Systematic (IUPAC) name
3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)- N,N-dimethyl-1-propanamine
Clinical data
Trade names Flexeril
AHFS/ monograph
MedlinePlus a682514
Pregnancy cat. Category B
Legal status Prescription only
Routes PO (Per Oral)
Pharmacokinetic data
Bioavailability 33% to 55% [1][2]
Metabolism hepatic
Half-life 18 hours (range 8–37 hours; n=18)
Excretion renal
CAS number 303-53-7 YesY
ATC code M03BX08
PubChem CID 2895
DrugBank APRD00213
ChemSpider 2792 YesY
KEGG D07758 YesY
Chemical data
Formula C20H21N 
Mol. mass 275.387 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Cyclobenzaprine is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions.[3] It is the most well-studied drug for this application,[4] and it also has been used off-label for fibromyalgia treatment.[5]


Mechanism of action

The mechanism of action for cyclobenzaprine is unclear. Studies from the 1980s in rats indicate that cyclobenzaprine activates the locus ceruleus in the brain stem, leading to an increased release of norepinephrine in the ventral horn of the spinal cord and the subsequent inhibitory action of norepinephrine on alpha motor neurons.[6]

Cyclobenzaprine has been considered structurally related to the first-generation tricyclic antidepressants.[7] Such tricyclics, including amitriptyline, act to inhibit the uptake of norepinephrine, resulting in increased transynaptic norepinephrine concentration. They have been shown to exert analgesic effects in chronic nerve and muscle pain. Cyclobenzaprine may have a similar effect.

Others contend that the structure is more closely related to cyproheptadine,[8][9] an antagonist at histamine H1 receptors, muscarinic acetylcholine receptors, and 5-HT2A serotonin receptors. Corroborating studies show that cyclobenzaprine causes inhibition of descending serotonergic systems in the spinal cord by blocking 5-HT2A and 5-HT2C receptors.[10] This action is thought to have an inhibitory effect on the alpha motor neurons in the ventral horn of the spinal cord, thereby resulting in decreased firing of alpha-motor neurons and a reduction in spinal mono- and polysynaptic reflexes.[11]


After sustaining an injury, muscle spasms may occur to stabilize the affected body part and prevent further damage. They also generate pain. Cyclobenzaprine is FDA-approved to treat such muscle spasm associated with acute, painful musculoskeletal conditions.[3] It decreases pain in the first two weeks,[4][12] peaking in the first few days, but has no proven benefit after two weeks.[4][13] Since no benefit is proven beyond that, therapy should not be continued long-term.[14] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[14][15]

Cyclobenzaprine has also shown effectiveness in the treatment of fibromyalgia symptoms, with a report of 4.8 patients needing treatment for each (1) patient reporting pain reduction (but no change in fatigue or tender points).[16] Like other tricyclic antidepressants, it is also prescribed off-label as a sleep-aid.[citation needed]

Formulations and dosages

Cyclobenzaprine 10mg

Cyclobenzaprine is marketed as Apo-Cyclobenzaprine (10 mg tablets), Flexeril (5 and 10 mg tablets) and Fexmid (7.5 mg tablet). Both Flexeril and Fexmid are available in generic form. A once-a-day extended-release formulation Amrix is available in 15- and 30-mg capsules.[17]

Cyclobenzaprine is regulated in the U.S. for prescription use only. Though it does not fall within most governmental guidelines as a controlled substance, possession of it without a valid or current prescription may be illegal, depending upon various state and local laws.

Side effects

Meta-analysis studies have found significantly increased rates of drowsiness (38% of patients), dry mouth (24%), dizziness (10%), and adverse events of any kind in patients taking cyclobenzaprine versus placebo.[13] Drowsiness and dry mouth appear to intensify with increasing dose.[18]

Other side effects are not significantly more common than they are in patients taking placebo. Some of these include blurred vision, fatigue, nausea, and headache.[18] The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors. Agitation is a common side effect observed especially in the elderly. In general, the NCQA recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.[19] There is one case report of overdose causing rhabdomyolysis (muscle breakdown).[20] Treatment protocols and support should follow the same as for any tricyclic antidepressant.[20]


The most common effects of overdose are drowsiness and tachycardia.[3] Rare but potentially critical complications are cardiac arrest, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.[3] Life-threatening overdose is rare,[3] however, as the median lethal dose is approximately 338 mg/kg in mice and 425 mg/kg in rats,[3]. The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.[3]


Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.[21]

The following substances may interact with cyclobenzaprine:


Cyclobenzaprine, N,N-dimethyl-3-(dibenzo[a,d]cyclohepten-5-ylidene)propylamine, is synthesized by reacting 5H-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropylmagnesium chloride and subsequent dehydration of the resulting carbinol in acidic conditions into cyclobenzaprine. Cyclobenzaprine synthesis.png

  • H.La Roche, GB 858187  (1961).
  • F.J. Villani, C.A. Ellis, C. Teihman, C. Biges, J. Med. Pharm. Chem., 5, 373 (1962).
  • Winthrop, S. O.; Davis, M. A.; Myers, G. S.; Gavin, J. G.; Thomas, R.; Barber, R. (1962). "New Psychotropic Agents. Derivatives of Dibenzo[a,d]-1,4-cycloheptadiene". The Journal of Organic Chemistry 27: 230. doi:10.1021/jo01048a057.  edit


  1. ^ Micromedex® 2010 - DRUGDEX® Evaluations (Cyclobenzaprine Hydrochloride)
  2. ^ Cyclobenzaprine HCl Oral tablets USP Revised, April 2005
  3. ^ a b c d e f g "Flexeril (Cyclobenzaprine HCl) Tablets" (pdf), U. S. Food and Drug Administration, 2003,, retrieved 26 July 2009 
  4. ^ a b c Chou R, Peterson K, Helfand M (2004). "Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review". Journal of Pain Symptom Management 28 (2): 140–175. doi:10.1016/j.jpainsymman.2004.05.002. PMID 15276195. 
  5. ^ "Cyclobenzaprine Hydrochloride" (subscription required). MicroMedex. 5 Feb 2010. Retrieved 16 Feb 2010. 
  6. ^ Commissiong JW; Karoum F; Reiffenstein RJ; Neff NH (Jan 1981). "Cyclobenzaprine: a possible mechanism of action for its muscle relaxant effect". Canadian Journal of Physiology and Pharmacology 59 (1): 37–44. PMID 7214207. 
  7. ^ E.J. Preston, C.B. Miller and R.K. Herbertson, A double-blind, multicenter trial of methocarbamol (Robaxin) and cyclobenzaprine (Flexeril(TM)) in acute musculoskeletal conditions. Today's Ther Trends 1 4 (1984), pp. 1–11.
  8. ^ Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al (2006). "DrugBank: a comprehensive resource for in silico drug discovery and exploration". Nucleic Acids Ressearch 34 (Database issue): D668–D672. 
  9. ^ Gillman PK (May 2009). "Is there sufficient evidence to suggest cyclobenzaprine might be implicated in causing serotonin toxicity?" (comment letter). The American Journal Of Emergency Medicine 27 (4): 509–10; author reply 510. PMID 19555629. 
  10. ^ Honda M, Nishida T & Ono H (2003). "Tricyclic analogs cyclobenzaprine, amitriptyline, and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors". European Journal of Pharmacology 458: 919. PMID 12498911. 
  11. ^ Kobayashi H, Hasegawa Y & Ono H (1996). "Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems". European Journal of Pharmacology 311: 29–35. doi:10.1016/0014-2999(96)00402-5. PMID 8884233. 
  12. ^ van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM (2003). "Muscle relaxants for non-specific low back pain". Cochrane Database Systematic Reviews 2: CD004252. PMID 12498911. 
  13. ^ a b Browning R, Jackson JL, O’Malley PG (2001). "Cyclobenzaprine and back pain: a meta-analysis". Archives of Internal Medicine 161 (13): 1613–1620. PMID 11434793. 
  14. ^ a b c "Cyclobenzaprine official FDA information, side effects, and uses". October 2009. Retrieved 19 Feb 2010. 
  15. ^ Ashby P, Burke D, Rao S, et al (1972). "Assessment of cyclobenzaprine in the treatment of spasticity". J Neurol Neurosurg Psychiatry 35 (5): 599–605. doi:10.1136/jnnp.35.5.599. PMC 494138. PMID 4563483. 
  16. ^ Tofferi JK, Jackson JL, O'Malley PG (15 Feb 2004). "Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis". Arthritis & Rheumatology 51 (1): 9–13. PMID 14872449. 
  17. ^ Amrix website
  18. ^ a b "Flexeril: Side effects". Retrieved 22 Feb 2010. 
  19. ^ "High risk medications" (pdf). National Committee for Quality Assurance. Retrieved 22 Feb 2010. 
  20. ^ a b Chabria, Shiven B (17 July 2006). "Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity". Journal of Occupational Medicine and Toxicology 1 (1): 16. doi:10.1186/1745-6673-1-16. PMC 1540431. PMID 16846511. 
  21. ^ Keegan MT, Brown DR & Rabinstein AA (2006). "Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs". Anesthesia & Analgesia 103: 14668. PMID 17122225.