DeForge et al. 2004; Canada
PEDro = 10
RCT
N=15
N SCI=11

Population: 11 subjects with SCI; Age 22-70 yrs; all subjects with diagnosis of AIS D; C3-T12 lesion level; 1-20 post-injury .
Treatment: Double-blind, placebo-controlled, crossover design; 4-Aminopyridine (4-AP): up-titration to 10 mg 4x/day stable dosing of 4-AP (n=15) versus Placebo (n=14), 2 weeks each condition
Outcome measures: Isometric muscle force, gait analysis.

1. Some positive effects for both placebo and 4-AP treatment when compared to baseline, but no changes between groups were significant.

van der Bruggen et al. 2001;
Netherlands
PEDro = 10
RCT
N=20

Population: Age 25-70 yrs; all subjects had an incomplete SCI; C2-L3 lesion level; 3-56 yrs post-injury.
Treatment: Double-blind, placebo-controlled, crossover design: up-titration to maximum of 15-45 mg, immediate-release 4-Aminopyridine capsules or Placebo, 4 weeks each condition.  2 week washout between conditions.
Outcome measure: comfortable and maximum walking speed.

1. No statistically significant, functional benefits were found.

Maric et al. 2008;
Switzerland
PEDro = 8
RCT with crossover
N = 12

Population: 12 subjects with incomplete SCI, 3 female, age 23-75, randomly divided into two groups.
Treatment: L-Dopa 200mg, and dopa decarboxylase inhibitor 50mg for 6 weeks placebo for another 6 weeks; physiotherapy for 45min 1-4hrs after L-dopa intake
Outcome Measures: ASIA motor score (AMS); Walking Index for Spinal Cord Injury II (WISCI II); Spinal Cord Independence Measure II (SCIM II).

1. The treatment group had greater improvement than control in AMS (+7.8 in treatment, vs. +6.6 in control) and SCIM (+16.6 vs. +11.7), but the difference was not significant.
2. The control showed greater average improvement than treatment group in WISCI II score (+2.9 in treatment, vs. +3.4 in control).

Walker & Harris 1993; USA
PEDro = 8
RCT
N=9

Population: Age 21-44 yrs; all subjects had an incomplete SCI; C5-L1 lesion level; 1-13 yrs post-injury
Treatment: Double-blind, placebo-controlled crossover study design: Intravenous GM-1 ganglioside (Sygen ®) or placebo + 2 hr PT (gait training) 6x/wk for 2 months, followed by switch of drug administration (total 4 months). All subjects given 6 months of PT before trial.
Outcome measures: Motor score, walking distance, and velocity.

1. GM-1 + PT resulted in increase in motor scores, walking distance, and walking velocity.

Stewart et al. 1991; Canada
PEDro = 8
RCT
N (enrolled) =12
N (completed) = 9

Population: 6 subjects with paraplegia, 3 subjects were paretic; age 19-57 yrs; AIS A-D; C7-T10 lesion level; 1-10 yrs post-injury.
Treatment: Double-blind, placebo-controlled, crossover design: Two periods of 4 weeks of medication (Clonidine (up to 0.1-0.5 mg daily) or Placebo, randomly assigned) separated by a 2 week washout period.
Outcome measures: Kinematic measures during body weight support gait, spasticity, adverse effects.

One paretic patient experienced improvement in locomotor function (progressed from non-ambulation to limited independent ambulation) resulting from Clonidine.
Clonidine did not elicit locomotor activity in the paraplegic patients, but there were reductions in stretch reactions and clonus during assisted locomotion.

Remy-Neris et al. 1999;
France
Downs & Black = 16
Prospective controlled trial
N = 11

Population: 2 males; age 26 and 23 yrs; T4-7 and C7-8 lesion level; 11 and 8 months post-injury
Treatment: 3 doses of 15-90 µg clonidine or placebo by lumbar puncture. Each injection separated by a minimum of 3 days.
Outcome measures: Spatiotemporal gait data, Ashworth scores, soleus H-reflex, and polysynaptic flexion reflexes recorded before and every hour for 4-6 hours after injection.

1. 3 of 8 ambulatory subjects had significantly greater maximum overground walking speed with clonidine. These subjects were more severely impaired and had shorter times post-injury.
2. Spasticity was significantly reduced after injection in all subjects.
3. Effects of intrathecal clonidine were dose dependent and subject-specific.

Wainberg et al 1990; Canada
Downs & Black = 10
Prospective controlled trial
N = 8

Population: 1 female, 2 wheelchair-bound; age 23-56 years; C4-T11 lesion level; 1-15 yrs post-injury
Treatment: Double-blind, placebo controlled, crossover design: Two periods of 3 weeks of medication (2-8 mg 3x daily Cyproheptadine or Placebo, randomly assigned) separated by a 1 week washout period. Four subjects continued in an open label, long term trial (>6 months)
Outcome measures: Temporal measures, EMG, joint angles, spasticity, comfortable walking speed. No statistical analysis.

1. Maximum comfortable walking speed increased in ambulatory subjects, with a decrease in cycle duration and double support duration.

Two patients that required body weight support during placebo could walk with full weight bearing during cyproheptadine therapy. Muscle coordination improved and clonus was reduced.

Segal & Brunnemann 1998; USA
Downs & Black = 14
Pre-post
N=9

Population: 9 males; age 28-60 yrs; subjects had diagnosis of AIS C-D; C2-L4 lesion level; 4-28 yrs post-injury
Treatment: 4-Aminopyridine (single 10mg immediate-release capsule).
Comparison of means at baseline and at intervals over 24-hour follow-up.
Outcome measures: Ambulation parameters.

1. Improvements in gait velocity (↑ by 36% from 24.1 ± 16.5 m/min to 32.7 ± 22.9 m/min; (p ≤ 0.04); in stride length (↑ from 0.9 ± 0.3 meters to 1.0 ± 0.3 meters, p≤ 0.02); ↑ cadence and gait cycle duration, but not significant.

Gait changes began 6 hours after drug administered and persisted the 24 hour follow-up.

Norman et al. 1998; Canada
Downs & Black = 13
Pre-post
N=12

Population: 12 males; age 19-35 yrs; subjects had diagnosis of AIS C-D; C4-T12 lesion level; 1.1-5.3 yrs post-injury
Treatment: 3 different oral tablets in order of convenience: Clonidine (≤0.25 mg/day) or Cyproheptadine (≤24 mg/day) or Baclofen (≤80mg/day): each drug trial had incremental increase to maximum dose and stable dosing over 3 weeks followed by incremental decrease from maximum dose and washout over 2 weeks.
Outcome measures: Surface EMG and kinematic gait analysis during treadmill walking. No statistical analysis.

1. 7/12 subjects had evaluations of all 3 drugs; adverse effects for 4/5 subjects prevented completion of all conditions. The greatest effects in more severely disabled subjects.

Cyprohyeptadine resulted in↓need for assistance, ↑ in maximum treadmill speed and ↓ clonus. Clonidine resulted in ↑maximal treadmill speed and a generally more upright posture. Baclofen resulted in minor changes in walking. Maximal treadmill speed increases and other changes were often retained following washout of drugs.