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Abstract
While several newer AEDs have study data that support monotherapy usage, most possess
FDA indications for adjunctive treatment of partial onset seizures, leading to their
initial (and often persistent) clinical use as adjunctive polytherapy for patients
with refractory epilepsy. This review considers a practical approach to the appropriate
role for polytherapy in epilepsy, presents the evidence for AED polytherapy, reviews
the mythic but practically reasonable concept of “rational polytherapy,” and concludes
with practical strategies for avoiding and employing polytherapy in clinical practice.
The appropriate indications for AED polytherapy include transitional polytherapy during
titration of a new adjunctive AED toward monotherapy or long-term maintenance AED
polytherapy in medically refractory epilepsy.
Better information of the natural history of epilepsy has important implications for understanding the underlying neurobiology, evaluating treatment strategies, and planning healthcare resources. The traditional pessimistic view has been dispelled by results from modern community based prospective studies, showing that over 60% of newly diagnosed patients will enter remission upon treatment. Recent outcome studies suggest that medical intractability may be predicted after failure of two antiepileptic drugs. Poor prognostic factors include a high initial seizure density, symptomatic aetiology, and presence of structural cerebral abnormalities, all of which can be identified early on. Among patients who have entered remission, many will remain seizure-free after antiepileptic drug treatment is withdrawn, suggesting that the underlying seizure generating factor has remitted. Whether some of these patients have entered remission "spontaneously" is contentious because, with effective pharmacotherapy for epilepsy in use for over 100 years, the natural history of untreated epilepsy is largely unknown. Circumstantial evidence, mostly arising from resource poor countries where antiepileptic drug treatment is not readily available, indicates that spontaneous remission may occur in up to 30% of cases. Observations from these complementary sources suggest that, at the population level, prognosis of newly diagnosed epilepsy may be broadly categorised into three groups: remission without treatment, remission with treatment only, and persistent seizures despite treatment. As understanding of the prognostic factors improves, the potential of a "prognostic group specific" management approach should be explored so that effective treatments may be used in a more rational and targeted fashion.
We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.
Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.
[*
]Address correspondence to this author at Department of Neurology, Mayo Clinic, 200
First Street Southwest, Rochester, MN 55905, USA; Tel: (507) 538-1038; fax: (507)
284-4074; E-mail:
StLouis.Erik@
123456mayo.edu
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