Aminopyridines for symptomatic treatment in multiple sclerosis.
BACKGROUND
Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS).


OBJECTIVE
To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS.


METHODS
Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies.


METHODS
Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints.


METHODS
We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers.


RESULTS
Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0).


CONCLUSIONS
Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.
Solari
A
A
Laboratory of Epidemiology, National Neurological Institute Carlo Besta, Via Celoria 11, Milan, Italy, 20133. solari@istituto-besta.it
Uitdehaag
B
B
Giuliani
G
G
Pucci
E
E
Taus
C
C
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000077770:Amifampridine; D018592:Cross-Over Studies; D006801:Humans; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy*; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D000077770:Amifampridine