Sublingual cyclobenzaprine for fibromyalgia: a critical evaluation of clinical development and therapeutic positioning

INTRODUCTION: Fibromyalgia combines widespread pain, nonrestorative sleep, fatigue, cognitive symptoms, and functional impairment. Sublingual cyclobenzaprine received US approval for fibromyalgia in August 2025. This narrative review evaluates its development, rationale, pharmacokinetics, efficacy, safety, and therapeutic positioning. DISCUSSION: The search covered PubMed/MEDLINE, trial registries, regulatory sources, and reference lists through 20 August 2026, with an update on 28 September 2026; primary reports and regulatory documents were prioritized. Two of three 5.6-mg phase 3 trials met the pain endpoint; earlier 2.8-mg trials did not. Mean placebo-adjusted pain reductions were 0.4-0.66 points in positive trials. One additional participant achieved ≥30% pain reduction per 6-9 treated; pooled safety data suggested one additional oral mucosal reaction per three treated. These estimates derive from different evidence sets and are not a formal benefit-harm ratio. Frequent oral sensory reactions may cause functional unblinding. Threshold-matched indirect responder benchmarks do not establish superiority over established therapies; altered pharmacokinetics do not establish less next-day impairment than low-dose oral cyclobenzaprine. Positive studies lasted 14 weeks; responder estimates were exploratory. Controlled long-term and comparative-effectiveness data remain limited. Sponsor involvement, the negative RALLY trial, limited geriatric evidence, and absence of active-comparator trials constrain interpretation. CONCLUSIONS: A monitored trial may be reasonable in selected adults with persistent, sleep-prominent symptoms despite multimodal care and low treatment risk, although this phenotype is unvalidated. Continuation should require net improvement in symptoms and daytime function. Independent active-comparator trials, particularly against low-dose bedtime oral cyclobenzaprine, assessing morning alertness, tolerability, and masking would most change the assessment.