Sublingual cyclobenzaprine (CBP SL) for fibromyalgia: efficacy and safety in two randomized placebo-controlled trials [118/375 characters, 14/75 words]

Fibromyalgia (FM) is a chronic pain disorder that affects approximately 2%-3% of US adults, occurs predominantly in women, and is characterized by widespread pain, nonrestorative sleep, fatigue, cognitive dysfunction, and functional impairment. Tonmya® (TNX-102 SL; cyclobenzaprine HCl sublingual tablets [CBP SL]) is US FDA-approved for the treatment of FM in adults based on the results from two Phase 3 trials (RESILIENT and RELIEF).

Here, the efficacy of CBP SL in the treatment of pain associated with FM is assessed via responder analyses from the RESILIENT and RELIEF trials; safety findings are also reported.

The prespecified primary endpoint in both studies was the change from baseline in weekly average of daily diary numeric rating scale (NRS) pain intensity scores at Week 14, analyzed using mixed model for repeated measures with multiple imputation for missing data. In both studies, CBP SL treatment resulted in significant improvements in the primary endpoint (RESILIENT, P<0.0001 and RELIEF, P=0.010). A responder analysis was conducted to evaluate clinically meaningful pain reduction, defined as a ≥30% reduction in NRS pain scores. A ≥50% responder analysis was also conducted. Safety assessments included reporting of adverse events (AEs).

In RESILIENT, CBP SL produced higher response rates than placebo for both the ≥30% response threshold (45.9% vs 27.1%; P<0.001, uncorrected) and the ≥50% response threshold (22.5% vs 13.3%; P=0.011, uncorrected). In RELIEF, corresponding uncorrected P-values were P=0.006 for ≥30% pain response, and P=0.141 for ≥50% pain response. CBP SL was generally well tolerated, with a safety profile consistent with prior studies and no new safety signals. The most common AE was transient tongue numbness, which was mild, self-limited, and uncommonly led to study discontinuation. Fatigue was the only systemic adverse event that occured in ≥3% of the pooled safety population with CBP SL treatment.

CBP SL treatment provided significant pain reductions that were clinically meaningful in the RESILIENT and RELIEF trials, making it a promising treatment option and the first US FDA- approved treatment for adults with FM in over 15 years. 

Fibromyalgia (FM) is a chronic pain disorder that affects approximately 2%-3% of US adults, occurs predominantly in women, and is characterized by widespread pain, nonrestorative sleep, fatigue, cognitive dysfunction, and functional impairment. More recently, FM has been understood as the prototypic “nociplastic syndrome”, as discussed by Clauw [1]. Nociplastic pain, a third category of pain distinct from nociceptive pain and neuropathic pain, is characterized by pain arising from altered nociception despite a lack of pathology in peripheral nociceptors. Nociplastic pain is driven by dysregulation in the processing of pain signals within the central nervous system (CNS) and may involve changes in neurotransmitter levels, central sensitization, insufficient deep restorative sleep, and maladaptive neuroplasticity, all of which can amplify pain perception
and contribute to the persistent, diffuse pain that typifies FM.

Approximately 50 years ago, Dr. Harvey Moldofsky recognized the role of nonrestorative sleep in the pathogenesis and persistence of FM [2,3]. Individuals with FM typically suffer from disruptions in the deep restorative stages of sleep, and poor sleep quality is highly associated with the exacerbation and perpetuation of nociplastic pain. Traditional analgesics like NSAIDs or opioids often prove ineffective if not deleterious in nociplastic syndromes; additionally, patient dissatisfaction is common with currently approved products for FM. Cyclobenzaprine HCl (CBP) is a tertiary amine tricyclic (TAT) metabolized in the liver via demethylation to norcyclobenzaprine (nCBP), an active secondary amine tricyclic metabolite (Figure 1). When administered daily as daily oral immediate-release (IR) cyclobenzaprine, the pharmacokinetic (PK) profile for parent CBP is dynamic, with a relatively short half-life. In contrast,  the nCBP metabolite has a significantly longer half-life, leading to its accumulation, a flattened PK profile, and steady-state concentrations that exceed those of CBP. nCBP not only interferes with the receptor binding of CBP but also is a uniquely potent inhibitor of the norepinephrine transporter, which may disrupt restorative sleep, acting against the proposed mechanism of the parent molecule. Like other TATs, oral IR CBP was poorly tolerated (ie, increased frequency of systemic adverse events) in clinical studies, potentially due to reduced receptor binding caused by nCBP accumulation over weeks with daily dosing. Previous studies of oral IR CBP in treating FM demonstrated short-lived improvements in sleep without significant benefits to pain or fatigue, as discussed by Carette et al. [4].

Tonmya® (TNX-102 SL; cyclobenzaprine HCl sublingual tablets [CBP SL]) is an innovative sublingual tablet formulation of CBP, distinct from oral CBP in providing rapid sublingual transmucosal absorption, greater bioavailability, and reduced production of nCBP due to bypassing of first-pass hepatic metabolism, as discussed by Daugherty et al. [5,6]. On the basis of the results from two phase 3 trials (RESILIENT and RELIEF), CBP SL is the first FDA-approved treatment for adults with FM in over 15 years [7,8]. Among its activities, CBP potently binds and antagonizes the 5-HT_2A- serotonergic, α₁-adrenergic, M₁-muscarinic acetylcholine, and H₁-histaminergic receptors, each of which impacts aspects of sleep architecture. CBP SL is hypothesized to work by targeting nonrestorative sleep, a core characteristic of FM.

Here, the efficacy of CBP SL in the treatment of pain associated with FM is assessed via responder analyses from the RESILIENT and RELIEF trials; safety findings are also reported. 

Two pivotal 14-week, randomized, double-blind, placebo-controlled studies were conducted in subjects with FM: RESILIENT (NCT05273749) and RELIEF (NCT04172831), each reported by Lederman et al. [7,8]. Both studies randomized subjects 1:1 to receive CBP SL 2.8 mg for 2 weeks followed by 5.6 mg for 12 weeks or matching placebo for 14 weeks. The primary endpoint was the change from baseline at Week 14 in weekly average of daily diary numeric rating (NRS) scale pain intensity scores analyzed by mixed-model repeated-measures analysis, with multiple imputation for missing data. In this responder analysis, we assessed clinically meaningful improvements in pain via proportions of subjects with a ≥30% and ≥50% improvement from baseline in the weekly average of daily diary pain intensity scores at Week 14. Safety was assessed by adverse events, vital signs/weight, physical exams, clinical lab tests, Columbia-Suicide Severity Rating Scale (C-SSRS), and Beck Depression Inventory II.

Baseline characteristics and demographics were well-balanced between CBP SL and placebo in both trials (Table 1). CBP SL treatment provided statistically significant improvements over placebo on the primary endpoint (pain reduction) at Week 14 in both trials, as shown in Figure 2. In RESILIENT, compared with the placebo group, the CBP SL group had a higher proportion achieving an  ≥30% pain response (45.9% vs 27.1%; P<0.001, uncorrected) and ≥50% pain response (22.5% vs 13.3%; P=0.011, uncorrected). In RELIEF, CBP SL treatment resulted in a higher proportion of patients with ≥30% pain response (46.8% vs 34.9%, respectively; P=0.006, uncorrected) and ≥50% pain response (24.2% vs 18.8%, respectively; P=0.141, uncorrected) compared with placebo (Figure 3). Significant improvements were also noted in the weekly average of the daily diary assessment of sleep quality, a key secondary endpoint, in both trials (Figure 4). CBP SL was generally well tolerated, with a low incidence of systemic TEAEs; fatigue was the only systemic TEAE that occurred at a rate ≥3% in the pooled safety population of the two studies. The most common TEAEs were oral administration site reactions, tongue/mouth numbness or tingling and bitter aftertaste, which were typically transient, self-limited, not severe, and uncommonly led to discontinuation (Table 2). 

FM is the prototypic nociplastic syndrome and chronic overlapping pain condition with CNS symptoms of widespread pain, nonrestorative sleep, fatigue, and cognitive dysfunction, and functional impairment. By pharmacologically targeting nonrestorative sleep, daily treatment with CBP SL at bedtime resulted in substantial and clinically meaningful pain relief. CBP SL was generally well tolerated, with an AE profile consistent with previous studies; no new safety signals were observed. Together, these findings are consistent with the concept that disturbed sleep in FM is an obstacle to recovery and pharmacological targeting of nonrestorative sleep may facilitate recovery.