The ﬁrst anti-convulsant to be studied in clinical trials was CBZ. The drug causes a decreased conductance in Na+ channels, inhibits ectopic discharges and has been shown to treat neuropathic pain in TN, painful diabetic neuropa- thy and PHN (Backonja 2000; Tremont-Lukats et al. 2000).
Optimal pharmacotherapy for epilepsy as well as for neuropathic pain re- quires that spontaneous activity is suppressed without interference with nor- mal nerve conductance. CBZ blocks the spontaneous activity of the A-δ and C ﬁbres responsible for pain and abnormal nerve conductance via frequency-
dependent inhibition of sodium currents (Tanelian and Brose 1991; Suzuki and
Dickenson 2000; Dickenson et al. 2002).
Rush and Elliott (1997) studied CBZ and phenytoin’s effects on a heteroge- neous population of Na+ channels in patch-clamped small cells from adult rat dorsal horn ganglia to show that TTX-R Na+ currents are inhibited by these anti-convulsant agents used as pain therapy. Future development of modality- speciﬁc treatment may be aided with the knowledge that different Na+ channels possess distinct activation proﬁles (Suzuki and Dickenson 2000).
The basic science research conduced by Fox et al. (2003) gives supporting evidence that the anti-convulsant CBZ and oxcarbazepine (as well as lamot- rigine and GBP) are effective in treating mechanical hyperalgesia and tactile allodynia in an animal model of neuropathic pain. The side-effect proﬁle of oxcarbazepine is improved compared to existing therapies. These data give
support for the use of these AEDs in the clinical treatment of neuropathic pain. Speciﬁcally, this study examines the effects of oxcarbazepine and the other AEDs in rat and guinea-pig models of neuropathic pain. The results of these drugs varied between the rat model and the guinea-pig model of neuropathic pain induced by partial sciatic nerve ligation. Oxcarbazepine and CBZ had no effect on mechanical hyperalgesia or tactile allodynia in the rat following drug administration. However, in the guinea-pig with the same model of neuropathic pain used in the rat, a 90% depression of mechan- ical hyperalgesia with oxcarbazepine and CBZ is seen. Also, a similar drop in mechanical hyperalgesia is observed solely in the guinea-pig pain model with the active human metabolite of oxcarbazepine, monohydroxy derivative (Fox et al. 2003).
Today, CBZ is the treatment of choice for TN as studied in three placebo- controlled trials (Campbell et al. 1966; Nicol 1969; Killian and Fromm 1968). CBZ has an NNT of 2.6 in TN (Wiffen et al. 2000; Jensen 2002). Second line drugs used to treat this neuropathic pain condition are phenytoin, baclofen, clonazepam and sodium valproate (Perkin 1999).
CBZ produces signiﬁcant pain reduction in patients suffering from painful diabetic neuropathy with an NNT of 3.3 based on a study by Rull et al. (Rull et al. 1969; McQuay et al. 1995). A 15-patient, double-blind, 3-phase, cross-over,
placebo-controlled trial by Leijon and Boivie (1989) studied the effect on central post-stroke pain (CPSP) of amitriptyline and CBZ. Compared to amitriptyline, CBZ was less effective in the treatment of CPSP and not statistically different
when compared to placebo (Leijon and Boivie 1989). The small number of patients studied could account for the results of this study.
The number needed to harm (NNH) for CBZ is 3.4 for minor side-effects and
NNH of 24 for severe effects. The common side-effects of CBZ are drowsiness, diplopia, blurred vision, nausea and vomiting. In treatment of the elderly population with this drug, one must be aware of possible cardiac disease, water retention, decreased osmolality and hyponatremia complications (Wiffen et al.
2000; Jensen 2002).
The second-generation AED, oxcarbazepine, the dihydro-ketone analogue of CBZ, provides signiﬁcant analgesia in TN, painful diabetic neuropathy and many other neuropathic pain conditions refractory to other AEDs like CBZ and GBP. The documented effects of oxcarbazepine in neuropathic pain as well as its improved safety proﬁle and low side-effects suggest that this drug should be considered as a treatment therapy for neuropathic pain (Carrazana and Mikoshiba 2003).
CBZ, oxcarbazepine and the dihydro-monohydroxy analogue of CBZ were examined by Farago et al. (1987) in 13 patients suffering from TN. Both ana-
logues reduced the pain or symptoms associated with TN in all patients. The effective dose was between 10 and 20 mg/kg in most patients. These analogues can be dispensed at higher doses than CBZ because adverse effects such as
dizziness and ataxia occur much less often with them (Farago 1987).
Zakrzewska et al. (1997) examined the effect of oxcarbazepine in six patients with TN who were unsuccessfully treated with CBZ. This study ﬁnds that oxcarbazepine has therapeutic effect in pain control of TN with no signiﬁcant side-effects.
Oxcarbazepine has a distinct pharmacokinetic proﬁle from oxcarbazepine. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbamaze-
pine, its active metabolite; neither oxcarbazepine nor its active metabolite in- duce hepatic oxidative metabolism with the exception of the P450IIIA isozyme of the cytochrome P450 family. Due to hyponatraemia observed in some pa- tients, ﬂuid restriction may be advisable in some epileptic patients in order to
reduce the risk of precipitating seizures secondary to low serum sodium. This drug appears to be a suitable substitute for CBZ in patients who do not tolerate CBZ or suffer from signiﬁcant drug interactions (Grant and Faulds 1992).
The FDA approved oxcarbazepine in 2000 for add-on treatment of partial seizures in adults. This anti-convulsant is a membrane stabilizer and acts as a weak hepatic inducer without auto-induction. Like CBZ, oxcarbazepine acts
to treat TN with comparable efﬁcacy and less side-effects. In comparison to CBZ, this newer AED has no hepatotoxicity or bone marrow suppression. The side-effect proﬁle includes nausea, vomiting or dizziness, skin rash and oedema. Oxcarbazepine may be used to treat refractory neuropathic pain
In summary, as the ﬁrst anti-convulsant drugs to be tested in controlled clin- ical trials, CBZ and phenytoin have proved to act effectively to relieve painful diabetic neuropathy and paroxysmal attacks associated with TN. CBZ, oxcar- bazepine and lamotrigine have replaced phenytoin because of its complicated pharmacokinetic proﬁle and undesired side-effects.
Oxcarbazepine has a side-effect proﬁle that is better tolerated than that of CBZ. Thus, oxcarbazepine has become the drug of choice to treat TN in many Western countries (Jensen 2002). At present, there is no explanation of why drugs that have actions on sodium channels have proven efﬁcacy in TNs rather than a broad action on pain from other areas of the body.
Valproic acid has a wide range of clinical uses today due to its multiple mech- anisms of action. It has often been suggested that valproic acid acts by a com- bination of several different mechanisms because of its wide range of therapy uses such as its use in different seizure types, bipolar and schizo-affective disorders, neuropathic pain and prophylactic treatment of migraine (Loscher
1999; Johannessen 2000). The ﬁrst studies on use of valproic acid to treat neu- ropathic pain appeared in the early 1980s; this drug caused a reduction of pain in 50%–80% of patients with TN (Peiris et al. 1980; Savitskaya 1980; Tremont- Lukats et al. 2000). Similar to other ﬁrst-generation anti-convulsant drugs such
as phenytoin and CBZ, valproic acid is used to treat central neuropathic pain
(Finnerup et al. 2002).
Preclinical animal models of seizures or epilepsy also reﬂect the wide range of therapeutic effects of valproate. Evidence shows that valproic acid increases GABA synthesis and release in the central nervous system (Dickenson et al.
2002), thus potentiating GABAergic functions (Lee et al. 1995; Loscher 1999).
Moreover, valproic acid prolongs the repolarization phase of voltage-sensi- tive sodium channels and modulates TCA cycle enzymes including succinate semialdehyde dehydrogenase (SSA-DH), GABA transaminase (GABA-T), and α-ketoglutarate dehydrogenase, thus affecting cerebral metabolism (Johan-
nessen 2000; Tremont-Lukats et al. 2000; Jensen 2002). In vitro studies show valproic acid as a potent inhibitor of SSA-DH. Also, only high concentrations of this drug inhibit GABA-T in brain homogenates, and there is possible inhi-
bition of α-ketoglutarate dehydrogenase of the TCA cycle. It has been thought that the GABA-mediated action of valproate is responsible for its use in neu- ropathic pain. The effect of the drug on excitatory neurotransmission and on
excitatory membranes is likely a result of its mechanisms in ’mood-stabilizing’ and in its use in migraine prophylaxis (Johannessen 2000; Johannessen and Johannessen 2003). Valproic acid seems to reduce γ-hydroxybutyric acid re- lease and alters neuronal excitation which is induced by NMDA-type glutamate
receptors. Additionally, valproic acid acts with direct effects on excitable mem- branes. Loscher (1999) has stated that microdialysis data support an alteration in dopaminergic and serotonergic function due to valproic acid. It is note-
worthy that valproic acid is metabolized into many pharmacologically active compounds. However, the low concentration levels in the plasma and brain makes it unlikely that they have a signiﬁcant role in the anti-convulsant or
toxic effects of valproic acid (Loscher 1999).
After four decades of investigation of the mechanisms of action of one of the most widely used anti-epileptic drugs, the cellular mechanisms of valproic acid on synaptic physiology remain unclear. Martin et al. (2004) examined valproic acid’s effects on synaptic transmission using the in vitro rat hippocampal slice technique. Results from this study suggest that the effects of valproate are caused in part by a decrease in excitatory synaptic activity by modula- tion of postsynaptic non-NMDA receptors while leaving synaptic inhibition unchanged (Martin and Pozo 2004).
Hardy et al. (2001) conducted a phase II study of sodium valproate for cancer-related neuropathic pain. Response to the drug was deﬁned as a decrease
in pain score without increased need for analgesic medications. This study’s response rate for average pain at day 15 is 55.6%. However, this study has a large variability in response rates, depending on the mode of analysis (Hardy
et al. 2001).
Unfortunately, in a randomized, double-blind, placebo-controlled, cross- over clinical study, valproic acid had no signiﬁcant effect when compared with placebo in painful polyneuropathy (Otto et al. 2004). Furthermore, sodium
valproate is found to have no analgesic effect in the only placebo-controlled study of acute pain (Wiffen et al. 2000). As it stands, the current literature is unable to explain the precise role of valproic acid in the symptom management of neuropathic pain, and further studies are needed to examine this drug’s role in peripheral neuropathic pain disorders such as painful diabetic neuropathy (Tremont-Lukats et al. 2000).
Early clinical reports that lamotrigine, a voltage-activated sodium channel blocker as well as a potential calcium channel blocker, confers beneﬁcial ther- apeutic effects in central pain have prompted studies of use of this drug in the treatment of neuropathic pain (Canavero and Bonicalzi 1996).
An in vitro study by Cheung et al. (1992) suggests a direct interaction of lamotrigine with voltage-activated sodium channels which results in a block of
sustained repetitive ﬁring of sodium-dependent action potentials in cultured neurons from mouse spinal cord, as well as an inhibition of sodium channel
binding in rat brain synaptosomes. This voltage-activated sodium channel blocker dampens the ectopic discharges in the peripheral nervous system associated with neuropathic pain in a use-dependent manner. Lamotrigine acts by decreasing the increased neuronal excitability of afferent ﬁbres and also by
acting at the synaptic contacts of these ﬁbres with the spinal cord (Blackburn- Munro and Fleetwood-Walker 1999; Dickenson et al. 2002; Jensen 2002).
Blackburn-Munro and Fleetwood-Walker (1999) examined the mechanism of action of lamotrigine on the sodium channel auxiliary subunits β1 and β2 in the spinal cord of neuropathic rats. It is known that Na+ channels are composed of a main subunit which can vary and two supporting subunits β1 and β2. These two β-subunits act to modulate the rate of channel activation and inactivation as well as to modify α-subunit density within the plasma
membrane. In a chronic constrictive nerve injury model, Blackburn-Munro and Fleetwood-Walker (1999) show that β1 messenger RNA (mRNA) levels in- crease with a corresponding decrease in β2 mRNA levels in laminae I and II on the ipsilateral side of the cord relative to β levels in the contralateral side of the
cord. This study suggests that the altered excitability of the central neurons as- sociated with neuropathic pain may be partly explained by altered expression of β Na+ channel subunit types (Blackburn-Munro and Fleetwood-Walker 1999; Blackburn-Munro et al. 2001). It also showed that the opioid/cholecystokinin
pathway is not involved in lamotrigine’s anti-nociceptive effects (Blackburn- Munro et al. 2001). It follows that lamotrigine inhibits the neuronal release of glutamate indirectly by blocking sodium channels (Klamt 1998).
Furthermore, lamotrigine is claimed to act to modulate central sensitization via high-threshold N-type calcium channels, although this is unlikely to be a major primary action of the drug (Gordon and Love 2004).
Early in vivo studies support the use of lamotrigine in the treatment of neuropathic pain. Hunter et al. (1997) have reported that lamotrigine reverses cold allodynia 1 h post dose in a chronic constriction injury rat model of neuropathic pain. Erichsen et al. (2003) have shown that lamotrigine signiﬁ- cantly modulates mechanical hyperalgesia in a rat spared nerve injury model. However, lamotrigine had no effect on mechanical or cold allodynia in either a photo-chemically induced model of nerve injury (Gazelius) or in a spared nerve injury model (Erichsen et al. 2003).
A study by Christensen et al. (2001) comparing GBP and lamotrigine in a rat model of trigeminal neuropathic pain found that repeated GBP but not lamot-
rigine partially alleviates the mechanical allodynia associated with trigeminal neuropathic pain states. Single doses of either GBP or lamotrigine produced no effect on the mechanical allodynia-like behaviour in this study (Christensen
et al. 2001). However, another study shows lamotrigine has an analgesic ef- fect in both short- and long-term models of hyperalgesia in rats. In a chronic constriction injury neuropathic model of hyperalgesia as well as a diabetic neu-
ropathic model induced by streptozotocin, Klamt (1998) found that intrathecal lamotrigine has a spinal, dose-dependent, long-lasting hyperalgesic effect.
Many randomized, controlled trials show lamotrigine to act as an effective treatment of neuropathic pain (Zakrzewska et al. 1997; Simpson et al. 2000;
Eisenberg et al. 2001; Simpson et al. 2003). To treat the pain associated with TN, lamotrigine has been found to have an NNT of 2.1 (Zakrzewska and Patsalos 2002).
Simpson et al. (2000) initially studied the effect of lamotrigine for the treatment of painful HIV-associated distal sensory polyneuropathy (DSP) in a randomized, double-blind, placebo-controlled study with titration of drug.
Of 42 patients, 13 did not complete the study, with 5 of these drop-outs due to the side-effect of rash. This rash showed a greater frequency in this study than in epilepsy studies. This initial study indicates lamotrigine for treatment in pain associated with HIV-related DSP (Simpson et al. 2000). Later, Simpson
et al. (2003) performed a randomized, double-blind, pharmacological study of patients with HIV-associated DSP. HIV-associated neuropathic pain pa- tients receiving concurrent lamotrigine treatment with anti-retroviral therapy
showed improvement in the slope of the change in Gracely Pain Scale score for average pain as compared to placebo. Also, no measurable difference from baseline in Gracely Pain Scale score for average pain vs placebo patients with
DSP was observed. Although further research is needed to understand the differences between HIV patients receiving ART and those not receiving ART, Simpson et al. (2003) have demonstrated that lamotrigine is well-tolerated and effective in the treatment of HIV-associated neuropathic pain in patients using
ART (Simpson et al. 2003).
Eisenberg et al. (2001) conclude that the therapeutic use of lamotrigine in pain control of diabetic neuropathy is effective and safe (Eisenberg et al. 2001). Although these studies show lamotrigine to act effectively in neuropathic pain
treatment, there is controversy surrounding the use of lamotrigine in these pain disorders. There are also studies that have produced negative results (Tremont- Lukats et al. 2000; McCleane 1999; Petersen et al. 2003; Wallace et al. 2004). A randomized, double-blind, placebo-controlled study examining lamotrigine in the treatment of 100 patients with neuropathic pain by McCleane (1999) ﬁnds that lamotrigine has no analgesic effect at a dose administration increasing to
200 mg (McCleane 1999).
A randomized, double-blind, placebo-controlled study by Petersen et al. (2003) concludes that oral lamotrigine (400 mg) does not reduce secondary hyperalgesia or acute thermal nociception. Also, lamotrigine has no hyperal- gesic effect in an intradermal capsaicin-induced hyperalgesia model, according to a placebo-controlled, randomized, double-blind study by Wallace (2004). These studies further add to the disparities in the reported effects of sodium channel blockers on preclinical models of cutaneous hyperalgesia or the clini- cal effects of lamotrigine in neuropathic pain. The lack of effect of lamotrigine in human experimental pain may be due to nerve injury associated irregular- ities that have not yet been replicated in healthy human volunteers. Further well-designed studies are necessary to better deﬁne the role of lamotrigine as a drug in the treatment regime of neuropathic pain (Petersen et al. 2003; Tremont-Lukats et al. 2000; Wallace et al. 2004).
The most common side-effects of lamotrigine are dizziness, unsteadiness and drowsiness (Ahmad and Goucke 2002; Jensen 2002). Furthermore, the side-effect proﬁle of lamotrigine requires slow titration of the drug due to possible severe rash and the possibly fatal epidermal necrosis Steven–Johnson syndrome (Gordon and Love 2004).
The second generation anti-epileptic drug topiramate may be used to treat central neuropathic pain (Finnerup et al. 2002). Topiramate has a research history similar to phenytoin and CBZ in that its use to treat neuropathic pain in humans preceded its systematic research in animals models of pain (Tremont-Lukats et al. 2000).
There are ﬁve known mechanisms by which topiramate acts to affect neu- ronal transmission: a dose-dependant inhibition of voltage-gated sodium ion channels, potentiation of the action of GABAA receptors and thus GABA- medicated chloride ion ﬂow, blocking of excitatory glutamate neurotransmis- sion, modulation of L-type voltage-gated calcium channels, and a weak inhibi- tion on carbonic anhydrase isozymes II and IV. The latter of these mechanisms of action may be responsible for the adverse effects of this drug, including perioral and digital paresthesias and nephrolithiasis. It is worth mentioning that all ﬁve of the known mechanisms of action of topiramate are regulated by protein phosphorylation (Chong and Libretto 2003). Like CBZ and GBP,
Topiramate modulates intracortical excitability via selective interactions on excitatory interneurons (Inghilleri et al. 2004). With the several mechanisms of action of this drug, topiramate should act to inhibit many of the known and assumed mechanisms involved in the pathophysiology of neuropathic pain. Jensen (2002) and Wieczorkiewicz-Plaza et al. (2004) have shown that chronic administration of topiramate signiﬁcantly reduces mechanical sensi- tivity and also the time course of allodynia in the rat Seltzer mononeuropathy model (Wieczorkiewicz-Plaza et al. 2004). Using two neuropathic pain models, a unilateral chronic constrictive injury (CCI) and a crush lesion of the sciatic nerve, moderate anti-hyperalgesic effects of topiramate were seen. Topiramate attenuates mechanical hyperalgesia and cold allodynia in the CCI model of neuropathic pain; it also attenuates thermal hyperalgesia and reduces cold allodynia at both the early and late phase of observation (Bischofs et al. 2004).
There is limited clinical documentation concerning the role of topiramate in the treatment of neuropathic pain. Potter et al. (1998) report a non-blind trial including many neuropathic pain conditions, with the exception of painful diabetic neuropathy, that ﬁnds signiﬁcantly improved pain scores in patients treated with topiramate as compared to pretreatment scores.
Currently, topiramate does not seem to have a beneﬁcial effect in the treat- ment of painful diabetic neuropathy: ﬁndings from three double-blind placebo- controlled trials do not ﬁnd signiﬁcant difference in topiramate and placebo in reduction of pain scores in patients with painful diabetic polyneuropathy. However, possible design features of these studies may explain a lack of ade- quate sensitivity to differentiate successful treatments from placebo (Thienel et al. 2004).
Topiramate exhibits adverse effects including dizziness, fatigue, ataxia, con- fusion, somnolence, nephrolithiasis, paraesthesia and weight loss (Glauser 1999).
GBP, with a favourable side-effect proﬁle, has proved to be quite effective in the treatment of neuropathic pain and is effective as add-on therapy for epilepsy (Maneuf et al. 2003). Speciﬁcally, GBP is an effective treatment for the pain associated with painful diabetic neuropathy, mixed neuropathies, PHN, phantom limb pain, Guillain-Barré syndrome and both acute and chronic pain associated with spinal cord injury (Tremont-Lukats et al. 2000; Jensen 2002; Dworkin et al. 2003). Furthermore, there have been positive studies of the effects of GBP in painful HIV-related peripheral neuropathy (La Spina et al.
2001) and neuropathic pain associated with cancer (Caraceni et al. 1999).
Currently, GBP has become the ﬁrst choice of treatment in neuropathic pain due to positive results from many clinical trials, as well as its effectiveness in ameliorating symptoms of thermo-allodynia, thermal hyperalgesia, me-
chanical allodynia and mechanical hyperalgesia in animal models (Backonja
2000; Levendoglu et al. 2004; Taylor 1997; Field et al. 1999; Maneuf et al. 2003; Dickenson et al. 2002).
GBP was originally designed as an anti-convulsant GABA mimetic capable of crossing the blood–brain barrier. There is now consensus that GBP is not a GABA mimetic (Maneuf et al. 2003). It is now known that GBP acts by increas- ing inhibitions not via an increased GABA synthesis, or any direct non-NMDA receptor antagonism, but by decreasing release of excitatory neurotransmit-
ters through binding to the α2δ subunit of voltage-dependent calcium channels
(VDCCs), a binding site expressed in high density within the peripheral and
central nervous systems (Gee et al. 1996; Maneuf et al. 2003; Bennett and Simp- son 2004; Marais et al. 2001; Luo et al. 2001; Matthews and Dickenson 2001). Treatment of neuropathic pain with GBP can modulate central sensitization by interacting with high-threshold (likely to be predominantly N-type due to a large body of evidence for a major role of these in animal models of nerve injury) calcium channels (Matthews and Dickenson 2001; Finnerup et al. 2002; Sutton et al. 2002; Gordon and Love 2004; Dickenson et al. 2002).
Sutton et al. (2002) were the ﬁrst to show the direct inhibition of voltage- gated Ca2+ channels by GBP in DRG neurons, illustrating a potential mecha- nism for this drug to modulate spinal anti-nociception. This group uses speciﬁc Ca2+ channel antagonists to study N-, L- and P/Q-type Ca2+ channels and show that GBP acts via inhibition of N-type Ca2+ channels. GBP acts to reduce a non- activating component of whole-cell current that is activated at comparatively depolarized potentials (Sutton et al. 2002). Using fura-2 based ﬂuorescence Ca2+ imaging and whole cell patch clamp techniques, this group shows that GBP causes voltage-dependent Ca2+ current inhibition, a signiﬁcant reduction of duration for 50% of the maximum response (W50), and a total Ca2+ inﬂux by 25%–30%. A dramatic decrease in current with the neutral amino acid l- isoleucine and a lack of effect in the presence of saclofen (200 μM), a GABA(B) antagonist, further exempliﬁes that GBP acts directly on the α2δ subunit of
the Ca2+ channel. Interestingly, GBP is the ﬁrst pharmacological agent known
to interact with an α2δ subunit of a voltage-dependent Ca2+ (Gee et al. 1996; Sutton et al. 2002). This is an auxiliary protein that modulates high-voltage
activated calcium channels. Three α2δ subunits are known: α2δ-1, α2δ-2 and α2δ-3. Each α2δ subunit is highly N-glycosylated with almost 30 kDa consisting of oligosaccharides with a large α2 protein and a smaller δ protein. According to Marais et al. (2001), α2δ-1 is detectable in all mouse tissue studied, α2δ-2 is found in high levels in mouse brain and heart tissue and α2δ-3 is observable only in mouse brain tissue. This study ﬁnds a high afﬁnity for α2δ-1 to bind to GBP with a Kd of 59 nM and α2δ-2 with a K+d of 153 nM. α2δ-3 does not bind GBP (Marais et al. 2001).
It is well known that neuroplasticity after peripheral nerve injury con- tributes to neuropathic pain. Data from Luo et al. (2001) suggest that dorsal root ganglia α2δ-1 regulation may contribute to the development of allodynia
after peripheral nerve injury. In vitro studies show that GBP binds to the α2δ-1 subunit of voltage-gated calcium channels. Gee et al. (1996), Sutton et al. (2002) and Luo et al. (2001) show a greater than 17-fold, time-dependant increase in α2δ-1 subunit expression in DRGs ipsilateral to nerve injury in a rat neuro- pathic pain model of tight ligation of the left ﬁfth and sixth lumbar spinal nerves characterized by GBP-sensitive tactile allodynia. α2δ-1 subunit expres- sion is also up-regulated in rats with unilateral sciatic nerve crush, but not in rats with dorsal rhizotomy, which suggests a peripheral origin of regulation of the subunit expression. α2δ-1 subunit expression precedes the onset of allo- dynia and is reduced in rats recovering from tactile allodynia. The DRG α2δ-1
regulation has been found by RNAse protection experiments to be regulated
at the RNA level (Luo et al. 2001).
Luo et al. (2002) examined the up-regulation of calcium channel α2δ-1 subunit in allodynic states occurring in different aetiologies to determine if
a common mechanism is responsible in these allodynic states. Interestingly, of all allodynic states in this study, only the mechanical and diabetic neuropathies exhibit up-regulation of DRG and/or spinal cord α2δ-1 subunits as well as GBP
sensitivity. It follows that the regulation of the α2δ-1 subunit in the DRG and
spinal cord is speciﬁc for distinct neuropathies and is a possible explanation
for GBP-sensitive allodynia (Lou 2002).
Dooley et al. (2000) use an in vitro superfusion model of stimulation- evoked neurotransmitter release using rat neocortical slices pre-labelled with [(3)H] norepinephrine [((3)H)NE] to examine the mechanism of action of GBP (Neurontin), PGB (Cl-1008, S-(+)-3-isobutylgaba), and its enantiomer R-(−)-3-isobutylgaba. This study ﬁnds that GBP and PGB act similarly to preferentially inhibit [((3)H)NE] release. Furthermore, longer slice exposure to GBP increased the inhibition caused by this drug (Dooley et al. 2000). However, this type of study, although showing a reduction in transmitter release, is likely to reﬂect actions in epilepsy rather than pain.
Hunter et al. (1997) compared GBP, lamotrigine and felbamate in acute and chronic pain models. All three drugs reverse cold allodynia. Interestingly, only GBP successfully treated tactile allodynia in the spinal nerve ligation model. The dosages at which these three drugs reversed allodynia were observed at levels that were too low to cause signiﬁcant effect on acute nociceptive function or locomotor activity. It is noteworthy that only GBP reversed both cold and tactile allodynia. Fox et al. (2003) report that GBP shows little activity against mechanical hyperalgesia in both rat and guinea-pig models of neuropathic pain, induced by partial sciatic nerve ligation, after a single oral administration
of (100 mg×kg−1). Still, upon repetitive dosage of the drug, GBP reduced mechanical hyperalgesia by 70% in the rat and by 90% in the guinea-pig. There
was, however, a signiﬁcant dose-related depression of tactile allodynia in the rat following a single administration of GBP.
Jun et al. (1998) show that GBP, administered spinally, acts in a dose-
dependent manner as an anti-hyperalgesic agent in a mild thermal injury
model. S(+)-3-Isobutyl GABA produces a similar dose-dependent reversal of the hyperalgesia in this pain model. However, a large dose (300 μM) of the R(−)-3-isobutyl GABA does not produce the same hyperalgesia as GBP and its stereoisomer. The effect of these gabapentinoids is a selective modulation of
spinal nociceptive processes that, clinically, are generated by persistent small afferent input generated by tissue injury (Jun and Yaksh 1998).
Clinically, Backonja and Glanzman (2003) found that, in the treatment of neuropathic pain in adults, GBP is effective and well tolerated at doses of
1,800 to 3,600 mg/day. Treatment should begin at 900 mg/day starting with
300 mg/day on day 1,600 mg/day on day two, and 900 mg/day on day three and additional titration to 1,800 mg/d for greater efﬁcacy. However, some patients needed doses of GBP up to 3,600 mg/day. This study looked at the effective use of GBP to treat painful diabetic neuropathy, PHN and other neuropathic pain syndromes. Symptoms of allodynia, burning pain, shooting pain and hyperaesthesia were relieved with GBP (Backonja and Glanzman
2003). Furthermore, this drug has proved effective in the treatment of many neuropathic pain states in multiple large randomized controlled trials with
a mean reduction in pain score of 2.05/11 is seen compared to 0.94/11 with a placebo. Approximately 30% of patients will have a greater than 50% pain relief with GBP (Bennett and Simpson 2004). In cancer pain, it is important
to note that, due to synergy, response rates to GBP may be increased when administered with opioids (Bennett and Simpson 2004).
The pain and sleep problems associated with PHN are effectively treated
with GBP therapy. Subsequently, mood and quality of life improve in PHN
patients treated with GBP (Rowbotham et al. 1998).
Neuropathic pain related to spinal cord injury is refractory and current treatments are ineffective. In a study designed by Levendoglu et al. (2004) with
20 paraplegic patients, GBP reduced the intensity and the frequency of pain, improved quality of life (p < 0.05) and relieved all neuropathic pain descriptors with the exception of itchy, sensitive, dull and cold types. GBP may now be
considered a ﬁrst-line medication to treat chronic neuropathic pain in spinal cord injury patients (Levendoglu et al. 2004).
Mild to moderate adverse effects of GBP subside within about 10 days from
the start of treatment (Backonja and Glanzman 2003). These adverse effects of GBP such as somnolence and dizziness are minor and may be experiences by about 30% of the patients (Bennett and Simpson 2004). The most com- mon adverse effects observed are dizziness, somnolence, peripheral oedema, headache and dry mouth (Sabatowski et al. 2004).
PGB is an α2δ ligand with analgesic, anxiolytic and anti-convulsant activ- ity. PGB effectively treats neuropathic pain associated with PHN, as seen in a
238-patient, multicentre, randomized, double-blind, placebo-controlled trial. Failure to respond to prior treatment for PHN with GBP at doses greater than or equal to 1,200 mg/day was part of the exclusion criteria for this study. Saba-
towski et al. (2004) discuss end-point mean pain scores as signiﬁcantly reduced
in patients treated with PGB 150 mg/day or 300 mg/day as compared to placebo. By 1 week, efﬁcacy of the drug was observed and maintained throughout the study. Furthermore, mean sleep interference scores were decreased at both doses by 1 week and health-related quality-of-life (HRQoL) measurements show improved mental health at both PGB doses. At 300 mg/day, body pain and vitality measurements were improved (Sabatowski et al. 2004).
Although the signiﬁcance of the altered channel expression remains un- clear, it was proposed to correlate with the development of tactile allodynia and relate to the injury-speciﬁc action of GBP (Luo et al. 2002). However, be- havioural hyperalgesia can be observed as early as 1 day after injury (Kim
1997), whilst channel α2δ-1 up-regulation is only evident after 7 days (Luo et al. 2001). Due to the ubiquitous nature of the channel α2δ-1 subunit in all calcium channels, a pharmacological block of this subunit would be expected
to result in signiﬁcant side-effects; however, this clearly is not the case for GBP. It has therefore been unclear how GBP differentiates and targets physiological vs pathophysiological activation of VDCCs. Even in the absence of the altered
subunit expression, GBP can exert anti-allodynic effects (Abe et al. 2002), pro- viding further evidence that up-regulation is not the only determinant of full GBP efﬁcacy. In normal animals with no nerve injury-induced changes, simply activating the 5HT3 receptor allowed GBP to inhibit—whereas block of the re-
ceptor or ablation of the neurokinin (NK)1-expressing neurons removed—the effectiveness of the drug after nerve injury. It would appear then that a channel α2δ-1 up-regulation and 5HT3 receptor activation may both determine efﬁcacy (Suzuki et al. 2005).
Although the role of high voltage-activated Ca2+ channels in nociception had been accepted as an important mechanism of pain transmission, Matthews and Dickenson (2001) were the ﬁrst to show a possible role for low voltage- activated Ca2+ channels in the transmission of pain with a study of spinal
ethosuximide in the Chung rodent model of neuropathy. In vivo electrophysi- ological examination of dorsal horn neurons show spinal ethosuximide exhibits dose-related inhibition of electrical, low-, and high-intensity mechanical and
thermal evoked neuronal responses in this model of neuropathy (Matthews and Dickenson 2001). Later, Dogrul et al. (2003) showed that systemic ethosuximide produces a dose-dependent inhibition of tactile and thermal hypersensitivities
in rats with spinal nerve ligation, which suggests that T-type calcium channels play a role in neuropathic pain states (Dogrul et al. 2003).
Flatters and Bennett (2004) show that ethosuximide almost completely in- hibits mechanical allodynia and hyperalgesia caused by paclitaxel (Taxol),
a chemotherapeutic used in the treatment of solid tumours. This study shows a dose-related consistent reversal of mechanical allodynia/hyperalgesia with
ethosuximide. This study also shows that ethosuximide inhibits paclitaxel- induced cold allodynia and vincristine-induced mechanical allodynia and hyperalgesia. Neither morphine nor the NMDA receptor antagonist MK-801 produced a signiﬁcant inhibition of mechanical allodynia or hyperalgesia.