Background/Purpose:

Tolperisone is a centrally-acting muscle relaxant being developed in the US as a treatment for acute and painful symptoms of neck and low back muscle spasms. Tolperisone historically has shown both muscle relaxant and analgesic effects without sedation in placebo-controlled and head-to-head clinical studies in Europe and Asia. The present study explores the impact of tolperisone on driving simulation endpoints, self-reported sleepiness, and cognition compared to placebo and cyclobenzaprine.

Methods:

The study was a 3-way, randomized, blinded, crossover study assessing the safety and cognitive effects of tolperisone in 31 healthy volunteers. Treatment groups included 450 mg tolperisone administered three-times-a-day (150 mg TID), 30 mg cyclobenzaprine (10 mg TID), and placebo (TID). Participants spent the first three days of three consecutive weeks in the research unit. Dosing occurred in the morning (AM) and at midday (PM) on Days 1-3 and at bedtime on Days 1 and 2. Subjects were administered a digit symbol substitution test followed by 100 km (60 minute) of simulated driving on Day 1 one hour after their midday dose (at drug Tmax), and again the morning of Day 2 (pre-dosing) to assess next day residual effects. They were also tested the morning of Day 3 (post-dose) to assess the drug at steady-state. Subjects returned to the clinic on Days 7 and 14 to repeat these procedures.

Results:

For the primary endpoint of Standard Deviation of Lateral Position (SDLP) over 100-km of driving, tolperisone was no different than placebo, whereas cyclobenzaprine showed significant impairment (p=<0.001). Results from secondary endpoints, including cognitive test findings, support this conclusion.

The distribution of SDLP for the placebo and tolperisone test conditions showed symmetry around zero, while cyclobenzaprine was markedly different; a subset of subjects in this study had a level of impairment associated with increased crash risk, as demonstrated by SDLP values above 4.4 cm in this test paradigm (consistent with normative Blood Alcohol Concentration (BAC) levels of above 0.05%).

Secondary measures confirmed the finding of absence of sedation for tolperisone relative to placebo: Digit Symbol Coding Day 1 p= 0.84, Day 2 p= 0.21, Day 3 p= 0.12; and Karolinska Sleepiness Scale: Day 1 p= 0.47, Day 2 p= 0.47, and Day 3 p= 0.49. Additional measures of driving indicated no impairment for tolperisone versus placebo.

Of note in this study, patients taking cyclobenzaprine perceived a distinct lack of effect discrimination and reported feeling safe to drive on Days 2 and 3, while demonstrating impairment based on their SDLP and other secondary endpoint outcomes.

Conclusion:

Tolperisone at a dose of 150 mg TID was found to have no impact, compared to placebo, on various measures of driving, self-reported sleepiness, and cognition, in contrast to the widely used muscle relaxant cyclobenzaprine at a dose of 10 mg TID. Because of its long half-life and anticholinergic activity, cyclobenzaprine is not recommended for use in the elderly and has been associated with an increase in falls and injury. Data from this study confirms impairment in cognition and driving for healthy subjects taking cyclobenzaprine.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/unique-skeletal-muscle-relaxant-tolperisone-in-a-crossover-driving-simulation-study-no-evidence-of-sedation-compared-to-cyclobenzaprine-and-placebo/