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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 16: 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, N=12; Potter et al. 1998, N=29; Cardenas et al. 2007, N=71).  Only Potter et al. (1998), using a sustained-release formulation of 4-AP (Fampridine-SR) reported a statistically significant reduction in spasticity as measured by the Ashworth (p<0.05, McNemar’s 2-tailed test).  Cardenas et al. (2007), also using Fampridine-SR, relied on the Ashworth and a Patient Diary Questionnaire (primary outcome measure covering 4 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 vs. placebo. A post hoc subgroup 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 3 group comparison (40 vs. mg bid. vs. placebo) did not result in significant differences (p <0.04).  A fourth study using intravenous administration of 4-aminopyridine showed marked spasticity improvement in 2 of 6 subjects (Hayes et al. 1994).  A subsequent intravenous administration, study (Donovan et al. 2000) concluded that this mode of administration is not optimal based on the observation of no short term benefits.  The remaining 2 pre-post studies, also not specifically designed to study spasticity alone, present only minimal evidence for the anti-spasmodic effects of 4-AP.  Phase 3 clinical trial results of Fampridine-SR in chronic SCI with spasticity as the primary outcome are yet to be published. It is important to note that although statistically significant reductions in spasticity was reported in 2 RCTs using validated outcome measures to study the effects of 4-AP, neither trial was specifically designed with spasticity as the primary outcome under study.  Additional studies did not further strengthen the evidence or did so minimally.

Conclusions

Limited level 1a evidence based on two RCTs in favour of the anti-spasmodic effects of a sustained-release formulation (Fampridine-SR) of 4-AP is tempered by a negative finding from a single RCT involving IV administration. Study results must be interpreted with caution given that spasticity results were secondary outcomes of the studies.  Phase 3 clinical trial results of Fampridine-SR effects on spasticity, as the primary outcome, in chronic SCI are yet to be published.

  • The usefulness of 4-Aminopyridine in the treatment of SCI spasticity requires confirmation through additional well-designed studies.