A New Treatment for Fibromyalgia?

Fibromyalgia can be characterized as widespread or multi-site pain that is present for at least three months and not attributed to another disease or condition.1 Many other symptoms that are non-pain in origin are present in fibromyalgia, including chronic fatigue, sleep disturbances, neurologic disturbances and disturbances of cognition and mood. Cognitive impairment can present as difficulty concentrating and forgetfulness as well as disorganized thinking. Other symptoms can include musculoskeletal stiffness and environmental sensitivity, such as sensitivity to bright lights, loud noises, perfumes and cold.

The prevalence of fibromyalgia in the U.S. is estimated to be 2–6.4%, and the condition is more common in women than in men. On physical examination, there is an absence of focal changes, suggestive of arthritis or enthesitis, and widespread tenderness.²

Patient Care

Fibromyalgia is managed with non-pharmacologic and pharmacologic therapies. Non-pharmacologic interventions include patient education about the disease and cognitive therapy, as well as increased activity and exercise routines. The most common medications prescribed for fibromyalgia, which are mostly off label, are tricyclic antidepressants, such as amitriptyline, and related medications (e.g., cyclobenzaprine); serotonin-norepinephrine reuptake inhibitors, such as duloxetine and milnacipran; and alpha-2 ligands, such as pregabalin and gabapentin.³

Only three medications have previously been approved by the U.S. Food & Drug Administration (FDA) to treat fibromyalgia:

• Pregabalin (Lyrica), which was approved on June 21, 2007;⁴
• Duloxetine (Cymbalta), which was approved on June 13, 2008;⁵ and
• Milnacipran (Savella), which was approved on Jan. 14, 2009.⁶

New Treatment

On Aug. 15, the FDA approved a new drug application for Tonmya (TNX-102 SL) for the treatment of adults with fibromyalgia.⁷ This agent is a rapidly disintegrating, sublingual tablet with 2.8 mg of cyclobenzaprine HCl.⁸ The FDA initially approved cyclobenzaprine as a skeletal muscle relaxant on Aug. 26, 1977.⁹ The agent has been widely used off label as a treatment for fibromyalgia and available as a generic medication for many years. The most common adverse reactions are drowsiness, dry mouth, dizziness and fatigue.

Developed by Tonix Pharmaceuticals, TNX-102 SL is designed to provide rapid transmucosal absorption and—due to its bypass of first-pass, hepatic metabolism—reduce the production of a long half-life active metabolite, norcyclobenzaprine.10 The medication was formulated for optimal delivery and absorption to improve sleep quality, while minimizing the potential residual effects of oral cyclobenzaprine formulations. It is a centrally acting analgesic that helps relieve pain by improving sleep.

The Latest Research

In the phase 3, RESILIENT trial (NCT05273749), patients with fibromyalgia treated with TNX-102 SL had significant reductions in daily pain and tolerated the medication well with minimal side effects.¹¹

This randomized, two-arm, placebo-controlled trial evaluated the efficacy and safety of TNX-102 SL for the management of fibromyalgia vs. placebo, enrolling 457 adults with fibromyalgia across the U.S.

During the study’s two-week, run-in period, patients received 2.8 mg of TNX-102 SL (one tablet) or placebo at bedtime. For the next 12 weeks, patients received 5.6 mg of TNX-102 SL (two tablets) or placebo at bedtime. The study’s primary end point was the change from baseline in the daily diary pain severity score at week 14. This measurement was attained using the weekly averages of the daily numerical rating scale scores, analyzed by mixed model repeated measures with multiple imputation.

The study’s secondary end points included the Patient Global Impression of Change (PGIC) responder analysis, Fibromyalgia Impact Questionnaire-Revised (FIQR) Symptoms and Function domain, the PROMIS (Patient Reported Outcomes Measurement Information System), and Sleep Disturbance and Fatigue instruments.

For the primary end point, a least-squares (LS) mean reduction of 1.8 points was observed on the 11-point, daily pain numeric rating scale for patients who received TNX-102 SL compared with a 1.2-point reduction for those who received placebo, achieving statistical significance. Additionally, statistically significant improvements were observed across all prespecified key secondary end points.

TNX-102 SL was generally well tolerated. The most common treatment-emergent adverse events were oral tingling/numbness and bitter or noticeable aftertaste. These adverse events were usually mild and lasted less than an hour. No medication-related serious adverse events or deaths were reported.

RELIEF Study Findings

Completed in 2020, the prior phase 3, RELIEF study (NCT04172831) had a similar design and results, enrolling 503 patients with fibromyalgia.^2,12 In this study, reductions in daily pain from baseline to week 14 was significantly greater in patients who received TNX-102 SL (LS mean change: –1.9 [95% confidence interval (CI) −2.1, −1.7]) compared with patients who received placebo (LS mean change: −1.5 [95% CI −1.7, −1.3]; P=0.01).

However, patients who received TNX-102 SL did not have significant improvement in PGIC scores at week 14. Improvements were observed in FIQR scores, PROMIS scores and daily sleep quality scores.

Overall, 59.7% of patients receiving TNX-102 SL and 46.3% receiving placebo reported treatment-emergent adverse events. The most commonly treatment-emergent adverse events were oral hypoesthesia (17.3% of patients treated with TNX-102 SL vs. 0.4% of patients treated with placebo), oral paresthesia (5.6% vs. 0.4%, respectively) and product taste abnormal (4.4% vs. 0.4%, respectively).

The study concluded that TNX-102 SL led to significant daily pain reductions with a good safety and tolerability profile.

Conclusion

Cyclobenzaprine hydrochloride in sublingual tablet form (TNX-102 SL; Tonmya) is the first medication to receive FDA approval for the treatment of patients with fibromyalgia in more than 15 years. Although it was well tolerated in clinical trials, these conditions are usually more ideal than in the real world.

Cyclobenzaprine has been around for more than four decades, so it is not a new pharmacologic agent, but rather a new dose and dosage form. Now that it is FDA approved, more widespread use of evening dosing of the agent, combined with real-world evidence, will demonstrate where it fits into the armamentarium for the management and care of patients with fibromyalgia.

Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Goldenberg DL, Kaplan M. Fibromyalgia: Treatment in adults. In: Wallace DJ, Case SM, eds. UpToDate. Wolters Kluwer. 2025 Jul.
2. Lederman S, Arnold LM, Vaughn B, et al. Efficacy and safety of sublingual cyclobenzaprine for the treatment of fibromyalgia: Results from a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2023 Nov;75(11):2359–2368.
3. Forte ML, Butler M, Andrade KE, et al. Treatments for Fibromyalgia in Adult Subgroups. Agency for Healthcare Research and Quality (U.S.); 2015 Jan.
4. Supplemental new drug application approval letter: Lyrica (pregabalin). U.S. Food & Drug Administration. 2007 Jun 21.
5. FDA approves Cymbalta for the management of fibromyalgia [news release]. Eli Lilly and Company. 2008 Jun 16.
6. New drug application approval letter: Savella (milnacipran). U.S. Food & Drug Administration. 2009 Jan 14.
7. Tonix pharmaceuticals announces FDA approval of Tonmya (cyclobenzaprine HCl sublingual tablets) for the treatment of fibromyalgia [news release]. Tonix Pharmaceuticals Holding Corp. 2025 Aug 15.  
8. TNX-102 SL. Tonix Pharmaceuticals Inc. 2025.
9. Flexeril (cyclobenzaprine): Package insert/prescribing information. Drugs.com. 2025 Mar 25.
10. Tonix Pharmaceuticals announces on-line publication of phase 3 Resilient trial results of TNX-102 SL for fibromyalgia in in the peer reviewed journal, Pain Medicine [news release]. Tonix Pharmaceuticals Inc. 2025 Jul 9.
11. A phase 3 study to evaluate the efficacy and safety of TNX-102 SL taken daily in patients with fibromyalgia (RESILIENT) [NCT05273749]. Tonix Pharmaceuticals Inc. ClinicalTrials.gov. 2025 Jan 22.
12. A study to evaluate the efficacy and safety of TNX-102 SL in patients with fibromyalgia (RELIEF) [NCT05273749]. Tonix Pharmaceuticals Inc. ClinicalTrials.gov. 2022 Aug 8.