Bruce Chamberlain, MD, FACPDirector, Palliative Consulting

Medical Director, Sunrise Hospice, Orem, UT

Disclosures: Nothing to disclose Resolution: N/A

Ricardo Alberto Cruciani, MD, PhDAssociate 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, PhDCyrus 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-WyethResolution: Treatment recommendations restricted to complementary and alternative therapies. Other input screened for bias by non-conflicted faculty. Bias was not detected.

Janice A. Knebl, DO, MBA, FACOI, FACP, CMDDallas Southwest Osteopathic Physicians’ Endowed Chairin Clinical Geriatrics, Professor of Medicine and Chief, Division of Geriatrics, General Internal Medicine and Endocrinology, Department of MedicineUniversity of North Texas Health Science Center at Fort Worth, Texas

Disclosures: Research support – Elan and NovartisResolution: No conflict identified, N/A

Gail Austin Cooney, MD, FAAHPMDirector & Medical Director EmeritusSari Asher Center for Integrative Cancer CenterWest Palm Beach, FLPresident Elect - American Academy of Hospice and Palliative MedicineDisclosures: Non-CME Speaker: Honorarium-Wyeth; JPM Supplement: Editorial Stipend – WyethResolution: 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 SocietyRadiation Oncology Nurse, Fort Worth, TexasDisclosures: Nothing to disclose Resolution: N/A

LeeAnne Vandergriff, RN, BSN, OCNOncology Nurse, Fort Worth, TexasDisclosures: Nothing to disclose Resolution: N/A

Content Planning Group

The University of North Texas Health Science Center has no relationships with commercial interests to disclose.

Commercial Support

This activity is commerciallysupported by Wyeth.

Learning ObjectivesAfter 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

Cancer Pain Relief and Palliative Care. Geneva, Switzerland; World Health Organization; 1990.

The World Health Organization’s Pain Relief

Ladder

Constipation

• 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.

Chronic Constipation: Defecation < 3 times per week

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 Opioid-Induced 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 takes opioids for

relief

Relief occursOpioid-induced

constipation

Patient reduces opioid use due to side effects

The Return of Pain

92% experienced

increased pain as a

result

86% said the pain affected their quality of life

86% said the pain affected their activities of daily living

Bell TJ et al. Pain Med. 2009. 10:35-42

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.

•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?

Communicate

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, TXLevel/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 Senna-based 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 absorptionMay 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 patientsReserve for use in patients with fecal impaction or those who cannot swallow oral preparationsConsider 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 constipationNot 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; 44:645-52.; 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

Yuan CS, Israel RJ. Expert Opin Investig Drugs. 2006;15:541-552.

• 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

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 inconclusiveBaker’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 treatment-

resistant OICSources: 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