International Journal of Nursing Studies 70 (2017) 27–37

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International Journal of Nursing Studies

journal homepage: www.elsevier.com/ijns

Review

Effects of acupressure on chemotherapy-induced nausea and

vomiting-a systematic review with meta-analyses and trial sequential
analysis of randomized controlled trials
Jing Miaoa , Xinyou Liub , Chaojun Wua , Hui Kongc, Weiping Xiec, Kouying Liua,c,*
a
School of Nursing, Nanjing Medical University, Jiangsu, China
b
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
c
Department of Respiration, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China

A R T I C L E I N F O A B S T R A C T

Article history: Background: Acupressure has been used as an effective way in treating with stomach upset. However the
Received 16 June 2016 efficacy of acupressure in preventing chemotherapy-induced nausea and vomiting is uncertain.
Received in revised form 6 February 2017 Objective: To assess the effectiveness of acupressure on three categories of chemotherapy-induced nausea
Accepted 9 February 2017
and vomiting.
Data sources: Databases had been retrieved from inception through February 2016 for the randomized
Keywords: controlled trials in accordance with the inclusion criteria, including PubMed, Cochrane Central Register of
Acupressure
Controlled Trials, Web of Science, EMBASE, Science Direct, CINAHL, China Biology Medicine, Chinese
Nausea
Vomiting
National Knowledge infrastructure, Wan Fang and Database for Chinese Technical Periodicals. Additional
Meta-analysis studies were identified through hand searches of bibliographies and Internet searches.
Design: Systematic review with meta-analyses and trial sequential analysis of randomized controlled
trials.
Review methods: Two reviewers selected relevant eligible articles, critical appraisal of the methodological
quality was conducted on the basis of using Cochrane Handbook. A standardized Excel form was used to
extract information. Meta-analysis and trial sequential analysis was performed using software RevMan
5.3 and TSA 0.9.
Results: Twelve studies with 1419 patients were included. Only three studies were assessed as high
quality, one study was evaluated as moderate, and eight studies were evaluated as poor. The meta-
analysis showed that acupressure reduced the severity of acute (SMD =
0.18, 95% CI
0.31 to
0.05,
p < 0.01) and delayed (SMD =
0.33, 95% CI
0.64 to
0.01, p = 0.04) nausea. However, there was no
benefit effect on the incidence or frequency of vomiting. No definitive conclusions were drawn from the
trial sequential analysis.
Conclusion: This systematic review suggested a protective effect of acupressure on chemotherapy-
induced nausea and vomiting, while more well-designed clinical trials with larger sample size were
needed to draw a definitive conclusion.
© 2017 Elsevier Ltd. All rights reserved.

What is already known about the topic?
 Chemotherapy-induced nausea and vomiting is one of the most
unbearable symptoms caused by chemotherapy.
 Acupressure has been thought as an effective way to relieve the
upset of stomach.
* Corresponding author at: School of Nursing, Nanjing Medical University,
Jiangsu, Nanjing, 210029, China.
E-mail addresses: 495831256@qq.com (J. Miao), 542443843@qq.com (X. Liu),
1328475487@qq.com (C. Wu), konghui@njmu.edu.cn (H. Kong),
wpxie@njmu.edu.cn (W. Xie), liuky188@126.com (K. Liu).
 Multiple studies have shown different conclusions about the
effect of acupressure.
What this paper adds
 Acupressure reduced the severity of acute and delayed nausea,
but had no effect on the incidence or the frequency of vomiting.
 A definitive conclusion about the effect of acupressure on
chemotherapy-induced nausea and vomiting cannot be drawn
through trial sequential analysis.

http://dx.doi.org/10.1016/j.ijnurstu.2017.02.014
0020-7489/© 2017 Elsevier Ltd. All rights reserved.
28 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
1. Introduction
Cancer has been part of the most important global health
problems. There are various methods of tumor therapies, such as
surgical resection, chemotherapy and radiotherapy. Among these
approaches applied to anticancer treatment, chemotherapy is
affecting patients’ quality of life by causing some serious problems
like nausea and vomiting, mouth ulcer, lack of appetite, constipa-
tion, and hair loss (Genc et al., 2013).
Nausea and vomiting are the most common and uncomfortable
side effects brought by chemotherapeutics. Chemotherapy-in-
duced nausea and vomiting consists of three major categories
(Jordan et al., 2014). Symptoms occurring within 24 h after
receiving chemotherapy are usually defined as acute nausea and
vomiting. Delayed nausea and vomiting has been thought to occur
at least 1 day to several days after receiving oncotherapy. Some
patients may experience nausea and vomiting triggered by taste,
sight or anxiety before the administration of chemotherapy, which
is considered to be anticipatory nausea and vomiting. Chemother-
apy-induced nausea and vomiting can cause a significant
decreasing on quality of life and serious metabolic complications,
such as hyponatremia, hypokalemia and metabolic acidosis
(Taspinar and Sirin, 2010).
As mechanisms of chemotherapy-induced nausea and vomiting
have become a more clearly recognize, these distress feelings,
especially acute symptoms, have been effectively controlled by the
use of advanced antiemetics such as 5-hydroxytriptamine-3 and
neurokinin-1 receptor antagonists (Jordan et al., 2015). Though
vomiting is fairly well controlled, nausea still remains a problem
(Einhorn et al., 2017), and such insufferable symptoms may
decrease the adherence to the treatment (Miller and Kearney,
2004). Acupoint stimulation has been recommended as a
complementary intervention to prevent chemotherapy-induced
nausea and vomiting by the National Institutes of Health
Consensus Statement (NIH Consens Statement, 1997). According
to the evidence practice guideline provided by the Oncology
Nursing Society, acupoint stimulation was considered as a
promising intervention for the management of chemotherapy-
induced nausea and vomiting (Tipton et al., 2007). Acupressure has
been used in alleviating nausea and vomiting in China for a long
time. Based on meridian theory, the purpose of acupressure
stimulation is to strengthen the energy flow (Qi), so that symptoms
can be managed (Complementary and Alternative Medicine
Editorial, 2002). Acupressure is easy to learn and can be performed
by patients themselves easily. Since it is noninvasive, adverse
reactions caused by insertion needles can be avoided (Lee and
Frazier, 2011).
Some systematic reviews of acupressure have been published,
and the authors recommended acupressure as a useful and
convenient method in the management of many symptoms, such
as pain, dyspnea, insomnia, fatigue, allergic disease, nausea and
vomiting (Lee and Frazier, 2011; Song et al., 2015). A subgroup
including 594 patients of a traditional meta-analysis published in
2006 got the conclusion that acupressure was effective for acute
nausea severity, but not effective for acute vomiting, delayed
nausea and vomiting (Ezzo et al., 2006). Conclusions from an well-
designed meta-analysis are usually reckoned as “the best
evidence”. Traditional meta-analysis may carry with the potential
problem of the inflation of Type I error (Brok et al., 2009;
Wetterslev et al., 2008), and cause false positive or negative
outcomes due to repeated significance testing (Kulinskaya and
Wood, 2014). This leads to the question that ‘the best evidence’
may not be ‘the abundant evidence’. Trial sequential analysis was
recommended as a new method to avoid these problems
(Kulinskaya and Wood, 2014). It is a methodology method to
calculate the required information size and the sequential
monitoring boundaries will be estimated to evaluate accumulate
evidence.
The aim of this systematic review was to evaluate the
effectiveness of acupressure as an additional intervention in
chemotherapy-induced nausea and vomiting control. It also
examined the sufficiency and conclusiveness of currently available
evidence.
2. Methods
2.1. Search strategies
Relevant studies were searched in 6 English databases and 4
Chinese databases, including PubMed, Cochrane Central Register of
Controlled Trials(CENTRAL),Web of Science, EMBASE, Science
Direct, CINAHL, China Biology Medicine(CBM), Chinese National
Knowledge infrastructure(CNKI), Wan Fang and Database for
Chinese Technical Periodicals(VIP) from inception to February
2016 for RCTs in accordance with inclusion criteria. Additional
studies were identified through hand searches of bibliographies
and Internet searches. Two reviewers (J.M and X.Y.L) indepen-
dently searched the article according to the systematic review
protocol. Chinese subject heading terms and text words included:
(“ ” (acupressure) OR “ ” (acupressure) OR “ ”
(Zhi Ya) OR “ ” (acupuncture therapy) OR “ ”
(Chinese traditional medicine)) AND (“ ” (nausea) OR “ ”
(vomiting) OR “ ” (emesis) OR “ ” (digestive tract) OR “ ”
(gastrointestinal tract)) AND (“ ” (cancer) OR “ ” (chemo-
therapy) AND “ ” (random) OR “ ” (control) OR “ ”
(placebo) OR “ ” (clinical trial)). Search strategies for
PubMed were shown in Table 1.
2.2. Inclusion and exclusion criteria
Randomized controlled trials were included if they met the
following criteria: (1) Population: patients were diagnosed with
cancer receiving chemotherapy through intravenous injection; (2)
Intervention: acupressure was used with or without antiemetic
medications; (3) Comparison: antiemetic medications or nursing
care were conducted; (4) Outcomes: chemotherapy-induced
nausea or vomiting, or both existed; (5) Language: English and
Chinese.
Trials were excluded for four reasons: (1) The article was not
acquired; (2) No available data; (3) Auricular therapy was used as
the intervention; (4) For the repetition of the published literature,
earlier one was chose.
2.3. Study selection
One review author (JM) screened titles and abstracts of the
candidate studies for relevant articles independently. This was
reviewed by another author (X.Y.L) independently. After full texts
of these potentially relevant articles were obtained, studies were
evaluated and selected by two reviewers (JM, X.Y.L) again
independently according to the inclusion criteria. Disagreements
were solved by consensus. The third reviewer (K.Y.L) was consulted
for a final selection if the consensus were not reached.
2.4. Quality critical appraisal
Assessment of bias was conducted using Cochrane risk-of-bias
tool (Higgins et al., 2011). Each included article was evaluated as
‘high’, ‘low’, or ‘unclear’ risk according to the bias tool with six
criteria, which were random sequence generation, allocation
concealment, blinding, incomplete data, outcome selective report-
ing, and others. High risk of bias was defined if any item was
 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37 29

Table 1
Search strategies for PubMed.

Search Strategies Results

1. Acupuncture points[MeSH] 4580
2. Acupressure[MeSH] 523
3. Medicine,Chinese Traditional [MeSH] 13937
4. (Acupoint* or “acupuncture point ” or acupressur* or shiat* or “Zhi Ya” or “Chih Ya”).mp.[mp = ti,ab] 4588
5. (“Chinese traditional medicine”or “traditional medicine,chinese”).mp.[mp = ti,ab] 13351
6. Or/1–5 21125
7. Nausea[MeSH] 16728
8. Vomiting[MeSH] 27102
9. (Nausea or vomiting).mp.[mp = ti,ab] 71444
10. Retching.mp.[mp = ti,ab] 884
11. emesis.mp.[mp = ti,ab] 5701
12. (Gastrointest* and toxicit*).mp.[mp = ti,ab] 9793
13. (Gastrointest* and reactio*).mp.[mp = ti,ab] 7554
14. (Intest* and toxicit*).mp.[mp = ti,ab] 4937
15. (Intest* and reactio*).mp.[mp = ti,ab] 12109
16. (drug and toxicit*).mp.[mp = ti,ab] 52097
17. (adverse and reactio*).mp.[mp = ti,ab] 48288
18. (adverse and event*).mp.[mp = ti,ab] 122174
19. Or/7–18 309738
20. Neoplasm[MeSH] 2750478
21. Carcinoma[MeSH] 530873
22. (Cance* or Tumou* or Tumor* or Marrow transplant*).mp.[mp = ti,ab] 2175538
23. (Neoplas* or carcinom*).mp.[mp = ti,ab] 800492
24. (chemoth* or chemical therapy).mp.[mp = ti,ab] 309148
25. Or/20–24 3450070
26. 6 and 19 and 25 196
27. Randomized controlled trials[MeSH] 101293
28. Random allocation[MeSH] 84997
29. Double blind method [MeSH] 132177
30. placebos[MeSH] 32896
31. Randomized controlled trial.pt. 403815
32. Controlled clinical trial.pt. 488937
33. (Single or double or random or placebo or sham).mp.[mp = ti,ab] 1851645
34. Or/27–33 2285507
35. 26 and 34 98
36. (animals NOT humans) [MeSH] 4189868
37. (animals NOT humans).mp.[mp = ti,ab] 5648903
38. Or/36–37 5712371
39. 35 not 38 89

considered as ‘high risk’. All domains were considered as ‘low risk’
when trials were evaluated as low risk of bias. Otherwise, trials
were assessed as unclear risk of bias.
The above process was performed by two authors (JM, C.J.W)
independently. The third reviewer (K.Y.L) was consulted for the
ultimate decision if disagreement still existed after negotiation.
2.5. Data extraction
Data extraction was conducted by two authors utilizing a
unified Excel form. Information such as the first author, publication
year, country, study design, sample size, age, cancer type, regiment
of chemotherapy, intervention, adverse events and outcomes were
collected. If the study designed as multiple crossover trial, first
cycle would be preferred.
2.6. Method of synthesis
Trial sequential analysis was applied to examine the sufficiency
and currently available evidence. If cumulative Z-curve steps
across the monitoring boundaries, a sufficient level of evidence for
the intervention effect may have been reached and no further
studies were needed. To perform trial sequential analysis, both
type I and II error were needed. In this review, the required
information size was estimated using a = 0.05 (two sided), b = 0.20
(power 80%). These trial sequential analyses were performed using
software TSA 0.9 (available from the website for free: http://www.
ctu.dk/tsa).
2.7. Sensitivity and subgroup analysis
Sensitivity analysis was conducted by eliminating every single
trial to confirm thestability of this systematic review once at a
time. For different acupressure protocols and sham versus non-
sham controlgroups, subgroup analysis was performed.

Meta-analyses were performed using software RevMan 5.3 3. Results

(available from the website for free: http://ims.cochrane.org/
revman). Relative risks (RRs) were calculated for dichotomous
data. Mean differences (MDs) were calculated for continuous data,
while standardized mean differences (SMDs) were calculated for
continuous outcomes from different measurement scales. I-square
(I2) test was used to measure statistical heterogeneity. Studies with
an I2 < 50% were considered to have low heterogeneity, a fixed
effect model was used. Otherwise, the random effect model was
applied. Results of meta-analysis were showed with corresponding
95%CI and p value. P  0.05 was considered statistically difference.
3.1. Search process
The results of the search process and the selection are presented
in Fig 1. The literature search of both databases and manual
resulted in 1326 relevant articles. Thirty-eight articles were
retained after removing duplicates and screening titles and
abstracts. Finally, 12 articles (Dibble et al., 2000; Kaur et al.,
2015; Molassiotis et al., 2007; Molassiotis et al., 2013; Noga et al.,
2002; Roscoe et al., 2005; Roscoe et al., 2002; Roscoe et al., 2003;
30 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
Fig. 1. Flow chart of selection process.
Suh, 2012; Treish et al., 2003; Min and Zhang, 2015; Wu and Wu,
2012) involving 1419 patients were eligible after full-text reading
3.2. Characteristics of included RCTs
The main characteristics details of included RCTs were given in
Table 2. Twelve articles of 1419 patients were included, ten were
written in English and the other two were written in Chinese.
Population sizes of the trials ranged from 17 to 500. Most of the
population was patients with breast cancer, gastrointestinal tumor,
hematologic neoplasm or lung cancer. One of the studies (Roscoe
et al., 2002) was designed as crossover study, others were designed
as parallel randomized control trials. Two articles did not report
chemotherapy regiment (Kaur et al., 2015; Wu and Wu, 2012),
other chemotherapy regimens with moderate to high emetogenic
risk of intravenous chemotherapeutic agents were contained. Only
one study used Neiguan (P6) and Zusanli (ST36) as main
acupressure points (Dibble et al., 2000), the rest of the studies
only using Neiguan (P6) as the acupressure points. Patients in the
intervention groups received acupressure with fingers or wrist
bands. All the patients received antiemetics as the conventional
treatment. Patients with wrist band acupressure were told to keep
wearing them for three to seven days, while the way of acupressure
with finger was varied (Dibble et al., 2000; Kaur et al., 2015; Min
and Zhang, 2015; Wu and Wu, 2012).
3.3. Quality critical appraisal
Of all the included studies, only two studies failed to report
details about random sequence generation (Roscoe et al., 2005; Wu
and Wu, 2012), three trials did not report the use of allocation
concealment (Min and Zhang, 2015; Roscoe et al., 2005; Wu and
Wu, 2012), and two trials have high risk of bias in allocation
concealment for the reason of using master list held in house-PC
(Noga et al., 2002; Treish et al., 2003,). Sham control was used in six
out of 12 trials (Noga et al., 2002; Roscoe et al., 2002; Treish et al.,
2003; Roscoe et al., 2005; Suh, 2012; Molassiotis et al., 2013). The
outcomes assessor was reported to be blinded in 7 trials
(Molassiotis et al., 2013; Molassiotis et al., 2007; Roscoe et al.,
2002; Roscoe et al., 2003; Roscoe et al., 2005; Suh, 2012; Treish
et al., 2003). One trial reported dropouts with the reason of
incomplete data (Roscoe et al., 2005), this led to the unclear risk of
incomplete outcome data bias. Most of the twelve trials had
reported that baseline characteristics were comparable between
Table 2
Main characteristics of included RCTs.

Author Country Study Sample Age Cancer type Chemotherapy Chemotherapy Acupressure Treatment Intervention (I) Control (C) Outcome Measurement Adverse Result of
design size x ðSDÞ regiment rating point report quality
(I/C) appraisal

Dibble et al. US parallel 8/9 49.5(6.0) breast CMFa or moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute Index of No adverse High risk
(2000) design doxorubicin high + Zusanli finger for maximum nausea nausea and effects of bias
contained emetogenicity (ST36) of three minutes. delayed vomiting and
Each point was held nausea retching
in the morning and (INVR)
as needed throught
the day.
Noga et al. US parallel 60/60 Couldn’t get hematologic cyclophosphamide high Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute Index of Some High risk
(2002) design emetogenicity band worn for 24 h (sham) + vomiting nausea and discomfort of bias
postchemotherapy antiemetic acute vomiting and noted with
nausea retching elastic
delayed (INVR) bands
vomiting
delayed

J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37

nausea
Roscoe et al. US crossover 14/28 49.7(9.27) breast, lung, doxorubicin, moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute 7-point rating Not Low risk
(2002) design ovarian, carboplatin, high band worn prior to (sham) + nausea scale reported of bias
colorectal cisplatin, emetogenicity chemotherapy and antiemetic delayed
fluorouracil for as long as helpful nausea
Roscoe et al. US parallel 251/ Not breast, doxorubicin or high Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute 7-point rating Three High risk
(2003) design 249 reported hematologic cisplatin based emetogenicity band worn for five vomiting scale reports of of bias
days acute skin
nausea irritation
delayed
vomiting
delayed
nausea
Treish et al. US Parallel 26/23 45.5 mixed cisplatin, high Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute Visual No adverse High risk
(2003) design cyclophosphamide, emetogenicity band worn for five (sham) + vomiting Analogue effects of bias
others days antiemetic acute Scale (VAS)
nausea
delayed
vomiting
delayed
nausea
Roscoe et al. US Parallel 32/31 49.5 breast doxorubicin, high Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute 7-point rating Not Unclear
(2005) design cancer cyclophosphamide emetogenicity band worn for five (sham) + nausea scale reported risk of
days antiemetic delayed bias
nausea
Molassiotis UK Parallel 17/19 49.5(10.5) breast FECb, CMFa moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute Index of No adverse High risk
et al. design cancer high band worn for five vomiting nausea and effects of bias
(2007) emetogenicity days acute vomiting and
nausea retching
delayed (INVR)
vomiting
delayed
nausea
Suh (2012) Korea Parallel 25/23 45.35(8.66) breast FACc, ACTd moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute Index of Not Low risk
design cancer high band worn for five (sham) + nausea nausea and reported of bias
emetogenicity days antiemetic and vomiting and
vomiting retching
delayed (INVR)
nausea
and
vomiting
Wu and Wu China Parallel 45/45 48.8(13.17) mixed not reported not reported Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute Visual Not High risk
(2012) design finger for 10 min, nausea Analogue reported of bias
30 min before acute Scale (VAS)
chemotherapy and vomiting
repeated in every 4 h

31
 32
Table 2 (Continued)
Author Country Study Sample Age Cancer type Chemotherapy Chemotherapy Acupressure Treatment Intervention (I) Control (C) Outcome Measurement Adverse Result of
design size x ðSDÞ regiment rating point report quality
(I/C) appraisal

Molassiotis US Parallel 168/166 I:  50y,54 mixed not reported moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic acupressure acute Index of Some Low risk
et al. design (number), high band worn for seven (sham) + vomiting nausea and patients of bias
(2013) >50y,114 emetogenicity days antiemetic acute vomiting and reported
(number)/ nausea retching painful,
C:  50y,55 delayed (INVR) irritation
(number), vomiting and
>50y,111 delayed discomfort
(number) nausea
Kaur et al. India Parallel 20/20 Not not not reported not reported Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute Multinational Not High risk
(2015) design reported reported finger for 5 min vomiting Association of reported of bias
before each meal acute Supportive
(total 4times in a nausea Care in Cancer
day) and anytime delayed Antiemesis
sensation of nausea vomiting Tool (MAT)
is felt delayed

J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37

nausea
Min and China Parallel 40/40 63.35(15.18) lung gemcitabine, moderate/ Neiguan (P6) Acupressure with acupressure + antiemetic antiemetic acute Assessment Not High risk
Zhang design cisplatin high finger for 10 min vomiting criteria made reported of bias
(2015) emetogenicity before delayed in ESMO
chemotherapy, and vomiting (1989)
worn bands for
three days

a:cyclophosphamide + methotrexate + fluorouracil b: cyclophosphamide + epirubicin + fluorouracil c: fluorouracil + adriamycin + cyclophosphamid d: adriamycin + cyclophosphamide + paclitaxel.
I2 < 50%, a fixed effect model was applied. Results of pooled trails
(n = 76) reported the frequency of the acute vomiting. Given
(n = 1406) evaluated the incidence of acute vomiting and two trials
trials (n = 941) evaluated the severity of acute nausea, seven trials
3.4.1.1. Chemotherapy-induced acute nausea and vomiting. Seven

3.4.1. Outcome from meta-analysis

3.4. Outcome pooled analysis

Fig. 2
‘unclear risk of bias’. Details of the risk of bias were summarized in
‘high risk of bias’. One trial (Roscoe et al., 2005) was evaluated as at
2015; Wu and Wu, 2012; Kaur et al., 2015) were evaluated as at
2003; Roscoe et al., 2003; Molassiotis et al., 2007; Min and Zhang,
of bias’, eight (Dibble et al., 2000; Noga et al., 2002; Treish et al.,
2013; Roscoe et al., 2002; Suh, 2012) were evaluated as at ‘low risk
were stopped in advance. Above all, three trials (Molassiotis et al.,
the groups except one trial (Kaur et al., 2015), and none of them

Fig. 2. Risk of bias summary of the included studies.

 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
Fig. 3. Effect of acupressure on chemotherapy-induced acute nausea and vomiting.
showed that acupressure decreased the severity of acute nausea
(SMD = -0.18, 95% CI
0.31 to
0.05, p < 0.01). There was no
evidence of benefit for acupressure on the incidence of acute
vomiting (RR = 0.84, 95% CI 0.69–1.02, p = 0.08) and frequency of
acute vomiting (MD = -0.15, 95% CI
0.42 to 0.12, p = 0.29) (Fig. 3).
However, findings differed for sham-controlled trials(MD =

0.28, 95% CI
0.90 to 0.34, p = 0.38) versus nonsham trials
(MD =
0.19, 95% CI
0.34 to
0.05, p = 0.008) for acute nausea and
sham-controlled trials (RR = 1.00, 95% CI 0.58–1.70, p = 0.99) versus
nonsham trials (RR = 0.77, 95% CI 0.62–0.95, p = 0.02) for the
incidence of acute vomiting. According to the trial conducted by
Suh, acupressure with bands (Suh, 2012) showed benefit for the
remission of acute nausea and vomiting symptom compared with
the sham group (MD =
4.80, 95% CI
9.05 to
0.55, p = 0.03).
Subgroup analysis based on the acupressure protocols showed
different outcomes. Acupressure with bands showed protective
effect for acute severity of nausea (SMD = -0.17, 95% CI
0.31 to

0.03, p = 0.02), while manual acupressure could decrease the
incidence of acute vomiting (RR = 0.48, 95% CI 0.28–0.83,
p = 0.009).
3.4.1.2. Chemotherapy-induced delayed nausea and vomiting. Two
of included trials (n = 408) evaluated the effects of acupressure on
the incidence of delayed vomiting (I2 = 0%, fixed effect model
chose), seven trials (n = 962) assessed its effect on delayed nausea
severity (I2 = 61%, random effect model chose) and four articles
(n = 802) identified the effects on the frequency of chemotherapy-
induced delayed vomiting (I2 = 18%, fixed effect model chose).
33
The results of pooled trails showed that acupressure combined
with antiemetic agents decreased the mean nausea severity
(SMD =
0.33, 95% CI
0.64 to
0.01, p = 0.04). However, there
were no benefit effect on the incidence (RR = 0.72, 95% CI 0.46–1.11,
p = 0.14) and mean number of delayed vomiting (MD =
0.12, 95%
CI
0.26 to 0.02, p = 0.11) (Fig. 4).
For sham-controlled trials versus nonsham trials, findings were
dissimilar for the incidence of delayed vomiting (sham-controlled
RR = 1.32, 95% CI 0.52–3.33, p = 0.56, nonsham trials RR = 0.63, 95%
CI 0.4–0.98, p = 0.04) and mean severity of delayed nausea(sham-
controlled MD =
0.13, 95% CI
1.34 to 1.59, p = 0.87, nonsham
trials MD =
0.57, 95% CI
1.10 to
0.04, p = 0.04). Compared with
sham controlled group, acupressure showed a protective effect on
chemotherapy-induced delayed nausea and vomiting according to
the study of Suh et al (MD =
5.59, 95% CI
9.45 to
1.73, p = 0.005)
(Suh, 2012).
Subgroup analysis based on the acupressure protocols showed
different outcomes. Acupressure with bands showed no protective
effect on delayed symptoms, while manual acupressure could
decrease the severity of delayed nausea (SMD =
0.98, 95% CI
1.53
to
0.42, p < 0.001).
3.4.1.3. Chemotherapy-induced anticipatory nausea and
vomiting. No data obtained from including RCTs.
3.4.2. Outcome from trial sequential analysis (Fig. 5)
As standardized mean difference was used, we failed to perform
trial sequential analysis to evaluate the effect on the severity of
34 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37

Fig. 4. Effect of acupressure on chemotherapy-induced delayed nausea and vomiting.

Fig. 5. Outcomes of Trial Sequential Analysis.

nausea. According to the theory of trial sequential analysis, the
cumulative Z-curve didn’t cross either the conventional or trial
sequential monitoring boundary, which indicated that the
evidence on the effect of the incidence of acute vomiting and
frequency of acute and delayed vomiting was insufficient. We
failed to evaluate the effect on the incidence of delayed vomiting
due to insufficient data ().
3.4.3. Sensitivity analysis
Sensitivity analysis was performed to evaluate the effect of an
individual study on the pooled estimates. Results of the effect on
the severity of delayed nausea, incidence of acute vomiting and
mean number of delayed vomiting were changed when studies
were eliminated. Excluded the study carried by Rescoe (Roscoe
et al., 2003), results of the effect on the incidence of acute vomiting
(RR = 0.74, 95% CI 0.57–0.98) and mean number of delayed
vomiting (MD =
0.28, 95% CI
0.53 to
0.04) showed a trend
towards significance favoring the treatment. As p value of 0.04 is
critical, after exclusion of four studies (Dibble et al., 2000; Treish
et al., 2003; Kaur et al., 2015; Molassiotis et al., 2007), the effect on
the severity of delayed nausea was changed, which means the
conclusion is unreliable. Further studies are needed.
 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
4. Discussion
4.1. Main findings
Our meta-analysis systematically reviewed currently available
literature, including 12 studies with 1419 patients. The pooled
results of the involved RCTs showed acupressure plus antiemetics
significantly reduced the severity of chemotherapy-induced acute
and delayed nausea. However, we could not make definitive
conclusions with current evidences according to the trial sequen-
tial analysis. We failed to evaluate the effect on anticipatory nausea
and vomiting due to insufficient research data. Furthermore,
different evaluation tools were used among the included RCTs,
resulting in that part of data may not be pooled. This may
downgrade the evidence level of outcomes.
P6 (Neiguan) was the most frequently used acupoint in our
study. Some other acupoints, such as Hegu and Zhongwan, may
have the same effect for controlling nausea and vomiting. The best
single and matching acupoints remains unknown at present. This
calls for future studies.
In our subgroup analyses of the severity of acute and delayed
nausea, nonsham controlled trials tended towards significance
while the sham controlled trials did not, suggesting potential
placebo effects in the sham controlled trials. The intervention was
deemed to be effective by outperforming a placebo. So, sham-
controlled trials were recommended to rule out the possibility that
the result was a function of bias from non-blind studies (Miller and
Miller, 2015). Inactive bands, sham point or location were used in
the sham control groups. Some acupuncturists considered
superficial stimulation was similarly effective (Yamashita and
Tsukayama, 2001). So, it is difficult to judge whether the
intervention used in the sham control has no effect on remission
of the symptoms. Reviews about sham methods used in acupunc-
ture clinical trials found that it was hard to determine whether
sham interventions could be considered as a true “placebo”
intervention (Dincer and Linde, 2003; Zhang et al., 2014), and
researchers recommended “not theoretically effective” and “non-
acupoints” as the most likely sham methods (Zhang et al., 2014).
Different acupressure protocols showed different outcomes. In
the subgroup analysis, we found acupressure with bands
decreased the severity of acute nausea, while manual acupressure
showed a protective effect on the incidence of acute vomiting and
delayed nausea symptoms. This indicated that combining different
protocols may have better results.
Depending on sensitivity analysis, results changed when four
articles (Dibble et al., 2000; Treish et al., 2003; Kaur et al., 2015;
Molassiotis et al., 2007) were excluded. The reasons were
considered as low quality in methodology, small sample size
and different acupressure protocols.
As symptoms caused by chemotherapy may create negative
impact on patients’ quality of life and other psychosocial problems,
some studies we included evaluated these as the secondary
outcomes (Treish et al., 2003; Roscoe et al., 2003; Roscoe et al.,
2005; Molassiotis et al., 2013). However, we failed to carry analysis
for data lacking. Details about the quality of life and the
psychosocial information should be provided in the further
studies.
4.2. Comparison with published meta-analysis
Several previous systematic reviews have been posted to
explore the effect of acupressure on chemotherapy-induced
nausea and vomiting. Lee reviewed the efficacy of acupressure
for symptom management, and regarded acupressure as an
effective way especially for patients with nausea and vomiting
caused by pregnancy and chemotherapy (Lee and Frazier, 2011).
35
Song assessed the efficacy and safety of self-acupressure for
symptom management, patients diagnosed with cancer in the self-
acupressure group showed a significant improvement in symptom
scores (Song et al., 2015). Specifically, a systematic review and
meta-analysis evaluated acupuncture-point stimulation by pool-
ing results of 11 RCTs from Cochrane Library showed that
acupressure had a different effect profile compared to other
acupuncture-point stimulation methods. The results got conclu-
sion that acupressure was helpful for the reduction of acute nausea
severity, but not for acute vomiting or delayed symptoms (Ezzo
et al., 2006). This review has been withdrawn for the reason of
being unable to update in 2014 (Ezzo et al., 2014).
Mata-analysis is now deemed as a well established principal
tool for the synthesis of evidence in clinical research. It is
commonly regarded as desirable that meta-analysis should be
routinely updated when a new trial results are published
(Kulinskaya and Wood, 2014). Traditional meta-analysis, under
the condition of insufficient sample size, constantly updated and
repeated significance testing will lead to a high risk of false positive
results, and exaggeration of effect will be evaluated due to small
sample size (Wang et al., 2013). So, there is a high risk that
traditional meta-analysis reports inaccurate effect (Kulinskaya and
Wood, 2014; Thorlund et al., 2009).
Our study focused on a non-invasive acupuncture-point
stimulation, acupressure. We found that our conclusions may be
different from the meta-analysis published before. More RCTs and
patients were included in this meta-analysis. We further applied
trial sequential analysis to provide a more conservative estimate.
Conclusions from this study indicated that acupressure can be
recommended as a useful non-pharmaceutical adjuvant therapy to
patients undergoing chemotherapy, especially for patients
experiencing nausea. Appropriate blinding should be applied in
further studies to rule out the possibility of placebo effect. Also,
RCTs with larger sample size and unified symptom assessment
scales are required to verify the effect on severity, frequency,
duration of nausea and vomiting.
4.3. Mechanism of acupressure
Neiguan (P6) and Zusanli (ST36) are the most commonly
recommended acupressure point to relieve upset of gastrointesti-
nal. Neiguan (P6) is located on the pericardium meridian
bilaterally, anterior surface of the forearm, approximately three
finger widths up from the first palm stripe (Hyde, 1989). Zusanli
(ST36) point is located bilaterally on the stomach meridian,
approximately four finger widths below the knee and one finger
width lateral to the tibia (Dibble et al., 2000).
Mechanism underlying the effect of acupuncture-point stimu-
lation on chemotherapy-induced nausea and vomiting is not clear.
Traditional Chinese Medicine and Western Medicine are different
in disease curing. Western Medicine theory is based on physiolog-
ical structures or anatomy, and the therapy goal is mainly on the
elimination or removal of the pathogen. However, the holistic
nature of the body is emphasized in Traditional Chinese Medicine,
and diseases result from an imbalance in the flow of energy or Qi
through the body, leading to internal organs dysfunction gradually.
Therapy goals of Traditional Chinese Medicine are the harmoniza-
tion of internal function and external natural environmental
changes (Liu et al., 2015a,b). Chemotherapy agents are considered
to have the high risk of disturbing gastrointestinal functions,
meanwhile ‘dysfunction of spleen in transportation’ and ‘stomach
disharmony’ are the principal pathogeneses caused by chemother-
apy (Tan et al., 2014). The energy or Qi will be restored by the use of
acupressure. On the other hand, studies reported that 5-
hydroxytriptamine-3 concentration decreased in plasma and
colonic tissue after acupoint (Neiguan, Zusanli) stimulation (Liu
36 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
et al., 2015a,b; Shi et al., 2015), which may possibly lead to
remission of nausea and vomiting.
4.4. Limitations
The quality of the evidence in this systematic review was
identified as low because only three studies evaluated as at low
risk of bias, meaning that further research might have an important
influence on our confidence of the overall effect estimate. We
downgraded the evidence for some articles failed to blind
participants and random allocation concealment. In addition, we
aimed to reduce heterogeneity through subgroup analysis based
on acupressure protocols and sham-controlled intervention, while
there were still some other confounding factors existing as
heterogeneity was present in most subgroups.
Only articles published in English or Chinese were selected due
to language constrains. Studies were not indexed which were
published in Japanese, Korean, German, Italian and so on. This may
cause a potential risk of publication bias.
5. Conclusions
Acupressure can be recommended as a non-pharmacological
method applied to patients undergoing chemotherapy, especially
for nausea controlled. Further well designed studies with larger
sample size and lower risk of bias on all domains especially
blinding and allocation concealment are still needed to determine
clinical relevance. With the increasing number of patients
experiencing anticipatory nausea and vomiting, following
researches could be carried.
Conflict of interest
No conflict of interest has been declared by the authors.
Funding
This work was supported by “Practice Innovative Project of
Universities in Jiangsu Province, 2015 (Grant Number:
SJLX15_0424).”
Ethical approval
None.
References
Brok, J., Thorlund, K., Wetterslev, J., Gluud, C., 2009. Apparently conclusive meta-
analyses may be inconclusive–trial sequential analysis adjustment of random
error risk due to repetitive testing of accumulating data in apparently
conclusive neonatal meta-analyses. Int. J. Epidemiol. 38 (1), 287–298.
Complementary, P.D.Q.C., Alternative Medicine Editorial, B., 2002. Acupuncture
(PDQ(R)): health professional version. PDQ Cancer Information Summaries.
National Cancer Institute (US), Bethesda (MD).
Dibble, S.L., Chapman, J., Mack, K.A., Shih, A.S., 2000. Acupressure for nausea: results
of a pilot study. Oncol. Nurs. Forum 27 (1), 41–47.
Dincer, F., Linde, K., 2003. Sham interventions in randomized clinical trials of
acupuncture–a review. Complement. Ther. Med. 11 (4), 235–242.
Einhorn, L.H., Rapoport, B., Navari, R.M., Herrstedt, J., Brames, M.J., 2017. 2016
updated MASCC/ESMO consensus recommendations: prevention of nausea and
vomiting following multiple-day chemotherapy, high-dose chemotherapy, and
breakthrough nausea and vomiting. Support. Care Cancer 25 (1), 303–308.
Ezzo, J., Streitberger, K., Schneider, A., 2006. Cochrane systematic reviews examine
P6 acupuncture-point stimulation for nausea and vomiting. J. Altern.
Complement. Med. 12 (5), 489–495.
Ezzo, J., Richardson, M.A., Vickers, A., Allen, C., Dibble, S., Issell, B.F., Lao, L., Pearl, M.,
Ramirez, G., Roscoe, J.A., Shen, J., Shivnan, J.C., Streitberger, K., Treish, I., Zhang,
G., Manheimer, E., 2014. WITHDRAWN: Acupuncture-point stimulation for
chemotherapy-induced nausea or vomiting. Cochrane Database Syst. Rev. 11,
CD002285.
Genc, A., Can, G., Aydiner, A., 2013. The efficiency of the acupressure in prevention of
the chemotherapy-induced nausea and vomiting. Support. Care Cancer 21 (1),
253–261.
Higgins, J.P., Altman, D.G., Gotzsche, P.C., Juni, P., Moher, D., Oxman, A.D., Savovic, J.,
Schulz, K.F., Weeks, L., Sterne, J.A., 2011. The Cochrane Collaboration’s tool for
assessing risk of bias in randomised trials. BMJ 343, d5928.
Hyde, E., 1989. Acupressure therapy for morning sickness. A controlled clinical trial.
J. Nurse. Midwifery 34 (4), 171–178.
Jordan, K., Gralla, R., Jahn, F., Molassiotis, A., 2014. International antiemetic
guidelines on chemotherapy induced nausea and vomiting (CINV): content and
implementation in daily routine practice. Eur. J. Pharmacol. 722, 197–202.
Jordan, K., Jahn, F., Aapro, M., 2015. Recent developments in the prevention of
chemotherapy-induced nausea and vomiting (CINV): a comprehensive review.
Ann. Oncol. 26 (6), 1081–1090.
Kaur, R., Madaan, D., Kaur, R., 2015. An experimental study to assess effectiveness of
acupressure on relief of chemotherapy induced nausea and vomiting among
cancer patients in selected hospital, Punjab. International. J. Pharm. Sci. Rev. Res.
34 (1), 243–246.
Kulinskaya, E., Wood, J., 2014. Trial sequential methods for meta-analysis. Res.
Synth. Methods 5 (3), 212–220.
Lee, E.J., Frazier, S.K., 2011. The efficacy of acupressure for symptom management: a
systematic review. J. Pain Symptom Manage. 42 (4), 589–603.
Liu, Y., Wang, M., Li, Q., Wang, L., Li, J., 2015a. Impacts of transcutaneous acupoint
electric stimulation on the postoperative nausea and vomiting and plasma 5-HT
concentration after cesarean section. Zhongguo Zhen Jiu 35 (10), 1039–1043.
Liu, Z.B., Yang, J.P., Xu, L.R., 2015b. Effectiveness and safety of traditional Chinese
medicine in treating acquired immune deficiency syndrome: 2004–2014. Infect
Dis. Poverty 4, 59.
Miller, M., Kearney, N., 2004. Chemotherapy-related nausea and vomiting - past
reflections, present practice and future management. Eur. J. Cancer Care (Engl.)
13 (1), 71–81.
Miller, L.R., Miller, F.G., 2015. Understanding placebo effects: implications for
nursing practice. Nurs. Outlook 63 (5), 601–606.
Min, Y.Y., Zhang, Y.L., 2015. Clinical observation of acupressure on 40 cases of lung
cancer patients with chemotherapy-induced nausea and vomiting. J. QILU Nur.
21 (9), 123–124.
Molassiotis, A., Helin, A.M., Dabbour, R., Hummerston, S., 2007. The effects of P6
acupressure in the prophylaxis of chemotherapy-related nausea and vomiting
in breast cancer patients. Complement. Ther. Med. 15 (1), 3–12.
Molassiotis, A., Russell, W., Hughes, J., Breckons, M., Lloyd-Williams, M., Richardson,
J., Hulme, C., Brearley, S., Campbell, M., Garrow, A., Ryder, W.D., 2013. The
effectiveness and cost-effectiveness of acupressure for the control and
management of chemotherapy-related acute and delayed nausea: Assessment
of Nausea in Chemotherapy Research (ANCHoR), a randomised controlled trial.
Health Technol. Assess. 17 (26), 1–114.
NIH Consens Statement, 1997. Acupuncture. NIH Consens Statement, , pp. 1–34 15
(5).
Noga, S., Tolman, A., Roman, J., 2002. Acupressure as an adjunct to pharmacologic
control of nausea, vomiting and retching (N/V) during blood and marrow
transplantation (BMT): a randomized, placebo-controlled, algorithm based
study. Proceedings of the American Society of Clinical Oncology 361a.
Roscoe, J.A., Morrow, G.R., Bushunow, P., Tian, L.L., Matteson, S., 2002. Acustimu-
lation wristbands for the relief of chemotherapy-induced nausea. Altern. Ther.
Health Med. 8 (4), 56-+.
Roscoe, J.A., Morrow, G.R., Hickok, J.T., Bushunow, P., Pierce, H.I., Flynn, P.J., Kirshner,
J.J., Moore Jr, D.F., Atkins, J.N., 2003. The efficacy of acupressure and
acustimulation wrist bands for the relief of chemotherapy-induced nausea
and vomiting: a University of Rochester Cancer Center Community Clinical
Oncology Program Multicenter study. J. Pain Symptom Manage. 26 (2), 731–742.
Roscoe, J.A., Matteson, S.E., Morrow, G.R., Hickok, J.T., Bushunow, P., Griggs, J., Qazi,
R., Smith, B., Kramer, Z., Smith, J., 2005. Acustimulation wrist bands are not
effective for the control of chemotherapy-induced nausea in women with breast
cancer. J. Pain Sympt. Manage. 29 (4), 376–384 (379p.).
Shi, Y., Chen, Y.H., Yin, X.J., Wang, A.Q., Chen, X.K., Lu, J.H., Ji, R., Bao, C.H., Sun, J., Zhao,
J.M., Wu, H.G., 2015. Electroacupuncture versus moxibustion for irritable bowel
syndrome: a randomized, parallel-controlled trial. Evid. Based Compl. Alter.
Med. 2015, 361786.
Song, H.J., Seo, H.-J., Lee, H., Son, H., Choi, S.M., Lee, S., 2015. Effect of self-
acupressure for symptom management: a systematic review. Complement.
Ther. Med. 23 (1), 68–78.
Suh, E.E., 2012. The effects of P6 acupressure and nurse-provided counseling on
chemotherapy-induced nausea and vomiting in patients with Breast cancer.
Oncol. Nurs. Forum 39 (1), E1–E9 (1p.).
Tan, J.Y., Molassiotis, A., Wang, T., Suen, L.K., 2014. Current evidence on auricular
therapy for chemotherapy-induced nausea and vomiting in cancer patients: a
systematic review of randomized controlled trials. Evid. Based Compl. Altern.
Med. 2014, 430796.
Taspinar, A., Sirin, A., 2010. Effect of acupressure on chemotherapy-induced nausea
and vomiting in gynecologic cancer patients in Turkey. Eur. J. Oncol. Nurs. 14 (1),
49–54.
Thorlund, K., Devereaux, P.J., Wetterslev, J., Guyatt, G., Ioannidis, J.P., Thabane, L.,
Gluud, L.L., Als-Nielsen, B., Gluud, C., 2009. Can trial sequential monitoring
boundaries reduce spurious inferences from meta-analyses? Int. J. Epidemiol.
38 (1), 276–286.
Tipton, J.M., McDaniel, R.W., Barbour, L., Johnston, M.P., Kayne, M., LeRoy, P., Ripple,
M.L., 2007. Putting evidence into practice: evidence-based interventions to
 J. Miao et al. / International Journal of Nursing Studies 70 (2017) 27–37
prevent, manage, and treat chemotherapy-induced nausea and vomiting. Clin. J.
Oncol. Nurs. 11 (1), 69–78.
Treish, I., Shord, S., Valgus, J., Harvey, D., Nagy, J., Stegal, J., Lindley, C., 2003.
Randomized double-blind study of the Reliefband as an adjunct to standard
antiemetics in patients receiving moderately-high to highly emetogenic
chemotherapy. Support. Care Cancer 11 (8), 516–521.
Wang, Q., Tian, J.H., Li, L., He, X.R., Shi, C.H., Yang, K.H., 2013. Brief introduction of
trial sequential analysis. Chin. J. Evid.-Based Med. 13 (10), 1265–1268.
Wetterslev, J., Thorlund, K., Brok, J., Gluud, C., 2008. Trial sequential analysis may
establish when firm evidence is reached in cumulative meta-analysis. J. Clin.
Epidemiol. 61 (1), 64–75.
37
Wu, J.X., Wu, L.H., 2012. Clinical observation of using acupressure combined with
ondansetron on patients undergoing chemotherapy. Strait Pharm. J. 24 (1), 103–
104.
Yamashita, H., Tsukayama, H., 2001. Minimal acupuncture may not always minimize
specific effects of needling. Clin. J. Pain 17 (3), 277.
Zhang, C.S., Yang, A.W., Zhang, A.L., May, B.H., Xue, C.C., 2014. Sham control methods
used in ear-acupuncture/ear-acupressure randomized controlled trials: a
systematic review. J. Altern. Complement. Med. 20 (3), 147–161.