Randomized Double-Blind Crossover Trial of Fampridine-SR (Sustained Release 4-Aminopyridine) in Patients With Incomplete Spinal Cord Injury

Abstract

A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 < 0.05) and quality of life scores (p2 < 0.01). Sensory scores (p1 < 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 < 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 < 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.

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

“…The lack of quantitative gait improvement contradicts studies that reported gait improvement of subjects. 8,12 This discrepancy between perceived changes in function and a lack of quantitative changes was also seen in the present trial and may be due to several issues. Positive comments from subjects may be attributed to a Hawthorne effect, high expectations 12 or differences in the definition of improvement.…”

“…8,12 This discrepancy between perceived changes in function and a lack of quantitative changes was also seen in the present trial and may be due to several issues. Positive comments from subjects may be attributed to a Hawthorne effect, high expectations 12 or differences in the definition of improvement. Clinicians equate improvement with quantitative measures while subjects may perceive general positive changes due to an increase in energy level and mood.…”

“…A possible psychotropic effect has been previously reported and the authors postulated that 4-AP may have an analgesic effect similar to morphine. 12 One subject in the present study experienced an increase in a positive mood. Despite the lack of objective changes in the present trial, 50% of the subjects reported improved gait when on the 4-AP condition.…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…[329][330][331] In people with incomplete SCI a sustained-release (oral) formula of 4-AP (Fampridine) was reported to improve sensory and motor function and reduce spasticity during treatment. 332 As a result of these encouraging data, Acorda Therapeutics (New York, USA) initiated two large, multicenter clinical trials testing 4-AP in chronic SCI (8) and published results of these trials may soon become available. 204 Animal experimentation with 4-AP is ongoing, in an effort to clarify the optimal parameters of 4-AP treatment.…”

Intrathecal administration of 4-aminopyridine in chronic spinal injured patients

“…6,7 Most recently, a double-blind placebo-controlled study of a sustainedrelease 4-AP formulation in chronic incomplete SCI patients has demonstrated signi®cant e cacy on a number of neurological measures. 8 Changes in conduction in motor pathways have also been documented electrophysiologically in man using transcranial magnetic stimulation. 9 Together with a longer series of equivalent trials in multiple sclerosis, 10 ± 12 these studies indicate that 4-AP may be useful in the treatment of conduction de®cits in demyelinating conditions.…”