The Snow Study
Using a randomized, double-blind, placebo-controlled, crossover study design, Snow et al. (1990) evaluated the safety and efficacy of BoNT-A in the treatment of lower-limb spasticity secondary to MS. Nine patients received injections of saline or BoNT-A (total dose: 400 units, diluted at 100 units/ml), divided among the leg adductors (adductor brevis, longus, and magnus). Patients were evaluated at two and six weeks after treatment. All patients were then crossed over and given repeated injections of either BoNT-A or saline after three months. The patients were re-evaluated at two and six weeks.
At week six, BoNT-A produced a significant reduction in spasticity scores (the sum of the Ashworth Scale [range, 0-5] and in the Spasm Frequency Score [range, 0-4]) (mean, 7.9 ± 4.87 to 4.7 ±4.31; P = .009).
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BoNT-A also significantly reduced caregiver burden (P = .009) and hygiene scores (P = .02), whereas placebo did not. No adverse drug events (ADEs) were reported in this trial (Level 1b evidence).
The Grazko Study
Grazko et al. (1995) evaluated BoNT-A in the treatment of spasticity using a randomized, double-blind, placebo-controlled, crossover design. In 12 patients with upper- or lower-limb spasticity caused by stroke, MS, traumatic brain injury, or perinatal hypoxia, 25 to 290 units of BoNT-A or saline was injected into the involved muscles. The injections were directed by “surface [anatomic] landmarks for motor points.” The mean dose was 138 units, and the concentration varied according to muscle size.
Patients were evaluated at two weeks after treatment, and the crossover injection was given at the return of baseline muscle tone. All patients achieved at least a two-point reduction in Ash-worth Scale scores as well as marked improvements in subjective functionality (ease of movement and posture) and nursing care. Patients with painful spasms reported a reduction in spasm frequency and intensity.
No placebo effect was observed in this trial. ADEs, such as injection-site pain, were generally mild and transient (Level 1b evidence).
The Simpson Study
Simpson et al. (1996) reported a randomized, double-blind, placebo-controlled, dose-ranging study of BoNT-A in the treatment of chronic upper-limb spasticity after stroke. Thirty-nine patients received injections of BoNT-A or matching placebo into the elbow and wrist flexors under electromyographic (EMG) guidance. The BoNT-A injections consisted of 75, 150, or 300 units, 3 ml in volume, with a concentration range of 25 to 100 units/ml. The patients were followed for 16 weeks.
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The authors concluded that the group receiving 300 units of BoNT-A experienced statistically and clinically significant mean reductions in baseline wrist flexor tone at the second, fourth, and sixth weeks and in elbow flexor tone at the second and fourth weeks (BoNT-A vs. placebo, P < .05), as measured on the Ash-worth Scale. Both the 75- and 300-unit BoNT-A patient groups showed significant improvement in Physician and Patient Global Assessment Scale scores (-4 to +4, with 0 representing no change) at weeks four and six (BoNT-A vs. placebo, P < .05).
No consistent differences were observed between the groups for other outcome measures, including the Functional Independence Measure, the Rand 36-Item Health Survey 1.0, and the Fugl-Meyer Scale. Nonserious and reversible treatment-related ADEs were reported, including injection-site pain and finger twitching, although their frequency did not differ significantly between groups (Level 1b evidence).
The Kirazli Study
Kirazli et al. (1998) compared phenol with BoNT-A in the treatment of post-stroke spastic foot through a randomized, double-blind, parallel-group study. Twenty patients with ankle plantar flexion and foot-inversion spasticity received either 400 units of BoNT-A (50 units/ml under EMG guidance) or 3 ml of 5% phenol (i.e., tibial nerve block via nerve stimulation guidance). The patients were then followed for 12 weeks.
Both treatment groups experienced significant reductions in mean tone at baseline, although changes in Ashworth Scale scores for dorsiflexion and eversion were superior with BoNT-A therapy at weeks two and four (BoNT-A vs. phenol, P < .05). Unlike phenol, BoNT-A significantly improved walking velocity at all follow-up visits; like phenol, it significantly reduced EMG-measured duration of clonus throughout the trial.
Both treatment groups achieved comparable gains in active and passive range of motion, although Patient Global Assessment Scale scores were better (P < .05) in the BoNT-A group at the second, fourth, and eighth weeks. No significant treatment-related ADEs were reported in the BoNT-A group, but 30% of the subjects in the phenol group developed dysesthesia that interrupted ambulation.
The study represented Level 1b-minus and was slightly downgraded because of differences in the baseline characteristics of the randomized subjects.