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44-1
CONSTIPATION
All Bound Up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II
Michelle Fravel, PharmD, BCPS
CASE SUMMARY
A 64-year-old woman with a history of hypertension, dyslipidemia,
diabetes mellitus type 2, hypothyroidism, and osteoarthritis with
recent TKA presents to the ED with complaints of constipation. She
has a number of drug therapy problems that students must identify;
she is also taking several medications that may be contributing to
her constipation. In developing a treatment plan for constipation,
students should consider general nonpharmacologic approaches
such as increased dietary fiber, fluid intake, and appropriate bowel
habits. A variety of medications are available for treating constipation. Students should be able to identify those that are first-line
choices for chronic use and those that should be reserved for acute
treatment, treatment failure, or intolerance. Given this particular
case, students should be able to identify appropriate therapy for
treatment and prevention of opioid-induced constipation. Students
should be able to identify laxatives that are first-line choices in this
setting and those that may be harmful.
QUESTIONS
Problem Identification
1.a. Develop a list of the potential drug therapy problems in this
patient other than those related to her constipation.
• Obesity: With a body mass index (BMI) of 41.3 kg/m2, the
patient is considered morbidly obese; significant weight loss
is indicated.
• Elevated glucose: This patient has type 2 diabetes, and the fasting blood glucose is elevated; however, her A1C (a measure of
blood glucose control over the past 3 months) is within target
levels. No further action is needed at this time.
• Cardiovascular risk: Low-dose aspirin therapy (75–162 mg
daily) is recommended for patients with diabetes and increased
cardiovascular risk (10-year risk >10%). This includes most
men >50 years and women >60 years who have at least one
additional cardiovascular risk factor (eg, premature family history, hypertension, dyslipidemia, smoking, and albuminuria).
Her current aspirin dose of 325 mg daily should be decreased.1
• Drug interaction: When used with diltiazem, the dose of simvastatin should not exceed 10 mg daily due to increased risk of
muscle injury, a simvastatin dose that would be considered low
intensity. The patient’s current statin and dose (simvastatin
20 mg) is considered moderate intensity statin therapy. The
2015 American Diabetes Association Standards of Medical
Care for diabetes recommends high-intensity statin therapy
for individuals between 40 and 75 years of age with diabetes
mellitus and cardiovascular risk factors (LDL >100 mg/dL,
hypertension, obesity, or smoking).1 This patient’s statin therapy should be changed to one of the high-intensity regimens
• A subjective report by the patient of abdominal cramping and
pain, bloating, and nausea/vomiting.
• A report of decreased bowel movement frequency (none in
last 6 days).
• Palpable stool and decreased bowel sounds on physical examination. (There was no evidence of rectal bleeding or anal fissures.)
• Rectal exam indicating fecal impaction.
• Abdominal computed tomography (CT) showed a large
amount of stool in the colon.
• The patient’s laboratory results ruled out hypokalemia, hypercalcemia, and endocrine disorders such as uncontrolled hypothyroidism that could be causing her constipation.
1.c. What are some of the possible nonpharmacologic contributors to her constipation?
• Limited mobility following TKA and decreased oral intake
may result in constipation.
1.d. What are some of the possible pharmacologic contributors
to constipation in this patient?
• Oxycodone: an opioid that slows peristalsis and overall bowel
transit.
• Diltiazem: a calcium channel blocker that causes relaxation of
the smooth muscle of the intestinal tract.
• Bulk-forming laxative (Metamucil): nondigestible colloids
that absorb water in the gastrointestinal tract to increase bulk,
thereby causing peristalsis. With opioid inhibition of peristalsis, this added bulk cannot stimulate movement, and instead
may lead to worsened constipation or even bowel obstruction.2
1.e. What information should be obtained from a patient who
presents with a chief complaint of constipation?
It would be helpful to obtain answers to the following questions:
• What are the symptoms and how long has the patient been
experiencing these symptoms?
• How long has it been since the last bowel movement? How
many times per week does the patient typically have bowel
movements?
• What drugs and doses is the patient currently taking?
• What high-fiber foods are included in the diet (specifically
fruits, vegetables, and grains)?
• How much fluid is the patient currently consuming?
• What is the patient’s recent activity level?
• What other symptoms is the patient experiencing (eg, bone
pain or rectal bleeding) that may lead you to believe there is
an underlying disease state contributing to the constipation?
• What, if anything, has the patient tried in the past for constipation, and how well did it work?
Desired Outcome
2.
What are the goals of pharmacotherapy in treating
constipation?
• Assuming that an underlying condition is not suspected, the
goals of therapy are to provide relief from acute constipation
and to prevent further episodes of constipation with minimal
adverse consequences.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Constipation
Beth Bryles Phillips, PharmD, FCCP, BCPS
1.b.What signs or symptoms are indicative of constipation in
this patient?
CHAPTER 44
44
(eg, atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin
20 mg, or rosuvastatin 40 mg), which would also eliminate the
drug interaction.
44-2
SECTION 4
• In this patient, appropriate goals are increased frequency of
bowel movements and prevention of recurrent constipation.
Therapeutic Alternatives
3.a. What are some nonpharmacologic steps useful in treating
constipation?
Gastrointestinal Disorders
• A diet high in fiber is beneficial to most patients with uncomplicated constipation. Patients should gradually increase
dietary fiber intake to 25–35 g per day. Foods with soluble
fiber, such as beans, peas, oat bran, and bananas, dissolve in
water to form a gel which assists in addressing constipation.
Foods containing insoluble fiber minimize constipation by
increasing bulk; examples of these foods include whole grains,
wheat bran, and dark green leafy vegetables.3
• Adequate fluid intake and mobility/ambulation are additional
general measures that may be taken to ensure proper bowel
function.
• Patients may also be instructed to set a regular time aside to
respond to the urge to go to the bathroom, particularly after
breakfast in the morning.
3.b.What are the pharmacologic options for the treatment of
constipation?
• See Table 44-1 for drug therapy alternatives.
3.c. Is this patient’s current regimen for hypertension appropriate? If not, what recommendations can you make to optimize this regimen?
• Diltiazem may be contributing to constipation and will
increase risk for recurrent constipation in the future. Alternative therapy for blood pressure control should be considered
that will not increase risk for constipation.
• Patients with hypertension, diabetes mellitus, and proteinuria
benefit from angiotensin-converting enzyme inhibitor (ACEI)
or angiotensin receptor blocker (ARB) therapy due to renal
protective effects and reduction in cardiovascular morbidity.
TABLE 44-1 Pharmacologic Options for the Treatment of Constipation
Onset of
Action
Medication
Drug/Dose
Mechanism of Action
Bulk-forming
laxatives
Psyllium (Metamucil, Perdiem, Fiberall):
one to two teaspoonfuls (or packets)
in 8 oz of water or juice TID
Methylcellulose (Citrucel): one
tablespoonful in 8 oz of water
daily to TID
Polycarbophil (FiberCon): 1 g PO QID
(maximum 6 g/day)
Increase bulk and decrease
transit time of stool in the
colon
Docusate sodium (Colace): 50–100 mg
PO BID
Lower stool surface tension
and promote the mixture of
aqueous and fatty materials,
resulting in softened stool
1–3 days
Coat and lubricate the stool
to allow easier passage
through the GI tract
1–3 days
Cause water retention in the
colon, which promotes
intestinal motility
1–3 days
Emollients
Docusate calcium (Surfak): 240 mg PO
daily
Lubricants
Osmotic
laxatives
Docusate potassium (Dialose): 100 mg PO
daily to TID Mineral oil: 5–30 mL PO daily
Poorly absorbed sugars:
Lactulose: 15–30 mL (10–20 g) PO daily
to BID
Sorbitol: 15–30 mL of a 70% solution
PO daily to BID
Polyethylene glycol (PEG)
PEG and electrolytes (Colyte, GoLYTELY):
17–36 g PO daily to BID
PEG 3350 (MiraLAX): 17–36 g PO daily
to BID
Saline laxatives:
Magnesium hydroxide (Phillips Milk of
Magnesia): 15–30 mL PO daily to BID
Sodium phosphate (Fleet Phospho-Soda):
20–45 mL PO × 1 dose
Glycerin: 3-g suppository
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
1–3 days
1–6 hours
1–6 hours
<30 minutes
Comments
Minimal systemic absorption
Relatively safe with low potential for adverse effects
May cause abdominal distention and flatulence
when initiating therapy; these effects tend to
resolve with time
It is important to take these products with plenty
of water to avoid obstruction in the esophagus,
stomach, and intestine
Efficacy in acute bouts of constipation not well
established
Used primarily to prevent constipation in situations
such as recovery from surgery when straining during
a bowel movement may be harmful to the patient
Relatively safe but may promote intestinal
absorption of some drugs
Long-term use can cause malabsorption of
fat-soluble vitamins and anal seepage
Lipoid pneumonia has occurred in patients
predisposed to aspiration
Adverse effects include flatulence, cramps, and
diarrhea
May cause electrolyte imbalances if used routinely.
Avoid lactulose in lactose-intolerant patients
Sorbitol is generally preferred over lactulose due to
equal efficacy and lower cost
Nausea, abdominal fullness, and bloating can occur
May cause less cramping than other osmotic
laxatives
Minimal absorption
PEG 3350 does not contain electrolytes and may
cause less electrolyte imbalances
Magnesium can be absorbed in the small intestines
Hypermagnesemia can occur in patients with renal
failure and in children
Hyperphosphatemia can occur in patients with renal
insufficiency
Sodium phosphate is typically used as a bowel
evacuant
Generally considered safe
Often used in children
May cause some rectal irritation
(continued)
44-3
Onset of
Action
Drug/Dose
Mechanism of Action
Stimulants
Diphenylmethane derivatives:
Bisacodyl (Dulcolax): 10–15 mg PO or
10 mg suppository
Anthraquinone derivatives:
Cascara sagrada: 5 mL or 325 mg
tablet PO
Senna (Senokot): dose varies depending
on formulation
Lubiprostone (Amitiza): 24 mcg PO BID
with food
Stimulates colonic motor
activity
Increases intestinal fluid
secretion
24 hours
5-HT4 agonist
Tegaserod maleate (Zelnorm)
Increases gastrointestinal
motility
1 week
mu-Opioid
antagonists
Methylnaltrexone bromide (Relistor):
<38 kg: 0.15 mg/kg
38–61 kg: 8 mg
62–114 kg: 12 mg
>114 kg: 0.15 mg/kg
Usual dose: one dose every other day; may
be administered no more than once daily
Alvimopan (Entereg): 12 mg PO administered 30 minutes to 5 hours prior to
surgery followed by 12 mg BID for up
to 7 days; maximum of 15 doses
Inhibit opioid-induced
slowing of gastrointestinal
motility
30 minutes
to 4 hours
N/A
Naloxegol (Movantik):
25 mg once daily, taken 1 hour prior to
the first meal of the day or 2 hours
after; dose may be reduced to 12.5 mg
daily if full dose is not tolerated
6–12 hours
Guanylate
cyclase-C (GC-C)
agonist
Linaclotide (Linzess): 145 mcg orally once
daily at least 30 minutes prior to the first
meal of the day
Agonism of GC-C increases
levels of cyclic guanosine
monophosphate (cGMP)
that leads to secretion of
chloride and bicarbonate
into the intestinal lumen,
causing an increase in intestinal fluid and faster transit
1 week
Chloride
channel
stimulator
6–12 hours
Comments
May cause severe abdominal cramping
Electrolyte disturbances may occur with repeated
use
Converted by colonic bacteria to active form
Abdominal cramping may occur
May cause melanosis coli
Optimal Plan
Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain
Efficacy not established in patients taking
methadone
May cause nausea, diarrhea, or headache
High cost may limit use to patients who failed or are
intolerant of other agents
Limited to use in patients 55 years of age and
younger with chronic constipation or IBS in
emergency situations due to cardiovascular risk;
request for use must be submitted to FDA
Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain
May cause nausea, gas, diarrhea, dizziness, or
sweating
High cost and SQ administration may limit use
Currently only approved for short-term hospital
use to accelerate the time to upper and lower GI
recovery following surgeries that include partial
bowel resection with primary anastomosis
Increased incidence of MI was seen in clinical trials
with long-term use
This medication is only available through the
restricted ENTEREG Access Support and Education
(E.A.S.E) Program
Approved for treatment of opioid-induced constipation in adults with chronic, noncancer pain
Dose reduction is necessary when used in combination with CYP3A4 inhibitors
High cost may limit use to patients who failed or are
intolerant of other agents
Discontinuation of laxatives is recommended prior
to initiation of naloxegol
Currently only approved for chronic idiopathic
constipation and constipation associated with
irritable bowel syndrome (higher dose indicated
for irritable bowel syndrome)
Contraindicated in pediatric patients (up to 6 years
old) and patients with gastrointestinal obstruction
Severe diarrhea may occur
4.After nonpharmacologic measures have been attempted, what
is the most appropriate drug regimen for her, including dose
and schedule? Provide the rationale for your answer.
opioid-induced constipation: slowed transit (offset by a stimulant laxative) and decreased fluid content in the stool, due to
increased time in the gastrointestinal tract (addressed by stool
softener).2,4 Refer to Table 44-1 for dosing guidelines. Therapy
should be continued until oxycodone is discontinued.
• Although randomized controlled trial evidence supporting the
use of nonprescription laxatives for the treatment of opioidinduced constipation is lacking, a combination stool softener/
stimulant regimen, such as docusate plus senna, is a common
recommendation in clinical practice because these medications address the two main physiological issues occurring in
• The selective mu-receptor antagonists, methylnaltrexone, alvimopan, and naloxegol, comprise a newer class of medications
with a mechanism of action specific for reversal of opioidinduced constipation. These medications antagonize the effects
that opioids have on the mu-receptors in the periphery
(ie, gastrointestinal tract). Due to their pharmacology, these
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Constipation
Medication
CHAPTER 44
TABLE 44-1 Pharmacologic Options for the Treatment of Constipation (continued)
44-4
SECTION 4
Gastrointestinal Disorders
agents do not cross the blood–brain barrier, and therefore do
not reduce the analgesic effect of opioids. Although mechanistically and theoretically ideal for treatment of all opioidinduced gastrointestinal adverse effects, the agents have been
studied in selected patient populations with small numbers of
patients and currently possess limited therapeutic indications.
Additional limiting factors for use of these agents include the
need for subcutaneous administration of methylnaltrexone,
restriction of alvimopan to in-hospital use, and high cost with
all three agents. Currently, no selective mu-receptor antagonist
is FDA approved for use in the treatment of constipation due
to acute opioid therapy. Furthermore, although efficacy has
clearly been demonstrated in certain populations and conditions, these agents may not be effective in all patient populations; 50% of patients in clinical trials failed to respond to this
type of therapy.5,6
• Lubiprostone is also approved for treatment of opioid-induced
constipation in patients with chronic noncancer pain. It
opposes the antisecretory effects of opioids by activating gastrointestinal chloride channels and increasing intestinal fluid
secretion to improve fecal transit. Limitations to widespread
use of lubiprostone include lack of demonstrated efficacy in
patients taking methadone and high cost.7
• The patient’s use of a bulk-forming laxative should be discontinued due to the acute worsening of constipation it may cause,
as described previously.
• Although not likely to cure the current issues with opioidinduced constipation, the patient’s diltiazem may be switched
to an alternative agent, as described previously, to prevent
future issues with recurrent constipation.
• The patient still requires pain control, so discontinuation of
the main offending agent (oxycodone) is not a feasible option.
Dose reduction may be considered; however, incomplete pain
control would be a major concern.
Outcome Evaluation
5.a. How would you monitor this patient to ensure that your pharmacotherapeutic goals have been achieved? How would you
follow-up with her to ensure resolution of the constipation?
• It is appropriate to monitor for a decrease in the subjective feeling of constipation. In addition, an increase in the frequency of
bowel movements, a decrease in straining and abdominal distention, and the presence of adverse events associated with the
medications are all appropriate symptoms or signs to monitor.
• A follow-up phone call in 1 week to assess this patient’s response
to your interventions is appropriate. She could be asked to be
seen in the outpatient clinic in approximately 1 month for a
more thorough follow-up of all of her medical problems.
Clinical Course
5.b. You reassure the patient that this problem can be prevented
with her next surgery and that you will discuss options with
her physicians. What regimen would you recommend for
preventing opioid-induced constipation in this patient if she
chooses to go through with the second TKA procedure?
• Because the docusate/senna combination regimen you recommended for the first episode was effective, this regimen would
be optimal to recommend for prevention with future opioid use.
• Use of stool softener monotherapy for the treatment of opioidinduced constipation should be avoided due to questionable
efficacy.8
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Patient Education
6.a. What education would you provide to this patient who has
concerns about recurrence of drug-induced constipation?
• It is essential to explain to the patient about all of the factors
that contributed to her past constipation and inform her as
to how these issues can be addressed in the future to prevent
constipation when opioids are used again.
• This conversation should include: (1) a warning against use
of bulk-forming agents while taking opioids; (2) an emphasis
on the importance of maintaining adequate hydration and
ambulation; (3) an explanation that a laxative regimen should
be started with the first dose of opioid therapy; and (4) a
recommendation that open communication with a provider
regarding any signs or symptoms of constipation should occur
immediately.
6.b. What education would you provide to this patient regarding
her concerns about laxative addiction?
• Medications such as oxycodone have a direct effect on the gastrointestinal tract, which causes constipation. Once analgesia
is no longer needed and opioid therapy can be discontinued,
bowel habits return to normal without the need for a laxative.
6.c. When instructing this patient on using a stimulant laxative,
what information should you convey to ensure appropriate
use of this product?
• Senna (Senokot) is a stimulant laxative that causes movement
in the intestine resulting in a bowel movement.
• The dose of senna depends on the individual product. Refer
to the dosing directions on the label of the product selected.
• Senna may be used as needed for constipation. In general,
senna is reserved for short-term use.
• Senna works relatively quickly: between 6 and 12 hours after
a dose is taken.
• Common adverse effects may include abdominal cramping
and diarrhea.
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1.American Diabetes Association. Standards of medical care in
diabetes—2016. Diabetes Care 2016;39:S1–S112.
2. Panchal SJ, Muller-Schwefe P, Wurzelmann JI. Opioid-induced bowel
dysfunction: prevalence, pathophysiology and burden. Int Clin Pract
2007;61:1181–1187.
3.Shah BJ, Rughwani N, Rose S. Constipation. Ann Intern Med.
2015;162:ITC1. doi:10.7326/AITC201504070.
4. National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology: Palliative Care. V.1.2016 [Online]. Available
at: http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf.
Accessed September 3, 2016.
5.Thomas J, Darver S, Cooney GA, et al. Methylnaltrexone for
opioid-induced constipation in advanced illness. N Engl J Med
2008;358:2332–2343.
6. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced
constipation in patients with noncancer pain. N Engl J Med
2014;370:2387–2396.
7. Davis M, Gamier P. New options in constipation management. Curr
Oncol Rep 2015;17:55.
8. Tarumi Y, Wilson MP, Szafran O, et al. Randomized, double-blind,
placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013;45:2–13.