Arch. Pharm. Res.
(2013) 36:237251
DOI 10.1007/s12272-013-0057-y
REVIEW
Implications and mechanism of action of gabapentin
in neuropathic pain
Ankesh Kukkar Anjana Bali Nirmal Singh
Amteshwar Singh Jaggi
Received: 20 September 2012 / Accepted: 14 December 2012 / Published online: 24 February 2013
The Pharmaceutical Society of Korea 2013
Abstract Gabapentin is an anti-epileptic agent but now it
is also recommended as first line agent in neuropathic pain,
particularly in diabetic neuropathy and post herpetic neu-
ralgia. a2d-1, an auxillary subunit of voltage gated calcium
channels, has been documented as its main target and its
specific binding to this subunit is described to produce
different actions responsible for pain attenuation. The
binding to a2d-1 subunits inhibits nerve injury-induced
trafficking of a1 pore forming units of calcium channels
(particularly N-type) from cytoplasm to plasma membrane
(membrane trafficking) of pre-synaptic terminals of dorsal
root ganglion (DRG) neurons and dorsal horn neurons.
Furthermore, the axoplasmic transport of a2d-1 subunits
from DRG to dorsal horns neurons in the form of antero-
grade trafficking is also inhibited in response to gabapentin
administration. Gabapentin has also been shown to induce
modulate other targets including transient receptor poten-
tial channels, NMDA receptors, protein kinase C and
inflammatory cytokines. It may also act on supra-spinal
region to stimulate noradrenaline mediated descending
inhibition, which contributes to its anti-hypersensitivity
action in neuropathic pain.
Keywords Gabapentin
Neuropathic pain

Diabetic neuropathy
Post herpetic neuralgia

Dorsal root ganglion
Descending inhibition
A. Kukkar
A. Bali
N. Singh
A. S. Jaggi (&)
Department of Pharmaceutical Sciences and Drug Research,
Punjabi University, Patiala 147002, Punjab, India
e-mail: amteshwarjaggi@yahoo.co.in
Introduction
Pain arising as direct consequence of a lesion on a nerve/
disease affecting the somato-sensory system, either at the
peripheral or central nervous system, is described as neu-
ropathic pain (Geber et al. 2009). Following peripheral
nerve injury, a cascade of events in the primary afferents
leads to peripheral sensitization which is characterized by
spontaneous nociceptor activity, decreased threshold
(allodynia) and increased response to supra-threshold
stimuli (hyperalgesia). A series of molecular changes in the
spinal cord and the different brain centres is associated
with central sensitization which is responsible for the pain
to non-injured extra-territory regions (extraterritorial pain)
and contra-lateral parts (mirror-image pain) (Jaggi and
Singh 2011).
There are various conditions associated with neuro-
pathic pain like diabetic neuropathy, post herpetic neural-
gia (PHN), cancer, trigeminal neuralgia etc. Diabetic
neuropathic pain is one of the long term complications of
diabetes mellitus and, both metabolic and ischemic mech-
anisms have a role in diabetic neuropathies (Said 2007).
The patients with Herpes zoster infection usually experi-
ence pain, however, some patients experience pain beyond
the typical 4-week duration. About 10 % patients develop
the distressing complication of PHN with complex patho-
physiology and involve both the peripheral as well as
central processes (Argoff 2011). Trigeminal neuralgia is
defined as sudden, usually unilateral, severe, brief, stabbing
recurrent episodes of pain within one or more branches of
the trigeminal nerve and it results from abnormalities in
trigeminal afferent neurons in the trigeminal root or gan-
glion (Zakrzewska and McMillan 2011). Neuropathic
cancer pain, commonly encountered in clinical practice,
may also be cancer-related due to tumor invasion in the
123
238
nerves, surgical nerve damage during tumor removal,
radiation-induced nerve damage or chemotherapy-related
neuropathy (Vadalouca et al. 2012).
The recommended first-line treatments for neuropathic
pain include antidepressants (tricyclic antidepressants and
dual reuptake inhibitors of both serotonin and norepi-
nephrine), calcium channel a2d ligands (gabapentin and
pregabalin) and topical lidocaine. Opioid analgesics and
tramadol are generally recommended as second-line treat-
ments that may be considered for first-line use in selected
clinical circumstances. Other medications that are generally
used as third-line treatments (may be used as second-line
treatments in some circumstances) are other antiepileptic
and antidepressant medications, mexiletine, N-methyl-D-
aspartate receptor antagonists, and topical capsaicin (Dworkin
et al. 2007).
Gabapentin is a structural analogue of GABA (Fig. 1)
and has been approved for adjunctive treatment of patients
(12 years or older) with partial seizures (with/without
secondary generalization), mixed seizure disorders and
refractory partial seizures in children (Honarmand et al.
2011). However, recent studies have also documented its
efficacy in ameliorating different types of neuropathic pain
in preclinical as well as in clinical settings. Earlier, gaba-
pentin was considered as second line treatment with
tricyclic antidepressants (TCA) as drug of choice. How-
ever, in patients with a history of cardiovascular disorders,
glaucoma, and urine retention, gabapentinoid drugs have
emerged as first-line treatment for neuropathic pain. In
addition, gabapentin has a more favourable safety profile
with minimal concerns regarding drug interactions and
showing no interference with hepatic enzymes, therefore, it
has been employed as first line agent in various neuropathic
conditions like diabetic neuropathy and PHN (Vranken
2009). More patients with neuropathic pain reported an
improvement with pregabalin (a2d ligands) (33 %) than
duloxetine (21 %). Duloxetine (38 %) had a higher fre-
quency of side effects compared to pregabalin (30 %)
(Mittal et al. 2011). In patients with spinal cord injury,
gabapentin has been shown to be more effective for pain
relief than amitriptyline (Selph et al. 2011). The present
review discusses the effectiveness of gabapentin in differ-
ent types of neuropathic pain in preclinical as well in
clinical settings and also discusses the possible mechanism
of action at different levels including at dorsal root
ganglion (DRG) and dorsal horn neurons along with at
supra-spinal centres.
Gabapentin in preclinical studies
There have been number of preclinical studies document-
ing the beneficial effects of gabapentin in different models
123
A. Kukkar et al.
OH
NH2
O
GABA
OH
O
NH2
Gabapentin
Fig. 1 Structures of GABA and gabapentin
of neuropathic pain. Back and co-workers demonstrated
that intraperitoneal (i.p.) injection of gabapentin at differ-
ent doses (30, 100, 300 mg/kg) significantly alleviates
mechanical, warm and cold allodynia in partial tail nerve
injury-induced neuropathic pain in a dose-dependent
manner (Back et al. 2004). The systemic (3060 mg/kg i.p.)
as well as the spinal (1020 lg) administration of gabapentin
in the adult rats has been shown to attenuate resiniferotoxin
(a potent TRPV1 agonist)-induced long-lasting changes in
mechanical and thermal sensitivities in a model of PHN
(Chen and Pan 2005). Walczak and co-workers demon-
strated the efficacy of gabapentin (50 mg/kg i.p.) in attenu-
ating cold as well as mechanical allodynia, but not
hyperalgesia, in a saphenous partial ligation (unilateral
partial injury to the saphenous nerve) rodent model of neu-
ropathic pain (Walczak et al. 2005). In chronic constriction
injury model of neuropathic pain, administration of gaba-
pentin (30, 100 and 300 mg/kg i.p.) every 12 h for 4 days has
been shown to reduce the development of hyperalgesia in a
rats (Coderre et al. 2007).
The systemic administration of gabapentin (i.p.) has
been shown to increase the paw withdrawal latency and
produce anti-allodynic effects in a mice model of partial
sciatic nerve ligation of neuropathic pain in a dose
dependent manner (Kusunose et al. 2010). A recent study
has shown the effectiveness of gabapentin (5 or 50 mg/kg, i.p.)
in attenuating neuropathic pain behavior in forelimb neuro-
pathic pain model (due to partial injury to medial and
ulner nerves) in a dose-dependent manner (Yi et al. 2011). An
intra-thecal administration of gabapentin at the dose
of 1.05 lmol/day for 14 days in a chronic constriction
injury model and at the dose of 20 lg/h for 7 days in spinal
nerve ligation model has also been shown to attenuate
Gabapentin in neuropathic pain
neuropathic pain in an effective manner in rats (Chu et al.
2011; Yeh et al. 2011)
Furthermore, the effectiveness of gabapentin in attenu-
ating pain behavior has also been described in chemother-
apeutic agents and viruses-induced peripheral neuropathic
pain. Xiao and co-workers demonstrated that systemic
multiple dosing of gabapentin (100 mg/kg i.p.) signifi-
cantly reduced paclitaxel- and vincristine-evoked mec-
hano-allodynia and mechano-hyperalgesia (Xiao et al.
2007). The systemic treatment with gabapentin has also
been shown to attenuate ddC (Zalcitabine), an anti-retro-
viral agent, and HIV-gp120, (delivered to the rat sciatic
nerve) (gp120 ? ddC)-induced neuropathic pain (Wallace
et al. 2007). Moreover, gabapentin (30 mg/kg i.p.) also has
also been shown to reverse Varicella Zoster virus-induced
increase in mechanical hypersensitivity (s.c. injection of
Varicella Zoster virus into the glabrous footpad of the hind
limb), a model which resembles Herpes Zoster virus-
induced clinical pain (Hasnie et al. 2007). Oral adminis-
tration of gabapentin (50 mg/kg twice a day for 5 days) is
reported to attenuate mechanical allodynia in a model of
diabetic neuropathy (Wodarski et al. 2009).
Apart from producing the direct beneficial effects in
neuropathic pain, the studies have also shown that it may
increase the effectiveness of co-administered drugs and
may result in synergistic effect. Gabapentin shows syner-
gistic effect with anti-depressant venlafaxine in treating
neuropathic pain. This combination was found to be
superior in comparison to gabapentin alone in the rat
spared nerve injury (SNI) model of neuropathic pain (Garry
et al. 2005). The studies have shown that co-administration
of gabapentin with benfotiamine or cyanocobalamin in a
fixed ratio markedly reduces spinal nerve ligation-induced
tactile allodynia, showing a synergistic interaction between
anticonvulsants and B vitamins. Oral administration of
gabapentin (15300 mg/kg), benfotiamine (30600 mg/kg)
or cyanocobalamin (0.36.0 mg/kg) has been shown to
significantly reduce neuropathic pain in rats (Mixcoatl-
Zecuatl et al. 2008). Co-administration of duloxetine with
gabapentin/donepezil (p.o.) is also shown to exhibit syn-
ergistic effect against spinal nerve ligation-induced neu-
ropathic pain. The combination of all three drugs was also
shown to produce synergistic action (Hayashida and
Eisenach 2008). The other studies have also demonstrated
that use of donepezil as an adjunctive to gabapentin
improves the therapeutic outcome in the management of
neuropathic pain in spared nerve injury model. Co-
administration of donepezil (0.5 mg/kg s.c.) and low doses
of gabapentin (10 and 30 mg/kg s.c.), both single dosing,
resulted in a three- to fourfold increase of the analgesic
effect, in comparison with gabapentin administered alone.
Addition of donepezil (1.5 mg/kg p.o.) from day 11 to day
239
20 to gabapentin (25 mg/kg p.o., once daily over 20 days)
treatment regimen was shown to improve analgesic effects
as compared to gabapentin monotherapy (Folkesson et al.
2010). In another study with same model, the intra-thecal
co-administration of gabapentin and clonidine at a ratio of
20:7 exerted a synergistic action on the mechanical anti-
allodynic effect (Yamama et al. 2010).
Gabapentin in clinical studies:
There have been number of clinical studies documenting
the beneficial effects of gabapentin in different types of
neuropathic pain like neuropathy due to cancer, HIV
infection, diabetic neuropathy, trigeminal neuralgia and
post-operative neuropathic pain (Table 1).
Cancer and chemotherapeutic agents-induced pain
Gabapentin monotherapy (300 mg/d to 1.8 g/d) has been
reported to beneficial and well tolerated in cancer as well
as chemotherapy-induced neuropathic pain (Ross et al.
2005). Administration of fixed low-dose of gabapentin
(800 mg/day) in anti-cancer drugs-induced neuropathic
pain is also reported to produce partial to complete
remission (Tsavaris et al. 2008). In randomized open
clinical trial, the combination of gabapentin with opioid
analgesics was shown to provide better relief in neuro-
pathic pain in cancer patients as compared to opioid
analgesics alone in terms of reduction in pain intensity for
burning and shooting pain at different days of the study.
Furthermore, the rate of side effects was also shown to be
comparatively less in combination therapy as compared to
opioid monotherapy (Keskinbora et al. 2007). Arai and
co-workers demonstrated that low dose gabapentin (200
400 mg/12 h)-imipramine (10 mg/12 h) combination with
opioids was effective in managing neuropathic cancer pain
(in terms of total pain score and paroxysmal pain episodes)
without severe adverse effects (Arai et al. 2010). In con-
trast, Takahashi and co-workers demonstrated that combi-
nation of gabapentin and opioid analgesic was of minimal
clinical benefit in the study conducted on Japanese patients
with neuropathic cancer pain in an open-label and single-
center clinical trial (Takahashi and Shimoyama 2010).
Patarica-Huber demonstrated that intergroup difference
between three groups i.e., gabapentin, gabapentin-NSAID,
gabapentin-NSAID-morphine was not statistically signifi-
cant in breast cancer patients. Although during the 6-week
study the decrease of pain intensity was significant in all 3
groups, the correlation between the increase trend of side
effects and the frequency of additional medication was also
significant (Patarica-Huber et al. 2011).
123
240 A. Kukkar et al.

Table 1 The summarized clinical implications of gabapentin in different forms of neuropathic pain
S. no. Types of pain Treatment schedule/general comments References

1. Cancer and chemotherapeutic
agents-induced pain
2. Trigeminal neuralgia
3. Diabetic neuropathic pain
4. Post-herpetic neuralgia
Gabapentin (800 mg/day) produce partial Tsavaris et al. (2008),
to complete remission Arai et al. (2010)
Low dose gabapentin (200400 mg/day)
? imipramine (10 mg/12 h) ? opioids
alleviate pain with minimal side effects
Gabapentin as second drug of choice; the Lemos et al. (2010)
combination with ropivacain produces
significant effect in carbamazepine resistant cases
Main stay drug for elderly patients at a doses Vranken (2009), Paradowski
of 1,8003,600 mg/d gabapentin is and Bilinska (2003)
Equivalent/better tolerated than TCA
with comparable/higher efficacy
Gabapentin is one of the first line treatment in PHN Jean et al. (2005),
600 mg/day may be the safe and effective Rice and Maton (2001)
starting dose with adequate relief at higher
doses (1,2002,400 mg/day)

Trigeminal neuralgia 1999). In a 12-week, open-label, prospective, randomized

In treating trigeminal neuralgia, gabapentin has been
considered as second drug of choice (20 % patients) as
compared to carbamazepine, employed in 70 % of patients
as the first choice drug (Cheshire 2007; Hon and Fei 2008).
Pandey and co-workers demonstrated the successful man-
agement of idiopathic trigeminal neuralgia in patients
resistant to carbamazepine without untoward side-effects
(Pandey et al. 2008). Lemos and co-workers demonstrated
that the combination of gabapentin and ropivacain (applied
as analgesic block to trigeminal neuralgia trigger points) is
more effective and safe in trigeminal neuralgia patients
resistant to carbamazepine (Lemos et al. 2010).
Diabetic neuropathic pain
The most of the diabetic patients require pain control therapy
and the TCA drugs remain a first-line approach with gaba-
pentin as alternative to TCA. However due to predictable and
troublesome side effects associated with TCA, gabapentin is
the main therapy in case of elderly patients with diabetic
peripheral neuropathy (Haslam and Nurmikko 2008; Vranken
2009) Gabapentin is described as first line agent for the
treatment of diabetic neuropathic pain in the United Kingdom
and is generally better tolerated than TCA (Boulton 2003).
The various studies have indicated the usefulness of gaba-
pentin in treating diabetic neuropathy comparable to TCA.
A randomized, double-blind, placebo-controlled study demon-
strated that gabapentin monotherapy (dose titrated from 900
to 3,600 mg/d or maximum tolerated dosage) for 8 weeks
significantly lowered the pain and enhanced the quality of
life as compared to placebo (Backonja et al. 1998). Further-
more, in a randomized, double-blind, crossover, 6 week study,
no significant difference between gabapentin (9001,800 mg/d)
and amitriptyline (2575 mg/d) was reported (Morello et al.
trial gabapentin (1,2002,400 mg/d) was shown to produce
greater improvement in pain and paresthesias associated
with diabetic neuropathy as compared to amitriptyline
(30 mg/d to 90 mg/d). Furthermore, gabapentin was shown
to be better tolerated than amitriptyline in diabetic neuro-
pathic pain patients (Dallocchio et al. 2000). The other
studies have also shown that gabapentin in doses of 1,800 to
3,600 mg/d is well tolerated, superior to placebo, and
equivalent to amitriptyline (Hemstreet and Lapointe 2001;
Backonja and Glanzman 2003; Paradowski and Bilinska
2003). In contrast to previous studies with indirect compar-
isons between TCA and gabapentin, Chou and co-workers
demonstrated the comparable effects of gabapentin and tri-
cyclic antidepressants for pain relief in patients with diabetic
neuropathy and PHN in a direct comparison study (Chou
et al. 2009). Besides peripheral neuropathic pain, diabetic
cardiac neuropathy also co-exists in diabetes patients and
studies have also demonstrated that therapeutic doses of
gabapentin not only alleviate neuropathic symptoms but also
improve cardiac autonomic function in diabetic patients with
peripheral neuropathy (Ermis et al. 2010).
The large placebo-controlled studies have also provided
the evidence of the efficacy of gabapentinoid group of
drugs (gabapentin and pregabalin) in diabetic pain. The
potential availability of less expensive generic formula-
tions of gabapentin, together with greater experience with
its use, favour gabapentin as the main antiepileptic drug for
alleviating diabetic neuropathy. Topiramate, lamotrigine,
sodium valproate and oxcarbazepine have been shown to
be effective in smaller studies but do not have the same
evidence base as the gabapentinoid group of drugs (Chong
and Hester 2007). Hanna and co-workers demonstrated that
co-administration of prolonged-release oxycodone and
existing gabapentin therapy (low dose) has a clinically
meaningful effect in painful diabetic neuropathy in a

123
Gabapentin in neuropathic pain
randomized, double-blind, placebo-controlled study con-
ducted for 12 weeks and this combination provides better
pain relief as compared to gabapentin monotherapy (Hanna
et al. 2008).
Post-herpetic neuralgia (PHN)
Initially, TCA were the most commonly used agents for
treating PHN patients and were effective in a significant
proportion of patients. However, various adverse events
including anticholinergic and sedative effects limit treat-
ment. These side effects tend to be more acute in the
elderly, the population most likely to suffer from PHN and
over past few years gabapentin has received increasing
attention due to its safety profile (Beydoun 1999). In a
randomized, double-blind, parallel-group trial of 9 weeks
duration clinical study, Chandra and co-workers described
that gabapentin was equally efficacious and better tolerated
as compared to nortriptyline and may be considered a
suitable alternative for the treatment of PHN (Chandra
et al. 2006). On the contrary, Oconnor and co-workers
demonstrated that desipramine (100 mg/day) is more
effective and less expensive than gabapentin (1,800 mg/day)
or pregabalin (450 mg/day) for the treatment of older
patients with PHN in whom it is not contraindicated
(OConnor et al. 2007). At present, the first-line treatments
for PHN include TCA, gabapentin, pregabalin, topical
lidocaine patch and opioids, tramadol, capsaicin cream and
patch are recommended as either second- or third-line ther-
apies in different guidelines (Argoff 2011).
The multicenter, randomized, double-blind, placebo-
controlled, parallel design, 8-week trial evidenced that
gabapentin is effective in the treatment of pain and sleep
interference associated with PHN. The mood and quality
of life was also shown to be improved with gabapentin
therapy (Rowbotham et al. 1998). Another multi-centre
double blind, randomized, placebo controlled 7-week study
described the efficacy and safety of gabapentin (1,800 or
2,400 mg/day) in treating PHN patients (Rice and Maton
2001). Berger and co-workers reported that initiation of
gabapentin therapy in patients with PHN was associated
with a reduction in the use of opioid analgesics (Berger
et al. 2003). Furthermore, Gilron and co-workers demon-
strated that morpine-gabapentin combination is having
better analgesic effect as compared to monotherapy with
these drugs at maximal tolerated dose in a randomized,
double-blind, active placebo-controlled, four-period cross-
over trial, for 5 weeks (Gilron et al. 2005).
Although gabapentin has been shown to provide pain
relief in PHN patients at dosage of 1,2002,400 mg/day,
Jean and co-workers demonstrated that 600 mg/day gaba-
pentin could be a safe and effective starting dose for PHN
patients (Jean et al. 2005). Due to circadian rhythm, the
241
concentrations of b-endorphin levels are significantly
higher in the morning as compared to the afternoon in both
human adults and neonates. It may be probably responsible
for the diurnal variation in neuropathic pain intensity,
however, the temporal profile appears to be unaffected by
treatment with gabapentin as it decreases the pain scores to
a similar degree at all study time points (Petraglia et al.
1983; Hindmarsh et al. 1989; Odrcich et al. 2006).
Side effects of gabapentin
The common adverse events experienced with the gaba-
pentin include dizziness (23.9 %), somnolence (27.4 %),
ataxia (7.1 %), peripheral edema (9.7 %) and confusion
(Backonja et al. 1998; Rowbotham et al. 1998). Jacob and
co-workers reported the development of asterixis (a nega-
tive myoclonus caused by sudden pauses of innervation for
more than 200 ms) in PHN patient treated with gabapentin
(Jacob 2000). Asterixis has been described to occur in
response to accumulation of endogenous benzodiazepine
receptor ligands that act on GABA-A receptors in the brain
(Butterworth 1996). The drugs such as phenobarbitone,
carbamazepine and valproate are known to produce aster-
ixis by enhancing GABA transmission (Bodensteiner et al.
1981). Accordingly, GABAergic mechanism in the form of
enhancement in GABA release (Taylor 1997) has been
described as the possible mechanism for the development
of asterixis in response to gabapentin therapy (Jacob 2000).
A case of cholestasis (jaundice, dark urine, pale stool,
fatigue, and epigastric tenderness) with serious hepato-
toxicity is also reported (Richardson et al. 2002). Parsons
and co-workers from 3 randomized, double-blind, placebo-
controlled, parallel-group studies of gabapentin in PHN
patients described that the safety concerns limit the titration
of gabapentin dosing (300 mg/d at the start to 1,800
3,600 mg/d as maintenance dose) to achieve optimal effi-
cacy. The incidence of peripheral edema was reported to be
increased with an increase in the dose of gabapen-
tin C1,800 mg/d (7.5 % vs. 1.4 %) (Parsons et al. 2004).
Due to development of peripheral edema with the recom-
mended doses of gabapentin, The New York Heart Asso-
ciation has issued a warning about using caution while
prescribing these drugs to type III-IV heart failure patients
(Erdogan et al. 2011). Bookwalter and Gitlin reported a
case of a 75-year-old man with renal dysfunction who
developed neurologic toxicity due to gabapentin accumu-
lation (Bookwalter and Gitlin 2005). Gabapentin is not
metabolized in the liver and is mainly excreted through
kidney, accordingly, in patients with renal dysfunctions the
gabapentin levels tend to rise and produce severe side
effects. A patient was described to develop delusions of
parasitosis after been initiated with gabapentin treatment
123
242
for neuropathic pain and complete disappearance of
symptoms was reported after discontinuation of the medi-
cation (Lopez et al. 2010). The patients tend to develop
dependence on gabapentin even after 3 weeks of admin-
istration and it is required to gradually taper the dose to
avoid withdrawal symptoms. See and co-workers have
reported the development of akthesia in response to gaba-
pentin withdrawal (at doses ranging from 4008,000 mg/day)
(See et al. 2011). The randomized, double-blind, placebo-
controlled studies have provided the evidence that extended
release gabapentin shows improved bioavailability, tolera-
bility, convenience, along with minimized incidence of
adverse events in treating neuropathic pain (Sandercock et al.
2009; Backonja et al. 2011).
The studies have shown that gabapentin causes sexual
dysfunction including loss of libido, anejaculation, anor-
gasmia, and impotence at a minimum total daily dose of
900 mg. However, a recent case report has suggested the
dysfunction at a daily dose of only 300 mg (Kaufman and
Struck 2011). Gabapentin-associated anorgasmia is dose
dependent and has been shown to be more common in
older patients (Perloff et al. 2011). Calcium channels are
widely present in the central nervous system; therefore,
inhibition of these channels is likely to influence many
neural functions including sexual behavior. It has been
hypothesized that gabapentin mediated inhibition of cal-
cium currents may lead to alterations in the levels of
neurotransmitters release (particularly dopamine, which
promotes sexual desire, and serotonin, which inhibits sex-
uality) and attenuate post-synaptic excitability required to
maintain sexuality (Calabro 2011). The incidences of
severe myopathy and rhabdomyolysis have also been
reported with gabapentin therapy (Tuccori et al. 2007;
Bilgir et al. 2009). The exact mechanism of gabapentin-
induced myopathy is not known. It may be possible that
gabapentin by acting on voltage-gated calcium and sodium
channels in muscle cells may cause alterations in the
intracellular calcium/sodium balance to promote myopathy
(Alden and Garcia 2001; Liu et al. 2006; Tuccori et al.
2007). In a retrospective real world study, it was demon-
strated that switching from long-term treatment with alpha-
lipoic acid to gabapentin in painful diabetic neuropathy led
to higher rates of side effects, frequencies of outpatient
visits, and daily costs of treatment (Ruessmann 2009).
Amongst the gabapentinoid drugs, the various studies
have shown the superiority of pregabalin over the gaba-
pentin. Perez and co-workers demonstrated that pregabalin
administration is associated with greater reduction in mean
weekly intensity of pain as compared to gabapentin, with
no significant differences in cost (Perez et al. 2010). In a
direct comparison study, it was demonstrated that the
analgesic action of pregabalin in PHN was six times that of
gabapentin in terms of effectiveness in dosage conversion
123
A. Kukkar et al.
(Ifuku et al. 2011). In an open, randomized, comparative
study suggested that the tramadol/acetaminophen combi-
nation treatment is as effective as gabapentin in the treat-
ment of painful diabetic neuropathy in patients with type 2
diabetes (Ko et al. 2010).
Mechanism of action
Gabapentin may produce pain attenuating effects by acting
on both the central nervous system (on the spinal and the
supra-spinal areas) and on the peripheral region (DRG
neurons) (Fig. 2). Accordingly, gabapentin has been found
useful in the spinal cord injury- induced pain as well as in
peripheral neuropathic pain (Attal et al. 2009). Gabapentin
acts peripherally to suppress the nociceptive afferent
stimuli from the injured DRG neurons (critical source of
triggering hyperalgesia and spontaneous pain) to the spinal
cord by reducing the sub-threshold membrane potential
oscillation (SMPO) (Yang et al. 2005). Gabapentin medi-
ated persistent inhibition of sodium current in chronically
compressed DRG neurons (A type) has been described to
produce inhibition of SMPO dependent repetitive firing and
bursting (Yang et al. 2009). Gabapentin was originally
designed as GABA mimetic with the intention that it would
be able to cross the bloodbrain barrier and interact with
GABAergic systems to enhance GABA mediated inhibi-
tion. However, the studies have shown that it produces pain
attenuating effects by modulating other targets.
DRG and dorsal horn neurons
Voltage gated calcium channels
a2d-1 subunit a2d subunit of the voltage gated calcium
channels on the DRG neurons has been defined as the main
molecular target for gabapentin and amongst the different
types of a2d, a2d-1 has been the key binding target of
gabapentin (Jaggi and Singh 2011). a2d-1 is the extracel-
lular auxillary subunit of voltage gated calcium channels
particularly the N- and L-types, but not the T- types
(Davies et al. 2007). The strongest evidence that the a2d-1
subunit is the key target for gabapentinoid drugs has come
from the genetic studies. The knock-in replacement of the
wild-type a2d-1 subunit with a mutant (a2d-1 R217A)
incapable of binding pregabalin has been shown to result in
complete loss of the drugs analgesic efficacy (Field et al.
2006). Although, there have also been some studies
reporting that gabapentin produces no effect on freshly
dissociated DRG neurons and inhibition of Ca2? channels
in this cell-type did not contribute to its mechanism of
action (Rock et al. 1993). Furthermore, several studies have
also reported that there is little/no acute inhibition of
Gabapentin in neuropathic pain
Fig. 2 Proposed sites of action of gabapentin. (A) dorsal horn of
spinal cord; (B) Locus coeruleus (LC); (C) dorsal root ganglion
(DRG). Bold arrows indicate magnification, broken arrows show
inhibition and normal arrows show signal pathway. (A) Gabapentin
inhibits anterograde trafficking of a2d-1 subunits from DRG to spinal
cord dorsal horn and further inhibits receptor trafficking from cytosol
to cell membrane at pre synaptic site, which as a result inhibits release
calcium currents either in neurons or in heterologous
expression systems (Li et al. 2006; Davies et al. 2007). The
disparity in results of heterologous expression system and
DRG neurons may be due to channel subunit heterogeneity
and the pathologic state of the tissue i.e., hyperalgesic or
normal. This point has been emphasized by a study
showing that gabapentin specifically inhibited Ca2? cur-
rents in mice over-expressing the a2d-1 subunits and did
not produce any effect in wild-type mice (Li et al. 2006).
The external application of gabapentin is not shown to
produce an acute effect on Ca2? channel current amplitude/
voltage dependent gating behavior. However, chronic
external exposure is shown to slow the rate of expression of
Ca2? channels indicating that gabapentin must be trans-
ported across the cell membrane to produce the inhibitory
effect (Mich and Horne 2008). It has also been shown that
inhibitory effects of gabapentin are eliminated by pre-
treatment with pertussis toxin suggesting involvement of G
protein in its inhibitory mechanism (Martin et al. 2002). In
contrast to an earlier study suggesting the time independent
effectiveness of gabapentin in a day (Odrcich et al. 2006),
243
of glutamate and substance P. It also inhibits the formation of Ca2?/
calmodulin-dependent protein kinase II (CaMKII). (B) Gabapentin
inhibits release of GABA pre synaptically which further increases
glutamate level which in turn causes release of NA in spinal cord
which stimulates descending inhibition. (C) Gabapentin blocks Na?
channel activity which further inhibits SMPO
Kusunose and co-workers reported the time-dependent
difference in the anti-allodynic effects of gabapentin and
attributed the difference in activity to the circadian oscil-
lation of calcium a2d-1 subunit expression in the DRG
(Kusunose et al. 2010).
Inhibition of membrane trafficking: Gabapentin binds to
the accessory a2d-1 subunits, not the major a1 pore-
forming unit, of the calcium channels and the major
function of a2d-1 subunits is to direct trafficking of pore
forming a1 subunits of Ca2? channels from the endoplas-
mic reticulum to the plasma membrane (membrane traf-
ficking) (Jarvis and Zamponi 2007). Earlier studies had
shown that the surface expression of Cav2.1 channels is
increased to 7-fold when a2d-1 is combined in Xenopus
laevis oocytes with a1 subunits (Gurnett et al. 1996).
Neuropathic pain, due to injuries to peripheral/central
nervous system, is associated with over-expression of the
a2d subunits of calcium channels (particularly N- types) in
the DRG neurons and the dorsal horn neurons of the spinal
cord. The binding of gabapentin to over-expressing a2d-1
proteins may be responsible for the down regulation of
123
244
N- type calcium channels in the spinal cord and pain
attenuating effects in neuropathic pain (Luo et al. 2002;
Bauer et al. 2009; Taylor 2009; Boroujerdi et al. 2011).
Gabapentin acts mainly on a2d-1 isoform of a2d with
lower affinity for a2d-2 isoform and no effect on other two
isoforms of a2d. The arginine residue of a2d-1 at position
217 close to the VWA (Von willbrand domain A) domain
is critical for gabapentin binding and subsequent calcium
channel inhibition (Davies et al. 2007). VMA is present on
the extracellular sequence of all a2d subunits and contains
a perfect metal ion dependent adhesion site (MIDAS),
which is essential for the trafficking function of a2d. The
mutation within the VWA domains prevents the trafficking
of voltage gated calcium channels from cytoplasm to the
plasma membrane and decreases the Ca2? currents
(Whittaker and Hynes 2002; Cant et al. 2005; Hoppa et al.
2012).
Inhibition of anterograde trafficking (axoplasmic
transport): Recently in spinal nerve ligation model, the protein
level of the a2d-1 subunit has been reported to be significantly
higher in the spinal dorsal horn and DRG on the injured side
(Morimoto et al. 2012). In contrast, the mRNA levels of the
a2d-1 subunit were shown to be selectively increased on the
injured side of L5 DRG, not in the dorsal horn, suggesting that
an increase in the a2d-1 subunit in the dorsal horn of the spinal
cord is secondary to increased a2d-1 levels in the DRG. Fur-
thermore, gabapentin was shown to suppress the elevated
protein levels of the a2d-1 subunits in the spinal dorsal horns
without affecting the mRNA levels of the a2d-1 subunit.
Therefore, it has been suggested that gabapentin inhibits the
anterograde (axonal) transport of a2d-1 subunits from L5 DRG
to the primary afferent nerve terminals in the L5 dorsal horn
and normalizes the a2d-1 protein level in the spinal dorsal horn
by inhibiting the transport of the a2d-1 subunit (Morimoto
et al. 2012). Furthermore, the continuous administration of
gabapentin is reported to alleviate neuropathic pain for several
days after the termination of the administration indicating that
several days are required for the recovery of the transport of the
a2/d-1 subunit from the DRG to the primary afferent nerve
terminals (Morimoto et al. 2012). An earlier study has also
suggested that chronic administration of gabapentinoid drug
(pregabalin) attenuated nerve injury-induced increased a2d-1
in the pre-synaptic terminals of the dorsal horns and ascending
axon tracts, without affecting a2d-1 mRNA and protein in the
DRGs neurons. It was concluded that anti-allodynic effect of
pregabalin is associated with impaired anterograde trafficking
of a2d-1 from DRG neurons to the pre-synaptic terminals of
the dorsal horns resulting in reduced neurotransmitter release
and spinal sensitization (Bauer et al. 2009).
Inhibition of neurotransmitter release: Gabapentin
mediated decrease in the density of calcium channels in the
pre-synaptic terminals leads to decreased release of neu-
rotransmitters such as glutamate, CGRP and substance P
123
A. Kukkar et al.
that are involved in neuropathic pain progression (Yaksh
2006; Quintero et al. 2011). The role of substance P in the
induction and the maintenance of neuropathic pain is well
defined (Cahill and Coderre 2002). It has been demon-
strated that gabapentin not only suppresses the release of
substance P but also decreases substance P induced-NFkB
activation which is an essential mediator of substance
P-induced cytokine synthesis. Therefore, gabapentin regu-
lates inflammation-related intracellular signaling in both
neuronal and glial cells that is effective in alleviating
symptoms of inflammatory and neuropathic pain (Park
et al. 2008). Gabapentin has also been shown to attenuate
paclitaxel and vinorelbine-induced substance P release
from cultured DRG neurons (Miyano et al. 2009).
Inhibition of inflammation: The a2d-1 dependent anal-
gesic actions of gabapentin in neuropathic pain have also
been correlated with inhibition of inflammatory cytokines
and inflammation. Wodarski and co-workers demonstrated
the effectiveness of gabapentin in attenuating allodynia in
STZ-induced diabetic neuropathic pain and correlated the
beneficial effect with decreased microglial activation (Iba-
1 as a marker) and reduced number of astrocytes (GFAP as
a marker) (Wodarski et al. 2009). Recently, it has been
reported that unilateral intra articular injection of CFA
[complete freunds adjuvent] associated up-regulation of
a2d-1 subunit is associated with activation of microglia
and astrocytes and increased expression of CX3CL1 and
CX3CR1 in the spinal cord. CX3CL1 is defined as a
potential trigger to activate microglia and is co-localized
with a2d-1 subunits in the spinal dorsal horn. Adminis-
tration of gabapentin was shown to down-regulate the
spinal a2d-1 subunit expression and decrease CX3CL1
levels suggesting the critical role of CX3CL1 in gabapentin
mediated analgesic effects (Yang et al. 2012).
b subunits The trafficking of voltage gated Ca2? channel
from cytoplasm to plasma membrane and Ca2? channel
surface density also depends on b-subunit of calcium
channels. Using whole cell patch clamp method and fura-2
fluorescence imaging, Martin and co-workers demonstrated
that inhibitory actions of gabapentin on voltage gated
channels are dependent on a2d-1 as well as on b subunits
(Martin et al. 2002). Amongst the different b variants, b4a
splice variant is largely expressed at synapses, whereas b4b
is found in cell bodies of neurons and glial cells (Vendel
2007). Furthermore, only b4a form is expressed in the
spinal cord (Helton et al. 2002). Mich and Horne demon-
strated that gabapentin reduces the plasma membrane
trafficking of b4a-bound Cav2.1 complexes in the heterol-
ogous expression system (Mich and Horne 2008). It was
demonstrated that the inhibitory effects of gabapentin on
Ca2? channel expression could be reversed by increasing
concentrations of b4a subunit suggesting that the drug
Gabapentin in neuropathic pain
competes with b4a subunits in the process responsible for
Ca2? channel trafficking. The competition was reported to
be specific for b4a subunit and gabapentin had no effect in
the presence of b4b. The presence of b4a subunit in the
spinal cord also supports that the analgesic actions of
gabapentin are dependent of presence of b4a subunits
(Mich and Horne 2008).
NMDA receptors
Glutamate is an excitatory neurotransmitter in the nervous
system and it is released from pre-synaptic terminals in an
activity dependent manner between the primary afferents
and the spinal neurons involved in pain processing. The
studies have suggested its key role in pain development via
activation of NMDA (ionotropic) receptors (Jaggi and
Singh 2011). Apart from gabapentin mediated decreased
release of glutamate from pre-synaptic terminals of DRG,
gabapentin has been shown to directly inhibit NMDA
receptors in Xenopus oocytes (Hara and Sata 2007) that
may also be responsible for its anti-nociceptive activity.
Gabapentin has been shown to significantly inhibit NMDA
receptor-activated ion current and protect against NMDA-
induced excitotoxicity in rat cultured hippocampal CA1
neurons (Kim et al. 2009). A recent study has reported that
NMDA receptors blocker, MK801, potentiates the neuro-
pathic pain attenuating effects of intrathecal gabapentin in
CCI model (Yeh et al. 2011). A prospective, double blind
clinical trial has also demonstrated the efficacy of low dose
ketamine, an NMDA receptor antagonist, as adjuvant to
gabapentin in chronic pain (Amr 2010).
Protein kinase C (PKC)
The nerve injury-induced pain behaviour is associated with
over-expression of PKC-c in the spinal cord and its
involvement in nociceptive neuroplasticity in the spinal
cord has been well defined (Polgar et al. 1999; Furuta et al.
2009). Yeh and co-workers demonstrated that gabapentin
suppresses the PKC-c over-expression at the end of first
week and attributed the analgesic effects to inhibition of
PKC-c (Yeh et al. 2011). The contribution of Ca2?/cal-
modulin-dependent protein kinase II (CaMKII) to the
analgesic effect of gabapentin in a chronic constriction
injury model has also been defined and the analgesic
effects of gabapentin has been related to decreased
expression and phosphorylation of CaMKII in the spinal
cord (Ma et al. 2011).
Transient receptor potential (TRP) ion channels
The key role of temperature-sensitive transient recep-
tor potential ion channels (TRPs) including TRPA1 as
245
important pain sensors has been defined in number of
studies (Jaggi and Singh 2011) and TRPA1-deficient mice
generally show lack of sensitivities to different chemical
ligands and inflammatory mediators (Bautista et al. 2006;
Kwan et al. 2006). Bang and co-workers demonstrated that
gabapentin suppresses cinnamaldehyde-induced increase in
TRPA1 activity in Chinese hamster ovarian (CHO) heter-
ologous expression system and in cultured trigeminal
neurons without affecting other TRPs. It probably suggests
that TRPA1 on the dorsal horns or DRGs may also be a
critical target in pain alleviating effects of gabapentin
(Bang et al. 2009).
Supra-spinal actions of gabapentin
Gabapentin may also act supra-spinally to treat neuropathic
pain by stimulating descending inhibition to produce anti-
hypersensitivity in peripheral nerve injury. Peripheral
nerve injury induces differential changes in the plasticity of
GABAergic neurons in the locus coeruleus (LC) (increase
in GABA release) and spinal dorsal horn (decrease in
GABA release) and gabapentin is reported to selectively
reduce pre-synaptic GABA release in the LC, not in the
spinal dorsal horn (Yoshizumi et al. 2012b). The gaba-
pentin mediated reduction in GABAergic activity in the LC
is associated with an increased noradrenaline release that in
turn suppresses neurotransmission of pain in the spinal cord
via activation of a2 adrenoceptors (activation of descend-
ing pain inhibitory pathway to the spinal cord) (Hayashida
et al. 2008; Takasu et al. 2008; Yoshizumi et al. 2012b).
The earlier studies have shown that the anti-hypersensi-
tivity effect of both systemic and intra cerebro-ventricular
gabapentin are blocked by intrathecal injection of selective
a2-adrenoceptor antagonist, idazoxan suggesting the key
role of increased noradrenaline release in gabapentin
mediated analgesic effects (Hayashida et al. 2008).
The studies have demonstrated that gabapentin-induced
increased norepinephrine release in the spinal cord may
lead to G protein coupled inwardly rectifying potassium
channels (GIRK) activation which may eventually partici-
pate in its anti-hypersensitivity effects (Jones 1991; Tanabe
et al. 2005; Hayashida et al. 2007). Gabapentin-induced
noradrenaline may also activate GABAergic neurons in the
spinal dorsal horn via a1 adrenoceptors, therefore, gaba-
pentin-induced increase in spinal noradrenaline release
may also contribute to increased spinal GABA release
(Baba et al. 2000; Gassner et al. 2009). PKA-mediated
phosphorylation seems to be important for supra-spinal
actions of gabapentin in neuropathic conditions and it has
been described that gabapentin produces PKA-dependent
pre-synaptic enhancement of inhibitory GABAergic syn-
aptic transmission (Takasu et al. 2008) A recent study has
shown that activation of BDNF-trkB signaling is essential
123
246
for gabapentin mediated activation of descending inhibi-
tory pathway involving a2 receptors (Hayashida and
Eisenach 2011).
There is involvement of glutamate dependent mecha-
nisms also in gabapentin stimulated descending inhibitory
pathway from activated LC neurons with an increased
spinal noradrenaline release in rats and humans (Hayashida
and Eisenach 2001; Hayashida et al. 2007). The anti-
hypersensitivity effects of systemically administered
gabapentin are shown to be blocked by intra-LC AMPA
receptor antagonist suggesting the key role of glutamate
signaling in gabapentin mediated effects in neuropathic
pain (Hayashida et al. 2001; Yoshizumi et al. 2012b).
Glutamate via activation of Ca2? permeable ionotropic
glutamate receptors increases intracellular Ca2? in astro-
cytes from internal stores through 1,4,5-inositol-trisphos-
phate signalling (Hansson et al. 2000; Verkhratsky and
Kirchhoff 2007). However in some astrocytes, glutamate
transporters (responsible for glutamate reuptake) may
also result in Ca2? influx (Kirischuk et al. 1997; Rojas
et al. 2007) and may paradoxically result in glutamate
release from astrocytes via Ca2? dependent mechanisms
(Malarkey and Parpura 2008).
Difference in mechanism for acute and chronic effects
of gabapentin
The slow developing and long lasting analgesic actions of
gabapentin are dependent upon inhibition nerve injury-
Fig. 3 Proposed mechanisms
for acute, transient and chronic,
sustained analgesic actions
of gabapentin
123
A. Kukkar et al.
induced up-regulation of a2d-1 subunits in the dorsal horn
neurons by anterograde trafficking (axoplasmic transport)
and by inhibiting trafficking from cytoplasm to plasma
membrane (membrane trafficking) of pre-synaptic mem-
branes of DRG neurons and dorsal horn neurons. Since
these actions of gabapentin may require exposures of hours
to days, therefore, these mechanisms have been suggested
to contribute to chronic and sustained actions of gabapen-
tin. The sustained actions of gabapentin after the termina-
tion of its administration may be probably attributed to
time required for transport of the a2/d-1 subunit from the
DRG to the primary afferent nerve terminals (Morimoto
et al. 2012). However, gabapentin also produces acute and
transient analgesic effects (Morimoto et al. 2012) which are
dependent on constitutively expressed and functional
spinal system that does not require additional changes in
protein expression/channel mobilization and extended drug
exposure (Takasusuki and Yaksh 2011). These mechanisms
may include decreased release of nociceptive neurotrans-
mitters in pain processing pathway as Takasusuki and co-
workers have reported that acute analgesic effects of
gabapentin are dependent on decreased release of sub-
stance P from small primary afferents (Takasusuki and
Yaksh 2011) (Fig. 3).
Gabapentin versus other neuropathic drugs
TCA including imipramine and amitriptyline have gener-
ally been the first drugs of choice for management of
Gabapentin in neuropathic pain
neuropathic pain. However, gabapentinoid drugs have
emerged as first-line treatment for neuropathic pain due to
better efficacy and safety profile (Haslam and Nurmikko
2008; Vranken 2009). In patients with the spinal cord
injury, gabapentin has been shown to be more effective for
pain relief than amitriptyline (Selph et al. 2011). Among
gabapentinoid drugs, gabapentin and pregabalin have been
shown to be equally in reducing pain intensity, improving
sleep quality and depression in patients with painful
peripheral neuropathy (Biyik 2012). However, Saldana and
co-workers have demonstrated the efficacy of pregabalin in
gabapentin refractory patients (Saldana et al. 2012). Some
other studies have also the superiority of pregabalin in
alleviating cancer related neuropathic pain (Mishra et al.
2012), PHN (Ifuku et al. 2011) and fibromyalgia (Lloyd
et al. 2012).
Synergistic effects of gabapentin and antidepressants
Gabapentin shows synergistic effect with anti-depressant
venlafaxine in treating neuropathic pain and the combina-
tion was reported to be superior in comparison to gaba-
pentin alone in the SNI model of neuropathic pain (Garry
et al. 2005). The combined gabapentin and nortriptyline
therapy has also been reported to be more efficacious than
either drug alone for neuropathic pain management (Gilron
et al. 2009). Arai and co-workers demonstrated that low
dose gabapentin (200400 mg/12 h)-imipramine (10 mg/
12 h) combination with opioids was effective in managing
neuropathic cancer pain without severe adverse effects
(Arai et al. 2010). The synergistic actions of gabapentin
and TCA may probably be attributed to potentiation of
noradrenaline mediated activation of descending pain
inhibitory pathway from the LC to the spinal cord. Gaba-
pentin by virtue of reduction in GABAergic activity in the
LC leads to an increased noradrenaline release, while
antidepressants increase noradrenaline levels by blocking
pre-synaptically located noradrenaline-serotonin reuptake
pump. An increase in noradrenaline release in the LC may
potentiate descending pain inhibitory pathway from the LC
to the spinal cord and attenuate neuropathic pain.
Conclusion
There preclinical and clinical evidences have shown the
importance of gabapentin in neuropathic pain management
and it has emerged as one of the first line agents for pain
management particularly in diabetic neuropathy and post-
herpetic neuralgia. The majority of its actions have been
ascribed to its binding to a2d-1 subunits leading to
decreased expression of voltage gated calcium channels on
247
dorsal horn neurons via inhibition of membrane and
anterograde trafficking. However, its analgesic actions
involve more targets whose critical participation in pain
alleviation needs more studies.
Acknowledgments The authors are grateful to Department of
Pharmaceutical Sciences & Drug Research, Punjabi University, Pat-
iala, India for providing technical facilities.
References
Alden, K.J., and J. Garcia. 2001. Differential effect of gabapentin on
neuronal and muscle calcium currents. Journal of Pharmacology
and Experimental Therapeutics 297: 727735.
Amr, Y.M. 2010. Multi-day low dose ketamine infusion as adjuvant
to oral gabapentin in spinal cord injury related chronic pain: A
prospective, randomized, double blind trial. Pain Physician 13:
245249.
Arai, Y.C., T. Matsubara, K. Shimo, K. Suetomi, M. Nishihara,
T. Ushida, K. Kobayashi, C. Suzuki, A. Kinoshita, M. Kondo,
S. Matsubara, R. Hayashi, Y. Tohyama, K. Nishida, and
M. Arakawa. 2010. Low-dose gabapentin as useful adjuvant to
opioids for neuropathic cancer pain when combined with low-
dose imipramine. Journal of Anesthesia 24: 407410.
Argoff, C.E. 2011. Review of current guidelines on the care of post
herpetic neuralgia. Postgraduate Medicine 123: 134142.
Attal, N., G. Mazaltarine, B. Perrouin-Verbe, T. Albert, and SOFMER
French Society for Physical Medicine and Rehabilitation. 2009.
Chronic neuropathic pain management in spinal cord injury
patients. What is the efficacy of pharmacological treatments
with a general mode of administration? (oral, transdermal, intra-
venous). Annals of Physical and Rehabilitation Medicine 52:
124141.
Baba, H., K. Shimoji, and M. Yoshimura. 2000. Norepinephrine
facilitates inhibitory transmission in substantia gelatinosa of
adult rat spinal cord (part 1): Effects on axon terminals of
GABAergic and glycinergic neurons. Anesthesiology 92:
473484.
Back, S.K., S.Y. Won, S.K. Hong, and H.S. Na. 2004. Gabapentin
relieves mechanical, warm and cold allodynia in a rat model of
peripheral neuropathy. Neuroscience Letters 368: 341344.
Backonja, M., A. Beydoun, K.R. Edwards, S.L. Schwartz, V.
Fonseca, M. Hes, L. LaMoreaux, and E. Garofalo. 1998.
Gabapentin for the symptomatic treatment of painful neuropathy
in patients with diabetes mellitus: A randomized controlled trial.
JAMA 280: 18311836.
Backonja, M.M., D.M. Canafax, and K.C. Cundy. 2011. Efficacy of
gabapentin enacarbil vs placebo in patients with postherpetic
neuralgia and a pharmacokinetic comparison with oral gabapen-
tin. Pain Medicine 12: 10981108.
Backonja, M., and R.L. Glanzman. 2003. Gabapentin dosing for
neuropathic pain: Evidence from randomized, placebo-con-
trolled clinical trials. Clinical Therapeutics 25: 81104.
Bang, S., S. Yoo, and S.W. Hwang. 2009. Gabapentin attenuates the
activation of transient receptor potential A1 by cinnamaldehyde.
Experimental Neurobiology 18: 17.
Bauer, C.S., M. Nieto-Rostro, W. Rahman, A. Tran-Van-Minh,
L. Ferron, L. Douglas, I. Kadurin, Y. Sri Ranjan, L. Fernandez-
Alacid, N.S. Millar, A.H. Dickenson, R. Lujan, and
A.C. Dolphin. 2009. The increased trafficking of the calcium
channel subunit alpha2delta-1 to presynaptic terminals in
neuropathic pain is inhibited by the alpha2delta ligand pregab-
alin. Journal of Neuroscience 29: 40764088.
123
248
Bautista, D.M., S.E. Jordt, T. Nikai, P.R. Tsuruda, A.J. Read, J.
Poblete, E.N. Yamoah, A.I. Basbaum, and D. Julius. 2006.
TRPA1 mediates the inflammatory actions of environment tal
irritants and proalgesic agents. Cell 124: 12691282.
Berger, A., E. Dukes, B. McCarberg, M. Liss, and G. Oster. 2003.
Change in opioid use after the initiation of gabapentin therapy in
patients with postherpetic neuralgia. Clinical Therapeutics 25:
28092821.
Beydoun, A. 1999. Postherpetic neuralgia: Role of gabapentin and
other treatment modalities. Epilepsia 40(Suppl 6): S51S56.
Bilgir, O., M. Calan, F. Bilgir, L. Kebapcilar, A. Yuksel, Y. Yildiz,
and I. Sari. 2009. Gabapentin-induced rhabdomyolysis in a
patient with diabetic neuropathy. Internal Medicine 48:
10851087.
Biyik, Z., Y. Solak, H. Atalay, A. Gaipov, F. Guney, and S. Turk.
2012. Gabapentin versus pregabalin in improving sleep quality
and depression in hemodialysis patients with peripheral neurop-
athy: A randomized prospective crossover trial. International
Urology and Nephrology, May 29. [Epub ahead of print].
Bodensteiner, J.B., H.H. Morris, and G.S. Golden. 1981. Asterixis
associated with sodium valproate. Neurology 31: 195196.
Bookwalter, T., and M. Gitlin. 2005. Gabapentin-induced neurologic
toxicities. Pharmacotherapy 25: 18171819.
Boroujerdi, A., J. Zeng, K. Sharp, D. Kim, O. Steward, and Z.D. Luo.
2011. Calcium channel alpha-2-delta-1 protein upregulation in
dorsal spinal cord mediates spinal cord injury-induced neuro-
pathic pain states. Pain 152: 649655.
Boulton, A.J. 2003. Treatment of symptomatic diabetic neuropathy.
Diabetes/Metabolism Research and Reviews 19(Suppl 1): S16
S21.
Butterworth, R.F. 1996. Neuroactive aminoacids in hepatic enceph-
alopathy. Metabolic Brain Disease 11: 165173.
Cahill, C.M., and T.J. Coderre. 2002. Attenuation of hyperalgesia in a
rat model of neuropathic pain after intrathecal pre- or post-
treatment with a neurokinin-1 antagonist. Pain 95: 277285.
Calabro, R.S. 2011. Gabapentin and sexual dysfunction: An over-
looked and underreported problem? Epilepsy & Behavior 22:
818.
Cant, C., M. Nieto-Rostro, I. Foucault, F. Heblich, J. Wratten, M.W.
Richards, J. Hendrich, L. Douglas, K.M. Page, A. Davies, and
A.C. Dolphin. 2005. The metal-ion-dependent adhesion site in
the Von Willebrand factorA domain of alpha2delta subunits is
key to trafficking voltage-gated Ca2? channels. Proceedings of
the National Academy of Sciences of the United States of
America 102: 1123011235.
Chandra, K., N. Shafiq, P. Pandhi, S. Gupta, and S. Malhotra. 2006.
Gabapentin versus nortriptyline in post-herpetic neuralgia
patients: A randomized, double-blind clinical trialthe GONIP
Trial. International Journal of Clinical Pharmacology and
Therapeutics 44: 358363.
Chen, S.R., and H.L. Pan. 2005. Effect of systemic and intrathecal
gabapentin on allodynia in a new rat model of postherpetic
neuralgia. Brain Research 1042: 108113.
Cheshire, W.P. 2007. Trigeminal neuralgia: For one nerve a multitude
of treatments. Expert Review of Neurotherapeutics 7: 15651579.
Chong, M.S., and J. Hester. 2007. Diabetic painful neuropathy:
Current and future treatment options. Drugs 67: 569585.
Chou, R., S. Carson, and B.K. Chan. 2009. Gabapentin versus
tricyclic antidepressants for diabetic neuropathy and post-
herpetic neuralgia: Discrepancies between direct and indirect
meta-analyses of randomized controlled trials. Journal of
General Internal Medicine 24: 178188.
Chu, L.C., M.L. Tsaur, C.S. Lin, Y.C. Hung, T.Y. Wang, C.C. Chen,
and J.K. Cheng. 2011. Chronic intrathecal infusion of gabapentin
prevents nerve ligation-induced pain in rats. British Journal of
Anaesthesia 106: 699705.
123
A. Kukkar et al.
Coderre, T.J., N. Kumar, C.D. Lefebvre, and J.S. Yu. 2007. A
comparison of the glutamate release inhibition and anti-allodynic
effects of gabapentin, lamotrigine, and riluzole in a model of
neuropathic pain. Journal of Neurochemistry 100: 12891299.
Dallocchio, C., C. Buffa, P. Mazzarello, and S. Chiroli. 2000.
Gabapentin vs. amitriptyline in painful diabetic neuropathy: An
open-label pilot study. Journal of Pain and Symptom Manage-
ment 20: 280285.
Davies, A., J. Hendrich, A.T. Van Minh, J. Wratten, L. Douglas, and
A.C. Dolphin. 2007. Functional biology of the alpha (2) delta
subunits of voltage gated calcium channels. Trends in Pharma-
cological Sciences 28: 220228.
Dworkin, R.H., A.B. OConnor, M. Backonja, J.T. Farrar, N.B.
Finnerup, T.S. Jensen, E.A. Kalso, J.D. Loeser, C. Miaskowski,
T.J. Nurmikko, R.K. Portenoy, A.S. Rice, B.R. Stacey, R.D.
Treede, D.C. Turk, and M.S. Wallace. 2007. Pharmacologic
management of neuropathic pain: Evidence-based recommenda-
tions. Pain 132: 237251.
Erdogan, G., D. Ceyhan, and S. Gulec. 2011. Possible heart failure
associated with pregabalin use: Case report. Agri 23: 8083.
Ermis, N., H. Gullu, M. Caliskan, A. Unsal, M. Kulaksizoglu, and
H. Muderrisoglu. 2010. Gabapentin therapy improves heart rate
variability in diabetic patients with peripheral neuropathy.
Journal of Diabetes and Its Complications 24: 229233.
Field, M.J., P.J. Cox, E. Stott, H. Melrose, J. Offord, T.Z. Su,
S. Bramwell, L. Corradini, S. England, J. Winks, R.A. Kinloch,
J. Hendrich, A.C. Dolphin, T. Webb, and D. Williams. 2006.
Identification of the a2-d-1 subunit of voltage dependent calcium
channels as a molecular target for pain mediating the analgesic
actions of pregabalin. Proceedings of the National Academy of
Sciences of the United States of America 103: 1753717542.
Folkesson, A., P.H. Honore, L.M. Andersen, P. Kristensen, and O.J.
Bjerrum. 2010. Low dose of donepezil improves gabapentin
analgesia in the rat spared nerve injury model of neuropathic
pain: Single and multiple dosing studies. Journal of Neural
Transmission 117: 13771385.
Furuta, S., T. Shimizu, M. Narita, K. Matsumoto, N. Kuzumaki,
S. Horie, T. Suzuki, and M. Narita. 2009. Subdiaphragmatic
vagotomy promotes nociceptive sensitivity of deep tissue in rats.
Neuroscience 164: 12521262.
Garry, E.M., A. Delaney, H.A. Anderson, E.C. Sirinathsinghji,
R.H. Clapp, W.J. Martin, P.R. Kinchington, D.L. Krah, C.
Abbadie, and S.M. Fleetwood-Walker. 2005. Varicella zoster
virus induces neuropathic changes in rat dorsal root ganglia and
behavioral reflex sensitisation that is attenuated by gabapentin or
sodium channel blocking drugs. Pain 118: 97111.
Gassner, M., R. Ruscheweyh, and J. Sandkuhler. 2009. Direct
excitation of spinal GABAergic interneurons by noradrenaline.
Pain 145: 204210.
Geber, C., U. Baumgartner, R. Schwab, H. Muller, P. Stoeter,
M. Dieterich, C. Sommer, F. Birklein, and R.D. Treede. 2009.
Revised definition of neuropathic pain and its grading system:
An open case series illustrating its use in clinical practice.
American Journal of Medicine 122(10 Suppl): S3S12.
Gilron, I., J.M. Bailey, D. Tu, R.R. Holden, A.C. Jackson, and
R.L. Houlden. 2009. Nortriptyline and gabapentin, alone and in
combination for neuropathic pain: A double-blind, randomised
controlled crossover trial. Lancet 374: 12521261.
Gilron, I., J.M. Bailey, D. Tu, R.R. Holden, D.F. Weaver, and R.L.
Houlden. 2005. Morphine, gabapentin, or their combination for
neuropathic pain. New England Journal of Medicine 352: 13241334.
Gurnett, C.A., M. De Waard, and K.P. Campbell. 1996. Dual function
of the voltage dependent Ca2? channel a2-d subunit in current
stimulation and subunit interaction. Neuron 16: 431440.
Hanna, M., C. OBrien, and M.C. Wilson. 2008. Prolonged-release
oxycodone enhances the effects of existing gabapentin therapy in
Gabapentin in neuropathic pain
painful diabetic neuropathy patients. European Journal of Pain
12: 804813.
Hansson, E., H. Muyderman, J. Leonova, L. Allansson, J. Sinclair,
F. Blomstrand, T. Thorlin, M. Nilsson, and L. Ronnback. 2000.
Astroglia and glutamate in physiology and pathology: Aspects
on glutamate transport, glutamate-induced cell swelling and
gap-junction communication. Neurochemistry International 37:
317329.
Hara, K., and T. Sata. 2007. Inhibitory effect of gabapentin on
N-methyl-D-aspartate receptors expressed in Xenopus oocytes.
Acta Anaesthesiologica Scandinavica 51: 122128.
Haslam, C., and T. Nurmikko. 2008. Pharmacological treatment of
neuropathic pain in older persons. Clinical Interventions in
Aging 3: 111120.
Hasnie, F.S., J. Breuer, S. Parker, V. Wallace, J. Blackbeard, I. Lever,
P.R. Kinchington, A.H. Dickenson, T. Pheby, and A.S. Rice.
2007. Further characterization of a rat model of varicella zoster
virus-associated pain: Relationship between mechanical hyper-
sensitivity and anxiety-related behaviour, and the influence of
analgesic drugs. Neuroscience 144: 14951508.
Hayashida, K., and J.C. Eisenach. 2008. Multiplicative interactions to
enhance gabapentin to treat neuropathic pain. European Journal
of Pharmacology 598: 2126.
Hayashida, K., and J.C. Eisenach. 2011. A tropomyosine receptor
kinase inhibitor blocks spinal neuroplasticity essential for the
anti-hypersensitivity effects of gabapentin and clonidine in rats
with peripheral nerve injury. Journal of Pain 12: 94100.
Hayashida, K., H. Obata, K. Nakajima, and J.C. Eisenach. 2008.
Gabapentin acts within the locus coeruleus to alleviate neuro-
pathic pain. Anesthesiology 109: 10771084.
Hayashida, K., R. Parker, and J.C. Eisenach. 2007. Oral gabapentin
activates spinal cholinergic circuits to reduce hypersensitivity
after peripheral nerve injury and interacts synergistically with
oral donepezil. Anesthesiology 106: 12131219.
Helton, T.D., D.J. Kojetin, J. Cavanagh, and W.A. Horne. 2002.
Alternative splicing of a b4 subunit proline-rich motif regulates
voltage-dependent gating and toxin block of Cav2.1 Ca2?
channels. Journal of Neuroscience 22: 93319339.
Hemstreet, B., and M. Lapointe. 2001. Evidence for the use of
gabapentin in the treatment of diabetic peripheral neuropathy.
Clinical Therapeutics 23: 520531.
Hindmarsh, K.W., L. Tan, K. Sankaran, and V.A. Laxdal. 1989.
Diurnal rhythms of cortisol, ACTH, and beta-endorphin levels in
neonates and adults. Western Journal of Medicine 151: 153156.
Hon, N.C., and Y.J. Fei. 2008. Prescription pattern of oral healthcare
professionals in the use of anticonvulsants for trigeminal
neuralgia. Annals of the Royal Australasian College of Dental
Surgeons 19: 162164.
Honarmand, A., M. Safavi, and M. Zare. 2011. Gabapentin: An
update of its pharmacological properties and therapeutic use in
epilepsy. Journal of Medical Sciences Research 16: 10621069.
Hoppa, M.B., B. Lana, W. Margas, A.C. Dolphin, and T.A. Ryan.
2012. a2d expression sets presynaptic calcium channel abun-
dance and release probability. Nature 486: 122125.
Ifuku, M., M. Iseki, I. Hidaka, Y. Morita, S. Komatus, and E. Inada.
2011. Replacement of gabapentin with pregabalin in postherpetic
neuralgia therapy. Pain Medicine 12: 11121116.
Jacob, P. C., R. P. Chand, and el-S. Omeima. 2000. Asterixis induced
by gabapentin. Clin. Neuropharmacol, 23, 53.
Jaggi, A.S., and N. Singh. 2011. Role of different brain areas in
peripheral nerve injury-induced neuropathic pain. Brain
Research 1381: 187201.
Jarvis, S.E., and G.W. Zamponi. 2007. Trafficking and regulation of
neuronal voltage gated calcium channels. Current Opinion in
Cell Biology 19: 474482.
249
Jean, W.H., C.C. Wu, M.S. Mok, and W.Z. Sun. 2005. Starting dose
of gabapentin for patients with post-herpetic neuralgiaa dose-
response study. Acta Anaesthesiologica Taiwanica 43: 7377.
Jones, S.L. 1991. Descending noradrenergic influences on pain.
Progress in Brain Research 88: 381394.
Kaufman, K.R., and P.J. Struck. 2011. Gabapentin-induced sexual
dysfunction. Epilepsy & Behavior 21: 324326.
Keskinbora, K., A.F. Pekel, and I. Aydinli. 2007. Gabapentin and an
opioid combination versus opioid alone for the management of
neuropathic cancer pain: A randomized open trial. Journal of
Pain and Symptom Management 34: 183189.
Kim, Y.S., H.K. Chang, J.W. Lee, Y.H. Sung, S.E. Kim, M.S. Shin,
J.W. Yi, J.H. Park, H. Kim, and C.J. Kim. 2009. Protective effect
of gabapentin on N-methyl-D-aspartate-induced excitotoxicity in
rat hippocampal CA1 neurons. Journal of Pharmacological
Science 109: 144147.
Kirischuk, S., H. Kettenmann, and A. Verkhratsky. 1997. Na?/Ca2?
exchanger modulates kainate-triggered Ca2? signaling in Berg-
mann glial cells in situ. FASEB Journal 11: 566572.
Ko, S.H., H.S. Kwon, J.M. Yu, S.H. Baik, I.B. Park, J.H. Lee, K.S.
Ko, J.H. Noh, D.S. Kim, C.H. Kim, J.O. Mok, T.S. Park, H.S.
Son, and B.Y. Cha. 2010. Comparison of the efficacy and safety
of tramadol/acetaminophen combination therapy and gabapentin
in the treatment of painful diabetic neuropathy. Diabetic
Medicine 27: 10331040.
Kusunose, N., S. Koyanagi, K. Hamamura, N. Matsunaga, M.
Yoshida, T. Uchida, M. Tsuda, K. Inoue, and S. Ohdo. 2010.
Molecular basis for the dosing time-dependency of anti-
allodynic effects of gabapentin in a mouse model of neuropathic
pain. Molecular Pain 6: 83.
Kwan, K.Y., A.J. Allchorne, M.A. Vollrath, A.P. Christensen, D.S.
Zhan, C.J. Woolf, and D.P. Corey. 2006. TRPA1 contributes
cold, mechanical, and chemical nociception but is n essential for
hair-cell transduction. Neuron 50: 277289.
Lemos, L., R. Fontes, S. Flores, P. Oliveira, and A. Almeida. 2010.
Effectiveness of the association between carbamazepine and
peripheral analgesic block with ropivacaine for the treatment of
trigeminal neuralgia. Journal of Pain Research 3: 201212.
Li, C.Y., X.L. Zhang, E.A. Matthews, K.W. Li, A. Kurwa, A.
Boroujerdi, J. Gross, M.S. Gold, A.H. Dickenson, G. Feng, and
Z.D. Luo. 2006. Calcium channel a2-d-1 subunit mediates spinal
hyperexcitability in pain modulation. Pain 125: 2034.
Liu, Y., N. Qin, T. Reitz, Y. Wang, and C.M. Flores. 2006. Inhibition
of the rat brain sodium channel Nav1.2 after prolonged exposure
to gabapentin. Epilepsy Research 70: 263268.
Lloyd, A., C.S. Boomershine, E.H. Choy, A. Chandran, and G. Zlateva.
2012. The cost-effectiveness of pregabalin in the treatment of
fibromyalgia: US perspective. Journal of Medicinal Economics
15: 481492.
Lopez, P.R., T. Rachael, S. Leicht, and R.D. Smalligan. 2010.
Gabapentin-induced delusions of parasitosis. Southern Medical
Journal 103: 711712.
Luo, Z.D., N.A. Calcutt, E.S. Higuera, C.R. Valder, Y.H. Song, C.I.
Svensson, and R.R. Myers. 2002. Injury type-specific calcium
channel alpha 2 delta-1 subunit up-regulation in rat neuropathic
pain models correlates with antiallodynic effects of gabapentin.
Journal of Pharmacology and Experimental Therapeutics 303:
11991205.
Ma, L.L., W. Liu, Y.G. Huang, N. Yang, and P.P. Zuo. 2011.
Analgesic effect of gabapentin in a rat model for chronic
constrictive injury. Chinese Medical Journal (English Edition)
124: 43044309.
Malarkey, E.B., and V. Parpura. 2008. Mechanisms of glutamate
release from astrocytes. Neurochemistry International 52:
142154.
123
250
Martin, D.J., D. McClelland, M.B. Herd, K.G. Sutton, M.D. Hall,
K. Lee, R.D. Pinnock, and R.H. Scott. 2002. Gabapentin-
mediated inhibition of voltage-activated Ca2? channel currents
in cultured sensory neurones is dependent on culture conditions
and channel subunit expression. Neuropharmacology 42: 353366.
Mich, P.M., and W.A. Horne. 2008. Alternative splicing of the Ca
channel beta4 subunit confers specificity for gabapentin inhibi-
tion of Cav2.1 trafficking. Molecular Pharmacology 74:
904912.
Mishra, S., S. Bhatnagar, G.N. Goyal, S.P. Rana, and S.P. Upadhya.
2012. A comparative efficacy of amitriptyline, gabapentin, and
pregabalin in neuropathic cancer pain: A prospective random-
ized double-blind placebo-controlled study. American Journal of
Hospice & Palliative Care 29: 177182.
Mittal, M., M. Pasnoor, R.B. Mummaneni, S. Khan, A. McVey, D.
Saperstein, L. Herbelin, L. Ridings, Y. Wang, M.M. Dimachkie,
and R.J. Barohn. 2011. Retrospective chart review of duloxetine
and pregabalin in the treatment of painful neuropathy. Journal of
Neuroscience 121: 521527.
Mixcoatl-Zecuatl, T., G.N. Quinonez-Bastidas, N.L. Caram-Salas,
M. Ambriz-Tututi, C.I. Araiza-Saldana, H.I. Rocha-Gonzalez,
R. Medina-Santillan, G. Reyes-Garcia, and V. Granados-Soto.
2008. Synergistic antiallodynic interaction between gabapentin
or carbamazepine and either benfotiamine or cyanocobalamin in
neuropathic rats. Methods and Findings in Experimental and
Clinical Pharmacology 30: 431441.
Miyano, K., H.B. Tang, Y. Nakamura, N. Morioka, A. Inoue, and Y.
Nakata. 2009. Paclitaxel and vinorelbine, evoked the release of
substance P from cultured rat dorsal root ganglion cells through
different PKC isoform-sensitive ion channels. Neuropharmacol-
ogy 57: 2532.
Morello, C.M., S.G. Leckband, C.P. Stoner, D.F. Moorhouse, and
G.A. Sahagian. 1999. Randomized double-blind study compar-
ing the efficacy of gabapentin with amitriptyline on diabetic
peripheral neuropathy pain. Archives of Internal Medicine 159:
19311937.
Morimoto, S., M. Ito, S. Oda, A. Sugiyama, M. Kuroda, and S.
Adachi-Akahane. 2012. Spinal mechanism underlying the anti-
allodynic effect of gabapentin studied in the mouse spinal nerve
ligation model. Journal of Pharmacological Science 118:
455466.
OConnor, A.B., K. Noyes, and R.G. Holloway. 2007. A cost-
effectiveness comparison of desipramine, gabapentin, and pre-
gabalin for treating postherpetic neuralgia. Journal of the
American Geriatrics Society 55: 11761184.
Odrcich, M., J.M. Bailey, C.M. Cahill, and I. Gilron. 2006.
Chronobiological characteristics of painful diabetic neuropathy
and postherpetic neuralgia: Diurnal pain variation and effects of
analgesic therapy. Pain 120: 207212.
Pandey, C.K., N. Singh, and P.K. Singh. 2008. Gabapentin for
refractory idiopathic trigeminal neuralgia. Journal of the Indian
Medical Association 106: 124125.
Paradowski, B., and M. Bilinska. 2003. Gabapentin in the treatment
of neuropathic pain in patients with type 2 diabetes mellitus. Pol
Merkur Lekarski 15: 6164.
Park, S., E.S. Ahn, D.W. Han, J.H. Lee, K.T. Min, H. Kim, and
Y.W. Hong. 2008. Pregabalin and gabapentin inhibit substance
P-induced NF-kappaB activation in neuroblastoma and glioma
cells. Journal of Cellular Biochemistry 105: 414423.
Parsons, B., L. Tive, and S. Huang. 2004. Gabapentin: A pooled
analysis of adverse events from three clinical trials in patients
with postherpetic neuralgia. American Journal of Geriatric
Pharmacotherapy 2: 157162.
Patarica-Huber, E., N. Boskov, and M. Pjevic. 2011. Multimodal
approach to therapy-related neuropathic pain in breast cancer.
Journal of BUON 16: 4045.
123
A. Kukkar et al.
Perez, C., A. Navarro, M.T. Saldana, X. Masramon, and J. Rejas.
2010. Pregabalin and gabapentin in matched patients with
peripheral neuropathic pain in routine medical practice in a
primary care setting: Findings from a cost-consequences analysis
in a nested case-control study. Clinical Therapeutics 32:
13571370.
Perloff, M.D., D.E. Thaler, and J.A. Otis. 2011. Anorgasmia with
gabapentin may be common in older patients. American Journal
of Geriatric Pharmacotherapy 9: 199203.
Petraglia, F., F. Facchinetti, D. Parrini, G. Micieli, S. De Luca, and
A.R. Genazzani. 1983. Simultaneous circadian variations of
plasma ACTH, beta-lipotropin, beta-endorphin and cortisol.
Hormone Research 17: 147152.
Polgar, E., J.H. Fowler, M.M. McGill, and A.J. Todd. 1999. The types
of neuron which contain protein kinase C gamma in rat spinal
cord. Brain Research 833: 7180.
Quintero, J.E., D.J. Dooley, F. Pomerleau, P. Huettl, and G.A.
Gerhardt. 2011. Amperometric measurement of glutamate
release modulation by gabapentin and pregabalin in rat neocor-
tical slices: Role of voltage-sensitive Ca2? a2d-1 subunit.
Journal of Pharmacology and Experimental Therapeutics 338:
240245.
Rice, A.S., and S. Maton. 2001. Gabapentin in postherpetic neuralgia:
A randomised, double blind, placebo controlled study. Pain 94:
215224.
Richardson, C.E., D.W. Williams, and J.G. Kingham. 2002. Gaba-
pentin induced cholestasis. BMJ 325: 635.
Rock, D.M., K.M. Kelly, and R.L. Macdonald. 1993. Gabapentin
actions on ligand- and voltage-gated responses in cultured rodent
neurons. Epilepsy Research 16: 8998.
Rojas, H., C. Colina, M. Ramos, G. Benaim, E.H. Jaffe, C. Caputo,
and R. DiPolo. 2007. Na? entry via glutamate transporter
activates the reverse Na?/Ca2? exchange and triggers Ca(i)2?-
induced Ca2? release in rat cerebellar Type-1 astrocytes.
Neurochemistry 100: 11881202.
Ross, J.R., K. Goller, J. Hardy, J. Riley, K. Broadley, R. Ahern, and
J. Williams. 2005. Gabapentin is effective in the treatment of
cancer-related neuropathic pain: A prospective, open-label study.
Journal of Palliative Medicine 8: 11181126.
Rowbotham, M., N. Harden, B. Stacey, P. Bernstein, and L. Magnus-
Miller. 1998. Gabapentin for the treatment of postherpetic
neuralgia: A randomized controlled trial. JAMA 280: 18371842.
Ruessmann, H.J. 2009. Switching from pathogenetic treatment with
alpha-lipoic acid to gabapentin and other analgesics in painful
diabetic neuropathy: A real-world study in outpatients. Journal
of Diabetes and Its Complications 23: 174177.
Said, G. 2007. Diabetic neuropathya review. Nature Clinical
Practice Neurology 3: 331340.
Saldana, M.T., C. Perez, A. Navarro, X. Masramon, and J. Rejas.
2012. Pain alleviation and patient-reported health outcomes
following switching to pregabalin in individuals with gabapen-
tin-refractory neuropathic pain in routine medical practice.
Clinical Drug Investigation 32: 401412.
Sandercock, D., M. Cramer, J. Wu, Y.K. Chiang, V. Biton, and
M. Heritier. 2009. Gabapentin extended release for the treatment
of painful diabetic peripheral neuropathy: Efficacy and tolera-
bility in a double-blind, randomized, controlled clinical trial.
Diabetes Care 32: e20.
See, S., E. Hendriks, and L. Hsiung. 2011. Akathisia induced by
gabapentin withdrawal. Annals of Pharmacotherapy 45: e31.
Selph, S., S. Carson, R. Fu, S. Thakurta, A. Low, and M. McDonagh.
2011. Drug class review: neuropathic pain: Final update 1
report [Internet]. Portland (OR): Oregon Health & Science
University.
Takahashi, H., and N. Shimoyama. 2010. A prospective open-label
trial of gabapentin as an adjuvant analgesic with opioids for
Gabapentin in neuropathic pain
Japanese patients with neuropathic cancer pain. International
Journal of Clinical Oncology 15: 4651.
Takasu, K., H. Ono, and M. Tanabe. 2008. Gabapentin produces
PKA-dependent pre-synaptic inhibition of GABAergic synaptic
transmission in LC neurons following partial nerve injury in
mice. Journal of Neurochemistry 105: 933942.
Takasusuki, T., and T.L. Yaksh. 2011. The effects of intrathecal and
systemic gabapentin on spinal substance P release. Anesthesia
and Analgesia 112: 971976.
Tanabe, M., K. Takasu, N. Kasuya, S. Shimizu, M. Honda, and H.
Ono. 2005. Role of descending noradrenergic system and spinal
alpha2-adrenergic receptors in the effects of gabapentin on
thermal and mechanical nociception after partial nerve injury in
the mouse. British Journal of Pharmacology 144: 703714.
Taylor, C.P. 1997. Mechanisms of action of gabapentin. Rev Neurol
(Paris) 153(suppl 1): 539545.
Taylor, C.P. 2009. Mechanisms of analgesia by gabapentin and
pregabalincalcium channel alpha2-delta [Cavalpha2-delta]
ligands. Pain 142: 1316.
Tsavaris, N., P. Kopterides, C. Kosmas, A. Efthymiou, H. Skopelitis,
A. Dimitrakopoulos, E. Pagouni, D. Pikazis, P.V. Zis, and C.
Koufos. 2008. Gabapentin monotherapy for the treatment of
chemotherapy-induced neuropathic pain: A pilot study. Pain
Medicine 9: 12091216.
Tuccori, M., G. Lombardo, F. Lapi, A. Vannacci, C. Blandizzi, and
M. Del Tacca. 2007. Gabapentin-induced severe myopathy.
Annals of Pharmacotherapy 41: 13011305.
Vadalouca, A., E. Raptis, E. Moka, P. Zis, P. Sykioti, and I. Siafaka.
2012. Pharmacological treatment of neuropathic cancer pain: A
comprehensive review of the current literature. Pain Practice 12:
219251.
Vendel, A. C., M. D. Terry, A. R. Striegel, N. M. Iverson, V.
Leuranguer, C. D. Rithner, B. A. Lyons, G. E. Pickard, S.
A. Tobet, and W. A. Horne. 2007. Alternative splicing of the
voltage-gated Ca2? channel b4 subunit creates a uniquely folded
N-terminal protein binding domain with cell-specific expression
in the cerebellar cortex. Journal of Neuroscience 26, 26352644
(2006).
Vranken, J.H. 2009. Mechanisms and treatment of neuropathic pain.
Central Nervous System Agents in Medicinal Chemistry 9:
7178.
Walczak, J.S., V. Pichette, F. Leblond, K. Desbiens, and P. Beaulieu.
2005. Behavioural, pharmacological and molecular character-
ization of the saphenous nerve partial ligation: A new model of
neuropathic pain. Neuroscience 132: 10931102.
Wallace, V.C., J. Blackbeard, A.R. Segerdahl, F. Hasnie, T. Pheby,
S.B. McMahon, and A.S. Rice. 2007. Characterization of rodent
models of HIV-gp120 and anti-retroviral-associated neuropathic
pain. Brain 130: 26882702.
Whittaker, C.A., and R.O. Hynes. 2002. Distribution and evolution of
von Willebrand/integrin A domains: Widely dispersed domains
251
with roles in cell adhesion and elsewhere. Molecular Biology of
the Cell 13: 33693387.
Wodarski, R., A.K. Clark, J. Grist, F. Marchand, and M. Malcangio.
2009. Gabapentin reverses microglial activation in the spinal
cord of streptozotocin-induced diabetic rats. European Journal
of Pain 13: 807811.
Xiao, W., A. Boroujerdi, G.J. Bennett, and Z.D. Luo. 2007. Chemo-
therapy-evoked painful peripheral neuropathy: Analgesic effects
of gabapentin and effects on expression of the alpha-2-delta type-1
calcium channel subunit. Neuroscience 144: 714720.
Verkhratsky, A., and F. Kirchhoff. 2007. Glutamate-mediated neu-
ronal-glial transmission. Anat 210: 651660.
Yaksh, T.L. 2006. Calcium channels as therapeutic targets in
neuropathic pain. Journal of Pain 7(1 Suppl 1): S13S30.
Yamama, Y., K. Nishikawa, T. Funao, T. Mori, and A. Asada. 2010.
Intrathecal gabapentin and clonidine synergistically inhibit
allodynia in spinal nerve-ligated rats. Life Sciences 87: 565571.
Yang, R.H., W.T. Wang, J.Y. Chen, R.G. Xie, and S.J. Hu. 2009.
Gabapentin selectively reduces persistent sodium current in
injured type-A dorsal root ganglion neurons. Pain 143: 4855.
Yang, R.H., J.L. Xing, J.H. Duan, and S.J. Hu. 2005. Effects of
gabapentin on spontaneous discharges and subthreshold mem-
brane potential oscillation of type A neurons in injured DRG.
Pain 116: 187193.
Yang, J.L., B. Xu, S.S. Li, W.S. Zhang, H. Xu, X.M. Deng, and Y.Q.
Zhang. 2012. Gabapentin reduces CX3CL1 signaling and blocks
spinal microglial activation in monoarthritic rats. Molecular
Brain 5: 18.
Yeh, C.Y., S.C. Chung, F.L. Tseng, Y.C. Tsai, and Y.C. Liu. 2011.
Biphasic effects of chronic intrathecal gabapentin administration
on the expression of protein kinase C gamma in the spinal cord
of neuropathic pain rats. Acta Anaesthesiologica Taiwanica 49:
144148.
Yi, H., M.A. Kim, S.K. Back, J.S. Eun, and H.S. Na. 2011. A novel
rat forelimb model of neuropathic pain produced by partial
injury of the median and ulnar nerves. European Journal of Pain
15: 459466.
Yoshizumi, M., J.C. Eisenach, and K. Hayashida. 2012a. Riluzole and
gabapentinoids activate glutamate transporters to facilitate
glutamate-induced glutamate release from cultured astrocytes.
European Journal of Pharmacology 677: 8792.
Yoshizumi, M., R.A. Parker, J.C. Eisenach, and K. Hayashida. 2012b.
Gabapentin inhibits c-amino butyric acid release in the locus
coeruleus but not in the spinal dorsal horn after peripheral nerve
injury in rats. Anesthesiology 116: 13471353.
Zakrzewska, J.M., and R. McMillan. 2011. Trigeminal neuralgia: The
diagnosis and management of this excruciating and poorly
understood facial pain. Postgraduate Medical Journal 87:
410416.
123