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Fibromyalgia patients hoping to see a more effective and convenient formulation of cyclobenzaprine at their local pharmacies must wait for an ongoing phase III trial -- the product's third -- to finish, as the first two delivered mixed results.

Findings from the positive RELIEF trial for the novel agent currently called TNX-102 (sublingual cyclobenzaprine) , showing a significant reduction in pain scores compared with placebo. But this follows another phase III study called RALLY for which the developer, Tonix Pharmaceuticals, said the (and which has not been formally published).

To break the tie, Tonix is enrolling patients in , with a target of 470 patients and by the end of 2023.

Cyclobenzaprine in ordinary pill form has been suggested as a potential fibromyalgia pain reliever for decades, but rigorous studies have not demonstrated a clear benefit. A report prepared for the Agency for Healthcare Research and Quality in 2020 found in fibromyalgia.

In the new RELIEF report, appearing in Arthritis Care & Research, Gregory Sullivan, MD, chief medical officer of Tonix, and colleagues explained that regular cyclobenzaprine has a metabolism problem. "A single 5-mg dose of oral cyclobenzaprine results in accumulation of norcyclobenzaprine, which generally antagonizes the same receptors as cyclobenzaprine but with lower potency," they wrote.

TNX-102 SL is designed for sublingual dissolution and absorption in the mouth, with once-daily dosing. As a result, it "bypasses first-pass hepatic metabolism and results in lower norcyclobenzaprine exposure relative to the parent," Sullivan and colleagues indicated.

In particular, it is to be taken at bedtime to help patients sleep better, while avoiding most of cyclobenzaprine's inherent side effects -- it's a derivative of tricyclic antidepressants -- such as drowsiness and dry mouth.

Patients in RELIEF averaged 50 years old and were almost all women. They'd been coping with fibromyalgia for a mean of 9 years, with pain scores averaging 6.1 on a 10-point scale. They had previously tried a range of drugs such as non-steroidal anti-inflammatory agents and other painkillers, antidepressants, antihistamines, and antacids. A total of 503 were randomized 1:1 to the active agent or placebo with the final evaluation at week 14.

As is often the case in chronic pain trials, the placebo group reported substantial pain relief, with a mean 1.51-point decrease in scores. With TNX-102 SL, the decline was 1.91 points (P=0.045). Similar results were found with more global fibromyalgia assessments including the Patient Global Impression of Change, the Fibromyalgia Impact Questionnaire, and the Patient-Reported Outcome Measurements Information System.

In the similarly sized RALLY trial, however, the difference between groups in pain relief and other outcomes was only about half as great and therefore fell short of statistical significance. One reason, according to Tonix, was that dropouts due to adverse effects were nearly twice as numerous in RALLY, in both study arms. Results for participants who withdrew prematurely were then imputed, as dictated by the prespecified protocol, and tended to exaggerate negative outcomes.

Tonix also has studied TNX-102 SL in other conditions, including post-traumatic stress disorder (PTSD) and post-acute COVID-19 syndrome. A phase II trial for the latter is now underway, with results expected this summer; a phase III study in PTSD was terminated and no further trials are in the offing.

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