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
ReviewAdverse effects of antiepileptic drugs
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
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