Daily Sublingual Cyclobenzaprine Improves Sleep, Pain Outcomes in Fibromyalgia Patients

Gregory Sullivan, MD

Investigative cyclobenzaprine HCl sublingual tablets (TNX-102 SL) may provide benefit to impaired sleep due to pain and symptoms brought on fibromyalgia.

New data presented by investigators from Tonix Pharmaceuticals at the American College of Rheumatology (ACR) 2021 Convergence this week suggested the company’s sublingual tablet therapy may reduce central sensitization—a constellation of fibromyalgia symptoms including chronic pain, fatigue, and nonrestorative sleep—by primarily improving patients’ rate of disturbed sleep.

Led by Gregory Sullivan, MD, Chief Medical Officer of Tonix, investigators conducted the phase 3 RELIEF trial to assess the efficacy and safety of 5.6 mg TNX-102 SL in patients with fibromyalgia. “Prior studies of TNX at a 2.8 mg dose in fibromyalgia showed signals for broad efficacy but narrowly missed significance on primary outcome of daily diary pain reduction,” investigators wrote. “This phase 3 trial evaluated efficacy and safety of TNX for fibromyalgia at twice the dose.”

Sullivan and colleagues observed an intent-to-treat cohort of 503 patients with fibromyalgia who received 2.8 mg TNX-102 SL or placebo for 2 weeks, followed by 5.6 mg TNX-102 SL or placebo for 12 weeks. Eligible patients met 2016 fibromyalgia diagnostic criteria and were enrolled at 39 sites across the US.

Investigators sought a primary outcome of change from baseline in weekly mean daily patient diary pain scores per a 0-10 Numerical Rating Scale (NRS) at week 14; they analyzed this outcome through mixed model repeated measures with multiple imputation. Key secondary analyses included:

• Patient Global Impression of Change (PGIC) responders by logistic regression
• Fibromyalgia Impact Questionnaire-Revised (FIQ-R) symptom domain
• FIQ-R function domain
• Patient Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance
• PROMIS Fatigue
• Daily diary NRS of sleep quality

TNX-102 SL was associated with decreased daily diary pain scores in patients with fibromyalgia versus placebo (P = .01); nearly half of all treated patients who responsed to therapy (46.8%) reported a ≥30% pain reduction versus 34.9% of patients on placebo (P = .006). Patients on TNX-102 SL were also more likely to achieve PGIC response than patients on placebo (37.5% vs 29.4%; P = .058).

Investigators additionally observed improvements in FIQ-R Symptoms (P = .007), function (P = .009), PROMIS Sleep Disturbance (P <.001) and fatigue (P = .018), as well as daily diary sleep quality (P <.001) in treated patients versus placebo.

Trial completion rates were similar between the TNX-102 SL and placebo groups (82.3% vs 83.5%). Somnolence/sedation was the lone systemic adverse event to occur in ≥5% of patients on therapy (5.6% vs 1.2% in placebo). Oral numbness occurred in 17.3% of patients administered TNX-102 SL, versus just 0.8% of placebo patients; however, it was deemed episodic, generally resolving in less than 60 minutes. Treatment-associated trial discontinuation occurred in 8.9% of patients in the TNX-102 SL arm.

Overall, however, the Tonix investigators concluded that bedtime administration of 5.6 mg TNX-102 SL “showed activity in improving sleep, fatigue, and other fibromyalgia symptoms and measures of function.”

“Taken together, these findings indicate TNX-102 SL primarily targets sleep quality and may thereby reduce central sensitization, leading to improvement at the syndromal level, manifesting as broad-spectrum activity across symptoms of fibromyalgia,” they wrote.

The study, “TNX-102 SL (Sublingual Cyclobenzaprine) for the Treatment of Fibromyalgia in the RELIEF Study: Positive Results of a Phase 3 Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy and Safety Trial,” was presented at ACR 2021.