1. Constipation: The Latest and Greatest Rosene Pirrello, RPh Solomon Liao, MD

2. Objectives By the end of this session, participants will be able to: Prevent constipation Select the appropriate laxative Select the appropriate enema Treat refractory opioid-induced constipation

3. Is She Constipated? 64 year-old recently started on Lasix for mild diastolic heart failure Usually bowel movement every other day Now bowel movement every 2-3 days and “harder” stools What would you recommend, if anything?

4. Definition What is your definition of constipation? “unsatisfactory defecation characterized by infrequent stool, difficult stool passage or both” (1) “reduced frequency or ease of stool passage from what is deemed the normal or expected pattern for that individual” (2) 1. American College of Gastroenterology Constipation Task Force Am J Gastroenterol 2005; 100 Supp 1:S1-4 2. Can J Gastroenterol. 2011 Oct; 25(Supp B): 7B-10B

5. Causes: Concurrent Diseases Hypothyroidism Diabetes Hypokalemia Hernia Hypercalcemia Rectocele Anal Fissure/Stenosis Mucosal Prolapse Colitis

6. Causes: Malignancy Intestinal obstruction tumor in bowel wall or external compression by abdominal or pelvic tumor Damage to lumbosacral spinal cord cauda equina or pelvic plexus.

7. Causes: Misc Inadequate food intake Low-fiber diet Dehydration Weakness Inactivity Depression Unfamiliar toilet arrangements

8. Pseudomyxoma Peritonei 28 year-old Ovarian cancer Subacute increased abdominal pain Generalized, 10/10 On long acting morphine 60 mg po q12 hrs Intermittent nausea On ondansetron 4 mg po q8 hrs prn nausea She has been eating + flatus, daily soft bowel movements.

9. How would you treat her pain? A) Increase her opioids B) Add a non-opioid pain medicine C) Give her an enema D) Start antibiotics E) Obtain an pain consult for a nerve block

10. Causes: Common Palliative Care Drugs Anticonvulsants Drugs with anticholinergic effects: Scopolamine, atropine, hyoscine Phenothiazines Tricyclic antidepressants Antiparkinsonian agents Antihistamines 5-HT 3 receptor antagonists Ondansetron, granisetron, dolasetron Opioids

11. Opioids: Effects on the gut Increased tone in ileocecal and anal sphincters Reduced peristalsis in small intestine and colon Impaired defecation reflex Reduced sensitivity to distention Increased internal anal sphincter tone

12. Causes: Drugs Antacids ( Ca ++ and Al +++ compounds) Diuretics Iron Vincristine Calcium Channel Blockers

13. Management: Prophylaxis Encourage activity, if possible Maintain adequate oral fluid intake Create a favorable environment Anticipate constipating effects of drugs Start a laxative prophylactically

14. Lung Cancer 80 year-old on long acting morphine For dyspnea and pain “diarrhea” started 2 days ago Abdominal distention Nausea Had been having “irregular bowel movement” before diarrhea What do you do?

15. Enemas Fleets Mineral oil Tap water Soap sod Lactulose Milk & Molasses Harris flush Flushing colonoscopy

16. Treatment Algorithm 1 st line: Prevention or Treatment Senna Bisacodyl MOM 2 nd line: Add or change to PEG Lactulose Sorbitol 3 rd line: Rescue therapy Suppository Enemas 4 th Line: Refractory therapy Peripheral opioid antagonist Chloride channel activator

17. Classification of Laxatives Predominantly softening/osmotic Lactulose Sorbitol PEG (Miralax) Saline Laxatives Bulk-forming Ca Channel Activator Lubiprostone (Amitiza®) Predominantly peristalsis stimulating Anthracenes (senna) Polyphenolics (bisacodyl) Peripherally-acting Opioid Antagonists Alvimopan (Entereg ® ) Methylnaltrexone (Relistor ® ) Naloxegol (Movantik ® )

18. Choice of Laxatives Practical considerations Renal patients: avoid Mg, Phos Liver patients: Lactulose Geriatric patients: don’t like sweet Avoid fiber laxatives With opioids, diuretics Unable to drink sufficiently

19. Cost DrugSupplyUCI Cost Senna100 tabs$1.87 Bisacodyl100 tabs$1.16 MOM355 mL$1.77 PEG526 g$9.33 Lactulose946 mL$9.01 Sorbitol960 mL$5.42 Fleets enema1 enema$0.72 Methylnaltrexone12 mg / SC daily$62.12 Naloxegol25 mg / PO daily$7.18 Alvimopan12 mg / PO BID$114.32 = $228.64 daily Lubiprostone24 mcg / PO BID$4.82 = $9.64 daily

20. Colon Cancer 45 year-old stage 4 colon cancer Peritoneal & small bowel metastases No bowel movement for 5 days Abdominal pain and distention Nausea but no vomiting Normal active bowel sounds No response to enemas What do you do?

21. Peripherally-acting Opioid Antagonist Methylnaltrexone Onset: 4 to 24 hours (SC) Dose: Usually 12 mcg SC; may repeat daily Naloxegol Onset: 4 to 24 hours (PO) Dose: 25 mg daily 1 hour before a meal (12.5 mg daily for CrCl <60)

22. Lubiprostone (Amitiza) Chloride channel activator: increases intestinal fluid secretion and motility Onset: 40% laxation within 24 hrs Dose: 24 mcg BID (PO) Adjust in liver disease: Child-Pugh B Class: 16 mcg BID Child-Pugh C Class: 8 mcg BID

23. Whipple 58 year-old pre-op for Whipple of pancreatic carcinoma No cardiac history Opioid naïve Post-op PCA planned What can help prevent an ileus?

24. Alvimopan (Entereg) Oral Peripherally-acting Opioid Antagonist FDA: Post-op ileus Short term hospital use only - 15 dose total Onset: 48 hrs Dose: First dose 90 minutes prior to surgery Then 12 mg PO BID; may repeat daily for up to 7 days Liver disease: Class C - Avoid use 1.3% MI in chronic opioid users Lancet. 2009 ;373:1198-206.

25. Conclusion Lots of causes of constipation Including drugs Ounce of Prevention Choice of laxatives – practical considerations Naloxegol is first line peripheral opioid antagonist