The Road to Opioid-Induced Constipation: Pathophysiology and Impact Kenneth C. Jackson, II, PharmD, CPE

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2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of March The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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4 The Road to Opioid-Induced Constipation: Pathophysiology and Impact Kenneth C. Jackson, II, PharmD, CPE Professor and Chair Department of Clinical and Administrative Sciences Larkin Health Sciences Institute College of Pharmacy Miami, FL

5 Pain is a Problem! Condition Incidence Source Chronic Pain Diabetes Coronary Heart Disease (heart attack and chest pain) Stroke 100 million Americans 25.8 million Americans (diagnosed and estimated undiagnosed) 16.3 million Americans 7.0 million Americans Institute of Medicine of The National Academies American Diabetes Association American Heart Association Cancer 11.9 million Americans American Cancer Society

6 Chronic Pain 22% of primary care visits focus on pain Chronic pain patients visit primary care providers up to 5 times more often than patients with other chronic conditions Cost to United States (US) healthcare is $ billion/year Lost productivity estimated $ billion/year Opioids accounted for 20% of overall drug cost $3.57 billion/year between Rasu RS, et al. J Manag Care Pharm

mg/capita US Opioid Consumption in 2011 300 250 200 150 mg/capita ME mg/capita 152.6069 195.3353 211.4415 281.2172 100 73.7779 73.7779 50 0 44.9918 48.8338 8.9984 7.4276 1.8314 1.

7 mg/capita US Opioid Consumption in mg/capita ME mg/capita Fentanyl Hydromorphone Methadone Morphine Oxycodone Meperidine ME=Morphine Equivalent Total Morphine Equivalence=

8 Opioid-Induced Adverse Effects Constipation Nausea/vomiting Sedation Pruritus Respiratory depression Androgen deficiency Psychotomimetic effects Hyperalgesia

9 Opioid-Induced Constipation (OIC) Pathophysiology The enteric nervous system is innervated by μ-, δ-, and κ-opiate receptors (MOR, DOR, and KOR) Opioid receptor agonists interact with these receptors Inhibit adenylate cyclase Decrease camp and PKA Activate K + channels Membrane hyperpolarization Inhibit Ca ++ channels Decrease neurotransmitter release Galligan JJ, et al. Am J Gastroenterol Suppl

10 OIC Mechanisms Increased ileocecal and anal sphincter tone Decreased defecation reflexes Decreased peristalsis and increased gastrointestinal (GI) tone Increased fluid absorption due to increased contact time Decreased enterocyte secretion Smith H, et al. Opioid Therapy in the 21 st Century

11 Constipation Defined: American College of Gastroenterology Unsatisfactory defecation characterized by: Infrequent stools Difficult stool passage Straining Sense of difficult stool passage Incomplete evacuation Hard lumpy stools Prolonged time to stool Need for manual maneuvers to pass stool Or infrequent stools and difficult stool passage Ford AD, et al. Am J Gastroenterol

12 Rome III Criteria: Functional Constipation Must include two or more of the following: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Sensation of anorectal obstruction/blockage for at least 25% of defecations Manual maneuvers to facilitate at least 25% of defecations (eg, digital evacuation, support of the pelvic floor) Fewer than three defecations per week Loose stools are rarely present without the use of laxatives Insufficient criteria for irritable bowel syndrome

13 What is OIC? Also known as: Opioid Bowel Dysfunction (OBD) and Opioid-Induced Bowel Dysfunction (OIBD) Characterized by: Hard, dry stools Straining to pass bowel movements Incomplete evacuation Bloating Abdominal distension Increased gastric reflux Bell TJ, et al. Pain Med

14 Bristol Stool Chart Constipation Diarrhea

15 Proposed Definition-OIC A change, when initiating opioid therapy, from baseline bowel habits, defecation patterns, and what individuals would consider as abnormal that is characterized by any of the following: Reduced frequency of spontaneous (in contrast to induced) bowel movements Development or worsening of straining to pass bowel movements A sense of incomplete rectal evacuation Harder stool consistency Gaertner J, et al. J Clin Gastroenterol

16 Incidence of OIC Acute Pain Hard to evaluate! Chronic Non-Cancer Pain (CNCP) Often cited as the most common and debilitating adverse effect Estimates of the frequency of constipation vary from 15-90% in patients receiving opioids for non-cancer pain Variation may be due to definition of opioid agent/type and actual frequency of use Abdominal pain as high as 58.2% Cancer Pain up to 90% Panchal SJ, et al. Int J Clin Pract. 2007; Thomas J. J Pain Symptom Manage. 2008; Dorn S, et al. Am J Gastroenterol Suppl

17 OIC in Chronic Non-Cancer Pain PROBE 1 The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey Survey of 322 patients with CNCP Daily use of opioids AND laxatives 45% of patients reported <3 bowel movements per week Constipation (81%) Straining to pass a bowel movement (58%) Rank order of most bothersome adverse effects by patients Constipation, straining, fatigue, small or hard bowel movements, and insomnia A third of patients had missed, decreased, or stopped using opioids in order to make it easier to have a bowel movement Bell TJ, et al. Pain Med

18 Chronic Pain Treatment Paradigm Physical Back exercises Aerobic exercise Behavioral Stress management Mental Health Pharmacotherapy

19 Physician and Nurse Perceptions of Most Difficult Symptoms in Palliative Care Primary Care Physicians Loss of appetite 49% Lost bowel control 43% Unpleasant smell 40% Lost bladder control 35% Breathlessness 35% Bedsores 34% Depression 31% Home Care Nurses Loss of appetite 54% Depression 54% Anxiety 51% Nausea/vomiting 37% Constipation 32% Breathlessness 31% Sleeplessness 30% Pain 26% Grande GE, et al. Palliative Medicine

20 Opioids: Ceiling Effect The dose at which further dose increases will not produce additional analgesia. Full agonists - no true ceiling effect Doses can be escalated as appropriate to treat pain Functional dose ceiling Adverse effects >>> Analgesia Example: Codeine in doses > mg produce significant GI effects that exceed any potential, incremental pain Partial and mixed agonist/antagonists exhibit ceiling effect Jackson KC, et al. Practical Pain Management. 3 rd Edition

21 Distinct Types of Opioid Tolerance Analgesia May occur in first days to weeks of therapy Rare after pain relief achieved with consistent dosing without increasing or new pathology Respiratory depression and sedation Predictable after 5-7 days of consistent opioid administration Constipation Tolerance does not occur Prophylactic treatment indicated with regularly scheduled opioids Jackson KC, et al. Practical Pain Management. 3 rd Edition

22 Potential Etiologies of Opioid-Associated Constipation Normal-transit constipation Slow-transit constipation Evacuation disorders Secondary causes of constipation: Medications Medical Conditions Malignancy, neurological disorders, metabolic disorders, endocrine disorders, myopathic disorders Mechanical obstruction Pregnancy Brenner DM, et al. Am J Gastroenterol Suppl

23 Monitoring Opioid Therapy Critical Outcomes Pain relief Function Physical Psychosocial Side effects Drug-related behaviors The 4-A's of Pain 1. Analgesia 2. Activities of daily living 3. Adverse effects 4. Aberrant drug-taking behaviors Passik SD, et al. Adv Ther

24 Starting the Journey and Staying the Course: Education, Prevention and First Line Treatment Leah Sera, PharmD, BCPS Assistant Professor Department of Pharmacy Practice and Science University of Maryland School of Pharmacy Baltimore, MD

25 Who s at Risk? Patients Taking Certain Medications Calcium channel blockers Antidepressants Antihistamines Metal ion containing agents Antipsychotics Antiepileptics Antiemetics Patients with Certain Medical Conditions Diabetes Parkinson s disease Pregnancy Hypothyroidism Multiple sclerosis Electrolyte imbalance Costilla VC, et al. Clin Geriatr Med

26 Who s at Risk? Functional Factors Poor appetite/food intake Low fiber diet Poor fluid intake Advanced age Inactivity/decreased mobility Depression/sedation Environment Larkin PJ, et al. Pall Med

27 Preventive Care Lifestyle modifications as needed Adequate hydration (especially fruit/fruit juice) Increase dietary fiber Increasing physical activity Access to laxatives if needed Patients taking opioids should use laxatives prophylactically Maintaining good bowel habits Don t suppress the urge to defecate Make sure patient has adequate privacy and assistance with toileting if needed

28 Assessing Constipation Ask about past and present bowel habits Ask about use of laxatives Ask about date of the most recent bowel movement Ask about associated symptoms Nausea/vomiting, abdominal pain, diarrhea Twycross R, et al. J Pain Symptom Manage

29 Bowel Function Index 3-question patient assessment scale On a scale of 0 (not at all) (very strong), over the last 7 days Ease of defecation Feeling of incomplete bowel evacuation Personal judgment of constipation Higher scores indicate greater constipation Ducrotté P, et al. Curr Med Res Opin

Triage and Red Flags Patient should contact a healthcare clinician if: No bowel movement in 4 days New or worsening constipation despite lifestyle modifications or OTC laxative use

30 Triage and Red Flags Patient should contact a healthcare clinician if: No bowel movement in 4 days New or worsening constipation despite lifestyle modifications or OTC laxative use Alternating diarrhea and constipation New or worsening abdominal pain Bloody stools Unintended weight loss Schisler RE, et al. J Palliat Med. 2012; Kumar L, et al. Gastroenterol Res Pract

31 Stimulant Laxatives Examples: Sennosides and bisacodyl Mechanism of Action Stimulate peristalsis directly by acting on intestinal smooth muscle Increases fecal water content by altering intestinal fluid and electrolyte secretion Contraindications Intestinal obstruction Acute or undiagnosed abdominal pain Adverse Effects Diarrhea Intestinal colic Rectal irritation (with rectal administration) Twycross R, et al. J Pain Symptom Manage

32 Osmotic Laxatives Examples: Polyethylene glycol, lactulose, and magnesium salts Mechanism of Action Draws water into the intestinal lumen Softens stool and causes bowel distention and stimulation of peristalsis Contraindications Caution in patients with renal impairment (Mg ++ salts) Adverse Effects GI upset (bloating and gas particularly with lactulose) Electrolyte imbalance Liu LW. Can J Gastroenterol

33 Docusate Mechanism of Action Lowers surface tension, allowing water and fat to penetrate and soften stool Contraindications Acute or undiagnosed abdominal pain Adverse Effects Generally well tolerated May see mild cramping and diarrhea Twycross R, et al. J Pain Symptom Manage

Mean Number of BMs Senna + Docusate: A Dynamic Duo? 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.8 0.64 Docusate + Sennosides vs. Placebo + Sennosides 0.74 0.68 0.94 0.8 0.82 0.81 0.76 0.75 0.73 0.65 0.

34 Mean Number of BMs Senna + Docusate: A Dynamic Duo? Docusate + Sennosides vs. Placebo + Sennosides Randomized, double-blind, placebo-controlled trial, N=74 No significant between-group differences in stool frequency, volume, or consistency; or difficulty or completeness of evacuation Study Day Docusate Placebo BM=Bowel movement Tarumi Y, et al. J Pain Symptom Manage

35 Bulk Forming Laxatives Examples: Psyllium, methylcellulose Mechanism of Action Increases fecal bulk, distends colon, and stimulates peristalsis NOT Recommended in OIC Opioids prevent peristalsis of fiber-increased bulk Can cause abdominal pain and lead to bowel obstruction Galligan JJ, et al. Gastroenterol Res Pract

36 Example Bowel Protocol Goal: Achieve a bowel movement every 1-3 days without straining (if more than 3 days since last bowel movement consider suppositories/enema) Start with senna 17.2 mg at bedtime Increase senna dose every hours as needed to maximum dose of 34.4 mg 3 times a day If no result at maximum tolerated dose, half senna dose and add osmotic laxative (eg, lactulose or polyethylene glycol) Twycross R, et al. J Pain Symptom Manage

37 Wrong Turn! Developing a New Plan James B. Ray, PharmD, CPE Pharmacy Clinical Coordinator Pain and Palliative Care University of Virginia Health System Charlottesville, VA Clinical Assistant Professor Virginia Commonwealth University School of Pharmacy Richmond, VA

38 Action of Opioids and PAMORAs in the CNS and GI Tract Becker G, et al. Lancet

39 Alvimopan First in PAMORA class Indicated for GI recovery following surgery Studied in OIC Improved SBMs at three dose levels compared to placebo over 6 weeks Cardiovascular risk signal Boxed warning Risk Evaluation Mitigation Strategies (REMS) program SBM=Spontaneous bowel movement Webster L, et al. Pain

40 Cardiovascular Risk June 2014 FDA advisory committee votes to not require cardiovascular outcome trials Post-approval data collection for cardiovascular safety /Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM pdf.

41 Methylnaltrexone Bromide Indications Patients with advanced illness not responding to laxatives (palliative care) OIC in adult patients with CNCP Formulations Subcutaneous injection, investigational oral form Thomas J, et al. N Engl J Med

42 Patients with Laxation Response (%) Methylnaltrexone Bromide in Advanced Illness Placebo (N=71) 15 48* Laxation within 4 Hr after the First Dose Methylnaltrexone (N=62) 8 52* Laxation within 4 Hr after 2 of the First 4 Doses No evidence of opioid withdrawal observed Abdominal pain & flatulence most common adverse events *P<.001 for both Thomas J, et al. N Engl J Med

43 Methylnaltrexone Bromide in CNCP 4-week Randomized Controlled Trial (RCT) of subcutaneous injection (12 mg daily or every other day) 28.9% of methylnaltrexone subcutaneous daily and 30.2% of methylnaltrexone subcutaneous every other day resulted in rescue-free bowel movements (RFBMs) within 4 hr compared to 9.4% daily and 9.3% every other day with placebo 12-week RCT of oral (150 mg, 300 mg and 450 mg for 4 weeks daily, then 8 weeks as needed) Dose dependent increase in RFBM and decreased time to 1 st RFBM compared to placebo Michna E, et al. J Pain. 2011; Rauck RL, et al. Gastroenterol

44 Methylnaltrexone Bromide Dosing Common Adverse Events <38 kg 0.15 mg/kg kg 8 mg kg 12 mg >114 kg 0.15 mg/kg Abdominal pain, diarrhea, nausea, hyperhidrosis Contraindications Known or suspected mechanical gastrointestinal obstruction

45 Naloxegol PEGylated form of naloxone Reduces passive permeability across the blood-brain barrier Substrate of P-glycoprotein transporter Metabolism CYP3A4, weak inhibitor of CYP2D6 & CYP2C19 Enterohepatic recycling Daily dosing: 25 mg orally 1 hour prior or 2 hours after a meal Avoid grapefruit juice Leonard J, et al. Ann Pharmacother

46 Naloxegol Primary Endpoint: Response* Study 1 (KODIAC-04) Placebo (N=214) 12.5 mg (N=213) 25 mg (N=214) Patients responding 63 (29%) 87 (41%) 95 (44%) 95% CI (2.4%, 20.4%) (5.9%, 24%) P value Study 2 (KODIAC-05) Placebo (N=232) 12.5 mg (N=232) 25 mg (N=232) Patients responding 68 (29%) 81 (35%) 92 (40%) 95% CI (-2.9%, 14.1%) (1.7%, 18.9%) P value *12-week response rate ( 3 spontaneous bowel movements per week and an increase from baseline of 1 spontaneous bowel movements for 9 of 12 weeks and for 3 of the final 4 weeks) Chey WD, et al. N Engl J Med

Patients (%) Patients (%) 50 40 30 20 10 0 29.4 40.8* Naloxegol 44.4* 29.3 34.9 39.7* Relative Risk (95% CI) 1.38 (1.06-1.80) 1.51 (1.17-1.95) 1.19 (0.91-1.55) 1.35 (1.05-1.74) No. Needed to Treat 8.

47 Patients (%) Patients (%) * Naloxegol 44.4* * Relative Risk (95% CI) 1.38 ( ) 1.51 ( ) 1.19 ( ) 1.35 ( ) No. Needed to Treat N= N=214; P= * N=213; P=.001 N=232 N= * N=232; P= * Relative Risk (95% CI) 1.48 ( ) 1.69 ( ) 1.35 ( ) 1.49 ( ) No. Needed to Treat *Statistically significant KODIAC-04 KODIAC-04 N=118 N=115; P=.03 N=117; P=.002 KODIAC-05 KODIAC-05 N=121 N=125 N=124; P=.01 Placebo Naloxegol 12.5 mg Naloxegol 25 mg Intent to Treat Population Inadequate Response to Laxative Population Chey WD, et al. N Engl J Med

48 Naloxegol Adverse Reactions Adverse Reactions in Patients with OIC and CNCP Naloxegol 25 mg (N=446) Naloxegol 12.5 mg (N=441) Placebo (N=444) Abdominal Pain 20% 12% 7% Diarrhea 9% 6% 4% Nausea 8% 7% 5% Flatulence 6% 3% 3% Vomiting 5% 2% 3% Headache 5% 4% 3% Hyperhidrosis 3% <1% <1% Chey WD, et al. N Engl J Med

49 Naloxegol Cautions Patients with known or suspected GI obstruction and patients at increased risk of recurrent obstruction due to the potential for GI perforation Patients receiving strong CYP3A4 inhibitors which can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms Dose adjustment for CrCl <60 ml/min, not recommended in patients with severe hepatic impairment FDA Prescribing Information.

50 Lubiprostone Chloride channel activator (ClC-2) Promotes fluid secretion increased motility Bypasses the antisecretory action of opioids Indications Chronic Idiopathic Constipation (CIC) in adults Opioid-Induced Constipation (OIC) in adults with CNCP 24 mcg orally twice daily Irritable Bowel Syndrome with Constipation (IBS-C) in women 18 years old 8 mcg orally twice daily

51 Lubiprostone for OIC in CNCP Study 1 Study 2 Study 3 Trial Design RCT, double-blind, placebocontrolled, 12 week (excluded methadone) 1 RCT, double-blind, placebocontrolled, 12 week 2 RCT, double-blind, placebocontrolled, 12 week 3 Response Lubiprostone-26.9% (N=214) Placebo-18.6% (N=217) P= Lubiprostone-3.3 SBMs (N=210) Placebo-2.4 SBMs (N=208) P= Lubiprostone-2.7 SBMs (N=235) Placebo-2.5 SBMs (N=216) P= Jamal MM, et al. Gastroenterol. 2012; 2 Cryer B, et al. Pain Med. 2014; 3 Spierings EL, et al. Gastroenterol

3 0 Lubiprostone Placebo 0 20 Time (Hours) 40 RCT, double-blind, placebo-controlled, 12 week (excluded methadone),

52 Response Rate (%) Lubiprostone for OIC in CNCP 30 Overall SBM Responders* 26.9% P=.035 Median Time to First SBM Placebo % P= Lubiprostone Lubiprostone Placebo 0 20 Time (Hours) 40 RCT, double-blind, placebo-controlled, 12 week (excluded methadone), primary efficacy endpoint: overall SBM response rate *Defined as having 3 or more SBMs per week for at least 9 weeks, and at least 1 additional SBM over mean baseline Jamal MM, et al. Gastroenterol

Mean Change from Baseline in SBM Frequency Lubiprostone 4 P=.005 P=.091 Placebo (N=208) Lubiprostone (N=210) 3 P=.004 2 1 0 Week 8 Week 12 Overall No.

53 Mean Change from Baseline in SBM Frequency Lubiprostone 4 P=.005 P=.091 Placebo (N=208) Lubiprostone (N=210) 3 P= Week 8 Week 12 Overall No. of Observations RCT, double-blind, placebo-controlled, 12 week Primary endpoint: change from baseline in SBM frequency at week 8 Cryer B, et al. Pain Med

54 Mean Score Mean Score Lubiprostone vs. Senna Gastrointestinal Outcomes: Patient Assessment in Constipation 1.5 PAC-SYM* Lubiprostone (N=28) Senna (N=28) PAC-QOL** Baseline Day 7 Baseline Day 7 There was no significant difference found between lubiprostone and senna in the change from baseline to day 7 for PAC-SYM (P=.89) or PAC-QOL (P=.30) *Higher numbers indicate more symptoms; **Higher numbers indicate better quality of life 0 Marciniak CM, et al. World J Gastroenterol

55 Lubiprostone Nausea most frequent adverse event Decreased when administered with food Cautions Reduce dose in moderate (16 mcg twice daily) to severe (8 mcg twice daily) hepatic impairment Development of diarrhea and dyspnea Methadone can inhibit lubiprostone s ability to activate CIC-2 channels in intestinal cells Pregnancy Category C Should not be used in women who are pregnant or trying to become pregnant FDA Prescribing Information.

56 The Horizon Investigational PAMORAs Axelopran (TD 1211) Bevenopran Naldemedine Other Agents Prucalopride (5-HT 4 agonist) Linaclotide Guanylate cyclase-c agonist

OPIOID-INDUCED CONSTIPATION DR ANDREW DAVIES

OPIOID-INDUCED CONSTIPATION DR ANDREW DAVIES Introduction Introduction Mean faecal weight 128 g / cap / day Mean range 51-796 g Absolute range 15-1505 g Main factors affecting mass are caloric intake,