Tonmya™ the new drug for fibromyalgia is no more useful than Flexeril™

Critical analysis: sublingual cyclobenzaprine (Tonmya™) vs oral cyclobenzaprine (Flexeril™)

Pradeep Chopra, MD, MHCM

Background – understanding the drug

Cyclobenzaprine is a tricyclic amine originally developed as an antidepressant. Its structure and pharmacology are like amitriptyline. The drug is a centrally acting muscle relaxant but most of its clinical effects stem from antagonism at several neurotransmitter receptors – it binds to serotonergic‑5‑HT2A, α1‑adrenergic, histamine‑H1 and muscarinic‑M1 receptors. These actions produce sedation, anticholinergic effects and suppression of arousal rather than true muscle relaxation In USA cyclobenzaprine has been prescribed for decades for acute musculoskeletal pain at doses of 5–10 mg up to three times per day, but it lacks robust evidence for long‑term benefit and is associated with significant drowsiness and anticholinergic adverse events. The drug’s mean elimination half‑life is about 18 hours (range 8–37 h) and can be as long as 30 hours meaning it accumulates with repeated dosing. Oral bioavailability is moderate – pharmacokinetic studies estimate that 33–55 % of an oral dose reaches systemic circulation and about 93 % is bound to plasma proteins. Cyclobenzaprine is metabolized primarily by hepatic CYP 3A4 and 1A2; the major metabolite is norcyclobenzaprine (nCBP).

Norcyclobenzaprine is not an inert metabolite. An American College of Rheumatology abstract measured plasma concentrations after a 5 mg oral dose and found that nCBP has a longer half‑life (≈73 h) and persists in the plasma at higher area‑under‑the‑curve values than cyclobenzaprine itself. In vitro, both cyclobenzaprine and nCBP display high‑affinity antagonism at 5‑HT2A and 5‑HT2C serotonin receptors, α1‑adrenergic receptors and H1 histamine receptors. The metabolite is therefore pharmacologically active and contributes to the drug’s sedative, antihistamine and sympatholytic effects. Because nCBP lacks a stable glucuronide, it clears more slowly and accumulates with chronic dosing.These data suggest that reducing formation of nCBP could reduce the duration of effect but may also shorten the drug’s sleep‑promoting action.

Claims made for Tonmya (sublingual cyclobenzaprine)

Tonix Pharmaceuticals’ product Tonmya (previously TNX‑102 SL) consists of 2.8‑mg cyclobenzaprine tablets formulated to disintegrate under the tongue. The company states that this design provides “rapid transmucosal absorption and reduced production of a long‑half‑life active metabolite, norcyclobenzaprine, due to bypass of first‑pass hepatic metabolism”. A Drugs.com review similarly notes that the sublingual formulation “offers advantages over traditional oral formulations by enabling rapid absorption into the bloodstream and bypassing first‑pass hepatic metabolism. This reduces the formation of norcyclobenzaprine which may improve tolerability”. These statements imply that sublingual delivery confers pharmacokinetic and clinical superiority over standard oral tablets.

Tonmya was evaluated in two phase‑III trials (RELIEF and RESILIENT). In the RELIEF trial (503 participants with fibromyalgia), patients started with 2.8 mg nightly and titrated to 5.6 mg; the reduction in average daily pain at week 14 was −1.9 on a 10‑point scale versus −1.5 with placebo – a statistically significant but clinically modest difference of 0.4 points. Treatment‑emergent adverse events were common (59.7 % with Tonmya vs 46.3 % with placebo); the most frequent were oral hypoesthesia (17.3 %), oral paraesthesia and abnormal taste. These adverse events are unique to the sublingual route and result from the eutectic excipients used to dissolve the tablet. Serious anticholinergic and central nervous system warnings still apply, and the product label advises avoiding hazardous activities due to possible impairment.

Critical examination of the pharmacokinetic rationale

1. First‑pass metabolism is not severe enough to make sublingual delivery novel. Oral cyclobenzaprine exhibits mean bioavailability between 33 % and 55 %. While first‑pass metabolism does reduce systemic exposure, roughly half of an oral dose still reaches the circulation. Sublingual absorption might modestly increase the proportion that bypasses the liver, but this advantage is mitigated by the drug’s long half‑life (18–37 h). With such a long half‑life, slight differences in the rate of absorption are unlikely to produce clinically meaningful changes in steady‑state concentrations.

2. Norcyclobenzaprine is an active component, not a toxin to be avoided. Tonix’s marketing implies that reducing formation of nCBP improves safety. However, the ACR study demonstrated that nCBP persists in plasma longer (T½ ≈ 73 h) and has receptor affinity values only slightly weaker than parent cyclobenzaprine (e.g., Ki ≈ 13 nM at 5‑HT2A vs 5.2 nM for cyclobenzaprine). Both compounds act as functional antagonists at 5‑HT2A, H1 and adrenergic receptors. It is therefore plausible that nCBP contributes to the drug’s sleep‑promoting effect. Reducing formation of this metabolite might decrease prolonged sedation, but it could also shorten therapeutic benefit and diminish improvements in sleep quality. Observational experience with low‑dose oral cyclobenzaprine (1–4 mg at bedtime) suggests that sustained sedative effects are critical for improving non‑restorative sleep in fibromyalgia.

3. Dose, not delivery route, explains lower drug exposure. Tonmya tablets contain 2.8 mg of cyclobenzaprine, whereas the commonly prescribed immediate‑release tablet is 5 mg. Because cyclobenzaprine demonstrates linear pharmacokinetics over the dose range 2.5–10 mg, halving the dose will roughly halve plasma concentrations regardless of route. There is no evidence that a person cannot simply take an oral 2.5 mg tablet (easily obtained as half of a 5 mg tablet) to achieve similar exposure. Moreover, the Therapeutics Initiative’s dose‑response analysis found that 5 mg three times daily was as effective as 10 mg three times daily but caused less sedation, and higher doses produced no additional analgesiat. The letter recommended trying 5 mg at bedtime and titrating only if needed, because there is little evidence that higher or more frequent doses improve outcomes. These findings indicate that low oral doses can already minimize sedation and maintain efficacy; a sublingual route is unnecessary to achieve this.

Clinical evidence for oral cyclobenzaprine in fibromyalgia

Cyclobenzaprine has been used off‑label to treat insomnia and pain in fibromyalgia. A review of placebo‑controlled trials found that only six RCTs studied cyclobenzaprine for fibromyalgia, with durations of 4 weeks to 6 months. A 3‑month trial showed modest improvements in patient‑reported sleep, pain and morning stiffness by the first week; however, the number needed to treat (NNT) for moderate improvement was 7–8, meaning most patients derive little benefit. Importantly, withdrawals due to adverse events were consistently higher with cyclobenzaprine than placebo, and the most common harms were drowsiness/fatigue, dizziness and dry mouth. The Therapeutics Initiative estimated a number needed to harm (NNH) of 4–5 over two weeks, reflecting a narrow therapeutic margin. Overall, the letter concluded that there is no compelling evidence that cyclobenzaprine is a true muscle relaxant and that its perceived benefits likely result from sedation. Thus, even the standard oral drug offers only modest symptom relief with frequent adverse effects.

Comparison of Tonmya to oral cyclobenzaprine

The sublingual formulation appears to offer pharmacokinetic differences on paper, yet clinical outcomes are strikingly similar:

Aspect

Evidence for oral cyclobenzaprine (Flexeril/low‑dose)

Evidence for sublingual Tonmya

Active ingredient

Cyclobenzaprine, a tricyclic amine acting as a 5‑HT2A, α‑adrenergic, H1 and muscarinic receptor antagonist.

Same active ingredient no new pharmacodynamics

Dose and administration

Typically 5–10 mg up to 3 ×/day for acute spasm; off‑label low‑dose 1–4 mg at bedtime for fibromyalgia.

2.8 mg tablet placed under tongue (Tonmya); titrated to 5.6 mg/night.

Pharmacokinetics

Oral bioavailability ~33–55 %; elimination half‑life 18–37 h; metabolized to active nCBP with half‑life ~73 h.

Sublingual avoids some first pass; manufacturer claims reduced nCBP formation. However, the half‑life of parent drug is unchanged; exposures largely reflect the lower dose.

Efficacy in fibromyalgia

NNT 7–8 for moderate improvement sedation improves sleep; benefits modest

Phase‑III RELIEF trial difference in pain score = −1.9 vs −1.5 (difference ~0.4). improvements modest, similar to oral low‑dose studies.

Adverse effects

Drowsiness/fatigue, dizziness, dry mouth common; NNH 4–5. sedation and anticholinergic effects dose‑limiting.

Oral hypoesthesia, taste alteration and mouth paraesthesia unique to sublingual route. Fatigue/drowsiness still reportedwarnings for CNS depression and anticholinergic reactions remain

Value proposition

Generic 5 mg tablets cost pennies; splitting yields ~2.5 mg dose.

Patented formulation with exclusivity until at least 2034significantly higher cost for the same drug.

Conclusion – why Tonmya is not meaningfully different from oral cyclobenzaprine

Sublingual Tonmya and oral cyclobenzaprine share the same active ingredient and same receptor‑binding profile. The claimed advantage of avoiding first‑pass metabolism is overstated, because oral cyclobenzaprine already achieves moderate bioavailability and the drug’s long half‑life makes minor differences in absorption clinically irrelevant. Moreover, norcyclobenzaprine – the metabolite Tonmya seeks to avoid – is itself a biologically active antagonist at 5‑HT2A, H1 and adrenergic receptors, and likely contributes to sleep maintenance. Reducing its formation could shorten sedation and potentially diminish benefit, undermining the rationale for bypassing first‑pass metabolism.

Evidence for cyclobenzaprine in fibromyalgia is weak: a comprehensive review concluded that most patients do not benefit and that any perceived relief results largely from sedation with a high rate of adverse events. The phase‑III trial of Tonmya produced a difference of only 0.4 points on a 10‑point pain scale, a magnitude similar to placebo‑controlled trials of low‑dose oral cyclobenzaprine. Importantly, Tonmya introduces new adverse events such as oral numbness and taste alteration.  without eliminating systemic sedative and anticholinergic risks. Low‑dose oral cyclobenzaprine (2–5 mg at bedtime) is inexpensive, widely available and already minimizes sedation; there is no compelling evidence that a 2.8 mg sublingual tablet offers superior efficacy or safety.

In summary, sublingual cyclobenzaprine (Tonmya) is essentially a repackaged low‑dose formulation of cyclobenzaprine, marketed as a novel drug through its patented delivery system. Its pharmacokinetic differences are small, its clinical benefit is modest and comparable to existing oral formulations, and its unique adverse effects may outweigh the theoretical advantage of reduced metabolite formation. Clinicians should therefore critically evaluate manufacturer claims and consider whether simple, low‑dose oral cyclobenzaprine would provide equivalent benefit at far lower cost.

In summary, the report concludes that Tonmya’s sublingual delivery offers only minor pharmacokinetic differences compared to oral cyclobenzaprine. Despite claims of reduced metabolite formation, the active metabolite norcyclobenzaprine remains pharmacologically relevant and may contribute to therapeutic effects. The analysis shows that dosing, rather than delivery route, largely explains any variation in drug exposure. It highlights that low-dose oral cyclobenzaprine already achieves similar outcomes and underscores that Tonmya’s modest pain reduction and unique oral adverse effects do not justify its higher cost or novelty. The conclusion advises clinicians to weigh claims critically and consider low-dose oral formulations as cost-effective alternatives.

‍

·  Tonix Pharmaceuticals. Tonix Pharmaceuticals Announces FDA Approval of Tonmya™ (cyclobenzaprine HCl sublingual tablets) for the Treatment of Fibromyalgia. This press release describes Tonmya and claims rapid transmucosal absorption with reduced production of norcyclobenzaprine due to bypass of first-pass metabolism.

https://ir.tonixpharma.com/news-events/press-releases/detail/1585/tonix-pharmaceuticals-announces-fda-approval-of#:~:text=About%20Tonmya™%C2%A0,now%20approved%20as%20a%20once

·  Therapeutics Initiative. [105] Is cyclobenzaprine useful for pain? This review discusses cyclobenzaprine’s pharmacokinetics, evidence from randomized controlled trials, adverse effects, and conclusions about its modest benefits and prominent sedative/anticholinergic effects. https://www.ti.ubc.ca/2017/07/24/105-cyclobenzaprine/#:~:text=Harm%20from%20cyclobenzaprine

·  American College of Rheumatology Meeting Abstract. Cyclobenzaprine and Its Major Metabolite Norcyclobenzaprine Are Potent Antagonists of Human Serotonin Receptor 2A, Histamine Receptor H‑1 and α‑Adrenergic Receptors. This abstract reports pharmacokinetic data showing persistent plasma norcyclobenzaprine after oral dosing and in vitro receptor-binding affinities for cyclobenzaprine and its metabolite.  

https://acrabstracts.org/abstract/cyclobenzaprine-cbp-and-its-major-metabolite-norcyclobenzaprine-ncbp-are-potent-antagonists-of-human-serotonin-receptor-2a-5ht2a-histamine-receptor-h-1-and-a-adrenergic-receptors-mechanistic-a/#:~:text=Results%3A%20The%20oral%20bioavailability%20of,50%7D%3D%205.3%20and%203.2%20μM

·  Drugs.com. Tonmya for fibromyalgia: uses, dosage, side effects, warnings. This entry notes that sublingual cyclobenzaprine offers rapid absorption and bypasses first-pass metabolism, reducing the formation of norcyclobenzaprine, and lists common and serious side effectsdrugs.com.

·  Souza et al., Pharmacokinetics and Bioequivalence Evaluation of Cyclobenzaprine Tablets. This study summarizes cyclobenzaprine’s bioavailability (33–55 %), high protein binding, hepatic metabolism, and variable elimination half-life

https://www.drugs.com/tonmya.html#:~:text=sublingual%20formulation%20of%20cyclobenzaprine%20offers,metabolite%2C%20which%20may%20improve%20tolerability

·  RELIEF trial (Efficacy and safety of sublingual cyclobenzaprine for the treatment of fibromyalgia). The trial’s abstract presents clinical outcomes for TNX‑102 SL, showing a modest reduction in pain and listing common adverse events such as oral hypoesthesia and taste change.

https://pubmed.ncbi.nlm.nih.gov/37165930/

·  StatPearls. Cyclobenzaprine. This reference outlines cyclobenzaprine’s pharmacologic mechanisms, approved and off-label uses, and common adverse effects such as somnolence, dry mouth, dizziness, and confusion

https://www.ncbi.nlm.nih.gov/books/NBK513362/#:~:text=provided%20in%20the%20manufacturer%27s%20product,13

‍

‍