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Gabapentin prophylaxis for postoperative nausea
and vomiting in abdominal surgeries: a quantitative analysis
of evidence from randomized controlled clinical trials
S. Achuthan1, I. Singh1*, S. B. Varthya1, A. Srinivasan1, A. Chakrabarti1 and D. Hota2
1
Department of Pharmacology, Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER),
Chandigarh 160012, India
2
Department of Pharmacology, AIIMS, Bhubaneshwar, India
* Corresponding author. E-mail: inderhazari@gmail.com
Editor’s key points
† The authors examined the
evidence base for the
effectiveness of
gabapentin in preventing
postoperative nausea and
vomiting (PONV).
† They found support for the
use of preoperative
gabapentin in PONV
prophylaxis, especially in
abdominal surgery.
† Interestingly, the benefits
of gabapentin appeared
reduced in the presence
of the use of propofol.
Introduction. Postoperative nausea and vomiting (PONV) is frequently encountered in the
surgical recovery room. Abdominal surgery is one important risk factor for increased
incidence of PONV. Gabapentin, an anticonvulsant with known postoperative analgesic
properties, has shown some activity against PONV. Results from clinical trials evaluating the
anti-emetic efficacy of gabapentin are conflicting. The present meta-analysis was
performed to examine this issue.
Methods. Seventeen randomized placebo-controlled trials reporting PONV with preoperative
gabapentin administration in patients undergoing abdominal surgery were included for
analysis. Outcomes evaluated were nausea, vomiting, composite PONV and the use of
rescue anti-emetic medication in the postoperative period.
Results. The pooled relative risk (RR), estimated using the random effects model of the
metafor package for R, was 0.76 (95% CI 0.58–0.98) for nausea, 0.62 (0.45–0.85) for
vomiting, 0.71 (0.39–1.28) for data represented as composite PONV (possibly biased by a
single study, as observed in the sensitivity analysis), and 0.6 (0.41–0.89) for rescue anti-
emetic use. There was a significant RR reduction for nausea and vomiting when propofol
was not used as induction and/or maintenance for anaesthesia. In the abdominal
hysterectomy subgroup, there was a significant RR reduction for vomiting but not for nausea.
Discussion. The present analysis provides evidence supporting preoperative gabapentin as a
pharmacotherapy for prevention of PONV in patients undergoing abdominal surgeries.
Future studies comparing preoperative gabapentin with 5HT3 antagonists are needed to
precisely define its role in PONV.
Keywords: gabapentin; hysterectomy; postoperative nausea and vomiting
Accepted for publication: 19 September 2014
Postoperative nausea and vomiting (PONV) in the surgical re-
covery room is a common occurrence. Despite being self-
limiting, it is associated with substantial distress to patients
in the early postoperative period. Its prevention and/or treat-
ment significantly improves patient satisfaction and quality
of life.1 – 3
PONV prevention can lead to a substantial reduction
in health care costs by reducing the duration of the post-
anaesthesia care unit (PACU) stay.4 5
It is estimated that
each episode of emesis delays discharge from the PACU by
approximately 20 min.6
Furthermore, serious complications,
including retinal detachment, aspiration, wound dehiscence,
oesophageal rupture, and subcutaneous emphysema, related
to PONV can be prevented. The general incidence of PONV
ranges from 25% to 30%,7
and in some subsets of high-risk
patients it can be as high as 80%,8
even after preventive
pharmacotherapy. The pharmacotherapies used in the preven-
tion/management of PONV include 5-HT3, dopaminergic, hista-
minic, and NK1 antagonists. Nevertheless, the need forcheaper
and more effective therapies cannot be disputed.
Gabapentin, an anticonvulsant, has been shown to be ef-
fective as a non-opioid ancillary agent for postoperative pain
management.9
The safety profile, minimal drug interactions,
pharmacokinetics (good oral bioavailability and renal elimin-
ation), and relatively flat dose–response relationship with
respect to safety and efficacy favour its clinical use.10 11
Inter-
estingly, in the recent past, gabapentin’s anti-nausea effects
were noted when there was a marked improvement in the
chemotherapy-induced nausea in breast cancer patients12
and subsequently was observed to possess activity against
PONV. The exact mechanism for gabapentin’s efficacy in
& The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
British Journal of Anaesthesia 114 (4): 588–97 (2015)
Advance Access publication 8 January 2015 . doi:10.1093/bja/aeu449
01
07/04/2015
Mdl. User
PONV is not known. While results of a few studies evaluating
the efficacy of preoperative gabapentin as a prophylaxis were
promising, the results of others did not reach statistical signifi-
cance and have been equivocal. Hence the present analysis
was performed to define the role of gabapentin as a preventive
therapy for PONV.
Methods
Randomized placebo-controlled clinical trials comparing pre-
operative gabapentin administration were identified for evalu-
ation for inclusion in the analyses. The criteria for inclusion
were (i) patients undergoing abdominal surgery (open or lap-
aroscopic) under general anaesthesia, (ii) preoperative admin-
istration of gabapentin irrespective of dose and timing of the
dose with respect to surgery, and (iii) trials reporting nausea,
vomiting, postoperative nausea and vomiting, or a proportion
of patients requiring rescue anti-emetic medication irrespect-
ive of the objective of evaluation were included in the final
analysis.Trialsevaluatingpostoperativedosingaloneorinadd-
ition to preoperative gabapentin were excluded from the final
analysis. A literature search using the terms ‘gabapentin’,
‘postoperative nausea and vomiting’, ‘abdominal surgery’,
and ‘postoperative pain’ was performed in Medline, Embase
and the Cochrane library. Additional studies were identified
through cross-references and meta-analyses conducted for
evaluation of gabapentin in postoperative pain. All human
studies published in full-text or abstract forms were initially
screened for inclusion without applying any language restric-
tions. Titles and abstracts from the electronic search were
reviewed. After initial review of the abstracts, the relevant
studies were identified and a detailed evaluation of the full
text was done. All data with regard to authorship, year of pub-
lication, study design, study population (i.e. type of abdominal
surgery), baseline patient characteristics, gabapentin dose,
type of surgery, type and duration of anaesthesia (when data
were not available, the duration of surgery was taken as the
duration of anaesthesia), number of patients, and relevant
outcomes were extracted from theselectedstudies. The meth-
odological quality of the included studies was assessed using
the Downs and Black score.13
The whole process was under-
taken independently by two authors and all the conflicts
were resolved by discussion among all authors.
Outcomes
Theoutcomesevaluatedwerepostoperativenausea,vomiting,
composite of nausea and vomiting (PONV, as some studies
had reported a composite outcome of nausea and vomiting),
and the proportion of patients requiring rescue anti-emetic
medication.
Statistical analyses
Statistical analyses were performed using the metafor
package for R.14
For each individual study the relative risk
(RR) was calculated using the reported events of relevant
outcomes. Pooled RR for individual outcomes was estimated
using the random effects model of the metafor package.
Heterogeneity was assessed based on the calculated I2
(the
proportion of total variabilityexplained by heterogeneity), esti-
mated using the restricted maximum likelihood–based
method. A moderator analysis was performed using the
mixed effects modelling approach (incorporating weighted
least squares regression for the moderator in the random
effects model) to assess the contribution of study level covari-
ates to the overall heterogeneityand their impact on the effect
size. Age, percentage of females in each study, postoperative
opioid consumption, and duration of anaesthesia were the
continuous variables, while surgery type and anaesthetic
agent used, dose of gabapentin, and timing of the dose were
the categorical variables used as covariates in the mixed
effects model. The effect of postoperative opioid consumption
was evaluated after computing the standardized mean differ-
ence between the placebo and gabapentin groups. To assess
thepublicationbiasweplottedthelogrelativeriskvsthestand-
ard error of the individual studies. The symmetry of the plot
was assessed using Egger’s test. The trim and fill method was
used to estimate the number of studies missing from the
meta-analysis due to the suppression of the most extreme
results on one side of the funnel plot. A Galbraith plot was
also plotted to assess the same. A sensitivity analysis was
conducted using leave-one-out analysis. Briefly, in this proced-
ure individual studies were excluded from the model and the
influence of the exclusion of that study on the model para-
meters was assessed.
Results
Seventeen studies were included in the final analysis. The lit-
erature search and study selection is represented in Fig. 1.
The characteristics of the included studies are shown in
Table 1. The included studies differed with respect to the type
of surgery and the gabapentin dose evaluated. The selected
studies contained a total of 1605 patients, with 810 in the
gabapentin group and 795 in the placebo group. Eight studies
were conducted in patients undergoing hysterectomy, three
studies each for open and laparoscopic cholecystectomy
patients, and one study each with donor nephrectomy, major
bowel surgery, and laparoscopic-assisted reproductive surgery
patients. Gabapentin was administered either 1 or 2 h prior
to surgery in all the studies. In two studies an additional dose
of gabapentin was administered the night before surgery.
The data primarily collected from the studies were the study
design; gabapentin dose; number of nausea, vomiting, and
PONV events; number of rescue anti-emetic events; and also
the induction and maintenance agents used for anaesthesia.
Outcomes
Postoperative nausea
Ten studies comprising atotal of 632 patients (324 in the gaba-
pentin group and 308 in the placebo group) were included for
pooling the RR for postoperative nausea. The pooled RR was
0.76 (95% CI 0.58–0.98). I2
was 5.8% and the test for hetero-
geneity was not significant (P¼0.36) (Fig. 2).
Gabapentin and postoperative nausea and vomiting BJA
589
Postoperative vomiting
Ten studies comprising atotal of 632 patients (324 in the gaba-
pentin group and 308 in the placebo group) were included for
pooling the RR for postoperative vomiting. The pooled RR was
0.62 (95% CI 0.45–0.85). I2
was0% and the test for heterogen-
eity was not significant (P¼0.5) (Fig. 3).
PONV
Seven studies comprising a total of 973 patients (487 each in
the gabapentin and placebo groups) were included for
pooling the RR for postoperative nausea. The pooled RR was
0.71 (95% CI 0.39–1.28). I2
was 94% and the test for hetero-
geneity was significant (P,0.0001) (Fig. 4).
Postoperative use of anti-emetic rescue medication
Seven studies comprising a total of 578 patients (289 each in
the gabapentin and placebo groups) were included for
pooling the RR for postoperative nausea. The pooled RR was
0.6 (95% CI 0.41–0.89). I2
was 70% and the test for heterogen-
eity was significant (P¼0.0045) (Fig. 5).
Moderator analysis
Continuous moderators, such as study level, differences in
age, percentage of females, standardized mean difference in
opioid consumption, and the duration of anaesthesia, did not
influence the outcome measures in the univariate moderator
analysis for nausea, vomiting, PONV, and rescue anti-emetic
use. The results of the categorical moderators are displayed
in Supplementary Figs. 6 and 7. There was a significant reduc-
tion in vomiting when gabapentin was used in abdominal
hysterectomies. The RR reduction was not statistically signifi-
cant in the cholecystectomy, nephrectomy, bowel surgery
and laparoscopic-assisted reproductive techniques (LART)
subgroups. The type of the surgery was not associated with a
reduction in RR when nausea was analysed. There was also a
significant reduction in the RR of both nausea and vomiting
when propofol was not used as an induction or maintenance
agent.
Sensitivity analysis and publication bias
The influence diagnostics and leave-one-out analysis of the
studies was conducted to assess whether the effect size of
Records identified through pubmed
database searching
(n=175)
Records identified through other sources (Cross
references, EMBASE, Cochrane library)
(n=56)
Records after duplicates removed
(n=196)
Articles assessed for eligibility
(n=42)
Records excluded
(n=154)
Studies included in qualitative
synthesis
(n=17)
Studies included in quantitative
synthesis (meta-analysis)
Outcomes (n)
Nausea (10)
Vomiting (10)
PONV (7)
Rescue antiemetic use (6)
Excluded-25
11- Abdominal surgery but not fitting
the criteria
8- Orthopedic surgery
5- Other surgeries
1- No placebo control
Fig 1 Flow diagram of the search strategy and study selection.
BJA Achuthan et al.
590
Table 1 Details of the included studies. AH, abdominal hysterectomy; DN, donor nephrectomy; H, halothane; I, isoflurane; LART, laparoscopic-assisted reproductive techniques; LC, laparoscopic
cholecystectomy; MBS, major bowel surgery; NR, not reported; OC, open cholecystectomy; P, propofol; PONV, postoperative nausea and vomiting; S, sevoflurane; T, thiopentone. *Downs and Black
score. †1, 1 h prior to surgery; 2, 2 h prior to surgery.
Study Ajori
et al.16
Durmus
et al.17
Frouzanfard
et al.18
Khademi
et al.19
Mohammadi
et al.20
Pandey
et al.21
Pandey
et al.22
Pandey
et al.23
Sen
et al.24
Srivastava
et al.25
Takmaz
et al.26
Turan
et al.27
Ghafari
et al.28
Ghai
et al.29
Behdad
et al.30
Siddiqui
et al.31
Bashir
et al.32
Year 2012 2007 2013 2010 2008 2004 2005 2006 2009 2010 2007 2004 2009 2011 2012 2014 2009
Surgery AH AH AH OC LART LC DN LC AH OC OC AH AH AH AH MBS LC
Randomization Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Blinded Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Quality score* 21 22 21 22 19 19 20 19 23 23 19 21 22 22 21 21 22
Gabapentin
dose (mg)
600 1200 1200 600 300 300 600 600 1200 1200 900/
1200
1200 300+300 900 100+300 600 600
Timing of dose† 1 1 2 2 1 2 2 2 1 2 1 2 1 1–2 2 1 2
Sample size (n)
Placebo 69 25 25 43 35 153 20 125 20 60 15 25 33 30 31 36 50
Gabapentin 69 25 25 44 35 153 20 125 20 60 15/15 25 33 30 30 36 50
Mean age,
years
(placebo)
48.3 48 44.6 52.18 31.9 43.49 41.5 41.8 46 44.7 43.5 50.4 48.16 43 44.55 37.2 NR
Opioid consumption, mean (SD)
Gabapentin 1.4 (0.6) 42.9
(10.09)
1.2 (2.8) 28.33
(12.9)
NR 221.16
(52.39)
563.3
(252.8)
221.2
(92.4)
31 (12) 253.9
(44.8)
165.1
(11.1)
270.4
(144.4)
15.78
(1.15)
54.40
(15.57)
NR NR NR
Placebo 2.5 (0.7) 66.45
(10.93)
5.2 (2.8) 35.1
(15.1)
NR 355.86
(42.04)
924.7
(417.5)
505.9
(82)
48 (17) 375.8
(83.5)
456
(35.6)
419.6
(83.6)
26.94
(2.28)
105
(23.6)
NR NR NR
Nausea, n (%)
Gabapentin 8 (11.6) 7 (28.0) NR NR 2 (5.7) NR 4 (20.0) NR 9 (45.0) NR 2 (13.3) 5
(20.0)
5 (15.2) NR 5 (16.1) 17 (47.2) NR
Placebo 19 (27.5) 9 (36.0) NR NR 9 (25.7) NR 3 (15.0) NR 8 (40.0) NR 9 (60.0) 7
(28.0)
7 (21.2) NR 5 (16.7) 17 (47.2) NR
Vomiting, n (%)
Gabapentin 5 (7.2) 3 (12.0) NR NR 0 (0.0) NR 1 (5.0) NR 8 (40.0) NR 1 (6.7) 6
(24.0)
4 (12.1) NR 5 (16.1) 5 (13.9) NR
Placebo 16 (23.2) 6 (24.0) NR NR 4 (11.4) NR 2 (10.0) NR 8 (40.0) NR 7 (46.7) 9
(36.0)
9 (27.3) NR 7 (23.3) 6 (16.7) NR
PONV, n (%)
Gabapentin NR NR 7 (28) 16 (36.4) NR 38
(24.8)
NR 46
(36.8)
NR 15 (25.0) NR NR NR 21 (70.0) NR NR 20 (40)
Placebo NR NR 24 (96.0) 28 (65.1) NR 8 (5.2) NR 75
(60.0)
NR 31 (51.7) NR NR NR 29 (96.7) NR NR 31 (62)
Rescue medication use, n (%)
Gabapentin 7 (10.1) NR NR NR 0 (0.0) NR NR NR 8 (40.0) 9 (15.0) 2 (13.3) 11 NR NR NR NR 17 (34)
Placebo 19 (27.5) NR NR NR 4 (11.4) NR NR NR 7 (35.0) 23 (38.3) 11 (73.3) 16 NR NR NR NR 27 (54)
Induction agent
T T T T P P P P P P T P T P P P P
Maintenance anaesthetic agent
I S I I P P P P S H S S I S p S P
GabapentinandpostoperativenauseaandvomitingBJA
591
gabapentinonthefourmainparameters,i.e.nausea,vomiting,
PONVand rescue anti-emetic use, was influenced by individual
studies. The pooled RR for PONV was not significant [0.71 (95%
CI 0.39–1.28)], butwhen thestudybyPandeyand colleagues21
was excluded, the RR was significant [0.59 (95% CI 0.5–0.7)]
and the I2
value for heterogeneity decreased from 94 to
27.2% (Supplementary Table 2). The Galbraith plot showed
no evidence of publication bias (Supplementary Figure 8). The
Egger’s test for asymmetry of the funnel plot was non-
significant (P¼0.27). The trim and fill method estimated the
number of missing studies in the funnel plot as one.
Discussion
The quantitative analysis of the collected data showed
that preoperative administration of gabapentin in patients
undergoing abdominal surgery was associated with a lower in-
cidence of nausea and vomiting. We observed a reduction of
24% for nausea, 38% for vomiting, no significant reduction in
the composite PONV (possibly biased by a single study), and
a 40% reduction in the rescue anti-emetic use in patients
who received preoperative gabapentin. An earlier analysis by
Alayed and colleagues15
also showed that there was a reduc-
tion in the incidence of postoperative nausea and vomiting.
However, the analysis was focussed on only abdominal hyster-
ectomy patients (11 studies). Also, we consider thatcombining
the composite PONV data in the analysis of both nausea
and vomiting outcomes as performed in that analysis could
possibly result in biased estimates. In the present analysis
we included studies on all abdominal surgeries16 – 32
that
evaluated only preoperative gabapentin (even postoperative
gabapentin use was included in the earlier analysis). We
Pooled Relative Risk for Nausea
Favors Gabapentin Favors Placebo
PlaceboGabapentin
Studies Events EventsSample SampleGabapentin Weights RR
(n) (N) Dose (mg) (n) (N) (95% Cl)
Mohamaddi et al
Behdad et al
Ajori et al
Pandey et al*
Ghafari et al
Siddiqui et al
Takmaz et al
Durmus et al
Sen et al
Takmaz et al
Turan et al
RE Model
2
5
8
4
5
17
7
7
9
2
5
0.01
9
5
19
3
7
17
9
9
8
9
0.22 (0.05, 0.96)
0.97 (0.31, 3.01)
0.42 (0.20, 0.90)
1.33 (0.34, 5.21)
0.71 (0.25, 2.02)
1.00 (0.61, 1.63)
0.78 (0.39, 1.54)
0.78 (0.34, 1.76)
1.12 (0.55, 2.32)
0.22 (0.06, 0.86)
7
35
30
69
20
33
36
15
25
20
15
25 0.71 (0.26, 1.95)
3.19%
5.22%
11.28%
3.64%
6.14%
24.61%
13.68%
9.74%
12.24%
3.69%
6.58%
0.76 (0.58, 0.98)100.00%
35
31
69
20
33
36
15
25
20
15
25
300
400
600
600
600
600
900
1200
1200
1200
1200
0.10 0.50 4.00
Relative risk (RR)
Fig 2 Pooled analysis of postoperative nausea.
BJA Achuthan et al.
592
additionally performed subgroup analysis to determine the
factors that could influence the effect of gabapentin on post-
operative nausea and vomiting (which was not performed in
the earlier analysis).
Previous studies have shown that the most reliable inde-
pendent predictors of PONV were female gender, history of
PONV or motion sickness, non-smoker, younger age, duration
of anaesthesia with volatile anaesthetics, and postoperative
opioids.33 34
From the extracted data we were able to analyse
whether age, female gender, duration of anaesthesia and
postoperative opioid use influence the effect of gabapentin
on postoperative nausea and vomiting. None of these factors
had a significant influence on the effect size of gabapentin’s
reduction in nausea and vomiting. The factors that seemed
to influence the efficacy of gabapentin in PONV were the type
of surgeryand the type of anaesthetic agent used for induction
and maintenance. The statistically significant reduction of
postoperative vomiting observed in the present analysis in
the subgroup of patients undergoing abdominal hysterectomy
concurs with the earlier findings in the same patient popula-
tion. However, the imprecise estimates found in the cholecyst-
ectomy group do not rule out the anti-emetic efficacy of
preoperative gabapentin. The same could explain the statistic-
ally non-significant effects in the individual dosage groups.
Also, the subgroups had significant heterogeneity, possibly
due to the small number of studies in the individual subgroups.
Moreover, the dose–response (efficacy) relationship curve of
gabapentin is likely to be flat, as observed in epilepsy,10
satur-
able absorption being a plausible explanation. Conversely, the
adverse events (commonly somnolence and dizziness) may
possibly have a relationship with dose.11
Although it is difficult,
based on the present analysis, to recommend a specific dose,
Pooled Relative Risk for Vomiting
Favors Gabapentin Favors Placebo
PlaceboGabapentin
Studies Events EventsSample SampleGabapentin Weights RR
(n) (N) Dose (mg) (n) (N) (95% Cl)
Mohamaddi et al
Behdad et al
Ajori et al
Pandey et al*
Ghafari et al
Siddiqui et al
Takmaz et al
Durmus et al
Sen et al
Takmaz et al
Turan et al
RE Model
0
5
5
1
4
5
6
3
8
1
6
0.01
4
7
16
2
9
6
7
6
8
7
0.11 (0.01, 1.99)
0.69 (0.25, 1.94)
0.31 (0.12, 0.81)
0.50 (0.05, 5.08)
0.44 (0.15, 1.30)
0.83 (0.28, 2.49)
0.86 (0.38, 1.95)
0.50 (0.14, 1.78)
1.00 (0.47, 2.14)
0.14 (0.02, 1.02)
9
35
30
69
20
33
36
15
25
20
15
25 0.67 (0.28, 1.59)
1.27%
9.91%
11.77%
1.96%
9.15%
8.84%
15.60%
6.55%
18.33%
2.72%
13.90%
0.62 (0.45, 0.85)100.00%
35
31
69
20
33
36
15
25
20
15
25
300
400
600
600
600
600
900
1200
1200
1200
1200
0.10 0.50 4.00
Relative risk (RR)
Fig 3 Pooled analysis of postoperative vomiting.
Gabapentin and postoperative nausea and vomiting BJA
593
a preoperative dose of 300 or 600 mg can be justified for
evaluation in future studies, providing evidence regarding the
benefit–risk profile of gabapentin in this clinical setting.
Another interesting finding not previously reported was
the differential efficacy of gabapentin with respect to the use
of propofol, either as a maintenance or induction agent.
In the pooled analysis of subgroup of studies using propofol,
the reduction in the nausea and vomiting events with gaba-
pentin was not statistically significant, but was significant
when propofol was not used. The anti-emetic properties of
propofol35
may explain the differential effects of gabapentin,
consequently negating the effects of the latter. This suggests
a complex interaction between gabapentin and propofol, al-
though synergistic effects between propofol and gabapentin
can be expected due to different pharmacological properties,
highlighting the need for additional studies. The anti-emetic
effectsofpropofolareshort-lived(upto6h),35
whilegabapentin
possibly provides long-lasting effects (possibly .24 h), as
it has been shown to be effective in delayed chemotherapy-
induced nausea and vomiting12
and has postoperative anal-
gesia even after 24 h36
. This precludes making an evaluation
on any temporal relationship, as the included studies re-
ported the events occurring only in the first 24 h postoperative
period.
The speculated mechanisms of anti-emetic properties of
gabapentin include decreased tachykinin neurotransmis-
sion,12 37 – 39
decreased calcium influx in area postrema,40 41
reduced inflammation at the surgical trauma site,42
as in-
flammationcouldleadtopostoperativeileusandsubsequently
to PONV,43
and reduced anxiety,44
apart from the direct effect of
decreased opioid consumption (seenwith preoperative gabapen-
tin use) on nausea and vomiting. Even though the postoperative
opioid consumption is significantly lower with preoperative gaba-
pentin as compared with the placebo group (observed in the pre-
vious analysis), we did not observe any influence on the effect
size of gabapentin on postoperative nausea and vomiting in the
Pooled Relative Risk for PONV
Favors Gabapentin Favors Placebo
PlaceboGabapentin
Studies Events EventsSample SampleGabapentin Weights RR
(n) (N) Dose (mg) (n) (N) (95% Cl)
Pandey et al
Ghai et al
Khademi et al
Pandey et al**
Shrivastava et al
Bashir et al
Frouzanfard et al
RE Model
38
21
16
46
15
20
7
0.01
8
29
28
75
31
31
24
4.75 (2.29, 9.84)
0.72 (0.57, 0.92)
0.56 (0.36, 0.87)
0.61 (0.47, 0.80)
0.48 (0.29, 0.80)
0.65 (0.43, 0.97)
0.29 (0.15, 0.55)
153
30
43
125
60
50
25
12.71%
15.37%
14.46%
15.27%
14.16%
14.69%
13.34%
0.70 (0.39, 1.28)100.00%
153
30
44
125
60
50
25
300
300
600
600
600
600
1200
0.10 0.50 4.00
Relative risk (RR)
Fig 4 Pooled analysis of composite postoperative nausea and vomiting.
BJA Achuthan et al.
594
moderator analysis. This shows that mechanisms other than the
decreased consumption of opioids are possibly responsible for
gabapentin’s anti-emetic property.
In the sensitivity analysis, the study by Pandey and collea-
gues21
had a significant impact on the results of the PONVend-
point. The pooled RR estimates showed that the effect of
gabapentin on the incidence of PONV was not significant [RR
0.71 (95% CI 20.39–1.28)]. Exclusion of this study resulted in
a statistically significant finding [RR 0.59 (95% CI 20.5–0.7)].
This study by Pandey and colleagues21
showed that preope-
rative gabapentin (300 mg) use caused an increased incidence
of PONV (38/153 compared with 8/153 in the placebo group).
However, in a study by the same authors in 2006,23
it was
shown that the preoperative use of gabapentin (600 mg)
indeed had a beneficial effect on the incidence of PONV (46/
125 compared with 75/125 in the placebo group). Both the
studies were done in laparoscopic cholecystectomy patients.
The reasons for this disparity are unknown; we believe
that this difference could be due to the fact that PONV was
not the primary endpoint in the first study, whereas it was
in the second. This could have led to differences in study
conduct and analysis. Similarly, concerns about the reliability
of the data not formally collected as the primary endpoint
were raised in another recent review.45
In the present analysis the observed reduction in post-
operative nausea and vomiting with preoperative gabapentin
support our recommendation of including gabapentin in
the armamentarium of pharmacotherapies for PONV in pati-
ents undergoing abdominal surgery. The current treatment
guidelines recommend 5-HT3, dopaminergic, and histaminic
antagonists as prophylaxis and treatment for PONV.34
Based
on the additional analgesic properties, safety profile, and
cost, gabapentin might be usefully included in the current list
of PONV prophylactic agents.
Pooled Relative Risk for Rescue Antiemetic Use
Favors Gabapentin Favors Placebo
PlaceboGabapentin
Studies Events EventsSample SampleGabapentin Weights RR
(n) (N) Dose (mg) (n) (N) (95% Cl)
Mohamaddi et al
Ajori et al
Shrivastava et al
Bashir et al
Takmaz et al
Sen et al
Takmaz et al
Turan et al
RE Model
0
7
9
17
12
8
2
11
0.01
4
19
23
27
11
7
11
16
0.11 (0.01, 1.99)
0.37 (0.17, 0.82)
0.39 (0.20, 0.77)
0.63 (0.40, 1.00)
1.09 (0.73, 1.62)
1.14 (0.51, 2.55)
0.18 (0.05, 0.68)
0.69 (0.40, 1.17)
35
69
60
50
15
20
15
25
1.69%
11.97%
13.89%
18.07%
19.40%
11.92%
6.34%
16.72%
0.60 (0.41, 0.89)100.00%
35
69
60
50
15
20
15
25
300
600
600
600
900
1200
1200
1200
0.10 0.50 4.00
Relative risk (RR)
Fig 5 Pooled analysis of postoperative use of rescue medication.
Gabapentin and postoperative nausea and vomiting BJA
595
Conclusion
The present analysis overcomes the limitations of earlier ana-
lyses and the additional moderator and sensitivity analyses
conducted provide strong evidence favouring preoperative
gabapentin as a pharmacotherapy for prevention of PONV in
patients undergoing abdominal surgeries. The use of propofol
in the perioperative period could possibly be an important
factor influencing the decision to use gabapentin as a prevent-
iveagent.Nevertheless,theanalgesicpropertiesandapossible
longer duration of action favour preoperative gabapentin
use irrespective of the anaesthetic agent. Future studies com-
paring the efficacy of gabapentin with the more commonly
used 5HT3 antagonists are needed to precisely define the
role of preoperative gabapentin in PONV.
Supplementary material
Supplementary material is available at British Journal of
Anaesthesia online.
Authors’ contributions
S.A., I.S., and S.B. were involved in the data extraction. S.A., I.S.,
A.S., D.H., and A.C. were involved in the data analysis and the
drafting and editing of the manuscript. D.H. and A.C. reviewed
and approved the final manuscript.
Declaration of interest
None declared.
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Handling editor: J. G. Hardman
Gabapentin and postoperative nausea and vomiting BJA
597
Annotations
Gabapentin prophylaxis for postoperative nausea and
vomiting in abdominal surgeries: a quantitative analysis of
evidence from randomized controlled clinical trials
Achuthan, S.; Singh, I.; Varthya, S. B.; Srinivasan, a.; Chakrabarti, a.; Hota, D.
01 Mendeley User Page no. 1
7/4/2015 9:45
Les NVPO sont un événement fréquent en post-anesthésie puisqu'ils touchent environ un tiers des
patients. Les différents scores et prophylaxies utilisées bien que souvent efficaces ne closent pas le
chapitre de leur prévention. La gabapentine, antivonvusilvant, a montré par ailleurs son effet
analgésique en post-opératoire.Plus récemment, la gabapentine a montré un effet anti-émétique
lorsqu'elle était administrée en prévention dans la chimiothérapie du cancer du sein.Cette étude est
une méta-analyse des essais randomisés de la gabapentine en prévention des NVPO. Elle conclut à
son efficacité, efficacité d'autant plus marquée que le propofol n'est pas utilisé comme agent
d'induction et/ou d'entretien.

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Bja 2015 114(4)

  • 1. Gabapentin prophylaxis for postoperative nausea and vomiting in abdominal surgeries: a quantitative analysis of evidence from randomized controlled clinical trials S. Achuthan1, I. Singh1*, S. B. Varthya1, A. Srinivasan1, A. Chakrabarti1 and D. Hota2 1 Department of Pharmacology, Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India 2 Department of Pharmacology, AIIMS, Bhubaneshwar, India * Corresponding author. E-mail: inderhazari@gmail.com Editor’s key points † The authors examined the evidence base for the effectiveness of gabapentin in preventing postoperative nausea and vomiting (PONV). † They found support for the use of preoperative gabapentin in PONV prophylaxis, especially in abdominal surgery. † Interestingly, the benefits of gabapentin appeared reduced in the presence of the use of propofol. Introduction. Postoperative nausea and vomiting (PONV) is frequently encountered in the surgical recovery room. Abdominal surgery is one important risk factor for increased incidence of PONV. Gabapentin, an anticonvulsant with known postoperative analgesic properties, has shown some activity against PONV. Results from clinical trials evaluating the anti-emetic efficacy of gabapentin are conflicting. The present meta-analysis was performed to examine this issue. Methods. Seventeen randomized placebo-controlled trials reporting PONV with preoperative gabapentin administration in patients undergoing abdominal surgery were included for analysis. Outcomes evaluated were nausea, vomiting, composite PONV and the use of rescue anti-emetic medication in the postoperative period. Results. The pooled relative risk (RR), estimated using the random effects model of the metafor package for R, was 0.76 (95% CI 0.58–0.98) for nausea, 0.62 (0.45–0.85) for vomiting, 0.71 (0.39–1.28) for data represented as composite PONV (possibly biased by a single study, as observed in the sensitivity analysis), and 0.6 (0.41–0.89) for rescue anti- emetic use. There was a significant RR reduction for nausea and vomiting when propofol was not used as induction and/or maintenance for anaesthesia. In the abdominal hysterectomy subgroup, there was a significant RR reduction for vomiting but not for nausea. Discussion. The present analysis provides evidence supporting preoperative gabapentin as a pharmacotherapy for prevention of PONV in patients undergoing abdominal surgeries. Future studies comparing preoperative gabapentin with 5HT3 antagonists are needed to precisely define its role in PONV. Keywords: gabapentin; hysterectomy; postoperative nausea and vomiting Accepted for publication: 19 September 2014 Postoperative nausea and vomiting (PONV) in the surgical re- covery room is a common occurrence. Despite being self- limiting, it is associated with substantial distress to patients in the early postoperative period. Its prevention and/or treat- ment significantly improves patient satisfaction and quality of life.1 – 3 PONV prevention can lead to a substantial reduction in health care costs by reducing the duration of the post- anaesthesia care unit (PACU) stay.4 5 It is estimated that each episode of emesis delays discharge from the PACU by approximately 20 min.6 Furthermore, serious complications, including retinal detachment, aspiration, wound dehiscence, oesophageal rupture, and subcutaneous emphysema, related to PONV can be prevented. The general incidence of PONV ranges from 25% to 30%,7 and in some subsets of high-risk patients it can be as high as 80%,8 even after preventive pharmacotherapy. The pharmacotherapies used in the preven- tion/management of PONV include 5-HT3, dopaminergic, hista- minic, and NK1 antagonists. Nevertheless, the need forcheaper and more effective therapies cannot be disputed. Gabapentin, an anticonvulsant, has been shown to be ef- fective as a non-opioid ancillary agent for postoperative pain management.9 The safety profile, minimal drug interactions, pharmacokinetics (good oral bioavailability and renal elimin- ation), and relatively flat dose–response relationship with respect to safety and efficacy favour its clinical use.10 11 Inter- estingly, in the recent past, gabapentin’s anti-nausea effects were noted when there was a marked improvement in the chemotherapy-induced nausea in breast cancer patients12 and subsequently was observed to possess activity against PONV. The exact mechanism for gabapentin’s efficacy in & The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com British Journal of Anaesthesia 114 (4): 588–97 (2015) Advance Access publication 8 January 2015 . doi:10.1093/bja/aeu449 01 07/04/2015 Mdl. User
  • 2. PONV is not known. While results of a few studies evaluating the efficacy of preoperative gabapentin as a prophylaxis were promising, the results of others did not reach statistical signifi- cance and have been equivocal. Hence the present analysis was performed to define the role of gabapentin as a preventive therapy for PONV. Methods Randomized placebo-controlled clinical trials comparing pre- operative gabapentin administration were identified for evalu- ation for inclusion in the analyses. The criteria for inclusion were (i) patients undergoing abdominal surgery (open or lap- aroscopic) under general anaesthesia, (ii) preoperative admin- istration of gabapentin irrespective of dose and timing of the dose with respect to surgery, and (iii) trials reporting nausea, vomiting, postoperative nausea and vomiting, or a proportion of patients requiring rescue anti-emetic medication irrespect- ive of the objective of evaluation were included in the final analysis.Trialsevaluatingpostoperativedosingaloneorinadd- ition to preoperative gabapentin were excluded from the final analysis. A literature search using the terms ‘gabapentin’, ‘postoperative nausea and vomiting’, ‘abdominal surgery’, and ‘postoperative pain’ was performed in Medline, Embase and the Cochrane library. Additional studies were identified through cross-references and meta-analyses conducted for evaluation of gabapentin in postoperative pain. All human studies published in full-text or abstract forms were initially screened for inclusion without applying any language restric- tions. Titles and abstracts from the electronic search were reviewed. After initial review of the abstracts, the relevant studies were identified and a detailed evaluation of the full text was done. All data with regard to authorship, year of pub- lication, study design, study population (i.e. type of abdominal surgery), baseline patient characteristics, gabapentin dose, type of surgery, type and duration of anaesthesia (when data were not available, the duration of surgery was taken as the duration of anaesthesia), number of patients, and relevant outcomes were extracted from theselectedstudies. The meth- odological quality of the included studies was assessed using the Downs and Black score.13 The whole process was under- taken independently by two authors and all the conflicts were resolved by discussion among all authors. Outcomes Theoutcomesevaluatedwerepostoperativenausea,vomiting, composite of nausea and vomiting (PONV, as some studies had reported a composite outcome of nausea and vomiting), and the proportion of patients requiring rescue anti-emetic medication. Statistical analyses Statistical analyses were performed using the metafor package for R.14 For each individual study the relative risk (RR) was calculated using the reported events of relevant outcomes. Pooled RR for individual outcomes was estimated using the random effects model of the metafor package. Heterogeneity was assessed based on the calculated I2 (the proportion of total variabilityexplained by heterogeneity), esti- mated using the restricted maximum likelihood–based method. A moderator analysis was performed using the mixed effects modelling approach (incorporating weighted least squares regression for the moderator in the random effects model) to assess the contribution of study level covari- ates to the overall heterogeneityand their impact on the effect size. Age, percentage of females in each study, postoperative opioid consumption, and duration of anaesthesia were the continuous variables, while surgery type and anaesthetic agent used, dose of gabapentin, and timing of the dose were the categorical variables used as covariates in the mixed effects model. The effect of postoperative opioid consumption was evaluated after computing the standardized mean differ- ence between the placebo and gabapentin groups. To assess thepublicationbiasweplottedthelogrelativeriskvsthestand- ard error of the individual studies. The symmetry of the plot was assessed using Egger’s test. The trim and fill method was used to estimate the number of studies missing from the meta-analysis due to the suppression of the most extreme results on one side of the funnel plot. A Galbraith plot was also plotted to assess the same. A sensitivity analysis was conducted using leave-one-out analysis. Briefly, in this proced- ure individual studies were excluded from the model and the influence of the exclusion of that study on the model para- meters was assessed. Results Seventeen studies were included in the final analysis. The lit- erature search and study selection is represented in Fig. 1. The characteristics of the included studies are shown in Table 1. The included studies differed with respect to the type of surgery and the gabapentin dose evaluated. The selected studies contained a total of 1605 patients, with 810 in the gabapentin group and 795 in the placebo group. Eight studies were conducted in patients undergoing hysterectomy, three studies each for open and laparoscopic cholecystectomy patients, and one study each with donor nephrectomy, major bowel surgery, and laparoscopic-assisted reproductive surgery patients. Gabapentin was administered either 1 or 2 h prior to surgery in all the studies. In two studies an additional dose of gabapentin was administered the night before surgery. The data primarily collected from the studies were the study design; gabapentin dose; number of nausea, vomiting, and PONV events; number of rescue anti-emetic events; and also the induction and maintenance agents used for anaesthesia. Outcomes Postoperative nausea Ten studies comprising atotal of 632 patients (324 in the gaba- pentin group and 308 in the placebo group) were included for pooling the RR for postoperative nausea. The pooled RR was 0.76 (95% CI 0.58–0.98). I2 was 5.8% and the test for hetero- geneity was not significant (P¼0.36) (Fig. 2). Gabapentin and postoperative nausea and vomiting BJA 589
  • 3. Postoperative vomiting Ten studies comprising atotal of 632 patients (324 in the gaba- pentin group and 308 in the placebo group) were included for pooling the RR for postoperative vomiting. The pooled RR was 0.62 (95% CI 0.45–0.85). I2 was0% and the test for heterogen- eity was not significant (P¼0.5) (Fig. 3). PONV Seven studies comprising a total of 973 patients (487 each in the gabapentin and placebo groups) were included for pooling the RR for postoperative nausea. The pooled RR was 0.71 (95% CI 0.39–1.28). I2 was 94% and the test for hetero- geneity was significant (P,0.0001) (Fig. 4). Postoperative use of anti-emetic rescue medication Seven studies comprising a total of 578 patients (289 each in the gabapentin and placebo groups) were included for pooling the RR for postoperative nausea. The pooled RR was 0.6 (95% CI 0.41–0.89). I2 was 70% and the test for heterogen- eity was significant (P¼0.0045) (Fig. 5). Moderator analysis Continuous moderators, such as study level, differences in age, percentage of females, standardized mean difference in opioid consumption, and the duration of anaesthesia, did not influence the outcome measures in the univariate moderator analysis for nausea, vomiting, PONV, and rescue anti-emetic use. The results of the categorical moderators are displayed in Supplementary Figs. 6 and 7. There was a significant reduc- tion in vomiting when gabapentin was used in abdominal hysterectomies. The RR reduction was not statistically signifi- cant in the cholecystectomy, nephrectomy, bowel surgery and laparoscopic-assisted reproductive techniques (LART) subgroups. The type of the surgery was not associated with a reduction in RR when nausea was analysed. There was also a significant reduction in the RR of both nausea and vomiting when propofol was not used as an induction or maintenance agent. Sensitivity analysis and publication bias The influence diagnostics and leave-one-out analysis of the studies was conducted to assess whether the effect size of Records identified through pubmed database searching (n=175) Records identified through other sources (Cross references, EMBASE, Cochrane library) (n=56) Records after duplicates removed (n=196) Articles assessed for eligibility (n=42) Records excluded (n=154) Studies included in qualitative synthesis (n=17) Studies included in quantitative synthesis (meta-analysis) Outcomes (n) Nausea (10) Vomiting (10) PONV (7) Rescue antiemetic use (6) Excluded-25 11- Abdominal surgery but not fitting the criteria 8- Orthopedic surgery 5- Other surgeries 1- No placebo control Fig 1 Flow diagram of the search strategy and study selection. BJA Achuthan et al. 590
  • 4. Table 1 Details of the included studies. AH, abdominal hysterectomy; DN, donor nephrectomy; H, halothane; I, isoflurane; LART, laparoscopic-assisted reproductive techniques; LC, laparoscopic cholecystectomy; MBS, major bowel surgery; NR, not reported; OC, open cholecystectomy; P, propofol; PONV, postoperative nausea and vomiting; S, sevoflurane; T, thiopentone. *Downs and Black score. †1, 1 h prior to surgery; 2, 2 h prior to surgery. Study Ajori et al.16 Durmus et al.17 Frouzanfard et al.18 Khademi et al.19 Mohammadi et al.20 Pandey et al.21 Pandey et al.22 Pandey et al.23 Sen et al.24 Srivastava et al.25 Takmaz et al.26 Turan et al.27 Ghafari et al.28 Ghai et al.29 Behdad et al.30 Siddiqui et al.31 Bashir et al.32 Year 2012 2007 2013 2010 2008 2004 2005 2006 2009 2010 2007 2004 2009 2011 2012 2014 2009 Surgery AH AH AH OC LART LC DN LC AH OC OC AH AH AH AH MBS LC Randomization Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Blinded Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Quality score* 21 22 21 22 19 19 20 19 23 23 19 21 22 22 21 21 22 Gabapentin dose (mg) 600 1200 1200 600 300 300 600 600 1200 1200 900/ 1200 1200 300+300 900 100+300 600 600 Timing of dose† 1 1 2 2 1 2 2 2 1 2 1 2 1 1–2 2 1 2 Sample size (n) Placebo 69 25 25 43 35 153 20 125 20 60 15 25 33 30 31 36 50 Gabapentin 69 25 25 44 35 153 20 125 20 60 15/15 25 33 30 30 36 50 Mean age, years (placebo) 48.3 48 44.6 52.18 31.9 43.49 41.5 41.8 46 44.7 43.5 50.4 48.16 43 44.55 37.2 NR Opioid consumption, mean (SD) Gabapentin 1.4 (0.6) 42.9 (10.09) 1.2 (2.8) 28.33 (12.9) NR 221.16 (52.39) 563.3 (252.8) 221.2 (92.4) 31 (12) 253.9 (44.8) 165.1 (11.1) 270.4 (144.4) 15.78 (1.15) 54.40 (15.57) NR NR NR Placebo 2.5 (0.7) 66.45 (10.93) 5.2 (2.8) 35.1 (15.1) NR 355.86 (42.04) 924.7 (417.5) 505.9 (82) 48 (17) 375.8 (83.5) 456 (35.6) 419.6 (83.6) 26.94 (2.28) 105 (23.6) NR NR NR Nausea, n (%) Gabapentin 8 (11.6) 7 (28.0) NR NR 2 (5.7) NR 4 (20.0) NR 9 (45.0) NR 2 (13.3) 5 (20.0) 5 (15.2) NR 5 (16.1) 17 (47.2) NR Placebo 19 (27.5) 9 (36.0) NR NR 9 (25.7) NR 3 (15.0) NR 8 (40.0) NR 9 (60.0) 7 (28.0) 7 (21.2) NR 5 (16.7) 17 (47.2) NR Vomiting, n (%) Gabapentin 5 (7.2) 3 (12.0) NR NR 0 (0.0) NR 1 (5.0) NR 8 (40.0) NR 1 (6.7) 6 (24.0) 4 (12.1) NR 5 (16.1) 5 (13.9) NR Placebo 16 (23.2) 6 (24.0) NR NR 4 (11.4) NR 2 (10.0) NR 8 (40.0) NR 7 (46.7) 9 (36.0) 9 (27.3) NR 7 (23.3) 6 (16.7) NR PONV, n (%) Gabapentin NR NR 7 (28) 16 (36.4) NR 38 (24.8) NR 46 (36.8) NR 15 (25.0) NR NR NR 21 (70.0) NR NR 20 (40) Placebo NR NR 24 (96.0) 28 (65.1) NR 8 (5.2) NR 75 (60.0) NR 31 (51.7) NR NR NR 29 (96.7) NR NR 31 (62) Rescue medication use, n (%) Gabapentin 7 (10.1) NR NR NR 0 (0.0) NR NR NR 8 (40.0) 9 (15.0) 2 (13.3) 11 NR NR NR NR 17 (34) Placebo 19 (27.5) NR NR NR 4 (11.4) NR NR NR 7 (35.0) 23 (38.3) 11 (73.3) 16 NR NR NR NR 27 (54) Induction agent T T T T P P P P P P T P T P P P P Maintenance anaesthetic agent I S I I P P P P S H S S I S p S P GabapentinandpostoperativenauseaandvomitingBJA 591
  • 5. gabapentinonthefourmainparameters,i.e.nausea,vomiting, PONVand rescue anti-emetic use, was influenced by individual studies. The pooled RR for PONV was not significant [0.71 (95% CI 0.39–1.28)], butwhen thestudybyPandeyand colleagues21 was excluded, the RR was significant [0.59 (95% CI 0.5–0.7)] and the I2 value for heterogeneity decreased from 94 to 27.2% (Supplementary Table 2). The Galbraith plot showed no evidence of publication bias (Supplementary Figure 8). The Egger’s test for asymmetry of the funnel plot was non- significant (P¼0.27). The trim and fill method estimated the number of missing studies in the funnel plot as one. Discussion The quantitative analysis of the collected data showed that preoperative administration of gabapentin in patients undergoing abdominal surgery was associated with a lower in- cidence of nausea and vomiting. We observed a reduction of 24% for nausea, 38% for vomiting, no significant reduction in the composite PONV (possibly biased by a single study), and a 40% reduction in the rescue anti-emetic use in patients who received preoperative gabapentin. An earlier analysis by Alayed and colleagues15 also showed that there was a reduc- tion in the incidence of postoperative nausea and vomiting. However, the analysis was focussed on only abdominal hyster- ectomy patients (11 studies). Also, we consider thatcombining the composite PONV data in the analysis of both nausea and vomiting outcomes as performed in that analysis could possibly result in biased estimates. In the present analysis we included studies on all abdominal surgeries16 – 32 that evaluated only preoperative gabapentin (even postoperative gabapentin use was included in the earlier analysis). We Pooled Relative Risk for Nausea Favors Gabapentin Favors Placebo PlaceboGabapentin Studies Events EventsSample SampleGabapentin Weights RR (n) (N) Dose (mg) (n) (N) (95% Cl) Mohamaddi et al Behdad et al Ajori et al Pandey et al* Ghafari et al Siddiqui et al Takmaz et al Durmus et al Sen et al Takmaz et al Turan et al RE Model 2 5 8 4 5 17 7 7 9 2 5 0.01 9 5 19 3 7 17 9 9 8 9 0.22 (0.05, 0.96) 0.97 (0.31, 3.01) 0.42 (0.20, 0.90) 1.33 (0.34, 5.21) 0.71 (0.25, 2.02) 1.00 (0.61, 1.63) 0.78 (0.39, 1.54) 0.78 (0.34, 1.76) 1.12 (0.55, 2.32) 0.22 (0.06, 0.86) 7 35 30 69 20 33 36 15 25 20 15 25 0.71 (0.26, 1.95) 3.19% 5.22% 11.28% 3.64% 6.14% 24.61% 13.68% 9.74% 12.24% 3.69% 6.58% 0.76 (0.58, 0.98)100.00% 35 31 69 20 33 36 15 25 20 15 25 300 400 600 600 600 600 900 1200 1200 1200 1200 0.10 0.50 4.00 Relative risk (RR) Fig 2 Pooled analysis of postoperative nausea. BJA Achuthan et al. 592
  • 6. additionally performed subgroup analysis to determine the factors that could influence the effect of gabapentin on post- operative nausea and vomiting (which was not performed in the earlier analysis). Previous studies have shown that the most reliable inde- pendent predictors of PONV were female gender, history of PONV or motion sickness, non-smoker, younger age, duration of anaesthesia with volatile anaesthetics, and postoperative opioids.33 34 From the extracted data we were able to analyse whether age, female gender, duration of anaesthesia and postoperative opioid use influence the effect of gabapentin on postoperative nausea and vomiting. None of these factors had a significant influence on the effect size of gabapentin’s reduction in nausea and vomiting. The factors that seemed to influence the efficacy of gabapentin in PONV were the type of surgeryand the type of anaesthetic agent used for induction and maintenance. The statistically significant reduction of postoperative vomiting observed in the present analysis in the subgroup of patients undergoing abdominal hysterectomy concurs with the earlier findings in the same patient popula- tion. However, the imprecise estimates found in the cholecyst- ectomy group do not rule out the anti-emetic efficacy of preoperative gabapentin. The same could explain the statistic- ally non-significant effects in the individual dosage groups. Also, the subgroups had significant heterogeneity, possibly due to the small number of studies in the individual subgroups. Moreover, the dose–response (efficacy) relationship curve of gabapentin is likely to be flat, as observed in epilepsy,10 satur- able absorption being a plausible explanation. Conversely, the adverse events (commonly somnolence and dizziness) may possibly have a relationship with dose.11 Although it is difficult, based on the present analysis, to recommend a specific dose, Pooled Relative Risk for Vomiting Favors Gabapentin Favors Placebo PlaceboGabapentin Studies Events EventsSample SampleGabapentin Weights RR (n) (N) Dose (mg) (n) (N) (95% Cl) Mohamaddi et al Behdad et al Ajori et al Pandey et al* Ghafari et al Siddiqui et al Takmaz et al Durmus et al Sen et al Takmaz et al Turan et al RE Model 0 5 5 1 4 5 6 3 8 1 6 0.01 4 7 16 2 9 6 7 6 8 7 0.11 (0.01, 1.99) 0.69 (0.25, 1.94) 0.31 (0.12, 0.81) 0.50 (0.05, 5.08) 0.44 (0.15, 1.30) 0.83 (0.28, 2.49) 0.86 (0.38, 1.95) 0.50 (0.14, 1.78) 1.00 (0.47, 2.14) 0.14 (0.02, 1.02) 9 35 30 69 20 33 36 15 25 20 15 25 0.67 (0.28, 1.59) 1.27% 9.91% 11.77% 1.96% 9.15% 8.84% 15.60% 6.55% 18.33% 2.72% 13.90% 0.62 (0.45, 0.85)100.00% 35 31 69 20 33 36 15 25 20 15 25 300 400 600 600 600 600 900 1200 1200 1200 1200 0.10 0.50 4.00 Relative risk (RR) Fig 3 Pooled analysis of postoperative vomiting. Gabapentin and postoperative nausea and vomiting BJA 593
  • 7. a preoperative dose of 300 or 600 mg can be justified for evaluation in future studies, providing evidence regarding the benefit–risk profile of gabapentin in this clinical setting. Another interesting finding not previously reported was the differential efficacy of gabapentin with respect to the use of propofol, either as a maintenance or induction agent. In the pooled analysis of subgroup of studies using propofol, the reduction in the nausea and vomiting events with gaba- pentin was not statistically significant, but was significant when propofol was not used. The anti-emetic properties of propofol35 may explain the differential effects of gabapentin, consequently negating the effects of the latter. This suggests a complex interaction between gabapentin and propofol, al- though synergistic effects between propofol and gabapentin can be expected due to different pharmacological properties, highlighting the need for additional studies. The anti-emetic effectsofpropofolareshort-lived(upto6h),35 whilegabapentin possibly provides long-lasting effects (possibly .24 h), as it has been shown to be effective in delayed chemotherapy- induced nausea and vomiting12 and has postoperative anal- gesia even after 24 h36 . This precludes making an evaluation on any temporal relationship, as the included studies re- ported the events occurring only in the first 24 h postoperative period. The speculated mechanisms of anti-emetic properties of gabapentin include decreased tachykinin neurotransmis- sion,12 37 – 39 decreased calcium influx in area postrema,40 41 reduced inflammation at the surgical trauma site,42 as in- flammationcouldleadtopostoperativeileusandsubsequently to PONV,43 and reduced anxiety,44 apart from the direct effect of decreased opioid consumption (seenwith preoperative gabapen- tin use) on nausea and vomiting. Even though the postoperative opioid consumption is significantly lower with preoperative gaba- pentin as compared with the placebo group (observed in the pre- vious analysis), we did not observe any influence on the effect size of gabapentin on postoperative nausea and vomiting in the Pooled Relative Risk for PONV Favors Gabapentin Favors Placebo PlaceboGabapentin Studies Events EventsSample SampleGabapentin Weights RR (n) (N) Dose (mg) (n) (N) (95% Cl) Pandey et al Ghai et al Khademi et al Pandey et al** Shrivastava et al Bashir et al Frouzanfard et al RE Model 38 21 16 46 15 20 7 0.01 8 29 28 75 31 31 24 4.75 (2.29, 9.84) 0.72 (0.57, 0.92) 0.56 (0.36, 0.87) 0.61 (0.47, 0.80) 0.48 (0.29, 0.80) 0.65 (0.43, 0.97) 0.29 (0.15, 0.55) 153 30 43 125 60 50 25 12.71% 15.37% 14.46% 15.27% 14.16% 14.69% 13.34% 0.70 (0.39, 1.28)100.00% 153 30 44 125 60 50 25 300 300 600 600 600 600 1200 0.10 0.50 4.00 Relative risk (RR) Fig 4 Pooled analysis of composite postoperative nausea and vomiting. BJA Achuthan et al. 594
  • 8. moderator analysis. This shows that mechanisms other than the decreased consumption of opioids are possibly responsible for gabapentin’s anti-emetic property. In the sensitivity analysis, the study by Pandey and collea- gues21 had a significant impact on the results of the PONVend- point. The pooled RR estimates showed that the effect of gabapentin on the incidence of PONV was not significant [RR 0.71 (95% CI 20.39–1.28)]. Exclusion of this study resulted in a statistically significant finding [RR 0.59 (95% CI 20.5–0.7)]. This study by Pandey and colleagues21 showed that preope- rative gabapentin (300 mg) use caused an increased incidence of PONV (38/153 compared with 8/153 in the placebo group). However, in a study by the same authors in 2006,23 it was shown that the preoperative use of gabapentin (600 mg) indeed had a beneficial effect on the incidence of PONV (46/ 125 compared with 75/125 in the placebo group). Both the studies were done in laparoscopic cholecystectomy patients. The reasons for this disparity are unknown; we believe that this difference could be due to the fact that PONV was not the primary endpoint in the first study, whereas it was in the second. This could have led to differences in study conduct and analysis. Similarly, concerns about the reliability of the data not formally collected as the primary endpoint were raised in another recent review.45 In the present analysis the observed reduction in post- operative nausea and vomiting with preoperative gabapentin support our recommendation of including gabapentin in the armamentarium of pharmacotherapies for PONV in pati- ents undergoing abdominal surgery. The current treatment guidelines recommend 5-HT3, dopaminergic, and histaminic antagonists as prophylaxis and treatment for PONV.34 Based on the additional analgesic properties, safety profile, and cost, gabapentin might be usefully included in the current list of PONV prophylactic agents. Pooled Relative Risk for Rescue Antiemetic Use Favors Gabapentin Favors Placebo PlaceboGabapentin Studies Events EventsSample SampleGabapentin Weights RR (n) (N) Dose (mg) (n) (N) (95% Cl) Mohamaddi et al Ajori et al Shrivastava et al Bashir et al Takmaz et al Sen et al Takmaz et al Turan et al RE Model 0 7 9 17 12 8 2 11 0.01 4 19 23 27 11 7 11 16 0.11 (0.01, 1.99) 0.37 (0.17, 0.82) 0.39 (0.20, 0.77) 0.63 (0.40, 1.00) 1.09 (0.73, 1.62) 1.14 (0.51, 2.55) 0.18 (0.05, 0.68) 0.69 (0.40, 1.17) 35 69 60 50 15 20 15 25 1.69% 11.97% 13.89% 18.07% 19.40% 11.92% 6.34% 16.72% 0.60 (0.41, 0.89)100.00% 35 69 60 50 15 20 15 25 300 600 600 600 900 1200 1200 1200 0.10 0.50 4.00 Relative risk (RR) Fig 5 Pooled analysis of postoperative use of rescue medication. Gabapentin and postoperative nausea and vomiting BJA 595
  • 9. Conclusion The present analysis overcomes the limitations of earlier ana- lyses and the additional moderator and sensitivity analyses conducted provide strong evidence favouring preoperative gabapentin as a pharmacotherapy for prevention of PONV in patients undergoing abdominal surgeries. The use of propofol in the perioperative period could possibly be an important factor influencing the decision to use gabapentin as a prevent- iveagent.Nevertheless,theanalgesicpropertiesandapossible longer duration of action favour preoperative gabapentin use irrespective of the anaesthetic agent. Future studies com- paring the efficacy of gabapentin with the more commonly used 5HT3 antagonists are needed to precisely define the role of preoperative gabapentin in PONV. Supplementary material Supplementary material is available at British Journal of Anaesthesia online. Authors’ contributions S.A., I.S., and S.B. were involved in the data extraction. 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  • 11. Annotations Gabapentin prophylaxis for postoperative nausea and vomiting in abdominal surgeries: a quantitative analysis of evidence from randomized controlled clinical trials Achuthan, S.; Singh, I.; Varthya, S. B.; Srinivasan, a.; Chakrabarti, a.; Hota, D. 01 Mendeley User Page no. 1 7/4/2015 9:45 Les NVPO sont un événement fréquent en post-anesthésie puisqu'ils touchent environ un tiers des patients. Les différents scores et prophylaxies utilisées bien que souvent efficaces ne closent pas le chapitre de leur prévention. La gabapentine, antivonvusilvant, a montré par ailleurs son effet analgésique en post-opératoire.Plus récemment, la gabapentine a montré un effet anti-émétique lorsqu'elle était administrée en prévention dans la chimiothérapie du cancer du sein.Cette étude est une méta-analyse des essais randomisés de la gabapentine en prévention des NVPO. Elle conclut à son efficacité, efficacité d'autant plus marquée que le propofol n'est pas utilisé comme agent d'induction et/ou d'entretien.