Content Planning Group
Bruce Chamberlain, MD, FACP
Janice A. Knebl, DO, MBA, FACOI, FACP, CMD
Director, Palliative Consulting
Medical Director, Sunrise Hospice, Orem, UT
Disclosures: Nothing to disclose
Resolution: N/A
Dallas Southwest Osteopathic Physicians’ Endowed Chair
in Clinical Geriatrics, Professor of Medicine and Chief, Division of Geriatrics,
General Internal Medicine and Endocrinology, Department of Medicine
University of North Texas Health Science Center at Fort Worth, Texas
Ricardo Alberto Cruciani, MD, PhD
Disclosures: Research support – Elan and Novartis
Resolution: No conflict identified, N/A
Associate Professor of Clinical Neurology,
The Saul R. Korey Department of Neurology
Assistant Professor, Department of Anesthesiology
Albert Einstein School of Medicine Yeshiva University, New York, NY
Disclosures: Non-CME Speaker: Honoraria – ENDO, Pfizer, Merck; Clinical
Trial: Research Support – Cephalon, FRALEX, GW Pharmaceuticals, Abbott;
Pain Course Organizer/Speaker – Grupo Ferret (Spain), Laboratories
Nolver (Venezuela)
Resolution: Input related to pain management and consequences of not
treating OIC considered. Other Input screened for bias by non-conflicted
faculty. Bias was not detected.
Chun-Su Yuan, MD, PhD
Cyrus Tang Professor of Anesthesia & Critical Care Department of
Anesthesia & Critical Care Director of the Tang Center of Chinese Herbal
Medicine , University of Chicago, Chicago, IL
Disclosures: Consulting Fee-Wyeth
Resolution: Treatment recommendations restricted to complementary
and alternative therapies. Other input screened for bias by non-conflicted
faculty. Bias was not detected.
Gail Austin Cooney, MD, FAAHPM
Director & Medical Director Emeritus
Sari Asher Center for Integrative Cancer Center
West Palm Beach, FL
President Elect - American Academy of Hospice and Palliative Medicine
Disclosures: Non-CME Speaker: Honorarium-Wyeth;
JPM Supplement: Editorial Stipend – Wyeth
Resolution: Input was restricted to reviewing content for clinical accuracy.
Input was screened for bias by non-conflicted faculty. Bias was not
detected.
Judy Lundgren, RN, MSN, AOCN®
Past President, Oncology Nursing Society
Radiation Oncology Nurse, Fort Worth, Texas
Disclosures: Nothing to disclose
Resolution: N/A
LeeAnne Vandergriff, RN, BSN, OCN
Oncology Nurse, Fort Worth, Texas
Disclosures: Nothing to disclose
Resolution: N/A
The University of North Texas Health Science Center has no relationships with commercial interests to disclose.
Commercial Support
This activity is commercially
supported by Wyeth.
Learning Objectives
After completing this activity, you should be able to:
• Recognize opioid-induced constipation (OIC) as one
of the most common side effects of opioid therapy
• Identify and implement steps to remove barriers to
effectively communicating with patients about OIC
and treatment options
• Determine appropriate prophylactic and prevention
measures for individual patients
• Employ an evidence-based OIC treatment protocol
which maintains patient dignity, quality of life and
pain control
The Problem is Pain
Aging population = increased need for pain
relief
Appropriate use of opioid therapy for pain
management increased in recent years
90% of chronic pain patients receive
opioids
Borowitz SM et al. Peds. 2005; Tassinari D, et al. J Palliat Med. 2008;11:492-501; 115:873-7; Benyamin R, et al. Pain Phy. 2008;11:S105-S120.
Bell TJ et al. Pain Med. 2009. 10:35-42;
Pain Management Guidelines
The World Health
Organization’s
Pain Relief
Ladder
Cancer Pain Relief and Palliative Care. Geneva, Switzerland; World Health Organization; 1990.
Constipation
Chronic Constipation:
Defecation < 3 times per week
• Primary: lifestyle issues
• Secondary: physiologic or metabolic cause
• Iatrogenic: pharmacologic agents or medical
interventions
OIC: Patient Perception is Key
Wright PS, Thomas SL; Semin Oncol Nurs; 1995;11:289-297; Thompson WG et al. Gut. 1999;45:1143-47;
Larkin PJ, et al. Palliat Med. 2008; 7:796-807;22:796-807; Droney J et al. Support Care Cancer. 2008;16(5):453-459.
Opioid-induced vs
Functional Constipation
Functional
OIC
Hard, dry stools
✔
✔
Straining
✔
✔
Incomplete emptying
✔
✔
Bloating
✔
✔
Abdominal distension
✔
✔
Gastric reflux
✔
Cramping
✔
Nausea
✔
Vomiting
✔
Improves over time
✔
De Luca A, Coupar IM. Pharm Therap. 1996;69:103-115; Goodheart CR, Leavitt SB. Pain Treat Topics. 2008. Fallon MT, Hanks GW. Palliat
Med. 1999;13(2):159-160;
What Happens in OIC?
Opioids bind to μ-opioid receptors
in GI tract
GI motility, secretion, fluid
absorption & blood flow affected
Colonic transit delayed
Sphincter tone increases
Defecation inhibited
Holzer P. Regul Pept. 2009 Apr 1.; Bell TJ et al. Pain Med. 2009. 10:35-42
Prevalence of OpioidInduced Gut Side Effects
Kalso E et al. Pain. 2004;112:372-380; Wirz S, Klaschik E. Am J Hosp Palliat Care. 2005;22:375-381; Bell TJ et al. Pain Med. 2009;10:35-42;
Impact on Quality of Life
Risk of bowel obstruction, rupture,
death
Persistent constipation = poor ECOG
score
Patients would rather return to the pain
than continue with the constipation
Choi YS, Billings JA. J Pain Symptom Manage. 2002;24:71-90. Benyamin R et al. Pain Phys. 2008:11:S105-120;
What Do Patients Do?
They skip doses,
reduce dosages or stop
taking their medication
altogether because of
opioid-induced side effects
Bell TJ et al. Pain Med. 2009. 10:35-42
The Return of Pain
Patient suffers
pain
Patient reduces
opioid use due to
side effects
Opioid-induced
constipation
Patient takes
opioids for relief
Relief occurs
The Return of Pain
92%
experienced
increased pain
as a result
Bell TJ et al. Pain Med. 2009. 10:35-42
86%
said the pain
affected their
quality of life
86%
said the pain
affected their
activities of
daily living
The Patient Speaks
“The [constipation] is terrible. I tell you, at
first I guess they didn’t tell me about it. And
I must have taken [a mild opioid with
acetaminophen] for some ungodly reason. I
don’t know why. But I took it. And I took it
for 24 hours or something like that. Anyway,
I had such terrible constipation. I mean, it
was just absolutely horrendous. Nobody
told me anything…I tell you, I was pretty
upset. I gave up on the pain medicine.”
--Patient with lung cancer
Schumacher KL, Cancer Nurs. 2002; 25:125-133.
Prescribing Opioids
Preventing Constipation
Set Realistic Expectations
Get baseline bowel history
Identify other medications that may cause or
exacerbate constipation (antihypertensives, antidepressives)
Provide pain/bowel movement log
Discuss lifestyle interventions
Plan follow-up communication
Drossman DA et al. Gastroenterology. 1982;83(3):529-534. Goodheart CR, Leavitt SB. 2008. Available at: http://www.webcitation.org/5fRvJ7Tv9.
Accessed March 21, 2009; OIC LEAP Group. February 17, 2009. Dallas, Tx;
Titrate Dosage
Does not prevent
constipation but. . .
• Provides opportunity
to identify when
constipation becomes
a problem
• Allows more
aggressive treatment
earlier
Explain to patient why
you started with lower
dose:
• Minimize side effects
(sedation, nausea,
confusion)
• Allow earlier
intervention when
side effects become a
problem
Swegle JM, Logemann C. Am Fam Physician. 2006 Oct 15;74(8):1347-54.
Opioid Induced Constipation Learning Experience Architectural Planning (LEAP) Group. February 17, 2009. Dallas, Tx.
Communicate
•Do you feel more constipated than normal?
•When was your last bowel movement?
•Can you describe the consistency?
•Has there been a change in the frequency
or type of BM you have?
•How does it feel during a BM?
(pain? straining?)
•How do you feel after defecation?
(completely empty?)
•When did the change occur?
•What are you doing about it?
Larkin PJ et al. Palliat Med. 2008;22:796-807;
Opioid Induced Constipation Learning Experience Architectural Planning (LEAP) Group. February 17, 2009. Dallas, Tx.
Evidence-Based Practice
Recommendation
OIC should be defined by both quantitative and
qualitative criteria, with the patient’s perception of
its impact on quality of life considered.
Patient/physician communication regarding the
likelihood of OIC, its prevention, treatment options
and treatment efficacy should be incorporated into
the overall treatment plan.
Sources: Larkin PJ et al. Palliat Med. 2008;22:796-807; OIC LEAP Group. February 17, 2009.
Dallas, TX
Level/type of evidence: Expert clinical opinion
OIC Prophylaxis: Lifestyle
Fluid intake
Diet/Fiber
Exercise/walking
Toileting routine/privacy
Swegle JM, Logemann. Am Fam Physician. 2006 Oct 15;74(8):1347-54.
Goodheart C, Leavitt S. Pain Treatment Topics. St. Louis MO; 2006.;
Prophylaxis
Dose Sennabased laxative
at bedtime
Docusate 100
mg bid
Advance as
needed
Swegle JM, Logemann. Am Fam Physician. 2006 Oct 15;74(8):1347-54.
Opioid Induced Constipation Learning Experience Architectural Planning (LEAP) Group. February 17, 2009. Dallas, Tx.
Evidence-based Practice
Recommendation
Patient education on lifestyle approaches that may
prevent OIC or reduce its severity should be
provided when opioids are prescribed.
Clinicians should also consider prophylactic laxatives
(bowel routine) based on individual patient needs.
Sources: Chou R et al. J Pain. 2009;10:113-130; Larkin PJ, et al. Palliat Med. 2008;22:796-807;
Level/type of evidence: Strong recommendation; moderate quality evidence; expert clinical
opinion
Treatment for
Opioid-induced
Constipation
Goals of Treatment
Increase gut
motility
Create a softer
stool
Maintain or
improve quality
of life
Swegle JM, Logemann. Am Fam Physician. 2006 Oct 15;74(8):1347-54.
Goodheart C, Leavitt S. Pain Treatment Topics. St. Louis MO; 2006.;
Opioid Induced Constipation Learning Experience Architectural Planning (LEAP) Group. February 17, 2009. Dallas, Tx.
Laxatives: Stool Softening
Surfactant
• Docusate
Osmotic
• Lactulose
• Magnesium
hydroxide
• Magnesium
sulfate
• Polyethylene
glycol
• Sodium
phosphate
Lubricant
• Mineral oil
• Do not use;
risk of
aspiration and
aspiration
pneumonia,
particularly in
the elderly
Avila JG. Cancer Control. 2004. 11:10-18; Miles CL et al. Cochrane Database Syst Rev. 2006;18:CD003448. Larkin et al. Palliat Med. 2008;
22:796-807;
Laxatives: Bulk Forming
Generally not used in this population
May lead to impaction and/or obstruction in people on
opioids who have difficulty moving the waste through
the colon
Particularly difficult for patients to get recommended
fluid and exercise required for efficacy
Avila JG.Cancer Control. May-Jun 2004;11:10-18; Thomas J. J Pain Symptom Manage. 2008;35(1):103-113.. Goodheart CR, Leavitt SB. Pain
Treat Top. August 2008. Available at: http://www.webcitation.org/5fRvJ7Tv9. Accessed March 21, 2009
Laxatives: Stimulant
Bisacodyl, senna, cascara sagrada
Induce peristalsis through nerve ending irritation
and inhibiting intestinal water absorption
May be used in conjunction with surfactant or
osmotic stool softener
Adverse effects: cramping, hypokalemia
Do not use if fecal impaction or obstruction
suspected
Xing JH, Soffer EE. Dis Colon Rectum. 2001. 44:1201-9; Thomas J. J Pain Symptom Manage. 2008;35:103-113; Hawley PH, Bevon JJ. J Palliat
Med. 2008;11:575-581.
Rectal Options
Bisacodyl suppositories
Phospho-Soda enemas
Contraindicated in neutropenic and
thrombocytopenic patients
Reserve for use in patients with fecal impaction or
those who cannot swallow oral preparations
Consider patient’s dignity and quality of life
Avila JG. Cancer Control. 2004; 11:10-18. Larkin PJ et al. Palliat Med. 2008;22(7):796-807.
Opioid Rotation
Morphine CR,
oxycodone CR,
transdermal fentanyl
Risk of constipation
78% higher in
oxycodone patients,
44% higher in morphine
CR (P=0.2242)
Donner B et al. Pain. 1996:64:527-534.Radbruch L et al. Palliat Med. 2000;14:111-119; Staats PS et al. South Med J. 2004;97:129-134;
Lubiprostone
• Selective chloride channel-2 activator
• Increases gut motility and stool passage
• Reduces straining, bloating and constipation
severity
• Indicated for chronic idiopathic constipation
Not indicated for opioid-induced constipation*
• Adverse effects include nausea, diarrhea,
headache, abdominal pain and distention
• Less common: dyspnea, chest tightness
• Clinical trial in OIC ongoing
U.S. Food & Drug Administration Center for Drug Evaluation & Research Approval History NDA 021908; Owen RT. Drugs Today. 2008; 44:64552.; OIC LEAP group meeting. Feb 17, 2009.
*as of April 2009
Opioid Antagonists:
Naloxone, Nalmefene, Naltrexone
– Systemic yet with low bioavailability
– May reverse OIC but . . .
• Cross blood/brain barrier
• May lead to opioid withdrawal and pain
Sykes NP. Lancet. 1991;337(8755):1475; Sykes NP. Palliat Med. 1996;10(2):135-144; Liu M, Wittbrodt E J. Pain Symptom Manag.
2002;23(1):48-53; Becker G, Blum HE. Lancet.2009; Epub.
Opioid Antagonist:
Methylnaltrexone
• Derivative of naltrexone
• Decreases lipid solubility so does not cross
Blood-Brain Barrier
• No effect on CNS
• High μ-affinity; low κ-affinity; no δ affinity
Yuan CS, Israel RJ. Expert Opin Investig Drugs. 2006;15:541-552.
Methylnaltrexone
in OIC
• Indicated for treatment of OIC in patients with
advanced illness who are receiving palliative care,
when response to laxative therapy has not been
sufficient
• No trials of use beyond 4 months
• Significantly reduces transit time and time to bowel
movement compared with placebo
• Subcutaneous injection only
• Most common adverse effects: orthostatic
hypotension (dose-limiting), abdominal cramps,
flatulence, abdominal pain, nausea.
U.S. Food & Drug Administration Center for Drug Evaluation & Research Approval History NDA 021964
Opioid Antagonists:
Alvimopan
• Does not cross BBB
• Higher-binding affinity for μ-opioid receptors and
higher potency than methylnaltrexone
• Active metabolite that is absorbed systematically
• Little-to-no effect on CNS-mediated effects
• Adverse effects include: low blood calcium levels,
anemia and gastrointestinal problems, including
constipation, dyspepsia and flatulence
Neary P, Delaney CP. Expert Opin Investig Drugs. 2005;14:479-488; Goodman AJ et al. ChemMedChem. 2007;2:1552-1570;
U.S. Food & Drug Administration Center for Drug Evaluation & Research Approval History NDA 021775
Alvimopan in OIC
•
•
•
•
•
805 patients with non-cancer chronic pain
2:1 randomization with placebo for 12 months
Increased risk of neoplasms: 2.8% vs 0.7%
Increased risk of MI (7 vs 0)
Approved for post-op ileus use only
Not indicated for opioid-induced constipation*
• Risk Evaluation and Mitigation Strategy (REMS)
U.S. Food & Drug Administration Center for Drug Evaluation & Research Approval History NDA 021775;
Becker G, Blum HE.. Lancet. 2009.
*as of April 2009
Complementary and
Alternative Therapies
Abdominal massage: May have some benefit
(limited data in children)
Hypnotherapy: Beneficial in IBS; Helpful in OIC?
Aromatherapy: No evidence
Biofeedback: No studies in cancer/chronic pain
patients; evidence in other patients inconclusive
Baker’s yeast: May have some benefit (uncontrolled
study) - Benefits in patients with OIC unknown
Wenk R et al. J Pain Symptom Manage. 2000;19:163-164. Kearney DJ et al. Cochrane Database Syst Rev. 2007:CD005110. Hughes D et al.
Oncol Nurs Forum. 2008;35:431-442; Kearney DJ et al. Nat Clin Pract Gastroenterol Hepatol. 2008;5:624-636; van Tilburg MA et al. BMC
Complement Altern Med. 2008;8:46. Woolery M et al. Clin J Oncol Nurs. 2008;12:317-337.
Evidence-based Practice
Recommendation
• Begin with stool softener + stimulant laxative
(senna preferred); increase dose and/or add
osmotic laxative if necessary
• Avoid bulking agents in those unable to consume
large amounts of fluid
• Consider opioid switching
• Consider adding methylnaltrexone in treatmentresistant OIC
Sources: Larkin et al. Palliat Med. 2008;22:796-807; Staats PS et al. South Med J. 2004; 97:129-134;
Radbruch L et al. Palliat Med. 2000;14:111-119; Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for
Opioid-Induced Constipation in Advanced Illness. N Engl J Med. 2008;358(22):2332-2343; Donner B et al.
Pain. 1996:527-534. OIC LEAP Group. February 17, 2009. Dallas, Tx.
Types/levels of evidence: Likely to be effective; clinical experience, randomized clinical trials
Summary
Patient/physician communication is key to
prevention and recognition of OIC
Consider prophylactic laxatives based on individual
patient needs
There is limited evidence of CAM therapies being
effective
Each patient is unique, as should be their care plan
Questions?
“Overzealous zookeeper Friedrich Riesfeldt of
Paderborn, Germany fed his constipated
elephant Stefan 22 doses of laxative and
more than a bushel of berries, figs and
prunes before the plugged-up pachyderm
finally let it fly, and suffocated the keeper under
200 pounds of poop! Investigators say ill-fated
Friedrich, 46, was attempting to give the ailing
elephant an olive oil enema when the relieved
beast unloaded on him.”
Again, each patient
is unique…treat
them that way