Current role of carbamazepine and oxcarbazepine in the management of epilepsy

There are close to 30 AEDs available in the US and a similar number available in the EU, including more than two thirds which have become available since the introduction of CBZ in 1963, and one third since the introduction of OXC in 2000 [, ]. The timing of the introduction of CBZ and OXC relative to the introduction of the other first, second and third generation AEDs is shown in Table 1.

Whilst there is only a small difference in structure between CBZ and OXC, their mechanisms of action and their metabolic pathways are substantially different [, ]. Both drugs are strong sodium channel blockers, but they modulate different types of calcium channels [, , ]. Furthermore, while CBZ is oxidized by the cytochrome P-450 system and is a potent inducer of most of the isozymes of cytochrome P-450, OXC is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite (monohydroxy derivative [MHD]). MHD, which is primarily responsible for the pharmacological effect of OXC, is subsequently metabolized by conjugation with glucuronic acid in the liver. As a result, OXC was shown to be a substantially weaker inducer of hepatic enzymes and is significantly less prone to drug-drug interactions compared with CBZ [].

Guidelines have evolved to reflect the evolution of the AED landscape. The main guidelines list CBZ and OXC as first-line options or second-line alternatives for the treatment of focal onset and primary generalized tonic-clonic seizures (Table 2).

Results of randomized clinical trials (RCTs) and recently published network analyses and systematic reviews complement guidelines recommendations and provide additional guidance towards evidence-based treatment choice.

Although there is evidence of efficacy under controlled research conditions for newer AEDs, their clinical effectiveness has been poorly studied [], and previous RCTs have limitations in informing the choice between all different AEDs []. Several large trials conducted after 2006 have nevertheless provided some limited information on their relative efficacy.

The Standard and New Antiepileptic Drugs (SANAD) study was a non-blinded RCT comparing CBZ, gabapentin, lamotrigine, OXC, and topiramate in focal epilepsy, conducted in 1721 hospital-based outpatient clinics in the UK []. In this study, CBZ was superior to gabapentin for time to 12-month remission and had a non-significant advantage over lamotrigine, topiramate, and OXC. However, for time to treatment failure, lamotrigine was superior to all other AEDs except for OXC.

It is important to note that the oldest head-to-head trials with CBZ (as is the case for SANAD) used the immediate-release formulation (CBZ-IR) on a BID schedule. Evidence indicates that CBZ is better tolerated with the controlled-release formulation (CBZ-CR), as suggested by studies conducted in the elderly population. For example, in a multicenter study comparing CBZ-IR with lamotrigine, the latter was significantly better tolerated than CBZ-IR []; however, an identical study comparing lamotrigine with CBZ-CR did not find any significant difference in tolerability between the two drugs [].

More recently, the efficacy and tolerability of a number of the newer AEDs, including levetiracetam, zonisamide, lacosamide, and eslicarbazepine were evaluated in head-to-head trials against CBZ-CR in adults with newly diagnosed epilepsy [, , , ]. No significant differences in efficacy or tolerability were observed.

Effectiveness, however, should not be the only factor to consider. The impact on quality of life (QOL) is another important variable, as not all adverse events (AEs) affecting QOL lead to drug discontinuation. This was suggested by the results of an open-label, single-arm study of patients aged ≥12 years with focal onset seizures, whereby patients who switched to OXC monotherapy due to lack of efficacy or poor tolerability on their current AED had significant and clinically relevant improvement in QOL [].

Recent network meta-analyses and Cochrane Reviews, based on individual participant data (IPD), presented below shed further light on how CBZ and OXC compare with other treatments.

Several network meta-analyses have recently been published that provide direct and indirect comparisons for all available AEDs (see Table 3a for a summary of the results).

Results of one of the largest and most recent network meta-analysis of IPD published in the Cochrane database of systematic reviews are in line with NICE guidelines, concluding that CBZ and lamotrigine are suitable first-line treatment options for individuals with focal onset seizures []. In addition, levetiracetam was listed among the most suitable alternatives. Generally, most AEDS in the network performed similarly in terms of seizure control, but older drugs performed worse in terms of long-term retention compared with the newer drugs, such as lamotrigine and levetiracetam (Table 3a).

Another large systematic review and network meta-analysis compared the relative efficacy and tolerability of 17 available AEDs used as monotherapy for the treatment of epilepsy (analyses done on focal epilepsy for efficacy, and all types of epilepsy for tolerability) []. The tolerability analyses again showed that newer drugs performed better than the oldest AEDs in terms of treatment withdrawal due to AEs, with CBZ ranking somewhat in the middle. In the efficacy analyses, CBZ performed better than the older drugs, primidone and phenobarbital, which were associated with a lower chance of achieving seizure freedom, and better than pregabalin in terms of withdrawals due to lack of therapeutic efficacy. No AED showed a significant improvement in any efficacy outcomes compared with CBZ, and OXC was listed among the drugs with the best efficacy profiles.

Taken together, these result indicate that while some new AEDs appear to be better tolerated than CBZ, none were more effective and some (primidone, phenobarbital, pregabalin) were less effective than CBZ based on certain efficacy measures. In several studies, levetiracetam showed comparable efficacy, and in one analysis, showed lower efficacy than CBZ in terms of seizure control [, ].

These overall findings are generally in line with results of pairwise comparisons based on IPD, as published in a series of Cochrane Reviews (Table 3b) [, , , , ].

The question of cost-effectiveness does not have a straightforward answer, as costs cannot be generalized worldwide. In addition, indirect costs are also an important factor to be taken into account and high quality cost-effectiveness studies are lacking [].

A cost-minimization analysis investigated the costs of treatment with lamotrigine, CBZ, phenytoin, and valproate in 12 European countries, taking into account each drug's side-effect and tolerability profiles. In each country considered, lamotrigine was twofold to threefold more expensive than the other drugs [].

A more recent study reviewing the scant health economic data on CBZ suggested that the use of this drug in epilepsy is cost-effective in certain contexts []. However, evidence from a prospective, randomized, controlled trial is lacking and uncertainty persists. In particular, cost-effectiveness remains to be demonstrated when used in certain patient subgroups, including the elderly, women of childbearing potential, and patients with learning difficulties. In the developing world, cheaper options such as phenytoin and phenobarbital should be considered. Furthermore, the economic effect on long-term side effects (particularly the potential effects on bone metabolism) drug-drug interactions, and teratogenicity was not incorporated into the analysis.

In spite of these uncertainties, the latest NICE guidelines, which included cost utility analyses of AEDs, concluded that lamotrigine was the most cost-effective monotherapy, but noted that CBZ may be as cost-effective [].

Guideline recommendations and clinical trial outcomes only partly reflect the place of AEDs in the epilepsy armamentarium. Real-world evidence studies and geographical variations in the use of AEDs in clinical practice are an important part of the picture, especially as they take into account essential factors, such as availability and cost in real-world settings. The authors of this review identified several studies conducted in different parts of the world that may help shed light on various clinical practices across countries. It should, however, be kept in mind that these examples are not full reflections of the situation in the countries considered. A summary of the findings is included in Table 4.

CBZ is a powerful inducer of hepatic enzymes (including both hetero and auto-induction) and is extensively metabolized in the liver (primarily by CYP3A4), causing numerous clinically relevant drug-drug interactions [] (Table 5). Auto-induction, in particular, results in nonlinear, time-dependent kinetics, with CBZ metabolism becoming more efficient as the duration of treatment increases; the steady-state concentration of CBZ is reduced by as much as 50% after 3 weeks of drug administration. As a result, during the introduction of CBZ, dose increases do not correlate with corresponding increases in the plasma levels and half-life of CBZ decreases with long-term use and polytherapy.

Not only does CBZ dose correlate poorly with blood levels, but also using the same dose, blood levels vary depending on gender, race, or age (e.g., women, children, or patients of African extraction often need higher doses than Caucasian men to reach similar blood concentrations). Following dosing recommendations and monitoring drug levels is thus critical to minimize drug interactions as well as early intolerance and subsequent reduced efficacy due to auto-induction (see Table 6 for recommendations on treatment optimization including management of side effects, such as rash and hyponatremia).

These recommendations include low initial dose and slow titration, as well as routine therapeutic drug monitoring (TDM) of CBZ to adjust the dose based on drug concentrations (using plasma reference range, Table 5) in order to optimize clinical outcome [, ]. TDM also helps to ensure compliance and to establish which level is suitable for a patient. However, in the experience of the authors of the present report, many centers only clinically follow patients and perform TDM in cases of specific indications rather than routinely (e.g. development of side effects or seizure occurrence).

Many patients are successfully managed using OXC based on the Prescribing Information-recommended titration schedule [, ]. Evolving clinical experience however suggests a number of additional treatment recommendations (Table 6). Recommendations on switching to OXC follow the results of the multicentre Italian PRIMO study []. While that it is not advisable to switch a patient with focal epilepsy stabilized on CBZ, switching to OXC in case of poor tolerability or scant clinical efficacy of CBZ was well tolerated in the vast majority of patients (87% still on OXC after one year). Retention rate was similar regardless of the reason of the switch (insufficient clinical efficacy or poor tolerability) suggesting that OXC can play a role in both scenarios, although it should be noted that significantly more patients needed combination therapy when switched due to poor efficacy. The CBZ/OXC ratio of 1/1.5 appears to be close to the optimal for the switch from CBZ to OXC, at least for patients treated with CBZ monotherapy.

As with other AEDs, including CBZ, TDM is a valuable adjunct in individualizing OXC treatment due to large individual differences in dose to plasma concentration relationship. Since OXC is rapidly transformed to its metabolite MHD, it is now routine practice to monitor only MHD concentration [].

In terms of AEs, there is a higher risk of hyponatremia with OXC compared with CBZ []. For both drugs the overall incidence varies greatly depending on the population studied and definition of hyponatremia (from 33% to 73% for OXC vs 5%–40% for CBZ) []. More recent studies of clinical trial data and experience reported rates of OXC-induced hyponatremia (serum sodium <135 mmol/l) of around 25% [] and 30% (vs 13% for CBZ-induced hyponatremia) [], and 3% for severe hyponatremia (serum sodium <125 mmol/l) []. Although hyponatremia is usually asymptomatic, routine serum sodium monitoring is recommended if relevant risk factors exist, including renal disease, or sodium-depleting comedications [, , , , , ]. It should also be noted that the authors of a recent real-world evidence study, including the EpiPGX Consortium [] found a higher risk than previously reported. Specific recommendations on the management of hyponatremia are included in Table 6.

Although, as mentioned above, drug interactions are less frequent with OXC compared with CBZ, OXC may reduce the effectiveness of hormonal contraception [, ].

The epilepsies of childhood are a heterogeneous group of disorders that include several different types of seizure with different causes, treatments, and outcomes [].

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Almost every AED has been associated with such risk []. CBZ and OXC, like many other AEDS, cross the placenta, with equivalent maternal blood and cord blood levels [, , ].

Although several observational studies have confirmed lower rates of major congenital malformations with use of CBZ during pregnancy compared with valproate [, ] (Perucca and Tomson 2011), CBZ, like valproate, has been associated specifically with the development of neural tube defects (NTDs), especially spina bifida []. Even with folate supplementation, women taking CBZ or valproate during pregnancy should avail themselves of prenatal diagnostic ultrasonography to detect NTD in the fetus. Based on the UK/Ireland epilepsy and pregnancy register, the overall major congenital malformations (MCMs) rates seen with exposure to CBZ and lamotrigine were not that different from background, particularly when taken in doses of less than 400 mg/day and 1000 mg/day, respectively []. However, there seems to be a dose related effect, which is steeper for CBZ than for lamotrigine. CBZ has been associated with a 2% risk when given at <500 mg daily, 3% at 500–1000 mg and 5% at >1000 mg []. In a recent Cochrane review of 50 studies, CBZ (as well as topimarate and valproate) was associated with higher rates of MCMs than levetiracetam and lamotrigine []. The same review did not identify any increased risk for MCMs for OXC. These results are in line with findings from a prospective cohort study of the EURAP registry which found that the risks of MCMs associated with OXC (3%), as well as with lamotrigine (2.9%) and levetiracetam (2.8%), were within the range reported in the literature for offsprings unexposed to AEDs []. The rate of MCMs observed in this study for CBZ was 5·5% and was 10·3% for valproate. Thus, overall, epilepsy and pregnancy registers are consolidating data, pointing to the use of lamotrigine, levetiracetam, OXC, and/or CBZ (lower dose) as those AEDs with the lowest risk of MCM [].

In addition to congenital malformation, exposure with AEDs during pregnancy has been associated with effects on cognitive functioning in children [] and increased behavioral difficulties [] compared with unexposed children. These, however, were mainly observed with valproate exposure which showed significant differences on social and attention problems and symptoms of ADHD [] compared with lamotrigine-, levetiracetam-, and CBZ‐exposed children. A prospective observational study of 311 children also showed that the IQ at age 6 years was significantly lower after exposure to valproate than to CBZ, lamotrigine, or phenytoin []. Children exposed to CBZ were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence [].

A higher proportion of conduct disorder were found in valproate and levetiracetam-exposed children, and a higher proportion of children exposed to lamotrigine in utero had clinical symptoms of autistic behavior []. In this study CBZ‐exposed children did not show higher proportions of clinical behavioral problems.

In a review of contemporary published evidence-based guidelines [], the avoidance of valproate and older AED during pregnancy remains the main focus. Avoidance of valproate and AED polytherapy is recommended during the first trimester to prevent MCM and throughout pregnancy to avoid reduced cognitive outcomes. Avoidance of phenytoin and phenobarbital during pregnancy may also be considered to prevent reduced cognitive outcomes.

Prescription pattern of AEDs during pregnancy have changed in line with the evolving evidence and guidelines. In Spain, for instance, there is increased use of levetiracetam, slight increased use of lamotrigine and OXC, and diminishing use of older agents, including phenytoin, phenobarbital, and CBZ []. In a recent worldwide survey of 642 participants in 81 countries, the most common first agents prescribed for young women with focal epilepsy were lamotrigine and levetiracetam, both of which appear to be relatively safe in pregnancy [].

The same survey, however, pointed out differences in treatment of epilepsy in pregnancy across the world, with the choice of first-line agent varying by the economic development status of the respondent's country []. Respondents from countries with developing economies were significantly more likely to prescribe CBZ and less likely to prescribe levetiracetam or lamotrigine. According to the authors, this probably reflects limited availability and prohibitive pricing of newer AEDs in the developing world, rather than better efficacy or safety of the newer AEDs.

Apart from the cost, there is a potential advantage of CBZ compared with lamotrigine in pregnancy, as it generally requires less frequent drug monitoring. While lamotrigine is known to have greatly increased clearance in pregnancy, CBZ clearance is not substantially affected, making it a relatively safe and cost-effective treatment option for pregnant women with focal epilepsy syndromes [, ]. Similarly to lamotrigine, OXC shows an increase in clearance during pregnancy (both AEDs being metabolized primarily by glucuronidation), with a peak in the second trimester to 1.63-fold baseline, and increased values persisting in the third trimester []. Therefore, early monitoring and dose adjustment is recommended for MHD to avoid increased seizure frequency [, ].

In summary, lower doses may be considered when using CBZ in pregnancy to minimize the risks of MCM with the advantage of less frequent monitoring; conversely, OXC requires more frequent dose monitoring but is listed among the safest drugs in terms of MCM.

The incidence of new-onset epilepsy is higher among the elderly than in any other age group []. In spite of this, there is relative scarcity of randomized-controlled trials involving older and newer AEDs in the geriatric population [].

The elderly population is characterized by altered physiology, decline in organ function, altered plasma protein binding and pharmacodynamics, as well as the presence of comorbidities and polypharmacy. All of these factors increase the chances of drug interactions, thereby making elderly patients with seizure disorder a challenging group to treat, and CBZ with its enzyme-inducing properties not the ideal drug in such a population [].

A systematic review and network meta-analysis of AEDs in the elderly showed no significant difference in efficacy across treatments, but CBZ had a poor tolerability profile, leading to higher withdrawal rates compared with levetiracetam and valproate []. OXC, with its low potential for enzyme induction, appears to be safe to use in elderly patients with evidence indicating that its tolerability in this age group is similar to that of younger adult patients [, ].

In spite of this, CBZ is still widely use in the elderly. This is (or was) the case in the UK according to a 2003 survey []. In a more recent Irish survey of 736 older adults with intellectual disabilities, the most prescribed drugs were valproic acid (48.7%) and CBZ (46.3%), followed by lamotrigine (27.8%) []. Recommendations in terms of careful CBZ dosing and serum monitoring is thus especially valuable in this population [].

Optimal use of CBZ in the elderly is dependent on a full understanding of the age-related alterations in pharmacokinetics and pharmacodynamics. Because of considerably lower metabolism rates, older patients require lower CBZ doses to achieve serum concentrations similar to younger adults []. A lower starting dose and careful titration according to response are recommended, and lower maintenance doses may be required on average to achieve optimal clinical effects. In case of bone health concerns, endocrine dysfunction, cholesterol, hyponatremia (higher in OXC than in CBZ) an alternative (e.g. lamotrigine, levetiracetam) should be considered [].

While the main goal of epilepsy treatment is to achieve seizure-freedom, another important aspect to consider is the management of comorbidities including neurological, psychiatric and cognitive comorbidities []. About one third to one half of patients with epilepsy also suffer from some type of psychiatric and/or neurological comorbidity []. The most common are mood disorders, anxiety disorders, and migraine, but stroke, dementia, or autistic spectrum disorder are common too. Psychiatric/neurological comorbidities are a greater determinant of QoL than seizure frequency in those with refractory epilepsy []. These comorbidities can cause or be caused by the onset of the seizure disorder, and may be influenced by AED treatment. Both AED treatment and treatment of comorbidities must be selected on the basis of the therapeutic or iatrogenic effects they may have with respect to the concomitant disorders.

Most AEDs are now tested for their prophylactic and analgesic effects in different types of migraine and neuropathic pain; OXC and CBZ have been shown to have some analgesic value in neuralgic pain []. In addition, CBZ and OXC have psychiatric benefits, acting as mood stabilizer, and anti-depressant and anti-manic therapies. Both drugs can therefore be considered in patients with a current or prior history of mood disorder []. However, it should be kept in mind that AEDs with enzyme-inducing properties, including CBZ and high dose OXC, can accelerate the clearance of some psychotropic drugs and limit their efficacy. Conversely, several psychotropic drugs (e.g. selective serotonin reuptake inhibitors [SSRI] antidepressants fluoxetine, fluvoxamine and paroxetine, some of the first-generation [haloperidol and loxapine] and second-generation [risperidone, quetiapine] antipsychotic drugs) can inhibit the clearance of some enzyme-inducing AEDs, including CBZ, and should be avoided [, ]. Moreover, SSRIs have been linked to osteopenia and osteoporosis, and SSRIs and serotonin-norepinephrine reuptake Inhibitor (SNRIs) can facilitate the development of hyponatremia, which should also be considered when prescribing CBZ or OXC concomitantly [].

AEDs with enzyme-inducing properties can also worsen neurological comorbidities. Discontinuation of CBZ has been showed to result in a notable reduction of LDL cholesterol and other lipid parameters, suggesting that enzyme-inducing AEDs including CBZ may increase the risk of cardiovascular and cerebrovascular disease []. Even OXC (>900 mg day) have been associated with potential atherogenic effect according to one study. However, it should be noted that some AEDs without enzyme-inducing properties have also been associated with such effect, and a history of epilepsy has been linked to an increased risk of stroke [].

Most AED taken at high dose have been associated with cognitive disturbances, and psychiatric or behavioral side effects. In a study part of the Columbia and Yale AED Database Project comparing each AED to lamotrigine, CBZ was found to have a significantly lower rate of psychiatric and behavioral side effects []. The cognitive and behavioral long-term effects of AEDs have also been the focus of a recent review [], confirming the benefits of CBZ-CR over lamotrigine in terms of behavioral effects, although lamotrigine may have a more favorable effect on cognitive function. The same review indicated that OXC monotherapy appears to have no adverse effect on cognition and would rather act as a stimulant leading to increased performance on focused attention task. These encouraging results should however be considered with caution and need to be replicated including a wider range of cognitive measures [, ].