THE BORDERLAND OF EPILEPSY
Why are antiepileptic drugs used for nonepileptic conditions?
Address correspondence to Meir Bialer, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. E-mail: firstname.lastname@example.org
Antiepileptic drugs (AEDs) are used to treat various nonepileptic central nervous system (CNS) disorders, both in neurology and psychiatry. Most AEDs have multiple mechanisms of action (MOAs), which include modulation of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellular signaling pathways. These MOAs may explain the efficacy of AEDs in the treatment of bipolar disorder and neuropathic pain. Bipolar disorder and epilepsy have some common features, such as their episodic nature and associated kindling phenomena, which led to the regulatory approval and use of the AEDs carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) in the treatment of bipolar disorder. A major limitation for the development of drugs with improved mood-stabilizing activity is the lack of knowledge on the mechanism of treatment for bipolar disorder. In contrast to epilepsy, no animal models in bipolar disorder are universally accepted and no model is able to exhibit the characteristic mood swings. Although most AEDs have now been investigated for their mood-stabilizing effects, only three (e.g., VPA, CBZ, and LTG) demonstrated clinical efficacy in patients. This suggests that the mechanism of drug action in mood disorder and in epilepsy only partially overlaps. Peripheral nerve damage leads to the initiation of cellular and molecular changes in the nervous system resulting in ectopic, repetitive firing perceived as chronic pain. Epileptic seizures are also characterized by hyperexcitability of neurons in the brain. The spontaneous electrogenesis in neuropathic pain has similarities to that of epilepsy. Alteration in sodium channels expression suggests that the mechanism underlying epileptic hyperexcitability may be similar to those underlying neuropathic pain. The AEDs gabapentin (GBP) and pregabalin (PGB) have become the mainstay of treatment for various neuropathic pain syndromes, owing to their ability to inhibit neuronal hyperactivity along the pain pathways. One explanation for how GBP and PGB relieve neuropathic pain is that they bind selectively to the Ca+2-channel subunit α2-δ in muscle tissue and brain. With 16 new AEDs having entered the market since 1990 the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2012 to the pharmaceutical industry, even though the clinical needs of refractory epilepsy remain unmet. Due to this situation, the future design of new AEDs must also include a potential in nonepileptic CNS disorders, such as bipolar disorder and neuropathic pain. The global market size of each of these two indications is similar to that of epilepsy, whereas they both currently have fewer approved drugs for treatment than epilepsy. Therefore, a new AED with additional approved indications in bipolar disorder and neuropathic pain might have a potential market size three times larger than that of epilepsy alone.
The Current Antiepileptic Drugs and Their Market
Between 1990 and 2012, the following 16 new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate (ESL), felbamate (FBM), gabapentin (GBP), lacosamide (LCS), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), perampanel (PER), pregabalin (PGB), retigabine (RTG) or ezogabine, rufinamide (RUF), stiripentol (STR), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). All AEDs introduced after 1990 that are not second-generation drugs (with the exception of VGB and TGB) were developed empirically (sometimes serendipitously) using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. These AEDs (except FBM) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability, and lower potential for drug interactions The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to tailor their drug choice better to the characteristics of individual patients (Bialer & White, 2010).
With 16 new AEDs having entered the market in the past 20 years, the AED market is crowded. Consequently, in 2012, epilepsy alone is not attractive to the pharmaceutical industry, even though there remains an unmet clinical need for refractory epilepsy. Due to this situation, future design of new AEDs must also have potential to help non-epileptic central nervous system (CNS) disorders, such as neuropathic pain, migraine prophylaxis, bipolar disorder, or fibromyalgia; this is demonstrated by the sales revenues of PGB, TPM, and valproic acid (VPA) for conditions other than epilepsy (Mackey, 2010).
The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. The total value of the AED market in the seven major markets (France, Germany, Italy, Japan, Spain, United States, and United Kingdom) was projected to decline from $13.6 billion in 2008 to $11.5 billion by 2010, due to erosion by generics. Forty percent of TPM’s 2008 sales revenues were derived from migraine and 40% of PGB’s 2008 sales were for neuropathic pain. Only LEV was used mainly in epilepsy; therefore, 91% of its 2008 sales revenue was for epilepsy (Mackey, 2010). In view of the high prescribing levels of TPM, LTG, and PGB in the respective indications of migraine, bipolar disorder, and neuropathic pain, nonepileptic CNS disorders, with a less crowded market compared to epilepsy, remain an attractive indication as well as provide expansion opportunities (i.e., line or patent extension) for AED manufacturers (Mackey, 2010).
AEDs are currently used to treat various nonepileptic CNS disorders, both in neurology and psychiatry (Macdonald & Young, 2002; Johannessen Landmark, 2008; Grunze, 2010). Most AEDs have multiple mechanisms of action that include modulation of γ-aminobutyric acid (GABA) ergic and glutamatergic neurotransmission and alteration of voltage-gated ion channels or intracellular signaling pathways (Rogawski & Loscher, 2004). These multiple mechanisms of action may explain the efficacy of AED in treating bipolar disorder and neuropathic pain. Although AEDs are routinely categorized according to a single mechanism of action (e.g., sodium channel blockade) to which their antiepileptic activity is attributed, all major AEDs have multiple mechanisms of action (Margineanu, 2011).VPA, an example of a major AED with multiple mechanisms of action, including histone deacetylase inhibition and other yet undiscovered mechanisms of action, is highly effective in both focal-onset and generalized-onset seizures and is the drug of first choice in generalized epilepsy (Loscher, 2002; Margineanu, 2011). Due to these multiple mechanisms of action, VPA is also effective and U.S. Food and Drug Administration/European Medicines Agency (FDA/EMA)–approved for the treatment of bipolar disorder and as migraine prophylaxis; it might also have potential in Alzheimer’s disease and cancer therapy (Nalivaeva et al., 2009).
An emerging theme that unifies epilepsy as well as nonepileptic CNS disorders is altered neuronal excitability, caused by abnormal expression and function of membrane ion channels (Mantegazza et al., 2010). Voltage-gated sodium channels are key mediators of intrinsic neuronal and muscle excitability and thus are appealing targets for pharmacologic intervention in various CNS disorders (Mantegazza et al., 2010).
Most AEDs have been initially approved for epilepsy, possible because of the relatively ease of quantification of outcome measure (e.g., seizures). Subsequently, AEDs have been approved by the FDA and EMA for the following nonepileptic CNS disorders: carbamazepine (CBZ), LTG, and VPA for bipolar disorder; GBP, PGB, and CBZ for neuropathic pain; and VPA and TPM for migraine prophylaxis. In 2007 the FDA approved PGB for fibromyalgia.
TPM is an AED with a sulphamate moiety in its chemical structure possessing multiple mechanisms of action, among which is inhibition of red blood cells and brain carbonic anhydrase (CA). TPM’s CA inhibition has been related to the loss of body weight associated with TPM therapy. In February 2012, the FDA Endocrinologic and Metabolic Drugs Advisory Board voted overwhelmingly in favor of Qnexa (Vivus, Mountain View, CA, U.S.A.) a combination of immediate-release phentermine and extended-release TPM for the treatment of obesity in patients. If approved, Qnexa would be recommended for obese patients with a body-mass index (BMI) >30 or 27 kg/m2 in patients with weight-related comorbidity. ZNS is another AED that inhibits CA isozymes, due to the sulfonamide moiety in its chemical structure that might have a potential as an emerging drug for the treatment of obesity (Supuran, 2012).
This article will focus on the use of AEDs in the treatment of bipolar disorder and neuropathic pain, two indications for which various AEDs received FDA and EMA approval and are widely used in the clinics.
AEDs in Bipolar Disorder
AEDs can be regarded as a clinical interface between psychiatry and neurology. In choosing an appropriate AED for an individual patient with epilepsy, clinicians should consider psychiatric comorbidities and which AED might best serve the patient in maximizing seizure control and minimizing psychiatric symptoms (Kaufman, 2011).
Lithium (Li+) has been the gold standard for prophylaxis and treatment of acute mania since the 1960s, receiving FDA approval in 1970. Nevertheless lithium therapy is associated with various limitations such as high percentage of nonresponders (∼40%), side effects due to its narrow therapeutic plasma concentration range, and the fact that lithium is less effective in depression than in mania. Given these limitations, the rapid expansion of AEDs in the treatment of bipolar disorder is a promising development, since it broadens the armamentarium of potentially effective options for the overall treatment of bipolar disorder (Weisler et al., 2006). VPA is effective in patients who don’t respond to lithium, with a more rapid antimanic effect than lithium and therapeutic benefit within 3–5 days. VPA’s therapeutic plasma levels in mania (90–120 mg/L) are similar to its antiepileptic plasma levels (Bowden et al., 2006).
The relationship between the antiepileptic and mood-stabilizing activity is particularly interesting, as it may reveal information about the molecular origins of bipolar disorder, a chronic and disabling illness, which affects 1% of the population and when untreated carries a 10–20% lifetime risk of suicide for the patients (Belmaker, 2004). Bipolar disorder and epilepsy have some common features, such as their episodic nature and their associated kindling phenomena (Rogawski & Loscher, 2004). The amygdala-kindled rat is a suitable anticonvulsant animal model that might have implications in bipolar disorder. Therefore AEDs with potent antikindling activity might have potential as mood stabilizers. Kindling reflects a cumulative and progressive unfolding of physiologic and behavioral changes in response to repeated stimulation over time, which occurs in seizures (Grunze, 2010). These changes are first triggered and then occur spontaneously due to the decreased threshold for epileptic seizure as a consequence of the repeated electrical stimulation. Epileptic seizures have some mechanism in common with bipolar disorder, and the amygdala complex plays a role in both disorders, nevertheless epilepsy and bipolar disorder are still two distinct different diseases. The three AEDs effective in bipolar disorders may develop tolerance and lead to insufficient suppression in the kindling model (Post & Weiss, 1996). Extrapolating this phenomenon in the rat kindling model may correspond to the development of tolerance or drug resistance after long-term treatment or discontinuation of mood stabilizers in some patients with bipolar disorder (Post & Weiss, 2004; Grunze, 2010).
Although pharmacologic treatment proves effective in many patients, relapse rates of bipolar disorder are 73% during five or more years, and about 30% of the patients with epilepsy are resistant to multiple AEDs. Furthermore, comorbidity (e.g., drug and alcohol addiction) and severe adverse effects can further complicate treatment in both disorders (Macdonald & Young, 2002). Hence, there is a pressing need to develop better and safer mood-stabilizing agents.
A major limitation for the development of drugs with improved mood-stabilizing activity is the lack of knowledge on exact mechanisms of action needed for the treatment of bipolar disorder. In contrast to epilepsy, no animal models in bipolar disorder are universally accepted and no model is able to exhibit the characteristic mood swings (Machado-Vieira et al., 2004). Although most AEDs have been investigated for their mood-stabilizing effects, only VPA, CBZ, and LTG have demonstrated clinical efficacy in patients and gained FDA/EMA approval (Macdonald & Young, 2002). CBZ and VPA are approved for acute mania and mixed episodes, whereas LTG is approved as maintenance therapy to delay the reoccurrence of depressive episodes (Weisler et al., 2006). The combination of VPA and LTG might be problematic due to VPA’s inhibition of the LTG major metabolic pathway (glucuronidation) (Garnett, 2002).
Bowden et al. examined VPA and lithium as compared to placebo in a double-blind, parallel-group study in patients with mania associated with bipolar disorder. Using the Mania Rating Scale of the Schedule for Affective Disorder and Schizophrenia as the main outcome measure, 48% of the patients in the VPA group (n = 68) showed improvements of >50%, which was comparable with lithium (49%; N = 35) and significantly more than placebo (25%; N = 73) p < 0.05) (Bowden, et al., 1994; Weisler et al., 2006). Calabrese et al. demonstrated significant improvement in depression rating scores of LTG in a double-blind, placebo-controlled trial of 195 bipolar disorder patients. The LTG (200 mg/day) group had a 51% responders rate compared to 25% of the placebo group (p < 0.05) (Calabrese et al., 1999). Two large, 3-week, double-blind, placebo-controlled randomized trials compared the efficacy of CBZ (extended-released formulation) to placebo in patients with bipolar disorder with acute mania (n = 443). CBZ gave greater decreases in Young Mania Rating Scale (YMRS) scores and higher responder rate (52% compared to placebo (26%) (p < 0.05) (Weisler et al., 2004, 2005).
VPA, CBZ, and LTG are the three approved AEDs for bipolar disorder; each is a sodium channel blocker but with additional mechanisms of action. TPM and OXC monohydroxy derivative (MHD or licarbazepine) and active entity are sodium channel AEDs that failed to demonstrate efficacy in bipolar disorder clinical trials (Souppart et al., 2008; Bialer & White, 2010). The fact that licarbazepine (MHD) failed while its first-generation drug CBZ succeeded casts some doubts on the hypothesis that sodium channel inhibition is a decisive factor for activity against bipolar disorder. Other AEDs such as GBP and TPM are effective as primary anti-manic treatments but they may be useful as adjunctive therapy for the treatment of comorbid conditions such as anxiety, pain, migraine, and weight problems. No controlled data are available for LEV, TGB, and ZNS (Weisler et al., 2006). This suggests that the mechanisms of action in mood disorder and in epilepsy only partially overlaps.
Electroconvulsive therapy is an old effective treatment of depression and mania (Mukherjee et al., 1994; Geddes, 2003). Paradoxically, electroconvulsive therapy has an anticonvulsant effect, as seizure threshold increases with every electroconvulsive treatment (Grunze, 2010). Possible mechanisms of action of AEDs that might explain their activity in bipolar disorder are the following: (1) modulation of GABA and N-methyl-d-aspartate (NMDA) neurotransmission; (2) modulation of ion channels and; (3) effects at the cellular levels like the inhibition of myoinositol phosphate (MIP) synthase and glycogen synthase kinase (GSK) (Grunze, 2010).
One approach to identify the targets of AEDs (e.g., VPA) in the treatment of bipolar disorder is to seek common effects with other mood stabilizers. Williams et al. (2002) have recently found that, in common with VPA, both lithium and CBZ increase the spreading of growth cones from rat dorsal root ganglia. This effect can be prevented by exogenous myoinositol. Furthermore, lithium and VPA lower in vivo concentrations of inositol and inositol-1,4,5-triphosphate (InsP3) in a range of cell systems. These findings fit the hypothesis originally proposed by Berridge et al. (1989) for lithium that mood stabilizers function by attenuation of an overactive inositol phosphate (InsP) signal transduction pathway. Several of the molecular VPA targets have been identified. VPA and a few of its CNS-active amide derivatives inhibit inositol synthase. thereby leading to depletion of the cellular concentration of myo-inositol (Berridge et al., 1989; Shaltiel et al., 2004, 2007). GSK is another identified target of VPA that might be implicated in the pathophysiology of bipolar disorder (Chen et al., 1999).
VPA is the leading mood stabilizer for the treatment of bipolar disorder. However VPA’s teratogenicity, shared by other mood stabilizers such as lithium CBZ or LTG, makes the use of these drugs problematic in women of childbearing age.
Valpromide (VPD) and its constitutional isomer valnoctamide (VCD) are two VPA amide derivatives that have been in clinical use in Europe for psychiatric disorders as well as epilepsy (Bialer, 1991; Bialer & Yagen, 2007; Bialer & White, 2010). VPD, that is VPA’s corresponding amide, is still used in France, Italy, Spain. and Holland. VCD (racemate) was in clinical use as an anxiolytic between 1964 and 2005 in France, Italy, Holland, and Switzerland, but its marketing was stopped due to low sales. Unlike VPD that serves in humans as a prodrug to VPA (Bialer, 1991), VCD acts as a drug on its own with minimal biotransformation to its corresponding acids and was nonteratogenic in mice strains that were susceptible to VPA-induced teratogenicity (Bialer & Yagen, 2007).
Recently, a successful double-blind controlled clinical trial with racemic-VCD in patients with mania was completed (Bersudsky et al., 2010). In all efficacy measures, VCD (1,200 mg/day; n = 15) was significantly more effective as an add-on to risperidone compared to placebo (n = 17). Mean VCD plasma levels were: 5.5 ± 1.2 mg/L (week 1), 4.1 ± 1.4 mg/L (week 2), 3.6 ± 2.1 mg/L (week 3), 5.1 ± 2.2 mg/L (week 4), and 3.7 ± 1.6 mg/L (week 5). There were no differences in the maximum risperidone dose between VCD (5.5 ± 1.2 mg) and placebo (5.6 ± 1.6 mg) (Bersudsky et al., 2010). This study shows that VCD could be an important substitute to VPA in women of childbearing age with bipolar disorder as the first effective mood stabilizer without significant teratogenicity.
Following this successful study, the Stanley Medical Research Institute (SMRI) that funded the above VCD Phase IIa study had a pre-IND meeting with the FDA (Division of Psychiatry Products). As requested by the FDA, they conducted teratogenicity studies comparing VCD to VPA (head-to-head) in mice, rats, and rabbits at Covance, in collaboration with Yissum (Hebrew University Technology Transfer Company and VCD patents’ owner). VCD was not teratogenic in mice and rabbits. In rats, there was some teratogenicity at plasma concentrations 15 times higher than VCD therapeutic plasma levels. Subsequently, VCD is currently undergoing a 3-week (SMRI-funded) phase IIb, randomized, double-blind, placebo- and risperidone-controlled, multicenter study enrolling 300 patients with bipolar manic episodes. The study is a three-arm monotherapy parallel group trial: (1) placebo (n = 120); (2) VCD (n = 120; 1,500 mg/day); and (3) risperidone (n = 60; up to 6 mg/day). The study’s major objective is to evaluate the efficacy of VCD compared to placebo in patients with acute manic or mixed episode. The role of risperidone in the trial is as an active control to ascertain the trial’s validity (Bialer et al., 2010; Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS, unpublished manuscript).
In conclusion, CBZ, VPA, and LTG are currently established treatment options in bipolar disorder that enrich the therapeutic arsenal in acute mania and maintenance treatment. However at present it is unclear which of the multiple mechanisms of action of these FDA/EMA-approved AEDs is more and which is less responsible for their activity in bipolar disorder (Grunze, 2010). It is also not clear why other AEDs with similar mechanisms of action failed in bipolar disorder clinical trials.
AEDs in Neuropathic Pain
Neuropathic pain affects between 3% and 8% of the world’s population, with unpleasant consequences on the patients’ quality of life, general mood, and occupational functioning (Gilron & Coderre, 2007). Many patients are resistant to current therapy, and thus there is a substantial need to further develop novel medications for the treatment of neuropathic pain (Yogeeswari et al., 2007). Neuropathic pain results from chronic injury to sensory neurons, leading to axonal sprouting and neuroma formation. After such an injury, there are marked changes in the expression of sodium channels leading to their abnormal accumulation in nociceptors and sensory nerves (Rogawski & Loscher, 2004).
Some AEDs have been found empirically to provide pain relief in patients with peripheral neuropathies. Among the pharmacotherapies currently used to treat neuropathic pain conditions are the AEDs: CBZ, GBP, and PGB that are among the first-line treatment options for several neuropathic pain conditions (McQuay et al., 1995; Blackburn-Munro & Erichsen, 2005; Finnerup et al., 2005; Goodyear-Smith & Halliwell, 2009). It is assumed that both epilepsy and neuropathic pain share an underlying common pathophysiology, enabling some AEDs to be useful for the treatment of several neuropathic pain conditions. Although the exact mechanisms of action of AED in neuropathic pain are not well understood, it is widely presumed to be due to suppression of epileptiform activity in CNS pain pathways. This hypothesis, however, does not account for the fact that some AEDs have analgesic effects while others do not (Devor, 2009).
Peripheral nerve damage leads to the initiation of cellular and molecular changes in the nervous system resulting in ectopic, repetitive firing perceived as chronic pain. Epileptic seizures are also characterized by hyperexcitability of neurons in the brain. The spontaneous electrogenesis in neuropathic pain has similarities to that of epilepsy. Alteration in sodium channels expression suggests that the mechanism underlying epileptic hyperexcitability may be similar to those underlying neuropathic pain (Rogawski & Loscher, 2004). Sodium channel-blocking AEDs (e.g., PHT and CBZ) are effective in pain states by virtue of the same selective blocking properties of high-frequency action-potential neuronal firing that account for their anti-seizure activity (Rogawski & Loscher, 2004). When administered locally, PHT and CBZ have anti-nociceptive efficacy in acute pain that is more potent than that of lidocaine (Todorovic et al., 2003).
The AEDs GBP and PGB have become the mainstay of treatment for various neuropathic pain syndromes owing, to their ability to inhibit neuronal hyperactivity along the pain pathways (Yogeeswari et al., 2007). One explanation on how GBP and PGB relieve neuropathic pain is that they bind selectively to the Ca+2 channel subunit α2-δ in muscle tissue and brain (Devor, 2006). It was suggested that with fewer Ca+2 channels delivered to the membrane of synaptic terminals in the spinal cord, synaptic transmission and hence pain will be attenuated. Another explanation is that GBP’s analgesic activity is mainly due to its suppression of neuropathic ectopia in the peripheral nerve system as it also binds to primary sensory neurons in the dorsal root ganglia (Taylor, 2009). According to this assumption, new drugs devoid of CNS activity will lack CNS side effects (e.g., somnolence, nausea) associated with drugs currently used for the treatment of neuropathic pain.
CBZ, GBP, and PGB are currently the only three AEDs approved by the FDA and EMA for the treatment neuropathic pain. GBP and PGB are widely presumed to act as Ca+2 channel blockers at intraspinal synapses, or by modulating the membrane trafficking of Ca+2 channels to the synaptic membrane (Taylor, 2009). Reduced Ca2+ entry at the presynaptic afferent terminal is expected to depress neurotransmission. However, these drugs are also known to suppress subtreshold oscillations and peripheral ectopia (Pan et al., 1999; Yang et al., 2009). There is evidence that the membrane stabilizing action is due to a selective action on the slow component of Na+ conductance (Yang et al., 2009), although it remains unclear whether this is a direct effect on Na+ channels or indirect via A2δ binding. Here too it is important to know which of the alternative effects is responsible for neuropathic pain treatment.
A recent Cochrane Library report reviewed 29 studies (3,571 participants) that examined GBP (1,200 mg/day or more) effect in 12 chronic pain conditions (Moore et al., 2011). In this report 78% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy, or mixed neuropathic pain. Using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trial (IMMPACT) definition of at least moderate benefit, GBP was superior to placebo in 14 studies with 2,831 participants, 43% improving with GBP and 26% with placebo; the NNT (number needed to treat to benefit) was 5.8 (95% confidence interval [CI] 4.8–7.2). Using the IMMPACT definition of substantial benefit, GBP was superior to placebo in 13 studies with 2,627 participants, 31% improving with GBP, and 17% with placebo; the NNT was 6.8 (95% CI 5.6–8.7). These estimates of efficacy are more conservative than those reported in a previous review. Adverse events were more common with GBP than placebo, with 66% of the patients having at least on adverse events. Dizziness (21%), somnolence (16%), peripheral edema (8%), and gait disturbance (9%) were the major adverse events. Serious adverse events (4%) were no more common than with placebo, but 12% withdrew because of GBP adverse events. The authors concluded that GBP provides pain relief of a high level in about one third of people who take it for painful neuropathic pain. Adverse events are frequent, but mostly tolerable (Moore et al., 2011).
A recent Cochrane Library report reviewed 19 studies (7,003 participants) that examined PGB (300, 450, and 600 mg/day) effect in patients with postherpetic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia (Moore et al., 2009). PGB was generally ineffective at 150 mg/day. Efficacy was demonstrated for dichotomous outcomes pooling together extent of pain relief, alongside with lower rates of lack of efficacy and discontinuations with higher dose. The best (lowest) NNT for each condition for at least 50% pain relief over baseline for 600 mg/day PGB (compared with placebo) was 3.9 (95% CI 3.1–5.1) for postherpetic neuralgia, 5.0 (95% CI 4.0–9.9) for painful diabetic neuropathy, 5.6 (95% CI 3.5–14) for central neuropathic pain, and 11.7 (95% CI 7.1–21) for fibromyalgia (Moore et al., 2009). Somnolence and dizziness occurred in 15–25% and 25–46% of the patients, respectively, on PGB (600 mg/day) and treatment was discontinued at 18–28%. The authors concluded that PGB provides a proven efficacy in neuropathic pain conditions and fibromyalgia, but with no benefit in acute pain scenarios. Due to the variability in patients’ response to PGB treatment, individualization is needed to maximize neuropathic pain relief and minimize adverse events (AE) (Moore et al., 2009).
A recent Cochrane review on lacosamide (LCS) efficacy in neuropathic pain and fibromyalgia included six studies: five (1,863 participants) in painful diabetic neuropathy and one (159 participants) in fibromyalgia (Hearn et al., 2012). All studies were placebo controlled and titrated to a target daily dose of 200, 400, or 600 mg. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to impart major bias, since adverse event withdrawal rates were high in the LCS studies. This, coupled with small numbers of patients and events for most outcomes, meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes of LCS (400 mg/day).
In painful diabetic neuropathy, LCS (400 mg/day) provided statistically increased rates of achievement of “moderate” and “substantial” benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively), and the patient global impression of change outcome of “much or very much improved.” For LCS 600 mg, there was no consistent benefit over placebo. There was no significant difference between any LCS dose and placebo for participants experiencing adverse effects, but adverse effect withdrawals showed a significant dose response. The number needed to treat to harm for adverse effect withdrawal was 11 at LCS 400 mg/day and 4 for 600 mg/day. The authors concluded that LCS has limited efficacy in treating peripheral diabetic neuropathy with limited beneficial effect at higher doses. They also criticized the outcome of the last observation carried forward due to the high AE withdrawals in the active treatment groups compared to the placebo group (Hearn et al., 2012).
In a recent evidence-based gridline for the treatment of painful diabetes neuropathy (PDN) of the American Academy of Neurology, PGB was ranked as the only level A drug for the relief of PDN. Venlafaxine, duloxetine, amitriptyline, GBP, VPA, opioids (morphine, tramadol, oxycodone) and capsaicin were considered as level B drugs for the treatment of PDN. In contrast to PGB, GBP, and VPA, the AEDs LCS, LTG, and OXC were not recommended for PDN treatment (Brill et al., 2011).
A similar Cochrane review showed nonconvincing data for VPA in neuropathic pain (Gill et al., 2011). Three studies were included: two in diabetic neuropathy (42 participants treated with VPA, 42 with placebo), and one in postherpetic neuralgia (23 treated with VPA, 22 with placebo). The study duration was 8 or 12 weeks. Only one study reported one of the Cochrane primary outcomes (>50% pain relief), whereas all three reported group means for pain reduction from baseline to endpoint. In all three studies, efficacy results were given only for participants who completed the study. There were more adverse events with VPA treatment than placebo, including nausea, drowsiness, and abnormal liver function tests. The authors concluded that these three studies only hint that VPA may reduce pain in diabetic neuropathy, and postherpetic neuralgia. Currently, there is insufficient evidence to support using VPA as a first-line treatment for neuropathic pain, particularly since a small number of the drugs (e.g., GBP) have shown more robust evidence of greater efficacy for a small number of other drugs (Derry et al., 2011).
Recently, VCD and two of its individual stereoisomers (2S,3S)-VCD and (2R,3S)-VCD were shown to be active in the Spinal Nerve Ligation (rat) model (Chung Model) for neuropathic pain, with median effective dose (ED50) values of 52, 61, and 39 mg/kg, respectively (Kaufmann et al., 2010). (2S,3S)-VCD was significantly more potent than (2R,3S)-VCD, but the opposite was true for the anticonvulsant effect. Racemic-VCD and/or its stereoisomers were 4–9 times more potent than VPA and have a wide safety margin; thus they have the potential to become candidates for development as new drugs for treating neuropathic pain.
With 16 new AEDs having entered the market in the last 20 years, the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2012 to the pharmaceutical industry, even though the clinical need for refractory epilepsy remains unmet. Due to this situation, the future design of new AEDs must also include therapeutic potential in nonepileptic CNS disorders, such as bipolar disorder and neuropathic pain. The global market size of each of these two indications is similar to that of epilepsy, whereas they both currently have fewer approved drugs for treatment than epilepsy. Therefore, a new AED with additional approved indications in bipolar disorder and neuropathic pain might have a potential market size three times larger than that of epilepsy alone.
Dr. Meir Bialer has received in the last 3 years speakers or consultancy fees from BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Lundbeck, Rekah, Sepracor, Tombotech, UCB Pharma, and Upsher Smith. Dr. Meir Bialer has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.