“I am Sick of Feeling Sick” Managing Nausea and Vomiting in the Palliative Patient

1. “I am Sick of Feeling Sick” Managing Nausea and Vomiting in the Palliative Patient Paul Daeninck WRHA Palliative Care Program Greg Harochaw Taché Pharmacy

2. Declaration • Advisor or Paid Speaker for the following: • Valeant Pharmaceuticals • Bayer • Wyeth Pharmaceuticals

3. Objectives • At the end of this session, the attendee will be able to: • Identify the numerous GI issues causing nausea and vomiting in the palliative patient • Discuss the principles in determining the therapies for specific situations of nausea and vomiting • Recognize the complex physiology and potential for use of alternative routes in treating nausea and vomiting

4. Medications Radiation Constipation Bowel obstruction Diarrhea Ascites Hemorrhage Viscus perforation Esophageal/gastric/ biliary duct obstruction Liver failure Pancreatic failure Absorption syndromes Infections Electrolytes GI Issues Causing Nausea/Vomiting

5. Approach To Symptom Control Thorough assessment history; physical examination Discussion goals of care, hopes, expectations, anticipated course of illness (impact on investigations & interventions) Investigations blood tests, X-Ray, CT, MRI, etc Treatments pharmacological and non-pharmacological; interventions Ongoing reassessment/review Options, goals, expectations, etc.

6. Pain Fatigue/Asthenia Constipation Dyspnea Nausea Vomiting Delirium Depression/suffering 80 - 90+% 75 - 90% 70% 60+% 50 - 60% 30% 30 - 90% 40 - 60% Symptom Prevalence

7. Mechanisms of Nausea & Vomiting • vomiting centre: medulla • activated by stimuli from: • Chemoreceptor Trigger Zone (CTZ) • area postrema, floor of 4th ventricle • outside BBB (fenestrated venules) • Upper GI tract & pharynx • Vestibular apparatus/Cerebellum • Higher cortical centres

8. Toxic Cancer Infection Radiation Drugs Chemotherapy Opioids Digoxin, etc Biochemical Uremia Hypercalcemia Sights, Smells Memories Opioids Cerebellar Tumor Integrative Vomiting Centre (IVC) Distension Over-eating Gastric Stasis Ext. Pressure Obstruction High, mid, low Constipation Chemical Irritants Blood, drugs Primary or Metastatic Tumor Chemoreceptor Trigger Zone Cerebral High CNS Vestibular Cerebellar GI Tract Vagal Increased Intracranial Press G. Michael Downing

9. Pathogenesis of chemo- & RT-induced emesis(CIE, RIE) 3rd vent Area postrema

10. N/V Related Problems • Medical • dehydration / electrolyte abnormalities • esophageal tears / GI bleed • aspiration pneumonia • Decreased QoL • weight loss / anorexia • weakness / lethargy • Psychological distress • Refusal of beneficial therapy

11. Principles of Therapy • Treat the underlying cause • Environmental measures • Antiemetic use: • anticipate need • use adequate, regular doses • aim at receptor involved • combinations if necessary • anticipate need for alternate routes

12. Environmental Measures • Limit exposure to food smells • open food trays prior to presentation • Bland foods (BRAT) • Small, frequent snacks/meals • Good oral hygene • Fresh air, calming environment • Sitting upright post meal • Avoid alcohol

13. Acupuncture/pressure • Not as well studied • Safe in trained hands • Often used in conjunction with meds • Some evidence in CINV, delayed NV • Theory behind wrist/pressure bands Dibble et al. Oncol Nurs Forum 2007 34:813-20 Weightman et al. BMJ 1987 295:1379

14. Anti-Emetic Agents • Transdermal scopolamine • Benzodiazepines • Antihistamines • Cannabinoids • Metoclopramide, Domperidone • Neuroleptics / Anti-psychotics • Corticosteroids • 5-HT3 Antagonists • NK1 Antagonists (aprepitant)

15. Integrative Vomiting Centre (IVC) Chemoreceptor Trigger Zone Cerebral High CNS D2 Antagonist Prochlorperazine Haloperidol Methotrimeprazine Gastrokinetics Metoclopromide 5HT3 Antagonist Ondansetron Granisetron Olanzepine? Benzodiazepines Cannabinoids Relaxation Vestibular Cerebellar H1 Antagonist Dimenhydrinate Methotrimeprazine Anticholinergic Scopolamine Atropine Cannabinoids GI Tract Vagal D2 Antagonist Gastrokinetics Metoclopromide Domeperidone Phenothiazines Methotrimeprazine 5HT4 Agonist Metoclopromide 5HT3 Antagonist Ondansetron Octreotide Dexamethasone Cannabinoids Anticholinergic Scopolamine Atropine H1 Antagonist Dimenhydrinate Cyclizine Methotrimeprazine 5HT2 Antagonist Methotrimeprazine 5HT3 Antagonist Ondansetron Increased Intracranial Press Dexamethasone ? VP Shunt G. Michael Downing

16. Antiemetics and Dosing Haloperidol 0.5 - 1 mg po/sq/iv q4-12h MTMZ 5 - 10 mg po/sl/sq q4-8h Prochlorperazine 5 - 20 mg po/pr/iv CPZ 25 - 50 mg po/pr/iv Scopolamine patch (Transderm-V) Metoclopramide 10 - 20 mg po/sq/pr q4-8h Domperidone 10 mg po q4-8h DOPAMINE ANTAGONISTS ANTIMUSCARINIC PROKINETIC

17. Antiemetics and Dosing Dimenhydrinate 25 - 100 mg po/pr q4-8h Promethazine 25 mg po/iv q4-6h (Not sq) Meclizine 25 mg po q6-12h Ondansetron 8 -16 mg q 12 h po/sq/iv Granisetron 1- 2 mg q 12 h po/sq Dexamethasone 4-16 mg po/sq/iv daily Lorazepam 0.5 - 1 mg po/sl q4-12h Nabilone 0.5-1 mg po/sl q8-12h Olanzepine 2.5-10 mg OD H1 ANTAGONISTS SEROTONIN ANTAGONISTS MISCELLANEOUS

18. Olanzepine • Atypical antipsychotic agent • Used in schizophrenia, delirium • Blocks multiple receptors • D1-4, 5-HT2/3/6, α1adrenergic, H1, M1-4 • High affinity for serotonin vs dopaminergic • Well tolerated • Few drug interactions

19. Olanzepine • Has been used in several case studies • Recently used in CINV and delayed NV • Good results with few problems • May also have some appetite benefits • Less expensive than 5-HT3 antagonists Navari et al. Support Care Cancer 2007 Mar 21 Navari et al. Support Care Cancer 2005 13:529-34 Passik et al. Cancer Invest 2004 22:383-8 Passik et al. JPSM 2003 25:485-89 Srivastava et al. JPSM 2003 25:578-82 Jackson et al. J Pall Med 2003 6:251-55

20. Cannabinoids & Nausea

21. TheNucleus of the Solitary Tract (NTS)receives information about: • Blood-borne emetics via the brainstem (BS) CTZ • Abdominal irritants via vagal afferents • NTS neurons, in turn, project to a BS central pattern generator, which coordinates emesis behavior • Higher cortical and limbic regions(governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea and vomiting through descending connections to the BS emetic circuitry • Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions • Indirect, partial actions on 5-HT and DA signaling via 5-HT3 and D2 receptors are implicated Cortex Limbic System Brainstem Emetic Circuitry Dorsal Vagal Complex—NTS Stomach Wall

22. Cannabinoids in CINV • 20 pts, RCT, P vs THC, X-over • 10 or 15 mg/m2 po q4h x 3, various tumours • Chemotherapy not specified • Anti-emetic effect seen in 14/20 THC vs 0/22 P (p<0.001) • No patients vomited while “high” Sallan et al, NEJM 1975 293: 795-797

23. Cannabinoids in CINV • 30 RCTs systematically reviewed • N=1366 pts; 25 trials X-over design • Nabilone, dronabinol, levonantradol (IM) • Stemitil, domperidone, metoclopramide • Variety of tumours • Low to highly emetogenic chemotherapies • Studied first 24 h (acute efficacy) Tramer et al, BMJ 2001 323:16-23

24. Oral nabilone (16) Oral dronabinol (13) IM levonantradol (1) Prochlorperazine (7) metoclopramide, alizapride domperidone (2) chlorpromazine, placebo (4) prochlorperazine (6) metoclopramide (2) haloperidol, placebo (6) chlorpromazine Cannabinoids in CINV Tramer et al, BMJ 2001 323:16-23

25. Cannabinoid Control (Placebo or Active) 70% 66% 59% 57% 57% 45% 43% 34% vs. Placebo vs. Active vs. Placebo vs. Active Nausea Vomiting Control of N/V with Cannabinoids: Systematic Review Event rate (%) active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride Tramèr MR, et al. BMJ. 2001;323:1-8.

26. Complete Control of N/V with Cannabinoids NNT (95% CI) Nausea 8.0 (4.0-775) Versus placebo (4 studies) 6.4 (4.0-16) Versus active control (7 studies) Vomiting 3.3 (2.4-5.7) Versus placebo (4 studies) 8.0 (4.5-38) Versus active control (6 studies) 0.5 1.0 1.5 2.0 2.5 Relative risk (95% CI) Favors cannabinoids NNT= number needed to treat; active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride. Tramèr MR, et al. BMJ. 2001;323:1-8

27. NNT (95% CI) Preference for cannabinoids Versus placebo (4 studies) 1.6 (1.4-1.8) Versus active control (14 studies) 2.8 (2.4-3.3) 0.5 1.0 2.0 4.0 6.0 8.0 10.0 Relative risk (95% CI) Favors cannabinoids Patients’ Preference for Cannabinoids NNT = number needed to treat; active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride Tramèr MR, et al. BMJ. 2001;323:1-8.

28. Cannabinoids in CINV • Cannabinoids may be superior to conventional therapies in low-moderate emetogenic setting • Patient preference for cannabinoids ranged from 38-90% (placebo 4-20%) • Cannabinoids produced significantly more side effects (good & bad), more pt withdrawals • “In selected patients, cannabinoids may be useful as mood enhancing adjuvants for the control of chemotherapy related sickness” Tramer et al, BMJ 2001 323:16-23

29. Cannabinoids in CINV • 8-THC less psychotropic, less $, stable • Less psychomimetic effects in children • Phase II trial, 8 pts (3-13 yrs) • Variety of cancers, chemotherapy • Starting dose of 5 mg/m2 • Nausea and vomiting eliminated • No psychotropic effects seen Abrahamov et al, Life Sci 1995 56:2097

30. Experimental Emesis • Linda Parker et al, Wilfred Laurier U. • Series of studies with rats/shrews • Model for anticipatory nausea • THC or CBD >> ondansetron • THC/CBD maybe most effective Limebeer and Parker Neuroreport 1999 Parker et al Neuroreport 2002 Parker et al Psychopharm 2004 Limebeer et al Physiol Behav 2006

31. Cannabinoids in CINV • Several RCTs in chemotherapy-induced emesis (CINV) • Pre 5-HT3 antagonist era (ondansetron) • Oral or IM meds vs best treatment • No comparison with 5-HT3 antagonist • No controlled trials of inhaled marijuana

32. Inhaled Marijuana • Cross-over CINV study, placebo control, marijuana vs dronabinol • n= 20 (15 men), 14 NSCLC • 25% no vomiting, 15% no nausea • 35% hallucinations or time perception changes • Preference: • 20% marijuana, 35% dronabinol, 45% no pref • THC > marijuana therapeutic potency Levitt et al, JCO 1984abstract C-354

33. Inhaled Marijuana • CINV, open trial, no control • n=74, chronic users, 25% dropped out • Preference: • 18 (34%) v effective, 26 (44%) mod effective 12 (22%) no benefit • Side Effects: • sedation 88%, dry mouth 77%, dizziness 39% 13% no A/E Vinciguerra et al, N Y State J Med 1988, 88:525

34. Special Situations • Constipation • Obstruction

35. Pain Fatigue/Asthenia Constipation Dyspnea Nausea Vomiting Delirium Depression/suffering 80 – 90+% 75 - 90% 70% 60+% 50 - 60% 30% 30 - 90% 40 - 60% Symptom Prevalence

36. Malignancy • Direct effects • obstruction by tumor in wall • external compression by tumor • neural damage • L/S spinal cord • cauda equina/pelvic plexus • hypercalcemia

37. Malignancy • Secondary effects • poor po intake • dehydration • weakness/inactivity • confusion • depression • unfamiliar toilet arrangements

38. Medications • Opioids • Ileocecal & anal sphincter tone • Peristaltic activity (SI & C) • Impaired defecation reflex •  sensitivity to distension •  internal anal sphincter tone •  Water, electrolyte absorption (SI & C)

39. Diabetes Hypothyroidism Hypokalemia Hernia Anal fissure/stenosis Hemorrhoids Autonomic neuropathy diabetes spinal cord disease chemotherapy Parkinson’s disease ALS/MS Dementia Concurrent Disease

40. Treatment • Prophylaxis • good symptom control • activity • adequate hydration • recognize drug effect • create a favorable environment

41. Treatment: Laxatives • >80% pts on opioids need laxatives • Little research to guide choice • Softener and stimulant best first choice • May require oral/rectal routes • Enemas useful in impaction • Bulk forming agents worsen situation

42. Treatment: Laxatives • Surfactants: docusate • Contact cathartics: senna, bisacodyl • Osmotic laxatives: lactulose • Saline osmotics: MgOH, Phosphasoda • Enemas: oil, saline, soap suds, Fleet

43. Other Approaches • Prokinetic agents: domperidone, metoclopramide • Antibiotics: erythromycin • Herbal preparations: mulberry, rhubarb, licorice, prune juice

44. New Agents • Selective opioid antagonists • Active in periphery, esp. gut • Methylnaltrexone, Alvimopan • Studies used IV and oral application • S/E • abd cramping, flatulence, nausea, dizziness

46. Bowel Obstruction • Common problem • Associated with advanced cancers • GI, ovarian, lymphoma • Relapse / local spread of intrabdominal tumour • Diffuse peritoneal carcinomatosis, encasement by tumour • Multiple partial bowel occlusions • (delaying or preventing propulsion of intestinal contents) • Symptoms of nausea/vomiting • abdominal pain, distention Pandha et al. Anti-Cancer Drugs, 1996; 7:5-10

47. Bowel Obstruction: Etiology • Mechanical obstruction causes: •  secretions, gas proximal to the obstruction • distention from gas, ingested fluids, digestive secretions in turn causes  secretions secretion distention Mercadante et al. JPSM 1997

48. Bowel Obstruction • Standard Therapy • NG tube/IV fluids (“drip & suck”) • Bowel rest • Pain control (opioids) • Radiological assessment • Surgical intervention

49. Bowel Obstruction • Palliative Therapy • Opioid analgesics, dexamethasone • Promotility agents • metoclopramide/domperidone • Octreotide (Sandostatin) • Hyoscine butylbromide (Buscopan)

50. Somatostatin Analogues • Octreotide, vapreotide, lanreotide • Receptor activity • brain, pituitary, pancreas, GI tract, immune cells • Used in many conditions • Prolongs GI transit time • fluid secretion in jejunum •  water/electrolyte absorption • decreases peristasis • reduces GI blood flow • Inhibits exocrine pancreatic secretion