation.21,22
• Endocrine or metabolic disorders: Hypothyroidism, hypercalcemia, hyperparathyroidism, and diabetes
• Neurologic conditions: Hirschsprung’s disease, autonomic neuropathy, multiple sclerosis, and Parkinson’s disease
• Structural abnormalities: Anorectal disorders, colonic strictures, colonic mass lesions with obstruction, and idiopathic
megarectum
• Psychogenic conditions: Anxiety, depression, somatization,
and eating disorders; also, antidepressants and psychotropic
agents
• Gastrointestinal tract conditions: Colon cancer, anal fissure,
mucosal prolapse, Crohn’s disease, and stricture pseudoobstruction
• Lifestyle: Inadequate dietary fiber or fluid intake, inactivity, and
ignoring the urge to defecate
Complications of Chronic Constipation
Chronic constipation may lead to additional health problems.
The following complications are sometimes associated with
chronic constipation:23
• Hemorrhoids, which can be caused by straining and pushing.
Hemorrhoids may be internal or external and cause rectal
bleeding.
• Fecal impaction refers to the accumulation of dry, hardened
feces in the rectum or colon, thus causing an obstruction. This
complication is the most common reason for hospitalization
due to chronic constipation.
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TABLE 2
Medications Commonly Associated
With Secondary Constipationa
• Anticholinergics
• Antidepressants
• Antihistamines
• Anticonvulsants
• Calcium-channel blockers
• Clonidine (Catapres)
• Diuretics
• Iron
• Levodopa (Larodopa)
• Narcotics
• Nonsteroidal anti-inflammatory drugs
• Opioids
• Psychotropics
• Sympathomimetics
a
Derived from Locke et al.9 and Prather and Ortiz-Comacho.18
• Volvulus refers to a twisting or looping of the bowel resulting
in obstruction; this can be a life-threatening complication.
• Ulcers may be caused by pressure from hardened stool in the
colon or rectum resulting in bleeding or even perforation of the
bowel.
• Rectal prolapse can be caused by weakened ligaments and
muscles in the rectum and results in protruding rectal tissue.
• Anal Fissures are tears in the rectal region that may cause anal
pain, rectal bleeding, pain when passing stools, and blood in
stools.
• Fecal incontinence may be caused by pelvic floor dysfunction
or inability to control rectal muscles.
• Diarrhea may occur when blockage causes only watery fecal
matter to be expelled.
■■ Diagnosis
A thorough medical history and physical examination, particularly a detailed rectal examination, is essential to evaluate
and diagnose a patient with symptoms of chronic constipation.
During the history, clinicians should request information about
current medications (including OTC and herbal agents in addition to prescription agents); health conditions; duration of constipation; and description of stool movements, frequency, and
formation. During the rectal examination, providers should first
look for perianal excoriation, skin tags/hemorrhoids, anocutaneous reflex, anal fissure, and prolapse during straining. Next,
a digital rectal examination should be performed to assess for
masses in the rectum and a rectocele (an outpouching typically in
the anterior rectal wall). Significant tenderness in the anal canal
may be suggestive of an anal fissure. Finally, an assessment of the
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anal sphincter resting tone and its augmentation during squeeze
and relaxation in simulated defecation should be assessed.
Along with a thorough history and physical examination,
basic laboratory testing—including complete blood count as
well as serum glucose, thyroid-stimulating hormone, calcium,
and creatinine levels—is recommended, although there are
limited data to support these recommendations.24,25 The role of
endoscopy in the evaluation of constipation is controversial. In a
retrospective study of 563 patients with constipation undergoing
colonic surveillance for colon cancer, researchers found a similar
colon cancer detection rate in asymptomatic historical controls.26
Colonoscopy is recommended for almost all patients ≥50 years of
age as part of routine colorectal screening.27 The American Society
of Gastroenterology Endoscopy guidelines do not recommend
routine colonoscopy for patients with chronic constipation in the
absence of alarm features or warning signs.28 These warning signs
include unintentional weight loss; family history of cancer, IBS, or
celiac disease; rectal bleeding; and iron deficiency anemia.
Diagnostic testing to evaluate colonic transit and pelvic floor
functioning can be useful, especially in patients with refractory
constipation. Procedures include the following 5 tests:
1.Colonic transit: The simplest method to measure colonic transit involves the ingestion of a single capsule containing radioopaque markers (i.e., Sitz marker), followed by a subsequent
plain x-ray of the abdomen 5 days after ingestion of the markers.29 This test is most helpful in distinguishing normal-transit
and slow-transit constipation. Radio nuclide scintigraphy is
another way to measure colonic transit; however, this test is not
widely available and is more expensive and time intensive than
the radio-opaque marker test.
2.Balloon expulsion: In this procedure, a latex balloon is inserted
into the rectum and filled with air or water. The patient is then
asked to expel the balloon. Failure to expel the balloon within
60 seconds is suggestive of pelvic floor dysfunction.
3.Anorectal manometry: This test is conducted by inserting a
pressure-sensitive catheter with a balloon at its tip through the
anal canal. This test provides an assessment of rectal sensation,
anorectal reflexes, rectal compliance, and anal sphincter pressures during squeeze and bear-down maneuvers.30
4.Dynamic pelvic magnetic resonance imaging (MRI): This test
provides an assessment of the functional anatomy during defecation and therefore may identify pelvic floor dyssynergia as
well as anatomical defects that entrap the rectum and obstruct
defecation.31
5.Defecography: Similar to dynamic MRI, defecography evaluates the functioning of the anorectum (e.g., anorectal angle and
pelvic floor descent) as well as anatomical abnormalities (e.g.,
internal rectal prolapse or a rectocele).
■■ Management Strategies
Most patients with chronic constipation should first attempt lifeS6 Supplement to Journal of Managed Care Pharmacy
JMCP
style modifications: increasing dietary fiber intake to 15-20 g per
day, drinking plenty of fluid, and maintaining a regular exercise
program. Despite limited data supporting their use in clinical
practice, these lifestyle changes promote general health and may
improve bowel symptoms in some patients.32-35 Another behavioral
modification to consider includes ensuring that patients spend an
adequate amount of time on the toilet for bowel movements, preferably at a regularly scheduled time (typically in the morning to
coincide with the body’s natural gastrocolic response).
For patients who continue to experience symptoms of chronic
constipation, additional treatment may be necessary. Current
OTC and prescription options include bulking agents; stool softeners; osmotic and stimulant laxatives; and lubiprostone, a chloride channel activator. The American College of Gastroenterology
(ACG) Task Force on Chronic Constipation’s systematic review
of the literature prior to 2005 concluded that there is little evidence to support the use of many of these agents in patients with
chronic constipation with the exception of the osmotic laxative
lactulose and polyethylene glycol (PEG), which were found to be
effective at improving stool frequency and stool consistency in
patients with chronic constipation.24 Recommendations by the
ACG Task Force as well as the level of evidence for treatment
options in chronic constipation are shown in Table 3.36-40 These
recommendations do not include lubiprostone which was not
approved by the U.S. Food and Drug Administration (FDA) until
January 2006.
Anorectal biofeedback provides patients with feedback on
their pelvic floor mechanics, particularly relaxation of the anorectal sphincter in association with defecation. Patients with pelvic
floor dysfunction should be treated with anorectal biofeedback
because they are more likely to respond to this technique (i.e.,
pelvic floor retraining) than to laxatives.24,41,42
Pharmacological Treatments
A majority (96%) of patients who seek consultation for constipation have already attempted self-medication with OTC products
including bulking agents, stimulants, saline laxatives, and stool
softeners.43 Despite their frequent use, a survey conducted several
years ago found that nearly one-half of patients with chronic constipation were not completely satisfied with the efficacy of these
treatments.5 The following text reviews some of the commonly
used treatment options for chronic constipation.
Bulk Laxatives (OTC)
Bulk laxatives, also known as fiber supplements, soften the stool
and increase bulk to facilitate defecation. They are generally considered to be first-line treatment for most patients with chronic
constipation. The primary, commercially available, bulk-forming
agents are psyllium, methylcellulose, and calcium polycarbophil,
which may have a 2- or 3-day onset of action. People who begin
using bulk agents and report no relief should first increase the
frequency and dosage to the maximum recommendations before
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TABLE 3
Treatment Agents: Dosage, Cost, and Comments36-40
Typea
Generic Name
Dosage
Bulking laxatives
Psyllium
Titrate up to 30 g per
day in divided doses38
ACG
Monthly Costb Gradec
Commentsd
$1.71-$10.26
B
$8.62-$27.49
B
$7.92-$31.69
B
$11.41-$22.82
B
$25.26
A
15-30 mL qd-bid 38
$18.72-$37.44
A
8.6-30 mg qd-bid 38
$8.11-$48.69
B
10-15 mg po daily 39
10-mg rectal
suppository daily 39
$4.74-$7.10
$37.48
B
Docusate
sodium
50-100 mg qd- bid 39
$2.93-$5.87
B
Ionic detergents that soften the stool by allowing water to interact
more effectively with solid stool; may have modest effects on
fluid absorption and secretion; efficacy in constipation is not well
established
Docusate
calcium
240 mg daily 39
Mineral oil
5-45 mL po qhs39
B
Alters stool by being emulsified into the stool mass and providing
lubrication for passage of the stool; long-term use can cause
malabsorption of fat-soluble vitamins, anal seepage, and lipoid
pneumonia in patients predisposed to aspiration of liquids
Methylcellulose Titrate up to 6 g per
Polycarbophil Titrate up to 4 g per
Taken from the ground seed husk of the ispaghula plant; needs to be
taken with plenty of water to avoid intestinal obstruction; undergoes
bacterial degradation that may contribute to side effects of bloating
and flatus; allergic reactions, such as anaphylaxis and asthma, have
been reported but are rare
Semisynthetic cellulose fiber relatively resistant to colonic bacterial
degradation; tends to cause less bloating and flatus than psyllium
Synthetic polymer of acrylic acid that is resistant to bacterial
degradation
Osmotic laxatives
Magnesium
hydroxide
Polyethylene
glycol
Lactulose
Stimulant laxatives
Anthraquinones
Sennosides
Diphenylmethane Bisacodyl
derivatives
30-60 mL daily 39
17 g per day 39
Small percentage is actively absorbed in the small intestine;
remainder draws water into the intestines along an osmotic gradient
Organic polymer that is poorly absorbed and not metabolized by
colonic bacteria
Synthetic disaccharide consisting of galactose and fructose linked by
a bond resistant to lactase and therefore not absorbed by the small
intestine; undergoes bacterial fermentation in the colon resulting
in formation of short-chain fatty acids; bacteria in the colon can
metabolize up to 80 g of lactulose each day; gas and bloating are
common side effects
Anthraquinones are converted by colonic bacteria to their active
form, which increase electrolyte transport into the bowel and
stimulate intestinal motility; may cause melanosis coli, a benign
condition that is usually reversible within 12 months; no definitive
association between anthraquinones and colon cancer or myenteric
nerve damage has been established
Hydrolyzed by endogenous esterases; stimulates secretion and
motility of small intestine and colon
Stool softeners
$6.29
Emollients
Chloride channel activator
Lubiprostone
$ 9.83-$29.50
Not Activates ClC-2s in the intestine, causing fluid secretion and
graded possible secondary effects on motility; nausea is common;
administer with food and water; approved for use in adults with
chronic constipation and in women >18 years of age with IBS-C
a
From: Lembo A. Chronic constipation. AGA Web site. Available at: www.gastro.org/user-assets/Documents/08_Publications/06_GIHep_Annual_Review/Articles/
Lembo.pdf.36
8 mcg bid (IBS-C)
24 mcg bid (chronic
constipation)40
$219.98b
$228.56b
b
Prices are estimated for a 30-day supply. Ranges are rough averages for minimum to maximum recommended doses. The costs were derived from the average of the prices
in August 2008 for 2-3 products for each agent at www.drugstore.com including 60 units of either 8 mcg or 24 mcg capsules of lubiprostone.
c
Grade “A” is supported by Level I evidence (randomized controlled trials [RCT] with appropriate methodology; Grade “B” is supported by Level II evidence (RCT with
inappropriate methodology); Grade “C” is supported by Level III evidence (nonrandomized trials with contemporaneous controls) or level IV evidence (nonrandomized
trials with historical controls). Graded Recommendations available at: www.gi.org/patients/ibsrelief/pdf/gs20037147p.pdf.
d
From: Lembo AJ. Clinical crossroads: a 54-year-old woman with constipation-predominant irritable bowel syndrome. JAMA. 2006;295(8):925-33. 37
ACG = American College of Gastroenterology; bid = twice daily; ClC-2 = type-2 chloride channel; IBS-C = irritable bowel syndrome with constipation; PEG = polyethylene
glycol; qd = every day; qhs = every night; po = by mouth.
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JMCP
switching to other agents. Some patients report a worsening in
bloating, flatulence, and abdominal pain with fiber supplements;
therefore, the dose should be gradually increased over several
weeks. Fiber supplements are generally safe, but they can interfere with absorption of some medicines (e.g., warfarin, digoxin,
nitrofurantoin, salicylates) as well as calcium and iron. Psyllium
can cause bowel obstruction if taken without sufficient water.
Bulk laxatives are most effective in patients with normal-transit
constipation. In one study, up to 80% of patients in that subgroup
reported complete relief of constipation symptoms in response to
fiber (15-30 g per day) compared with 20%-30% of patients with
a defecatory disorder or STC.44
Stimulant Laxatives (OTC)
Stimulants cause rhythmic muscle contractions in the intestines by acting on the nerve plexus of intestinal smooth muscle
as well as decrease absorption of water and electrolytes from
the large intestine. Their onset of action is generally between
6 to 12 hours. Due to the limited data currently available on
stimulant laxatives for chronic constipation, the ACG Task
Force concluded that there is insufficient evidence to make a
recommendation regarding the effectiveness of stimulant laxatives in patients with chronic constipation.25 Currently available
primary stimulants are senna and bisacodyl. Stimulants are generally taken at bedtime and may cause diarrhea, cramping, and
abdominal pain. In addition, senna products may discolor the
urine, and chronic use may cause melanosis coli, a brown-black
pigmentation of the colonic mucosa. This condition does not
lead to colon cancer and is reversible over time after discontinuation of use. Electrolyte imbalance can occur in patients who
experience significant diarrhea.
Stool Softeners (OTC)
Stool softeners are surface-acting agents that moisten the stool
through a detergent action. Available agents are docusate sodium
and docusate calcium, and they are commonly used in hospitalized patients, especially after childbirth or surgery. However, the
ACG Task Force found insufficient data to support their widespread use.25 Data suggest that stool softeners may be inferior to
psyllium in patients with chronic constipation. In a 2-week, multicenter, double-blind study, use of psyllium (5.1 g twice daily)
was found to be superior to docusate sodium (100 mg twice daily)
for increasing stool frequency.45
Emollients (OTC)
Emollients promote stool movement through the intestines by
softening and coating the stool. Mineral oil is the most common example. Chronic use of emollients may decrease absorption of fat-soluble vitamins (A, D, E, K) as well as some drugs.
Unfortunately, no placebo-controlled trials of emollients in adult
patients have been conducted; however, in pediatric patients with
chronic constipation, mineral oil was found to be superior to
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stimulant laxatives46 but inferior to osmotic laxatives.47 It should
be noted that children and elderly patients may accidently aspirate this agent, which could produce lipoid pneumonia.
Osmotic Laxatives (OTC and Prescription)
Osmotic agents draw water into the colon and facilitate passage of
stool. Agents include magnesium-based therapies, such as magnesium hydroxide (milk of magnesia) and citrate of magnesia;
poorly absorbed sugars, including sorbitol and prescription lactulose; and the chemically inert polymer PEG and PEG 3350. The
best-studied osmotic laxatives are PEG and lactulose (prescription only), and there are well-designed, randomized, placebocontrolled trials supporting their effectiveness in treating chronic
constipation.48,49 While both have been found to be effective, an
open-label trial found PEG to be superior to lactulose for increasing stool frequency and reducing straining.48 A 6-month placebocontrolled study of PEG 3350 found sustained and safe positive
effects in patients with chronic constipation. Fifty-two percent
in treatment versus 11% using placebo were successfully treated
based on efficacy measures. While adverse events, such as diarrhea, flatulence, and nausea, occurred more frequently with PEG,
the difference in occurrence was not statistically significant.49
No randomized placebo-controlled trials have been conducted
with magnesium products in patients with chronic constipation; therefore, the ACG Task Force found insufficient evidence
to make a recommendation about their effectiveness in chronic
constipation.24 Primary adverse effects are flatulence, bloating,
abdominal cramping, nausea, and diarrhea with higher doses.
Electrolyte imbalances have been reported with extended use,
especially in young children and people with renal insufficiency.
Chloride Channel Activators (Prescription)
Lubiprostone is the first chloride channel activator to be approved
by the FDA. As a novel bicyclic fatty acid, it works by activating
type-2 chloride channels on the surface of intestinal epithelial
cells to enhance intestinal fluid secretion and integrity of the
epithelial tight junctions. Lubiprostone is the only medication
approved by the FDA for long-term treatment of chronic idiopathic constipation in adult men and women. It is the only agent
for chronic constipation that is FDA approved for patients >65.
The recommended dose for chronic constipation is 24 mcg twice
daily. In April 2008, the FDA approved its use in women >18
years of age with IBS-C at a dosage of 8 mcg twice daily.50
In a randomized, double-blind, placebo-controlled trial,
lubiprostone 24 mcg twice daily resulted in a greater mean
number of spontaneous bowel movements (SBMs) than placebo
(5.7 vs. 3.5; P<0.001 at week 1). Within 24 hours of starting the
medication, 57% of those given lubiprostone reported an SBM
compared with 37% of those given placebo (P = 0.002). Stool
consistency, straining, and constipation severity also significantly
improved. The most common adverse effects of lubiprostone were
nausea (32%) and headaches (12%) compared with 3% and 6%,
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respectively, with placebo.51 It is recommended that patients take
lubiprostone with food to reduce the potential for nausea.40 In
addition, women who are capable of becoming pregnant should
have a negative pregnancy test before starting the medication and
should use effective contraception while taking lubiprostone.52
There are insufficient data regarding the safety of lubiprostone in
pregnancy; therefore, the manufacturer does not recommend its
use during pregnancy.40
■■ Peripheral Opioid Antagonists for
Opioid-Induced Constipation
Two peripherally active opioid antagonists were recently approved
by the FDA. A meta-analysis demonstrated that methylnaltrexone
and alvimopan were better than placebo in reversing opioidinduced increased gastrointestinal transit time and constipation.
The incidence of adverse events with opioid antagonists was
similar to placebo, and adverse events were generally mild to
moderate in severity. The authors concluded that while methylnaltrexone and alvimopan show promise, further data are required
to fully assess their place in therapy.53
Methylnaltrexone Bromide
In late April 2008, the FDA approved a new medication for
treating opioid-induced chronic constipation in terminally ill
patients with advanced conditions such as incurable cancer,
end-stage heart and lung diseases, and AIDS.54 Methylnaltrexone
bromide is a derivative of naltrexone that does not cross the
blood-brain barrier. It acts as a selective antagonist at peripheral
opioid receptors without blocking the central effects, as analgesia
does. Opioids interfere with normal bowel function by relaxing
intestinal smooth muscle cells, which prevents the intestine from
contracting normally.21 Methylnaltrexone bromide blocks opioid
receptors on the intestinal muscle cells, thus allowing the bowels
to function normally. The drug is not recommended for patients
with known or suspected intestinal obstructions.
Alvimopan
Alvimopan is a peripherally acting mu-opioid receptor antagonist
developed to block the adverse side effects of opioid analgesics on
the gastrointestinal tract. Like methylnaltrexone bromide, it acts
without blocking the central effects, as analgesia does. Along with
treating opioid-induced constipation, the FDA approved alvimopan
in May 2008 for use with post-operative ileus “to accelerate the time
to upper and lower gastrointestinal recovery following partial large
or small bowel resection surgery with primary anastomosis.”55
■■ Tegaserod: Removed From the Market
Tegaserod, a serotonin 5-HT4 receptor partial agonist, was
approved by the FDA in July 2002 for women with IBS-C and for
men and women <65 years of age with idiopathic constipation.
While found to be very effective, its safety profile came under fire
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when the FDA reviewed data from 29 clinical trials and more
than 18,000 patients and found a small increased risk in cardiovascular adverse events (including angina, heart attacks, and
stroke) when compared with controls taking placebo.56
In March 2007, marketing for tegaserod was discontinued.
However, the manufacturer initiated a restricted access program
in collaboration with the FDA in July 2007. After 8 months, this
access program was reassessed, and the product was voluntarily
withdrawn from the market in April 2008.57
■■ Future Therapy Options
Linaclotide
Linaclotide is a first-in-class compound that is being tested for
treatment of IBS-C, chronic constipation, and other gastrointestinal disorders. Linaclotide is an agonist of guanylate cyclase
type-c, which is a receptor found on the lining of the intestine.
In a phase 2b study, linaclotide was found to increase SBMs and
complete spontaneous bowel movements (CSBMs), with a significant, dose-related improvement in bowel habits. There was no
evidence of rebound constipation, and the most common adverse
event was dose-dependent diarrhea.58
Prucalopride
5HT-4 receptor agonists target serotonin-4 receptors, which are
involved in initiating peristalsis in the intestines. Prucalopride is
a highly selective complete 5-HT4 agonist that has been shown
to increase bowel movements and appears to be effective in the
treatment of chronic constipation. In a 12-week randomized,
placebo-controlled trial of prucalopride 2 mg and 4 mg daily,
bowel changes and adverse events were studied. The percentage
of participants in the treatment groups having 3 or more CSBMs
per week, averaged over the study period, was significantly
higher in the 2 treatment groups versus placebo (2 mg: 47.3%;
4 mg: 46.6%; placebo: 25.8%). The most frequently reported
adverse events included headache and abdominal pain, and no
significant cardiovascular effects occurred. These recent findings
hold promise that prucalopride may be a safe, effective treatment
for chronic constipation.59
■■ Cost of Treatment
Of the total costs for managing and treating constipation, a
large portion is spent by patients on OTC agents. Although few
prescription medications exist for constipation, acquisition costs
for these agents are high, and these costs must be considered
when managed care plans assess formularies and coverage. In
addition, diagnostic testing and surgeries contribute to the direct
costs reported for constipation. Managed care plans often weigh
the secondary and tertiary costs related to a condition to help
guide decisions on the appropriateness and level of coverage for
more expensive interventions.
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JMCP
Pharmacoeconomics
Laxatives
Because a majority of chronic constipation patients first attempt
to self-medicate the condition and because first-line treatments
for symptom relief are traditional OTC products, it is not surprising that expenditures for these treatments are high. An estimated
$800 million was spent on laxatives, stool softeners, and other
symptom-relieving products.10 Because these are OTC treatments, the cost burden is primarily (if not totally) shouldered
by the patients themselves. Unfortunately, very few studies have
directly compared treatment options for chronic constipation.
While prescription drugs may appear to be more effective, often
lower-cost (nonprescription) medications may be substituted
successfully.
With a captive audience, nursing homes are good sites to test
these hypotheses. For example, one nursing home lowered its
cost for constipation prevention and management by switching
from lactulose to regular use of sorbitol. In this population, the
efficacy of sorbitol was equivalent to prior use of lactulose, and the
need for additional laxatives and rescue products was reduced.
Overall, the nursing home reported a 27%-55% reduction in
costs compared with other management strategies reported in
the literature.60 An even less expensive alternative has been the
increasing use of oat bran in the diets of nursing home residents
with constipation. A small study examined the use of dietary
fiber compared with a control group. A dietary fiber supplement
in the form of an oat bran cake allowed 59% of the treatment
group to discontinue laxative use.61 While these switches may
not work for all patients, these results stress that, in terms of cost
savings, treatment can commence with simpler therapies (e.g.,
laxatives, fiber) and then proceed to more aggressive agents if
symptoms do not resolve.
Lubiprostone
Some health plans require patients to fail with more conservative
OTC therapies before authorizing coverage of lubiprostone.62,63
Lubiprostone may be placed on the highest copayment level
(nonpreferred or nonformulary) of multitier medication benefits
because many OTC products may be effective options when compared with this more expensive prescription medication. Still,
as part of a step therapy program, lubiprostone’s demonstrated
effectiveness makes it an important option for many patients who
are not successfully treated by OTC agents.
Methylnaltrexone Bromide
Methylnaltrexone bromide reduces the incidence of opioidinduced constipation when nearing the end of life. While this
medication is obviously targeted to a subcategory of patients,
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its subcutaneous injection administration and projected costs
make this an interesting case for managed care to weigh the
cost-benefits and cost-effectiveness when making formulary
inclusion decisions.
Although methylnaltrexone bromide may actually be administered either subcutaneously or intravenously, it is currently
only FDA approved for subcutaneous use. Ongoing clinical trials regarding the intravenous use of methylnaltrexone can be
found at www.clinicaltrials.gov (1 completed, 1 in progress, 1
recruiting). Past studies have already concluded that repeated
intravenous administration of methylnaltrexone appears to be
safe and effective, and intravenous doses of 0.32 mg per kg are
well tolerated.64,65
Technology and Diagnostic Testing Costs
Questions have been raised concerning which diagnostic tests are
the most appropriate to order and when they should be ordered.
In addition, some have questioned the effectiveness of these tests
in determining when surgery is warranted.66 Evidence to support routine laboratory testing is lacking. Similarly, there is a
paucity of data to support the use of radiography and endoscopy
in patients with constipation but no warning signs as part of a
routine workup. While certain diagnostic tools, such as colonic
transit, anorectal manometry, and balloon expulsion tests, are
useful in determining the abnormalities and possible etiology of
constipation symptoms, no single test can adequately define the
pathophysiology. Therefore, it is not always clear which tests have
the most utility or are the most cost-effective.66
■■ Conclusions
1.Chronic constipation is a prevalent condition that disproportionately affects women and the elderly.
2.Chronic constipation can be categorized as primary (idiopathic, functional) constipation or as secondary constipation
resulting from comorbidities or other factors, including medications. Diagnostic testing and tools are useful in determining
the etiology and classifying the subtype of constipation as well
as guiding recommended therapy.
3.Treatment begins with empiric recommendations including an
increase in fiber, exercise, and water intake and may include
OTC agents, such as osmotic and stimulant laxatives. Even
though evidence for the efficacy of many of these medications
is lacking, some patients find that these lifestyle changes and
therapies provide significant relief of symptoms.
4.There are a limited number of FDA-approved medications to
treat chronic constipation. Because of the expense of these
agents, they are typically only prescribed when traditional OTC
treatments fail.
November 2008
■■ Roundtable Discussion with James C. Eoff III, PharmD,
and Anthony J. Lembo, MD
Educating the Patient on Prevention and Management
When educating patients about prevention and treatment of
constipation, what should a provider stress?
Lembo: Lifestyle factors are what we should emphasize. First, stress
eating a healthy diet, such as limiting processed foods and increasing dietary fiber, typically to 20 g per day. In addition, patients
should also be educated to exercise regularly and to keep well
hydrated by drinking at least eight 8-ounce glasses of water a day.
Is there a distinction between dietary versus commercial
fibers? Are commercial fibers more effective?
Lembo: There’s no evidence that commercial fibers are more
effective than dietary fibers for chronic constipation. Psyllium is
the best studied of the commercial fibers, while bran is the best
studied of the dietary fibers. Both have strong evidence of their
effectiveness, especially in patients with mild to moderate constipation.44,45,61 Commercial fibers are more convenient for people,
and it is easier to control the amount of fiber intake. Instead of
making adjustments because of the variability of your diet from
day-to-day, you know exactly what you’re getting when you
take a commercial fiber. It is important to stress that the patient
should drink plenty of water when eating or taking a commercial
fiber, particularly psyllium.
How effective are OTC products?
Eoff: Many OTC products are quite effective if the right product
is used and used correctly. You will know whether most OTC
products are effective in the treatment of chronic constipation
within 6 weeks, but you need to ensure that patients use the
proper dose for the product. With fiber agents, taking the recommended dose for several weeks is very important. While you
will see initial effects within several days, this allows patients to
determine whether there is true relief and whether they are getting rid of any additional symptoms besides focusing solely on
the number of bowel movements. Are they still experiencing a lot
of straining, hard stools, or abdominal pain? If those symptoms
are continuing, then they may need to try other medicines. One
key question and concern is whether patients are taking the full
dose of the medicine. For example, while taking an agent like
psyllium, some people will use a teaspoon of the fiber product
rather than a tablespoon. They might then say, “Well, this is not
working.” Yet, it’s because they are not using the maximum dose
or are not dosing multiple times daily as recommended.
Also, it would be important to work with the patient to identify
what types of symptoms they are still experiencing. We know a
lot of people who still have other symptoms, even though they are
being treated for constipation and have increased the number of
bowel movements per week. How can we address those symptoms? Do patients continue to strain excessively, feel like they have
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Vol. 14, No. 9, S-a
not evacuated completely, or have very hard, dry stools? We would
then look at alternative agents and determine whether they really
need additional fiber. What type of fiber are they taking? Do they
need to shift to some osmotic agents (either saline or a PEG product), or should a stimulant with a stool softener be considered?
Many agents are available, and each has its own mechanism
of action. Approximately one-half of patients using treatments are
still not getting relief from symptoms.4 This suggests that they
may need to consult either their primary care provider or a pharmacist to determine whether they are using the right product and
whether alternative agents might be more effective in alleviating
their symptoms. Most algorithms suggest the use of OTC agents
first before you jump to a prescription agent, which can be more
expensive.24,25,65 The Johanson et al. survey of patients noted that
while 96% had used and 72% were currently using constipation relief therapy, 47% were not completely satisfied with their
treatment. This lack of satisfaction was primarily due to lack of
efficacy (82%).4
Lembo: This questionnaire asked patients whether they had
“complete” satisfaction with their treatment. Complete relief is
a high hurdle to overcome, especially with currently available
treatments. Because patients with significant but not “complete”
relief were not assessed by this study, it likely overestimates the
magnitude of dissatisfaction with currently available treatments.
Eoff: Will anybody ever be completely satisfied? Complete satisfaction would result from not needing to use any agents.
Lembo: Right. Still, it is important information and tells us
what goal we should strive for.
With continued use of laxatives, OTC agents, and prescriptions, are there any interactions with other drugs of which
people should be aware?
Lembo: Most of these agents are pretty well tolerated. We worry
about giving magnesium, such as milk of magnesia or magnesium citrate, to people with renal insufficiency or administering
phosphorus-based compounds.
Eoff: Although it was thought that psyllium may decrease
absorption of digoxin, warfarin, carbamazepine, and lithium,
there are no conclusive reports of this effect being clinically significant. Similarly, magnesium hydroxide may decrease absorption of warfarin, digoxin, and chlorpromazine, but no conclusive
research confirms this belief. I think the key would be to avoid
taking these agents at the same time during the day. For example,
take one agent in the morning and the other in the evening,
which may minimize any interactions. No clinically significant
interactions with PEG or lubiprostone have been reported.
Treatment
Are there algorithms for treatment?
Lembo: There are no evidence-based algorithms for the treatment of chronic constipation. Therefore, treatments are based on
November 2008
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FIGURE 2
Prescription Coverage
Shared Gastrointestinal
Dysmotility Symptomsa
Symptoms >3 mo
CC
IBS-C
Straining
+++
+++
Hard/lumpy stools
+++
+++
<3 BM per week
+++
+++
Feeling of incomplete evacuation
+++
+++
Bloating/abdominal distension
++
+++
Abdominal pain/discomfort
+
+++
CC and IBS-C lie along a spectrum of abdominal discomfort and pain
Abdominal Discomfort
+
CC
IBS-C
a
Derived from Thompson et al. (1999)68 and Drossman et al. (1997)69
BM = bowel movement; CC = chronic constipation; IBS-C = irritable bowel syndrome
with constipation.
consensus opinion. These opinions take efficacy data, costs, and
potential adverse reactions into account. Typical recommendations start with fiber and then add osmotic agents followed by
either stimulants or lubiprostone.24,25,67
Where do the prescription medications, such as lubiprostone,
fit into treatment?
Lembo: OTC products are usually the first line of therapy.
Managed care organizations realize that these may not be effective for all patients and managed care allows for the use of lubiprostone, often as the next step in therapy if OTC agents fail.
Is treatment of chronic constipation in pregnancy different?
Lembo: The American Gastroenterological Association Institute
published a Position Statement on the Use of Gastrointestinal
Medications in Pregnancy.52 In this statement, short-term use of
osmotic laxatives is considered to be low-risk treatment in pregnancy, but long-term use of saline osmotic laxatives, like magnesium citrate or sodium phosphate, should be avoided because
they can be harmful to the fetus. PEG, which has a pregnancy
class C rating, is considered to be low-risk treatment, and it’s
the preferred treatment for chronic constipation in pregnancy.
Docusate sodium is also considered to be a low-risk agent. Senna
and bisacodyl should be recommended only for short-term use.
Castor oil and mineral oil should be avoided because they can
be harmful. Although the statement does not mention lubiprostone, it also has a pregnancy class C rating, and it has been
associated with increased fetal loss of life in one animal model.
Because there are limited data for humans, it should be avoided
in pregnant women. It is recommended that a pregnancy test be
obtained prior to initiating lubiprostone in women who are of
childbearing potential, and women should be advised to use an
effective contraceptive while on this medication.40
JMCP
There are currently only a few prescription drugs for
constipation that would actually have to be covered by
managed care, isn’t that correct?
Eoff: That would be correct. Lubiprostone is one of them. PEG has
just been moved to OTC status, so managed care plans are likely
not going to be paying for that agent for the treatment of constipation, although PEG coverage will continue for bowel evacuant
purposes. A more recently approved product is methylnaltrexone
for opiate-induced constipation, but it is being studied for other
types of constipation.
Lembo: Methylnaltrexone is only approved for end-of-life
therapy (i.e., in patients who have a prognosis of 6 months or
less to live). Alvimopan, also recently approved by the FDA, is
an oral peripheral opioid antagonist. Because alvimopan is an
oral medication, it is likely to be better accepted for patients with
opioid-induced constipation.
Chronic Constipation Versus Irritable Bowel Syndrome With
Constipation
How do you differentiate between IBS-C and chronic
constipation?
Lembo: Sometimes it can be difficult to make a clear distinction between the 2 entities. There is significant overlap between
IBS-C and chronic constipation because they share features of
decreased, altered motility in the lower gastrointestinal tract.
The way they are distinguished clinically is by the presence and
severity of abdominal pain. The more pain that’s present, especially when it’s a predominant feature, the more consistent the
symptoms are with IBS-C. A lack of pain and discomfort would
be more consistent with chronic constipation. And, in between,
there is overlap between the two (Figure 2).68,69
Again, the criteria for chronic constipation and IBS are not the
same. Rome III Criteria for chronic constipation specifically state
that to receive a diagnosis of chronic constipation, “criteria for IBS
are not fulfilled” (Table 1); again, these IBS-C criteria include the
presence of pain or discomfort. The problem occurs when people
with chronic constipation symptoms have discomfort in their
abdomen, which is not uncommon. If you look at the IBS-C and
chronic constipation groups as a whole, what helps distinguish
between them — besides the discomfort of abdominal pain — is
the frequency of bowel movements. Bowel movement frequency
is usually greater in the IBS-C group than in the chronic constipation group.
Do treatments differ between IBS-C and chronic
constipation?
Lembo: In terms of treatment, you will treat constipation similarly in both cases. However, in the IBS-C group, you would also
try to treat the pain, which would not be a treatment factor in
chronic constipation. So, with IBS-C, once stool frequency and
November 2008
consistency are improved, you would use a visceral analgesic if
there are still symptoms of pain and discomfort. For example, a
tricyclic antidepressant would be an option. Antispasmodics may
help pain, but you have to use them sparingly because they are
constipating. Even though laxatives may help bowel function,
they probably don’t do much for pain in this group. Similarly,
there are good data suggesting that fiber can certainly help bowel
function, but it doesn’t help the pain associated with IBS-C.
Lubiprostone is the only FDA-approved medication for IBS-C. If
other therapies do not work, it is the next logical treatment step
for this condition.
changes into their daily lives. But then you have the bedridden
patient who can’t exercise at all. Although you want to make sure
that they get enough dietary fiber, that alone isn’t typically going
to help bedridden patients if they’re constipated. You need to look
at another agent to help with constipation and its accompanying
symptoms. For those who are mobile, more alternatives are readily available to try. The American Medical Directors Association
does provide clinical practice guidelines and a treatment algorithm for those in long-term care.71
Though antidepressants help IBS-C pain, aren’t they
associated with causing constipation?
Lembo: Yes, so you would want to use them sparingly and when
pain is the predominant feature, but only after bowel habits
have been improved. A Clinical Crossroads article published in
JAMA presents more information about the overlap and stresses
the fact that you have to watch for constipation with tricyclics.37
For example, selective serotonin-reuptake inhibitors may be a
better alternative for someone with IBS-C because they are less
constipating.
What role do you see the pharmacist playing in
constipation care?
Eoff: One way that the pharmacist can play an integral role is by
reviewing with patients all of the medications they are using and
then assessing whether these agents may be creating constipation
and whether alternatives are available. Another task is to assist
patients in taking a comprehensive, current medication history
and to provide them with documentation that they can maintain, update, and share with other providers. Pharmacists can
also promote lifestyle changes, such as moderate exercise and
increased dietary fiber. Finally, pharmacists can be on the alert
for “red flags”—those things that may warrant more extensive
investigation into the etiology of the constipation as opposed to
just idiopathic constipation. These would be some of the main
pharmacist responsibilities as patients seek to manage their constipation. Again, most patients will get some positive effects from
OTC agents, but it is important that they understand how to use
them appropriately. Be sure to ask whether they have allowed
enough time for the product to work and have used the product
as directed. Another important aspect of working with patients
concerns their out-of-pocket costs. OTC medications can be an
appropriate first choice of therapy for chronic constipation, generally with savings in direct drug costs compared with prescription
medication. Yet, with the exception of polyethylene glycol (PEG),
the data demonstrating effectiveness of OTCs are limited, and the
drug therapy ultimately most cost-effective for each patient will
depend on individual patient response to therapy.
Care in the Nursing Home
How do describe treatment strategies for people in nursing
homes, particularly those who are bedridden or immobile?
Lembo: The management of patients with constipation in nursing
homes is similar to the treatment of other patients. Constipation
in nursing home patients is usually multifactorial. Being bedridden, having multiple comorbid conditions, using multiple
medications, using narcotics, and other factors all contribute to
the high prevalence of constipation in nursing home residents. In
one study—which may still be the only study showing the incidence of constipation among new nursing home residents—7%
developed significant constipation within their first 3 months in
the nursing home.70 It is particularly challenging, and particularly
important, that they don’t become impacted or develop complications of constipation. Along with impaction, obstruction and stercoral ulcers are additional concerns. Therefore, I believe that most
patients should be placed on some type of prophylactic treatment
to prevent constipation.
Eoff: The American Medical Directors Association does provide clinical practice guidelines and a treatment algorithm for
those in long-term care.69 These may be useful as many residents
may have Medicare Part D coverage, which can affect a facility’s
medication use and reimbursements.
Do all facilities start new residents on prophylactics?
Lembo: Not all, but many do, especially if there is any evidence of
trouble or changes in bowel habits. Because constipation is very
common, facilities are particularly attuned to the development of
constipation and its sequelae, such as fecal impaction.
Eoff: Everybody recommends some exercise and some modification of diet for patients who are able to incorporate those
www.amcp.org
Vol. 14, No. 9, S-a
Pharmacist’s Role
It is important for pharmacists and providers to partner and
be consistent in educating the patient. Is there a formal way
of communicating information related to constipation?
Eoff: There are more formal communication processes for institutionalized and nursing home patients, but less formal processes
in a retail pharmacy setting. It is in the retail pharmacy where the
patient will show up and say, “I have been using this product and
it’s not working.” If the patient has gone through the gamut of OTC
medicines, then usually the pharmacist’s recommendation will be
to discuss these problems with a primary care provider. If there
are any red flags or warning signs, the patient may be advised
to see a gastroenterologist for an evaluation. The pharmacist’s
important role is not only to advise patients on agents, but also to
link them back into the health care system when necessary.
November 2008
JMCP
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59.Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med.
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residents with dementia: sorbitol effectiveness and cost. J Am Med Dir Assoc.
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61.Sturtzel B, Elmadfa I. Intervention with dietary fiber to treat constipation and reduce laxative use in residents of nursing homes. Ann Nutr Metab.
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49.Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic
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64.Yuan CS, Doshan H, Charney MR, et al. Tolerability, gut effects, and
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51.Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, doubleblind, randomized, placebo-controlled trial of lubiprostone, a locally-acting
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65.Foss JF, O’Connor MF, Yuan CS, Murphy M, Moss J, Roizen MF. Safety
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52.Mahadevan U, Kane S. American Gastroenterology Association Institute.
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68.Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel
disorders and functional abdominal pain. Gut. 1999;45(suppl 2):11,43-47.
69.Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome:
a technical review for practice guideline development. Gastroenterology.
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2008.
70.Robson KM, Kiely DK, Lembo A. Development of constipation in nursing
home residents. Dis Colon Rectum. 2000;43(7):940-43.
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57.Novartis. Zelnorm. Available at: www.zelnorm.com/index.jsp. Accessed
August 11, 2008.
www.amcp.org
Vol. 14, No. 9, S-a
November 2008
JMCP
C o n t i n u i n g E d u c at i o n
This is a self-study journal supplement designed for physicians and pharmacists. Participation should take approximately 1
hour. To complete this activity and receive credit, the participant should:
1. Read the continuing education program information, including learning objectives,
2. Read and review the educational supplement, and
3. Complete the posttest and evaluation form. Please go to the AMCP.org CME/CE Center to complete the Posttest and
Evaluation.
Accreditation
Physicians
This activity has been planned and implemented in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. and Medical Communications Media. AKH Inc. is accredited by the ACCME to provide continuing medical
education for physicians. AKH Inc. designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™.
Physicians should only claim credit commensurate with the extent of their participation in the activity.
Pharmacists
AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy
education. This program has been assigned the Universal Program Number 077-999-08-035-H01-P and is approved
for 1 contact hour (0.10 CEU). Initial release date: November 1, 2008; Expiration date: November 1, 2009.
Disclaimer
These materials and all other materials provided in conjunction with continuing medical education activities are
intended solely for purposes of supplementing continuing medical education programs for qualified health care professionals. Anyone using the materials assumes full responsibility and all risk for their appropriate use.
Continuing education for this activity is processed through the AMCP.org Online Learning Center site at www.amcp.
org (CE/CME Center). No mailed forms will be accepted.
The posttest worksheet on the following page is provided to assist you in marking your answers prior to entering the
online CE Center for submission.
To receive CE credit for this program, you must complete the following forms online:
1. Posttest form for this program, “Optimal Treatment of Chronic Constipation in Managed Care: Review and
Roundtable Discussion,” on the AMCP.org Online Learning Center site. To receive CE credit, you must receive a score
of at least 70%. You will have 2 opportunities to pass the posttest.
2. Activity evaluation form.
Upon successful completion of this activity, you will automatically receive your CE statement. Your CE credits will
be automatically archived and tracked for you on the AMCP.org (CE/CME Center) site. All information is kept confidential. Note: There is no fee to participate in this activity. Credit is available from November 1, 2008 through
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JMCP
November 2008
Vol. 14, No. 9, S-a
www.amcp.org
Worksheet: Optimal Treatment of Chronic Constipation in Managed Care: Review and Roundtable Discussion
7. True or False. Because most OTC medications are relatively mild, constipation during pregnancy can be treated
with the same agents used by nonpregnant females.
1. Which of the following is not a possible secondary cause
of constipation?
a. Eating disorders
b. Hyperthyroidism
c. Multiple sclerosis
d. Analgesic use
e. All are possible causes
True ______ False ______
8. Which constipation symptom is most commonly reported
by patients?
a. Hard stools
b. Bloating and gas
c. Decreased frequency of bowel movements
d. Straining
2. The distinguishing factor/s that separate/s IBS-C from
chronic constipation include/s:
a. Number of bowel movements is less and stools are
lumpier in chronic constipation
b. IBS-C is more prevalent in men
c. Blood pressure rises slightly higher with chronic
constipation
d. Abdominal pain/discomfort is part of the definition
of IBS-C but is not included in the definition of chronic constipation
9. Which diagnostic test is most helpful in distinguishing
between normal-transit and slow-transit constipation?
3. Constipation ______ with age.
a. Increases
b. Decreases
a.
b.
c.
d. Defecography
Colonic transit
Anorectal manometry
None of the above
10. Each year, ______ is spent on OTC laxatives.
4.
The most common subtype of constipation is:
a. Dyssynergic defecation
b. Slow-transit constipation
c. Normal-transit constipation
d. None of the above
a.
b.
c.
d. $1 billion
$800 million
<$100 million
$4 million
5. Alarm symptoms accompanying constipation that require
the need for diagnostic testing include:
a. IBS
b. Iron deficiency anemia
c. Rectal bleeding
d. All of the above
6. A study by Johanson et al.4 demonstrated that during the
first 24 hours of lubiprostone treatment, approximately
______% of patients reported spontaneous bowel
movements.
a. 15.9
b. 57
c. 90
d. <14
To complete this activity, go to www.amcp.org (CE/CME Center),
where you will access the posttest and evaluation form.
www.amcp.org
Vol. 14, No. 9, S-a
November 2008
JMCP
Supplement

Supplement November 2008 Optimal Treatment of Chronic Constipation in Managed Care:

Transcription

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