756

Journal of Pain and Symptom Management

Vol. 39 No. 4 April 2010

Review Article

A Systematic Review of the Treatment

of Nausea and/or Vomiting in Cancer
Unrelated to Chemotherapy or Radiation
Mellar P. Davis, MD, FCCP, and Gretchen Hallerberg, MS, MSLS, AHIP,
for the Palliative Medicine Study Group of the Multinational Association
of Supportive Care in Cancer
The Harry R. Horvitz Center for Palliative Medicine (M.P.D.) and Palliative Medicine & Supportive
Oncology Services (M.P.D.), Division of Solid Tumor, The Taussig Cancer Center, The Cleveland
Clinic; and Library (G.H.), The Cleveland Clinic, Cleveland, Ohio, USA

Abstract
Context. A systematic review of antiemetics for emesis in cancer unrelated to
chemotherapy and radiation is an important step in establishing treatment
recommendations and guiding future research. Therefore, a systematic review
based on the question What is the evidence that supports antiemetic choices in
advanced cancer? guided this review.
Objectives. To determine the level of evidence for antiemtrics in the
management of nausea and vomiting in advanced cancer unrelated to
chemotherapy and radiation, and to discover gaps in the evidence, which would
provide important areas for future research.
Methods. Three databases and independent searches using different MeSH
terms were performed. Related links were searched and hand searches of related
articles were made. Eligible studies included randomized controlled trials (RCTs),
prospective single-drug studies, studies that used guidelines based on the etiology
of emesis, cohort studies, retrospective studies, and case series or single-patient
reports. Studies that involved treatment of chemotherapy, radiation, or
postoperation-related emesis were excluded. Studies that involved the treatment
of emesis related to bowel obstruction were included. The strength of evidence
was graded as follows: 1) RCTs, A; 2) single-drug prospective studies, B1; 3) studies
based on multiple drug choices for etiology of emesis, B2; and 4) cohort, case
series, retrospective, and single-patient reports, E. Level of evidence was
determined by the Oxford Centre for Evidence-Based Medicine Levels of
Evidence (May 2001) (A, B, C, D).

This article was presented at the Ohio Hospice and

Palliative Care Organization Conference, November
5, 2008, Columbus, OH, USA, and the Toronto Pain
and Symptom Management Conference, November
22, 2008, Toronto, Ontario, Canada.
The Harry R. Horvitz Center for Palliative Medicine
is a World Health Organization Demonstration Project in Palliative Medicine.
2010 U.S. Cancer Pain Relief Committee
Published by Elsevier Inc. All rights reserved.

Address correspondence to: Mellar P. Davis, MD, FCCP,

Division of Solid Tumor, The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Center,
The Cleveland Clinic, 9500 Euclid Avenue, R35,
Cleveland, OH 44195, USA. E-mail: davism6@
ccf.org
Accepted for publication: August 4, 2009.

0885-3924/$esee front matter

doi:10.1016/j.jpainsymman.2009.08.010

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

757

Results. Ninety-three articles were found. Fourteen were RCTs, most of them of
low quality, based either on lack of blinding, lack of description of the method of
randomization, concealment, and/or attrition. Metoclopramide had modest
evidence (B) based on RCTs and prospective cohort studies. Octreotide,
dexamethasone, and hyoscine butylbromide are effective in reducing symptoms of
bowel obstruction, based on prospective studies and/or one RCT. There was no
evidence that either multiple antiemetics or antiemetic choices based on the
etiology of emesis were any better than a single antiemetic. There is poor evidence
for dose response, intraclass or interclass drug switch, or antiemetic combinations
in those individuals failing to respond to the initial antiemetic.
Conclusion. There are discrepancies between antiemetic studies and published
antiemetic guidelines, which are largely based on expert opinion. Antiemetic
recommendations have moderate to weak evidence at best. Prospective
randomized trials of single antiemetics are needed to properly establish evidencebased guidelines. J Pain Symptom Manage 2010;39:756e767. 2010 U.S. Cancer
Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Key Words
Nausea, vomiting, systematic review, antiemetic

Introduction
Evidence from published literature should
be integrated into a clinical decision guideline.
Such evidence requires adequately designed
and completed randomized controlled trials
(RCTs). A systematic review using predetermined criteria for selecting, appraising, interpreting, and summarizing data from original
studies can clarify the existing evidence
base.1,2 If more than one RCT of acceptable
quality and similar design are available, a quantitative meta-analysis may be performed, which
then would additionally support the development of treatment guidelines. If RCTs are
not available or are of poor quality, other types
of studies, including prospective or retrospective observational studies, cohort studies, and
single-case reports, must be used to inform
treatment decisions.3,4
Narrative reviews are subject to systematic
and random error. Systematic reviews are preferable because of their rigorous approach to
evidence review. This includes 1) an established preplanned search design; 2) a comprehensive search of all potentially available
articles; 3) reproducible criteria for the selection of articles, so that others may repeat the
review and come to the same number of studies; 4) a grading system of study quality; and 5)
a synthesis of the results.3

Treatment guidelines based on high-quality

RCTs are well established for chemotherapyrelated nausea and vomiting.5 The treatment
of nausea and vomiting unrelated to chemotherapy or radiation has previously undergone
a systematic review, which included 21 studies,
the great majority of which were not RCTs.6
Three studies using multiple antiemetics based
on the clinically determined mechanism of
emesis (etiology-based antiemetic trials or
EBAT) have been published.7e9 In addition,
multiple narrative reviews that have attempted
to collate studies have been published. We performed a systematic review of treatment trials
and narrative or systematic reviews that summarized studies of antiemetics in advanced
cancer. The objective of this systematic review
was to determine the level of evidence for antiemetics in the management of nausea and
vomiting in advanced cancer unrelated to chemotherapy and radiation. The second objective was to discover gaps in the evidence,
which would provide important areas for future treatment trials.

Materials and Methods

Studies that met the inclusion criteria were
those that 1) involved individuals with active
cancer; 2) included adults (age $18 years);

758

Davis and Hallerberg

3) evaluated a treatment for nausea and vomiting clinically determined to be related to the
cancer or as a complication from the cancer;
and 4) were characterized as RCTs, prospective
trials, treatment based on the etiology of nausea
and vomiting (EBAT), cohort studies, case series, and single-case reports. Studies that incorporated both cancer patients and individuals
without cancer or individuals treated for nausea
because of cancer and chemotherapy-induced
emesis were included. Most of these were earlier
treatment trials. Antiemetic trials for the management of chemotherapy-, radiation-, or
postoperation-related nausea and vomiting
were excluded. The systematic review was limited to studies published in English or for which
English abstracts were available. The period of
review was from 1950 to 2008.
The evidence was graded based on the determinants of quality of evidence published by the
American Thoracic Society dA: evidence from
RCT; B1: evidence from single-drug prospective
studies or in which single-drug activity could be
determined; B2: evidence from prospective
etiologic guideline trials or multiple drug combination studies in which single-drug activity
could not be determined; C: evidence from
cohort studies, retrospective studies, case series,
or single-case reports. The grade of recommendation is based on the Oxford Centre for
Evidence-Based Medicine Levels of Evidence
(May 21)dA: evidence from a systematic review
of RCT or a well-designed and executed RCT; B:
evidence from a systematic review of welldesigned and executed cohort studies or from
a well-designed and executed cohort, casecontrol study, or low-quality RCT; C: evidence
from case series or poor-quality cohort or casecontrol study; D: expert opinion. The quality
of RCTs was determined by the criteria published by Jadad et al.10 Reviews were included
if systematic or narrative reviews contained summaries of treatment trials. These were mostly
used for hand searches of references. Most
narrative reviews pre-dated the development
of systematic reviews. Reviews that provided
treatment guidelines only and pharmacological
reviews of antiemetics were excluded.
The systematic-review protocol included the
following elements:
1. An initial computerized search by a physician of the National Library of Medicine

2.

3.

4.

5.

Vol. 39 No. 4 April 2010

Medline database using the PubMed Entrez interface was selected for the initial
search. Medical subject heading (MeSH)
search terms were nausea and vomiting
and cancer or neoplasm or malignancy
and treatment or medications. An extensive related links and hand search for references was performed. This yielded 58
relevant studies or reviews.
A second systematic review by a physician
was done using Ovid Med. The search
terms were cancer or neoplasm or malignancy and nausea or vomiting and treatment or drugs or medications. This
search yielded 2,276 abstracts and eight
additional studies or reviews not found
in the initial PubMed review.
A third systematic review by a physician used
the Evidence-Based Medicine reviews:
Cochrane Central Register of Controlled
Trials and MeSH terms nausea, emesis or
vomiting and cancer or neoplasm or malignancy and treatment or drugs or medications. This search yielded 1,834 abstracts.
Related links from articles and hand
searches were done through studies found
in this review. Two reviews and one trial
were found in the search. Three additional
studies were obtained from hand searches
of articles, and six additional articles were
obtained from two reviews found through
the hand search.
An independent PubMed review was done
by G.H. using the terms any anti-emetics
or any nausea/drug therapy or any vomiting/drug therapy and advanced neoplasm
or advanced cancer. This yielded 150 abstracts and 27 studies, of which two were
not previously found (a case series and narrative review) in the first three searches.
A second independent PubMed search by
G.H. used any anti-emetics or any nausea/drug therapy or any vomiting/drug
therapy and any intestinal obstruction
or peritoneal implants or anxiety or any
anxiety disorder or any CNS disorders
or any CNS neoplasm/secondary or any
opioid analgesic/adverse effects, toxicity,
poisoning and any neoplasm. This review yielded 164 citations, five narrative
reviews, and three new case series.
Related links and hand searches yielded
five additional studies.

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

Table 1
Grade and Number of Studies (n 93)
Study Grade
A
B1
B2
C
Reviews

n (%)
14
13
6
46
14

(16)
(14)
(6)
(49)
(15)

6. A review using the ProQuest database for

dissertations/theses was performed. This
was done because these were mentor reviewed and, hence, would be considered
high-quality citations. No relevant citations were found in 82 references.

Results
Ninety-three articles were found that met the
inclusion criteria (Table 1). Only 14 were RCTs
and six were not blinded; the randomized
procedure was not explicitly published in most,
and the method of concealment was not
outlined11e24 (Table 2). Attrition rate was not
provided in the largest studies and was about
20% in trials for which there was information.
The longest duration for any study was 15 days.
Because the placebo response for nausea is not
established, the confidence interval for the
minimally important change on nausea cannot
be established by the present studies. Most of
the RCTs would be Level II evidence according
to the American College of Chest Physicians
Anti-thrombotic Consensus Conference Guidelines and Level 2b evidence according to the Oxford Centre for Evidence-Based Medicine Levels
of Evidence.25,26 Trial designs varied, five studies
involved bowel obstructions, and one was limited
to patients experiencing nausea and vomiting
because of morphine. Three studies were carried
out by a single group, which involved a similar
design and drugs and which may not have been
separate studies but staged reports of one or
two RCTs. These three studies20e22 had the
greatest number of participants, but they were
not blinded, and the methods of randomization
and attrition were not described (Table 2).
Responses were measured as reductions in the
severity of nausea and vomiting episodes or
reduction in the duration of nausea.
A meta-analysis of the existing data was not
possible because of heterogeneous patient
populations, different drugs and doses, and

759

varied study designs. Because of the low quality

of most of the RCTs, only Level B evidence
exists to support any treatment. Guidelines
cannot be constructed based on this systematic
review of studies, though treatment recommendations may be made, which can be modified once additional RCTs are completed. It is
clear that Level Ia and Ib evidence does not
exist for any antiemetic, as determined by the
Oxford Centre for Evidence-Based Medicine
Levels of Evidence.
There were 15 Level B1 studies found.
Seven were published in or before 1990.27e41
All of the trials involved phenothiazines (chlorpromazine, methotrimeprazine, olanzapine,
prochlorperazine, or thiethylperazine) or metoclopramide. Doses of phenothiazines were
generally higher in early studies32 than those
used in a recent RCT.22,23 Subjective responses
were assessed in most of the studies, though
responses were determined by different criteria among the studies. Phenothiazine switches
were attempted to reduce emesis and nausea
in those individuals not initially responding.
Some studies indicated that patients responded in narrative form. Three studies that
involved individuals with malignant bowel obstruction found benefits to corticosteroids or
octreotide in the management of bowel
obstruction.24,35,36,42
A dose-response relationship to antiemetics
cannot be obtained from RCT studies and
could not be established by prospective
studies.20e22,29,32 Results from B1 studies are
summarized in Table 3.7e9,43,44
Five studies had Level B2 evidence. Three
studies used EBAT. Treatment by EBAT was
successful in reducing nausea and vomiting
in most of the participants. However, only
100 individuals were treated in these three
trials. Two prospective studies found that
hyoscine butylbromide, haloperidol, and morphine reduced symptoms of bowel obstruction.43,44 Results from prospective B2 studies
are summarized in Table 4.
Forty-four studies were found with Level
C evidence, which accounts for most of the
studies.42,45e87 These studies add some weak
evidence for antiemetics to RCT or prospective
single-drug trials (chlorpromazine, olanzapine,
metoclopramide, octreotide, levomepromazine, and corticosteroids in the case of bowel
obstruction) and provide some published

760

Table 2
Summary of Randomized Controlled Trials
Method of
Randomization;
Concealment

CR vs. IR

Advanced cancer

34

; 

2. Bruera
et al. (2000)12

CR vs. placebo

Advanced cancer

26

; 

Advanced cancer

51

vs. levosulpiride

Advanced cancer

30

5. Hardy
et al. (2002)17

vs. ondansetron
vs. placebo

Advanced cancer;
on morphine
nausea

94

6. Brown
et al. (1992)11

Acupressure
bracelet

Hospice patients

; 

; 

7. Mystakidou
et al. (1997)22

Trop
Met
Chl
Dex
Trop
Met
Chl
Dex

Advanced cancer,
on opioids

120

; 

; 

Advanced cancer
with emesis on
standard
antiemetics

280

; 

; 

Duration of nausea/day
Emesis episodes/day

Advanced cancer
with emesis after
control with
Advanced cancer
with bowel
obstruction

160

; 

; 

Duration of nausea
Episodes of vomiting

10. Laval et al.

(2000)18

Trop
Chl
Dex
Methylprednisone
antiemetics

52

;

; 

Symptom
improvement

11. Hardy et al.

(1998)16

Ond
Met

Advanced cancer
with bowel
obstruction

25

; -

Response
Flatus, Light diet
No vomiting

3. Bruera
et al. (2004)13
4. Corli
et al. (1995)15

8. Mystakidou
et al. (1998)21

9. Mystakidou
et al. (1998)21

Drugs

PT Pop.

;
(parallel)
;

; 

;
(parallel)

; 

; 

Tools
VAS-nausea
CAT-nausea
Calories
VAS-nausea
Dyspepsia
NRS CAT
# vomiting: 24/hour
Presence/absence,
duration, intensity,
vomitingdpresence,
frequency, overall
nausea index
CAT intensity
Complete control
of emesis/nausea,
antiemetic rescue
Number of episodes
of emesis; duration
and severity of nausea
Duration of nausea,
episodes of vomiting

Duration
3 days

5/34 3

5 days

13/26 3

8 days

8/51 3

14 days

1/29  3

Placebo ondansetron
(prematurely stopped
because of difficulty
with recruitment)
Placebo band
acupressure band

24 hours

17/94 2

4 days

3/6 2

Met trop met

trop dex >> met
dex

15 days

NA/120
1

Trop trop met

trop met dex
trop chl trop
chl dex >> met
dex met chl
Trop trop chl
trop chl dex
>> chl dex
NG suction steroids
NG suction
No NGT steroids >
No NGT
Placebo
(8/14) (13/21)
(study
stoppeddpoor
accrual)

15 days

NA/280
1

15 days

NA/160
1

4 days

8/52 3

10 days

2/25 3

Outcomes
Met SR > IRdVAS
Met SR IRdCAT
Met SR IRdcalories
SR > placebodVAS
(17  12 mm vs.
12  10 mm)
Met met dex
Levosulpiride > met

Vol. 39 No. 4 April 2010

1. Bruera
et al. (1994)14

Study

Attrition
Reasonsa
dJadad

Davis and Hallerberg

Crossover;
Blinded

trop tropisetron; met metoclopramide; chl chlorpromazine; dex dexamethasone; ond ondansetron; VAS visual analog scale; PT pop. patient population; CAT categorical scale; NRS numerical rating scale; # number of individuals in the study; vs versus or compared to; CR continuous release; IR immediate release; SR sustained release; NA not assessed; NGT nasogastric tube;
NG nasogastric.
Jadad score 1e4 based on randomization, blinding, attrition and reasons for withdrawal, and method of randomization. Researcher concealment from randomization further reduces bias.
a
Reasons for attrition.

NA/68  2
6 days
; 
Advanced cancer
with bowel
obstruction
Octreotide,
hyoscine
butylbromide,
chlorpromazine
14. Mystakidou
et al. (2002)23

13. Ripamonti
et al. (2000)24

Advanced cancer
with bowel
obstruction
Advanced cancer
with bowel
obstruction
Octreotide vs.
hyoscine
butylbromide
Octreotide,
hyoscine
butylbromide
12. Mercadante
et al. (2000)19

68

; 

Diary of nausea/
vomiting by CATnausea in
duration  intensity
by CAT

0/17
01
3 days

Octreotide > hyoscine

butylbromide in
a subset treated
at home (10)
Octreotide > hyoscine
butylbromide
; 
; 
17

CAT-nausea

3/18 2
3 days
; 
; 
18

Episodes of emesis
Nausea by CAT

Octreotide > hyoscine

butylbromide

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

761

Table 3
Level B1 Evidence
Items
1
2
3
4
5
6
7
8

Outcomes from Studies

Chlorpromazine is an effective antiemetic32,55
Metoclopramide continuously infused or
given in high doses is an effective antiemetic29
Levomepromazine is an effective antiemetic30,34
Olanzapine is an effective antiemetic37
Prochlorperazine is an effective antiemetic31,33
Thiethylperazine is an effective antiemetic27
Octreotide is effective in the management
of bowel obstruction35,36,40
Corticosteroids reduce nausea and vomiting
in bowel obstruction38

experience with other medications (cannabinoids, ondansetron, mirtazapine, perphenazine, propofol, risperidone, or in the case of
nausea associated with leptomeningeal carcinomatosis, carbamazepine) or provide weak evidence for combination therapy. One study was
a retrospective audit of antiemetic practices in
the hospital.49 Two studies used a mixture of
antiemetics as initial treatment of emesis, one
of which had tolerance only as the outcome.59,84
Others involved individuals with bowel
obstruction.53e55,65,68,69 Results of Level C
studies are listed in Table 5.
There is significant publication bias, because
the non-RCTs were uniformly positive, and
negative results were reported only in RCTs.
Negative studies included 1) ondansetron and
metoclopramide for morphine-associated
emesis in cancer; 2) P6 acupressure bracelet
for cancer-associated nausea and emesis; and
3) the addition of corticosteroids to metoclopramide or chlorpromazine for cancerassociated nausea and emesis.11,13,17,20e22
Fifteen reviews have been published, in which
attempts have been made to summarize published studies.6,38,88e100 Most reviews pre-date
the development of the systematic review methodology. Reviews consist of single antiemetic
trials, studies that involve antiemetics for
opioid-induced emesis, and trials of medications
Table 4
Level B2 Evidence
Items
1
2

Outcomes from Studies

Etiology-based treatment guidelines for nausea
and vomiting are effective in greater than
50% of treated individuals7e9
A combination of an anticholinergic medication,
haloperidol, and an opioid relieves symptoms
from a bowel obstruction44,51

762

Davis and Hallerberg

Vol. 39 No. 4 April 2010

Table 5
Level C Evidence
Items
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26

Outcomes from Studies

46,55,60,64,71,72

Chlorpromazine is an effective antiemetic

Levomepromazine is an effective antiemetic41,45
Metoclopramide is an effective antiemetic and responses improve with dose47,48,73
Perphenazine is an effective antiemetic56,82
Thiethylperazine is an effective antiemetic86
Olanzapine is an effective antiemetic40,57,78
Risperidone is an effective antiemetic74
Mirtazapine is an effective antiemetic58,75,81
Thioperazine is an effective antiemetic85
Diphenhydramine is an effective antiemetic67
Ondansetron alone or the combination of ondansetron and haloperidol effectively relieves nausea and vomiting
unresponsive to initial treatment50,76
Cannabinoids are effective antiemetics62
Propofol reduces refractory nausea at the end of life61
Carbamazepine reduces nausea associated with meningeal carcinomatosis80
Patients frequently require more than one antiemetic combinations83
A combination of lorazepam, diphenhydramine, metoclopramide, and haloperidol is tolerable84
A cocktail of antiemetics is effective when used as first-line therapy (metoclopramide, diphenhydramine,
dexamethasone)59
Glycopyrrolate is effective in the management of nausea and vomiting in bowel obstruction51
The combination of hyoscine butylbromide and octreotide is effective in symptoms unresponsive to standard
therapy for bowel obstruction43
Corticosteroids reduce nausea and vomiting associated with bowel obstruction54,90
Sustained-release octreotide is effective in bowel obstruction35,65
Chlorpheniramine can be substituted for cyclizine as an antiemetic70
Chlorprophenpyridamine is an effective antiemetic42
Octreotide is an effective antiemetic for bowel obstruction36,69
Substituting one phenothiazine for another will reduce nausea and vomiting in those not responding to the first
antiemetic52,55
Antiemetic cocktails control nausea and are tolerable59,84

for nausea and vomiting associated with bowel

obstruction.39,89e91,94,99 One systematic review
involved complementary therapies as symptom
management, which included nausea and vomiting.96 These narrative summaries of studies
were helpful in finding references that were
missed with the MeSH term search.3,101 This
was particularly true for antiemetic studies published before 1960.71,86 A second set of narrative
reviews provided additional references in the
management of nausea associated with
intestinal obstruction. Only one was a formal
systematic review.6 Systematic reviews for the individual antiemetics droperidol and haloperidol are in progress, as is a systematic review for
antiemetics for opioid-related emesis.94,97,98

Discussion
This systematic review confirms many of the
findings from a previous systematic review,6
which included 21 studies. RCTs made up only
16% of the studies and were not of high quality.
The RCTs had lower response rates than single-

arm studies.6 Antiemetic doses in RCTs were

lower than those in earlier cohort studies, which
may be the reason for differences in response,
particularly when comparing prospective trials
of chlorpromazine.20,21,32,102 In earlier studies,
doses of chlorpromazine were started at 25 mg
four times daily and were titrated; these studies
suggested positive responses in 70% of the individuals treated.32,46,70,95,96,101 Doses of chlorpromazine in recent RCTs were much lower
(25 mg/day).20e22
There is moderate evidence for the use of metoclopramide as a first-line antiemetic (B) and
for octreotide in bowel obstruction (B). There
is no evidence for using multiple antiemetics as
the initial treatment. Treatment based on
EBAT cannot be shown to be better than that using a single emetic at effective doses.6e9,32,48
There is moderate evidence that dexamethasone does not add to the antiemetic efficacy of
phenothiazines or metoclopramide (B).13,20e22
Ondansetron or metoclopramide does not
reduce emesis from opioids (B).17 The addition
of antiemetics with complementary approaches
(such as adding Serotonin (5HT3) receptor

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

blockers to dopamine (D2) receptor blockers)

in those whose emesis is unresponsive to D2
receptor blockers has rationale behind the
recommendation but lacks evidence regarding
efficacy (C). In addition, switching antiemetics
is often done, but there is little evidence to guide
this practice.20e22 The best evidence for an antiemetic drug exists for metoclopramide, based
on the number and quality of studies.
This systematic review illustrates the poor
evidence available to guide antiemetic therapy.
Guidelines are largely expert opinions that influences practice.98,103 Published guidelines
have recommended dexamethasone in combination with metoclopramide, or cyclizine with
ondansetron for refractory emesis, with no
evidence to support this recommendation and,
in fact, evidence to the contrary.103 Haloperidol,
droperidol, dronabinol, dexamethasone, and
lorazepam have been listed as antiemetics within
guidelines, with no single-drug evidence to support this recommendation.99 Antiemetics, such
as chlorpromazine, levomepromazine, and
tropisetron, are not mentioned in expert opinion guidelines; yet, at least low-quality RCTs or
multiple prospective studies have demonstrated
responses. Cyclizine and haloperidol have been
included as antiemetics in EBAT guidelines; yet,
there is no single-drug evidence for such a recommendation.8,9,88 Diphenhydramine only has
weak evidence as an antiemetic; yet, cyclizine,
without even a cohort study, is recommended
as the broad-spectrum antihistamine of choice
in EBAT guidelines.67 It is, therefore, understandable that clinicians will fail to follow what
are considered to be guidelines, because there
is such a discrepancy between guidelines for
antiemetic choices by experts and evidence
based on treatment trials.49
Approaches to manage emesis that fails to respond to the initial antiemetic vary. Choices of antiemetics are largely guided by clinical experience
and personal choices. One approach mentioned
is to switch drugs within the drug class (phenothiazines) or to a closely-related drug class (atypical
antipsychotics).34,48,57,74,77,78,87 A second approach is to titrate the antiemetic to response,
because there is a presumed dose-response
relationship. A third approach is to switch drug
classes.20,34,71,72 The fourth approach is to add antiemetics with complementary receptor-binding
activity.50,59,83 All of these have a very low level
of evidence to guide practice (C).

763

Cohort studies, retrospective reviews, and

single-patient reports may provide some direction for future trials. For instance, anticonvulsants may reduce nausea from meningeal
metastases.80 Further studies would be important to be carried out in this area, because nausea from leptomeningeal metastases may be
relatively refractory to standard antiemetics.
Propofol may be an effective antiemetic at the
end of life, when palliative sedation is being considered.61 Mirtazapine may be an effective
antiemetic and would serve the dual purpose
of an antidepressant and an antiemetic.34
Levomepromazine may be an effective
antiemetic in those with advanced carcinoid.
Individuals are presently being treated by
prescriber-dependent N of 1 trials based on
drug choices from relatively weak evidence.
The results of this will reinforce bias, clinical
prejudice, and expert opinion.104 Keeley104
places the ethical imperative on doing wellconstructed trials in perspective: One objection to research is the risk that patients will
be subjected to untested or ineffective treatment. Yet this is precisely the care at the moment in large areas of symptom control where
decisions are made on the basis of anecdotebased medicine or eminence-based medicine . the truth is that autonomy can be little
respected at present, as there is little evidence
on which patients can make clear clinical
choices about the treatment they receive for
the control of symptoms.104

Summary
Guidelines cannot be established for antiemetics in advanced cancer with the present
available level of evidence. Based on a very
limited literature, a first-line therapy would
be metoclopramide. A phenothiazine, or
a 5HT3 antagonist, could be used based on
low-quality RCTs or multiple prospective trials.
Second-line treatment may involve a phenothiazine switch, an atypical neuroleptic, an interclass drug switch to a 5HT3 receptor
antagonist, dose titration, or the addition of
an antiemetic with complementary receptor
activity. The evidence supporting these recommendations is quite weak. Future prospective
and randomized studies will be needed to
confirm recommendations.

764

Davis and Hallerberg

Bowel obstruction should be managed with

butyrophenones or phenothiazines, an anticholinergic and/or octreotide, though the strength
of this recommendation is moderate (B). Dexamethasone improves the nausea and vomiting
associated with a bowel obstruction, based on
RCTs and confirmed by prospective studies. Neither ondansetron nor metoclopramide improve
opioid-induced emesis, based on an RCT.

References
1. Moher D, Jadad AR, Tugwell P. Assessing the
quality of randomized controlled trials. Current issues and further directions. Int J Technol Assess
Health Care 1996;12(2):195e208.
2. Moher D, Cook DJ, Jadad AR, et al. Assessing
the quality of reports of randomized trials: implications for the conduct of meta-analyses. Health
Technol Assess 1999;3(12):ieiv. 1e98.
3. Cook DJ, Greengold NL, Ellrodt AG,
Weingarten SR. The relation between systematic
reviews and practice guidelines. Ann Intern Med
1997;127(3):210e216.
4. Crowther MA, Cook DJ. Trials and tribulations
of systematic reviews and meta-analyses. Hematology Am Soc Hematol Educ Program 2007;
493e497.
5. Hesketh PJ. Chemotherapy-induced nausea
and vomiting. N Engl J Med 2008;358(23):
2482e2494.
6. Glare P, Pereira G, Kristjanson LJ, Stockler M,
Tattersall M. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with
far-advanced cancer. Support Care Cancer 2004;
12(6):432e440. [review].
7. Bentley A, Boyd K. Use of clinical pictures in
the management of nausea and vomiting: a prospective audit. Palliat Med 2001;15(3):247e253.
8. Lichter I. Results of antiemetic management in
terminal illness. J Palliat Care 1993;9(2):19e21.
9. Stephenson J, Davies A. An assessment of
aetiology-based guidelines for the management of
nausea and vomiting in patients with advanced cancer. Support Care Cancer 2006;14(4):348e353.
10. Jadad A, Moore A, Carroll D, Jeakinson C, et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials
1996;17:1e12.
11. Brown S, North D, Marvel MK, Fons R.
Acupressure wrist bands to relieve nausea and
vomiting in hospice patients: do they work? Am
J Hosp Palliat Care 1992;9(4):26e29.
12. Bruera E, Belzile M, Neumann C, et al. A
double-blind, crossover study of controlled-release
metoclopramide and placebo for the chronic

Vol. 39 No. 4 April 2010

nausea and dyspepsia of advanced cancer. J Pain

Symptom Manage 2000;19(6):427e435.
13. Bruera E, Moyano JR, Sala R, et al. Dexamethasone in addition to metoclopramide for chronic
nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage 2004;
28(4):381e388.
14. Bruera ED, MacEachern TJ, Spachynski KA,
et al. 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.
Cancer 1994;74(12):3204e3211.
15. Corli O, Cozzolino A, Battaiotto L. Effectiveness of levosulpiride versus metoclopramide for
nausea and vomiting in advanced cancer patients:
a double-blind, randomized, crossover study.
J Pain Symptom Manage 1995;10(7):521e526.
16. Hardy J, Ling PJ, Mansi J, et al. Pitfalls in
placebo-controlled trials in palliative care: dexamethasone for the palliation of malignant bowel
obstruction. Palliat Med 1998;12:437e442.
17. Hardy J, Daly S, McQuade B, et al. A
double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose
of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of
opioid-induced nausea and emesis in cancer patients. Support Care Cancer 2002;10(3):231e236.
18. Laval G, Girardier J, Lassauniere JM, et al. The
use of steroids in the management of inoperable intestinal obstruction in terminal cancer patients: do
they remove the obstruction? Palliat Med 2000;
14(1):3e10.
19. Mercadante S, Ripamonti C, Casuccio A,
Zecca E, Groff L. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal
symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 2000;8(3):188e191.
20. Mystakidou K, Befon S, Liossi C, Vlachos L.
Comparison of tropisetron and chlorpromazine
combinations in the control of nausea and vomiting
of patients with advanced cancer. J Pain Symptom
Manage 1998;15(3):176e184.
21. Mystakidou K, Befon S, Liossi C, Vlachos L.
Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the
treatment of emesis associated with far advanced
cancer. Cancer 1998;83(6):1214e1223.
22. Mystakidou K, Befon S, Trifyllis J, Liossi C,
Papadimitriou J. Tropisetron versus metoclopramide
in the control of emesis in far-advanced cancer.
Oncologist 1997;2(5):319e323.
23. Mystakidou K, Tsilika E, Kalaidopoulou O,
et al. Comparison of octreotide administration vs
conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blind,

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

controlled clinical trial. Anticancer Res 2002;

22(2B):1187e1192.
24. Ripamonti C, Mercadante S, Groff L, et al.
Role of octreotide, scopolamine butylbromide,
and hydration in symptom control of patients with
inoperable bowel obstruction and nasogastric tubes:
a prospective randomized trial. J Pain Symptom
Manage 2000;19(1):23e34.
25. Schunemann HJ, Jaeschke R, Cook DJ, et al.
An official ATS statement: grading the quality of evidence and strength of recommendations in ATS
guidelines and recommendations. Am J Respir
Crit Care Med 2006;174(5):605e614.
26. Oxford Centre for Evidence-Based Medicine.
Levels of evidence and grades of recommendation.
Available from: www.cebm.net/levels_of_evidence.
(last accessed date June 2008).
27. Browne D. Vomiting mechanisms: a clinical
study of thiethylperazine. South M J 1961;54:
953e961.
28. Bruera E, Michaud M, Partington J, et al. Continuous subcutaneous (CS) infusion of metoclopramide (MCP) using a plastic disposable infusor for
the treatment of chemotherapy-induced emesis.
J Pain Symptom Manage 1988;3(2):105e107.
29. Bryson SM, McGovern EM, Kelman AW, et al.
The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease. Br J Clin
Pharmacol 1985;19(6):757e766.
30. Eisenchlas JH, Garrigue N, Junin M, De
Simone GG. Low-dose levomepromazine in refractory emesis in advanced cancer patients: an
open-label study. Palliat Med 2005;19(1):71e75.
31. Fagnano G, Cristofari U. Use of prochlorperazine as adjuvant in therapy of secondary phenomena in cancer patients. Minerva Med 1959;50(44):
1748e1749.
32. Homburger F, Smithy G. Chlorpromazine in
patients with nausea and vomiting due to advanced
cancer. N Engl J Med 1954;251(20):820e822.
33. Homburger F, Smithy G. Proclorperazine for
the treatment of nausea and vomiting in patients
with advanced cancer and other chronic diseases.
N Engl J Med 1957;256(1):27.
34. Kennett A, Hardy J, Shah S, AHern R. An
open study of methotrimeprazine in the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 2005;13(9):
715e721.
35. Khoo D, Hall E, Motson R, et al. Palliation of
malignant intestinal obstruction using octreotide.
Eur J Cancer 1994;30A(1):28e30.
36. Mangili G, Franchi M, Mariani A, et al. Octreotide in the management of bowel obstruction in terminal ovarian cancer. Gynecol Oncol 1996;61(3):
345e348.

765

37. Passik SD, Lundberg J, Kirsh KL, et al. A pilot

exploration of the antiemetic activity of olanzapine
for the relief of nausea in patients with advanced
cancer and pain. J Pain Symptom Manage 2002;
23(6):526e532.
38. Philip J, Lickiss N, Grant PT, Hacker NF. Corticosteroids in the management of bowel obstruction
on a gynecological oncology unit. Gynecol Oncol
1999;74(1):68e73.
39. Ripamonti CI, Easson AM, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer
2008;44(8):1105e1115. [review].
40. Shima Y, Ohtsu A, Shirao K, Sasaki Y. Clinical
efficacy and safety of octreotide (SMS201-995) in
terminally ill Japanese cancer patients with malignant bowel obstruction. Jpn J Clin Oncol 2008;
38(5):354e359.
41. Skinner J, Skinner A. Levomepromazine for
nausea and vomiting in advanced cancer. Hosp
Med 1999;60(8):568e570.
42. Weston G. Control of nausea and vomiting: observations on the use of chlor-trimeton (chlorprophenpyridamine malate) syrup. CA Med 1957;
86(6):378e380.
43. De Conno F, Caraceni A, Zecca E, Spoldi E,
Ventafridda V. Continuous subcutaneous infusion
of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 1991;6(8):484e486.
44. Ventafridda V, Ripamonti C, Caraceni A, et al.
The management of inoperable gastrointestinal
obstruction in terminal cancer patients. Tumori
1990;76(4):389e393.
45. Amesbury B, Alloway L, Hickmore E,
Dewhurst G. High-dose levomepromazine (methotrimeprazine) to control nausea in carcinoid syndrome. J Palliat Care 2004;20(2):117e118.
46. Amols W, Merritt HH. Vomiting: neural mechanisms and control by chlorpromazine. Neurology
1955;5(9):645e653.
47. Bruera E, Brenneis M, MacDonald N. Continuous SC infusion of metoclopramide for treatment of
narcotic bowel syndrome. Cancer Treat Rep 1987;
71:1121e1122.
48. Bruera E, Seifert L, Watanabe S, et al. Chronic
nausea in advanced cancer patients: a retrospective
assessment of a metoclopramide-based antiemetic
regimen. J Pain Symptom Manage 1996;11(3):
147e153.
49. Burgess CL, Holman CD, Satti AG. Audit of
nausea and vomiting management in palliative
care hospital patients. J Pharm Pract Res 2007;
37(4):306e309.
50. Cole RM, Robinson F, Harvey L, Trethowan K,
Murdoch V. Successful control of intractable nausea
and vomiting requiring combined ondansetron and
haloperidol in a patient with advanced cancer.
J Pain Symptom Manage 1994;9(1):48e50.

766

Davis and Hallerberg

51. Davis MP, Furste A. Glycopyrrolate: a useful

drug in the palliation of mechanical bowel obstruction. J Pain Symptom Manage 1999;18(3):153e154.
52. Ernst EM, Snyder AM. Perphenazine in nausea
and vomiting, and anxiety states. Palliat Med J 1958;
61(3):355e359.
53. Fainsinger RL, Spachynski K, Hanson J, et al.
Symptom control in terminally ill patients with malignant bowel obstruction (MBO). J Pain Symptom
Manage 1994;9:12e18.
54. Farr WC. The use of corticosteroids for symptom management in terminally ill patients. Am
J Hosp Care 1990;1:41e46.
55. Fink S, Winslow WA. Anti-emetic effect of
chlorpromazine (thorazine) in cancer patients. Gastroenterology 1955;28(5):731e735.
56. Homburger F. Perphenazine as an antiemetic
agent in cancer and other chronic diseases. J Am
Med Assoc 1958;167(10):1240e1241.
57. Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat
Med 2003;6(2):251e255.
58. Kim SW, Shin IS, Kim JM, et al. Mirtazapine for
severe gastroparesis unresponsive to conventional
prokinetic treatment. Psychosomatics 2006;47(5):
440e442.
59. Kumar G, Hayes KA, Clark R. Efficacy of
a scheduled IV cocktail of antiemetics for the palliation of nausea and vomiting in a hospice population. Am J Hosp Palliat Care 2008;25(3):184e189.
60. Lucas J, et al. Thorazine as aid in management
of cancer patients. Proc Am A Cancer Res 1954;30.
61. Lundstrom S, Zachrisson U, Furst CJ. When
nothing helps: propofol as sedative and antiemetic
in palliative cancer care. J Pain Symptom Manage
2005;30(6):570e577.
62. Maida V, Ennis M, Irani S, Corbo M,
Dolzhykov M. Adjunctive nabilone in cancer pain
and symptom management: a prospective observational study using propensity scoring. J Support Oncol 2008;6(3):119e124.
63. Mangili G, Aletti G, Frigerio. Palliative care for
intestinal obstruction in recurrent ovarian cancer:
a multivariate analysis. Int J Gynecol Cancer 2005;
15(5):830e835.
64. Marks JH. Use of chlorpromazine in radiation
sickness and nausea from other causes. N Engl
J Med 1954;250(23):999e1001.
65. Massacesi C, Galeazzi G. Sustained release
octreotide may have a role in the treatment of
malignant bowel obstruction. Palliat Med 2006;
20(7):715e716.
66. Matulonis UA, Seiden MV, Roche M, et al.
Long-acting octreotide for the treatment and symptomatic relief of bowel obstruction in advanced
ovarian cancer. J Pain Symptom Manage 2005;
30(6):563e569.

Vol. 39 No. 4 April 2010

67. McCawley EL, Kulasavage RJ, Warrington WR,

Pasquesi TJ. The intravenous use of diphenhydramine hydrochloride in the control of nausea and
vomiting. Portland Clin Bull 1951;5(3):43e48.
68. Mercadante S, Maddaloni S. Octreotide in the
management of inoperable gastrointestinal obstruction in terminal cancer patients. J Pain Symptom
Manage 1992;7(8):496e498.
69. Mercadante S, Spoldi E, Caraceni A,
Maddaloni S, Simonetti MT. Octreotide in relieving
gastrointestinal symptoms due to bowel obstruction.
Palliat Med 1993;7(4):295e299.
70. Morita T, Tei Y, Shishido H, et al. Chlorpheniramine malate as an alternative to antiemetic cyclizine. J Pain Symptom Manage 2004;27(5):388e389.
71. Moyer JH, Kent B, Knight RW, et al. Clinical
studies of an antiemetic agent, chlorpromazine.
Am J Med Sci 1954;228(2):174e189.
72. Moyer JH, Morris GC Jr, Handley CA, Kent B,
Mathews W. Observations on an effective antiemeticdchlorpromazine. AMA Arch Intern Med 1954;
94(3):497e502.
73. Nelson KA, Walsh TD. Metoclopramide in
anorexia caused by cancer-associated dyspepsia
syndrome (CADS). J Palliat Care 1993;9(2):14e18.
74. Okamoto Y, Tsuneto S, Matsuda Y, et al. A retrospective chart review of the antiemetic effectiveness of risperidone in refractory opioid-induced
nausea and vomiting in advanced cancer patients.
J Pain Symptom Manage 2007;34(2):217e222.
75. Pae CU. Low-dose mirtazapine may be successful treatment option for severe nausea and vomiting. Prog Neuropsychopharmacol Biol Psychiatry
2006;30(6):1143e1145.
76. Pereira J, Bruera E. Successful management of
intractable nausea with ondansetron: a case study.
J Palliat Care 1996;12(2):47e50.
77. Shinjo T, Okada M. Olanzapine use in cancer
patients for refractory vomiting. Gan To Kagaku
Ryoho 2006 Mar;33(3):349e352.
78. Srivastava M, Brito-Dellan N, Davis MP,
Leach M, Lagman R. Olanzapine as an antiemetic
in refractory nausea and vomiting in advanced cancer. J Pain Symptom Manage 2003;25(6):578e582.
79. Stewart BL, Redeker AG. Emesis and hiccough;
treatment with chlorpromazine. Calif Med 1954;
81(3):203e205.
80. Strohscheer I, Borasio GD. Carbamazepine-responsive paroxysmal nausea and vomiting in a patient
with meningeal carcinomatosis. Palliat Med 2006;
20(5):549e550.
81. Thompson DS. Mirtazapine for the treatment
of depression and nausea in breast and gynecological oncology. Psychosomatics 2000;41(4):356e359.
82. Torres Del Toro JMT, Albertson HA. Chlorpromazine in the management of nausea and vomiting. Va Med Mon (1918) 1955 Jul;82(7):306e308.

Vol. 39 No. 4 April 2010 Treatment of Nausea/Vomiting Unrelated to Chemo- or Radiation Therapy

83. Walsh TD. Antiemetic drug combinations in

advanced cancer. Lancet 1982;1(8279):1018.
84. Weschules DJ. Tolerability of the compound
ABHR in hospice patients. J Palliat Med 2005;8(6):
1135e1143.
85. Wilson WL, Shane LL, Moyer JH. The use of
thioperazine as an antiemetic. Antibiotic Med Clin
Ther 1959;6(7):421e425.
86. Cox J, Collins JH. Nausea and vomiting: control by thiethylperazine. Curr Ther Res Clin Exp
1962;4:178e181.
87. Stephen CR, Dent S, Bourgeois-Gavardin M.
Control of nausea and vomiting with chlorpromazine; incidence of side-effects. AMA Arch Intern
Med 1955;96(6):794e798.
88. Critchley P, Plach N, Grantham M, et al.
Efficacy of haloperidol in the treatment of nausea
and vomiting in the palliative patient: a systematic
review. J Pain Symptom Manage 2001;22(2):
631e634. [review].
89. Dorman S, Perkins P. Droperidol for treatment
of nausea and vomiting in palliative care patients
(protocol). Cochrane Database Syst Rev 2008;(1).
CD006938.
90. Feuer DJ, Broadley KE. Systematic review and
meta-analysis of corticosteroids for the resolution
of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancers. Systematic
Review Steering Committee. Ann Oncol 1999;
10(9):1035e1041. [review].
91. Feuer DJ, Broadley KE. Corticosteroids for the
resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer.
[review]. Cochrane Database Syst Rev 2000;(2).
CD001219.

767

94. Koetter K, Kranke P. Prevention and treatment

interventions for nausea and vomiting during initiation of chronic opioid therapy (protocol).
Cochrane Database Syst Rev 2008;(1). CD006959.
95. Mercadante S, Casuccio A, Mangione S.
Medical treatment for inoperable malignant bowel
obstruction: a qualitative systematic review. J Pain
Symptom Manage 2007;33(2):217e223. [review].
96. Moyer JH. Effective antiemetic agents. Med
Clin North Am 1957;41(2):405e432. [review].
97. Pan CX, Morrison RS, Ness J, Fugh-Berman A,
Leipzig RM. Complementary and alternative
medicine in the management of pain, dyspnea,
and nausea and vomiting near the end of life.
A systematic review. J Pain Symptom Manage 2000;
20(5):374e387. [review].
98. Perkins P, Dorman S. Haloperidol for treatment of nausea and vomiting in palliative care patients (protocol). Cochrane Database Syst Rev
2009;(2). CD006271.
99. Rhodes VA, McDaniel RW. Nausea, vomiting,
and retching: complex problems in palliative care.
CA Cancer J Clin 2001;51(4):232e248.
100. Ripamonti C, Twycross R, Baines M, et al.
Clinical-practice recommendations for the management of bowel obstruction in patients with
end-stage cancer. Support Care Cancer 2001;9(4):
223e233.
101. Cook DJ, Mulrow CD, Haynes RB. Systematic
reviews: synthesis of best evidence for clinical decisions. Ann Intern Med 1997;126(5):376e380.
102. Conner PK Jr, Moyer JH. A therapeutic appraisal of antiemetic agents. GP 1956;14(5):
125e139. [review].

92. Frank C. Medical management of intestinal

obstruction in terminal care. Can Fam Physician
1997;43:259e265. [review].

103. Thompson I. The management of nausea and

vomiting in palliative care. Nurs Stand 2004;19(8):
46e53.

93. Glare P, Dunwoodie D, Clark K, et al. Treatment of nausea and vomiting in terminally ill cancer
patients. Drugs 2008;68(18):2575e2590.

104. Keeley P. Improving the evidence base in palliative medicine: a moral imperative. J Med Ethics
2008;34:757e760.