Planning Committee 10/22/2009. All other planners and staff involved in developing content had nothing to disclose.

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1 Planning Committee Catherine Eberle, MD Associate Professor Department of Internal Medicine Section of Geriatrics i & Gerontology University of Nebraska Medical Center Nothing to Disclose Richard Roberts, MD, JD, FAAFP, FCLM Professor University of Wisconsin Department of Family Medicine Dr. Roberts has disclosed that he has served on an advisory board for and received honoraria from Astellas No conflict identified Roy Martin, DMin Assistant t Professor, Clinical i l Ethics University of North Texas Health Science Center Nothing to Disclose Susan Franks, PhD Associate Professor University of North Texas Health Science Center Nothing to Disclose Expert Content Reviewers Note: reviewers did not develop content, but provided feedback as to accuracy of study interpretation, clarity of educational concepts and recommendations for content improvement Bruce Chamberlain, MD, FACP, FAAHPM Palliative Care Consultations Dr. Chamberlain has disclosed that he has served as a non CME speaker for Wyeth. Conflict resolved. Katherine Galluzzi, DO, FACOP Professor and Chairperson, Department of Geriatrics Philadelphia College of Osteopathic Medicine Nothing to Disclose Dennis McCullough, MD Community Geriatric Consultant Associate Professor Community and Family Medicine Dartmouth Medical School Nothing to Disclose All other planners and staff involved in developing content had nothing to disclose. 1

2 Presenting Faculty Disclosure Faculty Name: Dr. Lee A. Kral Title/affiliation: PharmD, BCPS, Center for Pain Medicine and Regional Anesthesia, University of Iowa Hospitals and Clinics City/state: Iowa City, IA Conflict of Interest Dr. Kral attended a speaker training course sponsored by Pricara in February Activity Name: Opioid Induced Constipation in Palliative Care Sponsored by Interstate Postgraduate Medical Education Objectives: Describe to patients and other members of the healthcare team why opioid induced constipation (OIC) should be a concern in palliative care; Educate patients and other members of the healthcare team about the physiologic mechanisms leading to constipation as a side effect of opioid therapy and how OIC differs from other types of constipation; and Recommend and implement practical lifestyle and medical strategies to assess for and manage OIC in the palliative care patients Faculty Name: Dr. Lee A. Kral, PharmD, BCPS, Center for Pain Medicine and Regional Anesthesia, University of Iowa Hospitals and Clinics, Iowa City Accreditation and Designation Statements Interstate Postgraduate Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Interstate Postgraduate Medical Association designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Acknowledgement of Commercial Support Interstate Postgraduate Medical Association and the Hospice and Palliative Care Association of Iowa gratefully acknowledge Wyeth Pharmaceuticals for providing an education grant in support of this activity. 2

3 Accreditation and Credit Sponsored By Interstate Postgraduate Medical Association Accreditation Statements Interstate Postgraduate Medical Association i is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement Interstate Postgraduate Medical Association designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity is supported by an educational grant from Wyeth Pharmaceuticals. Learning Objectives After taking part in this activity, participants should be better able to: Describe to patients and other members of the healthcare team why opioid induced induced constipation (OIC) should be a concern in palliative care; Educate patients and other members of the healthcare team about the physiologic mechanisms leading to constipation as a side effect of opioid therapy and how OIC differs from other types of constipation; and Recommend and implement practical lifestyle and medical strategies to assess for and manage OIC in palliative care patients. 3

4 Rome Criteria: Definition of Constipation The presence of two or more of the following symptoms for at least 12 weeks 1 Straining at least 25% of the time Hard stools at least 25% of the time Incomplete evacuation at least 25% of the time 2 or fewer bowel movements per week Patients who complain of constipation when symptoms do not satisfy these criteria may require treatment 2 1. Drossman DA, et al. Gastro Enterol. 1990;3: Larkin PJ et al. Palliative Med. 2008;22: Prevalence of Opioid Induced Gut Side Effects Results from a US and European Patient Survey (PROBE 1) % Bell TJ, et al. Pain Med. 2009;10:

5 Pathophysiology of Opioid Effects on Gut Motility Opioid binding to µ opioid receptors in the GI tract is primarily responsible for inhibition of gut motility (also kappa, sigma, delta) µ µ µ µ directly affects the myenteric plexus µ Kurz A, Sessler DI. Drugs. 2003;63: Actions of Opioids on the GI Tract Site of Action Pharmacologic Action Clinical effect Decreased pancreatic & biliary secretion Delayed digestion Small intestine Large intestine Reduced propulsion Increased fluid absorption Decreased propulsion Increased non propulsive contractions Increased fluid absorption Increased anal sphincter tone Delayed absorption of medications Hard, dry stool Straining, incomplete evacuation, bloating, abdominal distension, constipation Spasm, abdominal cramps, pain Hard, dry stool Incomplete evacuation Kurz A, Sessler DI. Drugs. 2003;63:

6 The Return of Pain Pain Returns Patient reduces opioid use due to side effects Pain Occurs Patient takes opioids for relief Opioidinduced constipation Pain Relieved The Challenge of Caring for the Palliative Care Patient with OIC: Other Contributors to Constipation Other constipating drugs (anticholinergics, NSAIDs, TCA, iron) Tumor compression Neural plexus invasion Constipation Autonomic failure Metabolic Disorders ( Ca, K, or hypothyroidism) Miles C, et al. Cochrane Database of Systematic Reviews. 2006, Issue 4. Art. No.: CD

7 The Challenge of Caring for the Palliative Care Patient with OIC: Lifestyle Contributes to Constipation Normal Bowel Activity Increased Risk of Constipation Normal exercise/ movement Lack of exercise/ movement Normal fiber intake Reduced fiber intake Normal fluid intake Reduced fluid intake Miles C, et al. Cochrane Database of Systematic Reviews. 2006, Issue 4. Art. No.: CD The Challenge of Caring for the Palliative Care Patient with OIC: Other Contributors to Constipation Patients May not report constipation due to embarrassment Healthcare professionals May neglect constipation among the myriad other end of life medical concerns 2 May be reluctant to become involved in this intimate personal issue 1 May be unaware of the high prevalence and impact of constipation in palliative care 2 1. Miles C, et al. Cochrane Database of Systematic Reviews. 2006, Issue 4. Art. No.: CD Larkin PJ et al. Palliative Med. 2008;22:

8 Clinical Symptoms & Patient Discomforts of Constipation Abdominal Anorexia 1 pain/distension1 1 Hlit Halitosisi 2 Nausea, vomiting 1 Headaches 2 Overflow diarrhea 1 Malaise 2 Impaction/bowel Confusion 1 obstruction 1 Restlessness 2 Hemorrhoids/rectal Anxiety/distress 1 fissures 1 Bowel perforation 1. Larkin PJ et al. Palliative Med. 2008;22: Miles C, et al. Cochrane Database of Systematic Reviews. 2006, Issue 4. Art. No.: CD EXPERT PANEL CONSENSUS: Informed Consent as a Partnership of Trust Set guidelines and goals with the patient Patients must take laxatives as prescribed, not prn Goal is bowel movements at least every other day Maintain i soft stool Clinician should be notified on third day if no bowel movement or if change in bowel movement to make adjustments 8

9 Obtain Assessment for OIC in the Palliative Care Patient Bowel history Medication history Perform Abdominal examination Abdominal radiograph (as indicated) Larkin PJ et al. Palliative Med. 2008;22: The Patient Interview 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? Adapted from Larkin PJ et al. Palliative Med. 2008;22:

10 Abdominal Radiograph Objective Assessment of Fecal Load Intractable cases When diagnosis is uncertain When obstruction is suspected Adapted from Larkin PJ et al. Palliative Med. 2008;22: Goals of Treatment of OIC Increase gut motility Create a softer stool Maintain or improve quality of life Opioid Induced Constipation Learning Experience Architectural Planning (LEAP) Group. February 17, Dallas, Tx. 10

11 Addressing the Problem: ABCs of Treatment of OIC in Palliative Care Anticipate Basic care Complex/ advanced constipation if opioids are for OIC care for OIC used 1 1. Larkin PJ et al. Palliative Med. 2008;22: Anticipate Constipation if Opioids are Used Preventive Care for OIC Prescribe laxatives concomitantly with opioids Eliminate other constipating drugs when possible Educate patient and family/caregiver about reasons for constipation and general measures to alleviate it Communicate the concept of partnership of trust t between ee patient/family tiet/f il and healthcare e provider Involve bridge personnel to ensure that constipation is not missed 11

12 Anticipate Constipation if Opioids are Used Preventive Care for OIC Increase fluid intake Increase dietary fiber (avoid excess fiber when hydration is suboptimal except for fruit fiber) Increase physical activity, if possible Establish a toileting routine Swegle JM, et al. Am Fam Physician. 2006;74: Laxative Effects in the Gut Stimulants Increase intestinal motility by stimulating peristalsis Stool Softeners Increase stool water content; intestinal water secretion; water in intestinal lumen Stimulate peristalsis Larkin PJ et al. Palliative Med. 2008;22:

13 Bulk forming Agents Not generally recommended in palliative care patients, whose intake of water may be inadequate Risk of bowel obstruction Larkin PJ et al. Palliative Med. 2008;22: Key Attributes of Some Laxatives for OIC Laxative Type Laxative Starting Dose Possible side effects Predominantly Lactulose (syrup) 15 ml Increased flatulence, softening twice cedaily cramps, ca ps,and ddsco discomforto Predominantly stimulating Polyethylene Glycol Docusate Senna Bisacodyl (powder for oral solution) 1 3 sachets daily in divided doses (capsules) Up to 500 mg daily in divided doses (tablet) 1 2 at bedtime; (syrup) 10 ml daily at bedtime (tablet) 1 2 at bedtime Abdominal distension, pain, nausea, diarrhea (may respond to dose) Diarrhea, nausea, cramps. skin rash Watery diarrhea Abdominal discomfort, diarrhea on occasion Larkin PJ, et al. Palliative Med. 2008;22:

14 Disclaimer The following pricing information is provided for comparative purposes using currently available information. It is not intended to promote one product over another nor should the information be considered an endorsement of any product or company. Information is current as of Sept and subject to change. Product SENNA Average Wholesale Prices of Some Laxatives for OIC Senna 8.6 mg tablets Senna 8.8 mg/5 ml syrup Price/Quantity $4.90 (100 tabs) $7.70 (100 unit dose tabs) [generic] $24.62 (100 tabs) [Purdue] $17.99 (240 ml) [generic] SENNA DOCUSATE SODIUM Senna docusate 50 mg 8.6 mg tablets Senna plus 50 mg 8.6 mg tablets Senokot S 50 mg 8.6 tablets $18.28 (100 tabs) [generic] $6.99 (60 tabs) [generic] $25.98 (60 tabs) $39.39 (100 unit dose tabs) [Purdue] Red Book Drug Topics. Thomson Healthcare/Thomson PDR

15 Product BISACODYL Bisacodyl 5 mg enteric coated tablets Dulcolax 5 mg enteric coated tablets Bisacodyl 10 mg suppository Average Wholesale Prices of Some Laxatives for OIC Dulcolax 10 mg suppository Price/Quantity $5.90 (100 tabs) $8.86 (100 unit dose tabs) [generic] $13.46 (100 tabs) [Boehringer Ingelheim] $17.99 (100) $3.25 (12) $31.68 (50) $11.56 (16) [Boehringer Ingelheim] Red Book Drug Topics. Thomson Healthcare/Thomson PDR Product Average Wholesale Prices of Some Laxatives for OIC Price/Quantity POLYETHYLENE GLYCOL Polyethylene glycol gm/dose powder Miralax 17 gm/dose powder LACTULOSE Lactulose 10 gm/15ml syrup METHYLNALTREXONE Relistor 12 mg/0.6 ml injection Red Book Drug Topics. Thomson Healthcare/Thomson PDR $39.06 (527 mg) $19.54 (12 count) [Teva] $19.68 (510 gm) $19.68 (12 count) [Schering Plough] $34.75 (473 ml) $18.28 (240 ml) $67.41 (960 ml) [generic] $336 (7 count) $48.00 (0.6 ml vial) [Wyeth] 15

16 Basic/Prophylactic Care for OIC in Palliative Care Stimulant laxative eg, senna 1 2 tablets, titrated to 2 4 tablets qid (avoid in fecal impaction or suspected obstruction) + Stool softener* eg, docusate (alternatives lactulose or polyethylene glycol if constipation is refractory) * Based on common clinical practice and lacking scientific evidence Larkin PJ et al. Palliative Med. 2008;22: Complex/Advanced Care Rectal Options Reserve for patients with fecal impaction or patients who cannot swallow oral preparations Contraindicated in neutropenic and thrombocytopenic patients Bisacodyl suppositories; Phospho Soda enemas Consider patient dignity and quality of life! 1. Larkin PJ et al. Palliative Med. 2008;22: Avila JG. Cancer Control. 2004;11(Suppl 1):

17 CNS Opioid Antagonists Naloxone, Nalamfene, Naltrexone Blood Brain Barrier Early opioid antagonists had limited systemic absoption Crossed the bloodbrain barrier GI Failed to restore GI function without reversing analgesia Becker G, Blum HE. Lancet. 2009;373: CNS GI Opioid Antagonists Naloxone, Methylnaltrexone & Alvimopan Blood Brain Barrier Methylnaltrexone derivative of naltrexone 1 Does not cross blood brain 1 barrier; no effect on CNS High µ affinity 1 Alvimopan* Does not cross blood brain barrier; few effects on CNS 2 Higher µ affinity it and higher potency than methylnaltrexone 3 *Not FDA approved for OIC 1. Yuan CS, Israel RJ. Expert Opin Investig Drugs. 2006;15: Neary P, Delaney CP. Expert Opin Investig Drugs. 2005;14: Becker G, Blum HE. Lancet. 2009;373:

18 Methylnaltrexone for Opioid Induced Constipation in Advanced Illness Thomas J, et al. N Engl J Med. 2008;358: Alvimopan Studies in OIC* *NOT indicated by FDA for opioid induced constipation Efficacy in OIC shown in phase II/III clinical trials, but serious adverse events led to FDA restrictions1 Increased risk of neoplasms (2.8% vs 0.7%) and MI (7 vs 0) with alvimopan found in a phase III placebocontrolled,12 mo study in 805 patients with noncancer pain treated with opioids and experiencing OIC1,2 Drug approved for postoperative ileus only, with a Risk Evaluation and Mitigation Strategy (REMS) 1. Becker G, Blum HE. Lancet. 2009;373: P & T Community. Available at: Accessed August 19,

19 Neostigmine Glycopyrrolate Infusion for Bowel Evacuation Spinal Cord Injury Patients Korsten MA, et al. Am J Gastroenterol. 2005;100: Opioid Rotation and OIC Oral morphine to transdermal fentanyl Morphine CR, oxycodone CR, or transdermal fentanyl Constipation and medication with laxatives decreased with fentanyl 1 Lower annual incidence density and risk of constipation with fentanyl 2 1. Donner B, et al. Pain. 1996;64: Staats PS, et al. South Med J. 2004;97:

20 Complementary & Alternative Therapies Abdominal massage: Possible benefit (limited data in children) 1 Hypnotherapy: Beneficial in IBD 2 Aromatherapy: No evidence 3 Biofeedback: No studies in cancer/chronic pain patients; evidence in other patients inconclusive 4,5 Baker s yeast: May have some benefit (uncontrolled study) 4 ; Benefits in OIC unknown 6 Culturally based alternatives (Yakima paste, papaya, magic bullets, milk and molasses enema 4 ) 1. Hughes D, et al. Oncol Nursing Forum. 2008;35: Kearney DJ, Brown Chang J. Nat Pract Gastroenterol Hepatol. 2008;5: Fellowes D, et al. Cochrane Database Syst Rev. 2008;8:CD Coulter ID, et al. Altern Ther Health Med. 2002;8: Woolery M, et al. Clin J Oncol Nurs. 2007;12: Wenk R, et al. J Pain Sympt Manage. 2000;19: EXPERT PANEL CONSENSUS: Stepwise Prevention & Management of OIC in Palliative Care Patients Prophylaxis with stool softener + stimulant (senna preferred). Increase dose and/or add osmotic laxative as needed Avoid bulking agents in patients unable to consume adequate fluids Consider adding methylnaltrexone in treatment resistant patients 20

21 EXPERT PANEL CONSENSUS: Follow up & Continuing Care for the OIC Patient in Palliative Care Establish and maintain regular communication with patient/family/caregiver & reinforce commitment to patient s best interests. Confirm and re confirm that OIC treatment is working. If not, intervene. Ensure that informedconsent is instituted each time treatment is adjusted. Emphasize compliance with prescribed OIC regimen; query patients with specific questions. Conclusions and Palliative Care Pearls Constipation can cause significant distress and unnecessary suffering, along with a cost burden to the health care system. OIC can be prevented by timely administration of a bowel regimen, which should begin when opioid therapy is started. Recall that constipation may present with atypical symptoms such as nausea, abdominal distension, overflow diarrhea, confusion. A need exists for evidence based studies to determine the relative efficacy of different regimens for OIC. 21

22 Conclusions and Palliative Care Pearls Caring for OIC patients should involve a partnership of trust between the health care professional and the patient, to ensure that treatment enhances the patient s comfort and improves his/her quality of life during this last phase of life. Cases 22

23 OLIVIA 70 year old nursing home resident with Alzheimer s disease and chronic back pain Olivia developed more severe back pain manifested by grimacing and aversion to movement. She was prescribed oxycodone 5 mg every 6 hrs. After complaining to family members about constipation, they brought her a home remedy of applesauce and wheat germ (unbeknownst to staff). The home remedy did not work. By the time the nursing staff was informed, Olivia was severely affected. Olivia was started on sennoside 8.6 mg plus docusate sodium 50 mg. The dose was increased after no response. (Opioid therapy was not altered.) OLIVIA 70 year old nursing home resident with Alzheimer s disease and chronic back pain Nursing home records showed no bowel movement in over a week. Olivia s family wanted to stop the oxycodone because it had caused the problem and re start the home remedy, saying the other therapy did not work. (Olivia s family was concerned because she was experiencing abdominal distension, loss of appetite, and nausea.) Olivia s doctor determinedthat her family might have been Olivia s doctor determined that her family might have been promoting Olivia s non compliance with medications. Still, he ordered a step up in her senna/docusate regimen. 23

24 OLIVIA 70 year old nursing home resident with Alzheimer s disease and chronic back pain After several episodes of vomiting undigested food, Olivia s physician ordered an abdominal flat plate, which revealed a small bowel ileus and large amount of stool in the colon. She was admitted to the hospital for IV hydration, enemas, manual disimpaction, and a surgical consult. Following initial treatments, a follow up radiograph still showed retained feces and a small bowel ileus. She was deemed not a good surgical risk. Instead she was prescribed methnaltrexone 8 mg sc. This produced a large formed bowel movement and follow up X rays showed that the ileus had resolved. OLIVIA 70 year old nursing home resident with Alzheimer s disease and chronic back pain To maintain healthy bowel movements while on opioids, Olivia was placed on a continuous regimen of PO sennoside and lactulose, with prn enemas for bowel movements less than 3 times per week. 24

25 Which of the following is NOT a risk factor for constipation in Olivia s case? A. Immobility B. Dementia * C. Dehydration D. Opioid analgesics E. Poor nutrition With inadequate fluid intake, Olivia s family home remedy may result in: A. Normal laxation due to high fiber intake B. Increased peristalsis itli due to mucosal irritation it ti C. Reduction in gut motility D. Intestinal obstruction * E. Diarrheal stools 25

26 Which of the following is TRUE with respect to use of enemas as part of a routine bowel regimen? A. Patient dignity is a primary concern * B. Best given using high h volume, hot water C. Patients should request them on a prn basis D. Daily enemas given at bedtime are preferred E. Best administered upon awakening prior to the morning meal WALTER 36 year old cancer patient, treated successfully with chemotherapy but developed peripheral neuropathy Walter s pain was so severe that he was unable to work or even stand. He consulted a physician at a pain clinic, and he was started on an opioid regimen. The treatment was very effective. Walter was able to move without pain and return to work. However, he developed constipation, and wanted to cut his dose of opioids. 26

27 WALTER 36 year old cancer patient, treated successfully with chemotherapy but developed peripheral neuropathy An evaluation revealed that Walter had not been taking his bowel regimen because of the pill burden (8 senna and 2 docusate). On restarting the constipation regimen, Walter found that it did not work as before. In discussion with his provider, it was decided to rotate the opioids to see if Walter s pain and constipation could be controlled on fewer pills. A switch to methadone and lactulose successfully controlled pain and constipation on fewer pills. With respect to opioid rotation, which of the following is associated with less constipation? A. Oxycodone B. Methadone C. Hydromorphone D. Fentanyl E. B and D * 27

28 ISABEL 57 year old woman with chronic progressive multiple sclerosis, receiving care at home During a recent pain crisis, Isabel requested morphine, whichhad had worked in another pain crisis. On the previous regimen of opioids, Isabel had difficult tomanage constipation which had resulted in hospitalization for fecal impaction. The patient and her family were concerned that this would happen again and thus requested guidance. When oral laxatives were recommended, the physician was told that Isabel had difficulty swallowing at times, but that she refused to have a standing regimen of enemas since she did not want her family to have to perform this task. ISABEL 57 year old woman with chronic progressive multiple sclerosis, receiving care at home The physician prescribed long acting morphine ER 15 mg every 12 hrs, with immediate release morphine 5 mg every 2 hrs for breakthrough pain. At the same time, the physician initiated a standing dose of docusate sodium 200 mg bid and sennoside 8.6 mg bid, ensuring the family that if constipation occurred for more than 3 days on this regimen, a subcutaneous injection of methylnaltrexone hl l would be prescribed. bd This satisfied the patient and family, knowing that Isabel would be able to obtain adequate pain relief and maintain bowel function at home. 28

29 The pathophysiology of constipation in patients with multiple sclerosis is due to inherent: A. Metabolic alterations B. Electrolyte l t imbalance C. Neurogenic bowel * D. Pain modulation mechanisms E. Lack of mobility Multifactorial issues leading to constipation in palliative care patients include all of the following EXCEPT: A. immobility B. reduced d intake of food C. inadequate fluid intake D. pain E. caregiver support * 29

30 Questions? 30