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The Price of Pain Relief: Opioid Induced Constipation Maria Foy, PharmD, BCPS, CPE Patient Care Coordinator, Palliative Care Abington-Jefferson Health Chris Herndon, PharmD, BCPS, CPE Associate Professor Southern Illinois University Edwardsville 2 Disclosures • Dr. Foy is on the speakers bureau for AstraZeneca • Dr. Herndon declares no conflicts of interest, real or • Target Audience: Pharmacists apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. • ACPE#: 0202-0000-16-056-L01-P • Activity Type: Application-based The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 3 4 Which of the following is the most commonly reported, troublesome side effect of opioids? Learning Objectives • Answer questions from patients and health care providers about a) b) c) d) the potential for constipation during opioid use. • Discuss lifestyle modifications that may help prevent and manage constipation associated with opioid therapy. • Compare current treatment options for the management of opioid-induced constipation. Constipation Drowsiness Nausea Indigestion • Evaluate patient cases and make clinical recommendations for patients with opioid-induced constipation. • Describe patient education strategies that promote adherence to therapy to prevent and manage opioid-induced constipation 5 © 2016 by the American Pharmacists Association. All rights reserved. 6 The inhibition of the _____________ plexus is the most likely cause of opioid induced constipation. a) b) c) d) Submucosal Myenteric Celiac Brachial Which lifestyle change can help prevent constipation? a) b) c) d) Eat primarily high fat foods Exercise Increase in intake of coffee Waiting until there is enough time to have a complete bowel movement 7 Which of the following options should NOT be a part of an opioid induced constipation (OIC) bowel regimen? Which of the following is a peripherally acting mu opioid antagonist? a) b) c) d) 8 Lubiprostone Senna Polyethylene glycol Methylnaltrexone a) b) c) d) e) Bisacodyl Suppository Docusate sodium Psyllium Sennasides Polyethylene glycol 9 Which opioid side effect is not associated with the development of tolerance? a) b) c) d) e) Nausea Respiratory depression Constipation Sedation Confusion 10 What is Opioid Induced Constipation (OIC)? • Cause of constipation differs from functional constipation • Suggested definition – Change in bowel habits after opioid therapy initiated • Decrease in bowel movement (BM) frequency from baseline • Increased straining during defecation • Feeling of incomplete evacuation of stool • Harder stools • Opioids may worsen constipation in patients with a predisposition 11 © 2016 by the American Pharmacists Association. All rights reserved. 12 Meet Caroline Etiologies of Constipation 52 year old female with persistent non-cancer pain due to osteogenesis imperfecta Type 1 PMHx: Osteogenesis Imperfecta, HTN, Depression Meds: Fentanyl TTS 75mcg/hr Q72 hours, hydromorphone IR Q8H as needed, lisinopril 40mg QD, citalopram 40mg QD, senna plus docusate 2 tablets Q12, PEG 17gms QD, lubiprostone 24mcg Q12 hours All: NKDA SHx: Denies tobacco use, EtOH, recreational drug use ROS: Unremarkable other than significant constipation. Last BM 5 days ago. Vitals: 130/74 mmHg, HR 90, RR 16, Temp 98.6 Labs: All within normal limits, specifically Ca and Mg Tests: Abdominal CT negative for diverticulitis Medications Pain Metabolic Bowel Dysfunction Mobility Diet Structural Autonomic 13 Incidence versus Bothersomeness of Common Opioid Adverse Effects Prevalence of OIC, Opioid Regimen 90 80 70 60 50 40 30 20 10 0 14 No Opioid PRN Opioid ATC Opioid PRN + ATC Villars P, et al. Differences in the prevalence and severity of side effects based on the type of analgesic prescription in patients with chronic cancer pain. J Pain Symptom Manage 2007;33:67-77. 15 Symptom % patients reporting Constipation 81 Bothersomeness Rank 1 Straining 58 2 Fatigue 50 3 Small / hard bowel movement 50 4 5 Insomnia 40 Incomplete evacuation 45 6 Passing gas 34 7 Bloating 33 8 Lower abdominal discomfort 31 8 Nausea 26 10 Bell TJ, et al. The prevalence, severity, and impact of opioid induced bowel dysfunction: Results of a US and European patient survey (Probe 1). Pain Medicine 2009;10:35-42. Opioid Induced Bowel Dysfunction The “Poop or No Poop” Game • • • • • • • • • • • Xerostoma Gastroesophageal reflux Retroperistalsis Bloating Abdominal pain Incomplete evacuation Opioid-induced constipation • 16 Each table will be one team One captain per table will control the buzzer Please turn your button on now The first team to press the button and answer the question correctly will get one point The team with the most points will get a nominally significant prize Brock C, et al. Opioid induced bowel dysfunction: Pathophysiology and management. Drugs 2012;72(14):1847-1865. 17 © 2016 by the American Pharmacists Association. All rights reserved. 18 Poop or No Poop Sample Question Poop or No Poop Which MLB team won the World Series in 2015? Which of the following opioid dosing strategies has the highest risk of constipation? a) b) c) d) e) St. Louis Cardinals Baltimore Orioles Cincinnati Reds Kansas City Royals Oakland Athletics a) b) c) d) around the clock dosing of opioid as need dosing of opioid around the clock and as needed dosing of opioid transdermal dosing of opioid 19 Pathophysiology of OIC 20 Opioid Receptors and the Intestine • • • • • • Reproduced with permission under Creative Commons via OpenStax CNX via Rice University Attribution: Download for free at http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22 21 Inhibition of distension-dependent peristaltic contractions Gastric emptying inhibition Gastrointestinal ion and fluid transport inhibition Increased pyloric resting muscle tone Elevation in resting anal sphincter pressure Decreased defecation response 1. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155:11-17. 2. Rosti G, et al. Opioid-related bowel dysfunction: Prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci 2010;14:1045-50. Poop or No Poop Risk Factors for OIC Which cooked vegetable has the highest dietary fiber content? • Female gender • Age > 70 years • Concurrent aluminum antacids, antidepressants, and a) b) c) d) e) asparagus cabbage peas* spinach squash antihistamines • Opioid dose • Magnesium and calcium status • Opioid type and route of administration 23 © 2016 by the American Pharmacists Association. All rights reserved. 22 1. Rosti G, et al. Opioid-related bowel dysfunction: Prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci 2010;14:1045-50. 2. Talley NJ, et al. Risk factors for chronic constipation based on a general practice sample. Am J Gastroenterology 2003;98:1107-1111. 3. Herndon CM, et al. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy 2002;22:240-250. 24 Assessment Tools Caroline’s Bowel History • • • • • • • • • Bristol Scale Constipation Assessment Scale Bowel Function Index Patient Assessment of Constipation Symptoms Hard, ball-like stool (Bristol Scale Type 1) Last BM 5 days ago Trialed sodium phosphate (Fleets) enema without laxation Normal BM frequency every other day in the morning Describing cramping and abdominal pain 25 Bristol-type Stool Assessment Scale Type Bowel Function Index (BFI) Description 1 Separate hard lumps, similar to nuts 2 Lumpy, sausage-like pieces 3 Like sausage, but with cracks 4 Like a sausage or snake, but smooth and soft 5 Soft blobs with definable edges 6 Fluffy, mushy pieces with ragged edges 7 Watery, no solid pieces Adapted from: http://www.bowelcontrol.nih.gov/Bristol_Stool_Form_Scale_508.pdf. Accessed Jan 7, 2016. ITEM 27 Constipation Assessment Scale Symptom Patient Rating Abdominal distension or bloating None / Some / Severe Change in amount of gas passed rectally None / Some / Severe Less frequent bowel movements None / Some / Severe Oozing liquid stool None / Some / Severe Rectal fullness or pressure None / Some / Severe Rectal pain with bowel movement None / Some / Severe Small volume of stool None / Some / Severe Unable to pass stool None / Some / Severe McMillan SC, et al. Validity and reliability of the Constipation Assessment Scale. Cancer Nurs 1989;12:183-8. © 2016 by the American Pharmacists Association. All rights reserved. 26 INTENSITIY Ease of defecation in the prior 7 days 1 2 3 4 5 6 7 8 9 10 Feeling of incomplete bowel evacuation 1 2 3 4 5 6 7 8 9 10 Patient’s personal assessment of constipation 1 2 3 4 5 6 7 8 9 10 Adapted from Validation of Drug Function Index to detect clinically meaningful changes in opioid induced constipation. Rentz AM, et. al. Journal of Medical Economics. (2009) 28 Assessment • Patient medical and medication history • Physical exam • Laboratory – Electrolyte abnormalities – Fluid status • Testing – Abdominal CT • Adherence 29 30 Current Therapeutic Approaches Poop or No Poop • • • • • • • • Which common drug is most likely to exhibit a side effect of constipation? Behavioral health changes Medication Rotation Oral stool softeners and laxatives Enemas or suppositories Manual disimpaction/evacuation Propulsion agents Ion channel modulators Peripherally acting mu opioid receptor antagonists a) b) c) d) e) metoprolol amlodipine sertraline aripiprazole metformin 31 Pharmacologic Treatment Options 32 Poop or No Poop Which laxative / stool softener has the quickest onset of action? • Bulk laxatives • Osmotic laxatives • Stimulant laxatives • Chloride channel activators • Peripherally acting mu opioid receptor a) b) c) d) e) senna polyethylene glycol lactulose magnesium citrate bisacodyl antagonists (PAMORA) 33 Bulk Forming Laxatives Poop or No Poop • Mechanism – Increases stool bulk – Colonic distension – Stimulates peristalsis • Commercially available – psyllium (Metamucil) – methylcellulose (Citrucel) – polycarbophil (FiberCon) – wheat dextrin (Benefiber) • Inconsistent clinical evidence of utility • Avoid in OIC due to risk of obstruction and lack of benefit 1. Bharucha AE, et al. American Gastroenterological Association technical review on constipation. Gastroenterol 2013;144(1):218-238. 2. Ramkumar D, et al. Efficacy and safety of traditional medical therapies for chronic constipation: Systematic review. Am J Gasterenterol 2005;100(4):936-971. © 2016 by the American Pharmacists Association. All rights reserved. 34 The recommended daily intake of dietary fiber for a healthy adult is: Psyllium 35 a) b) c) d) e) 5-10 g/day 10-15 g/day 15-20 g/day 20-25 g/day 25-30 g/day 36 Osmotic Laxatives Stimulant Laxatives • Pulls water into the colon, hydrating and softening stools • Types of osmotic laxatives • Mechanism – Increasing colonic muscle contractions facilitates peristalsis – Reduces intraluminal water and electrolyte absorption • Types of stimulant laxatives – Senna, bisacodyl most commonly used – Other options: cascara, aloe, castor oil • Dosing – Senna: 2 tablets at bedtime or twice daily – Can titrate as tolerated to 8 tablets/day – Scheduled bisacodyl suppositories every 2-3 days in NPO patients Senna 37 – Polyethylene glycol (PEG) – carbohydrate laxatives (lactulose, sorbitol) – phosphate, magnesium, or saline • PEG studied for OIC use – Increase of softened stools seen in study of methadone induced constipation – As effective as other laxatives in chronic constipation – Initial dose: 17 g daily • Lactulose studied for functional constipation – May be beneficial in concomitant liver disease – Initial dose: 30 ml daily Freedman MD, et al. J Clin Pharmacol 1997;37(10):904–907. Ramkumar D, et al. Am J Gastroenterol 2005;100(4):936–971. Ford AC, et al. Gut 2011;60(2):209–218. Adverse Effects of Laxatives Poop or No Poop • Generally well tolerated • Gastrointestinal side effects Which of the following therapies is not FDA indicated for opioid-induced constipation? a) b) c) d) – Nausea/vomiting – Diarrhea – Abdominal pain 38 naloxegol methylnaltrexone alvimopan lubiprostone • Tolerance to laxatives with long term use • Dysfunctional bowel syndrome may occur 39 Chloride Channel Activators 40 Opioid Antagonists • Mechanism • Naloxone primarily studied – Works by increasing fluid secretion and gut motility • Available agents • • • • – Low dose oral naloxone – Equivocal data in palliative care – Lubiprostone – Linaclotide Lubiprostone FDA approved for OIC in non-cancer pain – Efficacy lessened in trials including methadone – Linaclotide currently being studied, not yet approved Dosing: 24 mcg twice daily Generally well tolerated – N/V, diarrhea, abdominal pain reported in studies Cost: Approximately $6/dose Cryer B., et.al.. Pain Med 2014; 15: 1825–1834. Jamal MM, et al.. Am J Gastroenterology 2015; 110:725. © 2016 by the American Pharmacists Association. All rights reserved. • • • • • Oral bioavailability low Dose studied: 2-4 mcg three times a day Small number of patients enrolled Efficacy seen but reversal of analgesia occurred in up to 1/3 of patients Naloxone prolonged release (PR) added to oxycodone SR studied – Efficacious, but tolerability similar to placebo – Fixed dose studied, higher doses may cause withdrawal symptoms • Naloxone monotherapy not recommended for OIC 41 42 Peripherally Acting Mu Opioid Receptor Antagonists (PAMORA) Methylnaltrexone (Relistor) • Methyl group added to naltrexone allows blocking of opioid receptors in the gut without crossing the blood brain barrier – Analgesia not affected • Designed to antagonize peripheral mu opioid receptors in • Approved for OIC in both cancer and non-cancer opioid when other the gut without reversing analgesia therapies have failed • Dosing: – Does not cross the blood brain barrier – Will not produce withdrawal symptoms – 8-12 mg subcutaneously (SC) every other day for advanced illness • In patients >114 kg, weight based dosing is recommended – 12 mg SC daily recommended for non-cancer pain • Available agents – Methylnaltrexone (Relistor) – Naloxegol (Movantik) – Alvimopan (Entereg) • Generally well tolerated – GI side effects most common adverse reaction seen in studies • Cost: Approximately $55 per 12 mg dose 43 Naloxegol (Movantik) 44 Alvimopan (Entereg) • Polyethylene glycol group added to naloxone to prevent the naloxone • Potent peripheral mu receptor antagonist that blocks opioid receptors from crossing the blood brain barrier • First oral agent for treatment of OIC in non-cancer pain • Dosing in the gut without crossing the blood brain barrier • Indicated for prevention of post op ileus in colorectal and abdominal surgeries • Initial studies showed inconsistent results for OIC treatment • Recent meta-analysis of clinical trials (4) demonstrated potential – 25 mg po daily in the am on empty stomach – Reduce to 12.5 mg if 25 mg dose not tolerated – Reduce dose in renal impairment recommended (<60 ml/min) efficacy of alvimopan for OIC • Substrate of CYP3A4 metabolism and P-glycoprotein • Cardiovascular adverse events in early trials – Contraindicated in moderate/strong CYP3A4 inhibitors and strong CYP3A4 inducers • GI side effects most common • Cost: Approximately $10/dose – Seen in patients with previous CV events or were high risk for CV adverse reactions • Cost: Approximately $130 for 12 mg tablet – Lower doses studied for OIC 45 Ford AC, et al. Am J Gastroenterol 2013;108:1566–74 The Bottom Line on Docusate Other Anecdotal Options • Facilitates the incorporation of water and fats into the stool • Prucalopride • allowing for softening Not recommended as monotherapy for OIC – “You just get the mush, not the push” • Usually given in combination with a stimulant laxative – May be beneficial in patients who report hard stools • Efficacy not demonstrated in OIC studies when compared • • 46 – Selective 5HT4 receptor agonist – Stimulates gut motility – Usual dose: 2-4 mg/day Misoprostol Colchicine to placebo – NOT NEEDED in every patient who is on opioids – NOT NEEDED in patients receiving PEG therapy for OIC Tarumi Y, et al. J Pain Sympt Manage 2013; 45(1): 2–13. © 2016 by the American Pharmacists Association. All rights reserved. 47 Taqhavi SA, et al. Int J Colorectal Dis 2010;25(3):389-394. Roarty TP TP, et al. Aliment Pharmacol Ther 1997;11(6):1059-1066. 48 Additional Management Strategies How to Rotate to Another Opioids • Healthy bowel habits • Assess your patients for comorbidities that affect choices • Determine the correct dosing formulation • Individualize dosage based on pain control on current opioid and/or – – – – – Eat consistent meals at consistent times daily Smaller meals Eat breakfast! Increase non-caffeinated fluid intake Try to “schedule” bowel movements adverse reactions • Calculate current 24 hour opioid usage • Decrease for incomplete cross tolerance • • • • • Opioid dose decrease • Opioid rotation • Diary of bowel movements No correlation of tolerance between opioids Dose is typically reduced by 25-75% Decrease dose if pain controlled and switching to an alternative opioid No dose reduction needed when switching to the SAME opioid • Reassess, reassess, reassess 49 Treatment Algorithm 50 Tips for OIC Prevention • • • • Drink plenty of water Avoid high fat foods Avoid foods high in sugar Exercise AND…. IF YOU GET THAT FEELING, JUST GO!!!! Holding it in can make it worse. Don’t wait until you get home. 51 Fiber Content of Common Foods FOOD FIBER CONTENTS Various beans 5-16 g per 1 cup All bran cereal 10 g per ½ cup Corn 4 g per 1 cup Oatmeal 4 g per 1 cup Banana 3 g for medium size Whole wheat bread 2g Quinoa 8 g per 1 cup Various nuts 12-16 g per 1 cup Patient Education • • • • • 53 © 2016 by the American Pharmacists Association. All rights reserved. 52 Adequate fluid intake Maintain activity Dietary fiber intake Avoidance of bulk forming laxatives Avoidance of straining 54 Patient Education Strategies Patient Resources • Areas of focus for education • Patient Guide to Constipation Management – How to avoid OIC – Information on appropriate prevention strategies utilizing medications • Stool softener not enough! – Titration information based on response – Re-evaluation of bowel regimen with opioid dose changes – https://www.cmecorner.com/constipation/eimpacct_patient_guide.pdf • Pharmacist letter – Lets get going: what helps for constipation • Provide written education on the importance of constipation prevention • Develop a mechanism to ensure that EVERY patient on opioids • Harvard Patient Education Center – http://www.patienteducationcenter.org/articles/constipation-andimpaction/ receive information on constipation prevention • Individual PAMORA web sites 55 56 Return to Caroline Take Home • Patient is requesting rotation to different analgesics despite • OIC is a significant barrier to effective pain control • Aggressive anticipation, monitoring, and treatment greatly • • • favorable pain control She has trialed numerous commercially available treatment modalities Discussed with patient the pros and cons of either orally administered naloxone or misoprostol What wound up happening? improves patient-related outcomes • Discussing the bowel habits of a patient in pain is NOT taboo 57 Which of the following is the most commonly reported, troublesome side effect of opioids? a) b) c) d) Constipation Drowsiness Nausea Indigestion The inhibition of the _____________ plexus is the most likely cause of opioid induced constipation. a) b) c) d) 59 © 2016 by the American Pharmacists Association. All rights reserved. 58 Submucosal Myenteric Celiac Brachial 60 Which lifestyle change can help prevent constipation? a) b) c) d) Which of the following is a peripherally acting mu opioid antagonist? a) b) c) d) Eat primarily high fat foods Exercise Increase in intake of coffee Waiting until there is enough time to have a complete bowel movement Lubiprostone Senna Polyethylene glycol Methylnaltrexone 61 Which of the following options should NOT be a part of an OIC bowel regimen? a) b) c) d) e) Which opioid side effect is not associated with the development of tolerance? a) b) c) d) e) Bisacodyl Suppository Docusate sodium Psyllium Sennasides Polyethylene glycol 63 © 2016 by the American Pharmacists Association. All rights reserved. 62 Nausea Respiratory depression Constipation Sedation Confusion 64