Bedtime Sublingual Cyclobenzaprine in Fibromyalgia: Phase 3 Trial Readout

Key Takeaways

• This randomized, double-blind, placebo-controlled trial evaluated once-nightly sublingual cyclobenzaprine with a 2 week 2.8 mg lead-in followed by 12 weeks of 5.6 mg dosing.
• TNX-102 SL was associated with greater improvement than placebo on the primary pain outcome and across the six prespecified secondary endpoints at week 14.
• Oral cavity reactions were the most common adverse events overall, were described as transient and self-limited, and the authors noted limits on generalizability and longer-term follow-up.

Active treatment was administered once nightly, starting at 2.8 mg for 2 weeks and increasing to 5.6 mg for 12 weeks. This bedtime regimen was evaluated during a 14-week blinded treatment period in a multicenter setting. Researchers also reported benefits on prespecified measures of sleep, fatigue, and function.

In the multicenter phase 3 trial, 457 adults were randomized 1:1 to active treatment or matching placebo. The treatment period lasted 14 weeks after screening, washout, and a baseline run-in period. Eligible participants were 18 to 65 years old and met prespecified fibromyalgia diagnostic criteria with a 7-day baseline average daily pain intensity score of at least 4 and at most 9. The primary endpoint was change from baseline at week 14 in weekly average daily diary pain intensity; secondary measures included PGIC, FIQR domains, PROMIS Sleep Disturbance, PROMIS Fatigue, and diary sleep quality. This design assessed pain alongside related symptom domains during bedtime dosing.

At week 14, the study found significantly greater improvement with TNX-102 SL than placebo on the primary pain endpoint. The authors also reported significant improvement on all six prespecified secondary endpoints at the same time point. Exploratory analyses described larger proportions of participants receiving active treatment reaching at least 30% and 50% pain reduction. Together, these results outlined a symptom-spanning pattern within the randomized trial.

Sleep disturbance and diary-based sleep quality were among the patient-reported outcomes tracked during treatment. Fatigue and fibromyalgia-related function were also measured through PROMIS and FIQR instruments specified in the protocol. By week 14, researchers described improvement with active treatment versus placebo across these domains, extending beyond the primary pain measure.

The most common adverse events overall were local oral cavity reactions, including oral numbness (oral hypoesthesia), altered taste (product taste abnormal), and oral tingling (oral paresthesia), which were described as transient and self-limited. No deaths occurred, and the investigators reported no clinically meaningful changes in laboratory values or vital signs. Treatment-emergent adverse events led to study drug discontinuation in 6.1% of the active group and 3.5% of the placebo group. The authors noted limited generalizability because men were underrepresented, enrollment was capped at 65 years, some complex comorbidities were excluded, and longer follow-up is still needed. They framed the findings as support for a bedtime regimen associated with improvements in fibromyalgia symptoms and function in the enrolled population.