Best evidence for choosing anti-epileptic drugs in the older adult

By | January 11, 2015

There are few trials to support the choice of one medication for all older patients with epilepsy. However, some comparative head-to-head trials of anti-epileptic drugs in older adults have been conducted. Craig and colleagues compared valproic acid with phenytoin. A total of 166 patients over the age of 65 with adult-onset seizures were randomized to either valproic acid or phenytoin. The median age of patients was 78 years. The investigators found that 78% of valproic acid patients and 76% of phenytoin patients were seizure free at 6 months. Moreover, there were no cognitive differences that were noted between the two anti-epileptic drugs. This study was important in that this was one of the first trials to study older adult patients in a comparative, randomized trial. It was also the first trial to suggest that alternative agents other than phenytoin can be used as first-line therapy in older patients.

Recently, a VA Cooperative geriatric epilepsy study was completed. Rowan and colleagues evaluated the tolerability and efficacy of gabapentin and lamotrigine vs. carbamazepine in older adult patients. They randomized 593 individuals of age 60 years and older in a double-blind, double-placebo parallel study in patients with newly diagnosed seizures. Patients were assigned to one of the three treatment groups: gabapentin 1500 mg per day, lamotrigine 150 mg per day and carbamazepine 600 mg per day. The primary outcome measure was retention in the trial for a 12-month period. The mean age of their patients was 72 years, with individuals taking an average of seven co-medications. They reported early terminations of lamotrigine (44%), gabapentin (51%) and carbamazepine (64%). Terminations for adverse events included 12% for lamotrigine, 21% for gabapentin and 31% for carbamazepine. There were no significant differences in seizure-free rates at 12 months. The authors concluded that the main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine or gabapentin did better than those taking carbamazepine. They recommended that lamotrigine and gabapentin should be considered as initial therapy for older patients with newly diagnosed epilepsy. Similarly, Brodie and colleagues compared carbamazepine with lamotrigine in older adults and found that lamotrigine was equivalent in efficacy and better tolerated than carbamazepine. Other than these two studies, there are no randomized controlled trials (RCTs) evaluating anti-epileptic drugs in older adults.

Table Risks / benefits of specific epilepsy therapies in the older adult

Therapy Benefits Risks
Carbamazepine Efficacy Hyponatraemia, potential drug interactions, osteoporosis
Felbamate Efficacy, lack of impact on cognition, alerting effect Weight loss, risk of aplastic anaemia and hepatic failure, drug interactions, multiple daily doses
Gabapentin Limited drug interactions, multiple indications, minimal cognitive impact Limited efficacy, multiple daily doses
Lamotrigine Limited drug interactions, minimal cognitive impact, efficacy Rash potential, insomnia
Levetiracetam Limited drug interactions, minimal cognitive impact, efficacy Exacerbates depression, insomnia
Oxcarbazepine Efficacy Hyponatraemia, dizziness
Phenytoin Efficacy, once-daily dosing Imbalance, multiple drug interactions, risk of cognitive impairment, osteoporosis, potential for toxicity from zero-order kinetics, variable absorption in the very old
Phenobarbital Efficacy, once-daily dosing Sedation, cognitive impairment, depression, osteoporosis
Pregabalin Minimal drug interactions, multiple indications Limited efficacy, multiple daily dose, peripheral oedema
Surgery Potentially curative Serious surgical risks, including infection, haemorrhage, cognitive complaints
Tiagabine Minimal drug interactions Limited efficacy, multiple daily doses
Topiramate Efficacy, migraine treatment, paucity of drug interactions Cognitive complaints, glaucoma, nephrolithiasis, weight loss
Zonisamide Efficacy, once-daily dose, paucity of drug interactions Nephrolithiasis, weight loss
Vagus nerve stimulation Compliance assured, approved for depression Surgical risk, limited efficacy
Valproic acid Efficacy, migraine treatment Tremor

Despite the paucity of RCT evidence, there appears to be an emerging consensus regarding general principles of anti-epileptic drug use in older adults. Table Risks / benefits of specific epilepsy therapies in the older adult shows risk and benefits for various anti-epileptic drugs. Older adults tend to respond at lower doses than younger ones. It is important that one initiates anti-epileptic drugs at lower doses than one would for a younger adult. It is also important to simplify dosing regimens to accentuate compliance. If a patient reports an adverse event, it is important to listen to that patient and try to provide supportive care by identifying the offending agent. It is essential to always determine the overall need for each medication. One must not be afraid to adjust or discontinue medications. Anti-epileptic drug formulations, including extended-release preparations and agents with longer half-lives, may be of particular benefit in older adults due to the minimal number of daily doses that are required. Extended-release formulations can also be useful in decreasing peak-related adverse effects and improving efficacy with higher blood levels. Some older adults have dysphagia so variable formulations such as sprinkles, liquids and parenterals can be utilized and may be beneficial in these individuals who have difficulty with swallowing.

Selections from the book: “Therapeutic Strategies in Epilepsy” (2008)