Sublingual cyclobenzaprine fares well in fibromyalgia trial

Taking sublingual cyclobenzaprine (TNX-102 SL) at bedtime relieves fibromyalgia symptoms and improves function, a phase III study suggests.

“In this [study], treatment with TNX-102 SL was associated with significantly reduced daily pain compared with placebo at week 14, meeting the primary endpoint. Substantial pain reduction was achieved by week 1 and continued throughout the study,” the investigators said.

At week 14, the change in weekly average daily pain intensity scores from baseline was significantly greater with TNX-102 SL vs placebo (-1.82 vs -1.16; least squares mean difference [LSMD], -0.7; effect size, 0.38; p<0.001). [Pain Med 2026;27:86-94]

The effect size aligns with those of currently approved treatments for fibromyalgia, particularly duloxetine, milnacipran, and pregabalin. [Eur J Pain 2014;18:1067-1080; J Pain 2010;11:505-521; JAMA Netw Open 2022;5:e2212939]

More patients on TNX-102 SL than placebo achieved ≥30 percent (45.9 percent vs 27.1 percent) and ≥50 percent (22.5 percent vs 13.3 percent) pain reduction at week 14.

Sleep improvements

Compared with placebo, TNX-102 SL led to greater changes in PROMIS* Fatigue/Sleep Disturbance scores (LSMD, -3/-4.2) and weekly average of diary-reported sleep quality (LSMD, -0.6; p<0.001 for all).

“Clinically meaningful improvements in sleep quality are relevant because patients with fibromyalgia often report poor sleep quality as their most troublesome symptom, and it has the greatest impact on fatigue, pain, cognitive functioning, and other symptoms,” the researchers explained.

“[The] sleep improvements associated with TNX-102 SL may explain the cascade effect of clinically relevant improvements observed in other fibromyalgia symptoms and suggest long-term TNX-102 SL therapy may interrupt a decompensatory cycle of poor sleep and worse pain,” they continued.

The researchers attributed the improved sleep quality to the unique sublingual, transmucosal route at bedtime, which was designed to generate diurnal variation in peak-to-trough cyclobenzaprine levels, with levels exceeding background norcyclobenzaprine levels during the sleep phase even after chronic dosing. [Sullivan G, et al, ASCP 2019]

Safety profile

The most common systemic treatment-emergent adverse events (TEAEs) with TNX-102 SL and placebo were COVID-19 (4.3 percent vs 3.1 percent), headache (3 percent vs 1.8 percent), and somnolence (3 percent vs 1.3 percent).

The incidence of TEAEs leading to study drug discontinuation was low in both TNX-102 SL and placebo arms (6.1 percent and 3.5 percent), as were the rates of severe (1.3 percent for both) and serious (0.9 percent and 1.3 percent) TEAEs. There were no deaths.

Oral cavity-related TEAEs occurring in ≥2 percent of TNX-102 SL recipients included oral hypoesthesia (23.8 percent), abnormal product taste (11.7 percent), oral paraesthesia (6.9 percent), tongue discomfort (6.9 percent), oral mucosal erythema (2.6 percent), glossodynia (2.2 percent), and tongue disorder (2.2 percent). Of note, about two-thirds of these events resolved in <60 min.

“Oral hypoesthesia and oral paraesthesia were typically temporally related to dosing, transient, and self-limited, and are presumed to result from cyclobenzaprine’s weak antagonist activity on voltage-gated sodium channels,” the researchers noted.

Nociplastic chronic pain syndrome

Fibromyalgia is now recognized as the prototypic nociplastic chronic pain syndrome. [Lancet 2021;397:2098-2110; Pain 2024;165:970-971] The last fibromyalgia pharmacotherapy approved by the US FDA was in 2009. The fibromyalgia therapies approved for pain have limited efficacy for improving sleep quality and fatigue, potentially contributing to polypharmacy and increased opioid use. [Pain Med 2013;14:1400-1415; J Opioid Manag 2019;15:469-477]

“Given the modest efficacy and poor tolerability of current therapies, there remains a significant need for more tolerable therapies that provide long-term, broad symptom relief,” the researchers noted.

Though not approved for fibromyalgia, oral cyclobenzaprine was initially evaluated as a potential treatment owing to pharmacologic similarities with tricyclic antidepressants, but it failed to show substantial benefit. [Arthritis & Rheum 2004;51:9-13; Psychosomatics 2000;41:104-113] Compared with the oral formulation, TNX-102 SL was more rapidly absorbed, had higher bioavailability, and reduced 24-hr exposure to norcyclobenzaprine, the researchers noted.

Sleep disturbance a Tx target

A total of 457 patients (mean age 49.4 years, 95.4 percent women) were randomized 1:1 to TNX-102 SL at bedtime (2.8 mg for 2 weeks, then 5.6 mg for 12 weeks) or to placebo for 14 weeks. The mean duration of fibromyalgia was 9.2 years. The overall average self-reported pain score at baseline was 5.9/10.

Of note, men were underrepresented, and the study had an upper age limit of 65 years. Also, individuals with complex medical and psychiatric histories were excluded. According to the researchers, these may limit generalizability of the findings.

Given that fibromyalgia is a chronic disorder, they also called for longer-term studies to evaluate for sustained efficacy and safety.

Nonetheless, the study showed that TNX-102 SL significantly improved core symptoms of widespread pain, disturbed sleep, and fatigue in fibromyalgia patients and was generally safe and well-tolerated.

“Pharmacotherapy has the potential to provide relief and help [interrupt] nociplastic pain mechanisms underlying fibromyalgia and potentially other chronic overlapping pain conditions,” the researchers noted.

Moreover, the results support disturbed sleep as a target of fibromyalgia pharmacotherapy, they said. “Objective sleep measures, such as polysomnography, can strengthen the findings and can be considered for future trials.”