Bedtime Sublingual Cyclobenzaprine Improves Fibromyalgia Pain and Sleep

New phase 3 data report that bedtime sublingual cyclobenzaprine (TNX-102 SL) significantly reduced pain and improved sleep-related outcomes in adults with fibromyalgia, supporting a sleep-targeted therapeutic approach.

Study Findings

The multicenter, double-blind, placebo-controlled phase 3 trial evaluated the efficacy and safety of TNX-102 SL, a sublingual formulation of cyclobenzaprine designed for bedtime use. Investigators randomized patients 1:1 to TNX-102 SL or placebo. The active-treatment group received 2.8 mg nightly for 2 weeks, followed by 5.6 mg nightly for 12 weeks, while controls received matching placebo.

A total of 456 patients were included in the efficacy analysis. Trial completion rates were high and similar between groups: 81.0% (187/231) with TNX-102 SL and 79.6% (179/225) with placebo.

The primary endpoint was change from baseline to week 14 in weekly average daily diary pain intensity scores. TNX-102 SL produced a significantly greater reduction in pain compared with placebo (mean [SE], −1.8 [0.12] vs −1.2 [0.12]; P < .001). Importantly, all 6 prespecified secondary endpoints also favored TNX-102 SL (all P ≤ .001). These included Patient Global Impression of Change, Fibromyalgia Impact Questionnaire–Revised symptom and function domains, PROMIS Sleep Disturbance and Fatigue measures, and patient-reported daily sleep quality scores.

Regarding safety, the most common systemic treatment-emergent adverse events were COVID-19 infection, headache, and somnolence, each occurring in ≤4.3% of TNX-102 SL–treated patients. The most frequent overall adverse events were local administration-site reactions, including oral hypoesthesia (23.4%), abnormal taste (11.3%), and oral paresthesia (6.9%). These events were transient and self-limited.

Clinical Implications

These findings reinforce the emerging concept that targeting nonrestorative sleep can meaningfully reduce pain and functional impairment in fibromyalgia. Unlike traditional muscle relaxants or daytime analgesics, TNX-102 SL is administered at bedtime and designed to modulate sleep physiology, addressing a core pathophysiologic feature of fibromyalgia rather than pain alone.

For clinicians, the consistent improvements across pain, sleep, fatigue, and global function suggest potential utility for patients who remain symptomatic despite existing pharmacologic options. The low rates of systemic adverse events and absence of new safety signals are particularly relevant given the chronic nature of fibromyalgia treatment. However, clinicians should counsel patients about common local oral sensations associated with sublingual administration.

If approved, TNX-102 SL could expand the therapeutic landscape by offering a mechanistically distinct option that aligns symptom relief with improved sleep quality.

In this phase 3 trial, bedtime TNX-102 SL significantly improved pain, sleep, fatigue, and function in fibromyalgia and was generally well tolerated. The results highlight nonrestorative sleep as a viable therapeutic target and support further consideration of TNX-102 SL in fibromyalgia management strategies.

Reference:

Lederman S, Arnold LM, Vaughn B, Engels JM, Kelley M, Sullivan GM. Pain relief by targeting nonrestorative sleep in fibromyalgia: a phase 3 randomized trial of bedtime sublingual cyclobenzaprine.  Pain Med. 2026;27(1):86-94.  doi: 10.1093/pm/pnaf089.