Fampridine (4-Aminopyridine)
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).
| Author Year
Country Score |
Methods | Outcome |
| Cardenas et al. 2014
US and Canada RCT PEDro=6 Study SCI-F301 N=213 Study SCI-F302 N=204 |
Population: Individuals with incomplete chronic SCI from two identical double-blinded, placebo-controlled studies (SCI-F301 and SCI-F302), from 45 and 33 centres, respectively, in the US and Canada. Both individual populations were balanced at baseline rendering comparability of individual populations. SCI-F301: Placebo (n=98): Mean age: 40.1 yr; Gender: males=85, females=13. Fampridine-SR (n=114): Mean age: 41.6 yr, Gender: males=100, females=14. SCI-F301: Placebo (n=100): Mean age: 40.5 yr. Fampridine-SR (n=103): Mean age: 41.3 yr. Intervention. Individuals were randomly assigned to either fampridine-SR 25 mg or placebo, twice daily for 2 wk in addition to a 2 wk titration, 12 wk of stable dosing, 2 wk of downward titration and 2 wk of untreated follow-up. Within intervention groups, individuals were further stratified by concomitant antispasmodic medication within the two intervention groups. Outcome Measures: Ashworth Spasticity Scale (AS) scores for bilateral knee flexors and extensors, Subject Global Impression (SGI), Penn Spasm Frequency Scale (SFS), International Index of Erectile Function (IIEF), Bowel and Bladder assessments, Sexual function. |
1. Results from both studies showed that individuals who received famipridine-SR demonstrated greater improvements in spasticity, though differences between intervention groups in change from baseline for both primary endpoints were small and not statistically significant in both studies (Spasticity: p=0.439 for SCI-F301 and p=0.069 for SCI-F302; SGI: p=0.623 for SCI-F301 and p=0.310 for CI-F302). 2. The only statistically significant difference between treatments was on the Upper Extremity subscale in SCI-F302There were no significant between-group differences observed for bladder and bowel function in SCI-F301. The number of bowel movements was statistically significantly greater in fampridine-SR compared to placebo in SCI-F302. 3. There were no significant between-treatment differences except for an improvement among men treated with fampridine-SR on two IIEF domains, erectile function (p=0.016) and orgasmic function (p=0.032) in SCI-F301. |
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Cardenas et al. 2007 USA RCT PEDro=7 NInitial=91, NFinal=71 |
Population: Age range: 19-67 yr; Gender: males=72, females=19; Level of injury: paraplegia=18, tetraplegia=73; Level of severity: AIS C=44, AIS D=47; Time since injury range: 1-37 yr. Intervention: Group 1–Placebo; Group 2–25mg bid. Fampridine-SR; Group 3–40mg bid. Fampridine-SR. Outcome Measures: Individual Diary Questionnaire, ASIA International Standards, Ashworth Scale (AS), Spasm Frequency Scale (SFS), Tendon Reflex Scale; Subject Global Index of Global Impressions (GGI), Subject Summary Questionnaire, Safety Evaluation. |
1. Patients with an AS greater than one in Group 2 (25 mg) had a significant decrease in spasticity (p=0.02), as opposed to Group 1 (placebo). 2. ASIA Grades and GGI did not significantly improve within any group. 3. 71 (78%) of initial participants finished the study. 13/20 that dropped out were in Group 3 (40mg). 4. 18 subjects were lost due to adverse effects. The most common adverse events that occurred were hypertonia, generalized spasm, insomnia, pain, headache, constipation, dizziness and asthenia. Seizure and gastrointestinal bleeding occurred in two participants as well. |
| Donovan et al. 2000
USA RCT PEDro=9 N=12 |
Population: Injury etiology: SCI=12; Level of severity: complete, incomplete. Intervention: Drug or placebo was administered for 2 hr through an indwelling venous catheter attached to an infusion pump (4-AP reached doses of 30 to 80 ng/ml at the end of a 2 hr). Outcome Measures: Individuals were serially examined during and after infusion clinically for–Pain (McGill questionnaire), Sensorimotor function (ASIA), Hypertonicity (Ashworth scale (AS), Reflex scale), Electrophysiological measurements (Brain motor control assessment), Blood and CSF sampling. |
1. No significant differences were noted pre-post infusion between 4-AP and the placebo. No differences between the motor incomplete and the motor complete groups. 2. The intravenous route may not be the best way to administer this drug as no short-term benefits were observed. |
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Effect Sizes: Forest plot of standardized mean differences (SMD±95%C.I.) as calculated from pre- and post-intervention data.
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| Potter et al. 1998a
Canada RCT PEDro=10 N=29 |
Population: Injury etiology: SCI=29; Chronicity: chronic. Intervention: Subjects were randomized into one of two treatments and given either Fampridine-SR (12.5 mg bid to start with an increase to 17.5 mg bid) or placebo over a period of 2 wk then following a washout period they were given the alternate treatment. Outcome Measures: Motor index, Sensory index, Present pain intensity, Spasm Frequency Scale (SFS), Modified Ashworth Scale (MAS), Bowel and bladder scores, Clinical interview questionnaire, Global individual satisfaction questionnaire, Seven-point terrible delighted scale, Functional Independence Measure (FIM). |
Significant benefit of Fampridine-SR over placebo: 1. Motor scores (adjusted to only paretic segments; p<0.01). 2. Sensory scores (p<0.01), including both pin prick and light touch (p=0.059 and p=0.058). 3. Ashworth (p<0.05). 4. Patient satisfaction and quality of life scores (McNemar’s test, p<0.01 and p<0.05). 5. No statistical significance on measures of pain, bowel/ bladder/sexual function or FIM. 6. Side effects: lightheadedness and nausea–transient/trivial relative to efficacy. 7. ~30% of individuals reported a wish to continue to use. |
| Potter et al. 1998b
Canada Pre-Post N=3 |
Population: Injury etiology: traumatic SCI=3: Level of injury: cervical=3; Level of severity: incomplete=3. Intervention: Day 1-single 10 mg capsule of 4-AP followed by physical and neurophysiological examination pre-and post administration up to 24 hr. Day 4: 10mg bid to tid by Day 6, if tolerated. Tolerated dosing regimen continued for 4 mo. with prn intermittent assessments. Outcome Measures: A. Physical exam: ASIA motor and sensory classification; Modified Ashworth Scale (MAS). B. Neurophysiological exam: Motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex, quantitative assessment of ankle hypertonicity. C. Pharmacokinetics and Adverse Event monitoring. |
A. Physical Exam: 1. Improved bladder function (n=1). 2. Improved spasticity (UE n=1, LE n=2). 3. Reduced pain (n=1). 4. Improved motor function (n=3). 5. Improved gait (n=2). 6. Improved sensory function (n=1), 7. Improved penile tumescence (n=1) and a 8. Nonspecific but consistently “renewed vigour” (n=2). B. Neurophysiological Results; 9. MEPs increased in amplitude (n=1). 10. Ankle hypertonicity reduced (n=1). C. Pharmacokinetics and Adverse Events: 11. Pk: 1-1.5 h Tmax; 75.05-121.27 ng/ml Cmax; 5.21-12.61L/h CL; 139.84-306.84 /L Vss; 16.9-19.08h t1/2. 12. Wakefulness (1 case limited to bid rather than tid dosing) and transient light-headedness. |
| Hayes et al. 1994
Canada Pre-Post N=6 |
Population: Injury etiology: traumatic SCI=6; Chronicity: chronic. Intervention: Under fasting conditions, individuals received 24-25 mg 4-AP IV. Monitoring for effect pre-to 2 hr post and at 24 hr post drug administration. Outcome Measures: Neurophysiological and standard neurological examination, Adverse Event (AE). |
1. Enhanced somatosensory evoked potentials (n=3), Improved motor evoked potentials (n=4), Increased voluntary EMG interference (n=2). 2. Three of 6 individuals reported neurological benefits of the drug (n=2 for reduced spasticity; n=1 for pain; n=1 for increased sensation; n=3 for increased limb movement and n=1 for restored bowel control. 3. AE aching IV site (n=6), transient lightheadedness (n=2), mild perioral paresthesia (n=1), +20mmHg in systolic BP after 24 mg 4-AP (n=2), exacerbation of ankle phlebitis pain (n=1) and facial flushing after waking 1 day after the trial (n=1). |
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.
