Management of Nausea and Vomiting

1. Management of Nausea and Vomiting Jonathan Hsu MD Emory University Dept of Hospice and Palliative Care 5-2010

2. Disclosure Information • I have no financial relationships to disclose

3. Understand the pathophysiology of nausea and vomiting Identify common causes of nausea Select antiemetic therapy based underlying physiology Objectives

4. Sample Case: • P.T. is an 85-year-old farmer with diabetes, endstage heart disease, gastroesophageal reflux disorder, chronic shoulder pain from a war injury, stage 4 chronic kidney disease, and a history of alcoholism. His shoulder pain is well controlled with extended-release morphine, 30 mg PO bid, and gabapentin, 300 mg PO q HS. However, he complains of constant nausea that limits his ability to eat.

5. Nausea • An unpleasant sensation vaguely referred to the epigastrium and abdomen, with a tendency to vomit.

6. Vomiting • Forcible ejection of contents of stomach through the mouth.

7. Background • Nearly 60% of terminally ill cancer patients reported nausea1 • And 30% of these patients experienced vomiting • 33% of patients with ESRD5 • 17% of patients with HIV7 • 10-40% of patients treated with Opioids6

8. Consequences • Physical • Dehydration, Malnutrition, Anorexia, Weight Loss, Insomnia • Psychological Effects • Anxiety, Depression, Anger, • Nausea can be debilitating

9. Nausea is a Symptom….. • In order to treat nausea….. • Identify Causes • Treatment of Reversible Causes • Pharmacological and Non-Pharmacological Treatments

10. Pathophysiology: • Physiology of Nausea: • Activated by a cluster of neurons in the medulla known as the vomiting center: VC • Which receives stimuli from • Chemoreceptor Trigger Zone • GI Tract • Vestibular Apparatus in the inner ear • Cerebral Cortex

11. Pathophysiology • Chemoreceptor Trigger Zone: CTZ • Located in the floor of the 4th ventricle: lacks true blood brain barrier • Senses fluctuation in the bloodstream: medication and its rate of uptake, metabolic disturbances, and signals from the GI tract. • The CTZ triggers the VC by Neurotransmitters • Serotonin • Dopamine • Acetylcholine • Histamine

13. GABA CB M1 5HT M1 H1 Vomiting Center D2 NK 5HT D2 5HT H1 NK Histamine Dopamine Neurokinin M1 D2 GABA H1 NK CB 5HT Cannabinoids Serotonin Muscarinic

14. Causes of Nausea: • Cerebral Cortex • Vestibular Apparatus • Chemoreceptor Trigger Zone • Gastrointestinal Tract • Inputs to Vomiting Center • Emesis

15. Causes of Nausea: “M” • Metastasis • Meningeal Irritation • Movement • Medications • Mucosal Irritation • Mechanical Obstruction • Motility • Metabolic • Microbes • Myocardial

16. Cortical Causes of N/V • Tumor in CNS or Meninges: • Neurologic Signs or MS Changes • Dexamethasone, Consider palliative radiation • Increased Intracranial Pressure • Projectile Vomiting, HA • Dexamethasone • Anxiety, other conditioned responses: food, smell,etc • Anticipatory nausea, predictable vomiting • Counseling, Benzodiazepines • Uncontrolled Pain: • Pain Control

17. Vestibular/Middle Ear • Vestibular Disease: • Vertigo or vomiting after head motion • Meclizine: H1 blocker • Scopolamine: Anticholinergic (ACHm) • Promethazine • Middle Ear Infections • Ear pain, Bulging TM • Abx, decongestants • Motion Sickness • Travel Related nausea • Scopolamine, Dimenhydrinate, Diphenhydramine

18. Chemoreceptor Trigger Zone • Medication: • Opioids, Digoxin, Chemotherapy, Abx, Theophylline • Metabolic • Renal/Liver Failure, tumor products • Increase BUN/Cr/Bilirubin • Rx: Haldol • Hyponatremia/Hypernatremia • Confusion, Low Na+ • Hypercalcemia: • Somnolence, delirium, high Ca++ • Hydration, Pamidronate • Dexamethasone • Toxins: • Food poisoning, Tumor Products, Ischemic Bowel, Gut Obstructions: release of serotonin by gut irritation

19. Chemically Induced Nausea • Chemical Action Stimulate D2 (+/- 5HT3) in CTZ • Chemotherapy  Serotonin release in GI tract  5HT3 receptors on Vagus Nerve VC

20. Chemical/Metabolic Causes • Severe Persistent Nausea • Little relief from Vomiting • Small volume vomitus and/or retching

21. Gastrointestinal Tract • Irritation by Rx: NSAIDS, Fe, EtOH, Abx • PPI/H2 blocker, Misoprostol, or stop Rx • Tumor infiltration, radiation therapy of GI tract, infection • Txmnt of infection

22. Gastrointestinal Tract • Constipation/Impaction/Obstruction • Laxative, Manual Disimpaction, Enema • Metoclopromide (if no colic) • Scopolamine, Glycopyrolate (ACHm) if colic • Tube Feeding • Reduce volume • Remove tube if gag reflex • Thick Secretions: Cough induced vomiting • Nebulized saline expectorant • Anticholinergics

23. Gastric Stasis • Anticholinergic Drugs, Opioids • Ascites • Hepatomegaly • Gastric Mecho-ReceptorsVagal AfferentsVC

24. Bowel Obstruction • Intermittent/mild nausea • Nausea often relieved by vomiting • Large Volume Vomitus • Upper GI: early satiety, vomit after meals, undigested food • Lower GI: feculant vomitus, colic

25. Treat Reversible Causes!!! • Drugs • Hypercalcemia/Hyponatremia/Uremia • Anxiety • Constipation • Raised Intracranial Pressure • Tense Ascites • Severe Pain • Cough

26. Evaluation!! Detailed H+P • Detailed History • Severity of Nausea vs Vomiting • Relief or persistence of Nausea after Vomit • Timing of Vomiting and symptoms triggers (food, movement, smell, rx, etc) • Frequency of vomiting and temporal association • Content and volume of vomitus • Sputum vs regurgitation vs vomit • Associated symptoms: HA

27. Non-Rx Measures • Relaxation • Calm, reassuring environment • Small snacks/meals, bland food • Avoid odors • Mouth Care • Acupuncture/Acupressure P6 • NG/PEG tubes • Surgery/Stents • Chemoradiation

28. Pharmacologic Therapy

29. GABA CB M1 5HT M1 H1 Vomiting Center D2 NK 5HT D2 5HT H1 NK Histamine Dopamine Neurokinin M1 D2 GABA H1 NK CB 5HT Cannabinoids Serotonin Muscarinic

30. Prokinetic Agents • Metoclopramide: Reglan • Some CTZ anti-dopaminergic activity • Act mostly in gut: antagonize D2 and stimulate 5HT4 receptors • Stimulation of 5HT4 receptors  cause local ACH release  reversing gastroparesis • High doses: blocks 5HT3 receptors in the CTZ and gut • EPS Side-Effects at high doses • Caution in obstructed intestine: may induce colic • Increases pressure at lower esophageal sphincter

31. Antihistamine • Useful for vestibular causes of nausea and vomiting • Caution in constipation b/c of anticholinergic properties • Diphenhydramine • Meclizine (Antivert) • Hydroxyzine • Promethazine: watch for dystonia

32. Anticholinergics • Helpful for Motion/Movement related N/V • SE: dry mouth, blurred vision, confusion, constipation • Hyoscine Hydrobromide: Scopolamine • Glycopyrrolate • May cause/worsen obstruction • May be useful in colicky abdominal pain with obstruction: IE Tumor

33. Dopamine Antagonists • Useful for Medication or metabolic related nausea and vomiting • SE: Dystonia, IV can cause postural hypotension secondary to alpha receptor antagonism • Haloperidol: Haldol SC/IV = PO (1:2) • Chlorpromazine: Thorazine: more sedating IV=PO • Prochlorperazine: Compazine: IV=PO • Blocks D2 receptors, H1, ACH, Alpha Adenergic (chlorpromazine, prochlorperazine)

34. Serotonin 5HT3 Receptor Antagonist • Useful for Post OP N/V, Chemotherapy/Radiation related N/V or 2nd or 3rd line rx • Ondansetron: Zofran (ODT) • Granisetron: Kytril/Sancuso patch • Side Effect: Constipation, Headache • Clinical considerations -Equal safety and efficacy at equivalent doses -Single dose regimens have equal efficacy to multidose regimens -Oral and IV routes are equivalent

35. Dexamethasone • Mechanism of Action: unknown -Inhibition of prostaglandin synthesis? Decrease Inflammation -Decreased BBB permeability of chemotherapy agents -Inhibition of cortical input to vomiting center • Useful in: -Brain tumor or CNS involvement -Malignant bowel obstruction -Chemotherapy induced nausea and vomiting • Generally well tolerated -Fluid retention, restlessness, insomnia, hypertension -Watch blood glucose in diabetic patients

36. NK1 Receptor Antagonist • Aprepitant • Competitively antagonizes the NK1 receptors • FDA Approved for acute or delayed onset nausea associated with chemotherapy. • $$$$ • Adujvant Therapy • ?Mechanism of action? • Dronabinol, Nabilone • Adverse effects -Sedation, dizziness, hypotension, dysphoria $$$$ Cannabinoid

37. Receptor Binding Affinity (Potency) Peroutka and Snyder 8 Potency: the amount required to produce an effect of given intensity

38. GABA CB M1 5HT M1 H1 Vomiting Center D2 NK 5HT D2 5HT H1 NK Histamine Dopamine Neurokinin M1 D2 GABA H1 NK CB 5HT Cannabinoids Serotonin Muscarinic

39. Treatment: • Chemically induced Nausea: CTZ: D2, 5HT3 • Haloperidol (0.5-2mg IV/SQ/PO Q4-8hrs) • Prochlorperazine (5-10mg PO/PR/IV Q6-8hrs) • Ondansetron (8mg TID PO/IV) • Gastric Stasis: • Prokinetic agents: Metoclopramide (if no colic) • 10-30mg PO/PR/IV q4-6hrs • Scopolamine/Glycopyrolate (if colic) (Anticholinergic) • 0.2-o.6mg SL/SQ q4-8hrs (scopolamine) • 0.1-0.2mg IV/SQ Q4-8hrs, 1-2mg PO q8hrs • Dexamethasone 4-20mg po/IV qday • Odansetron (5HT3)

40. Treatment • Cortical Causes: Inc ICP, tumor, learned response • Dexamethasone, Promethazine, Prochlorperazine, and benzodiazepines. • Movement/Vestibular Dz • Meclizine, Scopolamine, Diphenhydramine, Promethazine

41. Sample Case: • P.T. is an 85-year-old farmer with diabetes, endstage heart disease, gastroesophageal reflux disorder, chronic shoulder pain from a war injury, stage 4 chronic kidney disease, and a history of alcoholism. His shoulder pain is well controlled with extended-release morphine, 30 mg PO bid, and gabapentin, 300 mg PO q HS. However, he complains of constant nausea that limits his ability to eat.

42. Summary • Remember that Nausea/Vomiting are symptoms and not diseases • Find and treat reversible causes of nausea. • Tailor prescription accordingly to sites of action

43. Thank You

44. References • 1. Reuben DB, Mor V. Nausea and vomiting in terminalcancer patients. Arch Intern Med. 1986;146(10):2021-2023. • 2. Herrinton LJ, Neslund-Dudas C, Rolnick SJ, et al. Complications at the end of life in ovarian cancer. J Pain Symptom Manage. 2007;34(3):237-243. • 3. Henry DH, Viswanathan HN, Elkin EP, Traina S, Wade S, Cella D. Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the U.S. [Epub ahead of print]. Support Care Cancer. Jan 17, 2008. • 4. Mannix KA. Palliation of nausea and vomiting. In: Doyle D, Hanks GWC, Cherny NI, Kalman S, eds. Oxford Textbook of Palliative Medicine. 3rd ed. Oxford, England: Oxford University Press; 2005:459-468. • 5. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis. 2007; 14(1):82-99. • 6. Baines MJ. ABC of palliative care. Nausea, vomiting, and intestinal obstruction. BMJ. 1997; 315(7116):1148-1150 • 7. Fantoni M, Ricci E, Del Borgo C, et al. Multicentre study on the prevalence of symptoms and symptomatic treatment in HIV infection. Central Italy PRESINT group. Journal of Palliative Care. 1997; 13(2), 9-13. • 8. Peroutka, S. J. and S. H. Snyder. Antiemetics: Neurotransmitter receptor binding predicts therapeutic actions. Lancet 1982; 1(8273): 658-9

45. References • Mannix, Kathryn A. Palliation of Nausea and Vomiting. Oxford Textbook of Palliative Medicine. 2010; 801-812. • Watson Max, Lucas Caroline, et al. Nausea and Vomiting, Oxford Handbook of Palliative Care. 2nd edition 2009; 308-315 • Sobel Jason MD, Policzer Joel MD, Management of Selected Nonpain Symptoms of Life-Limiting Illness Hospice and Palliative Care Training For Physiciains (UNIPAC U4 3rd edition). • Emanuel LL, Hauser JM, Bailey FA, Ferris FD, von Gunten CF, Von Roenn J. EPEC for Veterans: Education in Palliative and End-of-life Care for Veterans. Chicago, IL, and Washington, DC, 2010 • Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817