Aminopyridines for symptomatic treatment in multiple sclerosis: Cochrane systematic review

Abstract

Background

The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase nerve conduction in demyelinated nerve fibers, and have been proposed as a symptomatic therapy for people with multiple sclerosis (MS).

Objectives

To determine the efficacy and safety of aminopyridines for neurological deficits in adults with MS.

Search methods

We searched the Cochrane MS Group trials register (December 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (January 1966 to December 2004) and EMBASE (1974 to December 2004). We hand searched bibliographic references from retrieved studies and recent MS symposia reports, and contacted known studies' investigators.

Selection criteria

We included trials fulfilling all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints.

Data collection and analysis

Three reviewers independently extracted data and assessed trial quality from 17 full-paper studies.

Main results

Six studies (eight publications, 198 participants, all crossover trials) were considered. Five studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. Treatment duration ranged from hours to six months. Median quality score of the studies was three.

Of the 198 treated participants, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures.
Three studies (54 participants) assessed manual muscle testing, with 29 participants (54%) improving in at least one muscular district during study treatment versus four participants (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7 to 43.7). Nine out of 54 participants (17%) improved in ambulation during study treatment versus none during placebo (p < 0.001). A lower Expanded Disability Status Scale (EDSS) score was found in 13/198 participants during study treatment (7%) versus none during placebo (p < 0.001). No improvement in neuropsychological tests was found in three trials assessing cognitive function. Finally, 47/136 adults with MS (35%) felt better when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3 to 22.0).

Authors' conclusions

Currently available information allows no unbiased statement about safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs (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.

Author(s)

Solari Alessandra, Uitdehaag Bernard MJ, Giuliani Giorgio, Pucci Eugenio, Taus Cristiana

Summary

The effect of aminopyridine for the treatment of several symptoms in people with multiple sclerosis

Multiple sclerosis (MS) is a disease that affects young and middle-aged adults, causing different symptoms in individuals. It is caused by damage to the myelin sheaths (fibres that wrap around and protect the nerves and spinal cord). Potassium (a mineral) is important for nerve function, but may become too active when there is not enough myelin. Potassium blocking drugs (4-aminopyridine AP, and 3,4-daminopyridine DAP) may be able to improve nerve function in nerves without enough myelin. However, the review of trials found there is not enough evidence about the safety of these drugs or whether benefits are certain.

Reviewer's Conclusions

Implications for practice

This review cannot provide a reliable statement concerning the efficacy of AP or DAP for treating symptoms of people with MS. A conclusion on the safety of these preparations is even more problematic due to the limited power of the current systematic review to reliably detect major adverse events, and to the low external validity of the results (narrow entry criteria).

Implications for research

There is a clear need to make available to the scientific community the results of unpublished trials on safety and efficacy of the aminopyridines in people with MS. We do not therefore conclude that more trials are needed in this area, but that these studies should be published.

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