Implications and mechanism of action of gabapentin in ...€¦ · REVIEW Implications and mechanism...

REVIEW

Implications and mechanism of action of gabapentinin 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

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

A. Kukkar � A. Bali � N. Singh � A. S. Jaggi (&)

Department of Pharmaceutical Sciences and Drug Research,

Punjabi University, Patiala 147002, Punjab, India

e-mail: [email protected]

123

Arch. Pharm. Res. (2013) 36:237–251

DOI 10.1007/s12272-013-0057-y

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

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 (30–60 mg/kg i.p.)

as well as the spinal (10–20 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

OH

NH2

O

GABA

NH2

O

OH

Gabapentin

Fig. 1 Structures of GABA and gabapentin

238 A. Kukkar et al.

123

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 (15–300 mg/kg), benfotiamine (30–600 mg/kg)

or cyanocobalamin (0.3–6.0 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

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).

Gabapentin in neuropathic pain 239

123

Trigeminal neuralgia

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 (900–1,800 mg/d)

and amitriptyline (25–75 mg/d) was reported (Morello et al.

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

trial gabapentin (1,200–2,400 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

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

Gabapentin (800 mg/day) produce partial

to complete remission

Tsavaris et al. (2008),

Arai et al. (2010)

Low dose gabapentin (200–400 mg/day)

? imipramine (10 mg/12 h) ? opioids

alleviate pain with minimal side effects

2. Trigeminal neuralgia Gabapentin as second drug of choice; the

combination with ropivacain produces

significant effect in carbamazepine resistant cases

Lemos et al. (2010)

3. Diabetic neuropathic pain Main stay drug for elderly patients at a doses

of 1,800–3,600 mg/d gabapentin is

Vranken (2009), Paradowski

and Bilinska (2003)

Equivalent/better tolerated than TCA

with comparable/higher efficacy

4. Post-herpetic neuralgia Gabapentin is one of the first line treatment in PHN Jean et al. (2005),

Rice and Maton (2001)600 mg/day may be the safe and effective

starting dose with adequate relief at higher

doses (1,200–2,400 mg/day)


123

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, O’connor 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

(O’Connor 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 1,200–2,400 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

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

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 400–8,000 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

(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 blood–brain 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 drug’s 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


123

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),

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

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

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


123

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; Cantı 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 ofa2d-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

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 freund’s 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


123

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

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

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-

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

Fig. 3 Proposed mechanisms

for acute, transient and chronic,

sustained analgesic actions

of gabapentin


123

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 (200–400 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

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.

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