In 2000, Richardson et al. completed a 12-week, randomized, double-blind, placebo-controlled trial on the safety and efficacy of BoNT-A in the treatment of upper-limb and lower-limb spasticity secondary to stroke, traumatic brain injury, spinal cord injury, cerebral palsy, neoplasm, and hypoxia. Enrolled patients (n = 52) were stratified into upper-limb and lower-limb groups and were then randomly selected to receive a single treatment of BoNT-A (total dose: 30-500 units, diluted at 50 units/ml) or saline under EMG guidance. Outcome measures were assessed at baseline and at weeks three, six, nine, and 12. The investigators generated aggregate (overall) scores for each variable by summing the scores from each assessment.
Aggregate scores were significantly better in the BoNT-A group on the Modified Ashworth Scale (P < .02), in passive range of motion (P < .03), on the Rivermead Motor Assessment Scale (lower limb, P < .05), and in subjective ratings of problem severity (P < .025).
No significant between-group differences were found for other outcome measures, including the 10-meter Timed Walk Test (P > .30), the Rivermead Motor Assessment Scale (upper limb, P > .15), and the Modified Goal Attainment Scale. The only reported ADE was injection-site pain (Level 1b evidence).
The Brashear Study
In the largest controlled trial for BoNT-A in the treatment of spasticity, Brashear et al. (2002) randomly assigned 126 patients with upper-limb spasticity resulting from stroke to receive injections of placebo or BoNT-A (200-240 units) into the flexors of the wrist, fingers, and thumb (if involved). The concentration was not documented.
Subjects who received BoNT-A had superior improvement in flexor tone, in the wrist and fingers, according to Ashworth Scale scores, at all follow-up visits through the 12-week study period (P < .001 for all comparisons). At week six, 65% of patients in the BoNT-A group reported clinically meaningful functional improvement on the validated, four-point Disability Assessment Scale, compared with 27% of placebo subjects (P < .001).
Scores on the Physician and Patient/Caregiver Global Assessment Scales were significantly improved with BoNT-A at all follow-up visits through 12 weeks (BoNT-A vs. placebo, P < .002). The most frequently reported ADEs—incoordination, infection, and pain—did not differ significantly between groups (Level 1b evidence).
The Brashear Study
In a subsequent double-blind, randomized, placebo-controlled trial of post-stroke spasticity of the upper extremity by Brashear et al. (2004), 15 patients received injections of placebo or BoNT-B (total dose: 10,000 units; 5,000 units/ml) via electrical stimulation to confirm placement. The BoNT-B group achieved no statistically significant reductions in muscle tone, as measured by the Ashworth Scale, compared with placebo, in the elbow, wrist, or finger flexors over the 16-week study period, except in the wrist flexors at week two (P = .003).
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There were no significant differences in scores between the groups in the Physician, Patient, or Therapist Global Assessment Scales. No significant improvements were observed in subjective pain, passive or active range of motion, or in functional measures, such as the Nine-Hole Peg Test or the Jebsen Test of Hand Function, for BoNT-B compared with placebo.
In the safety assessment, dry mouth occurred in 89% of the subjects in the BoNT-B group and in 20% of those in the placebo group (Level 1b evidence).
The Childers Study
In a double-blind, placebo-controlled, dose-ranging study, Childers et al. (2004) randomly chose 91 patients with post-stroke, upper-limb spasticity to receive up to two treatments with 90, 180, or 360 units of BoNT-A or placebo using EMG guidance. Concentrations were varied to keep the volume constant at 4 ml.
Compared with placebo, significant mean reductions in wrist flexor tone, as measured by the Modified Ashworth Scale, were observed with BoNT-A 360 units at weeks one, two, three, six, and nine (P < .005); with BoNT-A 180 units at weeks one, three, and six (P < .046); and with BoNT-A 90 units at weeks one, three, six, and nine (P < . 034).
The results supported a dose-dependent response to BoNT-A, because the 360-unit group showed the largest response, compared with the placebo group, at all follow-up visits. Significant improvements over placebo in elbow flexor Modified Ashworth Scale scores were also observed with BoNT-A 360 units (P < .045) and with BoNT-A 180 units (P < .029) at weeks one to five and at week nine.
Improvements in finger flexor Modified Ashworth Scale scores were less robust, but they were significant at weeks one and three for the BoNT-A 360-unit group (P < .003). Significant, superior responses to treatment on the Global Assessment Scale were observed with 360 units (P < .001) and 180 units (P < .013), compared with placebo, but no dose dependence was evident. viagra soft
Generally, no differences were observed throughout the 24-week trial between the groups in functional disability, subjective pain, function (according to the Functional Independence Measure), or quality of life (according to the 36-Item Short-Form Health Survey).
Mild-to-moderate treatment-related ADEs occurred more frequently among subjects in the BoNT-A group, including severe arm pain and injection-site hematoma formation.
This study represented Level 1b-minus evidence and was downgraded because subject retention was below 80%.