Cyclobenzaprine

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Cyclobenzaprine
Cyclobenzaprine2.svg
Cyclobenzaprine 3D.gif
Systematic (IUPAC) name
3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)- N,N-dimethyl-1-propanamine
Clinical data
Trade names Amrix (former Flexeril)
AHFS/Drugs.com monograph
MedlinePlus a682514
Pregnancy cat. Category B
Legal status Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 33% to 55% [1][2]
Metabolism hepatic
Half-life 18 hours (range 8–37 hours; n=18)
Excretion renal
Identifiers
CAS number 303-53-7 YesY
ATC code M03BX08
PubChem CID 2895
DrugBank DB00924
ChemSpider 2792 YesY
UNII 69O5WQQ5TI YesY
KEGG D07758 YesY
ChEBI CHEBI:3996 YesY
ChEMBL CHEMBL669 YesY
Chemical data
Formula C20H21N 
Mol. mass 275.387 g/mol
 YesY (what is this?)  (verify)

Cyclobenzaprine, brand names Amrix, Flexeril and Fexmid, is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions.[3] It is the best-studied drug for this application,[4] it has also been used off-label for fibromyalgia treatment.[5] A new bedtime formulation of cyclobenzaprine is under development for the management of fibromyalgia syndrome.[6]

Medical use[edit]

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 spasms associated with acute, painful musculoskeletal conditions.[3] It decreases pain in the first two weeks,[4][7] peaking in the first few days, but has no proven benefit after two weeks.[4][8] Since no benefit is proven beyond that, therapy should not be continued long-term.[9] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[9][10]

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).[11]

In elderly patients, cyclobenzaprine HCl may be started at a lower dose and titrated slowly upward. Cyclobenzaprine is recommended for use up to 3 weeks, but clinical efficacy has not been demonstrated beyond this point and long term use of cyclobenzaprine is not recommended.[12] Cyclobenzaprine, however, has not been documented to cause intense physical and psychological withdrawal symptoms following discontinuation such as those which occur with its benzodiazepine, barbiturate, and carbamate alternatives, although the potential for rebound plasticity is of clinical relevance.

Side effects[edit]

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.[8] Drowsiness and dry mouth appear to intensify with increasing dose.[13]

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.[14] There is one case report of overdose causing rhabdomyolysis (muscle breakdown).[15] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[15]

Overdose[edit]

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[edit]

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.[16]

The following substances may interact with cyclobenzaprine:

If co-administered with opioids the dose of one or both medicines should be reduced accordingly. The patient should be monitored for excessive sedation.

Comparison to other medications[edit]

Cyclobenzaprine has been found to be non-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.[17] 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 7 of the treatment for all groups.[18]

Chemistry[edit]

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

Formulations[edit]

Cyclobenzaprine 10mg

Orally, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Flexeril, Fexmid and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[19] Cyclobenzaprine is also used by compounding pharmacies in topical creams.

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.

See also[edit]

References[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. ^ http://clinicaltrials.gov/ct2/show/NCT01903265?term=bestfit&rank=1
  7. ^ van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM (2003). "Muscle relaxants for non-specific low back pain". In Van Tulder, Maurits W. Cochrane Database Systematic Reviews 2 (1–2): 91–9. doi:10.1002/14651858.CD004252. PMID 12804507. 
  8. ^ 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. 
  9. ^ a b c "Cyclobenzaprine official FDA information, side effects, and uses". Drugs.com. October 2009. Retrieved 19 Feb 2010. 
  10. ^ 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. 
  11. ^ Tofferi JK, Jackson JL, O'Malley PG (15 Feb 2004). "Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis". Arthritis Rheum. 51 (1): 9–13. doi:10.1002/art.20076. PMID 14872449. 
  12. ^ Cyclobenzaprine Information and Uses - RxWiki.com
  13. ^ "Flexeril: Side effects". RxList.com. Retrieved 22 Feb 2010. 
  14. ^ "High risk medications" (pdf). National Committee for Quality Assurance. Retrieved 22 Feb 2010. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ http://www.medscape.com/viewarticle/572676_4.  Missing or empty |title= (help)
  18. ^ http://www.annemergmed.com/article/S0196-0644(04)01009-1/abstract.  Missing or empty |title= (help)
  19. ^ Amrix website