Cecilie Johannessen Landmark

Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy.

Antiepileptic drugs (AEDs) are used extensively to treat multiple non-epilepsy disorders, both in neurology and psychiatry. This article provides a review of the clinical efficacy of AEDs in non-epilepsy disorders based on recently published preclinical and clinical studies, and attempts to relate this efficacy to the mechanism of action of AEDs and pathophysiological processes associated with the disorders. Some newer indications for AEDs have been established, while others are under investigation. The disorders where AEDs have been demonstrated to be of clinical importance include neurological disorders, such as essential tremor, neuropathic pain and migraine, and psychiatric disorders, including anxiety, schizophrenia and bipolar disorder.Many of the AEDs have various targets of action in the synapse and have several proposed relevant mechanisms of action in epilepsy and in other disorders. Pathophysiological processes disturb neuronal excitability by modulating ion channels, receptors and intracellular signalling pathways, and these are targets for the pharmacological action of various AEDs. Attention is focused on the glutamatergic and GABAergic synapses.In psychiatric conditions such as schizophrenia and bipolar disorder, AEDs such as valproate, carbamazepine and lamotrigine appear to have clear roles based on their effect on intracellular pathways. On the other hand, some AEDs, e.g. topiramate, have efficacy for nonpsychiatric disorders including migraine, possibly by enhancing GABAergic and reducing glutamatergic neurotransmission.AEDs that seem to enhance GABAergic neurotransmission, e.g. tiagabine, valproate, gabapentin and possibly levetiracetam, may have a role in treating neurological disorders such as essential tremor, or anxiety disorders. AEDs with effects on voltage-gated sodium or calcium channels may be advantageous in treating neuropathic pain, e.g. gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine and valproate.Co-morbid conditions associated with epilepsy, such as mood disorders and migraine, may often respond to treatment with AEDs. Other possible disorders where AEDs may be of clinical importance include cancer, HIV infection, drug and alcohol abuse, and also in neuroprotection.A future challenge is to evaluate the second-generation AEDs in non-epilepsy disorders and to design clinical trials to study their effects in such disorders in paediatric patients. Differentiation between the main mechanisms of action of the AEDs needs more consideration in drug selection for tailored treatment of the various non-epilepsy disorders.Abstract Antiepileptic drugs (AEDs) are used extensively to treat multiple non-epilepsy disorders, both in neurology and psychiatry. This article provides a review of the clinical efficacy of AEDs in non-epilepsy disorders based on recently published preclinical and clinical studies, and attempts to relate this efficacy to the mechanism of action of AEDs and pathophysiological processes associated with the disorders. Some newer indications for AEDs have been established, while others are under investigation. The disorders where AEDs have been demonstrated to be of clinical importance include neurological disorders, such as essential tremor, neuropathic pain and migraine, and psychiatric disorders, including anxiety, schizophrenia and bipolar disorder. Many of the AEDs have various targets of action in the synapse and have several proposed relevant mechanisms of action in epilepsy and in other disorders. Pathophysiological processes disturb neuronal excitability by modulating ion channels, receptors and intracellular signalling pathways, and these are targets for the pharmacological action of various AEDs. Attention is focused on the glutamatergic and GABAergic synapses. In psychiatric conditions such as schizophrenia and bipolar disorder, AEDs such as valproate, carbamazepine and lamotrigine appear to have clear roles based on their effect on intracellular pathways. On the other hand, some AEDs, e.g. topiramate, have efficacy for nonpsychiatric disorders including migraine, possibly by enhancing GABAergic and reducing glutamatergic neurotransmission. AEDs that seem to enhance GABAergic neurotransmission, e.g. tiagabine, valproate, gabapentin and possibly levetiracetam, may have a role in treating neurological disorders such as essential tremor, or anxiety disorders. AEDs with effects on voltage-gated sodium or calcium channels may be advantageous in treating neuropathic pain, e.g. gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine and valproate. Co-morbid conditions associated with epilepsy, such as mood disorders and migraine, may often respond to treatment with AEDs. Other possible disorders where AEDs may be of clinical importance include cancer, HIV infection, drug and alcohol abuse, and also in neuroprotection. A future challenge is to evaluate the second-generation AEDs in non-epilepsy disorders and to design clinical trials to study their effects in such disorders in paediatric patients. Differentiation between the main mechanisms of action of the AEDs needs more consideration in drug selection for tailored treatment of the various non-epilepsy disorders.

Drug interactions involving the new second- and third-generation antiepileptic drugs

During the period 1989–2009, 14 new antiepileptic drugs (AEDs) were licensed for clinical use and these can be subdivided into new second- and third-generation AEDs. The second-generation AEDs comprise felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. The third-generation AEDs comprise eslicarbazepine acetate and lacosamide. The interaction propensity of AEDs is very important because all new AEDs are licensed, at least in the first instance, as adjunctive therapy. The present review summarizes the interactions (pharmacokinetic and pharmacodynamic) that have been reported with the newer AEDs. The pharmacokinetic interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the liver. Overall, the newer AEDs are less interacting because their pharmacokinetics are more favorable and many are minimally or not bound to blood albumin (e.g., eslicarbazepine, felbamate, gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) and are primarily renally excreted or metabolized by noncytochrome P450 or uridine glucoronyl transferases (e.g., gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) as opposed to hepatic metabolism which is particularly amenable to interference. Gabapentin, lacosamide, levetiracetam, pregabalin and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate are the most interacting. Furthermore, the metabolism of lamotrigine is susceptible to both enzyme inhibition and enzyme induction. While the metabolism of felbamate, tiagabine, topiramate and zonisamide can be induced by enzyme-inducing AEDs, they are less vulnerable to inhibition by valproate. Noteworthy is the fact that only five new AEDs (eslicarbazepine, felbamate, oxcarbazepine, rufinamide and topiramate) interact with oral contraceptives and compromise contraception control. The most clinically significant pharmacodynamic interaction is that relating to the synergism of valproate and lamotrigine for complex partial seizures. Compared with the first-generation AEDs, the new second- and third-generation AEDs are less interacting, and this is a desirable development because it allows ease of prescribing by the physician and less complicated therapeutic outcomes and complications for patients.

Antiepileptic Drug Interactions - Principles and Clinical Implications

Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs.

Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population

BACKGROUND Many new antiepileptic drugs (AEDs) have become available in recent years. Investigations of prescription patterns and exposure of AEDs to different patient groups are important regarding drug safety aspects. The aim of this study was to investigate the use of AEDs in epilepsy, with focus on exposure of AEDs, gender and age differences and changes in prescription patterns over time. METHOD The data consisted of all prescriptions of AEDs from Norwegian pharmacies from the Norwegian Prescription Database (NorPD) (2004-2009), which included 44,000-47,000 patients with epilepsy each year. Variables included age, sex, diagnosis-related reimbursement codes and the use of AEDs (defined daily doses (DDDs)). RESULTS Twenty two AEDs were in use. There were pronounced age- and gender differences regarding the use of AEDs in epilepsy. The most commonly used drugs were valproate and lamotrigine in children, carbamazepine and lamotrigine in adults, and carbamazepine and phenobarbital in the elderly. Lamotrigine and topiramate were predominantly used in female, and valproate and carbamazepine were predominantly used in male patients, respectively. Eighteen percent used polytherapy with AEDs. Of patients using lamotrigine, 14% received different generic preparations, in spite of the policy of restricted generic substitution. The use of AEDs in 2009 was 6.6 DDDs/1000 inhabitants/day, 49% of the use covered newer AEDs. CONCLUSION The use of AEDs in epilepsy (2004-2009) was investigated in detail. All AEDs showed pronounced age and gender differences. Newer AEDs covered 49% of the total use in 2009. The study contributes to pharmacovigilance, as it offers a basis of knowledge for national decision-making authorities in the field of drug utilization.

Antiepileptic drugs in epilepsy and other disorders—A population-based study of prescriptions

PURPOSE The aim of the study was to quantify the use of antiepileptic drugs (AEDs) in epilepsy and other indications in a nation-wide population using a prescription database. MATERIALS AND METHODS Prescription data of AEDs were collected from the Norwegian Prescription Database for the period 2004-2007, including 5.1 million prescriptions from 144,653 patients, all having at least one prescribed and dispensed AED. Diagnosis-related reimbursement codes were used as indicators for clinical use. RESULTS Of the AEDs used, 71% was in epilepsy, 15% in psychiatry, 13% in neuropathic pain, and <1% in migraine, trigeminus neuralgia and cancer adjuvance. The use in epilepsy increased steadily from 7.0 to 7.5 DDDs/1000 inhabitants/day (7%) from 2004 to 2007. The use of AEDs in other indications increased considerably more from 2004 to 2007: Neuropathic pain to 1.40 DDDs/1000 inhabitants/day (360%), psychiatry to 1.59 (200%), and migraine to 0.005 (642%). The prevalence of AED users increased and in 2007 it was 0.97% in epilepsy, 0.8% in neuropathic pain, 0.33% in psychiatry and 0.001% in migraine. In 2007, 49% of the AEDs used in epilepsy were a new drug, carbamazepine, lamotrigine and valproate being most frequently used. New AEDs were used in 96% in migraine prophylaxis, 94% in neuropathic pain, and 64% in psychiatry. CONCLUSIONS Based on a nation-wide prescription database, this study quantifies the wide and increasing use of AEDs, in particular the newer drugs.

Antiepileptic drug treatment in pregnancy: Changes in drug disposition and their clinical implications

Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large‐scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.

Pharmacological management of epilepsy: recent advances and future prospects.

There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches.Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet’s syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs.Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.

Host factors affecting antiepileptic drug delivery—Pharmacokinetic variability

Antiepileptic drugs (AEDs) are the mainstay in the treatment of epilepsy, one of the most common serious chronic neurological disorders. AEDs display extensive pharmacological variability between and within patients, and a major determinant of differences in response to treatment is pharmacokinetic variability. Host factors affecting AED delivery may be defined as the pharmacokinetic characteristics that determine the AED delivery to the site of action, the epileptic focus. Individual differences may occur in absorption, distribution, metabolism and excretion. These differences can be determined by genetic factors including gender and ethnicity, but the pharmacokinetics of AEDs can also be affected by age, specific physiological states in life, such as pregnancy, or pathological conditions including hepatic and renal insufficiency. Pharmacokinetic interactions with other drugs are another important source of variability in response to AEDs. Pharmacokinetic characteristics of the presently available AEDs are discussed in this review as well as their clinical implications.

Psychiatric comorbidity in patients with epilepsy: a population-based study

PurposePatients with epilepsy often suffer from concomitant psychiatric disorders. Treatment patterns and the extent of comorbidity are insufficiently investigated and appropriate methods are scarce. The purpose of the study was to estimate the prevalence of psychiatric comorbidity in patients with epilepsy and to investigate prescription patterns of drugs prescribed for psychiatric disorders in epilepsy.MethodsPrescription data from the Norwegian Prescription Database (NorPD) regarding the use of CNS-active drugs included anonymous data from almost 190,000 patients and 1.1–1.3 million prescriptions per year (2004–2007). Searches were based upon use of specific drugs, defined daily doses, number of patients, prescriptions, gender, and age. Reimbursement codes related to psychiatric diagnosis were used as indicators for clinical use.ResultsThe prevalence of psychiatric comorbidity in patients with epilepsy was estimated to be 32%. There were 56% women and 44% men participating in the study. Among patients using antidepressants two thirds were women, but no gender differences were seen with antipsychotic medication. Antidepressants and antipsychotics were used 3.4 (20.9%) and 5.8 (13.4%) times more frequently than in the general population, accounting for 7.88 and 1.99 defined daily doses (DDDs)/1,000 inhabitants/day/year respectively. Lamotrigine was the most commonly used antiepileptic drug (AED) in epilepsy, accounting for 33% of the use of AEDs (in total 5.65 DDDs/1,000 inhabitants/day/year). The use of benzodiazepines was 9.55 DDDs/1,000 inhabitants/day/year. The patients had complex pharmacotherapy with two to eight concomitant drugs.ConclusionThe present study gives an estimate of psychiatric comorbidity of 32% in patients with epilepsy in a nation-wide population. The pharmacotherapy in this patient population is complex. The results provide valuable data on prescription patterns that contribute to pharmacovigilance on a national scale.

Value of therapeutic drug monitoring in epilepsy

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) has made it possible to study the individual variations in drug utilization, to reveal noncompliance in patients and for quality assurance aspects. Even if there is a shortage of data from randomized controlled studies concerning the effectiveness of using TDM as an aid to dosage adjustment, experience from nonrandomized investigations and long-lasting clinical experience have shown that TDM of both older and newer AEDs may be of clinical benefit if used appropriately. The main situations for TDM include: after starting treatment to provide a baseline steady-state concentration for further evaluation of an individual therapeutic concentration; after change in drug dosage, in particular when nonlinear kinetics apply; at therapeutic failure to sort out a pharmacokinetic explanation for uncontrolled seizures or side effects; in case of drug interactions; and when pharmacokinetic changes due to physiological or pathological changes are foreseen (e.g., age-dependent conditions [children, elderly], pregnancy, hepatic disease, renal disease or gastrointestinal conditions potentially affecting drug absorption) and change in drug formulation (brand name/generic). Recently, new terminology and definitions have been suggested by the International League Against Epilepsy. The reference range is a range of drug concentrations quoted by laboratories and is not a therapeutic range. Emphasis should be placed on the concept of an individual therapeutic concentration.