Elsevier

The Lancet Neurology

Volume 11, Issue 9, September 2012, Pages 792-802
The Lancet Neurology

Review
Adverse effects of antiepileptic drugs

https://doi.org/10.1016/S1474-4422(12)70153-9Get rights and content

Summary

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects.

Introduction

Adverse effects are a leading cause of treatment failure with antiepileptic drugs. Not only do they result in early treatment discontinuation in up to 25% of patients, but also they preclude attainment of fully effective doses and have a negative effect on patient adherence.1, 2 Furthermore, adverse effects of antiepileptic drugs are a major source of disability, morbidity, and mortality3 and a substantial burden on use and costs of health care.4

Although adverse effects have been recorded since the dawn of antiepileptic drug treatment, only in recent years has substantial effort been made to define, quantify, and address their clinical relevance. In 1985, the Veterans Administration Cooperative I trial compared the effectiveness of carbamazepine, phenobarbital, phenytoin, and primidone.

“The outcome of this project underscores the unsatisfactory status of AED therapy with medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.”5

Systematic research into novel compounds, individualised antiepileptic drug regimens, and methods for assessment of toxic effects in everyday practice has resulted in more effective strategies to tackle adverse effects. Advances in epidemiology and pharmacogenetics have improved our understanding of the multifaceted aspects of antiepileptic drug toxic effects and allowed us to identify specific profiles of patients at increased risk for particular adverse effects.

In this Review, we discuss the adverse effect profiles of available antiepileptic drugs, highlight the clinical relevance of these side-effects, and provide practical recommendations for their prevention, assessment, and management. This is not a systematic review and reflects our own assessment of published work in this area and our personal experience of management of patients with epilepsy in specialised clinics.

Section snippets

Definitions, assessment, and prevalence

WHO defines an adverse drug effect as “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.6 Distinction between the terms adverse effect and adverse event is important. An adverse effect is an untoward experience that can be attributed, directly or indirectly, to the drug. An adverse event is an untoward experience arising during treatment that is not

Classification of adverse effects

Adverse drug effects can be classified by frequency, severity, symptoms, pathophysiological mechanisms, and affected organ or structure. We suggested previously2 that classification based on patterns of co-occurrence is feasible and potentially useful to elucidate underlying mechanisms. By application of factor analysis to the 19 items of the adverse event profile, we found that adverse effects of antiepileptic drugs segregated into five distinct biologically plausible classes: cognition and

Special populations

Assessment of adverse effects can be challenging in young children, particularly those with associated intellectual disability. Yet, children can be more vulnerable to adverse effects than adults, and the toxic effect profile of specific antiepileptic drugs can differ between children and adults. In particular, behavioural difficulties (such as hyperactivity, insomnia, and aggression) induced by barbiturates or benzodiazepines happen more frequently in children than in adults.30, 34 Children

Adverse effects and health-related quality of life

Health is defined by WHO as “a state of complete physical, mental, and social wellbeing and not merely the absence of disease and infirmity”.91 Adverse effects of antiepileptic drugs have emerged as one of the strongest predictors of impaired health-related quality of life, independent of seizure outcome. In a representative study on the long-term psychosocial outcomes of childhood-onset epilepsy, individuals in remission on antiepileptic drug treatment had worse ratings for health-related

Prevention and management

Minimisation of the adverse effects of antiepileptic drugs is a multistage process that requires implementation of preventive measures, careful monitoring, and prompt interventions, as needed. For this approach to succeed, a “therapeutic alliance” between the patient and the clinician is essential. Patients must be actively involved in all aspects of their care, including selection of the most appropriate treatment, early detection of adverse effects, and decisions about corrective actions.

The

Conclusions and future perspectives

Over the past few decades, advances in clinical trial methodology, drug surveillance systems, and understanding of pathophysiological mechanisms have permitted better characterisation of the adverse effect profile of individual antiepileptic drugs. In parallel, new knowledge has been acquired on risk factors for specific adverse effects and on strategies not only to minimise toxic effects, but also to improve their early detection and management. Doctors are increasingly aware of the importance

Search strategy and selection criteria

We searched PubMed up to June 7, 2012, with the terms: “adverse effects”, “side effects”, “adverse reactions”, “tolerability”, “toxicity”, “safety”, “antiepileptic drugs”, “quality of life”, “humans”, and generic and brand key names of individual antiepileptic drugs. We also identified relevant published work by searching the reference lists of retrieved papers and from our own files. Only papers published in English were reviewed. The final reference list was generated on the basis of

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