Cyclobenzaprine: Difference between revisions

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| pages = 91–9}}</ref> peaking in the first few days, but has no proven benefit after two weeks.<ref name = chou /><ref name = browning>{{cite journal

Revision as of 22:35, 13 March 2012

Cyclobenzaprine
Clinical data
Trade namesFlexeril
AHFS/Drugs.comMonograph
MedlinePlusa682514
Pregnancy
category
  • Category B
Routes of
administration		PO (Per Oral)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability33% to 55% [1][2]
Metabolismhepatic
Elimination half-life18 hours (range 8–37 hours; n=18)
Excretionrenal
Identifiers
  • 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)- N,N-dimethyl-1-propanamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.588 Edit this at Wikidata
Chemical and physical data
FormulaC20H21N
Molar mass275.387 g/mol g·mol−1
3D model (JSmol)
  • c3cc\2c(\C=C/c1c(cccc1)C/2=C/CCN(C)C)cc3
  • InChI=1S/C20H21N/c1-21(2)15-7-12-20-18-10-5-3-8-16(18)13-14-17-9-4-6-11-19(17)20/h3-6,8-14H,7,15H2,1-2H3 checkY
  • Key:JURKNVYFZMSNLP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Cyclobenzaprine, also known by the brand name Flexeril, 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]

Use

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]

Overdose

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]

Interactions

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:

Chemistry

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.

  • H.La Roche, GB 858187  (1961).
  • F.J. Villani, C.A. Ellis, C. Teihman, C. Biges, J. Med. Pharm. Chem., 5, 373 (1962).
  • Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/jo01048a057, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/jo01048a057 instead.

Notes

  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 2009Template:Inconsistent citations{{cite web}}: CS1 maint: postscript (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. doi:10.1139/y81-007. PMID 7214207.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ Gillman PK (May 2009). "Is there sufficient evidence to suggest cyclobenzaprine might be implicated in causing serotonin toxicity?". The American Journal of Emergency Medicine. 27 (4): 509–10, author reply 510. doi:10.1016/j.ajem.2009.03.001. PMID 19555629. {{cite journal}}: |format= requires |url= (help)
  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 (1–2): 91–9. doi:10.1016/S0014-2999(02)02735-8. 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 (1): 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 (1–2): CD004252. PMID 12804507. {{cite journal}}: More than one of |pages= and |page= specified (help)CS1 maint: multiple names: authors list (link)
  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. doi:10.1001/archinte.161.13.1613. PMID 11434793.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b c "Cyclobenzaprine official FDA information, side effects, and uses". Drugs.com. 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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. doi:10.1002/art.20076. PMID 14872449.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Amrix website
  18. ^ a b "Flexeril: Side effects". RxList.com. 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Keegan MT, Brown DR & Rabinstein AA (2006). "Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs". Anesthesia & Analgesia. 103 (6): 1466–8. doi:10.1213/01.ane.0000247699.81580.eb. PMID 17122225.


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