Carbamazepine and Oxcarbazepine

16 May

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

(Royal 2001).

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

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.

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