A sublingual formulation of cyclobenzaprine may be new treatment option for fibromyalgia.Findings from the phase III RESILIENT study show that a sublingual formulation of cyclobenzaprine (CBP SL) may benefit individuals with fibromyalgia.
“CBP SL significantly reduced pain and showed a favourable tolerability profile, including minimal impact on weight and blood pressure (BP),” said Dr Ernest Choy from Cardiff University School of Medicine, UK, at EULAR 2026.
The least-squares mean (LSM) change in Numeric Rating Scale Pain scores dropped from baseline as early as week 1 in the CBP SL group (p<0.01), and the curve continued to diverge from the placebo curve until week 14 (–1.8 vs –1.2; p<0.001).
CBP SL consistently outdid placebo across all secondary endpoints, such as the proportion of PGIC* responders (35.1 percent vs 19.1 percent), and the LSM CFB** in FIQR*** scores (Symptoms domain: –16 vs –8.4; Function domain: –12.2 vs –6.8), PROMIS# scores (Sleep Disturbance: –8.4 vs –4.2; Fatigue: –7.2 vs –4.2), and Diary Sleep Quality ratings (–1.8 vs –1.2; p<0.001 for all).
Week 14 also saw markedly greater improvements (LSM CFB) in sexual function among females on CBP SL vs placebo in the CSFQ##–14 orgasm/completion domain (0.6; p=0.007), desire/frequency domain (0.3; p=0.010), and total scores (1.4; p=0.010). Of note, sexual dysfunction is a common side effect of approved fibromyalgia treatments.
In the safety population, the CBP SL and placebo groups had no clinically meaningful differences in mean CFB in BP (systolic: 0.7 vs 0.5 mm Hg; diastolic: 1.1 vs 0.2 mm Hg) and weight (0.02 vs 0.2 kg) at week 14.
The CBP SL group had higher rates of systemic adverse events (AEs; COVID-19: 4.3 percent vs 3.1 percent; headache: 3 percent vs 1.8 percent; somnolence: 3 percent vs 1.3 percent) and oral cavity AEs, such as hypoaesthesia (23.8 percent vs 0.4 percent), abnormal product taste (11.7 percent vs 0.9 percent), paraesthesia (6.9 percent vs 0.9 percent), and tongue discomfort (6.9 percent vs 0 percent) than the placebo group.
Nonetheless, most AEs were mild or moderate in severity, and only 1.3 percent of participants in each group had severe AEs. The rates of treatment discontinuation due to AEs in the CBP SL and placebo groups were 6.1 percent and 3.5 percent.
SL better absorbed than oral CBP
Fibromyalgia mostly affects women and is characterized by widespread pain, nonrestorative sleep, fatigue, cognitive dysfunction, and functional impairment. [Nat Rev Neurol 2024;20:347-363; Ann Rheum Dis 2024;83:1421-1427]
Choy noted that there remains a significant unmet need in fibromyalgia despite approved treatments, because these are limited by intolerable side effects that often lead to poor adherence. [Pain Med 2012;13:1366-1376]
“[While] approved for different conditions … the efficacy and safety profile of CBP are limited due to its metabolite, norcyclobenzaprine, which is metabolized through the liver via the first-pass effect,” Choy explained.
Compared with oral immediate-release CBP, the SL formulation provides rapid transmucosal absorption, greater bioavailability, increased blood CBP levels, and reduced norcyclobenzaprine production. [Arthritis Care Res 2023;75:2359-2368] In theory, removing the metabolite may lead to improved efficacy and a better side-effect profile, Choy continued.
In RESILIENT, 456 participants (mean age 49.4 years, 95.4 percent women) were randomized to nightly CBP SL (2.8 mg for the first 2 weeks, then 5.6 mg for the next 12 weeks) or placebo for 14 weeks. The mean NRS score at baseline was 5.9.
Taken together, the results show that CBP SL outperformed placebo in reducing pain and improving patient-reported outcomes in the overall cohort, had favourable tolerability, and notably improved sexual function in women. “Along with its unique mechanism targeting nonrestorative sleep, these results support CBP SL as a new, well-tolerated treatment option for fibromyalgia,” Choy said.