Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

Abstract

Animal and human research have shown that the drug 4-aminopyridine (4-AP) may improve gait in spinal cord lesions by enhancing nerve transmission to affected muscles. Study design: Prospective, randomized, double-blind, placebo-controlled, crossover trial. Objectives: To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical gait patterns of chronic spinal cord injuries (SCI). Setting: The Rehabilitation Centre (Ottawa, Canada). Methods: In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40 mg/day, oral medication of either placebo or immediate-release, 4-AP and subsequently crossed over to the alternate medication for the following 2 weeks. Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks. Measures included dynamometer lower limb isometric muscle force and biomechanical gait measures including temporal-spatial parameters, electromyographic activation patterns, joint kinematics and kinetics. Subjective impressions of the drug by the participants were obtained from an exit survey. Results: Despite some positive comments from subjects, statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and objective gait analyses (ANOVA statistic P40.05). Conclusion: Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance gait for chronic, ambulatory SCI persons. Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations.

4-Aminopyridine Toxicity: a Case Report and Review of the Literature

“…Hematologic effects include thrombocytopenia. Posterior tibial artery vasospasm was discussed in one case and was successfully treated with oral nifedipine [20].…”

“…Unfortunately, research regarding its efficacy in SCI has been inconclusive. Although animal models and some early studies reported improvement in function and sensation, subsequent randomized, placebo-controlled studies have not demonstrated clinically significant benefits [16][17][18][19][20][21][22]. Summative interpretation of these results is difficult due to small numbers, mixed patient populations and variations in duration, dosage, and mechanism of administration.…”

No Evidence for Chronic Demyelination in Spared Axons after Spinal Cord Injury in a Mouse

“…One theory is that improvement results from blockage of potassium channels exposed on demyelinated, intact axons. However, 4-AP also potentiates synaptic transmission and skeletal muscle twitch tension (Smith et al, 2000) and human clinical trials of 4-AP in chronic SCI have been inconclusive so far where some report modest and temporary improvement on motor and sensory functions especially reduction in spasticity, whereas others do not find significant beneficial effects (Potter et al, 1998;van der Bruggen et al, 2001;Wolfe et al, 2001;DeForge et al, 2004).…”

The Ability to Walk After a Spinal Cord Injury with Emphasis on Exoskeletons: A Review

“…Literature shows that there are no benefits from the drugs Levodopa [35,42] and 4-Aminopyridine [43,44].…”