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

2. Audit Group Members and Meetings
Dr Richard Latten
Dr Seamus Coyle
Dr Laura McGlynn
Dr Paula Powell
Dr Jamie Barfield
Ann Griffiths
Sian Rae
Agnes Noble
Tracey Hindley
Tania Forrester
Dave Hewison
27th August th September st October th October th November rd December th December th December th January th January 2015

3. Session Overview Patient, Carer and Public Involvement
Literature Search and Review
Existing Standards
Audit Results
Recommendations
Questions

4. Patient, Carer and Public Involvement
Representative - Dave Hewison
Willowbrook Hospice Volunteer
Actively participated in several group audit meetings
No previous direct involvement with a specialist palliative care team

5. Key areas to recognise from a patient, public and carer view
COMMUNICATION
Inform the patient of their management plan
Discuss antiemetic choice and WHY
Help the patient to understand WHY are they are nauseated/vomiting
Assess how much information the patient would like
If further information requested seek ways to direct the patient to information sources

6. 3. HONESTY AND PROFESSIONALISM
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 appropriately
3. HONESTY AND PROFESSIONALISM
Open and honest approach

7. LITERATURE REVIEW

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

9. ANTIEMETICS SEARCHED Aprepitant Cyclizine Dexamethasone Domperidone
Granisetron
Haloperidol
Hyoscine hydrobromide
Hyoscine butylbromide
Levomepromazine
Lorazepam
Metoclopramide
Olanzapine
Ondansetron
Prochlorperazine

10. SELECTION CRITERIA INCLUSION EXCLUSION Humans Adult patients
Incurable conditions
Cancer and NON cancer diagnoses
Radiotherapy related N+V
Pharmacological management
English language
Publication Year 0-current
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

11. METHOD 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

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

13. LITERATURE SEARCH RESULTS

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

15. APREPITANT Substance P Neurokinin1 receptor antagonist
Licensed for moderate/highly emetogenic CINV
in 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

17. 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
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
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

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

19. Cyclizine Well established antihistamine Exact mechanism unknown
reduces lower oesophageal sphincter tone and labyrinthine apparatus sensitivity
50mg TDS oral, IV, SC
No relevant clinical trials
Can cause hallucinations and enhance euphoric effects of opioids
Limited evidence in relation to use in heart failure

20. Journal of Pain and Symptom Management 2012 Pharmacokinetics Study NA
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

21. Dr Laura McGlynn; Palliative Medicine ST4; Aintree Hospital
Metoclopramide

22. METOCLOPRAMIDE Prokinetic anti emetic D2 antagonist and 5HT4 agonist
Triggers a cholinergic system in the wall of the GI tract
Block the dopamine break on gastric emptying induced by stress, anxiety and nausea
Useful in N+V caused by
- GI disorders
- Chemotherapy and Radiotherapy
- Dysmotility dyspepsia, Heartburn, Migraine, Hiccups
MHRA guidance

23. 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
N = 280
Control of N+V
23.6% of MET+DEX patients % of TRO patients % of TRO+MET pts % of TRO+MET+DEX pts % of CHL+DEX pts % of TRO+CHL pts % 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.
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

24. 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
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

25. 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

26. 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)

27. 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 1st 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 B 0.699; p ! 0.005) or subjectively (4.10 B
0.738 vs B 0.994; p ! 0.005).

28. 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 mm visual analogue
scale and 0-3 categoric scale was 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.

29. Hyoscine Hydrobromide
Dr Richard Latten
Hyoscine Hydrobromide

30. HYOSCINE HYDROBROMIDE
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

31. HYOSCINE HYDROBROMIDE
Article title
Authors
Journal
Year
Type of study
Level of evidence
Key points
Transdermal Hyoscine (Scopolamine)
A preliminary review of its pharmacodynam ics 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.
Total of 17 articles – all abstracts reviewed. Only 1 full text reviewed – not specific to palliative care but did discuss potential side effects.

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

33. ONDANSETRON 5HT3 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

34. 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

35. Support Care Cancer (2012) 20:1673–1678
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
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 B 0.699; p ! 0.005) or subjectively (4.10 B
0.738 vs 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.

36. 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,
Vol. 16 No. 4 October 1998
1998
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,
Vol. 9No. 1 January 1994
1994

37. Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre
Dexamethasone

38. Dexamethasone
Corticosteroid Mechanism of action unclear Dose 8mg-16mg Extensive side-effect profile ‘Add-on’ anti-emetic when all else fails 2 Randomised controlled trials

39. Randomised controlled trial
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( ), X (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( ), (October 2004)
2004
Level 1-
Dexamethasone was not superior to placebo in the management of chronic nausea in patients with advanced cancer also taking Metoclopramide.

40. Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre
Haloperidol

41. Haloperidol
Antipsychotic D2 antagonist Precise mechanism of action unknown Extrapyramidal side-effects Dose: 1.5mg-5mg orally; 1.5mg-3mg SC (PCF/BNF dose) 4 studies

42. 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( ), (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( ), ; (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), ; X (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), ; (2004 Jun)
2004
Systematic review
3 Level 1 studies reviewed.
Very few good quality data available.
Result is uncertain.

43. Agnes Noble; Palliative Care CNS; Clatterbridge Cancer Centre
Domperidone

44. Domperidone
D2 receptor antagonist Acts on gastro-oesophageal and gastro-duodenal junctions – Pro-kinetic Acts on dopamine receptors in CTZ Less likely to cause central effects Increased risk of serious cardiac side-effects: MHRA guidance No relevant evidence within audit criteria

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

46. Hyoscine Butlybromide
Antimuscarinic Doesn’t cross blood-brain barrier – No central anti-emetic effects No drowsiness No relevant evidence within audit criteria

47. Dr Jamie Barfield; Palliative Medicine ST3; Aintree Hospital
Granisetron

48. Granisetron A serotonin 5-HT3 receptor antagonist
Main effect is to reduce the activity of the vagus nerve, which activates the vomiting centre in the medulla oblongata
metabolized 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 daily
Excreted by the liver and kidneys

49. 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

50. 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

51. 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
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 1st nausea 11 vs 1 day
Median time to 1st emesis 35 vs 9 days

52. 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
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%

53. Dr Jamie Barfield; Palliative Medicine ST3; Aintree Hospital
Levomepromazine

54. Levomepromazine Phenothiazine Low potency antipsychotic
(approximately half as potent as chlorpromazine)
Exerts its effects by blocking a variety of receptors
Adrenergic, dopamine, histamine, muscarinic, acetylcholine and serotonin
Serious side effects
tardive dyskinesia, akathisia, arrhythmias, hypotension and neuroleptic malignant syndrome

55. Levomepromazine
1 case report of a man with carcinoid treated with high dose levomepromazine that found 25mg TDS to be effective
1 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

56. High dose levomepromazine to control nausea in carcinoid syndrome
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

57. Dr Paula Powell; Community Consultant in Palliative Medicine
Olanzapine

58. Olanzapine
Second – generation antipsychotic
D1, D2, D3, D4, 5HT2A, 5HT2C, 5HT3 and 5HT6 antagonist
Binds to α1 adrenergic, H1 and muscarinic receptors
Phase 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.

59. Olanzapine
Incidence of drug induced movement disorders are less than with haloperidol
In use reported as less sedating than levomepromazine
Dose – 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.

60. Full 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
Case series
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
Ref BNF 68, Palliative Care Formulary Fourth Edition 2012

61. Dr Paula Powell; Community Consultant in Palliative Medicine
Prochlorperazine

62. Prochlorperazine
Phenothiazine antipsychotic and anti-emetic
D2, 5HT2, H1, α1 and ACHm antagonist
Most effective at chemoreceptor trigger zone.
Oral bio-availability is low due to high first pass metabolism
Buccal 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, mg IV 3-4 hrly. Max 40mg in 24 hrs

63. Ref: BNF 68. Palliative Care Formulary Forth Edition 2012
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
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:
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 :2
2000
RCT double blind
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

64. Systematic Reviews – Dr Richard Latten, Consultant Palliative Medicine
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)

65. Dr Richard Latten
CURRENT STANDARDS

66. Current Standards
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)

67. 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)

68. Questions to consider Cyclizine & heart failure Max dose cyclizine
Rationale for antiemetic choice incl combinations
E.g. Why not Prochlorperazine / Olanzapine / Granisetron
Especially given available evidence level
Process of deciding choice – patient centred approach