Clinical Concepts and Commentary

Bruno Riou, M.D., Ph.D., Editor

Perioperative Gabapentinoids
Choice of Agent, Dose, Timing, and Effects on Chronic
Postsurgical Pain
Peter C. Schmidt, M.D.,* Gabriela Ruchelli, B.A., Sean C. Mackey, M.D., Ph.D.,
Ian R. Carroll, M.D., M.S. Epi.
This article has been selected for the Anesthesiology CME Program. Learning objectives
and disclosure and ordering information can be found in the CME section at the front
of this issue.

Mechanisms of Action, Pharmacokinetics,

and Adverse Effects

HE gabapentinoids pregabalin and gabapentin are

both indicated for the treatment of postherpetic
neuralgia and as adjuvant therapy for seizure disorders.
Pregabalin is additionally approved for the treatment of
fibromyalgia and neuropathic pain associated with diabetes
mellitus or spinal cord injury. There are now more than
100 clinical trials examining the use of gabapentin perioperatively to reduce postoperative pain and a smaller but
growing number of clinical trials examining the efficacy of
pregabalin. As a body of work, they support the conclusion
that perioperative use of gabapentinoids reduces early postoperative pain and opioid use.13 This article describes how
this body of work may inform a surgeons or anesthesiologists optimization of perioperative use of gabapentinoids,
including choice of agent, dose, timing, and duration of
therapy. In addition, we described the less clear data for
and against gabapentinoid efficacy in preventing the emergence of chronic postsurgical pain.

* Clinical Instructor of Anesthesiology, Research Assistant,

Professor of Anesthesiology and Pain Medicine, Assistant Professor of Anesthesiology and Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Pain Medicine,
Stanford University, Palo Alto, California.
Received from the Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Pain Medicine, Stanford University, Palo Alto, California. Submitted for publication February 6,
2013. Accepted for publication June 27, 2013. Support was provided solely from institutional and/or departmental sources. The
authors declare no competing interests. Figures 13 were prepared
by Annemarie B. Johnson, C.M.I., Medical Illustrator, Vivo Visuals,
Winston-Salem, North Carolina.
Address correspondence to Dr. Carroll: Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Pain
Medicine, Stanford University, 1070 Arastradero Road Room 285,
MC 5596, Palo Alto, California 94304. irc39@pain.stanford.edu.
This article may be accessed for personal use at no charge through
the Journal Web site, www.anesthesiology.org.
Copyright 2013, the American Society of Anesthesiologists, Inc. Lippincott
Williams & Wilkins. Anesthesiology 2013; 119:121521

Anesthesiology, V 119 No 5

Although both of the gabapentinoids are structural analogs of -aminobutyric acid, neither has any activity at the
-aminobutyric acid receptors (fig.1). Instead, they bind to
the -2 subunit of presynaptic P/Q-type voltage-gated calcium channels, modulating the traffic and function of these
channels. This in turn is thought to modulate the subsequent
release of excitatory neurotransmitters from activated nociceptors.4 By modulating calcium-induced release of glutamate
from activated pain-transmitting neurons, these drugs may
inhibit pain transmission and central sensitization (fig.2).
Alternatively, some evidence indicates that their antinociceptive mechanism may arise through activation of noradrenergic
pain-inhibiting pathways in the spinal cord and brain.5
The principal differences between these two drugs arise
not from different modes of action but rather from differing
bioavailability. Although both drugs are absorbed by amino
acid carriers, gabapentin absorption is limited to a relatively
small part of the duodenum, whereas pregabalin is absorbed
throughout the small intestine. Once the active transport
of gabapentin in the duodenum is saturated, progressively
higher levels of gabapentin ingestion yield progressively
smaller increases in blood concentrations. Conceptually,
this provides an upper border not only to efficacy but also to
adverse effects. In contrast, pregabalin appears to be absorbed
throughout the small intestines and demonstrates linear
uptake without transporter saturation at therapeutic concentrations.6,7 Therefore, at least conceptually, pregabalin might
demonstrate both increased efficacy and increased side effects
in situations that require high doses. Both pregabalin and
gabapentin exhibit minimal protein binding and are renally
excreted without significant metabolism. Pharmacokinetic
interactions are minimal, though gabapentin absorption can
be significantly impaired by antacids, even when given up to
2h after dosing. This should be considered in preoperative

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November 2013

Use of Gabapentinoids in the Perioperative Setting

Cl-

GABA

these agents postoperatively, these side effects should be

sought and managed if needed through dose reduction.
Interestingly, available data suggest that perioperative gabapentin actually reduces the likelihood of postoperative
delirium15 and that pregabalin may reduce the incidence of
vomiting.10 These effects may be mediated through a reduction in opioid use.

Gabapentin/
pregabalin

Timing of Perioperative Dosing

Fig. 1. The gabapentinoids are not agonists at -aminobutyric
acid (GABA) receptors.

situations calling for the use of bicitra. The elimination halflife ranges of gabapentin and pregabalin are 4.88.7h and
5.56.3h, respectively.4 Dosing adjustments for both drugs
must be considered in cases of renal dysfunction8,9 (table1).
The gabapentinoids are generally very well tolerated.
The most common side effects reported with pregabalin are
sedation, dizziness or headache, and visual disturbances.10
In addition to sedation and dizziness, gabapentin users also
report peripheral edema.11 Even massive overdoses of both
drugs have been managed only with supportive care, typically on an outpatient basis.1214 However, when continuing

Sensory
cortex

Human clinical trials of perioperative gabapentinoids

support the belief that gabapentin is helpful in reducing
acute postoperative pain and opioid consumption whether
given preoperatively or postoperatively. At least two trials have directly compared the administration of gabapentin 2h preoperatively versus immediately postincision
via a nasogastric tube. Patients given gabapentin preoperatively as well as those given gabapentin immediately
postincision both demonstrated lower visual analog scale
scores at all time points and used less fentanyl compared
with the placebo group. However, there was no difference in total opioid consumption or pain scores at any
time point between the pre-and postincision gabapentintreated groups.16,17 More recently, Cheung et al. used a

Limbic
system

Gabapentin/pregabalin
2 subunit

Enhanced
locus ceruleus
activation

Calcium

Enhanced
descending
noradrenergic
inhibition

P/Q type
voltage gate
calcium
channel

Nociceptive
neuron

Inhibitory
noradrenergic
neuron

Painful
stimulus

Nociceptive
neuron

Postsynaptic
neuron

Fig. 2. Hypothesized mechanisms of action of gabapentin. Gabapentin binds to the -2 subunit of voltage-gated P/Q-type
calcium channels. This binding appears to modulate the function and traffic of these channels which appear on the synaptic
bulb of presynaptic neurons. Calcium influx through these channels after a pain-evoked action potential is believed to trigger
the fusion of synaptic vesicles with the neuronal membrane and consequent release of neurotransmitters in the dorsal horn of
the spinal cord. Gabapentin may exert its analgesic effect by inhibiting or modulating this process. In addition, gabapentin may
exert an analgesic effect by activating descending inhibitory noradrenergic pathways that regulate neurotransmission of pain
signals in the dorsal horn of the spinal cord.
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Schmidt et al.

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Table 1. Dosage Adjustments for Renal Impairment

Creatinine
Clearance,
ml/min

Maximum
Daily Pregabalin
Dose, mg

Maximum
Daily Gabapentin
Dose, mg

600
300
150
75

3,600
1,400
700
300

60
3060
1530
15

crossover design to examine the efficacy of preoperative

versus immediately postoperative administration of 75mg
of oral pregabalin. Patients were followed for 72h after
surgery, and the area under the curve for numerical rating scale in the first 24h was significantly lower at rest for
patients receiving postoperative pregabalin. However, the
overall impression conveyed by their data was that any difference that exists between preoperative dosing and postoperative dosing appears to be quite small.18 Similarly, in a
study that examined preoperative and postoperative gabapentin versus preoperative gabapentin alone, patients who
received gabapentin postoperatively used significantly less
morphine via patient-controlled analgesia at 24, 36, and
48h. Patients who received gabapentin postoperatively
also had significantly better active assisted knee flexion
on postoperative day 2 and postoperative day 3 compared
with those who received preoperative gabapentin alone.19
Furthermore, a Cochrane review that included data from
four unpublished studies concluded that gabapentin is
effective in already established acute postoperative pain
even when dosed solely postoperatively.20 Thus, the existing data are at odds with preconceptions that preoperative dosing is critical for reducing immediate postoperative

pain or opioid use. However, as detailed below, almost all

of the studies assessing the potential long-term benefits of
perioperative gabapentin did include preoperative dosing.
For this reason, we conclude that such a preoperative dose
is desirable, but the failure to give such a dose should not
dissuade the clinician from postoperative dosing.
Most of the studies that have examined the preoperative
administration of the gabapentinoids have administered the
preoperative dose between 1 and 2h before surgery. It has
been reported that the time to peak plasma level after oral
administration of gabapentin in humans is approximately
2h and the time to peak plasma level after oral administration of pregabalin is approximately 1h. However, it has also
been reported that the time to peak cerebrospinal fluid level
may be much longer. Among patients undergoing total knee
replacement, peak cerebrospinal fluid levels of pregabalin
occur at a median time of 8h after administration.21 These
data suggest that preoperative dosing may need to occur significantly earlier to exert its full opioid-sparing, pain-relieving (antihyperalgesic), and pain-preventing (preventative
analgesia) effects.

Optimal Perioperative Dose

The relatively few studies that have attempted to identify the
optimal dose of gabapentin or pregabalin for perioperative
use have generally enrolled too few patients per trial arm to
make definitive recommendations (table2 for summary)
though the results have been promising. For example, Khan
et al.17 studied 175 patients undergoing lumbar laminectomy
and found that patients who received either 900 or 1,200mg
of gabapentin (either pre- or postoperatively) had lower pain
scores throughout the entire first 24h than patients who
received either placebo or 600mg of gabapentin.

Table 2. Studies Addressing Optimal Dose

Authors

Surgery

Design

Khan et al.17

175 Laminectomy

Placebo, 600mg, 900mg, or

1,200mg of gabapentin given
preoperatively or postincision

Pandey et al.22

100 Discectomy

Placebo, 300mg, 600mg, 900mg, or

1,200mg of gabapentin given 2h
preoperatively

Van Elstraete
etal.23

67 Lumbar spinal
fusion

Kim et al.24

84 Lumbar spinal
fusion

Determination of optimal gabapentin dose for 30% reduction in

morphine use by an up-and-down
sequential allocation technique
Placebo, 75mg, or 150mg of pregabalin preoperatively

Jokela et al.25

90 Laparoscopic
gynecological surgery

Active placebo, 75mg of pregabalin, or 150mg of pregabalin

preoperatively

Results
Patients receiving either 900 or
1,200mg had lower pain scores during the first 24h compared with the
600mg and placebo groups
Patients receiving 600mg had lower
visual analog scores at all time
points compared with placebo or
300mg groups
Optimal dose for 3050% reduction inmorphine use calculated at
21.7mg/kg (1,500mg per 70kg)
Patient-controlled analgesia and adjuvant analgesic use were lower in the
150mg group but not in the 75mg
group compared with placebo
Pain scores at rest and in motion were
lower in the 150mg group but not
the 75mg group compared with
placebo

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Use of Gabapentinoids in the Perioperative Setting

These data were mirrored in 100 patients undergoing

lumbar discectomy in which the authors found that patients
who received either 600, 900, or 1,200mg of gabapentin had
lower visual analog scale scores at all time points than those
receiving either placebo or gabapentin 300mg.22 Similarly, a
study on the optimal dose of gabapentin to reduce morphine
consumption by 30% indicated that although lower doses
of preoperative gabapentin (300600mg) may reduce postoperative pain and opioid use, higher doses (9001,500mg)
may be even more effective.23
There also appears to be more significant efficacy with
regard to reducing opioid consumption after surgery when
higher doses of pregabalin are used. Two studies have found
that 150mg of pregabalin but not 75mg of pregabalin was
superior to placebo in reducing postoperative opioid consumption or pain scores.24,25
Overall, these data suggest that higher doses of preoperative gabapentin (1,200mg) and pregabalin (300mg) are
significantly more effective than lower doses. Furthermore,
continuing gabapentin or pregabalin postoperatively is
likely more effective than a single preoperative dose of either
gabapentinoids.

hysterectomy, patients were randomized to receive 300mg of

pregabalin, 900mg of gabapentin, or placebo 12h before
surgery. The pregabalin and gabapentin groups both had
lower pain scores in the first hour after surgery, and these
patients used smaller amounts of diclofenac compared with
placebo. Pregabalin showed a greater decrease in pain intensity in the first hour after surgery than gabapentin, but was
similar thereafter. The incidence of side effects was similar in
the pregabalin and gabapentin groups.29 Unfortunately, there
are no studies looking at long-term outcomes such as pain
at 1 month, 3 months, or a year after surgery that compare
gabapentin and pregabalin directly.
Another consideration in the choice of perioperative gabapentinoids is cost, as gabapentin is available in generic form,
whereas pregabalin is still patent-protected. This cost difference
can be significant if prolonged postoperative dosing is planned.
In conclusion, there is more and better overall evidence
for choosing gabapentin to reduce early postoperative pain.
However, there is sufficient evidence for clinicians to choose
pregabalin as an alternative. The question of whether one
agent is more efficacious or has fewer side effects would benefit from larger studies directly comparing the two drugs.

Gabapentin or Pregabalin?

Perioperative Gabapentinoids and Chronic

Postsurgical Pain

Far more studies have been done examining the use of gabapentin perioperatively than of pregabalin in the same context. However, the single best study (in terms of adequate
power and duration of follow-up) of perioperative gabapentinoids for reducing chronic pain was conducted using
pregabalin.26
Three meta-analyses of adjunctive use of gabapentin for
perioperative use have concluded that its use reduces early
postoperative pain and opioid use after surgery.13 In contrast,
a single meta-analysis from early 2010 examining the adjuvant
use of pregabalin for surgical pain concluded that although it
clearly reduced postoperative opioid use, there was insufficient
evidence to state that it also reduced early postoperative pain
scores.27 However, these results should be considered in light
of the fact that only 5 of 45 articles on pregabalin for postoperative pain published between the years 2000 and 2010 had
data that was included in this meta-analysis, and these studies
included only 223 patients who received pregabalin.
At the time of writing this article, only two studies have
examined the comparative effectiveness of gabapentin and
pregabalin for the reduction of perioperative pain. In the first
study, 90 patients undergoing laminectomy or discectomy
were randomly assigned to receive study medication 2h before
surgery and 10 and 22h after the operation. Study medication was either placebo, 150mg of pregabalin, or 600mg of
gabapentin. Pregabalin and gabapentin were both superior
to placebo in reducing the overall morphine consumption,
preoperative anxiety, pruritus, as well as improving overall
patient satisfaction. However, no difference in these measures
was found between gabapentin and pregabalin.28 In a second study that examined 90 women undergoing abdominal

In general, studies examining the effect of perioperative gabapentin on persistent postsurgical pain have been limited by
small sample size, limited follow-up, varied surgical populations, and widely varying dosing regimens. These regimens
have included preoperative dosing only, postoperative only, or
both pre- and postoperative dosing. The duration of postoperative dosing has varied from as little as one single postoperative
dose to repeated dosing for as long as 30 days. Studies have also
suffered from limited follow-up periods. The longest follow-up
to evaluate effects on chronic pain was only 6 months.
At least 16 trials have been conducted examining the effect
of perioperative gabapentinoids on long-term pain,26,3044
with 9 demonstrating positive results (tables3 and 4 for summary). Of note, the four trials of perioperative gabapentin that
failed to identify any positive benefit were all markedly underpowered for that comparison. Therefore, the failure to find an
effect should not be construed as strong evidence that an effect
does not exist. In these studies, the number of patients per
group that were available for long-term follow-up after taking
perioperative gabapentin ranged from only 15 to 28.33,39,40,44
The single best-powered study examining the perioperative effect of gabapentinoids on persistent postsurgical pain
was also conducted using pregabalin. Buvanendran et al. randomized 240 patients undergoing total knee replacements to
receive either placebo or pregabalin 300mg preoperatively,
150mg twice a day for the first 10 days and 50mg twice
a day from days 1014 after surgery. Most importantly, 6
months after surgery, 113 of the 120 patients initially randomized to pregabalin were still available for follow-up and
were analyzed in their intent-to-treat analysis. Range of

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Table 3. Studies Finding an Effect on Prolonged Postoperative Pain

Authors

Fassoulaki
etal.35

60

Abdominal
hysterectomy

Sen et al.43

60

Herniorrhaphy

Sen et al.42

60

Gabapentin 1,200mg 1h before surgery

Brogly et al.31

50

Abdominal
hysterectomy
Thyroidectomy
Mastectomy

Gabapentin 300mg/day starting the

night before surgery and continuing
for 10 days
Gabapentin 1,200mg/day for 10 days
after surgery
Pregabalin 300mg 12h before surgery
and a 14-day taper after surgery
Pregabalin 150mg 1h before surgery
and 150mg daily for 5 days
Pregabalin 300mg 90min before surgery and 150mg at 12 and 24h after
surgery

Amr and
Yousef30
Fassoulaki
etal.36
Buvanendran
etal.26
Pesonen
etal.41
Burke and
Shorten32

150
75
240
70
40

Surgery

Breast surgery
for cancer
Total knee
arthroplasty
Cardiac surgery
Lumbar
discectomy

Gabapentinoid Dose
Gabapentin 400mg every 6h beginning
preoperatively and continuing for 5
days
Gabapentin 1,200mg 1h before surgery

Gabapentin 1,200mg 2h before surgery

motion was improved in the pregabalin group at 30 days

after surgery, and the incidence of chronic postsurgical neuropathic pain was less frequent in the pregabalin group (0%)
compared with the placebo group (8.7 and 5.2% at 3 and
6 months, respectively). Of note, the long-term reduction
in pain produced by pregabalin was produced at the cost of
increased sedation and confusion on the day of surgery in
patients receiving pregabalin.26
Recently, Clarke et al.45 conducted a meta-analysis evaluating the combined trials of both pregabalin and gabapentin

Findings
Decreased incidence and intensity
of pain at 1 month
Decreased pain scores at 1, 3, and
6 months
Decreased incidence of incisional
pain at 1, 3, and 6 months
Decreased incidence of neuropathic pain at 6 months
Decreased incidence of burning
pain at 6 months
Decreased incidence of burning
pain at 3 months
Decreased incidence of neuropathic pain at 3 and 6 months
Decreased incidence of pain with
movement at 3 months
Decreased pain scores and
improved function at 3 months

to prevent chronic postsurgical pain. They concluded that

better designed and appropriately powered clinical trials
are needed, but the combined data supported the view that
perioperative administration of gabapentinoids is effective
at reducing chronic postsurgical pain. These conclusions
are weakened by the hazard of combining trials of different
agents, doses, and durations in a single meta-analysis.
Overall, the data regarding the use of gabapentinoids to
prevent chronic postsurgical pain are mixed. However, the
studies that have failed to find an effect have generally been

Table 4. Studies Finding No Effect on Prolonged Postoperative Pain

Authors

Surgery

Ucak et al.44

40

Clarke et al.33

126

Moore et al.39

44

Cesarean
section

Nikolajsen
etal.40

41

Lower limb
amputation

Gianesello
etal.37

60

Kim et al.38

94

Fassoulaki
etal.35

80

Lumbar laminectomy and

fusion
Endoscopic
thyroidectomy
Abdominal hysterectomy or
myomectomy

Coronary artery
bypass graft
Total hip
arthroplasty

Gabapentinoid Dose
Gabapentin 1,200mg before and for 2
days after surgery
Gabapentin 600mg 12h before surgery or 600mg immediately postoperatively
Gabapentin 600mg 1h before surgery
Gabapentin titrated to 2,400mg/day
beginning on the first postoperative
day and continuing for 30 days
Pregabalin 300mg 1h before surgery
for 2 days after surgery

Findings
No difference in pain scores at 1
and 3 months (all scores 1)
No difference in presence or severity of pain at 6 months
No difference in persistent pain or
abnormal wound sensation at 3
months
No difference in phantom or stump
pain at 3 and 6 months

Pregabalin 150mg 1h before surgery

and at 12h after surgery

No difference in pain scores at 3

months and 1 yr (quality of life
measures improved at 3 months)
No difference in pain or hypoesthesia at 3 months

Pregabalin 150mg every 8h starting

the afternoon before surgery and
continuing 5 days

No difference in presence of pain,

analgesic intake, or wound sensation at 1 and 3 months

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Use of Gabapentinoids in the Perioperative Setting

small and underpowered. The more numerous positive studies have had only modest power as well, suggesting the effect
size of gabapentinoids for preventing chronic pain may be
quite substantial and clinically relevant. As suggested by the
recent meta-analysis,45 it is now considerably more likely
than not that gabapentinoids do have a preventative effect
with regard to the formation of chronic postsurgical pain.

Pregabalin
At least 2 hours
prior to surgery

Consider dosing the

night prior to surgery
if clinical situation
allows (e.g. inpatient)

600mg
Postoperative
days 1-14

It should now be generally accepted that the gabapentinoids

are effective in reducing immediate postoperative pain and
opioid consumption. The clinician should recognize that
this has been better established for gabapentin than pregabalin. However, larger studies with both longer follow-up and
improved patient retention will be needed to more definitively test the efficacy of these agents to reduce the emergence of chronic postsurgical pain. When more studies on
both pregabalin and gabapentin have been done assessing the
effect of the gabapentinoids on chronic pain, another metaanalysis should examine the strength of the body of evidence
as a whole. However, the currently available data support the
conclusion that such a preventative analgesic effect is likely.
Further studies must also test the relative efficacy of gabapentin and pregabalin. Only then will the optimal gabapentinoid treatment become clear. Nonetheless, the existing
studies suggest that higher preoperative doses and additional
postoperative doses are advantageous in reducing immediate
postsurgical pain. Failure to give a preoperative dose should
not preclude the giving of intraoperative doses via nasogastric tube or postoperative doses alone.
Further definition of uncommon side effects, the optimal preoperative dose, postoperative dose, treatment duration, and timing of doses are needed before perioperative
gabapentinoids can be recommended as the standard of care
for all patients. However, we believe the current evidence is
sufficient to recommend that either gabapentin 1,200mg or
pregabalin 300mg should be given at least 2h before surgery for patients at risk of developing either severe acute pain
(e.g., the chronic opioid-consuming patient) or prolonged
pain after surgery (e.g., thoracotomy). Either gabapentin
or pregabalin should then be continued after surgery, but
the optimal duration of treatment is unknown. The positive outcomes reported by Buvanendran26 suggest that continued dosing of gabapentinoids for 14 days after surgery is
warranted. We recommend either postoperative gabapentin
600mg thrice a day or pregabalin 150mg twice a day (fig.3).
Postoperative gabapentinoid dosage should be decreased
or stopped in the face of sedation, dizziness, or confusion.
Given the evidence suggesting that it takes 8h for pregabalin
to reach peak cerebrospinal fluid levels21 (and possibly 46h
for gabapentin to reach peak cerebrospinal fluid levels),46,47
it is possible that starting dosing the night before surgery
may ultimately prove more beneficial than initiating dosing
2h before surgery, but this effect may be at the risk of inducing dizziness, sedation, or confusion at home before surgery.

1200mg

150mg

Conclusion and Recommendations

Anesthesiology 2013; 119:1215-21

300mg

Gabapentin

600mg
150mg

Monitor for excessive

sedation, dizziness, or
confusion

600mg

Fig. 3. Recommended dosing of perioperative gabapentinoids. Higher dose regimens appear more effective than lower
dose regimens. Dosing may be initiated preoperatively, intraoperatively, or postoperativelyall three regimens have been
shown to reduce early postoperative pain. Optimal duration
of treatment is unknown, but studies with the most compelling outcomes have given gabapentinoids for up to 2 weeks.
The single best study demonstrating reduction of chronic pain
was accomplished with pregabalin; however, gabapentin has
been studied perioperatively far more extensively. The overall
data for reducing early postoperative pain and opioid use are
most compelling for gabapentin. Either agents are appropriate and are recommended for patients at high risk of severe
postoperative pain or chronic postsurgical pain.

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