Nausea and Vomiting in Palliative Care - PowerPoint Presentation

Nausea and Vomiting in Palliative Care Audit Presentation January 15 th 2015

Dr Richard LattenDr Seamus CoyleDr Laura McGlynnDr Paula PowellDr Jamie BarfieldAnn Griffiths Sian Rae Agnes NobleTracey Hindley Tania ForresterDave Hewison Audit Group Members and Meetings 27 th August 2014 10 th September 2014 1 st October 2014 27 th October 2014 12 th November 2014 3 rd December 2014 17 th December 2014 30 th December 2014 7 th January 2015 14 th January 2015

Patient, Carer and Public Involvement Literature Search and Review Existing Standards Audit ResultsRecommendations Questions Session Overview

Representative - Dave Hewison Willowbrook Hospice VolunteerActively participated in several group audit meetingsNo previous direct involvement with a specialist palliative care team Patient, Carer and Public Involvement

Key areas to recognise from a patient, public and carer view COMMUNICATION Inform the patient of their management planDiscuss antiemetic choice and WHY Help the patient to understand WHY are they are nauseated/vomitingAssess how much information the patient would likeIf further information requested seek ways to direct the patient to information sources

2. EXPECTATIONS Discuss various antiemetics may be required to achieve symptom control Help the patient to remain confident that the healthcare professional is reviewing and managing appropriately3. HONESTY AND PROFESSIONALISM Open and honest approach

LITERATURE REVIEW

What is the evidence for the use of ANTIEMETIC ‘X’ in the management of nausea and vomiting in palliative care? Question

Aprepitant Cyclizine DexamethasoneDomperidone GranisetronHaloperidol Hyoscine hydrobromide ANTIEMETICS SEARCHED Hyoscine butylbromide Levomepromazine Lorazepam Metoclopramide Olanzapine Ondansetron Prochlorperazine

INCLUSIONHumans Adult patients Incurable conditionsCancer and NON cancer diagnosesRadiotherapy related N+V Pharmacological management English language Publication Year 0-current SELECTION CRITERIA EXCLUSION < 18 years of age Animals Non palliative care conditions Chemotherapy related nausea and vomiting Post operative nausea and vomiting Bowel obstruction Non pharmacological management Non English language

Search via NHS Evidence search MEDLINE/PUBMED/EMBASE/COCHRANE databases Search terms: “Nausea” OR “Vomiting” AND “Antiemetic” NOT “chemotherapy” 2 reviewers for each antiemetic searched METHOD

Filters: “Clinical Trials” “Evidence base” “Cochrane” “Humans” “Evidence based medicine” If zero articles from standard search some filters not selected and 2 nd search Abstract selection…full text reviewed….2 reviewers

LITERATURE SEARCH RESULTS

Aprepitant Sian Rae; Clinical Pharmacist, Whiston Hospital & Willowbrook Hospice

Substance P Neurokinin1 receptor antagonist Licensed for moderate/highly emetogenic CINVin combination with dexamethasone and ondansetron No other clinical trials published 120mg on day one; 80mg on days two and three IV fosaprepitant also available Weak/moderate CYP3A4 inhibitor e.g. 50% dexamethasone reduction required One palliative case study APREPITANT

Aprepitant (EMEND): the role of substance P in nausea and vomiting. Eric Prommer Journal of Pain & Palliative Care Pharmacotherapy 2005 Pharmacology Study NA Useful interactions summary Aprepitant --a novel NK1-receptor antagonist.   Expert Opinion on Pharmacotherapy 2003 Pharmacology Study NA Useful interactions table Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin M. Depré , A. Van Hecken , M. Oeyen , I. De Lepeleire , T. Laethem , P. Rothenberg, K. J. Petty, A. Majumdar , T. Crumley , D. Panebianco , A. Bergman, J. N. de Hoon European Journal of Clinical Pharmacology 2005 Pharmacology Study NA   Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone McCrea JB1, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA. Clinical Pharmacology and Therapeutics 2003 Pharmacology Study NA  

Cyclizine Tania Forrester; Community Palliative Care Nurse Specialist; WLS&F

Cyclizine Well established antihistamine Exact mechanism unknownreduces lower oesophageal sphincter tone and labyrinthine apparatus sensitivity50mg TDS oral, IV, SC No relevant clinical trials Can cause hallucinations and enhance euphoric effects of opioidsLimited evidence in relation to use in heart failure

Article title Authors Journal Year Type of study Level of evidence Key points The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients Jane W.A. Vella-Brincat, BSc, Pharma, Evan J. Begg, MD, Berit P. Jensen, PhD, Paul K.L. Chin, MBChB, Rebecca L. Roberts, PhD, Mary Fairhall, RN, MA, Sandy (A.D.) Macleod, MBChBb, Kate Reid, RN, MAe, Journal of Pain and Symptom Management 2012 Pharmacokinetics Study NA  

Metoclopramide Dr Laura McGlynn; Palliative Medicine ST4; Aintree Hospital

Prokinetic anti emetic D 2 antagonist and 5HT4 agonistTriggers a cholinergic system in the wall of the GI tract Block the dopamine break on gastric emptying induced by stress, anxiety and nauseaUseful in N+V caused by - GI disorders - Chemotherapy and Radiotherapy - Dysmotility dyspepsia, Heartburn, Migraine, Hiccups MHRA guidance METOCLOPRAMIDE

Article title Authors Journal Year Type of study Level of evidence Key points Dexamethasone in Addition to Metoclopramide for Chronic Nausea in Patients with Advanced Caner: A Randomized Controlled Trial Bruera E, Moyano JR, Sala R, Risco M, Bosnjak S et al. Journal of Pain and Symptom Management 2004 RCT Level 1- N= 51 Partial relief with oral metoclopramide for 48hrs Dexamethasone was not significantly better than placebo in the management of nausea Comparison of the Efficacy and Safety of Tropisetron, Metoclopramide and Chlorpromazine in the Treatment of Emesis Associated with Far Advanced Cancer Mystakidou K, Befon S, Liossi C and Vlachos L. CANCER   1998 RCT Level 1- N = 280 Control of N+V   23.6% of MET+DEX patients 78.9% of TRO patients 84.2% of TRO+MET pts 92.3% of TRO+MET+DEX pts 33.3% of CHL+DEX pts 84.6% of TRO+CHL pts 92.5% of TRO+CHL+DEX pts   Effectiveness of Levosulpiride versus Metoclopramide for Nausea and Vomiting in Advanced Cancer Patients: A Double-Blind, Randomized, Crossover Study Corli O, Cozzolino A, Battatiotto L.       Journal of Pain and Symptom Management       1995         Double blind, randomised crossover Study Level 2+       N = 30 Control of nausea was achieved 84.6% of pts treated with Levosulpiride and 42.3% Metoclopramide

A Double Blind Crossover Study of Controlled Release Metoclopramide and Placebo for the Chronic Nausea and Dyspepsia of Advanced Cancer Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N et al. Journal of Pain and Symptom Management 2000 Double blind crossover study Level 2+           N = 26 Nausea was lower in controlled release Metoclopramide group compared to placebo (12+/- 10mm, 17 +/-12mm) VAS 0-100mm A double blind, randomised, parallel group, multinational, multicentre study comparing a single dose of Ondansetron 24mg PO, with placebo and metoclopramide 10mg TDS PO in the treatment of opioid induced nausea and emesis in cancer patients Support Care Cancer Hardy J, Daly S, McQuade B, Albertsson M et al. 2002 Randomised parallel groups Level 2+ N= 92 patients No significant difference between any of the treatment groups in the control of nausea or emesis   Prophylactic use of tropisetron or Metoclopramide during adjuvant abdominal radiotherapy of seminoma stage I: a randomised open trial in 23 patients       Aass N, Hatun D, Thoresen M, Fossa S.     Radiotherapy and Oncology 1997 Open trial Level 2+? N = 23 3 week period of radiotherapy, Monday – Friday Nausea+Emesis lower in the TROP group compared with the MET group

The Effect of Antiemetics and Reduced Radiation Fields on Acute Gastrointestinal Morbidity of Adjuvant Radiotherapy in Stage I seminoma of the Testis: A Randomised Pilot Study Clinical Oncology Khoo V, Rainford K, Horwich A and Dearnaley D. 1997 Pilot Study Level 2+ N = 30 Ondansetron group experienced less nausea+ vomiting   Long Term Safety and Clinical Effectiveness of Controlled Release Metoclopramide in Cancer Associated Dyspepsia Syndrome: a Multicentre Evaluation Wilson J, Plourde J, Marshall D, Yoshida S et al. Journal of Palliative Care 2002 Open label evaluation 3 months Level 2- N = 48 patients 40-60% decrease in the severity of nausea over the first 2/52 50% reduction in severity of vomiting over the first 4/52 Most frequent adverse events: asthenia n=11, anorexia n=5, nausea n=5   Chronic Nausea in Advanced Cancer Patients: A Retrospective Assessment of a Metoclopramide Based Antiemetic Regimen Bruera E, Seifert L, Watanabe S, Babul N et al Journal of Pain and Symptom Management 1996 Non analytical Case note review Level 3 4 Step approach to management of nausea Nausea improved with stepwise fashion    

Prescribing for Nausea in Palliative Care: A Cross-Sectional National Survey of Australian Palliative Medicine Doctors Timothy H.M. 1,2 Meera Agar, Patsy Yates, and David C. Currow, JOURNAL OF PALLIATIVE MEDICINE Volume 17, Number 9, 2014 2014 Survey of palliative care clinician practice Level 4 105 responders For first-line therapy, 69% chose metoclopramide and 26% haloperidol. For second- line therapy, 47% chose haloperidol with much wider variation in the other nominated agents. Pharmacovigilance in Hospice / Palliative Care: Rapid Report of Net Clinical Effect of Metoclopramide David C. Currow, 1 Jane Vella-Brincat, Belinda Fazekas, Katherine Clark, Matthew Doogue, and Debra Rowett, JOURNAL OF PALLIATIVE MEDICINE Volume 15, Number 10, 2012 2012 Prospective observational cohort study Level 2- N=53 patients Across 12 hospices in AUS Majority cancer. Majority prescribed for prevention of N&V Average dose: 32.9mg/24hr (range 10-60mg) After 48hrs overall benefit reported in 43% (23/53) 32% (17/53) patients experienced 24 harms (Table 4). The most frequently encountered harms were akathisia (restlessness and motor agitation) (4 patients), headache (4 patients), and abdominal pain (4 patients) Bowel perforation (2 patients)

Initial selection of antiemetics in end of life care: A retrospective analysis McMath, Alt, Weschules & Knowlton International journal of pharmaceutical compounding Mar/Apr 2006; 10(2):147 2006 Retrospective analysis of hospice pharmacy records in US hospices Level 3 584 patient records evaluated   cancer population   Prochlorperazine most commonly prescribed 1 st line anti-emetic Then ABHR gel (Lorazepam / Diphenhydramine / metoclopramide / haloperidol) followed by metoclopramide   Report all were effective in reducing N&V Comparison of Ondansetron with Metoclopramide in the Symptomatic Relief of Uremia-Induced Nausea and Vomiting Dragan Ljutic´ Dijana Perkovic´ Zvonko Rumboldt Jugoslav Bagatin Izet Hozo Nediljko Pivac Kidney Blood Press Res 2002;25:61–64 2002 double-blind crossover study was done in 10 uremic patients Level 2+ 10 patients with uraemia 5 metoclopramide / 5 ondansetron   The antiemetic efficacy of ondansetron was clearly superior to that of metoclopramide scored either objectively (2.80 B 0.422 vs. 1.40 B 0.699; p ! 0.005) or subjectively (4.10 B 0.738 vs. 2.10 B 0.994; p ! 0.005).

Comparison of the Efficacy, Safety, and Pharmacokinetics of Controlled Release and Immediate Release Metoclopramide for the Management of Chronic Nausea in Patients with Advanced Cancer Eduardo D. Bruera, Tara J.MacEachern, Kathy A. Spachynski, Donald F. LeGatt, R. Neil MacDonald, Najib Babul, Zolfan Harsanyi, and Andrew C. Darke, Cancer : Volume 74, Issue 12 , 29 JUN 2006   2006 Randomized double blind cross over study comparing controlled release metoclopramide with immediate release metoclopramide Level 2+ Thirty-four patients with advanced cancer with nausea lasting more than 1 month and with no evidence of involvement of the gastrointestinal tract, peptic ulcer or gastritis, brain metastases, or metabolic abnormalities were randomized, in a double-blind cross-over study, to receive 40 mg of CRM every 12 hours or 20 mg of IRM every 6 hours for 3 days.   In 29 evaluable patients, the intensity of nausea on Day 3, measured by a 0-100-mm visual analogue scale and 0-3 categoric scale was 15 5 17 and 0.6 f 0.6 after IRM, versus 8 f 9 (P = 0.033) and 0.4 * 0.5 (P = 0.055) after CRM, respectively.

Hyoscine Hydrobromide Dr Richard Latten

Antimuscarinic drug Smooth muscle relaxant and anti secretory properties Indicated for prevention of motion sickness, drying secretions, smooth muscle spasm and paraneoplastic pyrexia and sweating Drug available as oral, subcut and transdermal preparations No evidence from literature search regarding use in nausea and vomiting HYOSCINE HYDROBROMIDE

Article title Authors Journal Year Type of study Level of evidence Key points Transdermal Hyoscine (Scopolamine) A preliminary review of its pharmacodynamics properties and therapeutic efficacy.   S.P. Clissold ,  R. C. Heel Drugs 1985 Expert Opinion Level 4 Adverse systemic effects include dry mouth, blurred vision, drowsiness, impairment of ocular accommodation, blurred vision, mydriasis, difficulty urinating, rashes and erythema.               HYOSCINE HYDROBROMIDE

Ondansetron Dr Richard Latten; Consultant in Palliative Medicine; Marie Curie

ONDANSETRON 5HT 3 antagonist Block the amplifying effect of 5HT on vagal nerve fibres Useful when excess 5HT are released from the body’s stores eg after chemotherapy or radiation induced damage of GI mucosa

Article title Authors Journal Year Type of study Level of evidence Key points A double blind, randomised, parallel group, multinational, multicentre study comparing a single dose of Ondansetron 24mg PO, with placebo and metoclopramide 10mg TDS PO in the treatment of opioid induced nausea and emesis in cancer patients     Support Care Cancer Hardy J, Daly S, McQuade B, Albertsson M et al. 2002 Randomised parallel groups Level 2+ Randomised to Oral Ondansetron 24mg OD, Metoclopramide 10mg TDS or placebo TDS Treatment of opioid induced emesis in cancer patients 24hr study treatment N= 92 patients 30 received placebo, 29 received Ondansetron and 33 received Metoclopramide No significant difference between any of the treatment groups in the control of nausea/emesis  

Comparison of Ondansetron withMetoclopramide in the Symptomatic Relief of Uremia-Induced Nausea and Vomiting Dragan Ljutic´ Dijana Perkovic´ Zvonko Rumboldt Jugoslav Bagatin Izet Hozo Nediljko Pivac Kidney Blood Press Res 2002;25:61–64 2002 double-blind crossover study was done in 10 uremic patients   10 patients with uraemia 5 metoclopramide / 5 ondansetron   The antiemetic efficacy of ondansetron was clearly superior to that of metoclopramide scored either objectively (2.80 B 0.422 vs. 1.40 B 0.699; p ! 0.005) or subjectively (4.10 B 0.738 vs. 2.10 B 0.994; p ! 0.005). Prophylaxis of radiotherapy-induced nausea and vomiting in the palliative treatment of bone metastases Kristopher Dennis & Janet Nguyen & Roseanna Presutti & Carlo DeAngelis & May Tsao & Cyril Danjoux & Elizabeth Barnes & Arjun Sahgal & Lori Holden & Florencia Jon & Shun Wong & Edward Chow Support Care Cancer (2012) 20:1673–1678 2012 Observational study   Patients receiving single (SF) or multiple fraction (MF) palliative radiotherapy (RT) of moderate or low emetogenic risk for bone metastases were prescribed prophylactic Ondansetron . The frequency and duration of prophylaxis and the use of rescue antiemetics were left to the discretion of the treating physicians.   Despite prophylaxis, RINV was common among patients receiving palliative radiotherapy for bone metastases, especially during the delayed phase.

  Ondansetron in Multiple Sclerosis   A. D. Macleod,   Journal of Pain and Symptom Management Vol. 20 No. 5 November 2000   2000   Case report     2 x case report of ondansetron relieving symptoms Ondansetron in Nausea and Vomiting Induced by Spinal Morphine Sebastiano Mercadante, MD, Monica Sapio, MD, and Roberto Serretta, Journal of Pain and Symptom Management Vol. 16 No. 4 October 1998 1998 Case report   1 x case report of response to ondansetron Successful Control of Intractable Nausea and Vomiting Requiring Combined ndansetron and Haloperidol in a Patient with advance Cancer Roger M. Cole, FRACP, Frances Robinson, MB, Len Harvey, FR4CP, Karen Trethowan, MB, and Veronica Murdoch, Journal of Pain and Symptom Management Vol. 9No. 1 January 1994 1994 Case report   1 x case report of response to ondansetron

Dexamethasone Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre

DexamethasoneCorticosteroidMechanism of action unclear Dose 8mg-16mg Extensive side-effect profile‘Add-on’ anti-emetic when all else fails2 Randomised controlled trials

Article title Authors Journal Year Type of study Level of evidence Key points Dexamethasone for the prophylaxis of radiation-induced emesis: A National Cancer Institute of Canada clinical trials group phase III study   Kirkbride P., Bezjak A., Pater J., Zee B., Palmer M.J., Wong R., Cross P., Gulavita S., Blood P., Sun A., Dundas G., Ganguly P.K., Lim J., Chowdhury A.D., Kumar S.E., Dar A.R.   Journal of Clinical Oncology, May 2000, vol./is. 18/9(1960-1966), 0732-183X (May 2000)   2000 Randomised controlled trial Level 2 Dexamethasone 2mg tds seems to be an effective prophylactic anti-emetic for radiation induced emesis. Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: A randomized controlled trial   Bruera E., Moyano J.R., Sala R., Rico M.A., Bosnjak S., Bertolino M., Willey J., Strasser F., Palmer J.L.     Journal of Pain and Symptom Management, October 2004, vol./is. 28/4(381-388), 0885-3924 (October 2004)   2004 Randomised controlled trial Level 1- Dexamethasone was not superior to placebo in the management of chronic nausea in patients with advanced cancer also taking Metoclopramide.

Haloperidol Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre

HaloperidolAntipsychotic D2 antagonist Precise mechanism of action unknown Extrapyramidal side-effectsDose: 1.5mg-5mg orally; 1.5mg-3mg SC (PCF/BNF dose)4 studies

Article title Authors Journal Year Type of study Level of evidence Key points The efficacy of haloperidol in the management of nausea and vomiting in patients with cancer.   Hardy J.R., O'Shea A., White C., Gilshenan K., Welch L., Douglas C.   Journal of Pain and Symptom Management, 2010, vol./is. 40/1(111-116), 0885-3924 (2010)   2010 Open label uncontrolled study 3 metropolitan hospitals in Australia Level 4 Haloperidol has some efficacy in the treatment of nausea and vomiting in the patient study group. Haloperidol for radiation sickness: Control of associated nausea, vomiting, and anorexia. Cole DR, Duffy DF   New York State Journal of Medicine, August 1974, vol./is. 74/9(1558-62), 0028-7628;0028-7628 (1974 Aug) 1974 Double blind study Level 2 Haloperidol was superior to placebo for nausea and vomiting in patients receiving radiation therapy. Haloperidol for the treatment of nausea and vomiting in palliative care patients.   Perkins P, Dorman S   Cochrane Database of Systematic Reviews, 2009, vol./is. /2(CD006271), 1361-6137;1469-493X (2009)   2009 Cochrane review Level 1 There is not enough evidence to be able to recommend Haloperidol for the treatment of nausea and vomiting in adult patients suffering from incurable progressive medical conditions. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with far-advanced cancer. Glare P, Pereira G, Kristjanson LJ, Stockler M, Tattersall M   Supportive Care in Cancer, June 2004, vol./is. 12/6(432-40), 0941-4355;0941-4355 (2004 Jun)   2004   Systematic review Level 2 3 Level 1 studies reviewed. Very few good quality data available. Result is uncertain.

Domperidone Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre

DomperidoneD2 receptor antagonist Acts on gastro-oesophageal and gastro-duodenal junctions – Pro-kinetic Acts on dopamine receptors in CTZLess likely to cause central effectsIncreased risk of serious cardiac side-effects: MHRA guidanceNo relevant evidence within audit criteria

Hyoscine Butylbromide Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre

Hyoscine ButlybromideAntimuscarinic Doesn’t cross blood-brain barrier – No central anti-emetic effects No drowsinessNo relevant evidence within audit criteria

Granisetron Dr Jamie Barfield; Palliative Medicine ST3; Aintree Hospital

GranisetronA serotonin 5-HT3 receptor antagonistMain effect is to reduce the activity of the vagus nerve, which activates the vomiting centre in the medulla oblongatametabolized slowly by the liver, giving it a longer than average half-life. One doses usually lasts 4 to 9 hours and is usually administered once or twice dailyExcreted by the liver and kidneys

Granisetron 3 open label trials, 2 RCT, 1 review Good control of radiation induced nausea with between 3-6mg IV over 24 hours or 2mg PO, Also used in bowel obstruction at 3mg IV daily with dexamethasone

Article title Authors Journal Year Type of study Level of evidence Key points Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation Spitzer TR, Friedman CJ, Bushnell W, Frankel SR, Raschko J. Bone Marrow Transplant. 2000 Double blind RCT Level 1+ N=34 Granisetron vs Ondansetron for Total Body Irradiation priori to BMT During first 24hrs Grnaisetron 61.1% vs Ondansetron 46.7% had no emesis vs control 6.7% Graniseton 33% and Ondansetron 26.7% had no vomiting over 4 days Complete response in 15/22 patients (68%)   The antiemetic effect of granisetron in lower hemibody radiotherapy Logue JP, Magee B, Hunter RD, Murdoch RD Clin Oncol 1991 Open Label Cohort study Level 2+ 9/13 patients had a complete response to 20mcg/kg 6/9 patietns had a complete response to 40 mcg/kg Intractable nausea and vomiting successfully treated with granisetron 5-hydroxytryptamine type 3 receptor antagonists in Palliative medicine Buchanan & Muirhead Pallitive Medicine 2007 Case reports Level 3 2 patients with intractable N&V who responded when other anti-emetics including ondansetron failed

Granisetron transdermal system improves refractory nausea and vomiting in gastroparesis Simmons & Parkman Dig Dis Sci 2014 Open label Cohort study Level 2+ Non-palliative patients with gastroparesis N=36 18 improved 15 same 2 worse Total body irradiation prior to bone marrow transplantation: efficacy and safety of granisetron in the prophylaxis and control of radiation-induced emesis Belkacemi et al Int J Radiatio Oncology Biol Phys 1996 Open Label Cohort Study Level 2+ Comppared 3mg IV oever 5 min (Tx A) + 3mg Granisetron over 24hrs IV (Tx B) for TBI TxA n=15 TxB n=21 TxA 67% complete control at 12 hrs vs TxB 81% The efficacy and safety of once daily Kytril (granisetron hydrochloride) tablets in ht eprophylaxis of nausea and emesis following fractionated upper abdominal radiotherapy Lanciano et al Cancer Investigations 2001 Double blind RCT Level 1++ Granisetron (n=134) vs placebo (n=126) post 10-30# XRT Median time to 1 st nausea 11 vs 1 day Median time to 1 st emesis 35 vs 9 days

Granisetron , a selective 5-HT3 receptor antagonist, for the prevention of radiation induced emesis during total body irradiation Hunter et al Bone Marrow Transplantation (ABSTRACT ONLY) 1991 Open Label Cohort Study To test efficacy for highly emetogenic irraiation Level 2+ n=32 18 (56.3%) got total protection 13 (40.6%) major protection   Granisetron in the prevention of irradiation-induced emesis Grant Prentice et al Bone Marrow Transplantation (ABSTRACT ONLY) 1995 RCT Double blind N=30 Level 1+ 1. Granisetron vs Metoclopramide / Dexamethasone/ Lorazepam 2. Granisetron significantly better at 24hr and 7day 3. At 24hr 53% complete response to Granisetron vs 13%

Levomepromazine Dr Jamie Barfield; Palliative Medicine ST3; Aintree Hospital

LevomepromazinePhenothiazine Low potency antipsychotic (approximately half as potent as chlorpromazine)Exerts its effects by blocking a variety of receptorsAdrenergic, dopamine, histamine, muscarinic, acetylcholine and serotoninSerious side effects tardive dyskinesia, akathisia, arrhythmias, hypotension and neuroleptic malignant syndrome

Levomepromazine 1 case report of a man with carcinoid treated with high dose levomepromazine that found 25mg TDS to be effective1 open label study of 70 patients given levomepromazine at doses from 3.12mg to 25mg subcut daily. No association between dose and efficacy or sedation

Article title Authors Journal Year Type of study Level of evidence Key points 1. Low-dose levomepromazine in refractory emesis in advanced cancer patients: An open-label study   Eisenchlas J.H.; Garrigue N.; Junin M.; De Simone G.G.   Palliative Medicine   2005 Open Label   Use of Levomepromazine to control N&V in advanced cancer Level 2+ n=70 Median distress from 8/10 to 1/10 in 2/7 Vomiting ceased in 92% cases S/E sedation 2/10 irrespective of dose used High dose levomepromazine to control nausea in carcinoid syndrome Amesbury et al J Palliative Care 2004 Case report Level 3 Outline of 1 successful case

Olanzapine Dr Paula Powell; Community Consultant in Palliative Medicine

Second – generation antipsychoticD1, D2, D3, D4, 5HT2A, 5HT2C, 5HT3 and 5HT6 antagonist Binds to α1 adrenergic, H1 and muscarinic receptorsPhase 1 and 2 trials for chemotherapy induced N+V have shown effectiveness as a broad spectrum anti-emetic.Excretion 60% renal, 30% faecal – variable between patients DI – Omeprazole, carbamazepine, rifampicin reduce plasma concentration. Fluvoxamine increases. Potentiates effect of other CNS depressants e.g. benzodiazepines SE – Drowsiness, constipation, dry mouth, hypotension, paradoxical agitation, extra – pyramidal. Lowers seizure threshold. Olanzapine

Incidence of drug induced movement disorders are less than with haloperidol In use reported as less sedating than levomepromazineDose – 1.25mg - 2.5mg oral or SC 2 hourly PRN and nocte . Can be increased to 5mg bd.Available as tablet, Oro-dispersible and injection IM or SC No site reactions reported with SC use If giving IM for the first time it is advised to monitor HR, RR, BP and conscious level for 4 hours. Olanzapine

Ref BNF 68, Palliative Care Formulary Fourth Edition 2012Full text articles reviewed for Olanzapine Medication Article title   Authors Journal Year Type of study Level of evidence Key points Olanzapine for Intractable Nausea in palliative Care patients W. Clay Jackson Laura Tavernier Journal of Palliative Medicine Volume 6, Number 2, 2003 2003 Case Series 3 6 patients with N+V not responding to usual anti-emetics. All resolved with oral olanzapine. Similar to levomepromazine May be less sedating. SE profile better than haloperidol .   Olanzapine as an Antiemetic in Refractory Nausea and vomiting in Advanced Cancer Manish Srivastava Norman Brito-Dellan Mellar P Davies Journal of Pain & Symptom Management Vol 25 No 6 June 2003 2003 Case series 3 2 cases. Patients not responded to multiple anti-emetics. Note – fewer interactions, lowers seizure threshold, ok in renal and liver dysfunction   A Pilot Exploration of the Antiemetic Activity of Olanzapine for the Relief of Nausea in patients with Advanced Cancer and Pain. Steven D Passik Jeremy Lundberg Kenneth L Kirsh Dale Theobald Journal of Pain & Symptom Management Vol 23 No 6 June 2002 2002 Open label pilot study. 2+ Well conducted. Small pilot 15 patients Significant reduction in nausea in patients taking opioids, no impact on cognition, no reported extra – pyramidal SE  

Prochlorperazine Dr Paula Powell; Community Consultant in Palliative Medicine

Phenothiazine antipsychotic and anti-emetic D2, 5HT2, H1, α1 and ACHm antagonistMost effective at chemoreceptor trigger zone. Oral bio-availability is low due to high first pass metabolismBuccal preparation is 2.5 X more bio-available Clinically important DI are unlikely but advised to monitor phenytoin levels. More likely extra-pyramidal SE if given with lithium Extra-pyramidal SE are infrequent, paradoxical agitation can occur. Available as oral, buccal and injection IV or IM. SC irritant. 3-6mg bd buccal , 5-10mg tds-qds , 5-10mg IM 3-4 hrly , 2.5-10mg IV 3-4 hrly . Max 40mg in 24 hrs Prochlorperazine

Article title Authors Journal Year Type of study Level of evidence Key points Antiemetic in the ED: a randomized controlled trial comparing 3 common agents. Darren Braude Tricia Soliz Cameron Crabndell Greg Hendey The American Journal of Emergency Medicine 2006 24,177-182 2006 RCT 1+ RCT comparison of 3 and placebo anti-emetics used IV in emergency dept. PCP no better than placebo. Relevance limited by population studied, route of administration and single use only.   A Prospective Randomized Double-Blind Trial Comparing Ondansetron Versus Prochlorperazine for the Prevention of Nausea and Vomiting in Patients undergoing Fractionated Radiotherapy. T J Priestman J T Roberts B K Upadhyaya Clinical Oncology (1993) 5:358-363 The Royal College of Radiologists 1993 RCT – multicentre double blind. 1+++ Comparator study. Ondansetron more effective than PCP. Relevant group. Prochlorperazine Versus Promethazine for Uncomplicated Nausea and Vomiting in the Emergency Department: A Randomized, Double-Blind Clinical Trial. Amy A Ernst Steven J Weiss Sun Park Kevin Takakuwa Annals of Emergency Medicine - August 2000 36:2 2000 RCT double blind 1+ Comparator study. Emergency Dept. IV single dose. PCP more effective than promethazine and faster onset of relief of symptoms Ref: BNF 68. Palliative Care Formulary Forth Edition 2012

A Systemic Review of the Treatment of Nausea and/or Vomiting in Cancer Unrelated to Chemotherapy or Radiation (2010) Systemic review of the efficacy of antiemetics in the treatment of nausea in patients with far advanced cancer (2004) Systematic Reviews – Dr Richard Latten, Consultant Palliative Medicine

CURRENT STANDARDS Dr Richard Latten

Any patient with a history of nausea and vomiting should have a full assessment including a history, clinical examination and appropriate investigations to try and identify a cause for the symptoms. (Grade D) Appropriate anti emetics should be prescribed on a regular and as required basis. (Grade D) If a patient is vomiting or nauseated for more than 24 hours, anti emetics should be given via the parenteral route. (Grade D) Current Standards

If combinations of anti emetics are required, drugs with different but complementary actions should be used. (Grade D ) Metoclopramide should not be prescribed if the vomiting is caused by complete intestinal obstruction. (Grade D)Symptoms of nausea and vomiting should be controlled within 72 hours. (Grade D)

Questions to considerCyclizine & heart failureMax dose cyclizine Rationale for antiemetic choice incl combinationsE.g. Why not Prochlorperazine / Olanzapine / GranisetronEspecially given available evidence levelProcess of deciding choice – patient centred approach