OIC, opioid-induced constipation.

Disclosures Charles E. Argoff, MD Speakers Bureau for Allergan, Inc., AstraZeneca plc, Depomed, Inc., Iroko Pharmaceuticals LLC, Janssen Pharmaceuticals, Inc., Millenium Laboratories, and Xenoport Inc. Grant/Research Support from Endo Pharmaceuticals Inc., Forest Laboratories, and Eli Lilly and Company. Consultant/Independent Contractor to AstraZeneca plc, Depomed, Inc., Endo Pharmaceuticals, Nektar Therapeutics, Pfizer Inc., Xenoport Inc., and Zogenix, Inc. Stock Shareholder of Depomed, Inc. and Pfizer Inc. Royalties from Elsevier B.V. Patricia Bruckenthal, PhD, ANP Speakers Bureau for AstraZeneca plc. Consultant/Independent Contractor for AstraZeneca plc and Pacira Pharmaceuticals Inc. Anthony J. Lembo, MD Consultant/Independent Contractor to AstraZeneca plc, Forest Laboratories, Ironwood Pharmaceuticals, Inc., Prometheus Laboratories Inc., and Salix Pharmaceuticals, Inc. Grant/Research Support from Prometheus Laboratories Inc. Educational Objectives Evaluate baseline bowel habits, risk factors for OIC development, and ongoing changes in bowel function in patients on long-term opioid therapy Implement a prophylactic treatment plan to address OIC concurrent with the initiation of opioid therapy Analyze current pharmacotherapies for OIC based on mechanisms of action and data on efficacy and safety Tailor treatment regimens for patients experiencing OIC according to symptom severity, past treatment responses, and patient preferences Discuss the essential elements of opioid pharmacology with specific focus on the effects of opioid receptor activation in the gastrointestinal tract Communicate with opioid-treated patients about treatment-emergent adverse events through open, patient-centered dialogue throughout the course of therapy OIC, opioid-induced constipation. 1

Demographic Question How many patients on chronic opioid therapy do you treat per week? 1. None 2. 1-10 3. 11-20 4. 21-30 5. >30 Demographic Question What percentage of your patients on chronic opioid therapy have experienced constipation symptoms? 1. 0%-25% 2. 26%-50% 3. 51%-75% 4. 76%-100% Preactivity Question 1 How confident are you CURRENTLY in your understanding of the effects of opioid receptor activation in the gastrointestinal (GI) tract? 1. Very confident 2. Somewhat confident 3. Not very confident 4. I do not understand the effects of opioid receptor activation in the GI tract 2

Preactivity Question 2 Among patients on chronic opioid therapy, studies suggest that what percentage of patients will develop opioidinduced constipation? 1. More than 90% 2. Approximately 50% 3. Approximately 25% 4. Less than 10% Preactivity Question 3 When should prescribers begin to assess bowel habits in a patient who is being treated with chronic opioid therapy? 1. At the visit when opioids are first prescribed 2. After 2 weeks of opioid treatment 3. After 1 month of opioid treatment 4. After 6 months of opioid treatment Preactivity Question 4 Which of the following increases the relative risk that a patient will develop opioid-induced constipation? 1. Female gender 2. Male gender 3. Age less than 45 years when beginning opioid therapy 4. Osteoarthritis pain as the primary reason for treatment with opioids 3

Preactivity Question 5 A 61-year-old male patient presents with constipation symptoms. For the last 5 years, he has been taking oxycodone ER 20 mg twice daily for osteoarthritis pain in his right knee. He has experienced an inadequate response to laxative therapy (3 bisacodyl 5 mg tablets and 3 docusate sodium 100 mg tablets daily). What would be the best course of action to relieve his constipation symptoms? 1. Discontinue opioid therapy 2. Add 2 servings of dietary fiber and 4 glasses of water daily to his current regimen, reassess in 1 month 3. Add 3 tablespoons of polyethylene glycol dissolved in liquid twice daily to his current regimen, reassess in 1 month 4. Prescribe an FDA-approved agent for treating opioid-induced constipation ER, extended-release. Preactivity Question 6 Which of the following statements is true about the FDAapproved treatments for opioid-induced constipation? 1. Lubiprostone, methylnaltrexone, and naloxegol are all peripherally acting μ-opioid receptor antagonists 2. Lubiprostone is an orally administered chloride channel activator, whereas methylnaltrexone and naloxegol are orally administered peripherally acting μ-opioid receptor antagonists 3. Lubiprostone is an orally administered chloride channel activator, methylnaltrexone is a subcutaneously injected peripherally acting μ-opioid receptor antagonist, and naloxegol is an orally administered peripherally acting μ-opioid receptor antagonist 4. Methylnaltrexone and naloxegol antagonize central and peripheral μ-opioid receptors Scientific Insights Into OPIOID- INDUCED CONSTIPATION Anthony J. Lembo, MD Associate Professor of Medicine Director, GI Motility Laboratory Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts 4

Scientific Insights Into Opioid-Induced Constipation Key Points Opioid analgesics bind to opioid receptors throughout the CNS and PNS, including in the gastrointestinal tract Opioid receptor activation in the gastrointestinal tract modulates physiologic processes from the lower esophageal sphincter to rectum By antagonizing μ-opioid receptor activity, opioid antagonists reverse the effects of opioid analgesics Peripherally acting μ-opioid receptor antagonists are intended to block opioid receptor activation outside of the CNS eg, the gastrointestinal tract CNS, central nervous system; PNS, peripheral nervous system. Brennan MJ, et al. J Multidiscip Health. 2013;6:265-280; Leppert W. Adv Ther. 2010;27(10):714-730; De Schepper HU, et al. Neurogastroenterol Motil. 2004;16(4):383-394; Holzer P. Eur Rev Med Pharmacol Sci. 2008;12(suppl 1):119-127. Rising Rates of Chronic Pain 100 million US adults currently affected by chronic pain Prevalence predicted to increase with aging population Arthritis Prevalence (1000x) a 80,000 65+ years old 70,000 45-64 years old 18-44 years old 60,000 50,000 40,000 30,000 20,000 10,000 0 2005 2010 2015 2020 2025 2030 Year a Projected prevalence of doctor-diagnosed arthritis in the US by age. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011; Hootman JM, Helmick CG. Arthritis Rheum. 2006;54(1):226-229. Number of Prescriptions (millions) Rise in Therapeutic Opioid Use Opioid Prescriptions Dispensed by US Pharmacies, 1991-2013 250 200 150 100 50 0 Total Hydrocodone Oxycodone 138 142149155163 105 116126 94 97 76 79 82 85 87 Year IMS Health National Prescription Audit (NPA) & Vector One : National (VONA). Data extracted 2011 and 2014. 202 210219217 207 174 184196 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 124 53 5

Opioid-Induced Constipation Constipation is most common adverse effect of prescription opioid analgesics 1,2 Up to 1 in every 2 patients on opioid therapy will experience constipation symptoms 3 1 in every 3 patients on opioid therapy does not discuss their constipation symptoms with their clinician 4 Constipated Not Constipated Silently Suffering Discusses Constipation Discusses Constipation Patients may not discuss constipation symptoms because they are embarrassed or worried that the opioid treatment will be reduced or discontinued. 4 1. Chou R, et al. J Pain. 2009;10(2):113-130; 2. Moore RA, McQuay HJ. Arthritis Res Ther. 2005;7(5):R1046-R1051. 3. Cook SF, et al. Aliment Pharmacol Ther. 2008;27(12):1224-1232; 4. Coyne KS, et al. Clinicoecon Outcomes Res. 2014;6:269-281. Opioid-Induced Constipation Multidisciplinary Working Group Definition A change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following: Reduced bowel movement frequency Development or worsening of straining to pass bowel movements A sense of incomplete rectal evacuation Harder stool consistency Camillieri M, et al. Neurogastroenterol Motil. 2014;26(10):1386-1395. Constipation What Does It Mean to Your Patient? Infrequent Stools Pain Straining Hard Stools Incomplete Evacuation Bloating Lacy BE, et al. Ther Adv Gastroenterol. 2012;5(4):233-247; Coyne KS, et al. Clinicoecon Outcomes Res. 2014;6:269-281. 6

Development of OIC Risk Factors Patient Characteristics Female gender Advanced age Dietary Considerations Dehydration Nutritional deficits Drug Regimen Opioid type/ strength Medical Issues Relative immobility Nausea/vomiting after starting opioids Mechanical obstruction Recent hospitalizations Ahmedzai SH, Boland J. BMJ Clin Evid (Online). 2010;pii:2407; Clemens KE, Klaschik EK. Ther Clin Risk Manag. 2010;6:77-82; Wan Y CS, et al. Las Vegas, Nevada; 2013; Abstract 132. The Critical Roles of Nurses in OIC Management Educate patients on the risk of developing OIC Most patients on chronic opioid therapy will develop constipation symptoms Increased likelihood if patients have certain risk factors Engage patients in open conversations about their bowel habits Evaluate changes in bowel function at each appointment Ask open-ended questions How Should We Assess Patients on Long-term Opioid Therapy for Constipation Symptoms? 7

Patient Resources Patient Educational Tool Patient Conversation Guide www.exchangecme.com/oic2015 Beginning the Conversation With Your Patients Bowel movements per week 0 1 2 3 4 5 6 7 8 9 10 None Weekly Approaching the Patient Potential Dialogue NURSE Let me be more specific, how Have many you bowel had any movements problems are moving you having your bowels per week? lately? PATIENT NURSE Has that changed since beginning opioid therapy? NURSE No, not 1 really. or 2 PATIENT Well, I used to go more often. Okay, let s use a bowel assessment tool to get a better idea about how things have changed. 8

ARS Question How often do you CURRENTLY inquire about bowel habits when following up with patients on chronic opioid therapy? 1. At every follow-up appointment 2. At 75% of follow-up appointments 3. At 50% of follow-up appointments 4. At 25% of follow-up appointments 5. Never 6. I do not manage patients on long-term opioid therapy ARS Question How often do you CURRENTLY use a specific assessment tool to evaluate the bowel habits of your patients on chronic opioid therapy? 1. At every follow-up appointment 2. At 75% of follow-up appointments 3. At 50% of follow-up appointments 4. At 25% of follow-up appointments 5. Never 6. I do not manage patients on long-term opioid therapy Assessment of Bowel Habits Tools for Stools Bowel Function Index Bristol Stool Form Scale Patient Assessment of Constipation www.exchangecme.com/oic2015 Rentz AM, et al. J Med Econ. 2009;12(4):371-383; Frank L, et al. Scand J Gastroenterol. 1999;34(9):870-887; Lewis SJ, Heaton KW. Scand J Gastroenterol. 1997;32(9):920-924. 9

Bristol Stool Form Scale Type 1 Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Separate hard lumps, like nuts Sausage-like but lumpy Like a sausage but with cracks in the surface Like a sausage or snake, smooth and soft Soft blobs with clear-cut edges Fluffy pieces with ragged edges, a mushy stool Watery, no solid pieces Lewis SJ, Heaton KW. Scand J Gastroenterol. 1997;32(9):920-924. Bowel Function Index (BFI) Scored by numerical assessment scale (0-100, free from symptom to most severe symptom experienced) for prior 7 days Ease of defecation Feeling of incomplete evacuation Personal judgment of constipation BFI score is the mean of the 3 component scores Rentz AM, et al. J Med Econ. 2009;12(4):371-383. Patient Assessment of Constipation (PAC-SYM) 12-item questionnaire of patient-reported symptoms over the 2 prior weeks, using 3 subscales Bowel movements Rectal symptoms Abdominal symptoms Scored from no problems (score 0) to very severe symptoms (score 4) Frank L, et al. Scand J Gastroenterol. 1999;34(9):870-887. 10

The Critical Roles of Nurses in OIC Management Administer tools for stools Visual stool description Bristol Stool Form Scale Quantitative assessment of bowel function BFI PAC-SYM Assess patient response over time Use same tool(s) to compare current results with those obtained at baseline and previous appointment Practice Pearl A 62-year-old man returns 1 month after starting opioid therapy for his chronic low back pain. When should this patient s bowel habits be evaluated? Which of the bowel assessment tools should we use? What Prophylactic and Initial Management Options Are Available? 11

Implementation of Prophylactic Treatment Guidelines on long-term opioid therapy recommend that all patients be advised on a prophylactic bowel regimen 1,2 Adequate dietary fiber Adequate water intake Regular exercise Laxatives? Patients who receive prophylactic laxative therapy are less likely to experience constipation 3,4 1. Chou R, et al. Pain. 2009;10(2):113-130; 2. Department of Veterans Affairs/Department of Defense. http://www.healthquality.va.gov/guidelines/pain/cot/cot_312_full-er.pdf. Accessed August 18, 2015. 3. Myotoku M, et al. J Palliat Med. 2010;13(4):401-406; 4. Ishihara M, et al. Clin J Pain. 2012;28(5):373-381. Commonly Used Laxatives to Treat Constipation Type of Laxative Stool Softener Stimulant Osmotic Lubricant Bulking Agent Specific Example Docusate sodium, docusate calcium Senna, bisacodyl, castor oil Polyethylene glycol, lactulose Mineral oil Psyllium, bran, methylcellulose Ford AC, Suares NC. Gut. 2011;60(2):209-218; Lee YY. Front Med (Lausanne). 2014;1-5; Pare P, Fedorak RN. Can J Gastroenterol Hepatol. 2014;28(10):549-557. Practical Issues Related to Laxative Treatment Bulking agents and medicinal fiber, such as psyllium, should be avoided 1,2 Efficacy data are lacking May further harden the patient s stool Laxatives may have side effects 3,4 Nausea, vomiting, diarrhea, abdominal pain all of which usually dissipate after bowel movement May increase the chance of poor adherence High dosages of laxatives and stimulants may be needed to improve bowel patterns 4 May increase the chance of poor adherence 1. Pare P, Fedorak RN. Can J Gastroenterol Hepatol. 2014;28(10):549-557; 2. Yang J, et al. World J Gastroenterol. 2012;18(48):7378-7383; 3. Mueller-Lissner SA, Wald A. BMJ Clin Evid. 2010;2010. pii: 0413; 4. Sykes NP. J Pain Symptom Manage. 1996;11(6):363-369. 12

ARS Question How satisfied are you with the efficacy of laxative therapy for relieving opioid-induced constipation in your patients? 1. Very satisfied 2. Somewhat satisfied 3. Not very satisfied 4. Not at all satisfied 5. I do not prescribe laxative therapy for my patients on chronic opioid treatment Practice Pearl A 47-year-old woman is prescribed opioids to control her chronic foot pain as a result of diabetic peripheral neuropathy, after an inadequate response to duloxetine. What would be the best prophylactic bowel regimen for this patient? Guidelines on Opioid Rotation Calculate new opioid dose based on equianalgesic table Identify dose reduction window 25% to 50% lower than equianalgesic dose (not for methadone or fentanyl) Switching to methadone: identify window 75% to 90% lower than equianalgesic dose Switching to transdermal fentanyl: calculate dose conversions based on ratios included in the product information Choose smaller (25% of dose) or larger (50% of dose) reduction based on characteristics of regimen or patient Larger reductions for patients on high current opioid doses, non-caucasians, and older or medically frail individuals Reassess pain and other biopsychosocial characteristics to determine whether an additional 15% to 30% dose increase or decrease is needed Repeatedly assess response and titrate new opioid to optimize outcomes Fine PG, et al. J Pain Symptom Manage. 2009;38(3):418-425. STEP 1 STEP 2 13

The Critical Roles of Nurses in OIC Management Review prophylactic treatment plan Stress importance of adherence to opioid therapy and bowel regimen What Are the Additional Treatment Options for Opioid-Induced Constipation? Practice Pearl A 71-year-old man with knee and hip osteoarthritis pain has been taking opioids for 9 months. He has reported infrequent and hard, lumpy stools since starting opioids. A 6-week trial of stool softeners and stimulant laxatives has not provided adequate relief from his symptoms. What factors would you consider before selecting additional pharmacologic therapy to ease his constipation symptoms? 14

Currently Approved Therapies Agent Lubiprostone Methylnaltrexone Naloxegol Mechanism of Action Mode of Administration Recommended Dose Dosing Frequency Chloride channel activator Take with food and water May be used concomitantly for length of opioid treatment May be less effective in Clinical patients taking methadone Considerations Peripherally acting μ-opioid receptor antagonist (PAMORA) Oral Subcutaneous Oral 24 µg 12 mg/0.6 ml 25 mg/12.5 mg Twice daily Once daily Once daily Discontinue laxative therapy prior to use Need close proximity to toilet once administered May be used concomitantly for length of opioid treatment Monitor for signs of opioid withdrawal Discontinue laxative therapy prior to use Take on an empty stomach and avoid grapefruit consumption May be used concomitantly for length of opioid treatment Monitor for signs of opioid withdrawal Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 18, 2015. Mean Change From Baseline in SBM Frequency 5 4 3 2 1 BID, twice daily; SBM, spontaneous bowel movement. N=418 patients with noncancer pain. Cryer B, et al. Pain Med. 2014;15(11):1825-1834. Lubiprostone Chloride Channel Activator P=0.005 P=0.091 3.3 3.4 2.4 0 Week 8 Week 12 Overall 14-week, double-blind, randomized, placebo-controlled, phase 3 clinical trial 2.6 Lubiprostone 24 µg BID (n=210) Placebo (n=208) 2.2 P=0.004 Primary Endpoint: Change at week 8 from the baseline weekly frequency of SBMs (bowel movement without the use of laxatives or stool softeners within the last 24 h) 1.6 AE, No. (%) of Patients Lubiprostone 14-Week Safety Data AE, adverse event. a P values are from Fisher s exact test. b AEs in patients who received 1 dose of study medication. Cryer B, et al. Pain Med. 2014;15(11):1825-1834. Placebo BID (n=206) Lubiprostone P value 24 µg BID (n=208) a 1 AE b 112 (54.4) 132 (63.5) 0.072 AEs in 5% of either treatment arm Nausea 12 (5.8) 35 (16.8) <0.001 Diarrhea 6 (2.9) 20 (9.6) 0.007 Abdominal distention 5 (2.4) 17 (8.2) 0.014 1 treatment-related AE 48 (23.3) 76 (36.5) 0.004 Treatment-related AEs in 2% of either treatment arm Nausea 11 (5.3) 32 (15.4) 0.001 Abdominal distention 5 (2.4) 16 (7.7) 0.023 Diarrhea 3 (1.5) 15 (7.2) 0.006 Flatulence 5 (2.4) 8 (3.8) 0.575 Vomiting 4 (1.9) 5 (2.4) 1.000 Upper abdominal pain 7 (3.4) 1 (0.5) 0.037 Abdominal pain 1 (0.5) 8 (3.8) 0.037 15

Patients Achieving Primary Endpoint, % 70 60 50 40 30 20 10 Methylnaltrexone Peripherally Acting μ-opioid Receptor Antagonist Response Rates in the mitt Population a 59 38 0 Methylnaltrexone 12 mg QD (n=150) Placebo (n=162) 4-week, double-blind, randomized, placebo-controlled, phase 3 clinical trial Primary Endpoint: % patients with 3 SBMs per week, during 4-week period SBM, defined as a BM with no laxative use within prior 24 hours. a P<0.001 vs placebo; QD, once daily. N=312 patients with chronic noncancer pain. mitt, modified intent-to-treat population, included all randomized patients who received 1 dose of double-blind study medication. Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 18, 2015. Adverse Event Methylnaltrexone 4-Week Safety Data Methylnaltrexone 12 mg QD (n=150), % Placebo (n=162), % Adverse events occurring in 1% of patients receiving methylnaltrexone and at an incidence greater than placebo Abdominal pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot flush 3% 2% Tremor 1% <1% Chills 1% 0% Adverse events leading to treatment discontinuation Any adverse event 7% 3% Safety data from 48-week, open-label, uncontrolled study (N=1034) were consistent with 4-week results. Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 18, 2015. Patients Achieving Primary Endpoint, % 75 50 25 Naloxegol Peripherally Acting μ-opioid Receptor Antagonist Response Rates in the ITT Population Placebo Naloxegol 12.5 mg QD Naloxegol 25 mg QD a a 44.4 40.8 34.9 29.4 29.3 n=214 n=213 n=214 n=232 n=232 n=232 0 Study 04 Study 05 Two 12-week, double-blind, randomized, placebo-controlled, phase 3 clinical trials Primary Endpoint: 12-week response rate ( 3 SBM/week and increase over baseline of 1 SBM for 9 of 12 weeks and 3 of the final 4 weeks) SBM, defined as a BM with no laxative use within prior 24 hours. a P<0.05 vs placebo in each study; N=652 patients with noncancer pain, Study 04; N=700 patients with noncancer pain, Study 05. ITT, intention-to-treat. Chey WD, et al. N Engl J Med. 2014;370(25):2387-2396. a 39.7 16

Naloxegol 12-Week Safety Data Study 04 Study 05 Adverse event, Naloxegol Naloxegol Naloxegol Naloxegol Placebo Placebo 25 mg 12.5 mg 25 mg 12.5 mg (n=213) (n=231) (n=214) (n=211) (n=232) (n=230) Any AE a 131 (62.2) 104 (49.3) 100 (46.9) 160 (69.0) 137 (59.6) 136 (58.9) AE leading to 22 (10.3) 9 (4.3) 12 (5.6) 24 (10.3) 12 (5.2) 12 (5.2) discontinuation Serious AE 7 (3.3) 11 (5.2) 11 (5.2) 8 (3.4) 14 (6.1) 12 (5.2) AEs in 5% of any treatment arm b Abdominal pain 27 (12.6) 18 (8.5) 7 (3.3) 44 (19.0) 25 (10.9) 18 (7.8) Diarrhea 20 (9.3) 7 (3.3) 9 (4.2) 21 (9.1) 18 (7.8) 10 (4.3) Nausea 16 (7.5) 15 (7.1) 10 (4.7) 20 (8.6) 14 (6.1) 10 (4.3) Flatulence 12 (5.6) 9 (4.3) 4 (1.9) 14 (6.0) 4 (1.7) 7 (3.0) Upper abdominal pain 11 (5.1) 3 (1.4) 4 (1.9) 6 (2.6) 5 (2.2) 3 (1.3) Vomiting 6 (2.8) 3 (1.4) 7 (3.3) 14 (6.0) 7 (3.0) 6 (2.6) Safety data from 52-week, open-label, parallel-group phase 3 study (N=804) with patients randomized 2:1 to either naloxegol 25 mg/day or usual care were similar to 12-week results. 2 a Occurring during either the treatment or posttreatment follow-up period. b Occurring during the treatment period. 1. Chey WD, et al. N Engl J Med. 2014;370(25):2387-2396; 2. Webster L, et al. Aliment Pharmacol Ther. 2014;40(7):771-779. Emerging μ-opioid Receptor Antagonists for Treatment of OIC Agent 1 Naldemedine Bevenopran Axelopran Mode of Administration Oral Oral Oral Mechanism of Action Peripherally selective μ-opioid receptor antagonist Peripherally acting μ-opioid receptor antagonist Peripherally selective μ-opioid receptor antagonist Current Developmental Stage Phase 3 Phase 3 Phase 2, completed The opioid agonist/antagonist combination of prolonged-release oxycodone and naloxone was shown to reduce OIC in a 3-week, open-label phase 3b study. 2 1. www.clinicaltrials.gov Information updated as of August 18, 2015. 2. van Dongen VC, et al. Int J Clin Pract. 2014;68(11):1364-1375. The Critical Roles of Nurses in OIC Management Ensure patients understand prescribing instructions for selected medications Review possible adverse events and discuss an action plan should side effects emerge Communicate with other members of health care team 17

Choose-A-Case Anthony J. Lembo, MD Associate Professor of Medicine Director, GI Motility Laboratory Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts Choose-A-Case Please Use Your ARS Device to Select a Case 1. An emotional Diane complains of increased bloating and cramping, and fewer bowel movements 2. Susan has multiple comorbidities and notes infrequent bowel movements despite a multimodal laxative regimen 3. Matthew is reluctant to discuss changes in bowel patterns and experiences periods of uncontrolled pain 4. A frustrated Tom requests a switch in therapy due to infrequent bowel movements and abdominal pain Diane Patient Background 59-year-old school teacher Medical history Presented 2 years prior following 2 back surgeries for an L4/L5 herni Oxycodone ER 40 mg twice daily (recently increased from 20 mg twice daily) 3 bisacodyl 5 mg tablets once daily 1 cap of polyethylene glycol dissolved in liquid twice daily Hypertension Lisinopril 10 mg once daily Osteoporosis Denosumab 60 mg subcutaneously every 6 months ER, extended release. 18

Diane Follow-up Frequent bloating and abdominal cramping 3 months after increase in oxycodone ER dose Infrequent bowel movements and stool is more lumpy BFI, 67 (baseline score, 45) Bristol Stool Form Scale, Type 1 Prescribed naloxone 4 mg once daily After 6 weeks, constipation symptoms improved, but pain is now not adequately controlled BFI, Bowel Function Index. Diane Case Question How would you manage Diane s constipation? 1. Stop naloxone and rotate to an alternative opioid 2. Stop naloxone and reduce oxycodone ER dose from 40 mg twice daily to 20 mg twice daily 3. Stop naloxone and add a stool softener to her current regimen 4. Reduce the naloxone dose to 2 mg once daily and continue oxycodone ER 40 mg twice daily Diane Treatment Tailoring Discontinue naloxone Add 3 docusate sodium 100 mg tablets once daily to her current regimen Diane calls 1 month later Pain is better controlled Constipation symptoms have returned 19

Diane Case Question What would be your next step in managing Diane s constipation? 1. Reevaluate Diane in 6 weeks 2. Prescribe naloxone 2 mg once daily 3. Prescribe methylnaltrexone 12 mg subcutaneously once daily 4. Prescribe naloxegol 25 mg once daily 5. Prescribe lubiprostone 24 µg twice daily Susan Patient Background 47-year-old woman referred by her PCP Medical history Serious work-related accident 2 years ago Back surgery for L4/L5 herniation with severe pain in lower back and down right leg Physical therapy 3 times each week Transdermal fentanyl 25 μg/h changed every 72 hours Insomnia Amitriptyline 25 mg once daily Seasonal allergies Loratadine 10 mg once daily Hypertension Diltiazem 60 mg 3 times daily Susan Bowel Function Initial bowel regimen Well-rounded diet and increased water intake 1 cap of polyethylene glycol dissolved in liquid twice daily 3-month follow-up visit Pain well-controlled (VAS, 4/10) Decreased frequency of bowel movements BFI, 55 (baseline score, 49) Bristol Stool Form Scale, mostly Type 2 (baseline, Type 2 and 3) Add 3 tablets of senna 8.6 mg before bed Bowel patterns have not improved at next appointment BFI, 51 Bristol Stool Form Scale, mostly Type 2 BFI, Bowel Function Index; VAS, visual analog scale. 20

Susan Case Question How would you manage Susan s ongoing constipation? 1. Rotate to an alternative opioid 2. Add 3 docusate sodium 100 mg tablets once daily after breakfast 3. Prescribe methylnaltrexone 12 mg subcutaneously once daily 4. Prescribe naloxegol 12.5 mg once daily 5. Prescribe naloxegol 25 mg once daily 6. Prescribe lubiprostone 24 µg twice daily Susan Follow-up Visit Prescribed peripherally acting μ-opioid receptor antagonist Bowel patterns have not improved at 6-week follow-up appointment BFI, 49 Bristol Stool Form Scale, mostly Type 2 Susan Case Question What is the most likely cause of Susan s constipation? 1. Transdermal fentanyl 2. Inadequate water intake and dietary fiber 3. Sedentary lifestyle 4. Side effect from her other medications 21

Matthew Patient Background 54-year-old accountant referred by his PCP Medical history Ongoing back pain after L5-S1 laminectomy 5 years ago Currently treated with hydromorphone ER 8 mg once daily (started 1 year ago) Major depressive disorder Bupropion 150 mg once daily in the morning Current prophylactic bowel regimen Well-rounded diet and increased water intake 3 bisacodyl 5 mg tablets once daily Today s Appointment Pain not adequately controlled and missing work Hydromorphone ER dose increased to 12 mg once daily ER, extended release. Matthew 4-Week Follow-up Pain not well-controlled Has been missing a few doses of hydromorphone ER each week Infrequent bowel movements, cramping, and bloating Not adhering to the prescribed laxative regimen Skipping hydromorphone ER doses often results in bowel movement BFI, 67 Bristol Stool Form Scale, mostly Type 2 with some Type 1 BFI, Bowel Function Index. Matthew Case Question How would you manage Matthew s pain and constipation? 1. Switch to a nonopioid analgesic 2. Rotate to an alternative opioid 3. Encourage adherence to current pain and bowel regimens (hydromorphone ER 12 mg once daily and 3 bisacodyl 5 mg tablets before bed) 4. Lower the hydromorphone ER dose to 8 mg once daily and begin a multimodal laxative regimen (3 docusate sodium 100 mg tablets after breakfast, 3 bisacodyl 5 mg tablets before bed, and 1 capful of polyethylene glycol powder in a cup of liquid prior to breakfast and dinner) 22

Matthew Treatment Tailoring Dose of hydromorphone ER reduced to 8 mg once daily Matthew encouraged to adhere to his pain and bowel regimens 6-week follow-up appointment Matthew reports that he has been taking all of his analgesic and laxative medications Although pain is well-controlled, his bowel patterns have not improved Matthew Case Question How would you manage Matthew s constipation? 1. Rotate to an alternative opioid 2. Prescribe methylnaltrexone 12 mg subcutaneously once daily 3. Prescribe naloxegol 25 mg once daily 4. Prescribe lubiprostone 24 µg twice daily Tom Patient Background 74-year-old retired dentist Gained 15 lbs in last year due to more sedentary lifestyle Medical history Osteoarthritis in right knee Oxycodone ER 40 mg twice daily, recently increased from 20 mg twice daily Dyslipidemia Rosuvastatin 20 mg once daily Hypertension Atenolol 100 mg once daily 23

Tom Today s Appointment Tom requests a switch in analgesic medication Pain is controlled since dose titration Constipation is intolerable Currently taking 3 bisacodyl 5 mg tablets each night before bed Strains to move bowels Painful bloating and cramping BFI, 68 Bristol Stool Form Scale, mostly Type 2 Tom Case Question What would be your next step in managing Tom? 1. Rotate to an alternative opioid 2. Lower the oxycodone ER dose to 20 mg twice daily 3. Continue oxycodone ER 40 mg twice daily and add 3 docusate sodium 100 mg tablets after breakfast in addition to 3 bisacodyl 5 mg tablets before bed 4. Continue oxycodone ER 40 mg twice daily and add 1 capful of polyethylene glycol powder in a cup of liquid prior to breakfast and dinner in addition to 3 bisacodyl 5 mg tablets before bed Tom Laxative Therapy Prescribed 3 docusate sodium 100 mg tablets once daily 6-week follow-up Bowel patterns slightly improved Still irritable and uncomfortable Infrequent bowel movements and abdominal pain continue Has abandoned laxative therapy due to lack of efficacy BFI, 65 (previously, 68) Bristol Stool Form Scale, mostly Type 2 (unchanged) 24

Tom Case Question What would be your next step in managing Tom s constipation? 1. Lower oxycodone ER dose to 20 mg once daily 2. Rotate to an alternative opioid 3. Prescribe methylnaltrexone 12 mg subcutaneously once daily 4. Prescribe naloxegol 25 mg once daily 5. Prescribe lubiprostone 24 µg twice daily Conclusions OIC is common in patients on long-term opioid therapy Prophylactic treatment regimens can reduce risk of constipation Routine bowel function assessment is imperative Multimodal laxative therapy can be effective in some patients Approved pharmacologic therapies include Oral and injectable peripherally acting μ-opioid receptor antagonists Chloride channel activator Postactivity Question 1 How confident are you NOW in your understanding of the effects of opioid receptor activation in the gastrointestinal (GI) tract? 1. Very confident 2. Somewhat confident 3. Not very confident 4. I do not understand the effects of opioid receptor activation in the GI tract 25

Postactivity Question 2 Among patients on chronic opioid therapy, studies suggest that what percentage of patients will develop opioidinduced constipation? 1. More than 90% 2. Approximately 50% 3. Approximately 25% 4. Less than 10% Postactivity Question 3 When should prescribers begin to assess bowel habits in a patient who is being treated with chronic opioid therapy? 1. At the visit when opioids are first prescribed 2. After 2 weeks of opioid treatment 3. After 1 month of opioid treatment 4. After 6 months of opioid treatment Postactivity Question 4 Which of the following increases the relative risk that a patient will develop opioid-induced constipation? 1. Female gender 2. Male gender 3. Age less than 45 years when beginning opioid therapy 4. Osteoarthritis pain as the primary reason for treatment with opioids 26

Postactivity Question 5 A 61-year-old male patient presents with constipation symptoms. For the last 5 years, he has been taking oxycodone ER 20 mg twice daily for osteoarthritis pain in his right knee. He has experienced an inadequate response to laxative therapy (3 bisacodyl 5 mg tablets and 3 docusate sodium 100 mg tablets daily). What would be the best course of action to relieve his constipation symptoms? 1. Discontinue opioid therapy 2. Add 2 servings of dietary fiber and 4 glasses of water daily to his current regimen, reassess in 1 month 3. Add 3 tablespoons of polyethylene glycol dissolved in liquid twice daily to his current regimen, reassess in 1 month 4. Prescribe an FDA-approved agent for treating opioidinduced constipation Postactivity Question 6 Which of the following statements is true about the FDAapproved treatments for opioid-induced constipation? 1. Lubiprostone, methylnaltrexone, and naloxegol are all peripherally acting μ-opioid receptor antagonists 2. Lubiprostone is an orally administered chloride channel activator, whereas methylnaltrexone and naloxegol are orally administered peripherally acting μ-opioid receptor antagonists 3. Lubiprostone is an orally administered chloride channel activator, methylnaltrexone is a subcutaneously injected peripherally acting μ-opioid receptor antagonist, and naloxegol is an orally administered peripherally acting μ-opioid receptor antagonist 4. Methylnaltrexone and naloxegol antagonize central and peripheral μ-opioid receptors Postactivity Question 7 How often do you NOW PLAN TO inquire about bowel habits when following up with patients on chronic opioid therapy? 1. At every follow-up appointment 2. At 75% of follow-up appointments 3. At 50% of follow-up appointments 4. At 25% of follow-up appointments 5. Never 6. I do not manage patients on long-term opioid therapy 27

Postactivity Question 8 How often do you NOW PLAN TO use a specific assessment tool to evaluate the bowel habits of your patients on chronic opioid therapy? 1. At every follow-up appointment 2. At 75% of follow-up appointments 3. At 50% of follow-up appointments 4. At 25% of follow-up appointments 5. Never 6. I do not manage patients on long-term opioid therapy ASK THE EXPERTS: QUESTION & ANSWER SESSION 28