Anthony G. Marson MD, MRCP*
David W. Chadwick MD**
* Lecturer in Neurology, Department of Neurological Science, University of Liverpool; and Senior Registrar, The Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
** Professor of Neurology, Department of Neurological Science, University of Liverpool; and Consultant Neurologist, The Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
Gabapentin is one of the newer antiepileptic drugs, which was licensed for use in the United Kingdom and the United States in 1993. The previous chapters in this section outline our current knowledge of the mechanisms of action and the pharmacokinetic properties of gabapentin. In this chapter, we summarize our current knowledge about the clinical effects of gabapentin and hence the evidence that informs its clinical use. Given that randomized controlled trials are the most reliable method for assessing the effects of treatments (1,2), the focus of this chapter is on the results of randomized controlled trials.
At present, antiepileptic drugs are investigated first of all in drug-refractory populations (3), most of whom have localization-related (partial) epilepsy. Once an effect is demonstrated, the new drug may then be tested as monotherapy in a less refractory or drug-naive population. In this chapter, we follow the development of gabapentin and outline evidence about its effect as an add-on treatment before discussing evidence for its effect as monotherapy.
Drug-Refractory Localization-Related Seizures
The effect of gabapentin on seizure frequency in patients with drug-resistant localization-related seizures was investigated in six randomized placebo controlled trials (4, 5, 6, 7, 8,9), one of which recruited children (4), with the remainder recruiting adults. For the trial recruiting children, 85% of the participants had localization-related seizures and 15% had generalized seizures, and the data from this trial are discussed here. A systematic review and meta-analysis of these trials have been reported (10,11). The primary outcome of this systematic review was whether patients had a 50% or greater reduction in seizure frequency during the treatment phase of the trial compared with a prerandomization baseline phase. One of the six trials (5) did not have a baseline phase and could not contribute to the meta-analysis. The remaining trials recruited 750 adults and 247 children and had treatment phases ranging from 12 to 14 weeks (Table 30.1). In the adult trials overall, patients were allocated to doses of 600, 900, 1200 or 1,800 mg/day, whereas in the trial recruiting children, doses ranging from 600 to 1,800 mg/day were taken depending on weight.
Ignoring dose, the overall relative risk (95% confidence intervals) for a ≥50% reduction in seizure frequency was 1.81 (1.32 - 2.49), a finding indicating a statistically significant effect of gabapentin. Data from the adult studies were used in regression models for dose, and they showed increasing effect with increasing dose (Table 30.2). At 1,800 mg/day, 28.5% of patients had a ≥50% reduction in seizure frequency, a finding indicating that approximately seven patients would need to be treated to see one with a 50% response. Regression models show no plateau of effect at the doses tested, and it could be that higher doses would show a greater effect.
As a global outcome measure, this systematic review reported the proportion of patients who had treatment withdrawn during the course of the trial. The relative risk of treatment withdrawal for gabapentin compared with placebo was 1.04 (0.71 to 1.52), indicating no significant effect, although the confidence intervals are wide. This systematic review also reported side effects, and the following were significantly associated with gabapentin (relative risk 99% confidence intervals), dizziness 2.19 (1.24 to 3.89), fatigue 2.30 (1.11 to 4.75), somnolence 1.91 (1.20 to 3.05).
The effect of add-on gabapentin on cognition in patients with localization-related seizures was reported in one crossover trial (5). No effect on cognition was found, although the trial was small and lacked the power to detect
potentially important effects because only 28 patients were randomized.
TABLE 30.1. TRIALS CONTRIBUTING TO THE METAANALYSIS
The effect of gabapentin on drug-refractory generalized seizures was investigated in one randomized controlled trial (12). This trial had a treatment period of 14 weeks, and the published report gives data for 71 patients who were randomized to placebo and for 58 who were randomized to gabapentin. There was a nonsignificant trend in favor of gabapentin for the outcome ≥50% reduction in the frequency of generalized tonic clonic seizures, with 17.5% of the placebo group and 27.5% of the gabapentin group achieving this outcome. There was no clear trend for absence or myoclonic seizures.
There is clear evidence that gabapentin reduces seizure frequency and appears well tolerated when it is used as an add-on treatment for patients with localization-related seizures. The maximum dose tested was 1,800 mg, but given that no plateau of therapeutic effect was seen at doses tested, it is likely that higher doses would show a greater effect. There is insufficient evidence to support the use of gabapentin as an add-on treatment for patients with generalized seizures.
TABLE 30.2. RESULTS OF REGRESSION MODELS FOR DOSE IN METAANALYSIS
The evidence discussed so far was generated primarily by or in collaboration with the pharmaceutical industry, with the primary objective being to meet the requirements of regulatory authorities rather than to inform clinical practice. As a result, the evidence reviewed so far has certain important limitations, which need to be borne in mind when one tries to use this evidence to inform clinical practice.
First, these trials are all placebo-controlled trials. The clinician, however, has numerous drugs to choose from and needs to know how gabapentin compares with other drugs such as lamotrigine or topiramate rather than placebo. This issue will need to be addressed in head-to-head randomized controlled trials. Second, epilepsy is a chronic condition, and trials of 12 to 14 weeks' duration are too short to inform us of the longer-term effects of antiepileptic drugs. Third, outcomes such as percentage reduction in seizure frequency and ≥50% reduction in seizure frequency have little clinical meaning and are difficult to put into context at the bedside. In view of these and other difficulties, there is a clear need for more evidence about the effects of gabapentin add-on therapy from trials that both reflect and inform clinical practice.
Gabapentin was compared with carbamazepine in one randomized controlled trial that recruited patients with newly diagnosed localization-related seizures (13). This study was undertaken with the purpose of demonstrating an effect for the purpose of pursuing a possible monotherapy license. This trial had a treatment phase of 24 weeks' duration, with 74 patients allocated to 600 mg of carbamazepine per day
and 72, 72, and 74 patients allocated to 300 mg, 600 mg, and 1,800 mg of gabapentin per day, respectively. Two main outcomes were reported, the first of which was “time to trial exit.” Patients could exit the trial if they experience one tonic-clonic seizure, three simple or complex partial seizures, or status epilepticus or if they developed a new seizure type necessitating drug withdrawal. For this outcome, patients taking 900 and 1,800 mg gabapentin had significantly longer times to exit than patients taking 300 mg gabapentin. However, no difference was found between 900 or 1,800 mg of gabapentin and 600 mg of carbamazepine, although the trend was in favor of carbamazepine. The second outcome combined time to exit as stated earlier with time to treatment withdrawal resulting from adverse effects. For this outcome, no significant differences were found, although the trend was in favor of 900 mg of gabapentin. The authors reported the difference in the proportion of patients not exiting the trial for individual doses of gabapentin compared with carbamazepine. For this second outcome, there were estimated to be 9.6% more patients staying on 900 mg gabapentin than 600 mg of carbamazepine. The 95% confidence intervals were -6.5% to 26%. Although these confidence intervals do not indicate a significant difference, the lower confidence interval indicates that gabapentin is not more that 6.5% worse for this outcome, and this would be in keeping with the concept of noninferiority (14). This finding must be treated with caution, however, given that numerous comparisons have been made, and this observation could be a chance effect.
One randomized controlled trial was reported in which the effect of gabapentin monotherapy was investigated in a population with refractory localization-related seizures (15). In this trial, patients taking one or two antiepileptic drugs and experiencing a minimum of four seizures during an 8-week prospective baseline period were randomized to 600 mg (94 patients), 1,200 mg (90 patients), or 2,400 mg (91 patients) of gabapentin per day. There was no standard comparator (e.g., carbamazepine) in this trial, and the primary aim was to demonstrate an increase in effect with increasing dose of gabapentin monotherapy. The treatment period was of 26 weeks' duration. In the first 10 weeks, gabapentin was added, and an attempt was made to convert to gabapentin monotherapy. The primary outcome in this trial was time to exit, in which patients could exit the trial if they had status epilepticus or met certain criteria for worsening of seizure frequency or intensity. This trial found no difference among doses for this outcome, with median times to exit of 77, 81, and 75 days for 600, 1,200, and 2,400 mg/day, respectively. Because there was no standard comparator, this trial provides no evidence of how gabapentin monotherapy compares with a standard alternative. Given that no dose effect was found, this trial provides no evidence to support an effect of gabapentin monotherapy.
A third monotherapy study was reported (16), which used the “surgical paradigm.” This trial recruited patients who had had their antiepileptic drugs withdrawn while they were undergoing seizure monitoring with a view to epilepsy surgery. Patients were allocated to 300 mg (42 patients) or 3,600 mg (40 patients) of gabapentin per day, with a treatment period of 8 days. The primary outcome was time to study exit measured in hours, in which exit criteria included a single tonic-clonic seizure, four simple or complex partial seizures, and status epilepticus. Time to exit was significantly longer (p = .001) for patients allocated to 3,600 mg gabapentin. Although this trial provides evidence of an effect of gabapentin monotherapy, it does not reflect and does little to inform clinical practice.
The only reported trials of gabapentin monotherapy in patients with generalized seizures recruited children presenting with childhood absence epilepsy. Trudeau and colleagues (17) report combined data from two identical trials in which gabapentin monotherapy was compared with placebo. The trials had a treatment phase of 2 weeks' duration, and 15 patients were randomized to gabapentin and 18 to placebo. The primary outcome was the reduction in seizure frequency at the end of the treatment period compared with the prerandomization baseline period. Seizure frequency was assessed using ambulatory electroencephalographic monitoring, with patients monitored for 24 hour before randomization and at the end of the treatment period. No significant difference between gabapentin and placebo was found, and hence there is no evidence to support the use of gabapentin in the treatment of absence seizures.
There is no evidence from randomized controlled trials to support an effect of gabapentin in patients with generalized seizures. There is some evidence from two trials of an effect of gabapentin monotherapy against localization-related seizures; however, one of these trials does not inform clinical practice (16). In the second trial (13), some evidence of a dose effect for gabapentin was found, although compared with carbamazepine, no significant advantage was found for any of the doses of gabapentin tested. Confidence limits for 900 mg of gabapentin would be consistent with noninferiority. Given that this was not seen for 1,800 mg of gabapentin and that this observation could be a chance effect, this trial does not provide any strong evidence that would support the use of gabapentin monotherapy in patients with localization-related seizures. From the perspective of informing clinical practice, this trial has other limitations. In particular it is of relatively short duration (24 weeks), and the outcomes (time to exit) do not reflect outcomes of importance in every day practice, such as time to 12-month remission.
IMPLICATIONS FOR RESEARCH
Clearly, many questions relating to the clinical effects of gabapentin, both as monotherapy and as add-on therapy, remain unanswered. What evidence there is has been generated by or in collaboration with the pharmaceutical industry, with the primary aim of meeting the requirements of regulatory authorities, rather that to inform clinical practice. There is a clear need for further pragmatic randomized controlled trials of gabapentin as well as other newer antiepileptic drugs. Such trials should both reflect and inform clinical practice and should use outcomes of importance to both patients and clinicians. One such trial is under way in the United Kingdom (18) and compares monotherapy with gabapentin, lamotrigine, oxcarbazepine, topiramate, carbamazepine, and valproate.