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Tolperisone, a centrally-acting muscle relaxant, may treat symptoms of acute muscle spasms without the sleepiness and cognitive effects associated with other skeletal muscle relaxants, data from the phase II trial suggested.

In the dose-ranging study, patients with acute, painful back muscle spasms who received 200 mg of oral tolperisone three times a day experienced the largest clinically meaningful decrease in "right now" pain intensity relative to placebo, reported Randall Kaye, MD, chief medical officer of Neurana Pharmaceuticals in San Diego, at the American Society of Interventional Pain Physicians (ASIPP) virtual meeting.

Tolperisone did not increase sleepiness compared with placebo. In earlier research, Kaye and colleagues also showed that patients who took 150 mg tolperisone three times a day experienced , self-reported sleepiness, or cognition compared with placebo. In that study, most individuals on cyclobenzaprine (Flexeril) performed similar to people with a blood alcohol concentration above 0.05% (above the legal limit in most states) on the driving test and were unaware of their impairment.

"Tolperisone, if approved, could be the first muscle relaxant for the treatment of symptoms associated with acute and painful muscle spasms of the back without the drowsiness and cognitive function impairment typically seen with currently available skeletal muscle relaxants," Kaye told MedPage Today.

While its mechanism is not fully known, tolperisone inhibits spinal reflexes through presynaptic blockade of voltage-gated sodium and calcium channels. "In a pre-clinical model, analgesic effects have been observed," Kaye said.

Tolperisone is used in , Asia, South America, and Africa to treat post-stroke spasticity, and in some countries, acute and painful muscle spasms, Kaye noted. In Germany, to tolperisone have been reported post-marketing.

"The formulation available outside the U.S. contains a degradant, 4-MMPPO [2-methyl-1-(4-methylphenyl) propenone], that exceeds guidelines," Kaye pointed out. Neurana has developed an ultra-pure formulation of tolperisone not available in other countries that has a lower degradant yield and meets ICH guidance, he said.

In the U.S., acute muscle spasms with non-pharmacologic therapy (such as superficial heat compresses or physical therapy), and oral or topical drugs like NSAIDs and acetaminophen. Skeletal muscle relaxants are effective but central nervous system adverse events, mainly sleepiness, limit their use. Opioids also are sometimes used.

In STAR, researchers evaluated the safety and efficacy of four doses of tolperisone -- 50 mg, 100 mg, 150 mg, or 200 mg three times a day -- versus placebo. A total of 415 patients, ages 18 to 65, with acute back muscle spasm were included and treated for 14 days; approximately 80 participants were in each group.

All participants had back pain or stiffness due to acute, painful muscle spasm starting at least 7 days before joining the study and continuing for more than 8 weeks. Pain was localized below the neck and above the inferior gluteal folds, with an intensity of 4 or higher on a "right now" pain numerical rating scale (NRS) in which 0=no pain and 10=worst possible pain. Patients discontinued all other medications used to treat pain or muscle spasm on day 1 of the study.

Participants in the tolperisone groups had an average age of about 44; 54.6% were female, 37.4% were Black, and 21.7% were Hispanic or Latino. In the placebo group, mean age was about 42; 62.8% were female, 38.5% were Black, and 20.5% were Hispanic or Latino. Average BMI was about 28.5 across all groups.

Adverse events occurred in 14.1% of placebo patients and ranged from 12.2% in the 50-mg group to 23.5% in the 200-mg group. No serious adverse events or deaths were reported.

Headache was the most common adverse event in the treatment groups, ranging from 3.7% in the 50-mg group to 9.6% in the 150-mg group and 9.4% mg in the 200-mg group. Headache generally resolved over the first 24 to 48 hours of dosing. Somnolence was reported by 1.2% of patients receiving tolperisone and 2.6% of placebo patients. Four people treated with tolperisone reported hypersensitivity events; all were mild or moderate.

The overall trend of decreasing pain "right now" ratings trended toward statistical significance across dose groups (P=0.0539). Three of four doses were within range of expected results, with the greatest numerical difference and statistical significance emerging between the tolperisone 200-mg group and placebo, the researchers said.

"Based on the efficacy and safety results from this study, a tolperisone dose of 200 mg TID may be a promising treatment for the management of acute muscle spasm without the somnolence typically experienced with skeletal muscle relaxants," they wrote.

"The current phase III study of tolperisone is designed to assess the safety and efficacy of tolperisone in the management of pain due to muscle spasm that are of acute onset," Kaye said. "The tolperisone doses selected for the phase III study -- 100 and 200 mg three times a day -- are based on efficacy and safety results from the phase II STAR study, which assessed tolperisone for 14 days of treatment in a similar patient population."

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