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Background and Purpose-Spasticity is a frequently observed motor impairment that develops after stroke; it can cause pain and disability in those affected. The objective of the present study was to evaluate the safety and efficacy of tizanidine, a centrally acting ␣ 2 -adrenergic agonist, in the treatment of stroke-related spasticity. Methods-Forty-seven patients, who were a minimum of 6 months poststroke and had significant spasticity, were studied at 4 centers.Tizanidine was administered in an open-label manner for 16 weeks, beginning at 2 mg/d and slowly titrated to a maximum of 36 mg/d. The Modified Ashworth Scale, muscle strength testing, functional assessments, and Pain and Functional Spasticity Questionnaires were administered at baseline and at 4, 8, 16, and 18 weeks (after 1 week off tizanidine). Results-Spasticity was significantly improved between baseline and week 16, with a decrease in total upper extremity Modified Ashworth Scale score of 2.80Ϯ0.47 (PϽ0.0001). No decline in strength was noted. Treatment with tizanidine resulted in a significant improvement in pain intensity (Pϭ0.0375), quality of life (Pϭ0.0001), and physician assessment of disability (Pϭ0.0001). The most frequent side effects were somnolence (62%) and dizziness (32%). No serious adverse events were considered to be drug related. Ten of 47 patients (21%) were able to reach the maximum daily dosage of 36 mg. Conclusions-Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while reducing muscle tone and painful spasms in affected patients.

Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.