Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

Abstract

BackgroundThe safety profile of anti-epileptic drugs (AEDs) is an important consideration for the regulatory bodies, owners and prescribing clinicians. Information on their adverse effects still remains limited. A systematic review including a meta-analytic approach was designed to evaluate existing evidence for the safety profile of AEDs in canine patients. Electronic searches of PubMed, CAB Direct and Google scholar were carried out without date or language restrictions. Conference proceedings were also searched. Peer-reviewed full-length studies reporting adverse effects of AEDs in epileptic and healthy non-epileptic dogs were included. Studies were allocated to three groups based on their design. Individual studies were evaluated based on the quality of evidence (study design, study group sizes, subject enrolment quality and overall risk of bias) and the outcome measures reported (proportion of specific adverse effects for each AED, prevalence and 95 % confidence interval of the affected population in each study and comparative odds ratio of adverse effects for AEDs).ResultsNinety studies, including six conference proceedings, reporting clinical outcomes of AEDs’ adverse effects were identified. Few studies were designed as blinded randomised controlled clinical trials. Many studies included low canine populations with unclear criteria of subject enrolment and short treatment periods. Direct comparisons suggested that imepitoin and levetiracetam might have a better safety profile than phenobarbital, whilst the latter might have a better safety profile than potassium bromide. However, none of these comparisons showed a statistically significant difference. Comparisons between other AEDs were not possible as a considerable amount of studies lacked power calculations or adequate data to allow further statistical analysis. Individual AED assessments indicated that levetiracetam might be one of the safest AEDs, followed by imepitoin and then phenobarbital and potassium bromide; these findings were all supported by a strong level of evidence. The safety profile in other AEDs was variable, but weak evidence was found to permit firm conclusions or to compare their safety to other AEDs.ConclusionsThis systematic review provides objective evaluation of the most commonly used AEDs’ adverse effects. Adverse effects usually appeared mild in all AEDs and subsided once doses and/or serum levels were monitored or after the AED was withdrawn. Although phenobarbital might be less safe than imepitoin and levetiracetam, there was insufficient evidence to classify it as an AED with a high risk of major adverse effects. It is important for clinicians to evaluate both AEDs’ effectiveness and safety on an individual basis before the selection of the appropriate monotherapy or adjunctive AED therapy.

Clinical evaluation of a combination therapy of imepitoin with phenobarbital in dogs with refractory idiopathic epilepsy

“…Since its introduction in 2013, imepitoin has become one of the two AEDs with the highest level of evidence for efficacy for the treatment of generalized tonic-clonic seizures, with an improved safety profile compared to phenobarbital [10, 11]. Imepitoin currently has no specific add-on therapy label for combination treatment with other AEDs.…”

Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

“…Imepitoin side effects were generally mild and short-lived, with a significant reduction in the number and severity of side effects observed after the initial 2 weeks of treatment. Ataxia, a common AED side effect [30] was mild or not present in the majority of cases, in line with recent objective evidence demonstrating reduced levels in IE patients treated with imepitoin compared to phenobarbitone [31]. A greater number of side effects were seen in dogs treated with imepitoin alongside other AEDs, which is in line with recent studies; for example, when imepitoin was used as an add-on therapy to phenobarbital, or vice versa, the number of side effects increased [32].…”

Suspected Phenobarbital‐Induced Pseudolymphoma in a Dog

“…Phenobarbital is a commonly used anti‐epileptic drug that has many known adverse reactions, both dose‐dependent and idiosyncratic. A recent systematic review of the safety of anti‐epileptics in dogs reported that over 50% of dogs receiving phenobarbital had an adverse reaction; however, these are usually mild and resolve with a lower dose or if the medication is withdrawn . The most commonly reported adverse reactions to phenobarbital are dose‐dependent (type 1) and include increased serum ALP and ALT activity, sedation, polydipsia/polyuria, ataxia, polyphagia, and chronic hepatopathy.…”

“…The most commonly reported adverse reactions to phenobarbital are dose‐dependent (type 1) and include increased serum ALP and ALT activity, sedation, polydipsia/polyuria, ataxia, polyphagia, and chronic hepatopathy. Reported idiosyncratic (type 2) reactions to phenobarbital are much less common and include blood dyscrasias, pancreatitis, necrolytic dermatitis, and dyskinesia . Due to the rare occurrence of these idiosyncratic reactions, they might go unrecognized for long periods of time.…”