Lower Limb Table 18: Studies of Combined Gait Training and Pharmacological Interventions

Author Year; Country
Research Design
Sample Size
Methods Outcomes

Duffell et al. 2015




Level 1

N= 48

Population: 26 individuals in locomotor treadmill training group (LTT)- 19 males and 7 females; mean age= 46.6 ± 12.6y; years post injury= 9.3 ± 8.9y; 22 individuals in combined LTT and tizanidine group- 15 males and 7 females; mean age= 46.5 ± 11.9y; years post injury= 10.2 ± 10.4y; Level of injury 30 C and 15 T

Treatment: Participants were randomly assigned into one of two intervention groups; LTT alone (LTT; n = 26) or combined LTT and Tizanidine (TizLTT; n = 22). Participants assigned to the TizLTT group, were initially provided with Tizanidine alone for a period of 4 weeks, and results for that period have been presented elsewhere, together with the LTT group clinical outcomes. Outcomes were measured at 0, 1, 2 and 4 weeks from the start of LTT for both groups

Outcome Measures: Timed up and go (TUG), 10MWT, 6MWT, MAS, Maximum voluntary isometric contractions (MVIC), active range of motion (AROM), Peak isokinetic velocity (Vp)

  1. Both LTT and TizLTT improved in walking speed and dorsiflexion maximum strength, with no significant differences between them, using group-averaging analysis at 0, 1, 2 and 4 weeks from the start of LTT for both groups.
  2. A higher proportion of participants in the TizLTT group achieved the MID for walking speed (40%) compared with LTT alone (13%)
  3. Those that achieved the MID for walking speed were significantly higher functioning at baseline than those that did not in the TizLTT group, and the change in walking speed was associated with the change in dorsiflexion peak velocity.

Duffel et al. 2015



Level 2

N= 83

Population: 29 individuals in control group- 9 males and 10 females; mean age= 47.8 ± 13.1y; years post injury= 8.1 ± 8.1y; 27  individuals in lokomat group- 19 males and 8 females; mean age= 46.6 ± 12.6y; years post injury= 9.3 ± 8.9y; 27 individuals in tizanidine group- 19 males and 8 females; mean age= 47.4 ± 11.6y years post injury= 10.9 ± 10.8y; motor incomplete SCI, AIS C or D

Treatment: Participants were assigned to 3 groups: no intervention, Lokomat, or tizanidine. For the Lok group, locomotor training was provided using a robot-assisted locomotor training device. This device provides bodyweight- supported gait assistance. For the Tiz group, 0.03 mg/kg of tizanidine was administered 4 times a day for 4 weeks.

Outcome Measures: Timed up and go (TUG), 10MWT, 6MWT, MAS

  1. There was no difference between interventions, though overall walking speed and endurance did improve.
  2. Only a small number of participants achieved the MID. Both MID and GMM-RCR analyses revealed that tizanidine improved endurance in high-functioning participants.
  3. GMMRCR classification also showed that speed and mobility improved after locomotor training.

Leech et al. 2014


Randomized Cross Over Design

Level 2

N= 10

Population: 10 individuals; level of injury ranging from C2 to C7; months post injury= 12 – 301 months;

Treatment: Participants were involved in a double-blinded, randomized, cross-over design to assess the effects of acute pharmacological manipulation of 5HT transmission on various measures of locomotor performance. The agents used were overencapsulated, orally administered doses of a selective serotonin reuptake inhibitor (SSRI): 10 mg of escitalopramoxalate and a 5HT antagonist: 8 mg of cyproheptadin. Participants participated in 2 days of testing separated by at least 1week. Before initial locomotor testing, a licensed physical therapist assessed standardized measures of strength, spastic motor activity, and walking ability.

Outcome Measures: AIS Lower Extremity Motor Scores, Spinal Cord Assessment Tool for Spastic Reflexes, Modified Ashworth Scale, The Walking Index for Spinal Cord Injury II, EMG, O2 consumption

  1. Neither medication led to improvements in locomotion, with a significant decrease in peak overground gait speed observed after 5HT antagonists.
  2. Additionally, 5-HT medications had differential effects on EMG activity, with 5HT antagonists decreasing extensor activity and SSRIs increasing flexor activity

DeForge et al. 2004; Canada

PEDro = 10


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.
Effect Sizes

van der Bruggen et al. 2001;

The Netherlands

PEDro = 10


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.

Grijalva et al. 2010; Mexico

PEDro = 9



Population: 10 males, 4 females; mean age 29; average YPI 6.2; 8 cervical SCI, 6 thoracic

Treatment: Phase 1: protocol found in Grijalva et al., 2003

Phase 2 (3 months): Administration of 10mg/day of 4-AP the first week, 20 mg/day the second week, 30 mg/day the third week, and 10mg increase per day every 2-3 months if patients were not experiencing any adverse reactions.

Outcome Measures: AIS motor and sensory scale, SCIM, SEPs

  1. 7/12 patients who completed the second phase protocol had higher clinical scores and SEPs improvement.
  2. 3/12 patients achieved walking with the assistance of orthopaedic devices, physical therapists and trained family members.
  3. 1/12 changed from complete SCI to incomplete SCI after treatment.
  4. Two patients experienced adverse reactions severe enough to cause drop out; one of them had epileptic seizures and the other persistent anxiety and insomnia.
Effect Sizes

Maric et al. 2008;


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: AMS; WISCI 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


Population: Age 21-44 yrs; all subjects 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

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.

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

Rêmy-Néris et al. 1999;


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.

Norman et al. 1998; Canada


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.
  2. Cyprohyeptadine resulted in decreased need for assistance, an increase in maximum treadmill speed and decreased clonus. Clonidine resulted in an increase 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.


Segal and Brunnemann 1998;



Population: 9 males; age28-60 yrs; subjects had diagnosis of AIS C-D; C2-L4 lesion level; 4-28 yrs post-injury

Treatment: 4-AP (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 (increased by 36% from 24.1(16.5) m/min to 32.7 (22.9) m/min; in stride length (increased from 0.9 (0.3) meters to 1.0 (0.3) meters); increased cadence and gait cycle duration, but not significant.
  2. Gait changes began 6 hours after drug administered and persisted after the 24-hour follow-up.

Azouvi et al. 1996;


Prospective pre-post

N = 18

Population: 12 of 18 subjects with SCI (Frankel A-D); age 21-59; C4-T11 lesion level; 0.5-27 years post-injury.

Treatment: Implanted intrathecal baclofen pump. 17 patients had an electronically driven programmable pump filled with 18 cc of 500 or 2000 ug/cc baclofen delivered by continuous infusion or by intermittent bolus. One patient had a manually operated pump delivering a bolus of 50 ug. Follow up assessment was 6-72 months after implantation.

Outcome Measures: Ashworth scale, spasm frequency scores, FIM. No statistical analysis on FIM walking score.

  1. One patient’s treatment interrupted after 9 months due to severe side effects.
  2. In 5 patients, mean (SD) FIM walking score increased(3.6 (0.87) to 5.8 (0.2) at 6 months), 2 patients acquired ability to climb stairs.
  3. Ashworth scale and spasm frequency scores were significantly less at 6 months.

Wainberg et al 1990; Canada

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.
  2. 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.