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1.
Guberman  A Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 1998;25S3- S8
PubMed
2.
Mattson  RHCramer  JACollins  JF  et al.  Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313145- 151
PubMedArticle
3.
Beghi  ETognoni  G Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Epilepsia 1988;29236- 243
PubMedArticle
4.
Schmidt  D Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24368- 376
PubMedArticle
5.
Theodore  WHPorter  RJ Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13320- 324
PubMedArticle
6.
Brodie  MJ Monostars: an aid to choosing an antiepileptic drug as monotherapy. Epilepsia 1999;40(suppl 6)S17- S22
PubMedArticle
7.
Schneiderman  JH Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 1998;25S9- S13
PubMed
8.
Collaborative Group for the Study of Epilepsy, Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term course of epilepsy. Epilepsia 1992;3345- 51
PubMedArticle
9.
Heller  AJChesterman  PElwes  RDC  et al.  Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;5844- 50
PubMedArticle
10.
de Silva  MMacArdle  BMcGowan  M Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347709- 713
PubMedArticle
11.
Perucca  ETomson  T Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999;33247- 262
PubMedArticle
12.
Theodore  WHRaubertas  RFPorter  RJ  et al.  Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991;32392- 397
PubMedArticle
13.
Faught  ESachdeo  RCRemler  MP  et al.  Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology 1993;43688- 692
PubMedArticle
14.
Glauser  TANigro  MSachdeo  R  et al. Oxcarbazepine Pediatric Study Group, Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology 2000;542237- 2244
PubMedArticle
15.
Schachter  SCVazquez  BFisher  RS  et al.  Oxcarbazepine: double-blind, randomized, placebo-control monotherapy trial for partial seizures. Neurology 1999;52732- 737
PubMedArticle
16.
Pledger  G Monotherapy trials: presurgical studies. Epilepsy Res 2001;4567- 71
PubMedArticle
17.
Kwan  PBrodie  MJ Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 2003;60(suppl 4)S2- S12
PubMedArticle
18.
Beydoun  AKutluay  E Conversion to monotherapy: clinical trials in patients with refractory partial seizures. Neurology 2003;60(suppl 4)S13- S25
PubMedArticle
19.
Chadwick  DWAnhut  HGreiner  MJ  et al.  A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;511282- 1288
PubMedArticle
20.
Brodie  MJChadwick  DWAnhut  H  et al.  Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002;43993- 1000
PubMedArticle
21.
Brodie  MJOverstall  PWGiorgi  LThe UK Lamotrigine Elderly Study Group, Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999;3781- 87
PubMedArticle
22.
Brodie  MJRichens  AYuen  AW Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345476- 479
PubMedArticle
23.
Reunanen  MDam  MYuen  AWC A randomised open multicenter comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res 1996;23149- 155
PubMedArticle
24.
Dam  MEkberg  RLoyning  YWaltimo  OJakobsen  K A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;370- 76
PubMedArticle
25.
Christe  WKramer  GVigonius  U  et al.  A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26451- 460
PubMedArticle
26.
Bill  PAVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27195- 204
PubMedArticle
27.
Guerreiro  MMVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27205- 213
PubMedArticle
28.
Kälviäinen  RÄikiä  MSaukkonen  AMMervaala  ERiekkinen  PJ  Sr Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy: a randomized, controlled study. Arch Neurol 1995;52989- 996
PubMedArticle
29.
Tanganelli  PRegesta  G Vigabatrin vs carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study. Epilepsy Res 1996;25257- 262
PubMedArticle
30.
Frank  LMEnlow  THolmes  GL  et al.  Lamictal monotherapy for typical absence seizures in children. Epilepsia 1999;40973- 979
PubMedArticle
31.
Sachdeo  RKramer  LDRosenberg  ASachdeo  S Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol 1992;32386- 392
PubMedArticle
32.
Gilliam  FVazquez  BSackellares  JC  et al.  An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;511018- 1025
PubMedArticle
33.
Brodie  MJYuen  AW Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26423- 432
PubMedArticle
34.
Jozwiak  STerczynski  A Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure 2000;9486- 492
PubMedArticle
35.
Ben-Menachem  EFalter  UThe European Levetiracetam Study Group, Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;411276- 1283
PubMedArticle
36.
Beydoun  ASachdeo  RCRosenfeld  WE  et al.  Oxcarbazepine monotherapy for partial-onset seizures. Neurology 2000;542245- 2251
PubMedArticle
37.
Schachter  SC Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 1995;36(suppl 6)S2- S6
PubMedArticle
38.
Sachdeo  RCReife  RALim  PPledger  G Topiramate monotherapy for partial onset seizures. Epilepsia 1997;38294- 300
PubMedArticle
39.
Devinsky  OFaught  REWilder  BJ  et al.  Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995;20241- 246
PubMedArticle
40.
Bergey  GKMorris  HHRosenfeld  W  et al.  Gabapentin monotherapy: an 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49739- 745
PubMedArticle
41.
Crawford  P Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16263- 272
PubMedArticle
42.
Kwan  PBrodie  MJ Early identification of refractory epilepsy. N Engl J Med 2000;342314- 319
PubMedArticle
43.
Karceski  SMorrell  MCarpenter  D The expert consensus guideline series: treatment of epilepsy. Epilepsy Behav 2001;2(suppl 6)A1- A50Article
Neurological Review
September 2004

Monotherapy in EpilepsyRole of the Newer Antiepileptic Drugs

Author Affiliations

Author Affiliation: Department of Neurology, NYU School of Medicine, New York, NY.

 

DAVID E.PLEASUREMD

Arch Neurol. 2004;61(9):1361-1365. doi:10.1001/archneur.61.9.1361
Abstract

Background  Monotherapy is the goal for pharmacological treatment of epilepsy. Well-controlled trials have established the efficacy of some of the newer antiepileptic drugs (AEDs) as monotherapy.

Objective  To review clinical data and expert opinions pertinent to the evaluation of most of the newer AEDs as monotherapy for epilepsy.

Data Sources  The MEDLINE database was searched for clinical trials using newer AEDs. Reference sections of review articles were manually searched to identify relevant studies not retrieved in MEDLINE.

Study Selection  The resulting list of references was manually reviewed to identify monotherapy studies.

Results  Lamotrigine and oxcarbazepine demonstrated efficacy in randomized active-control trials in patients with newly diagnosed epilepsy and in substitution trials in patients refractory to conventional AEDs.

Conclusion  Lamotrigine and oxcarbazepine are as effective as conventional AEDs at controlling partial seizures and are better tolerated.

Monotherapy is preferred when treating epilepsy, although previous reports indicate that polytherapy was sometimes the standard of care and given routinely as initial treatment.1 Polytherapy began to be questioned shortly after studies showed that 50% to 75% of patients who started on monotherapy remained seizure free for at least 1 year and that monotherapy is equally or more effective, better tolerated, and associated with fewer drug interactions compared with polytherapy.27 Other advantages of monotherapy include better compliance, lower costs, and improved quality of life.1

The efficacy of conventional antiepileptic drugs (AEDs), including phenytoin, carbamazepine, phenobarbital, and valproate, as monotherapy is accepted,710 but efficacy of monotherapy with some of the newer AEDs has been established in well-controlled trials. To protect patients from the potential dangers of a noneffective agent used as monotherapy, many newer medications were initially studied as adjunctive therapy in refractory patients,1 and when efficacy and tolerability as adjunctive treatments were established, newer medications were then studied as monotherapy.11 However, felbamate and oxcarbazepine were studied as adjunctive therapy and monotherapy simultaneously.1215 Sufficient data are now available to establish the efficacy and tolerability of some of the newer AEDs as monotherapy. This article reviews data pertinent to evaluating the role of the newer AEDs, including felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, and topiramate, as monotherapy.

EVALUATING MONOTHERAPY CLINICAL TRIALS

The long-term, randomized, double-blind, placebo-controlled clinical trial of monotherapy in epilepsy is generally untenable for new AEDs because of possible harm arising from withholding active treatment. Randomized active-control trials comparing monotherapy with a test medication and monotherapy with a reference medication (typically a conventional AED with established efficacy) in newly diagnosed patients are the next best alternative, allowing assessment of efficacy and tolerability under conditions approximating clinical use.11 Because a new drug would not be expected to surpass the high (70%-80%) seizure remission rates achieved with established agents, demonstration of comparable efficacy of the test and reference medications is interpreted as evidence of the test medication’s efficacy.

Randomized, double-blind substitution trials gradually transition refractory patients to monotherapy with either a new AED or a conventional AED as the reference medication.11 As with double-blind, head-to-head monotherapy trials, demonstration of comparable efficacy of the test and reference medications is interpreted as evidence of efficacy of the test medication.

While clinicians generally accept comparable efficacy of test and reference medications in double-blind comparator trials as evidence of the test medication’s efficacy, regulatory authorities considering whether to approve new medications as monotherapy may not. To be statistically powered to show equivalence between the comparator medications, these trials generally need to include a prohibitively large number of patients. If a study is underpowered, a demonstration of apparent comparable efficacy cannot exclude the possibility that test and reference medications are both ineffective. In this case, a demonstration of superior efficacy of the test medication over the reference medication provides the only incontrovertible evidence of its efficacy. This hurdle is too high for most test AEDs to overcome, although the test drug may be effective as monotherapy in the clinical setting.11

Several alternative study designs compare test medication with a suboptimal treatment, which may be a nontherapeutic dose of the same drug, a different drug, or a placebo. Presurgical trials compare high doses of a test AED with placebo in patients with refractory seizures who need to discontinue their current therapy for evaluation before epilepsy surgery.16 These trials are of short duration because of the risks patients are exposed to in the placebo arm (ie, no AED treatment). This trial design compares the seizure frequency between the study drug and placebo, just as in other placebo-controlled trials. In open-label substitution trials, a high dosage of the test medication is compared with a suboptimal dosage of the same drug or with either a suboptimal drug or an effective dosage of a different one.11 When ethically feasible, a placebo group sometimes takes the place of the active comparator in substitution trials.

These alternative study designs require relatively few patients to demonstrate statistically significant effects of treatment. However, because of short duration and lack of flexibility for titrating doses to optimum levels, the practical relevance of data derived from these studies is limited.

A full discussion of all the complexities of monotherapy trial designs is beyond the scope of this article. The reader is encouraged to refer to other reviews for a more complete discussion of trial designs for monotherapy studies in epilepsy.11,1618

DATA FROM THE STUDIES

Clinical studies of the newer AEDs as monotherapy were identified through searches of the National Library of Medicine’s PubMed database, using as key words the names of the newer AEDs (ie, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) and the term “clinical trial.” No date limits were applied. The resulting list of references was manually reviewed to identify monotherapy studies. Reference sections of review articles on AEDs were manually searched to identify relevant studies not identified in the PubMed searches. Data presented at professional meetings in abstract form are not included in this review. Because no clinical studies on zonisamide as monotherapy were identified with the methods described above, that agent is not discussed in this review.

RANDOMIZED ACTIVE-CONTROL TRIALS

Numerous active-control comparisons of new AEDs with conventional medications have been conducted in patients with newly diagnosed epilepsy, and results of several open-label comparisons are also available.1929 Three of the studies employed a randomized, open-label design,23,28,29 1 randomized study had both an open-label and a double-blind component,19 and the other 7 were randomized, double-blind trials.2022,2427 Most of these studies were of sufficient duration (approximately 1 year) to allow assessment of long-term effects of the drugs on seizure control. Furthermore, many of these studies employed flexible dose-titration schedules, allowing investigators to adjust doses.

Gabapentin, lamotrigine, oxcarbazepine, and vigabatrin have been compared with conventional AEDs in patients with newly diagnosed epilepsy in randomized active-control trials. Except for vigabatrin, which compared with carbamazepine was associated with a higher percentage of discontinuations because of lack of efficacy,28 the studies show that newer agents are as effective in controlling seizures as reference AEDs including carbamazepine, phenytoin, and valproate. Seizure-free rates with both test and reference AEDs ranged from approximately 40% to 75%, consistent with rates historically observed with conventional AEDs.2,810

One randomized, active-control study compared 2 newer AEDs rather than a newer AED with a conventional one.20 That study, a randomized, double-blind, flexible-dose comparison of lamotrigine and gabapentin, demonstrated that both drugs were well tolerated and comparably effective in patients with newly diagnosed partial and tonic-clonic seizures, with 76% of patients in each group remaining seizure free for the last 12 weeks of monotherapy.

The newer AEDs were nearly always better tolerated, as reflected in lower frequencies of adverse events or lower rates of withdrawal from the study because of adverse events. Gabapentin (1 study), lamotrigine (3 studies), oxcarbazepine (1 study), and vigabatrin (2 studies) were each better tolerated than carbamazepine; oxcarbazepine was better tolerated than phenytoin (2 studies).19,2224,2629

Lamotrigine and oxcarbazepine consistently demonstrate efficacy in randomized active-control trials.2027 Furthermore, monotherapy with these drugs is better tolerated than monotherapy with conventional AEDs. Additional study of the other newer AEDs is warranted before definitive conclusions can be drawn about them: gabapentin was effective vs a conventional AED in 1 active-control study19; mixed results have been obtained with vigabatrin28,29; and felbamate, levetiracetam, tiagabine, and topiramate have not been assessed in published, randomized active-control studies in patients with newly diagnosed epilepsy.

PLACEBO-CONTROLLED TRIAL IN ABSENCE SEIZURES

Data from active-control studies are supplemented by a placebo-controlled trial of the efficacy of lamotrigine (median dose, 15 mg/kg per day) for absence seizures in 45 children aged 3 to 15 years with newly diagnosed epilepsy.30 A placebo control group was feasible because of the relatively benign nature of absence seizures; withholding effective treatment from the placebo group for the brief, 4-week treatment period would not endanger patients because this trial employed an escape design. When patients entered the double-blind phase, their absence seizures were fully controlled. Patients would exit the double-blind arm as soon as they were no longer seizure free. Therefore, the only patients exposed to placebo for 4 weeks were those who remained seizure free. Lamotrigine was significantly more effective than placebo, with 64% of patients receiving lamotrigine monotherapy free of absence seizures during the 4-week double-blind phase compared with 21% of placebo recipients. Lamotrigine was well tolerated, and no patient withdrew from the study because of adverse events.

SUBSTITUTION TRIALS

Several double-blind and open-label substitution trials have been conducted with the newer AEDs.13,3138 These trials generally enrolled patients with epilepsy refractory to conventional AEDs and were initiated with add-on phases during which patients were introduced to increasing doses of the test AED while their current AED was discontinued. A period of monotherapy with the test drug ensued. Patients with worsening epilepsy (usually measured by an increase in seizure frequency, severity, or the emergence of a new seizure type) or patients who did not tolerate the test AED were withdrawn from the study.

Active-control substitution trials were conducted with felbamate (2 studies) and lamotrigine (1 study), both of which were significantly more effective as monotherapy than low-dose or a minimally effective dose of valproate.13,31,32 In the only long-term, placebo-controlled substitution trial, 3000 mg of levetiracetam was significantly more effective than placebo during 12 weeks of monotherapy.35 Substitution trials comparing low and high doses of the test AED have been carried out with oxcarbazepine (300 mg/d vs 2400 mg/d), tiagabine (6 mg/d vs 36 mg/d), and topiramate (100 mg/d vs 1000 mg/d).3638 In all comparisons, the high dose of study medication was more effective at controlling seizures or prolonging time in the study. Generally, overall retention rates in these studies are low, and occurrence of adverse effects may be due to the high doses and rapid titration used.

Overall, substitution trials are consistent with randomized active-control trials in demonstrating efficacy of newer AEDs. The data for felbamate, lamotrigine, and levetiracetam are most robust because they were obtained from studies using an active comparator or a placebo control group.13,31,32,35 The other studies, which either were open-label and did not include a comparator or compared low and high doses of the test AED, should be interpreted cautiously because of the lack of a reference treatment.33,34,3638

Substitution trials extend the data from the trials in patients with newly diagnosed epilepsy by showing that seizures can be controlled with the newer medications in many patients refractory to conventional AEDs. The findings should be generalized to clinical practice carefully because these treatment-resistant patients may not be representative of typical clinical populations of patients with epilepsy.

PRESURGICAL TRIALS

Presurgical trials have been conducted with felbamate, gabapentin, oxcarbazepine, and tiagabine.15,37,39,40 In 3 placebo-controlled studies (felbamate, oxcarbazepine, and tiagabine), the test AED was more effective than placebo at reducing seizure frequency or prolonging time in the study.15,37,39 In the fourth comparison, a higher daily dose of gabapentin (3600 mg) was more effective than a lower dose (300 mg) in prolonging time in the study.40 Presurgical trials, while having the benefit of a placebo group, provide limited information because their design does not mimic clinical practice. These trials are of short duration (ie, 8-10 days), the inpatient setting is more controlled (ie, supervised) than an outpatient setting, study medication is administered via unorthodox conditions (ie, with rapid-dose escalation after abrupt withdrawal of the patient’s usual AED), and AED doses cannot be titrated as they would be in clinical practice.

OTHER FACTORS TO CONSIDER IN EVALUATING MONOTHERAPY

Because currently available AEDs are generally not distinguishable on the basis of efficacy data from clinical trials, factors such as mechanism of action, spectrum of activity, neuropsychiatric profile, sedative burden, long-term adverse effects, and ease of dosing need to be considered in choosing AEDs for monotherapy.6 Many of these features are not directly assessed in clinical trials. Taking into account these features and others, the newer AEDs lamotrigine, gabapentin, oxcarbazepine, and vigabatrin are considered to have better profiles as AED monotherapies than the conventional AEDs phenobarbital, phenytoin, carbamazepine, and valproate. Specific advantages of the newer AEDs include better tolerability, predictable kinetics, and broad-spectrum efficacy or well-defined spectrum of efficacy.

In addition to these characteristics of AEDs, medication effects in special patient populations warrant consideration.6 It is important to be aware that some AEDs (phenobarbital, phenytoin, carbamazepine, oxcarbazepine, felbamate, and topiramate) increase the metabolism of hormonal contraceptives, while others (valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, and levetiracetam) do not interact with hormonal contraceptives.41 Drugs with cognitive adverse effects should be avoided in elderly patients, who may be particularly susceptible to central nervous system toxicity.

Finally, there is evidence to suggest that the majority of patients who achieve seizure freedom with AEDs do so with monotherapy. The results of a prospective study evaluating AED response in patients with newly diagnosed epilepsy suggest that, regardless of the drug, only a relatively small percentage of patients who do not achieve seizure control with monotherapy will achieve control with polytherapy. Of the 64% of patients naïve to AEDs before the start of the study who became seizure free, 61% achieved seizure freedom with monotherapy, while the remaining 3% were seizure free with a 2-drug regimen.42 The finding that only 3% of the 64% of patients who were seizure free required polytherapy suggests that, for most patients who are responsive to pharmacotherapy, monotherapy is an effective treatment regimen.

Leaders in the field of epilepsy recommend valproate and lamotrigine as first-line monotherapy for generalized tonic-clonic seizures; valproate, ethosuximide, and lamotrigine for absence seizures; and valproate and lamotrigine for myoclonic seizures. Lamotrigine was recommended as first-line treatment for idiopathic generalized epilepsy among women of reproductive age, including those who are pregnant or breastfeeding; elderly patients; and those with intellectual impairment.43 Oxcarbazepine is currently approved by the Food and Drug Administration as monotherapy for partial seizures in adults, and lamotrigine is Food and Drug Administration-approved for conversion to monotherapy in adults with partial seizures.

COMMENT

Long-term, randomized, double-blind, placebo-controlled trials are not appropriate to evaluate monotherapy because of the risks involved in withholding active treatment from a patient. Therefore, several alternative designs are generally used. It is important to keep the strengths and weaknesses of these trial designs in mind when interpreting results and evaluating options for monotherapy.

Results of several clinical trials demonstrate that the newer AEDs can be as effective as monotherapy for epilepsy. Efficacy is particularly well established for lamotrigine and oxcarbazepine, and compared with conventional AEDs such as carbamazepine, phenytoin, and valproate, both are equally effective at controlling seizures and are better tolerated. Data for the other newer AEDs are both less voluminous and less consistent than those for lamotrigine and oxcarbazepine, and additional clinical study is warranted before the place of these medications can be established.

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Article Information

Correspondence: Blanca Vazquez, MD, NYU Comprehensive Epilepsy Center, 403 East 34th St, RIV Fourth Floor, New York, NY 10016-4998 (blancavs@netscape.net).

Accepted for Publication: Feburary 4, 2004.

References
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Guberman  A Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 1998;25S3- S8
PubMed
2.
Mattson  RHCramer  JACollins  JF  et al.  Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313145- 151
PubMedArticle
3.
Beghi  ETognoni  G Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Epilepsia 1988;29236- 243
PubMedArticle
4.
Schmidt  D Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24368- 376
PubMedArticle
5.
Theodore  WHPorter  RJ Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13320- 324
PubMedArticle
6.
Brodie  MJ Monostars: an aid to choosing an antiepileptic drug as monotherapy. Epilepsia 1999;40(suppl 6)S17- S22
PubMedArticle
7.
Schneiderman  JH Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 1998;25S9- S13
PubMed
8.
Collaborative Group for the Study of Epilepsy, Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term course of epilepsy. Epilepsia 1992;3345- 51
PubMedArticle
9.
Heller  AJChesterman  PElwes  RDC  et al.  Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;5844- 50
PubMedArticle
10.
de Silva  MMacArdle  BMcGowan  M Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347709- 713
PubMedArticle
11.
Perucca  ETomson  T Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999;33247- 262
PubMedArticle
12.
Theodore  WHRaubertas  RFPorter  RJ  et al.  Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991;32392- 397
PubMedArticle
13.
Faught  ESachdeo  RCRemler  MP  et al.  Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology 1993;43688- 692
PubMedArticle
14.
Glauser  TANigro  MSachdeo  R  et al. Oxcarbazepine Pediatric Study Group, Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology 2000;542237- 2244
PubMedArticle
15.
Schachter  SCVazquez  BFisher  RS  et al.  Oxcarbazepine: double-blind, randomized, placebo-control monotherapy trial for partial seizures. Neurology 1999;52732- 737
PubMedArticle
16.
Pledger  G Monotherapy trials: presurgical studies. Epilepsy Res 2001;4567- 71
PubMedArticle
17.
Kwan  PBrodie  MJ Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 2003;60(suppl 4)S2- S12
PubMedArticle
18.
Beydoun  AKutluay  E Conversion to monotherapy: clinical trials in patients with refractory partial seizures. Neurology 2003;60(suppl 4)S13- S25
PubMedArticle
19.
Chadwick  DWAnhut  HGreiner  MJ  et al.  A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;511282- 1288
PubMedArticle
20.
Brodie  MJChadwick  DWAnhut  H  et al.  Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002;43993- 1000
PubMedArticle
21.
Brodie  MJOverstall  PWGiorgi  LThe UK Lamotrigine Elderly Study Group, Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999;3781- 87
PubMedArticle
22.
Brodie  MJRichens  AYuen  AW Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345476- 479
PubMedArticle
23.
Reunanen  MDam  MYuen  AWC A randomised open multicenter comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res 1996;23149- 155
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