Context The past decade has brought many advances to the treatment of epilepsy,
including many new pharmacological agents. Primary care physicians often care
for patients with epilepsy and therefore should be familiar with the new options
available.
Objective To review data regarding the efficacy and tolerability of antiepileptic
drugs introduced in the past decade.
Data Sources A search of the Cochrane Central Register of Controlled Trials was performed
to identify all published human and English-language randomized controlled
trials evaluating the efficacy and tolerability of the antiepileptic drugs
that have been approved for use in the United States since 1990. Additional
reports evaluating pharmacokinetic properties were identified through a MEDLINE
search as well as review of article bibliographies.
Study Selection and Data Extraction Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were
reported as major outcome measures. Included studies (n = 55) enrolled a minimum
of 20 adult subjects and had a treatment period of at least 6 weeks.
Data Synthesis Eight new antiepileptic drugs have been approved for use in the United
States in the past decade. Each new antiepileptic drug is well tolerated and
demonstrates statistically significant reductions in seizure frequency over
baseline. No randomized controlled trials have compared the new antiepileptic
drugs with each other or against the traditional antiepileptic drugs. Although
there is no evidence to suggest that the newer medications are more efficacious,
several studies have demonstrated broader spectrum of activity, fewer drug
interactions, and overall better tolerability of the new agents.
Conclusions New antiepileptic drugs offer many options in the treatment of epilepsy,
each with unique mechanisms of action as well as adverse effect profiles.
The new antiepileptic drugs are well tolerated with few adverse effects, minimal
drug interactions, and a broad spectrum of activity.
Quiz Ref IDEpilepsy is defined as a chronic neurological condition
characterized by recurrent, unprovoked seizures.1 It
is one of the most common serious neurological disorders in the United States
and often requires long-term management. Each year 150 000 people in
the United States are newly diagnosed as having epilepsy, with the cumulative
lifetime incidence approaching 3%.2,3 The
incidence is highest during the first year of life and in elderly persons.2 Although most people with epilepsy become seizure-free
with appropriate therapy, 30% to 40% of patients will continue to have seizures
despite the use of antiepileptic drugs either alone or in combination.4 Patients with uncontrolled seizures experience significant
morbidity and mortality and face social stigma and discrimination as well.
In the United States, only 17% of patients with new-onset epilepsy are
initially seen by a neurologist.5 Furthermore,
primary care physicians provide approximately 40% of the long-term management
of epilepsy patients with or without initial consultation with a specialist.6 Unfortunately, a survey of general practitioners revealed
that only 40% of responders felt confident in their knowledge of epilepsy
and two thirds were unfamiliar with the new antiepileptic drugs.7 A
recent survey of 71 patients with epilepsy who are treated exclusively by
general practitioners showed that 45% had experienced a seizure within the
past year, 68% complained of drowsiness or difficulty in concentration with
their current medications, and 28% were prescribed polytherapy.8 Therefore,
general practitioners play a vital role in the treatment of epilepsy patients
with ongoing seizures.
Prior to 1993, the choice of an anticonvulsant medication was limited
to phenobarbital, primidone, phenytoin, carbamazepine, and valproate. Although
these "traditional" anticonvulsants have the advantage of familiarity as well
as proven efficacy, many patients are left with refractory seizures as well
as intolerable adverse effects. Since 1993, 8 new medications have been approved
by the US Food and Drug Administration (FDA), expanding treatment options
(Table 1). The newer antiepileptic
drugs offer the potential advantages of fewer drug interactions, unique mechanisms
of action, and a broader spectrum of activity. With more options, however,
comes the challenge of determining what role the new antiepileptic drugs play
in optimizing treatment in addition to understanding important adverse effects
and drug interactions of these increasingly prescribed medications. The purpose
of this article is to familiarize primary care clinicians with the efficacy,
tolerability, and pharmacokinetic properties of the new antiepileptic drugs.
We searched the Cochrane Central Register of Controlled Trials to identify
all published human and English-language randomized controlled clinical trials
evaluating the efficacy and tolerability of antiepileptic drugs that have
been FDA approved since 1990. Additional reports evaluating pharmacokinetic
properties were identified through a MEDLINE search as well as review of article
bibliographies. Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were
reported as major outcome measures. Included studies (n = 55) enrolled a minimum
of 20 adult subjects and had a treatment period of at least 6 weeks.
Quiz Ref IDThe majority of the new antiepileptic drugs gained
initial FDA approval based on randomized, double-blind, placebo-controlled
clinical trials in which the new antiepileptic drug was used as adjunctive
treatment. Typically, trials enrolled patients with refractory partial-onset
seizures to receive either the study drug or placebo in addition to their
original medication(s). Patients were followed up for 6 to 8 weeks to establish
a baseline seizure frequency, then randomly assigned to either placebo or
study drug and followed up for 8 to 12 weeks while seizure frequency and tolerability
were monitored. The primary outcome measure was a reduction in seizure frequency
over baseline compared with placebo. A "responder rate" is reported as the
number of patients who achieved a 50% or greater reduction in seizure frequency
from baseline.
There are obvious limitations to this trial design. Efficacy is often
underestimated and responder rates are typically less than 50% because the
study population with refractory seizures has typically not responded to multiple
antiepileptic drugs and is therefore not comparable to patients in a typical
clinical practice. Toxicity is often overestimated because adverse effects
may be additive and not specifically due to the add-on therapy. In addition,
many of the new antiepileptic drugs were titrated more rapidly during clinical
trials than is currently recommended, further overestimating the risk of toxicity
and adverse effects. Finally, the variability in study groups and trial designs
makes direct comparisons among trials impossible. Despite these drawbacks,
adjunctive clinical trials are overall the safest and most ethical means of
testing new antiepileptic compounds.
Few of the new antiepileptic drugs have been evaluated in monotherapy
trials and fewer yet have been FDA approved for use as monotherapy. This presents
a dilemma that has led to frequent off-label use because monotherapy offers
many advantages over polytherapy, including fewer adverse effects, less drug
interactions, lower cost, and improved compliance. The reason for fewer monotherapy
approvals stems from the difficulty in trial design. There are 2 common approaches
to monotherapy trials. An active-control comparison typically randomly assigns
patients with new-onset seizures to receive either the study drug or a well-established
antiepileptic drug at low therapeutic doses. Conversion to monotherapy trials
assigns patients to be converted from their current antiepileptic drug(s)
to either a subtherapeutic dose of the test drug (referred to as pseudoplacebo)
or a higher dose of the test drug that is thought to be efficacious. Efficacy
is measured as completion rate or mean time to exiting the study. Exit criteria
consist of either an increase in seizure frequency above baseline, a prolonged
generalized seizure, or status epilepticus. In addition, the percentage of
patients discontinuing due to adverse effects is reported. Agents that show
efficacy in placebo-controlled trials are considered acceptable proof of efficacy
for FDA approval; however, this trial design raises obvious ethical concerns.
To demonstrate efficacy in active-control comparison trials, the study drug
must show superiority over the control and not merely equivalency.9
Felbamate was the first new antiepileptic drug to gain FDA approval
(in 1993) and its introduction was met with much enthusiasm and initial success.
It is a broad-spectrum agent approved for both monotherapy and adjunctive
treatment of partial-onset seizures in adults as well as partial- and generalized-onset
seizures associated with Lennox-Gastaut syndrome (LGS) in children.10,11 Several mechanisms of action have
been identified, including sodium channel blockade, calcium channel blockade,
and antagonism of N-methyl-D-aspartate
(NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
receptors (Figure 1).12-15 The
efficacy of felbamate as adjunctive therapy for partial seizures has been
evaluated in 2 outpatient crossover trials.16,17 The
smaller trial enrolled 30 patients and found no significant decrease in seizure
frequency during the felbamate treatment period, while there was a 23% decrease
in seizure frequency in a larger trial of 67 patients (P = .02).
Felbamate has also shown efficacy as monotherapy in 2 trials that compared
felbamate, 3600 mg/d, with low-dose valproate.18,19 A
total of 138 patients were randomized, and there were significantly higher
completion rates in both felbamate groups (60% vs 22% and 86% vs 10%, P<.01). More importantly, felbamate has shown great
success in the treatment of LGS, a childhood-onset epilepsy consisting of
severe cognitive dysfunction accompanied by seizures of many types, including
atonic seizures (drop attacks), which are notoriously treatment resistant.
Two studies support the efficacy of felbamate as add-on therapy in adults
with LGS, with responder rates up to 50% and a decrease in drop attacks of
30%.20,21
The most commonly documented adverse effects with felbamate include
gastrointestinal disturbances, anorexia, and insomnia.18,19 Unfortunately,
a year after FDA approval, reports of rare idiosyncratic reactions began to
emerge. Aplastic anemia has been reported in 34 cases with an incidence of
approximately 1 in 8000 patient exposures.22,23 Hepatotoxicity
was also reported at a slightly lower incidence of 1 in 10 000, which
parallels the risk with valproate therapy.22 Felbamate
remains on the market but with a black box warning for aplastic anemia and
hepatic failure and is currently not considered a first-line anticonvulsant
medication. However, felbamate can still be useful for patients with LGS or
partial-onset seizures refractory to other antiepileptic drugs, but it is
recommended to obtain informed consent and monitor hematologic function frequently.
Quiz Ref IDGabapentin was approved for use in 1993 and is currently
indicated as adjunctive therapy for partial seizures with and without secondary
generalization in persons 3 years and older.10 Interestingly,
more than 80% of prescriptions for gabapentin are for off-label uses such
as neuropathic pain, migraine headache, spasticity, and bipolar disorder.24 Although structurally related to γ-aminobutyric
acid (GABA), its precise mechanism of action in humans is unknown (Figure 1).25 Four
initial add-on trials enrolling more than 700 patients with refractory partial-onset
epilepsy led to the FDA approval of gabapentin.26-29 Dosages
ranged from 1200 to 1800 mg/d with 25% to 33% demonstrating a greater than
50% reduction in seizure frequency from baseline (Table 2).
Gabapentin has also been evaluated in 2 large monotherapy trials (Table 3). The first study, a dose-response,
pseudoplacebo-controlled trial (n = 275), randomly assigned patients to 1
of 3 daily doses (600 mg, 1200 mg, and 2400 mg) and found no significant difference
in completion rates, which were meager and ranged from 15% to 26%.30 The second study compared gabapentin at 3 different
daily doses (300 mg, 900 mg, and 1800 mg) with an active control (carbamazepine,
600 mg/d). There was no significant difference in completion rates (38% vs
37%), suggesting equivalent but not superior efficacy of gabapentin to carbamazepine.
In addition, the time to study exit was significantly longer for the patients
in the gabapentin group administered 900 or 1800 mg/d compared with those
in the 300-mg/d group.31 The most common reason
for exit from the study was an increase in seizure frequency above baseline.
Although gabapentin had modest efficacy as monotherapy in this single study,
it is not FDA approved as such. A single study evaluated the efficacy of gabapentin
for generalized-onset seizures and showed no change in seizure frequency from
baseline.32
Adverse effects that were reported more often in patients taking gabapentin
than placebo included somnolence, dizziness, and fatigue, which usually resolved
within the first 2 weeks of therapy. Modest weight gain has also been observed
in postmarketing studies but no serious idiosyncratic reactions or organ toxicities
have been identified.33 Gabapentin possesses
several desirable pharmacokinetic properties: it does not undergo hepatic
metabolism and is excreted unchanged in urine.34 In
addition, gabapentin does not affect plasma concentrations of other antiepileptic
drugs, oral contraceptives, or probenecid.35,36 Coadministration
with antacids causes a decrease in bioavailability of gabapentin, while cimetidine
decreases oral clearance by 14%, which is of unknown clinical significance.10 Gabapentin offers the unique advantages of a wide
margin of safety with good tolerability in the absence of any significant
drug interactions but with modest efficacy.
Lamotrigine is a broad-spectrum agent that was approved for use in 1994
as an adjunctive treatment in adults with partial-onset seizures.10 Later approval was granted for use in adults and
children aged 2 years and older with generalized seizures associated with
LGS and for conversion to monotherapy.10 Lamotrigine
exhibits its antiepileptic effect primarily by blockade of sodium channels
and, to a lesser extent, calcium channels (Figure 1).37 Seven clinical trials
have shown lamotrigine's efficacy as an adjunctive agent in partial seizures
with responder rates ranging from 17% to 67% in dosages up to 500 mg/d (Table 2).38-44 In
addition, 2 smaller trials evaluating the efficacy of lamotrigine as adjunctive
therapy in partial seizures failed to show statistically significant reductions
in seizure frequency from baseline.45,46 The
efficacy of lamotrigine as monotherapy was established in a multicenter study
of 156 patients comparing lamotrigine (500 mg/d) with low-dose valproate (1000
mg/d).47 Fifty-eight percent of the patients
in the lamotrigine group completed the study vs 31% in the valproate group
(P = .001). In addition, active control monotherapy
trials have compared lamotrigine to phenytoin as well as carbamazepine and
found lamotrigine to have similar efficacy but fewer adverse effects and lower
withdrawal rates (Table 3).48-50 Two studies have
evaluated the efficacy of lamotrigine in generalized seizures associated with
LGS.51,52 The largest study enrolled
169 patients and demonstrated a 33% responder rate (P =
.01) and a 34% decrease in drop attacks.
Pooled clinical trial data showed that adverse effects necessitated
withdrawal of lamotrigine therapy in 10.2% of patients (n = 3501), with rash
being the most common cause for discontinuation (3.8%).53 In
addition, there have been reports of lamotrigine-associated rash requiring
hospitalization, some progressing to Stevens-Johnson syndrome.54 However,
a recent review of 73 cases of antiepileptic drug–related Stevens-Johnson
syndrome and toxic epidermal necrolysis found lamotrigine to be associated
with a lower relative risk compared with phenobarbital, phenytoin, and carbamazepine.55 Subsequent review of published and unpublished clinical
trial data showed that severe rashes occur more often with rapid titration
and in pediatric patients as opposed to adults (1% vs 0.3%).56 It
has also been recognized that the risk of skin rash is significantly higher
when lamotrigine is coadministered with valproate because valproate markedly
slows the metabolism of lamotrigine. This risk can be reduced with lower initial
doses and slower titration schedules.57 Lamotrigine
undergoes hepatic metabolism through glucuronidation but does not induce or
inhibit hepatic enzymes and thus has no significant effects on the metabolism
of other antiepileptic drugs or oral contraceptives.58-60 Lamotrigine
provides the advantage of a broad-spectrum agent with minimal sedation or
drug interactions, but its most significant drawback is a slow titration schedule
requiring 8 to 12 weeks to reach therapeutic maintenance doses and even longer
when used in conjunction with valproate.
Topiramate is another broad-spectrum agent approved as adjunctive treatment
in adults and children 2 years or older with partial seizures, primary generalized
seizures, and seizures associated with LGS.10 Multiple
mechanisms of action have been shown in preclinical studies including sodium
and calcium channel blockade, GABA potentiation, and glutamate receptor antagonism
(Figure 1).61-63 The
efficacy of topiramate as adjunctive therapy is supported by 6 multicenter
trials that enrolled 580 patients with refractory partial-onset seizures (Table 2).64-69 Responder
rates were 35% to 48% with daily doses ranging from 300 to 800 mg. The 2 largest
trials randomly assigned patients to multiple doses and found no significant
increase in efficacy for dosages higher 400 mg/d.64,65 Topiramate
has also shown efficacy against generalized-onset seizures including refractory
seizures seen in LGS.70,71 In
a study of 98 patients with LGS, 33% had a 50% reduction in tonic-clonic seizures
as well as drop attacks (P = .002).71 A
single pseudoplacebo-controlled monotherapy trial in 48 patients demonstrated
a 54% completion rate for patients taking 1000 mg/d vs 17% completion rate
for those taking 100 mg/d (P = .002).72 However,
topiramate is not FDA approved for monotherapy.
Adverse effects that were seen more commonly for patients taking topiramate
than placebo in clinical trials included ataxia, decreased concentration,
confusion, dizziness, and fatigue, most of which occurred in patients taking
more than 600 mg/d or with relatively rapid titration to maintenance dose
in 3 to 4 weeks.73 No idiosyncratic reactions
or organ toxicities have been reported to date. Other clinically relevant
adverse effects include nephrolithiasis, with a reported incidence of 1.5%,
and mild weight loss averaging 1 to 6 kg predominantly in the first 3 months
of therapy.73,74 Topiramate exerts
no significant effects on other antiepileptic drugs or on serum norethindrone
levels but decreases serum estradiol levels by 30% and serum digoxin levels
by 12%.75,76 Topiramate offers
the advantage of a broad-spectrum agent with minimal drug interactions, the
absence of serious adverse effects, and the potential for weight loss but
with the slight risk of kidney stones and a slow titration schedule (8-12
weeks).
Tiagabine was FDA approved for use in 1997 for the adjunctive treatment
of partial-onset seizures in persons 12 years or older.10 It
has a novel mechanism of action, blocking reuptake of GABA into neurons and
glial cells (Figure 1).77 Three multicenter studies evaluated the efficacy
and tolerability of tiagabine as adjunctive therapy (Table 2).78-80 The
smallest trial enrolled 154 patients and showed a responder rate of 14%, which
was not significantly greater than placebo. However, more than 600 patients
enrolled in 2 additional trials showed modest but significant responder rates
of 29% and 31% at doses of 56 and 32 mg/d. The most common adverse effects
included dizziness, tremor, and impaired concentration, most often seen with
twice-daily dosing and much less frequently with either 3- or 4-times daily
dosing.
Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450
system but has not been shown to induce or inhibit hepatic enzyme function
and thus has negligible effects on other drugs, including other antiepileptic
drugs, warfarin, digoxin, cimetidine, triazolam, antipyrine, and theophylline.80-83 At
low doses of 8 mg/d, tiagabine demonstrated no effect on oral contraceptive
metabolism but patients taking higher doses were not evaluated.84 Concurrent
use of tiagabine and hepatic enzyme–inducing antiepileptic drugs (phenobarbital,
phenytoin, and carbamazepine) reduces the half-life of tiagabine while coadministration
of cimetidine and tiagabine has no effect on tiagabine pharmacokinetics.83 The effects of other drugs that impact the cytochrome
P450 system have not been extensively evaluated. Of some concern are rare
reports of tiagabine precipitating nonconvulsive status epilepticus, in particular,
absence status epilepticus.85,86 Tiagabine
offers a novel mechanism of action with modest efficacy in partial-onset seizures.
Levetiracetam was approved in 1999 for the adjunctive treatment of adults
with partial-onset seizures.10 Its exact mechanism
of action is unknown but it does not appear to have activity against traditional
drug targets.87 Four multicenter trials with
levetiracetam as add-on therapy enrolled more than a thousand patients and
showed a responder rate of between 32% and 48% with doses ranging from 2000
to 3000 mg/d (Table 2).88-91 In
the US trial, patients were titrated to maintenance dose over a 4-week period
with minimal adverse effects and a median reduction in seizure frequency of
26% to 30% within the first 2 weeks.88 Betts
et al91 evaluated the tolerability and efficacy
of 2000 and 4000 mg/d started without titration and found both to be well
tolerated but, interestingly, higher responder rates were seen in patients
receiving 2000 mg/d.
Common adverse effects of levetiracetam in clinical trials included
somnolence, asthenia, headache, and infection. The majority of adverse effects
occurred in the first 4 weeks of therapy and did not appear to be dose related.
In addition, behavioral disturbances such as agitation and anxiety were reported
in up to 13% of the study cohort.88-91 The
pharmacokinetic profile of levetiracetam is favorable, with absence of hepatic
metabolism and low protein binding.92 No significant
interaction was reported with coadministration of other antiepileptic drugs,
oral contraceptives, digoxin, warfarin, or probenecid.92 Additionally,
levetiracetam has the highest safety margin in animal models compared with
all other antiepileptic drugs.93 Levetiracetam
offers the advantage of a favorable pharmacokinetic profile and high safety
margin with the capability of rapid dosage titration.
Oxcarbazepine, an analogue of carbamazepine, is available for use as
monotherapy or adjunctive therapy in the treatment of partial-onset seizures
in persons aged 4 years and older.10 It was
designed to have similar efficacy to carbamazepine but fewer adverse effects,
largely due to its lack of formation of the toxic metabolite carbamazepine10,
11 epoxide.94 Like carbamazepine, its principal
mechanism of action is via sodium channel blockade (Figure 1).95 Oxcarbazepine has been
evaluated as adjunctive therapy for partial seizures in 2 clinical trials
(Table 2).96,97 The
larger trial enrolled 694 patients who were randomly assigned to receive placebo
or oxcarbazepine in dosages of 600 mg/d, 1200 mg/d, or 2400 mg/d. Responder
rates were 27%, 42%, and 50%, respectively, for the oxcarbazepine groups (P<.001).97 However, a
similar but much smaller and shorter study enrolling 48 patients failed to
show a significant decrease in seizure frequency.96 Oxcarbazepine
was also evaluated in 6 monotherapy trials (Table 3).98-103 Four
active-control trials compared oxcarbazepine with carbamazepine, phenytoin,
or valproate and found similar efficacy but a statistically significant decrease
in adverse effects in the oxcarbazepine group in 3 of the trials. In addition,
2 pseudoplacebo-controlled trials in 230 patients compared the efficacy of
300 mg/d vs 2400 mg/d of oxcarbazepine and demonstrated a significantly higher
completion rate in the high-dose group (P<.001).102,103
Common adverse effects of oxcarbazepine in clinical trials were dose
related and included dizziness, diplopia, somnolence, nausea, and ataxia,
particularly in patients receiving 2400 mg/d. Allergic skin reactions occurred
less frequently than with carbamazepine, although a cross-sensitivity of approximately
30% has been demonstrated in patients with hypersensitivity to carbamazepine.104 Hyponatremia has also been reported, particularly
in elderly persons. In a large postmarketing study, 23% of 350 patients receiving
oxcarbazepine were found to have a serum sodium level lower than 135 mEq/L,
although only 1% required discontinuation of the drug.105 Oxcarbazepine
does not induce its own metabolism or hepatic microsomal enzymes and is not
affected by concurrent administration of erythromycin, as seen with carbamazepine.106,107 In addition, oxcarbazepine has
not been shown to interact with other antiepileptic drugs, cimetidine, warfarin,
or dextropropoxyphene.10 However, oxcarbazepine
decreases serum levels of oral contraceptives and felodipine.108,109 Oxcarbazepine
offers similar efficacy to carbamazepine but with fewer drug interactions
and overall fewer adverse effects, with the exception of hyponatremia.
Zonisamide is a broad-spectrum anticonvulsant that has been available
in the United States since 2000 but has had widespread clinical use in Japan
since 1989. It is a sulfonamide derivative that acts by blocking sodium as
well as T-type calcium channels (Figure 1).110,111 Two multicenter
trials carried out in the United States and Europe in 342 patients evaluated
the efficacy and tolerability of zonisamide for partial-onset seizures.112,113 The patients randomly assigned
to receive zonisamide were titrated up to a dose of 400 to 500 mg/d and had
a responder rate of 30% to 43% (Table 2). Although FDA approved for use only in partial-onset seizures,
case studies have demonstrated dramatic improvement with zonisamide in patients
with generalized-onset seizures, particularly myoclonus.114,115
Statistically significant adverse effects were reported in up to 59%
of study patients compared with 28% in the placebo group and included fatigue,
dizziness, ataxia, and anorexia. An earlier open-label study reported a 3.5%
incidence of renal calculi that initially halted the drug's development, but
this finding was not reproduced in subsequent studies.116 In
the pediatric population there have been rare reports of high fever secondary
to hyperhidrosis.117 Zonisamide has the advantage
of a long half-life, averaging 63 to 69 hours in healthy volunteers, making
once-daily dosing possible.118 Low protein
binding as well as partial liver metabolism via conjugation contributes to
its minimal interaction with other medications, including other antiepileptic
drugs and cimetidine.10 Because zonisamide
is a sulfonamide derivative its use is contraindicated in patients with a
known sulfonamide allergy. Zonisamide is efficacious as adjunctive therapy
for many seizure types, particularly myoclonus, with the advantage of once-daily
dosing.
Is There a Superior New Antiepileptic Drug?
Unfortunately, to our knowledge there have been no randomized controlled
clinical trials comparing the efficacy and tolerability of the new antiepileptic
drugs. Although most of the individual drugs were approved based on add-on
trials with similar study designs, varying study populations and titration
schedules make direct comparisons difficult. Quiz Ref IDNevertheless,
Marson et al118 performed a meta-analysis of
published and unpublished randomized controlled trials in which gabapentin,
lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide were compared
with placebo as add-on therapy in patients with refractory partial-onset seizures.
The odds ratio for a 50% or greater reduction in seizure frequency was calculated
for each individual drug. There was no conclusive evidence for a difference
in efficacy or tolerability among the drugs because the 95% confidence intervals
(CIs) overlapped. However, topiramate had the highest odds ratio for 50% responders
(4.22; 95% CI, 2.80-6.35), which was almost twice that of the lowest odds
ratio (2.29; 95% CI, 1.53-3.43) for patients taking gabapentin. In addition,
the odds ratios for withdrawal from treatment for patients taking lamotrigine
or gabapentin were no higher than placebo.
In addition to differences
in study populations and nonrandomized comparisons, shortcomings of this analysis
include the absence of comparative data in patients taking felbamate, oxcarbazepine,
or levetiracetam as well as exclusion of monotherapy studies and studies evaluating
generalized-onset seizures. Although these results do not allow
the physician to make an evidence-based decision in choosing an antiepileptic
drug, they do highlight some potential differences among these drugs that
future studies may further differentiate.
Are the New Antiepileptic Drugs Superior to the Traditional Antiepileptic
Drugs?
There was much enthusiasm with the arrival of the new antiepileptic
drugs, especially considering the number of patients who were taking combinations
of the traditional antiepileptic drugs and continuing to have frequent breakthrough
seizures coupled with intolerable adverse effects. Despite the lack of comprehensive
clinical trials comparing the new and traditional antiepileptic drugs, there
is evidence to suggest some advantages of the new agents. Gabapentin, lamotrigine,
and oxcarbazepine have each been compared with carbamazepine as monotherapy
in partial-onset seizures and found to have better tolerability, although
there was no difference in efficacy.48,96,99,119 Lamotrigine,
topiramate, and zonisamide have been shown to have broad-spectrum activity
with efficacy against generalized as well as partial-onset seizures while
valproate is the only traditional antiepileptic drug with this spectrum of
activity.51,52,70,71,114,115
Most of the new antiepileptic drugs lack hepatic enzyme induction and
have not been shown to interact with other hepatically metabolized medications
unlike phenobarbital, phenytoin, and carbamazepine.34,35,92 Finally,
only felbamate and lamotrigine have demonstrated potentially life-threatening
adverse effects, which have been well documented with phenytoin, carbamazepine,
and valproate.22,54 However, the
new anticonvulsant medications are significantly more expensive than the traditional
drugs, and ad hoc studies have not shown evidence of superior cost-effectiveness.120
Is Routine Serum Monitoring Required?
Quiz Ref IDRoutine monitoring of serum drug concentrations has
traditionally been used to guide dosage adjustments in patients taking antiepileptic
drugs, despite the fact that "therapeutic ranges" in the literature often
do not correlate with a given individual's response. Therefore, titration
to clinical efficacy is recommended not only for the traditional antiepileptic
drugs but for the newer agents as well. However, if a patient does not respond
to a particular therapy as expected, checking the serum drug concentration
may aid in determining compliance and identifying potential pharmacokinetic
interactions. Serum drug level tests are commercially available, although
there are not sufficient data available to determine the optimum serum concentrations
of many of the new antiepileptic drugs.
Since many of the traditional antiepileptic drugs are associated with
rare but potentially serious bone marrow suppression as well as hepatotoxicity,
baseline as well as routine monitoring of hematological and liver functions
is recommended. Of the new antiepileptic drugs, the only medication that has
been associated with serious organ toxicity is felbamate, with rare but potentially
fatal cases of aplastic anemia and hepatotoxicity.22,23 Therefore,
felbamate is the only new antiepileptic drug that requires routine monitoring
of complete blood cell counts and liver function.10
What Dosage Adjustments Are Required in the Setting of Hepatic Disease
or Renal Insufficiency?
Studies have been performed evaluating the pharmacokinetic effects of
hepatic and renal disease on most of the newer antiepileptic drugs. However,
few data are available regarding the clinical significance of these effects.
For patients with hepatic disease, there is insufficient information available
to make any recommendations on the necessity of dosage adjustments. However,
since gabapentin and levetiracetam both lack significant hepatic metabolism,
both of these drugs theoretically should be safe choices in patients with
hepatic dysfunction.
Since gabapentin and levetiracetam are primarily nonmetabolized and
excreted through the kidneys, the dosage should be decreased for patients
with renal dysfunction. The manufacturers of both drugs have established specific
dosing guidelines based on creatinine clearance (Table 4). The elimination half-lives of topiramate, oxcarbazepine,
and zonisamide are prolonged in the setting of moderate to severe renal disease
and therefore dosage adjustment is recommended in patients with renal dysfunction,
although no specific guidelines have been published. There are insufficient
data available on the use of felbamate, lamotrigine, or tiagabine in patients
with renal dysfunction.
Epilepsy is a prevalent, serious medical condition that is treated largely
by general practitioners. The development of new antiepileptic drugs has expanded
treatment options and offered significant advantages to patients, particularly
those with adverse effects or frequent breakthrough seizures with traditional
antiepileptic drugs. Randomized controlled clinical trial data support the
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