Palliative Medicine 2004; 18: 5 ¡/11

Review

Gabapentin in the treatment of neuropathic pain

Michael I Bennett St Gemma‘s Hospice, Leeds and Karen H Simpson
St James‘s University Hospital, Leeds

Abstract: This paper reviews the pharmacology and clinical effectiveness of gabapentin in
the treatment of neuropathic pain. Gabapentin has antihyperalgesic and antiallodynic
properties but does not have significant actions as an anti-nociceptive agent. Its
mechanisms of action appear to be a complex synergy between increased GABA synthesis,
non-NMDA receptor antagonism and binding to the a2 d subunit of voltage dependent
calcium channels. The latter action inhibits the release of excitatory neurotransmitters.
Clinically, several large randomized controlled trials have demonstrated its effectiveness in
the treatment of a variety of neuropathic pain syndromes. Patients with neuropathic pain
can expect a mean reduction in pain score of 2.05 points on an 11 point numerical rating
scale compared with a reduction of 0.94 points if they had taken the placebo. Around 30%
of patients can expect to achieve more than 50% pain relief and a similar number will also
experience minor adverse events; the most common of which are somnolence and
dizziness. In patients with neuropathic pain due to cancer, higher response rates might be
observed with gabapentin when administered with opioids because of a synergistic
interaction. Palliative Medicine 2004; 18: 5 ¡/11

Key words: Gabapentin; neuropathic pain

Introduction since the 1940s.1 This practice was based on observations

that the paroxysmal pain of trigeminal neuralgia, or tic
Drug development douloureux, resembled epilepsy and led to the term
Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, ‘epileptiform neuralgia’.2 Current evidence suggests that
was licensed for use as an antiepileptic agent in the UK in the pathophysiology of paroxysmal pain may be related
1993 and in the USA in 1994. It was originally to bursts of ectopic discharges from damaged nerves. The
synthesized as a cyclic analogue of gamma aminobutyric mechanism responsible for spontaneous ectopic firing is
acid (GABA) to be used to reduce seizure frequency membrane remodelling. This results in an excess of
when added to conventional antiepileptic drugs. GABA
voltage sensitive sodium channels in the area of nerve
is a principal neurotransmitter found in inhibitory
damage at either end-bulbs 3 ,4 or demyelinated areas.5
interneurones in the dorsal horn. Like GABA, gabapen-
Phenytoin and carbamazepine may block use-dependent
tin is lipophylic and therefore able to pass through the
sodium channels in preference to inactive channels6,7 and
blood ¡/brain barrier easily. Gabapentin gained a UK
phenytoin has been shown to reduce ectopic discharges in
licence for the treatment of neuropathic pain in 2000. It is
vitro. 8
available as tablets or capsules. The marketing authoriza-
Other important approaches to the control of chronic
tion allows a maximum of 1.8 g per day in three divided
neuropathic pain have involved GABA mechanisms.
doses for this indication. However, it is sometimes used
Activation of GABA-mediated inhibition can result in
clinically in higher doses.
analgesia and a number of agents have been examined in
this context. Sodium valproate enhances GABA function
Rationale for antiepileptics in neuropathic pain
by an unknown mechanism, but it is thought to be either
Conventional antiepileptic drugs, such as phenytoin and through binding to the GABA A complex or enhancing
carbamazepine, have been used to treat neuropathic pain
GABA synthesis or release.9 Anecdotal evidence exists
Address for correspondence: Michael Bennett, St Gemma’s
for sodium valproate’s analgesic effect in the treatment of
Hospice, 329 Harrogate Road, Leeds LS17 6QD, UK. trigeminal and post herpetic neuralgia.10 ,1 1 Benzodiaze-
E-mail: m.bennett@st-gemma.co.uk pines, such as clonazepam (that bind to GABAA /
# Arnold 2004 10.1191/0269216304pm845ra
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6 MI Bennett and KH Simpson

benzodiazepine receptor complexes to enhance GABA- Site of action of gapapentin

mediated inhibition) have little evidence to support their The mechanism of action of gabapentin remains un-
role in neuropathic pain.1 2 Baclofen is a GABAB agonist known. Evidence suggests that it is most likely to be the
that results in a presynaptic reduction of excitatory result of a complex synergy between increased GABA
neurotransmitter release and postsynaptic inhibition of synthesis, non-NMDA receptor antagonism and binding
neuronal response.13 There is good evidence that baclo- to the a2 d subunit of voltage dependent calcium channels.
fen is effective in trigeminal neuralgia.14 Vigabatrin, a The latter action inhibits the release of excitatory
newer antiepileptic drug, competitively inhibits GABA neurotransmitters.
aminotransferase, and thus enhances synaptic concentra- Although it was expected to act as a GABA agonist,
tions of GABA. This drug may have a future role in the gabapentin does not act directly on GABA receptors, 22 ,2 3
treatment of neuropathic pain, but no data are available nor does it influence the reuptake of GABA.2 4 It does
to support this at present. increase the synthesis of GABA from glutamate and
enhances its release from astrocytes.25 ,2 6
Antiepileptics and analgesia Initially, gabapentin was also thought to behave as an
There have been two systematic reviews of randomized, antagonist at NMDA receptors, but the situation appears
controlled trials of antiepileptic drugs used to treat all more complex. Kaneko et al .27 found that gabapentin did
pain types.1 5,16 These demonstrated little evidence for not behave like an NMDA antagonist in rat models of
their use in acute pain, but significant benefit over neuropathic pain, and they concluded that it was unlikely
placebo was seen for chronic neuropathic pain condi- to act directly on NMDA receptors. Furthermore, Chen
tions, such as diabetic neuropathy and trigeminal neur- et al.28 have demonstrated a synergistic action between a
algia. non-NMDA receptor antagonist and gabapentin when
Against this background, gabapentin, that was thought both drugs were administered intrathecally. This supports
to be active on GABA mechanisms, was used in the the view that gabapentin can modify the spinal transmis-
treatment of neuropathic pain from the late 1990s. sion of noxious mechanical input to spinal neurones via
non-NMDA receptor antagonism.
The most important action of gabapentin appears to
be binding to the a2 d subunit of voltage dependent
Pharmacology calcium channels.29 These binding sites are located in the
spinal cord, with particularly high density in the super-
Pharmacokinetics
ficial laminae of the dorsal horn. The action of gaba-
Following oral administration, gabapentin is absorbed
pentin at these sites may inhibit the release of excitatory
from the small intestine rapidly and reliably. This occurs
neurotransmitters and reduce glutamate availability at
via a specific, though unidentified, transport mechanism
NMDA and non-NMDA receptors.30 ,3 1
that becomes saturated at higher doses.1 7 This has the
effect of reducing bioavailability at higher doses. The
bioavailability of a 300 mg dose is approximately 60%, for Pharmacodynamics
600 mg it is 40% and only 35% with 1.6 g given three To better understand the effects of potential agents on
times daily.18 ,1 9 Gabapentin has no significant protein neuropathic pain, it is useful to clarify some definitions.
binding and maximum plasma concentrations (Cm a x ) are ‘Antinociceptive’ refers to the ability of an agent to reduce
reached after around 3.2 hours following oral ingestion. 1 8 the reception of noxious stimuli at the level of the sensory
In healthy subjects, age has no effect on Cm a x or time to organ, e.g., the action of aspirin in reducing inflamma-
Cm ax but a 25% increase in Cm ax was observed in females tory activation of cutaneous nociceptors at nerve end-
compared to males owing to gender differences in body ings. ‘Antalgesic or analgesic’ refers to the action of an
size.20 Gabapentin has a half life of 6 ¡/8 hours, hence the agent in modulating the neural pathways that transmit
need for three daily doses. pain. If pain is the result of increased sensitivity to a
In common with other newer antiepileptics, gabapentin painful stimulus, and treatment restores the sensitivity to
is excreted unchanged through the kidneys. It does not normal, the effect is termed ‘antihyperalgesic’. If a
induce or inhibit hepatic enzymes. It does not signifi- normally non-painful stimulus evokes pain because of
cantly interact with other antiepileptics.17 The predomi- increased sensitivity (e.g., lightly brushing the skin), and
nant influence on gabapentin pharmacokinetics is renal treatment restores the sensitivity to normal, the term
function. An inverse linear correlation exists between ‘antiallodynic’ is used.
creatinine clearance and Cm ax , time to Cm ax and half Animal studies of the action of gabapentin suggest that
life.2 1 That is, impaired renal function results in higher it has antihyperalgesic and antiallodynic effects rather
gabapentin concentrations and a longer elimination half than antinociceptive effects.32 ,3 3 Furthermore, a dose ¡/
life. Renal function rather than age accounts for clinically response relationship has been demonstrated for these
different effects seen in the elderly. effects.

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 Gabapentin in neuropathic pain 7

Formalin injected into rat paws results in an initial levels of extracellular opioid peptide in rat brains
painful inflammatory response (lasting around 10 min- following a single dose of gabapentin. Shimoyama et
utes) followed by a later second phase of hyperalgesia al.41 demonstrated a synergistic effect between morphine
(lasting around 45 ¡/60 minutes). When gabapentin has and gabapentin that was significantly greater than the
been studied in this context, Kaneko et al .2 7 have effects of either drug alone, in a rat tail flick latency test
demonstrated that it has no effect on the initial phase, to radiant heat.
but significantly reduces hyperalgesia in the late phase.
They also showed that gabapentin was about three times
as potent as an antihyperalgesic agent if it was given Clinical studies
before formalin injection, rather than if it was given 7 ¡/8
minutes after injection. This suggests that gabapentin is Numerous case studies have been published describing
effective at preventing the initial development of hyper- the effects of gabapentin in a variety of neuropathic pain
algesia and allodynia. conditions. Examples include complex regional pain
Abdi et al .3 4 examined the effects of systemic gaba-
syndromes (CRPS), deafferentation neuropathies, central
pentin, amitriptyline and lidocaine on ectopic discharges post stroke pain and pain associated with multiple
from injured sensory fibres in rats. Their study showed sclerosis.4 2 ¡ 4 5 In general, treatment with gabapentin
significant reductions in discharges after amitriptyline was successful in reducing pain and the doses used were
and more dramatically after lidocaine, but gabapentin between 900 and 1200 mg in three divided doses.
was without effect. In contrast, Pan et al.3 5 found a Following the apparent success of gabapentin described
dose ¡/response effect after intravenous gabapentin on in case reports, randomized placebo controlled trials were
ectopic discharge activity from injured nerves in rats. The undertaken in various defined neuropathic pain condi-
mechanism of this peripheral effect remains unclear. tions.
Although an action on voltage sensitive sodium channels
would fit with the known actions of other antiepileptic
Post herpetic neuralgia
drugs, there is only weak evidence to support this. Rock
Two large randomized controlled trials have been con-
et al.36 failed to show any effect of gabapentin on sodium
ducted on the use of gabapentin in the treatment of post
channels, but Wamil and McLean3 7 did demonstrate an
herpetic neuralgia. The first study recruited 229 patients
inhibitory effect in vitro.
from North American pain services in whom doses were
Welty et al.38 found that after gabapentin administra-
titrated up to 3600 mg of gabapentin or placebo over a
tion, the antihyperalgesic effects occur much more
four week period. 46 Treatment was maintained at max-
rapidly than the antiepileptic effects. The antiepileptic
imum dose for a further four weeks; concomitant
effect of gabapentin may rely on active cellular entry of
antidepressants, used as coanalgesics, were continued if
gabapentin into astrocytes, but it appears that the
therapy was stabilized and remained constant. Around
antihyperalgesic effects do not rely on this process. This
80% of patients in each arm completed the study; median
indicates that there may be separate underlying mechan-
age was 73 and 74 years in the gabapentin and placebo
isms for the action of gabapentin in epilepsy and in
groups, respectively. There were no significant differences
neuropathic pain.
in other medication taken during the study; 72% took no
Gabapentin has been shown to have a superior anti-
other medication, 12% took tricyclic antidepressants and
allodynic profile than morphine or amitriptyline in work
19¡/27% took opioids.
by Field et al .3 9 These authors induced static and
In those that received gabapentin, the average daily
dynamic allodynia in rats through streptozocin injection
pain score was significantly reduced from 6.3 to 4.2
into the hind paw. Amitriptyline and morphine dose
points on an 11-point numerical rating scale. In this
dependently blocked static allodynia, but not dynamic
group, at least 83% received 2400 mg and 65% received at
allodynia. Gabapentin blocked both types of allodynia in
least 3600 mg of gabapentin. This compares with a
a dose dependent manner between 10 and 100 mg/kg.
reduction from 6.5 to 6.0 in those that received placebo
These studies suggest that gabapentin has significant
(P B/0.001). Other outcome measurements including
antihyperalgesic and antiallodynic effects. It suggests that
quality of life, sleep interference and mood also showed
these are mediated predominantly at a spinal or suprasp-
significant improvement with gabapentin. The numbers
inal level through stabilization of dorsal horn neurones,
of withdrawals in each group were similar, but patients
and to a lesser extent at a peripheral level.
taking gabapentin reported more somnolence, dizziness
and ataxia than those taking placebo. The authors
Interaction with opioids concluded that gabapentin was safe and efficacious at
Although there is no evidence to support a direct effect of these doses in a predominantly elderly population.
gabapentin on opioid pathways, animal studies have The second and more recent study recruited 334
pointed to an indirect effect. Rocha et al .4 0 found raised patients from UK pain clinics using similar methodol-

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8 MI Bennett and KH Simpson

ogy.47 Patients were randomized to receive 1800 mg neuropathic pains. These patients are often defined by
gabapentin, or 2400 mg gabapentin or placebo. The their pain symptoms and signs rather than discrete
rationale for the study was to examine whether lower diseases. To address this issue, a further clinical trial of
doses would be as efficacious as higher doses, but would gabapentin was undertaken that recruited 307 patients
have a lower incidence of side effects. This trial excluded with various neuropathic pain syndromes (excluding
patients who had previously failed to respond to gaba- cancer) from pain clinics in the UK and Ireland. 49
pentin. Patients taking active treatment were titrated up Eligible patients were those with mean daily pain scores
to 1800 mg gabapentin over two weeks and then up to of at least 4, on an 11 point numerical rating scale, prior
2400 mg by week 3 for those randomized to receive the to entry. Patients were also required to have at least 2 of
higher dose. All doses remained stable between weeks 3 ¡/ the following symptoms and signs; allodynia, burning
7. Median age of patients recruited was around 75 years pain, shooting pain, hyperalgesia. The median age of
in all three groups. Average daily pain score showed recruited patients was around 57 years in both groups.
significant improvements after both 1800 and 2400 mg In this study, patients were randomized to receive
gabapentin; 6.5 to 4.3 and 6.5 to 4.2, respectively, on an placebo or to be titrated up to receive 2400 mg of
11 point numerical rating scale (P B/0.001). In compar- gabapentin over five weeks to be followed by a three week
ison, the reduction for the placebo group was 6.4 to 5.3 period where doses were stable. By week 5 in the
points. This translates to an 18.8% reduction in daily pain gabapentin arm, 101 patients received 2400 mg, 19
score using gabapentin instead of placebo. These differ- received 1800 mg and 27 received 900 mg daily. The
ences were apparent from the end of the first week of mean weekly pain scores at week 8 showed significant
treatment. Between 32 and 34% of patients taking differences for gabapentin. In this group, pain scores were
gabapentin achieved more than 50% pain relief compared reduced from 7.1 to 5.6 points on an 11 point numerical
to only 14% taking placebo. Predominant side effects in rating scale compared with a reduction from 7.3 to 6.3 in
the treatment arms were dizziness (31 ¡/33%) and somno- the placebo group (P B/0.001). This difference was
lence (17.4¡/20.4%). Between 13 and 17% of patients significant at the end of week 1 and remained similar
taking gabapentin withdrew because of side effects. for most of the weeks throughout the study period. No
significant difference was seen in the number of patients
Diabetic neuropathy who achieved more than 50% pain relief between the two
Another large randomized, placebo controlled study of groups (21% for gabapentin and 14% for placebo).
gabapentin was conducted in patients with diabetic Interestingly, significant improvements in burning pain
neuropathy 48 attending pain clinics in the USA. Of the and hyperalgesia were seen, but this was not observed for
165 patients recruited, 84 were randomized to receive allodynia or shooting pain, when gabapentin was com-
gabapentin and 81 to receive placebo. The methodology pared with placebo. Significant improvements were also
and dosing schedule was similar to that used in the trial seen after gabapentin in various quality of life measures
by Rowbotham et al .46 Two thirds of the patients taking particularly social and emotional functioning. The most
gabapentin were titrated to 3600 mg daily. frequent side effects with gabapentin compared with
This study also showed a significant reduction in placebo were dizziness (24.2 versus 7.9%) and somno-
average daily pain score for the gabapentin group from lence (14.4 versus 5.3%).
6.4 to 3.9 points on a numerical rating scale. This
compares with a reduction from 6.5 to 5.1 in the placebo
group. Quality of life measures, sleep and mood all Cancer neuropathic pain
improved significantly in those taking gabapentin, and To date there have been no randomized trials of
47% of the gabapentin group achieved a ‘much or gabapentin in patients with neuropathic pain due to
moderately improved’ rank on a global change score cancer. One open-label trial has been reported in which
compared with 25% of those receiving placebo. Although 22 patients with cancer, whose neuropathic pain was not
the median age in this study was 53 years (20 years controlled by opioids, were given gabapentin as ‘add-on’
younger than the post herpetic neuralgia trials), the treatment. 50 The dose of gabapentin was titrated over
frequency of side effects was similar. Significant differ- three to seven days up to a mean daily dose of around
ences between gabapentin and placebo were observed for 1004 mg (range 600¡/1800 mg). Opioid doses were
dizziness (23.8 versus 4.9%) and somnolence (22.6 versus unchanged throughout the study period. Compared to
6.2%). baseline scores, mean global pain scores on a numerical
rating scale were reduced from 6.4 to 3.2 points at the
Mixed neuropathic pain final assessment that took place 7 ¡/14 days later. Symp-
Despite the apparent efficacy of gabapentin in post toms of burning pain, shooting pain and allodynia were
herpetic neuralgia and diabetic neuropathy, clinical all also significantly reduced compared to baseline.
practice is characterized by patients with a variety of Overall, no additional side effects were attributed to

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 Gabapentin in neuropathic pain 9

gabapentin treatment, apart from one case of sedation this was not a study of clinical neuropathic pain, the
and one case of dizziness. results are interesting. Neither gabapentin nor morphine
This study was commented upon in a letter by had any significant effect on pain threshold, but mor-
Chandler and Williams,51 who argued that gabapentin phine had a significant effect on pain tolerance. Im-
has a much lower incidence of efficacy in this context portantly, the combination of the two drugs significantly
based on their experience. They reported on a retro- raised pain threshold and tolerance (above that of
spective review of 20 patients with neuropathic pain due morphine alone). This synergistic effect had been pre-
to cancer who were treated with gabapentin in addition to viously demonstrated in rats.4 1 It also supports the
their usual analgesia. Only nine patients reported sig- findings of Caraceni et al .,5 0 suggesting that gabapentin
nificant improvement and six others discontinued gaba- augments the action of morphine via an unexplained
pentin because of side effects. In the remaining five mechanism.
patients, efficacy could not be established. Further
analysis of the data in the Caraceni et al. study 5 0 shows Meta-analyses
that 13 of 22 (59%) patients achieved more than 50% pain Information from meta-analyses and systematic reviews
relief compared to 45% (assuming ‘significant relief’ is allows comparisons of effectiveness of drugs in various
equivalent) in Chandler and Williams’s series. Both of neuropathic pain conditions. These are expressed as
these series compare favourably to larger randomized NNT (number needed to treat) and NNH (number
controlled trials,4 7,49 which were performed in presum- needed to harm).1 6,55 ,5 6 In post herpetic neuralgia, the
ably fitter patients, where between 21 and 34% achieved NNT for gabapentin was 3.2 (C.I. 2.4¡/5.0) which
this degree of pain relief. compares with 2.3 (C.I. 1.7¡/3.3) for tricyclic antidepres-
sants and 2.5 (C.I. 1.6¡/5.1) for oxycodone. In diabetic
Comparative studies with other drugs neuropathy, the NNTs are; gabapentin 3.8 (2.4 ¡/8.7),
A small number of studies exist that directly compare the tricyclic antidepressants 3.0 (2.3 ¡/4.3) and carbamazepine
effectiveness of gabapentin against other analgesics in the 2.3 (1.6 ¡/3.8). Using the calculation for NNT suggested
treatment of neuropathic pain. Dallocchio et al .5 2 by Cook and Sackett,57 and the data for mixed neuro-
randomized 25 patients with diabetic neuropathy to pathic pain syndromes, 49 the NNT for gabapentin in this
receive amitriptyline (mean dose 53 mg daily) or gaba- context is 14.
pentin (mean dose 1785 mg daily) in an open label trial. In diabetic neuropathy studies, the NNH for minor
Doses were titrated over four weeks and maintained for events is 2.5 (2.0 ¡/3.2) for gabapentin, 3.7 (2.4 ¡/7.8) for
carbamazepine and 2.8 (2.0 ¡/4.7) for tricyclic antidepres-
eight weeks. Pain scores were measured on a five point
scale (0 ¾/none, 4 ¾/excruciating). Baseline pain scores in sants. The NNH for major events (drug related with-
the gabapentin group were reduced by a mean of 1.9 drawal from study) is 20¡/40; this is broadly similar for
(2.9 ¡/1.0) and those in the amitriptyline group were tricyclic antidepressants and anticonvulsants (excluding
reduced be a mean of 1.3 (2.75¡/1.5), P B/0.026. Sig- gabapentin). In relation to gabapentin, three of the four
nificant differences in the reduction in paraesthesia major trials in neuropathic pain demonstrate no differ-
scores also favoured gabapentin. Adverse events were ences between study withdrawals in those taking placebo
more frequent in the amitriptyline group and these compared with those taking active treatment. 4 6,48 ,4 9 In
limited dose escalation according to the authors. the fourth study,47 6.3% subjects withdrew whilst taking
However, an earlier double blind, randomized cross- placebo compared to 13 and 17.6% of those taking
over trial had not found any difference in efficacy gabapentin 1800 and 2400 mg, respectively; these results
between the two drugs in patients with painful diabetic were not assessed statistically. It has been argued that
neuropathy.5 3 In this study, 21 of the 25 patients enrolled earlier studies of treatments in neuropathic pain (that
completed the six week trial of each drug with a one week have contributed to meta-analyses) may have been less
washout period in between drug dosing (mean doses were able to detect and report adverse events. This would lead
59 mg amitriptyline and 1565 mg gabapentin). Pain score to an overestimation of NNH for older anticonvulsants
and tricyclic antidepressants (i.e. they appear better
diaries showed no statistical differences for patients
taking either treatment; 11 (52%) taking amitriptyline tolerated than is the case in clinical practice), when
experienced moderate or greater pain relief compared to compared with more recent studies of gabapentin.
14 (67%) of those taking gabapentin.
Eckhardt et al.54 have compared morphine, gabapentin
and combined treatment with both drugs in a double Summary
blind, placebo controlled four way crossover study. This
was conducted in 12 volunteers whose pain tolerance and Gabapentin appears to be an effective treatment for
pain threshold were measured during forearm immersion neuropathic pain, acting centrally to reduce hyperalgesia
in cold water under experimental conditions. Although and allodynia, but it does not have significant actions as

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10 MI Bennett and KH Simpson

an anti-nociceptive agent. Based on large clinical trials, it 12 Reddy S, Patt R. The benzodiazepines as adjuvant
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