Bruce Chamberlain, MD, FACP Director, Palliative Consulting Medical Director, Sunrise Hospice, Orem, UT Disclosures: Nothing to disclose Resolution: N/A Ricardo Alberto Cruciani, MD, PhD 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. Janice A. Knebl, DO, MBA, FACOI, FACP, CMD 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 Disclosures: Research support – Elan and Novartis Resolution: No conflict identified, N/A 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 Content Planning Group 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 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 FunctionalOIC 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 occurs Opioid-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.
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.. 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? 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, 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 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
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; 44:645- 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 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 treatment- resistant 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
“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