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Gabapentin and postoperative pain—a systematic review of randomized

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 Pain 126 (2006) 91–101
www.elsevier.com/locate/pain

Gabapentin and postoperative pain – a systematic

review of randomized controlled trials
Kok-Yuen Ho *, Tong J. Gan, Ashraf S. Habib
Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA

Received 7 February 2006; received in revised form 13 May 2006; accepted 12 June 2006

Abstract

The objective of this systematic review was to evaluate the efficacy and tolerability of perioperative gabapentin administration for
the control of acute postoperative pain. We searched Medline (1966–2006), the Cochrane Library (2006), Scopus, CINAHL and
bibliographies from clinical trials and review articles. We included randomized controlled trials (RCTs) comparing gabapentin with
inactive controls in surgical patients. Sixteen valid RCTs were included. Weighted mean difference (WMD) for postoperative pain
intensity (0–100 mm visual analogue scale) was 16.55 mm at 6 h and 10.87 mm at 24 h for treatment with a single preoperative
dose of gabapentin 1200 mg. Cumulative opioid consumption at 24 h was also significantly decreased with gabapentin (WMD,
27.90 mg). When gabapentin was administered at doses less than 1200 mg, pain intensity was also lower at 6 h (WMD,
22.43 mm) and 24 h (WMD, 13.18 mm). Cumulative 24 h opioid consumption was also lower (WMD, 7.25 mg). Gabapentin
was associated with an increased risk of sedation (Peto OR 3.86; 95% CI 2.50–5.94) but less opioid-related side effects such as vom-
iting (Peto OR 0.58; 95% CI 0.39–0.86) and pruritus (Peto OR 0.27; 95% CI 0.10–0.74). In conclusion, gabapentin has an analgesic
and opioid-sparing effect in acute postoperative pain management when used in conjunction with opioids.
 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Keywords: Systematic review; Meta-analysis; Pain; Analgesia; Surgery; Postoperative; Gabapentin

1. Introduction dependent calcium ion channels and blocks the develop-

Gabapentin is an anticonvulsant that has antinoci-
ceptive and antihyperalgesic properties (Rose and
Kam, 2002). It has a well-established role in the treat-
ment of chronic pain (Wiffen et al., 2005). In particular,
it is effective for neuropathic pain (Bennett and Simp-
son, 2004), diabetic neuropathy (Backonja et al.,
1998), postherpetic neuralgia (Rowbotham et al., 1998)
and complex regional pain syndrome (van de Vusse
et al., 2004). It binds the a-2-d subunits of voltage-
ment of hyperalgesia and central sensitization.
The use of gabapentin in acute postoperative pain
management has been evaluated in recent studies. These
studies sought to determine whether perioperative gaba-
pentin was effective in reducing postoperative pain and
whether it had opioid sparing effects. However, differ-
ences in the gabapentin dosages, the dosing regimen
and types of surgery have yielded contrasting results.
This systematic review will consider the available evi-
dence for the efficacy of perioperative gabapentin in
the control of acute postoperative pain.

2. Methods
*
Corresponding author. Tel.: +1 919 681 4660; fax: +1 919 681
7901. We followed the QUOROM guidelines for reporting meta-
E-mail address: hokokyuen@yahoo.com.sg (K.-Y. Ho). analyses (Moher, 1999).

0304-3959/$32.00  2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2006.06.018
92 K.-Y. Ho et al. / Pain 126 (2006) 91–101
2.1. Search
Published reports of randomized controlled trials (RCTs)
that investigated perioperative gabapentin administration for
postoperative pain management were searched in Medline
(1966–2006), The Cochrane Central Register of Controlled
Trials (2006), Scopus and CINAHL. Free text and MeSH
terms ‘gabapentin’, ‘pain’, ‘analgesia’, ‘analgesic’, ‘postopera-
tive’ and ‘surgery’ were used for searching. Search was per-
formed without language restriction but limited to RCTs in
humans. The last electronic search was in January 2006. Addi-
tional studies from the bibliographies of reviews or reports
were also identified. Authors of original reports were contacted
for additional information if needed.
2.2. Selection criteria
Only randomized, placebo-controlled trials that reported
on relevant pain outcomes such as pain scores, time to first
analgesic request and postoperative cumulative opioid con-
sumption were included. Reviews and abstracts were not con-
sidered. Studies incorporating a local anesthetic technique or
nerve block as part of the anesthetic regimen were excluded.
2.3. Validity assessment
One author (K.Y.H.) screened the abstracts of all retrieved
reports andexcluded thosethat did notmeet the inclusion criteria.
All included reports were then independently read by two review-
ers (K.Y.H. and A.H.) who assessed the validity of the studies
using the modified Oxford Scale (Box 1) (Pasquina et al., 2003;
Elia and Tramer, 2005). The minimum score of an included trial
was 1 and the maximum was 7. Discrepancies were resolved by
discussion or by consulting the third reviewer (T.J.G.).
Box 1: Modified Oxford Scale
Validity score (0–7)
Randomization
0 None
1 Mentioned
2 Described and adequate
Concealment of allocation
0 None
1 Yes
Double blinding
0 None
1 Mentioned
2 Described and adequate
Flow of patients
0 None
1 Described but incomplete
2 Described and adequate
2.4. Data abstraction
A data abstraction form was created and the following data
were collected: (i) type of surgery; (ii) number of patients; (iii)
gabapentin dosage and regimen; (iv) study design and dura-
tion; (v) analgesia outcome measures; and (vi) adverse effects.
The following adverse effects were noted for analysis: nau-
sea, vomiting, sedation and dizziness. Side effects reported as
drowsiness and somnolence were grouped under sedation.
Reports of lightheadedness and vertigo were analyzed together
with dizziness.
Pain intensity measured on the visual analogue scale (VAS,
0–100 mm, 0 = no pain and 100 = maximum pain), was ana-
lyzed quantitatively. Pain verbal rating scale (VRS) reported
on a 0–10 scale was converted to 0–100. The reporting of pain
scores in the randomized trials was highly disparate. Pain
scores were documented at different time intervals and some
of these studies ended before 24 h from the end of surgery.
To facilitate pooling of data, only pain scores in the immediate
(within 6 h from end of surgery) and late (24 h from end of sur-
gery) postoperative period were analyzed. Pain scores that
were reported at 2 or 4 h postsurgery were grouped under
the immediate postoperative period and analyzed together if
data at the 6 h time point were not reported. Clinical trials that
were less than 24 h in duration would not have 24 h pain scores
for data analysis. All postoperative opioid consumption was
converted to morphine equivalents (Macintyre and Ready,
2001).
2.5. Meta-analyses
Both dichotomous and continuous data were extracted. Con-
tinuous data were analyzed as weighted mean differences
(WMD) with 95% confidence intervals (CI). When mean values
and standard deviations were not reported, the authors of the
studies were contacted. If they did not reply and the data were
presented graphically, data were extracted from the graphs. If
this was not possible, the data were not considered. Dichoto-
mous data on adverse effects were summarized using relative risk
(RR) with 95% CI. For rare outcomes, Peto odds ratios (OR)
that deal better with zero cells were computed. A random effects
model was used by default. If the statistical test for heterogeneity
was negative, a fixed effects model was utilized. If the 95% CI
included 1, it was assumed that there was no statistically signif-
icant difference between gabapentin and control. Analyses were
performed using Review Manager Software (version 4.2.8,
Cochrane Collaboration). Data were graphically plotted using
forest plots to evaluate treatment effects. For statistically signif-
icant differences in the incidence of adverse effects between treat-
ment and control groups, Number-Needed-to-Treat (NNT) or
Number-Needed-to-Harm (NNH) was calculated to estimate
the clinical impact of the beneficial or harmful effect of the
intervention.
3. Results
Twenty publications that described the use of gaba-
pentin in postoperative pain management were identi-
fied between 2002 and 2006 (Fig. 1). All reports were
published in English. Four were excluded; two were
not clinical trials (Dahl et al., 2004; Wiffen et al.,
2005), one was only published in abstract form (Gregg
et al., 2001), and one was excluded because eutectic mix-
ture of local anesthetics cream and a nerve block with
ropivacaine were used in addition to general anesthesia
 K.-Y. Ho et al. / Pain 126 (2006) 91–101
Potentially relevant publications identified and
screened for retrieval (n=20)
Papers did not meet
inclusion criteria (n=3)
Randomized controlled trials considered for inclusion
(n=17)
Trial with treatment and
control groups not
suitable for comparison
(n=1)
Analyzed randomized controlled trials (n=16)
Fig. 1. Flow chart of screened, excluded and analyzed papers.
(Fassoulaki et al., 2005). Sixteen valid randomized trials
with 20 treatment arms were therefore included in the
analysis (Table 1). We contacted the authors of 10
reports to obtain additional information; but only two
answered. A total of 1151 patients were studied, of
whom 614 patients received gabapentin.
The types of surgery and gabapentin dosing regi-
mens used are presented in Table 1. Gabapentin was
given as a single preoperative dose in 11 (Dirks et al.,
2002; Pandey et al., 2004a,b, 2005a,b; Turan et al.,
2004a,b,c; Menigaux et al., 2005; Tuncer et al., 2005),
as two separate preoperative doses in 1 (Radhakrishnan
et al., 2005), and as more than two doses in the periop-
erative period in four clinical trials (Fassoulaki et al.,
2002; Dierking et al., 2004; Gilron et al., 2005; Turan
et al., 2006). The dosages of gabapentin administered
ranged between 300 and 1200 mg. To facilitate quanti-
tative analysis, three subgroups were created: (i) group
receiving single dose of gabapentin 1200 mg preopera-
tively; (ii) group receiving single dose of gabapentin
that is less than 1200 mg preoperatively; and (iii) group
receiving multiple doses of gabapentin in the perioper-
ative period. Pain intensity, total analgesic consump-
tion and time to first request for rescue analgesia
were analyzed separately in each subgroup. The num-
ber of trials analyzed for each outcome is presented
in Fig. 2.
Twelve studies reported VAS pain intensity at rest
as mean with standard deviation. Among these stud-
ies, only 1 reported VAS pain intensity on movement
(Fassoulaki et al., 2002) and meta-analysis was there-
93
fore not possible. Pain scores from three studies were
excluded from the analysis as the scores were present-
ed as median with ranges (Dirks et al., 2002; Turan
et al., 2004a; Radhakrishnan et al., 2005). One study
did not present data on pain scores (Turan et al.,
2006).
Total analgesic consumption at 24 h postsurgery
was used for analysis. Intravenous morphine con-
sumption was used as the standard and fentanyl con-
sumption reported in some studies was converted to
equianalgesic morphine-equivalent doses based on a
200 mcg fentanyl to 10 mg morphine conversion (Mac-
intyre and Ready, 2001). Data for morphine consump-
tion at 24 h were not available in four studies (Dirks
et al., 2002; Gilron et al., 2005; Radhakrishnan
et al., 2005; Tuncer et al., 2005). Three other studies
were also excluded from the analgesic consumption
analysis: one used IV tramadol for postoperative anal-
gesia (Turan et al., 2004b), one used intramuscular
diclofenac postoperatively (Turan et al., 2004c), and
one used a combination of propoxyphene, paraceta-
mol and codeine (Fassoulaki et al., 2002). Time to
first request for rescue analgesia was only reported
in four trials (Fassoulaki et al., 2002; Rorarius
et al., 2004; Turan et al., 2004c; Menigaux et al.,
2005).
Adverse effects were analyzed separately in each
of the three subgroups based on the gabapentin dos-
age and dosing regimen. Because of the small num-
ber of clinical trials in each subgroup, adverse
effects were also combined and analyzed together.
This included all 16 clinical trials. The most com-
monly reported adverse effects were nausea, vomit-
ing, sedation and dizziness. Opioid-related side
effects were also reported in some studies. We spe-
cifically identified nausea, vomiting, sedation, dizzi-
ness, pruritus, urinary retention, constipation and
respiratory depression.
3.1. Gabapentin 1200 mg single dose preoperatively
Eight trials used a single preoperative dose of
1200 mg gabapentin in the treatment group (Dirks
et al., 2002; Rorarius et al., 2004; Turan et al.,
2004a,b,c; Menigaux et al., 2005; Tuncer et al., 2005;
Pandey et al., 2005a).
3.1.1. Pain intensity
Data from six studies were analyzed. Two studies did
not report pain scores as mean and standard deviation
(Dirks et al., 2002; Turan et al., 2004a). Combined data
showed a significant decrease in pain intensity at rest
with gabapentin compared with control in the early
(WMD, 16.55 mm; 95% CI 25.66 to 7.44) and late
(WMD, 10.87 mm; 95% CI 20.90 to 0.84) postop-
erative period at 6 and 24 h, respectively (Fig. 3).
 94
Table 1
Randomized, double-blinded, placebo-controlled trials of gabapentin for postoperative pain management
Clinical trial Quality Number of Dose of gabapentin Time of gabapentin Type of surgery Pain scores TAR TFA Adverse effects
score patients (G/C) administration
Turan et al., 2006 7 25/25 1200 mg Preop, 1POD Abdominal P < 0.05 P < 0.05 – NS
and 2POD hysterectomy
Tuncer et al., 2005 1 30 (two G 800 and 1200 mg Preop Major orthopedic NS P < 0.05 – NS
treatment arms)/15 surgery
Radhakrishnan et al., 2005 5 30/30 400 mg (two doses) Preop Lumbar laminectomy/ NS NS – NS
diskectomy
Menigaux et al., 2005 7 20/20 1200 mg Preop Arthroscopic knee NS P < 0.01 P < 0.01 NS
surgery
Pandey et al., 2005a 3 80 (four G 300, 600, 900 and Preop Lumbar diskectomy P < 0.05 P < 0.05 – NS

K.-Y. Ho et al. / Pain 126 (2006) 91–101

treatment arms)/20 1200 mg
Pandey et al., 2005b 5 20/20 600 mg Preop Open donor P < 0.05 P < 0.05 – NS
nephrectomy
Gilron et al., 2005 7 23/24 600 mg (three Preop and 1POD Abdominal P < 0.05 P < 0.05 – More sedation in
doses in 24 h) hysterectomy G group (P < 0.05)
Pandey et al., 2004a 2 153/153 300 mg Preop Laparoscopic P < 0.05 P < 0.05 – More sedation and
cholecystectomy PONV in G group
(P < 0.05)
Pandey et al., 2004b 2 28/28 300 mg Preop Lumbar discoidectomy P < 0.05 P < 0.05 – NS
Dierking et al., 2004 7 39/32 1200 mg, then 600 mg · Preop and 1POD Abdominal NS P < 0.01 – NS
three doses in 24 h hysterectomy
Turan et al., 2004a 7 25/25 1200 mg Preop Spinal surgery P < 0.01 P < 0.01 – Less vomiting and
urinary retention in
G group (P < 0.05)
Turan et al., 2004b 7 25/25 1200 mg Preop Abdominal P < 0.01 P < 0.01 – NS
hysterectomy
Turan et al., 2004c 5 25/25 1200 mg Preop ENT P < 0.01 P < 0.01 P < 0.01 More dizziness in
G group (P < 0.05)
Rorarius et al., 2004 6 38/37 1200 mg Preop Vaginal hysterectomy NS P < 0.01 NS NS
Dirks et al., 2002 7 31/34 1200 mg Preop Radical mastectomy NS for pain at P < 0.01 – NS
rest; P < 0.05
for pain on
movement
Fassoulaki et al., 2002 7 22/24 400 mg tid Preop till 10POD Cancer breast surgery P < 0.05 P < 0.05 NS NS
G, gabapentin group; C, control; TFA, time to first analgesia; TAR, total analgesic requirement; NS, no significant difference between the groups; Preop, before surgery; POD, postoperative day.
P values indicate beneficial effects for gabapentin group unless otherwise indicated.
 K.-Y. Ho et al. / Pain 126 (2006) 91–101 95

Fig. 2. Number of randomized controlled trials analyzed for each outcome.

3.1.2. Twenty-four hour cumulative opioid consumption
Three studies reported on opioid consumption at 24 h
(Turan et al., 2004a; Menigaux et al., 2005; Pandey
et al., 2005a). Combined data showed that the WMD
of 27.9 mg (95% CI 31.52 to 24.29) was in favor
of gabapentin (Fig. 4).
3.1.3. Time to first request for rescue analgesic
Three studies reported data on the time to first
rescue analgesic. Out of these three studies, only
two studies had suitable data available. One study
measured time to first request for analgesic from
the instance the study drug (gabapentin or placebo)
was administered and not from the end of surgery
(Turan et al., 2004c). Meta-analysis of the remaining
two studies showed that gabapentin produced a sta-
tistically significant delay in time to first request for
analgesia (WMD 7.42 min; 95% CI 0.49–14.34)
(Fig. 5).
3.1.4. Adverse effects
Data from six studies showed that single preoperative
dose of 1200 mg gabapentin were associated with a low-
er risk of vomiting (Peto OR 0.42; 95% CI 0.24–0.76)
(Rorarius et al., 2004; Turan et al., 2004a,b,c; Tuncer
et al., 2005; Pandey et al., 2005a). NNT was 8. Patients
in the gabapentin group were at less risk of urinary
retention too (Turan et al., 2004a,b). NNT was 7. There

Fig. 3. Meta-analysis: VAS of pain intensity (0–100 mm) at 6 and 24 h in patients receiving 1200 mg gabapentin preoperatively. VAS, visual
analogue scale; WMD, weighted mean difference; CI, confidence interval.
96 K.-Y. Ho et al. / Pain 126 (2006) 91–101
Fig. 4. Meta-analysis: 24 h morphine consumption (mg) in patients receiving 1200 mg gabapentin preoperatively. WMD, weighted mean difference;
CI, confidence interval.
was no difference between gabapentin and control
groups for the other adverse effects.
3.2. Gabapentin <1200 mg single dose preoperatively
Five studies with seven treatment arms used a single
preoperative dose of gabapentin that was less than
1200 mg (Pandey et al., 2004a,b, 2005a,b; Tuncer
et al., 2005). The dose range was between 300 and
900 mg.
3.2.1. Pain intensity
Combined data from all five RCTs showed a statisti-
cally significant decrease in pain intensity at rest with
gabapentin compared with control in the early postoper-
ative period at 6 h (WMD, 22.43 mm; 95% CI 27.66
to 17.19). Combined data from four RCTs (Pandey
et al., 2004a,b, 2005a,b) showed lower pain scores at rest
in the gabapentin group in the late postoperative period
at 24 h (WMD, 13.18 mm; 95% CI 19.68 to 6.68)
(Fig. 6).
3.2.2. Twenty-four hour cumulative opioid consumption
Combined data from four RCTs (Pandey et al.,
2004a,b, 2005a,b) showed that gabapentin reduced post-
operative morphine consumption compared with con-
trol (WMD, 15.98 mg; 95% CI 23.45 to 8.50)
(Fig. 7).
3.2.3. Time to first request for rescue analgesic
None of the five studies measured time to first analge-
sia as an outcome.
Fig. 5. Meta-analysis: time to first request for rescue analgesic (min) in patients receiving 1200 mg gabapentin preoperatively. WMD, weighted mean
difference; CI, confidence interval.
3.2.4. Adverse effects
Sedation risk was higher in the group receiving less
than 1200 mg gabapentin when compared to control
(Peto OR 6.95; 95% CI 3.96–12.20). NNH was 4. Data
were only available from two studies (Pandey et al.,
2004a, 2005b) and results might have been skewed by
outcome from one of the studies (Pandey et al.,
2004a). There was no difference between gabapentin
and control groups for the other adverse effects.
3.3. Gabapentin given as multiple doses perioperatively
Five studies were included in this subgroup. Gaba-
pentin was administered as two separate 400 mg doses
preoperatively in one study (Radhakrishnan et al.,
2005). Gilron et al. administered gabapentin 600 mg
1 h preoperatively and then three times a day for 24 h
postoperatively (Gilron et al., 2005). Dierking et al.
administered 1200 mg of gabapentin before surgery fol-
lowed by 600 mg 8 hourly for an additional three doses
(Dierking et al., 2004). One study had patients in the
treatment group take 400 mg gabapentin the night
before surgery and then 400 mg three times a day for
10 days (Fassoulaki et al., 2002). The most recent trial
by Turan and co-workers had patients take 1200 mg
gabapentin preoperatively, followed by 1200 mg on the
morning of the first and second postoperative day
(Turan et al., 2006).
3.3.1. Pain intensity
Only two out of the five trials had data suitable for
meta-analysis (Fassoulaki et al., 2002; Gilron et al.,
 K.-Y. Ho et al. / Pain 126 (2006) 91–101 97

Fig. 6. Meta-analysis: VAS of pain intensity (0–100 mm) in patients receiving single dose of gabapentin <1200 mg preoperatively. WMD, weighted
mean difference; CI, confidence interval.

2005). Combined data did not show any difference
between gabapentin and control groups at both 6 and
24 h after surgery.
3.3.2. Twenty-four hour cumulative opioid consumption
Only one study measured 24 h morphine consump-
tion as an outcome (Turan et al., 2006). It showed a
24% reduction in total patient-controlled analgesia mor-
phine usage in the gabapentin group compared with the
control group.
3.3.3. Time to first request for rescue analgesic
Only one study presented these data as an outcome
and reported no difference between the gabapentin and
control groups (Fassoulaki et al., 2002).
3.3.4. Adverse effects
A statistically significant lower incidence of nausea
was observed in the patients receiving multiple doses
of gabapentin perioperatively (Peto OR 0.54; 95% CI
0.31–0.95). NNT was 9. Data were obtained from five
studies (Fassoulaki et al., 2002; Dierking et al., 2004;
Gilron et al., 2005; Radhakrishnan et al., 2005; Turan
et al., 2006). The gabapentin group was also associated
with a lower incidence of pruritus (Peto OR 0.21; 95%
CI 0.05–0.87) (Gilron et al., 2005; Radhakrishnan
et al., 2005; Turan et al., 2006). NNT was 13. Peto
OR was 0.12 (95% CI 0.02–0.9) for a lower incidence
of constipation in the gabapentin group based on one
study (Turan et al., 2006). NNT was 6. There was no dif-
ference between gabapentin and control groups for the
other adverse effects.
3.4. Adverse effects
In the subgroup analyses of adverse effects, the
number of clinical trials analyzed for each adverse
effect was small because adverse effects were variably
reported. Therefore we pooled data on adverse effects
from all studies to perform a meta-analysis (Fig. 8).
All 16 studies reported nausea as an adverse outcome.
Three studies did not report the incidence of vomiting

Fig. 7. Meta-analysis: 24 h cumulative morphine consumption (mg) in patients receiving single dose of gabapentin <1200 mg preoperatively. WMD,
weighted mean difference; CI, confidence interval.
98 K.-Y. Ho et al. / Pain 126 (2006) 91–101

Fig. 8. Meta-analysis: Adverse effects (nausea, vomiting, sedation, dizziness, pruritus, urinary retention, constipation and respiratory depression).
OR, odds ratio; WMD, weighted mean difference; CI, confidence interval.
 K.-Y. Ho et al. / Pain 126 (2006) 91–101
(Dirks et al., 2002; Gilron et al., 2005; Menigaux
et al., 2005). One study reported nausea and vomiting
collectively as a single adverse event and these data
were not included in the meta-analysis (Pandey
et al., 2004a). Quantitative analysis showed that
patients who received gabapentin experienced less
vomiting (Peto OR 0.58; 95% CI 0.39–0.86) compared
to controls with a NNT of 11. On the other hand, the
incidence of sedation was higher in the gabapentin
group (Peto OR 3.86, 95% CI 2.50–5.94) with a
NNH of 8. There was no statistically significant differ-
ence between the groups in the incidence of nausea
(Peto OR 0.72; 95% CI 0.51–1.01) or dizziness (Peto
OR 1.34; 95% CI 0.86–2.10).
Six trials reported on the incidence of pruritus
(Turan et al., 2004a,b, 2006; Gilron et al., 2005;
Radhakrishnan et al., 2005; Pandey et al., 2005b).
Combined data showed that gabapentin was associat-
ed with less pruritus compared with control (Peto OR
0.27; 95% CI 0.10–0.74) with a NNT of 15. Four tri-
als reported urinary retention as an adverse effect
(Turan et al., 2004a,b, 2006; Radhakrishnan et al.,
2005). Meta-analysis showed no statistically significant
difference in the incidence of urinary retention
between gabapentin and the control group (Peto OR
0.51; 95% CI 0.23–1.14). Only three trials reported
on the incidence of constipation and combined data
again demonstrated no statistically significant differ-
ence between gabapentin and the control group (Peto
OR 0.34; 95% CI 0.11–1.11) (Turan et al., 2004a,b,
2006). Combined data from two studies (Pandey
et al., 2004a, 2005a) did not show any difference in
the incidence of respiratory depression between gaba-
pentin and the control group (Peto OR 1.07; 95%
CI 0.21–5.49).
4. Discussion
4.1. Efficacy and adverse effects
This systematic review demonstrated that preopera-
tive gabapentin administration was useful for postoper-
ative pain management. A single preoperative dose of
gabapentin, 1200 mg or less, effectively reduced pain
intensity and opioid consumption for the first 24 h after
surgery. In the subgroup that received a single 1200 mg
of gabapentin preoperatively, the time to first request
for rescue analgesia was also prolonged. However, mul-
tiple dosing with gabapentin preoperatively and contin-
ued postoperatively did not appear to reduce VAS pain
scores.
This systematic review therefore demonstrates a
potential role for preemptive gabapentin as an adjunct
to standard postoperative pain management. In the
groups receiving a single dose of gabapentin preopera-
tively, the reduction in pain scores appeared to be more
99
pronounced in the early postoperative period. However,
this reduction was still significant at 24 h and was
associated with a significant reduction in opioid con-
sumption. Gabapentin given as multiple doses perioper-
atively did not demonstrate lower VAS pain scores
compared to the control group. However, this result
should be interpreted with caution, as there were only
two studies with appropriate data for meta-analysis in
this subgroup.
While this analysis demonstrated a statistically signif-
icant prolongation to the time of first request for rescue
analgesics, the prolongation was only by about 7 min
and therefore is of no clinical importance. However, this
outcome was only reported in four of the 16 randomized
controlled trials.
Pain after surgery is predominantly nociceptive in
nature. However, prolonged central sensitization mani-
festing as hyperalgesia does occur after surgical trauma
(Field et al., 1997). Gabapentin has been shown to pre-
vent central sensitization by reducing hyperexcitability
of secondary nociceptive neurons in the dorsal horn.
This may be related to suppression of noxious stimu-
lus-induced excitatory amino acid release in the spinal
cord (Feng et al., 2003). Little is known about how
gabapentin modulates postoperative pain in the pres-
ence of opioids. Gabapentin and morphine may be syn-
ergistic due to their separate action on the peripheral
and central nervous system (Matthews and Dickenson,
2002). Gabapentin may also decrease postoperative
morphine requirement through preventing the develop-
ment of opioid tolerance (Gilron et al., 2003).
The incidence of postoperative vomiting and pruritus
was significantly lower in the gabapentin group. This
may be explained by a reduction in opioid consumption
and the associated decrease in opioid-related adverse
effects. There was also a trend towards a lower incidence
of nausea, urinary retention and constipation in the
gabapentin group, but the difference did not achieve sta-
tistical significance. One study however reported a sig-
nificantly greater incidence of postoperative nausea
and vomiting in patients undergoing laparoscopic sur-
gery who had received gabapentin (Pandey et al.,
2004a). This study was not included in our systematic
review since the authors did not report the incidence
of nausea and vomiting separately but reported the inci-
dence of both outcomes collectively. The incidence of
sedation was significantly higher in the gabapentin
group. There was also a trend for more dizziness in
patients receiving gabapentin. This was in line with the
side effect profile of gabapentin and might limit the use-
fulness of gabapentin in ambulatory settings. Whether
this effect is clinically significant and whether it leads
to prolongation of recovery time and postanesthesia
care unit stay needs further evaluation. No serious
adverse effects were reported with the perioperative
administration of gabapentin.
100 K.-Y. Ho et al. / Pain 126 (2006) 91–101
4.2. Limitations
A limitation of this systematic review is the wide var-
iability in type of surgery, gabapentin regimen, type of
postoperative rescue analgesic and reported outcomes.
Minimally invasive surgery such as laparoscopic chole-
cystectomy or arthroscopic knee surgery is not expected
to be as painful as spine surgery or abdominal surgery.
Differences in gabapentin doses as well as frequency of
administration will undoubtedly introduce disparity in
the pain outcomes. The use of tramadol and non-opioid
analgesics as rescue agents in some trials made pooling
of data from such studies for meta-analysis impossible.
Finally, outcomes measures were not consistent and
only a handful of studies reported time to first request
for analgesia. Presentation of data was also unsatisfac-
tory in some studies. Results were either reported with-
out data or data were presented as figures only. Authors
were unwilling or unable to respond to our request for
more information. As a result, data pooling was not fea-
sible in certain subgroups for some outcomes. Further-
more, most trials included a small sample size.
Respiratory depression is an adverse event that can
occur with the use of postoperative opioids. Unfortu-
nately, only two of the 16 clinical trials included in this
systematic review reported respiratory depression as an
adverse event (Pandey et al., 2004a, 2005a). Respiratory
depression may be defined as respiratory rate less than 8
per minute, arterial oxygen saturation of less than 90%
on pulse oximetry monitoring or the need for intubation
and assisted ventilation. It was not defined in these two
studies.
This review did not include any data on the efficacy of
gabapentin in the reduction of chronic pain. This effect
was only explored in one study that involved patients
undergoing breast cancer surgery (Fassoulaki et al.,
2005). This study was excluded from the meta-analysis.
The authors employed a multimodal analgesic regimen
including gabapentin, EMLA cream application to the
wound and brachial plexus block with ropivacaine.
The incidence of chronic pain was significantly lower
three months after surgery in the gabapentin group
but there was no difference at six months.
4.3. Research agenda
This systematic review identifies some areas where
future research with gabapentin in the perioperative
area is warranted. Future clinical trials should examine
the analgesic efficacy of gabapentin in major or painful
surgery to better evaluate the opioid-sparing effect of
gabapentin. Trials should also include long-term follow
up to investigate the influence of perioperative gabapen-
tin administration on preventing chronic pain syn-
dromes. Trials should also be adequately powered to
detect differences in pain outcomes and adverse effects.
A focus on the possible impact of sedation on recovery
profile, especially of ambulatory patients, is warranted.
Respiratory depression should be clearly defined and
clinical trials should attempt to compare its incidence
between gabapentin and control groups. Adequately
powered dose response studies are also needed to deter-
mine the optimal regimen for the perioperative adminis-
tration of gabapentin. To date, only one study
compared the perioperative administration of gabapen-
tin with that of non-steroidal anti-inflammatory drugs
(NSAIDs) and reported no difference in efficacy (Turan
et al., 2006). The lack of effect on platelets, gastric muco-
sa and renal function may give gabapentin advantages
over NSAIDs in the perioperative period. Further stud-
ies evaluating the analgesic and side effect profiles of
gabapentin compared with NSAIDs, and the potential
benefit of combining both agents are required. Finally,
there is a need to explore possible pharmacokinetic
and pharmacodynamic interactions with other drugs
administered in the perioperative period.
4.4. Conclusion
The perioperative administration of gabapentin is
effective in reducing pain scores, opioid requirements
and opioid-related adverse effects in the first 24 h after
surgery. Sedation was associated with its use but no seri-
ous adverse effects were observed. Future trials should
investigate the effect of perioperative gabapentin on
the development of chronic postsurgical pain.
Acknowledgements
Special thanks to Dr. M. Radhakrishnan and Dr. A.
Fassoulaki for responding and providing us with addi-
tional information for our review.
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