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Fampridine (4-Aminopyridine)

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Beginning in 1993, anecdotal reports emerged on the antispasmodic effects of a new class of K+ channel blocking drug, 4-aminopyridine (4-AP, immediate release oral and IV; Hansebout et al. 1993; Hayes et al. 1994; Potter et al. 1998a; Segal et al. 1999). This drug, with a putative mechanism of overcoming conduction deficit associated with demyelination, has potential wide-ranging effects within the CNS and there is some evidence of its use to enhance walking ability in persons with MS (Hayes 2007).

Table 21: Summary of 4-Aminopyridine Studies for Reducing Spasticity

Discussion

Three randomized, placebo-controlled trials for 4-Aminopyridine all employed the Ashworth measure of spasticity but none of the studies were specifically designed to study spasticity (Donovan et al. 2000; Potter et al. 1998a; Cardenas et al. 2007). Using a sustained-release formulation of 4-AP (Fampridine-SR), only Potter et al. (1998a) reported a statistically significant reduction in spasticity as measured by the Ashworth (p<0.05, McNemar’s two-tailed test). Cardenas et al. (2007), also using Fampridine-SR, relied on the Ashworth and a Patient Diary Questionnaire (primary outcome measure covering four functional domains including spasticity and overall patient reported health status). A Subject Global Impression quality of life rating was used to confirm any benefits detected with the functional measures and resulted in a significant difference (p<0.02) in favour of 25 mg BID treatment versus placebo. A post-hoc sub-group analysis of subjects with more marked spasticity at baseline resulted in a significant treatment (25 mg BID) related improvement in spasticity (p<0.25) compared to placebo treatment. The three group comparison (25 mg versus 40 mg bid versus placebo) did not result in significant differences (p<0.04). The third RCT used intravenous administration (Donovan et al. 2000) and concluded that this mode of administration is not optimal based on the observation of no short-term benefits; however, a fourth study using intravenous administration of 4-aminopyridine in a pre-post study design showed marked spasticity improvement in two of six subjects (Hayes et al. 1994). While Hayes et al. (1994) and Potter et al. (1998b) present evidence for the anti-spasmodic effects of 4-AP, their contribution is mnimized gien these pre-post studies were not specifically designed to study spasticity alone.

Just one phase three clinical trial of Fampridine-SR (25 mg BID) was studied by Cardenas et al. (2014) among individuals with chronic SCI with moderate to severe spasticity as the primary outcome and reported no significant differences between groups.

Conclusions

There is level 1a evidence (from two large-scale RCTs; Cardenas et al. 2014; Cardenas et al. 2007) that indicate no significant anti-spasmodic effects of Fampridine-SR compared to placebo; however, this is tempered by positive findings from level 1b evidence (from one small RCT and one pre-post study; Potter et al. 1998a; Potter et al. 1998b) on the beneficial anti-spasmodic effects of Fampridine-SR. Study results must be interpreted with caution given that spasticity results were secondary outcomes of all studies except the phase 3 clinical trial results from Cardenas et al. (2007).

There is conflicting level 1b evidence (from one RCT and one pre-post study; Donovan et al. 2000; Hayes et al. 1994) that intravenous administration of Fampridine has no significant anti-spasmodic effect. Study results must be interpreted with caution given that spasticity results were secondary outcomes of the studies.

  • Fampridine-SR is not significantly efficacious for the treatment of spasticity in chronic SCI.Intravenous Fampridine is not significantly efficacious for the treatment of spasticity in chronic SCI.