Spasticity

Tizanidine

Tizanidine is an orally-administered imadazoline-based compound that is widely used to reduce spasticity in a variety of conditions with most evidence for its effectiveness coming from trials with MS patients (Kaman et al. 2008). As an a2-adrenergic agonist it acts at both a spinal and supraspinal level.

Author Year

Country
Research Design

Score
Total Sample Size

 Methods Outcome
Chu et al. 2014

USA

RCT Crossover

PEDro=7

N=10

Population: Mean age: 48.9 yr; Gender: males=10, females=0; Level of severity: AIS C=4, AIS D=6; Mean time since injury: 138.7 mo.

Intervention: Individuals were randomly allocated to the order in which they received oral administration of baclofen (30 mg), tizanidine (4 mg), and placebo (10 mg). Assessments were done at baseline and 90 to 120 min after the administration of each drug.

Outcome Measures: Ankle stretch reflex torque, Isokinetic knee extension torque, Isometric knee extension torque.

1.     There was a significant decrease in stretch reflex torque after tizanidine (p=0.034) but not baclofen (p=0.116) compared to placebo.

2.     Peak knee flexion torque during extension decreased significantly after baclofen (p<0.001) but not after tizanidine (p=0.20) when compared to placebo.

3.     Peak knee extension torque during flexion decreased significantly after baclofen (p=0.014) and tizanidine (p<0.001) compared to placebo.

4.     No significant changes in isokinetic knee torque were shown for either drug compared to placebo (p=0.179).

5.     Knee flexion torque significantly increased after tizanidine compared to placebo (p=0.033).

6.     Compared to placebo, there was a significant increase in isometric knee extension torque for both baclofen (p<0.001) and tizanidine (p=0.001).

7.     Changes in peak torque for baclofen (p=0.066) and tizanidine (p=0.99) did not differ significantly from placebo.
Nance et al. 1994

USA/Canada

RCT

PEDro=10

N=118

Population: SCI with moderate spasticity.

Intervention: Tizanidine.

Outcome Measures: Ashworth Scale (AS) (hip adductors, knee flexors/extensors–bilateral), Pendulum, modified Klein-Bell scale (ADL), Global evaluation of antispastic efficacy, Adverse Events (AE).

1.     AS: Tizanidine produced significantly (p<0.0001) greater decreases in muscle tone from baseline to end of titration (T3), end of plateau (P2) and end point (EP) as compared with placebo.

2.     Pendulum: Tizanidine produced significantly greater decreases in the swing parameters from based to T3 (p<0.0135), P2 (p<0.0401) and EP (p<0.0038) as compared to placebo.

3.     Modified Klein-Bell showed no change from baseline in their ADL score.

4.     Global changes were larger in Tizanidine versus Placebo but were not significant between groups.

5.     AEs significantly greater in Tizanidine versus Placebo (p=0.002).
Mirbagheri et al. 2013b

USA

Prospective Controlled Trial

N=50

Population: Individuals with SCI with ankle spasticity and incomplete loss of movement. Control group was age-matched to the intervention group.

Intervention: Individuals were given 2 mg of tizanidine 4x/day for 4 wk. Dosage began low and progressively ramped up to the full dosage during the first wk. Outcomes were assessed at baseline, 1, 2 and 4 wk.

Outcome Measures: Intrinsic ankle stiffness, Reflex ankle stiffness.

1.      Tizanidine produced a decrease in reflex ankle stiffness over four wk.

2.      Tizanidine produced a decrease in intrinsic ankle stiffness in some individuals.

3.      A reduction in spasticity can decrease intrinsic ankle stiffness.
Mirbagheri et al. 2010

USA

Prospective Controlled Trial

N=38

Population: SCI group (n=20): Mean age: 37.6 yr; Level of injury: >T10; Level of severity: AIS C/D; Mean time since injury: 8.5 yr. Control group (no SCI; n=20).

Intervention: Intervention group- perturbations were applied to the spastic ankle joint, a single oral dose of Tizanidine; Control-perturbations were applied to the spastic ankle joint, no dose of Tizanidine given.

Outcome Measures: Joint torque, Peak torque, Reflex stiffness, Intrinsic muscle stiffness.

Treated Group:

1.      Stretch evoked joint torque at the ankle decreased significantly (p<0.001).

2.      The peak-torque was reduced between 15% and 60% among the spinal cord injured subjects, and the average reduction was 25%.

3.      Reflex stiffness decreased significantly across a range of joint angles (p<0.001) after using tizanidine.

4.      There were no significant changes in intrinsic muscle stiffness after the administration of tizanidine.
Mathias et al. 1989

UK

Pre-Post

N=10

Population: Injury etiology: SCI=10.

Intervention: Single-dose (8 mg), tizanidine. Three pre-drug measurements 15 min apart after breakfast and 30 min equilibration. Observations continued at 0.5, 1.0, 1.5, 2.0, 3, 4, 5, 6, 12, 24 hr. These measurements were repeated on a separate occasion (except measurements of sedation and blood collection) without drug administration.

Outcome Measures: Ashworth Scale (AS), Manual muscle testing, Vitals, Sedation, Pharmacokinetics (Pk), Adverse events (AE).

1.     AS: peak reduction between 1-1.5 hr (p<0.05) with spasticity returning to baseline by 4th hr; no rebound spasticity measured at 12 and 24 hr.

2.     Muscle power: no effects on impaired or unimpaired muscles at any stage of the study.

3.     No significant changes to vitals except with heart rate (decrease in HR; 0.05 after 1.5 hr)

4.     Sedation: Sedation in tetras>paras but increased in both with considerable variability. Peak within first hr with gradual waning to fully awake by 3rd hr.

5.     Pk–Plasma levels rose at 0.5 hr and peaked by 1 hr. At 6 hr, level was at 85% peak and still detectable but low levels at 12 and 24 hr. Plasma half-life was 2.7±0.06 hr.

6.     AE: Sedation and dry mouth.

Discussion

A randomized, placebo-controlled trial specifically conducted to elucidate the anti-spasmodic effect of tizanidine revealed significant spasticity improvements in favour of tizanidine over placebo where Ashworth and Pendulum were the primary measures used (p<0.0001 and 0.002, respectively; Nance et al. 1994). Although this study represents level 1b evidence, it is noteworthy to mention that 34% of subjects who received study treatment and discontinued prematurely due to adverse events, lack of efficacy and other reasons not specified, were not included in the study analysis. Another single dose, pre-post test study (Mathias et al. 1989) presented evidence to corroborate the reduction in spasticity as measured by Ashworth and furthermore revealed that muscle power was not affected at any stage in the study. That tizanidine did not have a negative impact on muscle strength was also reported by Chu et al. (2014). Tizanidine was found to have a stronger inhibitory effect on knee extensors and plantar flexors when compared to baclofen (Chu et al. 2014). The reverse was true for antispastic effects on knee flexors (Chu et al. 2014). More specifically, the impact of tizanidine on the spastic muscle was examined in a non-RCT (Mirbagheri et al. 2010) where there was an average of 25% reduction in peak-torque in the SCI subjects. Significant decreases in reflex stiffness post-tizanidine were found but not in intrinsic muscle stiffness. The latter was clarified in subsequent work of Mirbagheri et al. (2013) where several spasticity reduction patterns were observed: continuous reduction over the four-week treatment period; more pronounced reduction during the first week of treatment, significant reduction only over time; or no improvement in intrinsic stiffness. This suggests that tizanidine reduces reflex stiffness and intrinsic stiffness for a subset of patients.

Conclusions

There is level 1a evidence (from two RCTs and one prospective controlled trial: Chu et al. 2014; Nance et al. 1994; Mirbagheri et al. 2013b) to support the use of tizanidine in reducing spasticity.

Tizanidine is likely useful in treating SCI spasticity.

Chapter Downloads
Patient Handouts
Outcome Measures
Toolkits
Videos
Active Clinical Trials