Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships

The primary objective of anti-epileptic therapy is to obtain complete control of seizures while minimizing the occurrence of adverse events and improving the patient's quality of life [1]. Unfortunately, a sizeable minority (15% to 30%) of patients with partial epilepsy are unsuccessfully treated with concurrent use of up to three established anti-epileptic drugs [2‐4]. Such patients are candidates for adjunctive therapy with one of the many newer drugs available for epilepsy, which tend to be better tolerated than the commonly used first-line therapies and have a low propensity for drug-drug interactions [5]. While all of the new anti-epileptic drugs have satisfied the requirements of regulatory authorities by demonstrating superior efficacy relative to placebo without undue toxicity, lack of comparative, controlled clinical trial data precludes making a recommendation regarding their relative merits as adjunctive therapies.

Pregabalin and gabapentin, α2-δ ligands, are both licensed as adjunctive treatment for partial epilepsy, however head-to-head comparisons of their efficacy and safety have not been conducted. In the absence of direct, prospective, comparative studies to guide medical decision-making in the adjunctive treatment of partial epilepsy, alternative approaches are required to assess the relative value of a particular intervention versus other relevant comparators. In recent years, the role of meta-analysis has developed substantially in medical applications [6‐9] and is regarded as a well accepted method of generating evidence in the context of medical decision-making and cost-effectiveness modelling [10‐12]. An indirect comparison is an extension of traditional meta-analysis and includes dose-response comparisons across a range of interventions. Thus, an indirect comparison of two interventions can be made via a common comparator. In effect, an indirect comparison informs decision-makers by determining estimates of treatment effects and their statistical significance with respect to their capacity to induce an outcome of interest in the absence of direct evidence [13, 14]. Therefore, we conducted an indirect comparison to assess the clinical value of adjunctive pregabalin relative to gabapentin in the management of patients with refractory partial epilepsy, with respect to the responder rate (where response was defined as a ≥50% reduction from baseline in the number of seizures) and change from baseline in seizure-free days over the last 28 days (SFD).

Eight original research articles were identified that fulfilled the data extraction phase (Table 1). Four studies each pertained to randomized, placebo-controlled studies of pregabalin [20‐23] and gabapentin [24‐27]. All studies were Pfizer registration trials. The indirect comparisons in the base-case analysis involved 1911 patients, of which 674 received placebo, 807 received pregabalin, and 430 received gabapentin (Table 1). Table 1 also summarizes the number of patients completing each trial for pregabalin and gabapentin who were included in the sensitivity analyses. Most studies randomized an equal proportion of men and women, and most patients were white. In the gabapentin studies, the mean age range was 30 to 39 years. The median range of epilepsy duration across the studies was 17 to 23 years, and the median range for baseline seizure rate was ≥4 to 13 per 28 days. Overall, 51% to 68% of patients were on two concomitant anti-epileptic drugs and 0.3% to 3.0% were reported to be on three. The mean age range (36 to 41 years) in the pregabalin studies was narrower than in the gabapentin studies. The reported mean range of epilepsy duration across the studies was 23 to 27 years, and the median range for baseline seizure rate was 9 to 12 per 28 days. Relative to the gabapentin studies, the range for the proportion of patients on two concomitant anti-epileptic drugs was slightly lower in the pregabalin studies (48% to 51%) but the range for the proportion of patients on three concomitant anti-epileptic drugs was far higher (19% to 30%). Given also that around 1% of patients were on more than three concomitant anti-epileptic drugs in the pregabalin studies, it is conceivable that the pregabalin cohort had more severe refractory epilepsy than the gabapentin cohort.

The objective of this analysis was to utilize existing data to compare the efficacy of pregabalin and gabapentin in order to better inform healthcare decision-makers of the relative benefits of the two treatments in the current absence of direct head-to-head comparisons. A randomized, double-blind, flexible-dose trial (ClinicalTrials.gov Identifier: NCT00537940) of pregabalin versus gabapentin as adjunctive therapy in patients with partial seizures is ongoing although the results will not be available until at least 2012.

Since all trials included in this analysis were placebo-controlled, placebo was used as the common comparator. Our base-case findings, based on ITT LOCF analysis, were that 12 weeks of mid- and high-dosage pregabalin was more efficacious than corresponding dosages of gabapentin in terms of responder rates, and that all dose levels of pregabalin were more efficacious than corresponding dosages of gabapentin in terms of SFD. A sensitivity analysis of responder rates in the completer population confirmed the benefit of mid- and high-dose pregabalin, respectively, over mid- and high-dose gabapentin, although the small sample sizes meant that the comparisons were not able to detect statistically significant between-treatment differences. Nevertheless, the data generated in the base-case analysis for the comparison between high-dose pregabalin and gabapentin was reproduced in the analysis of completers, inferring that pregabalin 600 mg is twice as likely to induce a response as gabapentin 1800 mg. In the analysis of responders, the trend in favor of pregabalin remained but statistical separation between the two drugs was not detected. One possible explanation for the observed efficacy advantage in favor of mid- and high-dose, but not low-dose, pregabalin relative to corresponding doses of gabapentin, is inherent differences in the pharmacokinetic profiles of the two drugs. Unlike pregabalin, gabapentin exhibits saturable absorption at clinically relevant dosages resulting in non-linear pharmacokinetics [29‐32]. Less than dose proportional increases in gabapentin exposure are due to a saturable absorption mechanism mediated by a low capacity l-amino acid transporter found only in the upper small intestine, where gabapentin is primarily absorbed [31, 33]. As the bioavailability of gabapentin decreases proportionally as the dose is increased, it is logical that statistical separation regarding responder rates is manifested at the mid- and high-dose comparisons only.

Since the two relative efficacy estimates for pregabalin and gabapentin were based on indirect comparisons, there is a greater potential for bias than if the comparisons were based on a direct prospective, randomized controlled trial comparing the two agents. Prospective, randomized controlled trials versus placebo were included in this indirect comparative analysis although it is unlikely that randomization would have held in its entirety across the studies. As a result, there was a risk that patients assigned to the different trials were not comparable regarding certain demographics and clinical characteristics. Thus, in order to minimise any bias resulting from this risk, we included in our indirect comparison only those studies that reported and were well matched regarding baseline patient characteristics (e.g., gender, age, duration of disease, baseline seizure rate). Of note, pregabalin was demonstrated to be more efficacious than gabapentin in this analysis despite one of the pregabalin studies including patients with an extremely high baseline seizure rate (21 to 25 seizures per month) [21].

Other sources of potential bias relevant to this analysis were that the included studies used slightly different designs to measure treatment effects, and that there was a relatively large time span over which the studies were conducted and published (1990 to 2005). The use of slightly different designs to measure treatment effects is not expected to impact on the conclusions of the analysis. The timing bias is more likely to be unfavourable for pregabalin. In particular there was significant growth between 1990 and 2005 in the number of alternative add-on treatments for partial epilepsy such that if patients felt they were not adequately responding to pregabalin then they were probably more likely to switch to an alternative treatment option.

All three efficacy analyses used in this study provide useful information as to the relative merits of pregabalin and gabapentin. ITT LOCF analysis will tend to overestimate response rates to pharmacotherapies in partial epilepsy trials [17], while an ITT missing equals failure analysis on the population may provide a more representative picture of real-world practice. However, an ITT missing equals failure analysis can blur the difference between two treatments when comparing a more efficacious drug associated with a high dropout rate to a less efficacious drug associated with a low dropout rate. While all three analyses showed that pregabalin was numerically more efficacious than gabapentin, the statistically significant differences in response rate for pregabalin 300 mg versus gabapentin 1200 mg and pregabalin 600 mg versus gabapentin 1800 mg derived from the base-case analysis were not achieved in the sensitivity analyses. This observation is due in part to the reduced numbers of patients in the completer analysis and the inherent variability in the data. In addition, as there were more non-completers in the placebo arm of pregabalin than gabapentin studies, the higher non-completer rate among pregabalin than gabapentin recipients may suggest that study conditions (rather than the treatments) played a role in premature patient withdrawal. One reason for the higher proportion of non-completers in the pregabalin than gabapentin trials may have been the short titration period used to achieve target pregabalin dose levels (which was one week or less in two studies and absent in the other two studies). In this regard, the sensitivity analysis may not reflect current use of pregabalin. As the pregabalin studies were conducted more recently than the gabapentin studies, another reason for the higher drop-out rates observed in the placebo arm of the pregabalin studies could be the greater availability of alternative treatment options, as discussed above.

The results generated by this analysis are consistent with findings from two meta-analyses of randomized, controlled double-blind trials, in which adjunctive pregabalin (RR 3.56; 95% CI 2.60 to 4.87; n = 1397) and adjunctive gabapentin (OR 1.93; 95% CI 1.37 to 2.71, n = 997) were significantly more likely than placebo to provide a ≥50% reduction in baseline seizures in patients with treatment-resistant partial epilepsy [34, 35]. Consistent with our indirect comparison, these meta-analyses revealed that response rates increased with pregabalin dose (from 150 to 600 mg/day) and gabapentin dose (600 to 1800 mg/day), showing no evidence of an effect plateau at the doses tested [34, 35]. Based partly on the conclusions reached by these systematic reviews [9, 34, 35], current epilepsy treatment guidelines recommend that partial epilepsy refractory to up to three anti-epileptic agents be adjunctively treated with pregabalin [5].

The current analysis demonstrates that pregabalin, administered twice or three times daily for up to 12 weeks, is likely to be a more efficacious adjunctive treatment for partial epilepsy than gabapentin three times daily. Although an indirect comparison has certain inherent limitations, we believe that the performed analysis has relevancy for clinical decision-making in the treatment of partial epilepsy, in particular until the results of the direct head-to-head comparison become available.