Cyclobenzaprine: Muscle Relaxant and Fibromyalgia Research

Cyclobenzaprine is a prescription muscle relaxant that has been sold in the United States since the 1970s. For most of that time it had one approved job: easing muscle spasm for a few weeks after a strained back or neck. In August 2025 a very different version of the same drug, a low-dose tablet that dissolves under the tongue at bedtime, became the first new medicine approved for fibromyalgia in more than 15 years. This page sets out what the drug is, what its official label says, what the research on back pain, neck pain and fibromyalgia found, and what the label and the trials report about side effects and risks.

Table of Contents

  1. What Cyclobenzaprine Is
  2. How It Is Thought to Work
  3. The Long-Standing Approved Use
  4. Back Pain and Neck Pain Research
  5. Early Fibromyalgia Research
  6. The Bedtime Under-the-Tongue Tablet Trials
  7. The 2025 Fibromyalgia Approval
  8. Side Effects Reported on the Labels and in Trials
  9. Interactions and Contraindications on the Label
  10. Older Adults and the Beers Criteria
  11. What Is Not Known
  12. Key Research Papers
  13. Connections
  14. Featured Videos

What Cyclobenzaprine Is

Cyclobenzaprine is a centrally acting skeletal muscle relaxant. "Centrally acting" means it works in the brain and spinal cord rather than in the muscle itself. It does not paralyse muscle the way a surgical relaxant does; it dampens the nerve signals that keep a muscle locked in spasm.

Chemically it is a close cousin of the older antidepressants. The United States prescribing label describes cyclobenzaprine as "closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine." The two molecules share the same three-ring backbone, and the label notes that in animal studies cyclobenzaprine behaved much like those antidepressants, including strong anticholinergic effects (the drying, atropine-like effects behind dry mouth) and sedation. That family resemblance explains a great deal about the drug: why it makes people sleepy, why it interacts with antidepressants, and why its warnings about the heart read like a tricyclic antidepressant's.

According to the label, the drug is absorbed fairly poorly by mouth (an estimated 33% to 55% reaches the bloodstream), and it leaves the body slowly, with an effective half-life of about 18 hours (range 8 to 37 hours). Taken several times a day, it builds up over 3 to 4 days to blood levels about four times higher than a single dose gives. The sublingual (under-the-tongue) label gives the first United States approval of cyclobenzaprine as 1977.

The drug now comes in three forms: an ordinary swallowed tablet, a once-daily extended-release capsule, and, since 2025, a low-dose under-the-tongue (sublingual) tablet taken at bedtime for fibromyalgia.

How It Is Thought to Work

For muscle spasm, the label states that cyclobenzaprine relieves spasm "of local origin" without interfering with muscle function, and that it acts mainly within the central nervous system at the level of the brain stem rather than the spinal cord. Its net effect, in the label's words, is "a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems". In plain terms, it turns down the steady background signal that holds a muscle tight. The label also states that it does not work for spasticity caused by brain or spinal cord disease, or in children with cerebral palsy.

For fibromyalgia, the newer label is blunt: "The mechanism of action of cyclobenzaprine for the treatment of fibromyalgia in adults is unknown." In laboratory tests it blocks four kinds of receptors: serotonin 5-HT2A receptors, alpha-1 adrenergic receptors, H1 histamine receptors and M1 muscarinic (acetylcholine) receptors. A 2026 review argues that the fibromyalgia effect comes mainly from blocking the 5-HT2A and alpha-1 receptors, acting on how the brain processes pain and on sleep, "rather than peripheral muscle relaxation". That fits the modern view of fibromyalgia as a disorder of central sensitization and nociplastic pain, in which the nervous system amplifies pain signals, and in which poor, unrefreshing sleep is a core feature.

The same review describes why the bedtime under-the-tongue tablet was designed the way it was. Absorbed through the lining of the mouth, it reaches its peak blood level 4 to 5 hours after bedtime, so the highest drug exposure falls in the middle of the night's sleep rather than the next day.

The Long-Standing Approved Use

The swallowed tablet's label, published on DailyMed by the United States National Library of Medicine, states the approved use this way:

"Cyclobenzaprine HCl is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions."

Three parts of that wording matter for readers:

The label lists the benefits it means by "relief" as easing of the spasm itself and its associated pain, tenderness, limited motion and restriction in daily activities.

Back Pain and Neck Pain Research

Cyclobenzaprine is, in the words of a 2001 review, "frequently prescribed" for back pain, and its record in research is mixed: it beats placebo in older trials, the effect is modest and front-loaded, and newer trials and reviews are less encouraging. The low back pain page covers the condition itself.

The 2001 meta-analysis

A 2001 review pooled placebo-controlled trials of cyclobenzaprine in adults with back pain. People taking the drug were nearly five times as likely to report improvement by day 14 (odds ratio 4.7), and slightly fewer than 3 people needed treatment for 1 to improve. The authors described the size of the improvement as modest (an effect size of 0.38 to 0.58 across local pain, muscle spasm, tenderness, range of motion and daily activities). The benefit was greatest in the first 4 days and declined after the first week, and the drug brought more side effects, drowsiness above all. The authors concluded that shorter courses "may be better".

Lower doses

Two placebo-controlled trials published in 2003 enrolled 1,405 adults with acute muscle spasm, two thirds with low back pain and one third with neck pain. The trials gave 2.5 mg, 5 mg or 10 mg three times a day for 7 days. The 5 mg and 10 mg regimens scored better than placebo; 5 mg worked as well as 10 mg with less sedation; 2.5 mg was not significantly better than placebo. At least one side effect was reported by 54.1% on 5 mg and 61.8% on 10 mg, against 35.4% on placebo, in the first trial. A later open-label trial of 867 adults with acute neck or back pain and spasm found that adding the anti-inflammatory ibuprofen to cyclobenzaprine 5 mg three times daily was not better than cyclobenzaprine alone after 7 days; that trial had no placebo group.

The emergency department trial

A 2015 randomized, double-blind trial in a New York City emergency department followed 323 adults with recent low back pain (2 weeks or less, no nerve pain down the leg). Everyone got the anti-inflammatory naproxen; on top of that they got placebo, cyclobenzaprine or an opioid-acetaminophen combination. At one week, adding cyclobenzaprine did not improve function or pain compared with naproxen plus placebo (a difference of 0.3 points on a 24-point disability scale). The authors wrote that the findings "do not support use of these additional medications in this setting."

The 2021 review of all muscle relaxants

A 2021 review in the BMJ analysed 31 trials with 6,505 participants. It grouped cyclobenzaprine with drugs such as tizanidine and methocarbamol as "non-benzodiazepine antispasmodics". For acute low back pain, very low certainty evidence showed these drugs reduced pain at two weeks or less by 7.7 points on a 0 to 100 scale, which the authors judged "small but not clinically important", with no reduction in disability, and they might raise the risk of a side effect (relative risk 1.6). The authors wrote that "considerable uncertainty exists".

Neck pain and long-term use

Research on neck pain alone is thinner; most trials mixed neck and back patients. A 2024 systematic review of muscle relaxants taken for a month or longer for chronic pain (30 randomized trials with 1,314 people and 14 cohort studies with 1,168; seven studies on cyclobenzaprine) found the strongest evidence of benefit for trigeminal neuralgia, neck pain and painful cramps, while for low back pain, fibromyalgia and headaches long-term use did not appear better than placebo. Most of those studies lasted only 4 to 6 weeks. Sedation and dry mouth were the most common side effects.

Early Fibromyalgia Research

Cyclobenzaprine was studied and prescribed for fibromyalgia long before any approval; a 2026 review notes that the oral drug "has been used off label for decades". Off-label use means prescribing a drug for a condition that is not on its label.

A 2004 meta-analysis gathered five randomized, placebo-controlled trials of ordinary oral cyclobenzaprine in fibromyalgia. People on the drug were three times as likely to report overall improvement (odds ratio 3.0), and about 4.8 people needed treatment for 1 to improve. Pain improved early in treatment, sleep improved moderately, but there was no improvement in fatigue or tender points at any time. A 2026 review notes that at conventional doses the number of people who need treatment for one to benefit is close to the number who need treatment for one to have a side effect, which limited the drug's usefulness.

That problem led researchers to very small doses at bedtime. In a 2011 trial, 36 people with fibromyalgia and unrefreshing sleep were randomized to placebo or very low dose cyclobenzaprine; the trial gave 1 to 4 mg at bedtime for 8 weeks. Compared with placebo, the drug improved pain, tenderness and a depression score. Overnight brain-wave recordings showed that more people on the drug had an increase in nights of restorative sleep, and those sleep changes tracked improvements in fatigue and mood. The trial was small, and one of its authors is also first author of the later phase 3 trials of the under-the-tongue tablet. A separate page on sleep and non-restorative sleep in fibromyalgia covers that side of the condition.

The Bedtime Under-the-Tongue Tablet Trials

The newer form is a low-dose under-the-tongue (sublingual) tablet taken at bedtime. Both phase 3 trials described below gave 2.8 mg nightly for 2 weeks, then 5.6 mg nightly for 12 more weeks, and both measured the change in average daily pain (on a 0 to 10 scale) at week 14. Both were run by the drug's developer, with authors employed by the developer.

RELIEF

The RELIEF trial randomized 503 people with fibromyalgia: 248 to the tablet and 255 to placebo. At week 14, daily pain fell by 1.9 points on the tablet and 1.5 points on placebo, a difference that was statistically significant (P = 0.01). The tablet did not significantly improve the patients' own global rating of change at week 14, but it was linked to better scores on a fibromyalgia impact questionnaire, on sleep disturbance and fatigue measures, and on daily sleep quality. Side effects were reported by 59.7% on the tablet and 46.3% on placebo. The most common were numbness in the mouth (17.3% versus 0.4%), tingling in the mouth (5.6% versus 0.4%) and an abnormal taste (4.4% versus 0.4%).

RESILIENT

A second phase 3 trial, which a 2026 review names RESILIENT, randomized patients one to one; 81.0% of 231 patients on the tablet and 79.6% of 225 on placebo finished the trial. Daily pain fell by 1.8 points on the tablet versus 1.2 on placebo (P < .001), and all six secondary measures, including the patients' global rating, fibromyalgia symptoms and function, sleep disturbance, fatigue and daily sleep quality, improved more on the tablet. The most common whole-body side effects were COVID-19 (4.3% versus 3.1%), headache (3.0% versus 1.8%) and sleepiness (3.0% versus 1.3%). The most common side effects overall were at the site of the tablet: numbness in the mouth (23.4% versus 0.4%), abnormal taste (11.3% versus 0.9%) and tingling in the mouth (6.9% versus 0.9%), described as passing and self-limited.

A trial that did not separate from placebo

The label lists three trials of the tablet in fibromyalgia, with 1,474 patients in total. In two of them (RELIEF and the trial reported in Pain Medicine) the tablet reduced pain significantly more than placebo. In the third, in the label's words, "there was no statistically significant treatment group difference"; the label adds that its results "may not have been generalizable due to the presence of factors outside the conduct of the study." In the three trials, 95% of patients were women and the mean age was 49.

Pooled analyses

A 2026 meta-analysis of four trials with 1,684 participants found the tablet raised the share of people whose pain fell by at least 30% (relative risk 1.44) and by at least 50% (relative risk 1.43), and improved the global rating of change (relative risk 1.52), but did not significantly improve the fibromyalgia impact questionnaire score. Side effects were more frequent (relative risk 1.41), driven by the mouth effects, while the rate of stopping treatment was similar to placebo, and no deaths were reported.

A larger independent network meta-analysis, also from 2026, compared drug treatments for fibromyalgia across 151 trials with 32,592 participants. It found that no drug's average effect on pain reached the threshold the authors set for clinical importance. For cyclobenzaprine, along with sodium oxybate and two classes of antidepressants, responder analyses showed that a potentially important share of patients reached at least a 30% pain reduction. The authors graded the overall evidence as low certainty and described the benefits of the drugs studied as "typically small". A separate page on non-opioid medications for chronic pain covers the other drug options in that comparison.

The 2025 Fibromyalgia Approval

On 15 August 2025, the United States Food and Drug Administration (FDA) approved the sublingual cyclobenzaprine tablet for the treatment of fibromyalgia in adults, according to a 2026 drug-approval summary indexed in PubMed. A 2026 review describes it as the first new medicine approved for fibromyalgia in more than 15 years.

The approval covers only the bedtime under-the-tongue tablet. It does not extend to the ordinary swallowed tablets or capsules, whose label still covers short-term muscle spasm only. The approval summary also lists other conditions in which the sublingual form was being developed, including post-traumatic stress disorder; none of those uses is approved.

The fibromyalgia label notes that the mouth is moistened with sips of water before the tablet is placed under the tongue, and that the tablet is not swallowed whole, cut, crushed or chewed, and it lists a lower dose for people 65 and older and for people with mild liver impairment.

Side Effects Reported on the Labels and in Trials

The ordinary tablet

In the label's placebo-controlled trials, the most common side effects were:

Side effects reported by 1% to 3% of patients included dizziness, nausea, constipation, abdominal pain, acid reflux, irritability, nervousness and decreased mental sharpness. The label states the drug may impair the mental or physical abilities needed to drive or operate machinery, and that it may enhance the effects of alcohol, barbiturates and other sedating drugs. It also notes that stopping suddenly after long use "rarely may produce nausea, headache, and malaise."

The bedtime under-the-tongue tablet

Across the three fibromyalgia trials on its label (735 on the tablet, 739 on placebo), the most common side effects were:

Counting all mouth reactions together (numbness, tingling, discomfort, pain, irritation, inflammation and sores), the label reports 43% on the tablet against 8% on placebo. They typically began within minutes of a dose and most resolved within 60 minutes; five patients had severe mouth reactions, most of which cleared within days of stopping. The label states that moistening the mouth with sips of water before a dose reduces the risk of numbness.

The fibromyalgia label also carries a pregnancy warning based on animal data: in rabbits given the highest dose tested, neural tube defects (malformations of the developing spine) were seen. The label calls for a pregnancy test before starting in women who could become pregnant, and for effective contraception during treatment and for two weeks after the last dose.

Interactions and Contraindications on the Label

Both labels list the same situations in which the drug is contraindicated (not to be used):

The label explains the heart warnings through the family resemblance: tricyclic antidepressants "have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke."

Serotonin syndrome

The label warns that a potentially life-threatening serotonin syndrome has been reported when cyclobenzaprine is combined with other drugs that raise serotonin, naming selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil and MAO inhibitors. Several of these are common in people with fibromyalgia or chronic pain. The label lists the signs: confusion, agitation or hallucinations; sweating, fast heartbeat, unstable blood pressure or high temperature; tremor, loss of coordination, overactive reflexes, muscle jerks or rigidity; and nausea, vomiting or diarrhoea. Hospitals treat these signs as an emergency. A separate page on methylene blue drug interactions and serotonin syndrome explains the syndrome in more depth.

Other label cautions

Older Adults and the Beers Criteria

The ordinary tablet's label reports that in people 65 and older, average blood levels of the drug were about 1.7 times higher than in younger adults, and about 2.4 times higher in older men. It states that in older people "the frequency and severity of adverse events" are increased. None of the patients in the fibromyalgia trials of the under-the-tongue tablet were 65 or older.

The American Geriatrics Society Beers Criteria, a widely used list of medicines that are potentially inappropriate for adults 65 and older, lists cyclobenzaprine among the skeletal muscle relaxants; the criteria describe the medicines on the list as ones "typically best avoided by older adults in most circumstances or under specific situations". Its 2023 update gives the reason: these drugs "are poorly tolerated by older adults due to anticholinergic adverse effects, sedation, and increased risk of fractures; effectiveness at dosages tolerated by older adults is questionable." The 2023 list also names cyclobenzaprine among drugs with strong anticholinergic properties.

What Is Not Known

Decisions about prescription medicines belong with the prescriber who knows a person's other medicines and heart history.

Key Research Papers

  1. Lederman S, Arnold LM, Vaughn B, Kelley M, Sullivan GM. Efficacy and Safety of Sublingual Cyclobenzaprine for the Treatment of Fibromyalgia: Results From a Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Care Res (Hoboken). 2023;75(11):2359-2368. PubMed PMID: 37165930
  2. Lederman S, Arnold LM, Vaughn B, Engels JM, Kelley M, Sullivan GM. Pain relief by targeting nonrestorative sleep in fibromyalgia: a phase 3 randomized trial of bedtime sublingual cyclobenzaprine. Pain Med. 2026;27(1):86-94. PubMed PMID: 40627411
  3. Abd-Elsayed A, Knezic A, Asfour J, Dewan P, Hasoon J, Reilly M. Sublingual Cyclobenzaprine for Fibromyalgia: Pharmacokinetic Rationale, Clinical Evidence, and Place in Therapy. Curr Pain Headache Rep. 2026;30(1):89. PubMed PMID: 42479282
  4. Blair HA. Sublingual Cyclobenzaprine: First Approval. Clin Drug Investig. 2026;46(1):107-114. PubMed PMID: 41405805
  5. Al-Qudah AA, Al-Hanaktah M. Short-term efficacy and safety of sublingual cyclobenzaprine for fibromyalgia: A systematic review and meta-analysis. Clin Rheumatol. 2026;45(3):1947-1957. PubMed PMID: 41318845
  6. Zeraatkar D, Lima JP, Kirsh S, Ling M, Movahed H, Li H, Huynh A, Jassal T, Walch A, Raji Lahiji M, Pitre T, Couban RJ, Sadeghirad B, Agoritsas T, Busse JW. Drug treatments for fibromyalgia: systematic review and network meta-analysis of randomised trials. BMJ Med. 2026;5(1):e002902. PubMed PMID: 42851751
  7. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis Rheum. 2004;51(1):9-13. PubMed PMID: 14872449
  8. Moldofsky H, Harris HW, Archambault WT, Kwong T, Lederman S. Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study. J Rheumatol. 2011;38(12):2653-2663. PubMed PMID: 21885490
  9. Browning R, Jackson JL, O'Malley PG. Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med. 2001;161(13):1613-1620. PubMed PMID: 11434793
  10. Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther. 2003;25(4):1056-1073. PubMed PMID: 12809957
  11. Childers MK, Borenstein D, Brown RL, Gershon S, Hale ME, Petri M, Wan GJ, Laudadio C, Harrison DD. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21(9):1485-1493. PubMed PMID: 16197668
  12. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, Bijur PE, Gallagher EJ. Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA. 2015;314(15):1572-1580. PubMed PMID: 26501533
  13. Cashin AG, Folly T, Bagg MK, Wewege MA, Jones MD, Ferraro MC, Leake HB, Rizzo RRN, Schabrun SM, Gustin SM, Day R, Williams CM, McAuley JH. Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis. BMJ. 2021;374:n1446. PubMed PMID: 34233900
  14. Oldfield BJ, Gleeson B, Morford KL, Adams Z, Funaro MC, Becker WC, Merlin JS. Long-Term Use of Muscle Relaxant Medications for Chronic Pain: A Systematic Review. JAMA Netw Open. 2024;7(9):e2434835. PubMed PMID: 39298168
  15. By the 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. PubMed PMID: 37139824

PubMed Topic Searches

  1. PubMed: cyclobenzaprine and fibromyalgia
  2. PubMed: sublingual cyclobenzaprine
  3. PubMed: cyclobenzaprine and low back pain
  4. PubMed: cyclobenzaprine and serotonin syndrome

Other Sources

  1. DailyMed: cyclobenzaprine hydrochloride tablets, prescribing label (United States National Library of Medicine)
  2. DailyMed: cyclobenzaprine hydrochloride sublingual tablets for fibromyalgia, prescribing label (United States National Library of Medicine)

Connections