Implications and mechanism of action of gabapentin in neuropathic pain
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- Kukkar, A., Bali, A., Singh, N. et al. Arch. Pharm. Res. (2013) 36: 237. doi:10.1007/s12272-013-0057-y
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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 neuralgia. α2δ-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 α2δ-1 subunits inhibits nerve injury-induced trafficking of α1 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 α2δ-1 subunits from DRG to dorsal horns neurons in the form of anterograde trafficking is also inhibited in response to gabapentin administration. Gabapentin has also been shown to induce modulate other targets including transient receptor potential 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.
KeywordsGabapentin Neuropathic pain Diabetic neuropathy Post herpetic neuralgia Dorsal root ganglion Descending inhibition
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 neuropathic 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 neuropathic pain like diabetic neuropathy, post herpetic neuralgia (PHN), cancer, trigeminal neuralgia etc. Diabetic neuropathic pain is one of the long term complications of diabetes mellitus and, both metabolic and ischemic mechanisms have a role in diabetic neuropathies (Said 2007). The patients with Herpes zoster infection usually experience pain, however, some patients experience pain beyond the typical 4-week duration. About 10 % patients develop the distressing complication of PHN with complex pathophysiology 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 ganglion (Zakrzewska and McMillan 2011). Neuropathic cancer pain, commonly encountered in clinical practice, may also be cancer-related due to tumor invasion in the 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 norepinephrine), calcium channel α2δ ligands (gabapentin and pregabalin) and topical lidocaine. Opioid analgesics and tramadol are generally recommended as second-line treatments 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 in preclinical studies
There have been number of preclinical studies documenting the beneficial effects of gabapentin in different models of neuropathic pain. Back and co-workers demonstrated that intraperitoneal (i.p.) injection of gabapentin at different 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 μg) 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 demonstrated the efficacy of gabapentin (50 mg/kg i.p.) in attenuating cold as well as mechanical allodynia, but not hyperalgesia, in a saphenous partial ligation (unilateral partial injury to the saphenous nerve) rodent model of neuropathic pain (Walczak et al. 2005). In chronic constriction injury model of neuropathic pain, administration of gabapentin (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 neuropathic 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 μmol/day for 14 days in a chronic constriction injury model and at the dose of 20 μg/h for 7 days in spinal nerve ligation model has also been shown to attenuate neuropathic pain in an effective manner in rats (Chu et al. 2011; Yeh et al. 2011)
Furthermore, the effectiveness of gabapentin in attenuating pain behavior has also been described in chemotherapeutic agents and viruses-induced peripheral neuropathic pain. Xiao and co-workers demonstrated that systemic multiple dosing of gabapentin (100 mg/kg i.p.) significantly reduced paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia (Xiao et al. 2007). The systemic treatment with gabapentin has also been shown to attenuate ddC (Zalcitabine), an anti-retroviral 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 administration 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 synergistic 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 synergistic effect against spinal nerve ligation-induced neuropathic 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:
The summarized clinical implications of gabapentin in different forms of neuropathic pain
Types of pain
Treatment schedule/general comments
Cancer and chemotherapeutic agents-induced pain
Gabapentin (800 mg/day) produce partial to complete remission
Low dose gabapentin (200–400 mg/day) + imipramine (10 mg/12 h) + opioids alleviate pain with minimal side effects
Gabapentin as second drug of choice; the combination with ropivacain produces significant effect in carbamazepine resistant cases
Lemos et al. (2010)
Diabetic neuropathic pain
Main stay drug for elderly patients at a doses of 1,800–3,600 mg/d gabapentin is
Equivalent/better tolerated than TCA with comparable/higher efficacy
Gabapentin is one of the first line treatment in PHN
600 mg/day may be the safe and effective starting dose with adequate relief at higher doses (1,200–2,400 mg/day)
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 neuropathic 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 contrast, Takahashi and co-workers demonstrated that combination 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 significant 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).
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 management 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 gabapentin 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 gabapentin in treating diabetic neuropathy comparable to TCA. A randomized, double-blind, placebo-controlled study demonstrated 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). Furthermore, 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 neuropathic 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 comparisons between TCA and gabapentin, Chou and co-workers demonstrated the comparable effects of gabapentin and tricyclic 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 formulations 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 randomized, double-blind, placebo-controlled study conducted 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 treatment. 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 therapies 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 demonstrated 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 crossover 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 gabapentin could be a safe and effective starting dose for PHN patients (Jean et al. 2005). Due to circadian rhythm, the concentrations of β-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 gabapentin 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 negative 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 asterixis 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 hepatotoxicity 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 efficacy. The incidence of peripheral edema was reported to be increased with an increase in the dose of gabapentin ≥1,800 mg/d (7.5 % vs. 1.4 %) (Parsons et al. 2004). Due to development of peripheral edema with the recommended doses of gabapentin, The New York Heart Association has issued a warning about using caution while prescribing these drugs to type III-IV heart failure patients (Erdoğan 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 accumulation (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 for neuropathic pain and complete disappearance of symptoms was reported after discontinuation of the medication (Lopez et al. 2010). The patients tend to develop dependence on gabapentin even after 3 weeks of administration 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 gabapentin 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, tolerability, 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, anorgasmia, 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 calcium currents may lead to alterations in the levels of neurotransmitters release (particularly dopamine, which promotes sexual desire, and serotonin, which inhibits sexuality) and attenuate post-synaptic excitability required to maintain sexuality (Calabrò 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 demonstrated 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 gabapentin. Pérez 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 (Pérez 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 combination treatment is as effective as gabapentin in the treatment of painful diabetic neuropathy in patients with type 2 diabetes (Ko et al. 2010).
Mechanism of action
DRG and dorsal horn neurons
Voltage gated calcium channels
α2δ 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 α2δ, α2δ-1 has been the key binding target of gabapentin (Jaggi and Singh 2011). α2δ-1 is the extracellular 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 α2δ-1 subunit is the key target for gabapentinoid drugs has come from the genetic studies. The knock-in replacement of the wild-type α2δ-1 subunit with a mutant (α2δ-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 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+ currents in mice over-expressing the α2δ-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 transported 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 oscillation of calcium α2δ-1 subunit expression in the DRG (Kusunose et al. 2010).
Inhibition of membrane trafficking: Gabapentin binds to the accessory α2δ-1 subunits, not the major α1 pore-forming unit, of the calcium channels and the major function of α2δ-1 subunits is to direct trafficking of pore forming α1 subunits of Ca2+ channels from the endoplasmic reticulum to the plasma membrane (membrane trafficking) (Jarvis and Zamponi 2007). Earlier studies had shown that the surface expression of Cav2.1 channels is increased to 7-fold when α2δ-1 is combined in Xenopus laevis oocytes with α1 subunits (Gurnett et al. 1996). Neuropathic pain, due to injuries to peripheral/central nervous system, is associated with over-expression of the α2δ 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 α2δ-1 proteins may be responsible for the down regulation of 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 α2δ-1 isoform of α2δ with lower affinity for α2δ-2 isoform and no effect on other two isoforms of α2δ. The arginine residue of α2δ-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 α2δ subunits and contains a perfect metal ion dependent adhesion site (MIDAS), which is essential for the trafficking function of α2δ. 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; Cantí et al. 2005; Hoppa et al. 2012).
Inhibition of anterograde trafficking (axoplasmic transport): Recently in spinal nerve ligation model, the protein level of the α2δ-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 α2δ-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 α2δ-1 subunit in the dorsal horn of the spinal cord is secondary to increased α2δ-1 levels in the DRG. Furthermore, gabapentin was shown to suppress the elevated protein levels of the α2δ-1 subunits in the spinal dorsal horns without affecting the mRNA levels of the α2δ-1 subunit. Therefore, it has been suggested that gabapentin inhibits the anterograde (axonal) transport of α2δ-1 subunits from L5 DRG to the primary afferent nerve terminals in the L5 dorsal horn and normalizes the α2δ-1 protein level in the spinal dorsal horn by inhibiting the transport of the α2δ-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 α2/δ-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 α2δ-1 in the pre-synaptic terminals of the dorsal horns and ascending axon tracts, without affecting α2δ-1 mRNA and protein in the DRGs neurons. It was concluded that anti-allodynic effect of pregabalin is associated with impaired anterograde trafficking of α2δ-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 neurotransmitters 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 demonstrated 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 regulates 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 α2δ-1 dependent analgesic 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 α2δ-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 α2δ-1 subunits in the spinal dorsal horn. Administration of gabapentin was shown to down-regulate the spinal α2δ-1 subunit expression and decrease CX3CL1 levels suggesting the critical role of CX3CL1 in gabapentin mediated analgesic effects (Yang et al. 2012).
The trafficking of voltage gated Ca2+ channel from cytoplasm to plasma membrane and Ca2+ channel surface density also depends on β-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 α2δ-1 as well as on β subunits (Martin et al. 2002). Amongst the different β variants, β4a splice variant is largely expressed at synapses, whereas β4b is found in cell bodies of neurons and glial cells (Vendel 2007). Furthermore, only β4a form is expressed in the spinal cord (Helton et al. 2002). Mich and Horne demonstrated that gabapentin reduces the plasma membrane trafficking of β4a-bound Cav2.1 complexes in the heterologous 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 β4a subunit suggesting that the drug competes with β4a subunits in the process responsible for Ca2+ channel trafficking. The competition was reported to be specific for β4a subunit and gabapentin had no effect in the presence of β4b. The presence of β4a subunit in the spinal cord also supports that the analgesic actions of gabapentin are dependent of presence of β4a subunits (Mich and Horne 2008).
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 neuropathic 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-γ in the spinal cord and its involvement in nociceptive neuroplasticity in the spinal cord has been well defined (Polgár et al. 1999; Furuta et al. 2009). Yeh and co-workers demonstrated that gabapentin suppresses the PKC-γ over-expression at the end of first week and attributed the analgesic effects to inhibition of PKC-γ (Yeh et al. 2011). The contribution of Ca2+/calmodulin-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 receptor 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) heterologous 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 gabapentin 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 α2 adrenoceptors (activation of descending 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-hypersensitivity effect of both systemic and intra cerebro-ventricular gabapentin are blocked by intrathecal injection of selective α2-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 participate 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 α1 adrenoceptors, therefore, gabapentin-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 synaptic transmission (Takasu et al. 2008) A recent study has shown that activation of BDNF-trkB signaling is essential for gabapentin mediated activation of descending inhibitory pathway involving α2 receptors (Hayashida and Eisenach 2011).
There is involvement of glutamate dependent mechanisms 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 astrocytes from internal stores through 1,4,5-inositol-trisphosphate 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
Gabapentin versus other neuropathic drugs
TCA including imipramine and amitriptyline have generally been the first drugs of choice for management of 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 (Saldaña 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 combination was reported to be superior in comparison to gabapentin 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. Gabapentin 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.
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 α2δ-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.
The authors are grateful to Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India for providing technical facilities.