NEW TREATMENTS TO CONTROL CONSTIPATION
From Topics and Advances in Internal Medicine, sponsored by the University of California, San Diego, School of
Medicine
Jay R. Thomas, MD, PhD, Associate Clinical Professor of Medicine, University of California, San Diego, School of
Medicine, and Clinical Medical Director, San Diego Hospice and Palliative Care Center
Educational Objectives
| The goal of this program is to improve the management of constipation. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Describe the pathophysiology of opioid-induced constipation (OIC).
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| 2. Review types of laxatives available and their mechanisms of action.
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| 3. Evaluate treatment options for OIC.
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| 4. Anticipate side effects of drugs used to treat OIC.
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| 5. Discuss the burdens of current therapies for constipation.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Thomas
has received honorarium as an advisor for Wyeth Pharmaceuticals. The planning committee reported nothing to disclose.
Acknowledgments
Dr. Thomas was recorded at Topics and Advances in Internal Medicine, held March 6-12, 2008, in San Diego, CA,
and sponsored by the University of California, San Diego, School of Medicine. The Audio-Digest Foundation thanks
Dr. Thomas and UCSD School of Medicine for their cooperation in the production of this program.
| Case: woman, 28 yr of age, with pseudomyxoma peritonei, presented with subacute onset of increased abdominal pain described
as difficult to localize, sharp, 10 on a scale of 1 to 10, and associated with intermittent nausea; patient had been on
long-acting morphine 60 mg q12h and ondansetron 4 mg q8h, as needed, for nausea; she was still eating and passing gas;
denied fever and chills; reported daily soft bowel movements; no other significant medical history; physical
examination—bowel sounds present but diminished; abdomen grossly distended and dull to percussion; no clear shifting
dullness; diffuse tenderness to palpation without rebound; rectal examination showed normal tone with soft claylike
stool in vault; hospital course—for severe pain, patient started on morphine and titrated to 18 mg subcutaneously (SC;
equivalent to 1.3 g/day oral morphine); only moderate control of pain achieved; patient became more lethargic; kidney,
ureter, and bladder (KUB) x-ray performed, with stool found throughout entire colon; rectal intervention, including bisacodyl
suppositories, sodium phosphate (Fleet) enemas, and oral polyethylene glycol (PEG) provided; patient had multiple
bowel movements; pain controlled at previous dose of opioids
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| Physiology: functions of colon—water resorption (≈11 L enter small intestine, reduced to 150 mL); storage of residual
food contents (feces); mixing through segmental contraction; peristalsis (specialized coordinated contraction); coordination
with rest of body (gastrocolonic response); distention of stomach triggers transmitters in stomach, leading to increased
colonic motility; fight or flight (in certain situations, sympathetic nervous system reduces blood flow to
gastrointestinal [GI] tract and slows motility); extrinsic innervation—autonomic nervous system composed of parasympathetic
and sympathetic nervous system with innervations in GI tract; enteric nervous system neuronal “brain” in GI
tract; also myenteric and submucosal plexuses of nerves; interstitial cells of Cajal (ICC)—specialized nerve cells in GI
tract; have tight junctions and electrically connected; similar to pacemaker cells of heart; have own rhythmic electrical
activity; neurons in GI tract integrate electrical impulses from extrinsic nervous system, rhythmic automatic activity of
ICC, and local events; enterochromaffin cells—line mucosa; contain serotonin (95% of body’s serotonin in GI tract);
specialized cells sensitive to chemical stimuli and mechanical perturbation (eg, luminal stretch causes mechanical perturbation
of membranes, leading to dumping of serotonin); serotonin—important mediator; binds to receptor, setting off
wave of peristalsis
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| Causes of constipation: congenital (eg, Hirschsprung’s disease [congenital aganglionosis]); mechanical (eg, bulky tumors
that obstruct); myopathic; endocrine (eg, hypothyroidism, hypercalcemia); neurologic (eg, paraneoplastic syndrome);
psychologic (eg, depression); medications (eg, anticholinergic agents, antiserotonergic agents [eg, ondansetron];
opioids)
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| Opioid-induced constipation (OIC): in patients with advanced illness being managed with long-term opioid therapy,
incidence approaches 90%; causes significant suffering (eg, bloating, severe pain); delayed gastric emptying leads to increased
reflux; increased volume of stool and gas causes inhibition of diaphragmatic excursion, worsening dyspnea, nausea,
and vomiting (leads to aspiration pneumonia); urinary retention (increased volume in pelvis flexes neck of bladder; can lead
to delirium); fecal impaction (also causes delirium; bowel obstruction if severe enough; possibly fatal); tolerance does not
appear to develop over time; etiology—histologic studies show mu receptors localized to enteric neurons; when opioids
bind to mu receptors, several processes ensue, ie, suppression of forward peristalsis (disrupts coordination required for peristalsis,
leading to more segmental contraction, stasis, and passive absorption of water, causing stools to become harder and
dryer), reduction in GI secretions, and increase in sphincter tone
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| Treatment: detergent laxatives (stool softeners); osmotic agents; stimulant (irritant) laxatives; serotonin agonists (prokinetic
agents); selective chloride channel agonist
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| Detergent laxatives: docusate (eg, Colace) most commonly used; breaks up fat to allow greater water penetration; approved
by Food and Drug Administration (FDA); some evidence for efficacy; other mechanism (aside from detergent
action) increase in secretions
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| Osmotic laxatives: work by pulling water into GI tract; magnesium salts—concern with overuse (magnesium toxicity);
lactulose or sorbitol—disaccharides; not digestible by intestinal enzymes; passed on to colon, pulling water with
them by osmotic force; metabolized by gut bacteria, producing gas; can lead to intolerable cramping and bloating;
PEG—tasteless, odorless, and inert; comes in 2 flavors; formulation with electrolytes (GoLYTELY); specifically formulated
so no net flux of water or electrolytes across lumen; powder formulation without electrolytes (MiraLAX; flux
of water or electrolytes into lumen); when compared head-to-head with lactulose and tegaserod, found as effective and
better tolerated; decreases GI transit time, suggesting effect on motility
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| Stimulant laxatives: affect motility; when applied directly to small bowel, induce immediate smooth muscle contraction
(possibly mediated by prostaglandins); senna and bisacodyl prodrugs (need to be metabolized to active form);
senna—activated by colonic bacteria; predominant effects in colon; some concerns with long-term use (melanosis
coli; neurotoxicity) but no definitive evidence in humans; long-term studies in rats show no evidence of increased risk
for cancer or link to neurotoxicity; bisacodyl—activated by enzymes of small intestine; more peristalsis in small intestine
(more complaints of cramping)
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| Serotonin agonists: several serotonin subtypes; 5HT4 and 5HT1P most involved in coordinating forward peristalsis; partial
5HT4 agonists—metoclopramide (eg, Reglan) effective in increasing gastric motility but not for constipation;
cisapride withdrawn from market due to cardiotoxicity; tegaserod FDA-approved for constipating phase of irritable
bowel syndrome and idiopathic constipation but withdrawn from market due to cardiovascular effects (available only
on restricted basis)
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| Selective chloride channel agonists: lubiprostone; chloride channels found on apical surface of luminal epithelium and
when activated, increase secretion of chloride-rich fluid into lumen; decrease GI transit time; effect possibly similar to
osmotic laxative; clinical studies show reasonable incidence of side effects (30% had nausea)
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| Cholinergic agents: acetylcholinesterase inhibitors—pyridostigmine and neostigmine; effective for Ogilvie’s syndrome
and for palliative care patients; cholinergic agonists—bethanechol; adverse effects include cramping, nausea,
diaphoresis, and bradycardia
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| Misoprostol: synthetic prostaglandin E1 analogue; triggers contraction and secretion; small trial in patients with refractory
chronic constipation showed some efficacy, but one-third of patients dropped out due to cramping; also used as enema
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| Colchicine: some trials in idiopathic chronic constipation; microtubular inhibitor; causes diarrhea; as shown in placebo-
controlled trials, increases frequency of bowel movements and accelerates colonic transit; fairly well tolerated; adverse
effects include increased abdominal pain, neutropenia, and neuromyopathy
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| Evidence for use in treatment of OIC or opioid bowel dysfunction (OBD): little in literature; study by
Sykes—used loperamide (peripherally restricted mu agonist; causes constipation without central opioid effects); 3 arms
with 10 participants each; included in different regimens (lactulose, senna, and combination of danthron and docusate),
self-titrated to point of clinically significant bowel movements that relieved constipation; all 3 agents found effective;
median dose needed for lactulose, 55 mL po bid; for senna, 8 tablets/day (in some cases, ≤12 tablets), and for danthron
and docusate, 7 tablets/day; highest frequency of adverse events (ie, cramping) seen with senna, lowest frequency seen
with danthron and docusate
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| Guidelines: laxatives poorly studied (usually chronic idiopathic constipation and usually compared to placebo, ie, few
head-to-head comparisons); recommended that patient on opioids start with combination of stool softener and stimulant
laxative before constipation occurs
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| Burdens of current therapies: medication burden; discomfort of rectal interventions for patient and caregiver; sugar
osmotics can cause bloating and cramping; stimulants can induce cramps; when senna used long-term, risk for melanosis
coli and neurotoxicity; loss of control; cost; lack of efficacy
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| Naloxone: neutral systemically active opioid antagonist; because of poor oral bioavailability due to high first-pass effect,
expected to allow high enteric concentrations with low systemic concentrations; does induce laxation; however, unpredictable
systemic withdrawal precipitated; in some studies, even if systemic withdrawal not seen, patients experienced local
GI tract withdrawal, with increased cramping and diarrhea; those on highest doses of opioids most sensitive to
systemic withdrawal
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| Alvimopan: overall neutral molecule; zwitterion (has positive and negative charge); polar molecule (even though not
charged), therefore, little or no ability to cross blood-brain barrier; only oral form studied in clinical trials; trial—
double-blind randomized placebo-controlled; participants had OIC and using opioids long-term for nonmalignant pain or
opioid dependence, were taking 10 mg of oral morphine equivalent, and were experiencing constipation (defined as <3
bowel movements/wk, with associated symptoms [eg, hard stool, straining]); patients allowed to continue baseline laxatives,
but no rescue laxatives administered during study; median opioid dose 100 mg oral morphine-equivalent/day; 3
arms included placebo, alvimopan 0.5 mg, and alvimopan 1 mg; primary outcome proportion of patients with ≥1 bowel
movement within 8 hr of study drug on each day during 21-day treatment; placebo found to have reasonably good response;
alvimopan caused clinically significant increase in laxation, and dose response present; median time to laxation
21 hr for placebo, 7 hr for alvimopan 0.5 mg, and 3 hr for alvimopan 1 mg; no decrease in laxative use; no signs of systemic
withdrawal or increase of pain; dose-related adverse events included abdominal cramping, flatulence, nausea, vomiting,
and diarrhea; 11% of alvimopan 1-mg group dropped out (3% of 0.5-mg alvimopan group and 2% of placebo
group); trial presently on hold because of asymmetry between cardiovascular events in alvimopan and placebo arms
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| Methylnaltrexone (MNTX): from morphine molecule (systemically active mu agonist) to naltrexone (systemically
active mu receptor antagonist) to MNTX (positively charged quaternary amine); because of charge, does not cross blood-
brain barrier; oral, SC, and intravenous forms; study—double-blind randomized placebo-controlled evaluation of SC
MNTX in hospice population; constipation defined as no bowel movement for >48 hr while on stable opioid and laxative
regimen for ≥3 days; average oral morphine dose 70 to 100 mg/day; 3 arms included placebo, low-dose (weight-based;
0.15 mg/kg) MNTX, and high-dose (0.3 mg/kg) MNTX; simple 4-hr assessment, with secondary end point at 24 hr; results
showed both doses of MNTX significantly different from placebo rate of ≈13%; no dose response (both doses
equally efficacious); qualitatively significant difference in time response (time from administration of dose until bowel
movement); some patients had bowel movement 10 min after receiving dose of MNTX; ≈60% of participants responded,
then response plateaued; median times to laxation 45 min and 1 hr; for subset of participants who responded, median time
30 min (in contrast, for placebo arm >24 hr); no withdrawal and no increase in pain scores; dose response seen for some
side effects; abdominal cramping most common, followed by flatulence, nausea, and dizziness; diarrhea not commonly
seen (unlike naloxone study); no clear signs of local GI tract withdrawal; phase 3 trial—similar hospice or advanced-illness
population received MNTX or placebo every other day for 2 wk; efficacy seems to persist and remains statistically
significant for >2 wk, compared to placebo
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| PEG-naloxol: modified version of naloxone “hooked” to PEG; does not cross blood-brain barrier; administered orally;
oral-cecal transit time reduced 61%; no evidence of reversal of opioid effects; now entering phase 2 trials
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| Questions about peripheral antagonists: rescue vs prevention? how to manage patients who do not respond? in
other nonresponders, which other laxatives would best synergize? what about other peripheral mu receptor agonists (eg,
lung, bladder, chemoreceptor trigger zone, immune cells)? cost issues? class side effects?
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| Summary: OIC common and causes patients suffering; current regimens poorly studied and burdensome; further study of
existing agents and discovery of new agents needed; peripheral opioid agonists possibly useful new agents
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| Questions and answers: psyllium fiber (eg, Metamucil)—reasonable option for constipation; nondigestible bulking
agent that causes luminal stretch and triggers enterochromaffin cells and release of serotonin; hydrophilic; acceptable
as long as patients able to ingest enough water; in advanced illness, if patients not taking psyllium with enough water,
constipation worsened; docusate (eg, Colace)—some evidence of efficacy in constipation; small clinical trial of stool
softener combined with stimulant showed efficacy and possible decrease in side effects; mineral oil (oral)—possibly
effective, but no studies; risk for lipoid pneumonia; speaker does not typically use orally; enemas—used but no evidence
that one better than other; mechanical action; Harris flush variant of enema; rectal stimulation may trigger peristalsis;
danthron—stimulant laxative similar to senna; how colchicine causes diarrhea—colchicine blocks mitosis
by affecting microtubules; affects function of rapidly dividing cells, causing diarrhea (similar to chemotherapeutic
agents); role of selective serotonin reuptake inhibitors (SSRIs) in chronic constipation—not well studied; 17 subtypes
of serotonin receptors; physiology and treatment of laxative abuse—in rat studies, long-term use of senna
showed no increased risk for cancer or neurotoxicity; no human data; whether one opioid causes more constipation
than others—some studies suggest yes; problem of whether one opioid has exactly same mu agonist strength as other;
speaker believes all opioids cause constipation; speaker uses low-dose methadone to rotate with high-dose opioid for
improvement of analgesia with less constipation; which opioids recommended for prophylaxis—best empiric recommendation
(and supported somewhat by Sykes study) to start prophylactically with combination of senna and docusate;
senna has less small intestinal contraction than oral stimulant bisacodyl; docusate shown effective; titrate to
maximum level, then add osmotic; speaker initially uses sugar osmotics because less expensive; if cramping seen with
sugar osmotic, switch to PEG powder; when prescribing opioids, speaker’s personal practice to give bowel regimen
prophylactically and warn patients about opioid-induced nausea (patients become tolerant in 2-3 days);
metoclopramide—dual-action; predominantly promotility at stomach and also dopaminergic at chemoreceptor trigger
zone
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Suggested Reading
Bleser SD: Practical symptom-based evaluation of chronic constipation. J Fam Pract 55:580, 2006; DiPalma JA et
al: A comparison of polyethylene glycol laxative and placebo for relief of constipation from constipating medications.
South Med J 100:1085, 2007; Hsieh C: Treatment of constipation in older adults. Am Fam Physician 72:2277, 2005;
Iantorno G et al: Audit of constipation in a gastroenterology referral center. Dig Dis Sci 52:317, 2007; Kalish VB et
al: Clinical inquiries. What is the best treatment for chronic constipation in the elderly? J Fam Pract 56:1050, 2007;
Kamm MA: Clinical case: chronic constipation. Gastroenterology 131:233, 2006; Lacy BE: Defining and treating
constipation in older adults. Am Fam Physician 74:715, 2006; Staats PS et al: Incidence of constipation associated with
long-acting opioid therapy: a comparative study. South Med J 97:129, 2004; Talley NJ: Managing chronic constipation
from constipating medicines. South Med J 100:1070, 2007; Thomas J et al: Methylnaltrexone for opioid-induced constipation
in advanced illness. N Engl J Med 358:2332, 2008; van der Spoel JI et al: Laxation of critically ill patients
with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med
35:2726, 2007.
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