New onset geriatric epilepsy. A randomized study of gabapentin, lamotrigine and carbamazepine
Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, et al.;
Commented by , 16 Jun 2005
Background
There is a paucity of controlled trials addressing the best treatment for newly diagnosed epilepsy in the elderly.
Aim
To compare the relative efficacy and tolerability of carbamazepine, gabapentin and lamotrigine in patients with epilepsy.
Methods
- A prospective, randomized, double-blind, double-dummy controlled trial.
- The study included 593 patients aged 60 or older, newly diagnosed with epileptic seizures (mostly partial, at least one seizure in the previous 3 months), and previously untreated or undertreated.
- Patients received carbamazepine (titrated from 200 to 600 mg/day over 4 weeks), lamotrigine (from 25 to 150 mg/day over 5 weeks) and gabapentin (from 300 to 1500 mg/day over 12 days). Carbamazepine and gabapentin were given t.i.d. and lamotrigine b.i.d. Dosages could be adjusted based on clinical response.
- Primary endpoint was retention in the trial for 12 months.
Results
Early terminations were significantly more common with carbamazepine (64%) than with gabapentin (51%) or lamotrigine (44%).
Differences in retention were ascribed to different rates of adverse drug reactions rather than differences in efficacy. There were no significant differences in seizure-free rates at 12 months.
Hypersensitivity reactions and hyponatremia were more common with carbamazepine. Weight gain and water retention were more common with gabapentin.
Professor Perucca's comments
This is the largest randomized trial ever performed in elderly seizure patients, and most likely it will have a major influence on clinical practice, particularly in the U.S.
The authors conclude that "patients taking lamotrigine or gabapentin do better than those taking carbamazepine" because they experience fewer adverse effects. For lamotrigine, a similar conclusion had been reached in a previous smaller double-blind trial in the UK (ref. 1).
This study has several positive features:
- A large sample size and rigorous methodology (randomized, double-blind), minimizing assessment bias
- A relatively long observation period (12 months), during which dose adjustments were permitted
- Carbamazepine and gabapentin were given t.i.d, unlike the U.K. study where b.i.d dosing in both treatment arms placed carbamazepine ad disadvantage in the comparison.
There were, however, a number of shortcomings to be considered:
- The term "newly diagnosed epilepsy" was not clearly defined and patients could enter the study after one seizure, which may argue against a solid diagnosis of epilepsy. Patients who had one seizure are less likely to have recurrences, possibly resulting in reduced power to discriminate between a more and a less efficacious drug.
- Almost one-half (43%) of the patients had been treated previously, mostly with phenytoin at concentrations in the low range. This could have led to a selection bias, possibly excluding those patients who respond particularly well to a drug with a pharmacological profile similar to that of phenytoin (e.g., carbamazepine);
- Despite the authors’ claims to the contrary, titration rates were relatively fast and target dosages relatively high (in the UK study, the median effective daily dosages were 400 mg for carbamazepine and 100 mg for lamotrigine). Use of unnecessarily high dosages may have biased the assessment of comparative tolerability.
- Carbamazepine was used as an immediate release formulation, which may be less tolerated than the sustained release form. In fact, a recently completed 40-week European randomized double-blind trial in 184 elderly patients failed to identify differences in retention between sustained release carbamazepine (target dose 400 mg/day) and lamotrigine (target dose 100 mg/day) (67% vs 73% retention, respectively) (ref. 2).
- Most patients were men and many were not very old (mean age was 72), which may limit generalization of these findings.
Conducting clinical trials in the elderly is no easy task, and the VA group has to be commended for a most valuable effort. However, it is regrettable that some of the above shortcomings were not addressed in the planning stage of the study.
References
1. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res. 1999; 37; 81-7
2. Saetre E, Perucca E, Isojärvi J, Gjerstad L, on behalf of the LAM 40089 Study Group. An international multicenter double-blind randomised comparative trial of lamotrigine and slow release carbamazepine in elderly patients with newly diagnosed epilepsy. To be presented at the Annual Meeting of the American Epilepsy Society, Washington DC, December 2005