Similar Adverse Effects for Epilepsy Patients on Monotherapy or Polytherapy

Pauline Anderson

April 23, 2010

April 23, 2010 — Although adverse effects are common among patients treated with antiepileptic drugs (AEDs), a new study has found that these effects are about the same among those taking a single drug and those taking several drugs and may be more related to factors such as individual responsiveness, the type of drug combination, and physician treatment skills, rather than the actual number of drugs used.

The findings suggest that the relationship between AED load and toxicity burden may be more complex than originally thought, and that the current trend to reject polytherapy for fear of increased toxicity may not be warranted, the researchers speculate.

However, the study's lead author, Emilio Perucca, MD, professor of clinical pharmacotherapy at the University of Pavia, Italy, stressed that physicians should not conclude from the study that polytherapy is always the same as monotherapy when it comes to adverse effects. "The paper does not show that polytherapy is as well tolerated as monotherapy; it simply shows that some individuals tolerate polytherapy and some individuals tolerate monotherapy."

Results of this study were published in Epilepsia, the journal of the International League Against Epilepsy.

The analysis included 809 consecutive patients (344 men and 465 women) aged 16 years or older with epilepsy who attended 11 tertiary referral centers in Italy. Patients were drug refractory and had at least 1 seizure during the previous 6 months.

Mean duration of epilepsy was over the course of 20 years. Most patients (86.4%) had cryptogenic or symptomatic localization-related epilepsy. The median seizure frequency was 2.5 per month. More than three quarters of the patients had failed to respond to at least 3 AEDs given alone or in combination.

Most Common Epilepsy Drugs

Less than 25% of patients were being managed on a single AED, with the most common drugs being carbamazepine, oxcarbazepine, and lamotrigine. The most commonly used agents in polytherapy were levetiracetam, followed by carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, phenobarbital, and clobazam. Of those receiving polytherapy, 90.6% received at least 1 new-generation AED, and 43.5% received at least 2 of these agents in combination.

Through unstructured interviews, 36.5% of patients reported adverse effects. Of these, 62.7% reported 1 adverse effect, 22% reported 2 adverse effects, 11.5% reported 3 adverse effects, and 3.7% reported 4 or more adverse effects. The most common adverse effects were somnolence, followed by tremor, memory problems, and visual disturbances. There were no major differences between the polytherapy and monotherapy groups.

The researchers also used the Adverse Event Profile (AEP) questionnaire to determine frequency of adverse effects. Here, nervousness and/or agitation, tiredness, sleepiness, and memory problems were the most commonly reported adverse effects for all patients. The number of adverse effects per patient correlated significantly with the number identified by the interview.

Comparable AEP Scores

Drug loads, defined as the sum of ratios between actual prescribed daily doses and the average therapeutic dose, or defined daily dose, of each drug, were higher for patients on polytherapy than for those on monotherapy (3.1 vs 1.2; P < .0001). Despite the fact that AED load in patients increased with increasing number of coprescribed drugs, AEP scores in patients receiving 1 AED (42.8) were comparable to those in patients receiving 2 AEDs (41.9), 3 AEDs (43.1), or 4 or more AEDs (44.9).

There are several possible explanations for the lack of correlation between adverse effects and total AED load. For one thing, many patients were taking newer-generation AEDs, which have improved tolerability. In addition, the cross-sectional nature of the study provided a setting in which physicians were able to optimize AED choices, doses, and combinations, the authors write.

Individual Sensitivity

"If you have excellent skilled physicians doing the job, you would by definition expect everyone to have the same level of side effects, because it's a compromise irrespective of the treatment," added Dr. Perucca. "What the patient can tolerate depends on the individual susceptibility [and] sensitivity to side effects, as well as the type of drugs chosen."

Combining 2 different AEDs, each at the respective defined daily dose, is unlikely to produce the same effects as doubling the dose of 1 AED, the authors write. They also noted that some drug combinations are better tolerated than others.

There is increasing awareness, said the authors, that response to AED combinations is influenced not only by the relative drug doses but also by the pharmacologic properties of specific AED combinations. There is even some evidence that certain combinations have infra-additive toxicity, and possibly synergistic therapeutic effects.

Despite the availability of 20 different AEDs, about one third of people with epilepsy still fail to become seizure-free, according to background information in the study. The consensus is that newly diagnosed patients are best treated with a single AED.

This study was conducted under the auspices of the Italian League Against Epilepsy and the Italian Pharmacological Society and was supported by the Italian Medicines Agency within the independent drug research program. Dr. Perucca received speakers' or consultancy fees and/or research grants from Novartis, Bial, Pfizer, GlaxoSmithKline, Schwartz Pharma and UCB Pharma, Valeant, Sanofi-Aventis, Eisai, and Johnson & Johnson. Maria Paola Canevini served as a paid consultant for UCB Italy, UCB Europe, and Medtronic. Angela La Neve received speakers' fees and support for congress participation from Cyberonics, Eisai, GSK, Novartis, Pfizer, Sanofi-Aventis, and UCB Pharma, and in the last years she received research grants from UCB Pharma. The remaining authors have disclosed no relevant financial relationships.

Epilepsia. Published online April 20, 2010.