2. Nausea & Vomiting Dr. Lucy Harris SpR Palliative Medicine September 2014

3. A Starting Point - Definitions Nausea: An unpleasant sensation of the need to vomit, often accompanied by autonomic symptoms – sweating, salivation, tachycardia. Vomiting: Forceful expulsion of gastric contents through the mouth, caused by forceful and sustained contraction of the abdominal muscles and diaphragm. Anticipatory vomiting: Vomiting in the absence, but caused by anticipation, of the stimulus e.g. chemotherapy Retching: Rhythmic, laboured, spasmodic movements of the diaphragm and abdominal muscles against a closed glottis

4. It’s all in the history…. Regurgitation – The movement of contents of the stomach into the oesophagus and / or from the oesophagus into the mouth. Rumination – The controlled, voluntary regurgitation of undigested food from the stomach into the mouth (food often then swallowed again). Often associated with psychiatric disorders Oesophageal secretions - Frothy, stringy white or colourless secretions, associated with oesophageal cancer. May respond to steroids.

5. Why Is It Important? About 60 % of patients with advanced cancer will experience nausea and / or vomiting at some point Prevalence of about 40% in the last six weeks of life More common in: Stomach / Breast Cancers Women Patients under 65 Least common in: Lung Cancer Arch Intern Med. 1986;146(10):2021-2023.

6. Pathophysiology Emetic process not fully understood Awareness of physiology of vomiting and main neurotransmitters involved can help in assessment and choice of appropriate anti- emetic

7. Cortex CTZ Vestibular GI VOMITING CENTRE (Medulla) VOMITING REFLEX

8. Receptor Sites Cortical Structures ( eg. anxiety, sights, smells, raised ICP): GABA Vomiting Centre: Muscarinic (Ach) Histamine (H 1 ) Serotonin (5HT 2 ) Chemoreceptor Trigger Zone: Serotonin (5HT 3 ) Dopamine (D 2 ) Vestibular Apparatus: Muscarinic (Ach) Histamine (H 1 ) Gut Mucosa: Dopamine (D 2 ) Serotonin (5HT 3 ) Serotonin (5HT 4 )

9. The Vomiting Reflex Involves multiple structures - the pharynx, larynx, upper GI tract, the muscles of the thorax, abdomen and diaphragm and the respiratory and salivatory centres. It causes ; 1) Nausea, with autonomic symptoms 2) Gastric stasis / atony (relaxation of smooth muscle wall of stomach) 3) Retching with closure of vocal cords 4) Elevation of palate (to close nasopharynx) 5) Reverse peristalsis 6) Contraction of the abdominal wall and chest muscles

10. Consideration of Causes in the Palliative Setting Case Example 1: 75 man, CA lung with bone metastases lower back. Started regular oromorph for back pain Complaining predominantly of nausea. Case Example 2: 60 women, CA breast with liver, bone and brain metastases. On morphine for several weeks. Not constipated. Complaining of N&V. Vomiting does not relieve nausea.

12. Management Approach…. ESTABLISH THE CAUSE Investigations Examination History Urine Dip, U&Es, Calcium, Relevant Drug Levels, ?AXR, Brain imaging Hydration, Temperature, Mouth, Abdomen, Rectum, Fundi, Neurology Onset, Timing, N vs V, Triggers, Associated factors, Content of Vomitus, Drugs

13. Principles of Treatment 1: Treat the cause 2: Non-pharmacological approaches 3: Anti-emetics The most common mistakes in treating nausea & vomiting are: – not considering reversible factors – using oral route for anti-emetics in established nausea & vomiting

14. Non-Pharmacological Approaches Control Malodour (eg: fungating tumours) Consider environment - away from sight and smell of food. Ask others to take on role of food preparation Meal Size - Small snacks regularly Complementary Therapy eg: acupressure bands / Acupuncture Distraction

15. Approach to Anti-emetics: Anticipate Regular doses and consider most appropriate route of delivery Target the relevant receptors according to cause Consider Combination

16. Antiemetic Choice – Think receptors!

17. StimulusAreaReceptors Drugs,Metabolic Chemoreceptor trigger zone D2 5HT3 Motion,PositionVestibular Muscarinic (Ach) Histamine VisceralOrgans D25HT3 ? Non- specific CNS Cannabinoid ↑ ICP Cerebral cortex Histamine Mike Harlos, Manitoba Receptors in Vomiting Pathways

18. Mike Harlos, Manitoba Antiemetics – site of action CTZ Haloperidol Metoclopramide Domperidone Levomepromazine Ondansetron Granisetron GI Metoclopramide Domperidone Ondansetron Granisetron VOMITING CENTRE Vestibular Hyoscine hydrobromide Cyclizine Prochlorperazine Levomepromazine Hyoscine hydrobromide Cyclizine Prochlorperazine Levomepromazine

19. Management Pharmacological

20. Other drugs used to manage nausea and vomiting Dexamethasone Decreases permeability at CTZ, inhibits central PG synth Ranitidine Decreases volume of gastric secretions Octreotide Decreases GI secretions (useful for large volume vomits in malignant bowel obstruction) PPI Decreases acidity Antifungals Treat oropharyngeal candida Benzodiazepines For anxiety, ??GABA effect

21. Antiemetic Ladder STEP 2 2nd line narrow spectrum eg ondansetron OR combination eg cyclizine+haloperidol OR broad spectrum eg levomepromazine STEP 1 Narrow spectrum Metoclopramide Cyclizine Haloperidol

22. Route is important Essential to consider antiemetic route if already vomiting / absorption concerns Transdermal: Scopaderm TTS releases 0.5m hyoscine hydrobromide / 72 hrs Buccal: Buccastem (Prochlorperazine tab absorbed from buccal mucosa) 3mg/12hrs Rectal: Prochlorperazine (25mg tds) Domperidone (30-60mg qds) S/C: Cyclizine (100-150mg/24hrs) – does not combine well in csci Haloperidol (2.5-10mg/24hrs) Levomepromazine (6.25-100mg/24hrs) (2:1 conversion for po : sc) Metoclopramide (30-120mg/24hrs) Octreotide (100-1200mcg/24hrs)

23. Additional Hints If using more than one anti-emetic, use those that act on different receptors 30% pts require 2 anti-emetics If previously on regular antiemetics add to these to a syringe driver if started for other reasons Avoid dopamine antagonists (esp; metoclopramide, haloperidol) in PD Reassess regularly!

24. Summary N+V are common in end-stage disease, and significantly affect QOL. Determining and reversing cause(s) if possible is paramount, often multi-factorial Usually easily treated, many anti-emetics – choice depends on cause. Use regular antiemetics, by appropriate route, with PRN provision Oral medication rarely works if established vomiting or severe nausea.

25. Cause of Vomiting1 st Line AntiemeticDose2 nd Line Antiemetic Dose Drugs / ToxinsHaloperidol1.5-3mg nocte/bdLevomepromazine6.25 -25mg / 24 hrs RadiotherapyOndansetron8mg stat, then bd for 5/7Haloperidol1.5-3mg nocte/bd ChemotherapyOndansetron Dexamethasone 8mg stat, then bd for 5/7 4-8mg od Metoclopramide20mg tds/qds Metabolic (eg.↑Ca/Uraemia) Haloperidol1.5mg nocte/bdLevomepromazine Cyclizine 6.25-25mg / 24 hrs 50mg tds Raised ICPCyclizine + Dexamethasone 50mg tds 8-16mg / 24hrs Levomepromazine + Dexamethasone 6.25-25mg / 24hrs 8-16mg / 24hrs Bowel Obstruction (with colic) Cyclizine +/- Buscopan +/- Octreotide +/- Dexamethasone 150mg / 24hrs 40-100mg /24hrs s/c 300-1000mcg/24hrs s/c 8-16mg / 24hrs Haloperidol Levomepromazine +/- Buscopan / Octreotide / Dexamethasone 1.5-3mg od/bd 6.25-25mg / 24hrs Delayed Gastric Emptying Metoclopramide10-20mg tds/qdsDomperidone10-20mg qds Gastric IrritationPPI for gastritis Stop irritants- NSAIDs Cyclizine50mg tds Ondansetron Metoclopramide Levomepromazine 8mg bd 10-20mg tds/qds 6.25-25mg / 24hrs

26. Pharmacokinetics Of Antiemetics DrugOnset of action Duration of Action Half-lifeMechanism Of Action Place Of Action Side Effects Metoclopramide10-15 mins1-2 hrs2.5-5 hrsProkinetic (D2 antagonist, 5HT4 agonist, 5HT3 antagonist) Intestinal CTZ Extrapyramidal Colic (in intestinal obstruction) Domperidone30 mins8-16 hrs14 hrsProkinetic (D2 antagonist) IntestinalColic (in intestinal obstruction) Cyclizine<2 hrs4-6 hrs5 hrsAnti-histamine (H1 receptor) Anticholinergic (ACh receptor) Vomiting Centre Dry Mouth Drowsiness Ondansetron<30 mins PO < 5 mins IV 12 hrs3 hrs5HT3 antagonistCTZConstipation Headache Levomepromazine1-4 hrs PO 30-90 mins SC 12-24 hrs13-30 hrsBroad Spectrum (ACh, H1, 5HTs, D2 receptors) Vomiting Centre CTZ Sedative Antimuscarinic Anxiolytic Buscopan1-2 hrs PO 3-5 mins SC 15 mins a/spasmotic 1-9 hrs a/secretory 5-6 hrsAnticholinergic (ACh receptor) Vomiting Centre Dry Mouth Drowsiness Confusion Haloperidol10-15 mins s/c >1hr PO Up to 24hrs13-35 hrsNeuroleptic (D2 antagonist) CTZSedation Extra-pyramidal

27. Questions?