Chemistry:Cyclobenzaprine

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Short description: Muscle relaxant medication
Cyclobenzaprine
Cyclobenzaprine.svg
Cyclobenzaprine 3D.gif
Clinical data
Trade namesFlexeril, Amrix, others
AHFS/Drugs.comMonograph
MedlinePlusa682514
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability33–55%[1][2]
Protein binding93%
Metabolismmajor: CYP3A4, CYP1A2; minor: CYP2D6, N-demethylation[3]
MetabolitesNorcyclobenzaprine
Elimination half-life32 hours (extended-release, range 8–37 hours),[3] 18 hours (immediate release, range 8–37 hours)[4]
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC20H21N
Molar mass275.395 g·mol−1
3D model (JSmol)
  (verify)

Cyclobenzaprine, sold under several brand names including, historically, Flexeril, is a muscle relaxer used for muscle spasms from musculoskeletal conditions of sudden onset.[5] It is not useful in cerebral palsy.[5] It is taken by mouth.[5]

Common side effects include headache, feeling tired, dizziness, and dry mouth.[5] Serious side effects may include an irregular heartbeat.[5] There is no evidence of harm in pregnancy, but it has not been well studied in this population.[5] It must not be used with an MAO inhibitor.[5] How it works is unclear.[5]

Cyclobenzaprine was approved for medical use in the United States in 1977.[5] It is available by prescription as a generic medication.[5] In 2021, it was the 45th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[6][7] It was not available in the United Kingdom as of 2012.[8]

Medical use

Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.[9] After sustaining an injury, muscle spasms occur to stabilize the affected body part, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions.[10] It decreases pain in the first two weeks,[11][12] peaking in the first few days, but has no proven benefit after two weeks.[11][13] Since no benefit is proven beyond that, therapy should not be continued long-term.[10] It is the best-studied muscle relaxer.[11] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[10][14]

A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points.[15] A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.[16] It may also be used along with other treatments for tetanus.[17]

Side effects

Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).[13] Drowsiness and dry mouth appear to intensify with increasing dose.[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. Some experts[who?] believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment.[19][20] In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.[21]

Dysphagia, a life-threatening side-effect, may rarely occur.[22] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[23]

Overdose

The most common effects of overdose are drowsiness and tachycardia.[10] Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome.[10] Life-threatening overdose is rare,[10] however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats.[10] The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes other drugs.[10]

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.[24]

These substances may interact with cyclobenzaprine:

Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.[25]

Pharmacology

Cyclobenzaprine is a centrally acting muscle relaxant.[26] Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves.[27]

Pharmacodynamics

Cyclobenzaprine (and metabolite)[28]
Site CBP NCBP Action
5-HT1A 5300 3200 Agonist
5-HT2A 5.2 13 Antagonist
5-HT2B 100 ??? Antagonist
5-HT2C 5.2 43 Antagonist
α1A 5.6 34 ND
α2A 4.3 6.4 Antagonist
α2B 21 150 ND
α2C 21 48 ND
H1 1.3 5.6 ND
M1 7.9 30 ND
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Pharmacokinetics

Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute.[26][29][30]

Comparison to other medications

Cyclobenzaprine has been found to be not inferior to tizanidine, orphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment). No differences in pain or spasm scores were noted among these agents, nor when compared to benzodiazepines.[31] However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice. Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.

In a study on the treatment of musculoskeletal pain treatment with cyclobenzaprine alone or in combination with ibuprofen, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day seven of the treatment for all groups.[32]

Formulations

Cyclobenzaprine 10mg tablets

By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[33] Cyclobenzaprine is also used by compounding pharmacies in topical creams.[citation needed]

References

  1. ↑ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
  2. ↑ "Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only". nih.gov. http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=18929. 
  3. ↑ 3.0 3.1 Teva Pharmaceuticals USA, Inc (May 2016). "AMR40470 (Amrix) Prescribing Information". https://www.amrix.com/Content/Pdf/prescribing-information.pdf. 
  4. ↑ U.S. Food and Drug Administration. "NDA 17-821/S-045 Flexeril (Cyclobenzaprine HCl) Tablets". https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/017821s045lbl.pdf. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 "Cyclobenzaprine Monograph for Professionals". AHFS. https://www.drugs.com/monograph/cyclobenzaprine.html. 
  6. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  7. ↑ "Cyclobenzaprine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Cyclobenzaprine. 
  8. ↑ Fibromyalgia, psychiatric comorbidity, and the somatosensory cortex. 5. 2012. p. a522. http://www.bjmp.org/content/fibromyalgia-psychiatric-comorbidity-and-somatosensory-cortex. 
  9. ↑ "Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review". Journal of the American Academy of Dermatology 77 (6): 1170–1172. December 2017. doi:10.1016/j.jaad.2016.12.017. PMID 29132849. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 "Cyclobenzaprine- cyclobenzaprine hydrochloride tablet, film coated". 30 December 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b12fb4ea-182e-462b-b6ed-cfd2f6bb71e8. 
  11. ↑ 11.0 11.1 11.2 "Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review". Journal of Pain and Symptom Management 28 (2): 140–75. August 2004. doi:10.1016/j.jpainsymman.2004.05.002. PMID 15276195. 
  12. ↑ Van Tulder, Maurits W, ed (2003). "Muscle relaxants for non-specific low back pain". The Cochrane Database of Systematic Reviews 2 (2): CD004252. doi:10.1002/14651858.CD004252. PMID 12804507. 
  13. ↑ 13.0 13.1 "Cyclobenzaprine and back pain: a meta-analysis". Archives of Internal Medicine 161 (13): 1613–20. July 2001. doi:10.1001/archinte.161.13.1613. PMID 11434793. 
  14. ↑ "Assessment of cyclobenzaprine in the treatment of spasticity". Journal of Neurology, Neurosurgery, and Psychiatry 35 (5): 599–605. October 1972. doi:10.1136/jnnp.35.5.599. PMID 4563483. 
  15. ↑ "Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis". Arthritis and Rheumatism 51 (1): 9–13. February 2004. doi:10.1002/art.20076. PMID 14872449. 
  16. ↑ "Cyclobenzaprine for the treatment of myofascial pain in adults". The Cochrane Database of Systematic Reviews 2009 (3): CD006830. July 2009. doi:10.1002/14651858.CD006830.pub3. PMID 19588406. 
  17. ↑ Smith, Blaine T. (2014). Pharmacology for Nurses. Jones & Bartlett Publishers. p. 122. ISBN 9781449689407. https://books.google.com/books?id=7P-9BQAAQBAJ&pg=PA122. 
  18. ↑ "Flexeril: Side effects". RxList.com. http://www.rxlist.com/cgi/generic/cyclobnz_ad.htm. 
  19. ↑ "Long-term Use of Cyclobenzaprine for Pain: A Review of the Clinical Effectiveness". CADTH Rapid Response Reports. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health. 23 February 2015. 
  20. ↑ Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. [1]
  21. ↑ "High risk medications". National Committee for Quality Assurance. http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf. 
  22. ↑ "MEDICATIONS AND DYSPHAGIA/ SWALLOWING RISKS". http://www.ct.gov/dds/lib/dds/health/attacha_med_dsyphagia_swallowing_risks.pdf. 
  23. ↑ "Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity". Journal of Occupational Medicine and Toxicology 1 (1): 16. July 2006. doi:10.1186/1745-6673-1-16. PMID 16846511. 
  24. ↑ "Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs". Anesthesia and Analgesia 103 (6): 1466–8. December 2006. doi:10.1213/01.ane.0000247699.81580.eb. PMID 17122225. 
  25. ↑ Medical Practice of William H. Gorman, M.D. (18 February 2014). "Medications to Avoid, Continue, or Stop - Before & After Surgery". https://www.whgormanmd.com/blog/2014/1/3/medications-to-avoid-continue-or-stop-before-surgery. 
  26. ↑ 26.0 26.1 "Cyclobenzaprine". https://www.drugbank.ca/drugs/DB00924. 
  27. ↑ "Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems". European Journal of Pharmacology 311 (1): 29–35. September 1996. doi:10.1016/0014-2999(96)00402-5. PMID 8884233. 
  28. ↑ "Cyclobenzaprine (CBP) and Its Major Metabolite Norcyclobenzaprine (nCBP) Are Potent Antagonists of Human Serotonin Receptor 2a (5HT2a), Histamine Receptor H-1 and α-Adrenergic Receptors: Mechanistic and Safety Implications for Treating Fibromyalgia Syndrome by Improving Sleep Quality" (in en-US). 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/. 
  29. ↑ "Cyclobenzaprine" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/cyclobenzaprine#section=ATC-Code. 
  30. ↑ "Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency". Journal of Clinical Pharmacology 42 (1): 61–9. January 2002. doi:10.1177/0091270002042001007. PMID 11808825. 
  31. ↑ "Medscape: Medscape Access". medscape.com. http://www.medscape.com/viewarticle/572676_4. 
  32. ↑ "Comparison of cyclobenzaprine alone versus cyclobenzaprine plus ibuprofen in patients with acute musculoskeletal spasm and pain". Annals of Emergency Medicine 44 (4): S87–S88. 2004. doi:10.1016/j.annemergmed.2004.07.286. https://www.annemergmed.com/article/S0196-0644(04)01009-1/fulltext. 
  33. ↑ "Patient Web site for Amrix (Cyclobenzaprine Hydrochloride Extended-Release Capsules)". amrix.com. http://www.amrix.com/. 

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