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

Author Year
Country
Score
Research Design
Total Sample Size

Methods

Outcome

Cardenas et al. 2014
US and Canada
RCT
PEDro=6
Study SCI-F301 N=213
Study SCI-F302 N=204

Population: Patients 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 patient populations were balanced at baseline rendering comparability of patient 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. Patients 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 treatment groups, patients were further stratified by concomitant antispasmodic medication within the two treatment 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 patients who received famipridine-SR demonstrated greater improvements in spasticity, though differences between treatment 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.

 

Effect Sizes

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: Patient 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: Patients 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.
Effect Sizes

 

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 patient 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 patients 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.
 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).

Neurophysiological Results;

  1. MEPs increased in amplitude (n=1).
  2. Ankle hypertonicity reduced (n=1).

Pharmacokinetics and Adverse Events:

  1. 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.
  2. 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, patients 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 patients 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).

Note: AIS=ASIA Impairement Scale; BP=blood pressure; CSF=cerebrospinal fluid; FIM=Functional Independence Scale; IV=intraveneous; LE=lower extremity; UE=upper extremity

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