Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease

Andrea Diana, Rita Pillai, Paolo Bongioanni, Aidan G O'Keeffe, Robert G Miller, Dan H Moore

Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS. To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions. On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries. Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies. We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low. According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.