Cyclobenzaprine Reimagined: Clinical Insights Into Tonmya for Fibromyalgia

Abstract

Objective: To review the efficacy, safety, and tolerability of a sublingual formulation of cyclobenzaprine for the treatment of fibromyalgia. Data Sources: A literature search was conducted through PubMed and DrugBank using the following terms: cyclobenzaprine, fibromyalgia, sublingual, Tonmya, and TNX-102 SL. Study Selection and Data Extraction: Articles describing the pharmacology, pharmacokinetics, efficacy, safety, and/or tolerability of sublingual cyclobenzaprine were included in this review. Data Synthesis: Cyclobenzaprine is a tricyclic antidepressant like agent which exhibits sedative and muscle relaxant effects in the treatment of fibromyalgia. Clinical trials have demonstrated improvements in daily pain scores compared with placebo. Common adverse events associated with this agent include oral hypoesthesia, oral paresthesia, and abnormal taste. Conclusions: Pharmacologic agents receive a weak recommendation for use in the treatment guidelines and include agents such as duloxetine, pregabalin, tramadol, amitriptyline, and a nonsublingual formulation of cyclobenzaprine. Tonmya, the newest agent approved for fibromyalgia, provides clinicians with an additional treatment option in a convenient dosage form for this potentially debilitating condition.

Introduction

Fibromyalgia (FM) is a chronic pain condition affecting approximately 10 million Americans. Although FM can affect patients of any age, the diagnosis of FM is usually made between the ages of 20 and 50 years old. In addition to widespread pain, FM can result in poor sleep, fatigue, memory impairment, anxiety, and depression.^1,2 Risk factors associated with the development of FM include genetics, female sex, inflammatory conditions, as well as mental health disorders. ³ The diagnosis of FM is confirmed when symptoms have been present for at least 3 months and include generalized pain in at least 4 of 5 regions in addition to a widespread pain index (WPI) ≥7 and symptom severity scale (SSS) ≥5 OR WPI between 4 and 6 and SSS ≥9 (detailed information can be found in Table 1). ⁴

Table 1.

Assessment of Widespread Pain Index and Symptom Severity Scale. ⁴

Widespread Pain Index (WPI): assign 1 point for each area the patient has experienced pain in over the past week [maximum score = 19]
Left upper region	Right upper region	Left lower region	Right lower region	Axial region
Jaw a Shoulder Girdle Upper Arm Lower Arm	Jaw a Shoulder Girdle Upper Arm Lower Arm	Hip Upper Leg Lower Leg	Hip Upper Leg Lower Leg	Neck Upper Back Lower Back Chest a Abdomen a
Symptom Severity Scale (SSS) [maximum score = 12]: The sum of the severity scores for fatigue, waking unrefreshed, and/or cognitive symptoms plus the presence of headaches, pain or cramps in lower abdomen, and/or depression in past 6 months  • Indicate the level of severity for each of the following symptoms over the past week (0 = no problem, 1 = slight or mild problem, 2 = moderate, considerate problem, 3 = severe)   ○ Fatigue   ○ Waking unrefreshed   ○ Cognitive symptoms  • Indicate the number for each of the following symptoms that patient has been bothered by over the past 6 months (0-1)   ○ Headaches   ○ Pain or cramps in lower abdomen   ○ Depression

^aNot included in generalized pain assessment.

Individualized aerobic and resistance exercise represents the most effective treatment for FM and is the only modality to receive a strong recommendation in the guidelines. ⁵ Current guidelines also acknowledge several other nonpharmacologic interventions; however, these receive only weak recommendations. Such interventions include cognitive behavioral therapy, acupuncture, hydrotherapy, and meditative movement practices, notably tai chi and yoga. ⁵ Pharmacologic interventions for FM are also assigned weak recommendations in the guidelines. These include duloxetine, pregabalin, and tramadol for severe pain, as well as amitriptyline, oral cyclobenzaprine, and pregabalin for significant sleep disturbances. ⁵

Cyclobenzaprine has been used off label for the treatment of FM for decades. In fact, a meta-analysis published in 2004 showed patients with FM experienced moderate improvements in sleep and modest reductions in pain as a result of treatment with cyclobenzaprine 10 mg. ⁶ Results from a more recent study utilizing a lower dose of cyclobenzaprine (1-4 mg) showed patients with FM experienced improvements in pain, tenderness, fatigue, mood, and sleep quality. ⁷ Tonmya, a sublingual (SL) low-dose cyclobenzaprine formulation, represents the first potential pharmacologic advancement for FM in over 15 years.

Data Selection

A literature search was conducted using PubMed and DrugBank with an end search date of November 30, 2025, with the following key-words: cyclobenzaprine, fibromyalgia, sublingual, Tonmya, and TNX-102 SL. All relevant English-language studies assessing the pharmacology, pharmacokinetics, efficacy, safety, and tolerability of sublingual cyclobenzaprine were reviewed. In addition, FDA product labeling information for Tonmya was reviewed.

Pharmacology

Cyclobenzaprine, the active ingredient in Tonmya, is structurally related to tricyclic antidepressants (TCAs). Although its precise mechanism in FM is unknown, in vitro studies demonstrate functional antagonism at several receptor sites, including 5-HT₂A, α₁-adrenergic, H₁-histaminergic, and M₁-muscarinic acetylcholine receptors. Animal pharmacology studies reveal similarities to TCAs, such as norepinephrine potentiation, reserpine antagonism, and both central and peripheral anticholinergic effects. These properties contribute to its sedative and muscle relaxant effects, which may underlie its therapeutic benefit in FM. ⁸

Pharmacokinetics

Following sublingual administration, cyclobenzaprine exhibits dose-proportional increases in peak plasma concentration (C_max) and systemic exposure (AUC). The median time to peak concentration is approximately 4.3 hours. Steady-state accumulation is observed with daily dosing, reaching approximately 2.5-fold after 20 days. Food intake reduces C_max by approximately 10% without affecting overall exposure. Cyclobenzaprine is extensively metabolized via CYP3A4, CYP1A2, and to a lesser extent CYP2D6, and is primarily excreted as glucuronides via the kidneys. The elimination half-life is approximately 36 hours. In geriatric patients and those with hepatic impairment, AUC is increased, warranting dosage adjustments. ⁸

Clinical Trials

Food and Drug Administration approval of Tonmya for FM stemmed from results of the RELIEF and RESILIENT trials discussed within this section.^9,10 A similar trial, the RALLY trial, was stopped early due in part to high discontinuation rates related to adverse events. The high discontinuation rates may have been due to the timing of the trial as it occurred during the peak of COVID-19. ¹⁰ In addition, interim results revealed no significant differences in pain scores compared with placebo. ¹¹

The RELIEF trial consisted of a randomized, double-blind, multicenter, phase 3 placebo-controlled trial of treatment of FM with TNX-102 (cyclobenzaprine) SL 5.6 mg once daily at bedtime over a 14-week period. ⁹ Patients included in this study were between the ages of 18 and 65 years with primary FM. Additional inclusion criteria included: generalized pain, similar level of pain for >3 months, WPI >7 and SSS >5 OR WPI between 4 and 6 and SSS >9, and absence of other conditions that could justify the pain experienced. The primary endpoint consisted of the change from baseline in weekly average of daily pain scores. The secondary endpoints included: Fibromyalgia Impact Questionnaire Revised (FIQR) symptom and function scores, Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance and fatigue scores, the proportion of patients reporting “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC) scale, and weekly average of patient reported daily sleep quality. The treatment group consisted of 248 patients and the placebo group contained 255 patients with 204 patients and 213 patients, respectively, completing the study. A larger percentage of patients experienced a ≥30% reduction in the primary endpoint in the treatment group (46.8%) as compared with the placebo group (34.9%) (odds ratio 1.67; 95% CI [1.16, 2.40]; P = 0.006). Significant between-group differences were observed for all secondary endpoints except PGIC scores. Although PGIC scores did not meet the predefined threshold for statistical significance, a nominal improvement was noted in the TNX-102 SL group. Treatment-emergent adverse events (TEAEs) rated as mild to moderate in severity occurred in 59.7% of TNX-102 SL recipients and 46.3% of placebo recipients. The most common AEs associated with TNX-102 SL were oral hypoesthesia (17.3% vs 0.4%), oral paresthesia (5.6% vs 0.4%), and abnormal taste (4.4% vs 0.4%). Based on these results, the investigators concluded that treatment with TNX-102 SL over 14 weeks was correlated with a decrease in daily pain in comparison.

The RESILIENT trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of bedtime TNX-102 SL in adults with FM. ¹⁰ The trial enrolled 457 participants aged 18 to 65 years who had generalized pain in 4 of 5 regions for ≥3 months and a WPI ≥7 with a SSS ≥5, or WPI 4 to 6 with SSS ≥9. Eligible participants were randomized 1:1 to receive TNX-102 SL 2.8 mg nightly for 2 weeks followed by 5.6 mg nightly for 12 weeks or matching placebo, for a total 14-week treatment duration and 2-week safety follow-up. The primary endpoint was change from baseline to week 14 in the weekly average of daily diary pain intensity scores. Key secondary endpoints included the proportion of patients reporting “much improved” or “very much improved” on the PGIC scale, changes in the FIQR symptoms and function domain scores, PROMIS sleep disturbance and fatigue scores, and weekly average of daily diary sleep quality scores. Treatment with TNX-102 SL produced significant improvements in the primary pain endpoint compared with placebo (least-squares mean [LSM] change −1.8 vs −1.2; difference = −0.7 [95% CI, −1.0 to −0.3]; P < 0.001), corresponding to an effect size of 0.38 which is comparable to currently FDA-approved FM pharmacotherapies such as duloxetine (0.36), pregabalin (0.31), and milnacipran (0.22). Notably, 45.9% of patients receiving TNX-102 SL achieved ≥ 30% pain reduction compared with 27.1% on placebo, and 22.5% achieved ≥ 50% pain reduction versus 13.3% with placebo. Significant improvements were also observed across all prespecified secondary endpoints. TEAEs occurred in 58.9% of TNX-102 SL recipients and 36.7% of placebo recipients, with most events mild or moderate in severity. The most common associated with TNX-102 SL were oral hypoesthesia (23.8% vs 0.4%), abnormal taste (11.7% vs 0.9%), and oral paresthesia (6.9% vs 0.9%); however, these were transient and self-limited, typically resolving within less than 60 minutes. Systemic TEAEs were uncommon and similar between groups, with COVID-19 (4.3%), somnolence (3.0%), and headache (3.0%) most frequent. No clinically meaningful changes were observed in vital signs, laboratory parameters, or suicidality assessments. Overall, the RESILIENT trial confirmed that TNX-102 SL 5.6 mg nightly significantly improves the core FM symptoms of pain, sleep disturbance, and fatigue while maintaining a favorable tolerability profile. These findings were consistent with outcomes from the earlier phase 3 RELIEF trial and demonstrated improved safety relative to the RALLY trial.

Safety

The safety of Tonmya has been evaluated in 2 pivotal phase 3, double-blind, placebo-controlled clinical trials which enrolled more than 1100 adults with FM who received treatment for 12 to 14 weeks.^{8 -10} Safety data from clinical trials are summarized in Table 2. The most frequently reported adverse events included oral hypoesthesia, oral discomfort, abnormal taste, somnolence, oral paresthesia, oral pain, fatigue, and dry mouth. Serious adverse events were uncommon and occurred at rates similar to placebo. In the RESILIENT study, suicidal ideation was reported in 3 patients receiving Tonmya and 2 receiving placebo. No suicidal behavior or Columbia-Suicide Severity Rating Scale type 3 to 5 events were observed. ¹⁰

Table 2.

Safety Data From Trials of Sublingual Cyclobenzaprine for the Treatment of Fibromyalgia.^9,10

	RELIEF (2023)		RESILIENT (2025)
	Tonmya 5.6 mg (n = 365)	Placebo (n = 374)	Tonmya 5.6 mg (n = 231)	Placebo (n = 226)
≥ 1 treatment-emergent adverse event	59.7%	46.3%	58.9%	36.7%
Serious adverse events	–	–	0.9%	1.3%
Discontinuations due to adverse events	8.9%	3.9%	6.1%	3.5%
Suicidal ideation	–	–	1.3% (3 patients)	0.9% (2 patients)
Most common TEAEs (≥5%)	Oral hypoesthesia, oral paresthesia, abnormal taste, somnolence	—	Oral hypoesthesia, oral discomfort, somnolence, dry mouth	—

Adverse reactions reflected the pharmacologic activity of cyclobenzaprine and included central nervous system (CNS) effects such as somnolence and fatigue as well as anticholinergic effects such as dry mouth and urinary retention. Tonmya carries warnings for serotonin syndrome (when used with serotonergic agents), atropine-like reactions, and additive CNS depression that may impair driving or operation of machinery. ⁸

Overall, Tonmya demonstrated a favorable tolerability profile. Adverse events were primarily localized to the oral cavity or limited to short-lived sedation following bedtime dosing. Consistent safety findings across RELIEF and RESILIENT support its use as a once-nightly sublingual therapy for FM with minimal systemic toxicity and low discontinuation rates.^8-10

Drug Interactions

Tonmya, a tricyclic compound, exhibits several clinically significant drug interactions. Concomitant use with monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of life-threatening hyperpyretic crises and serotonin syndrome. ¹² Caution is advised when administered with other serotonergic agents (eg, SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil), as postmarketing cases of serotonin syndrome have been reported. ⁸ If symptoms such as confusion, autonomic instability, or neuromuscular abnormalities occur, patients should be instructed to discontinue Tonmya immediately.

Tonmya may potentiate CNS depressant effects when used with alcohol, barbiturates, or other CNS depressants, increasing the risk of sedation and impaired motor function. Co-administration with tramadol may elevate seizure risk. In addition, Tonmya may interfere with the antihypertensive efficacy of guanethidine and similar agents.^8,13 Clinical judgment should guide the decision to use Tonmya alongside serotonergic or CNS-active medications, with close monitoring during initiation and dose adjustments. Patients should be counseled on potential interaction risks and advised to report any concerning symptoms promptly.

Dosing and Administration

Tonmya is available as a 2.8 mg sublingual tablet. Dosing should follow a 2-week titration period beginning with 2.8 mg nightly on days 1 through 14, then increasing to the target dose of 5.6 mg nightly from day 15 onward. The maximum recommended dose is 5.6 mg once daily. ⁸

In geriatric patients, the recommended and maximum dosage is 2.8 mg nightly because of increased sensitivity to CNS and anticholinergic effects. For patients with mild hepatic impairment (Child Pugh A), the same 2.8 mg nightly dose is advised, while Tonmya is not recommended for those with moderate or severe hepatic impairment (Child Pugh B or C). No dosage adjustment is required for renal dysfunction. ⁸

Before administration, patients should ensure the mouth is moist by taking a few sips of water. The tablet is then placed under the tongue until fully dissolved and should not be swallowed, cut, or chewed. Food and beverage should be avoided for at least 15 minutes after dosing; preferably until the following morning. Patients should also refrain from talking for approximately 5 minutes after administration. If a dose is missed, it should be taken the next evening at the regular bedtime; missed doses should not be taken during the day. ⁸

Pregnancy testing is recommended in females of reproductive potential before initiating therapy due to the risk of embryofetal toxicity. Tonmya is contraindicated in patients with hypersensitivity to cyclobenzaprine; use of MAOIs within 14 days; acute recovery phase of myocardial infarction; arrhythmias, heart block, or heart failure; or hyperthyroidism. ⁸

Place in Therapy

Each of the pharmacologic agents for FM receive, at best, a weak recommendation in the treatment guidelines. In addition, individual agents come with their own limitations for use, especially when considering the chronic nature of FM. The pharmacologic agents include duloxetine, pregabalin, and tramadol for severe pain and amitriptyline, cyclobenzaprine, and pregabalin for significant sleep disturbances. ⁵ The use of duloxetine may be limited by CNS related adverse effects such as dizziness, drowsiness, and difficulty concentrating, as well as drug interactions due to CYP2D6 inhibition. ¹⁴ Like duloxetine, pregabalin can produce CNS side effects, as well as respiratory depression. ¹⁵ Pregabalin and tramadol are both classified as controlled substances, thus, chronic use requires careful consideration. Amitriptyline, a TCA, can cause anticholinergic side effects and should be avoided in some patient populations (such as those with preexisting cardiovascular disease). ¹⁶ Treatment guidelines supporting cyclobenzaprine use were based on traditional dosing (10-40 mg), which often resulted in high rates of treatment discontinuation due to dose dependent anticholinergic side effects. ⁵ Table 3 summarizes the major similarities and differences among these first-line therapies and offers practical counseling points to support clinical decision-making in the management of fibromyalgia.

Table 3.

Pharmacologic Therapies for the Treatment of Fibromyalgia. ⁸ ,^14-17

Medication name	Dosing a	Mechanism of action	Common adverse effects	Serious risks/warnings	CYP drug interactions	Monitoring parameters
Duloxetine (Cymbalta)	60 mg PO once daily	5HT and NE reuptake inhibitor	-Nausea -Dry Mouth -Somnolence -Fatigue -Constipation -Dizziness -Difficulty concentrating	-Suicidality -Serotonin syndrome -Abnormal bleeding -Hypotension and syncope -CNS depression	-CYP2D6 inhibitor -CYP1A2 substrate	-BP -HR -Signs or symptoms of bleeding -Suicidal thoughts
Pregabalin (Lyrica)	75 to 150 mg PO twice daily	Unknown (GABA analogue, reduces neuronal calcium currents)	-Dizziness -Somnolence -Dry mouth -Edema -Blurred vision -Weight gain -Difficulty concentrating	-Suicidality -Respiratory depression -Angioedema -Potential misuse (schedule V) -CNS depression	N/A	-Suicidal thoughts -RR
Tramadol (Ultram)	100 to 300 mg PO once daily (ER)	Opioid agonist and 5HT/NE reuptake inhibitor	-Nausea -Constipation -Dry mouth -Somnolence -Dizziness	-Suicidality -Serotonin syndrome -Respiratory depression -Potential misuse (schedule IV) - CNS depression	-CYP2D6 substrate -CYP3A4 substrate	-LFTs -SCr -Suicidal thoughts -RR
Amitriptyline (Elavil)	10 to 50 mg PO once daily	Not fully understood (affects uptake of 5HT and NE; also histamine and cholinergic effects)	-Drowsiness -Dizziness -Difficulty concentrating -Memory impairment	-Pre-existing CVD -Suicidality -Serotonin syndrome -CNS depression	-CYP2D6 substrate	-BP -ECG -HR -LFTs -TFTs -Suicidal thoughts
Cyclobenzaprine (Flexeril)	10 to 40 mg PO daily	Unknown (antagonizes 5HT, α-1, H1, and M1 receptors)	-Drowsiness -Dizziness -Constipation -Headache -Fatigue	-CNS depression -Pre-existing CVD -Hyperthyroidism -Serotonin syndrome	-CYP1A2 substrate -CYP3A4 substrate -CYP2D6 substrate	-TFTs
Cyclobenzaprine (Tonmya)	2.8 to 5.6 mg SL once daily	Unknown (antagonizes 5HT, α-1, H1, and M1 receptors)	-Oral numbing, discomfort, pain -Abnormal taste -Somnolence -Fatigue -Dry mouth	-Serotonin syndrome -Atropine like reactions -CNS depression	-CYP1A2 substrate -CYP3A4 substrate -CYP2D6 substrate	-TFTs

Abbreviations: BP, blood pressure; CVD, cardiovascular disease; ECG, electrocardiogram; ER, extended release; HR, heart rate; LFTs, liver function tests; NE, norepinephrine; PO, by mouth; RR, respiratory rate; SCr, serum creatinine;; SL, sublingual; TFTs, thyroid function tests; 5HT, serotonin.

^aTypical dosing in adults for FM.

Tonmya delivers pain relief along with improvements in fatigue and sleep disturbances at a lower dose than traditional cyclobenzaprine therapy for FM, while offering an enhanced dosage form. Despite its proven efficacy, use of Tonmya may be cost prohibitive for some patients due to a cash price of up to $1900 for a 30-day supply of 2.8 mg tablets. ¹⁸ This is in comparison to costs of approximately $20 to 30 per month for many of the other treatment options used for FM. ¹⁹

Conclusion

Tonmya is the newest medication for fibromyalgia approved in the past 15 years. Data from clinical trials show this agent decreases pain while also providing additional benefits on sleep and fatigue. Its unique dosage form allows for potentially quicker onset of action compared with traditional agents used for FM. Postmarketing surveillance data on Tonmya will provide further insight into its long-term safety and efficacy, helping to clarify its role in fibromyalgia treatment.