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Cyclobenzaprine

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Cyclobenzaprine
File:Cyclobenzacne.svg
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
  • 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-propan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.588 Edit this at Wikidata
Chemical and physical data
FormulaC20H21N
Molar mass275.395 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
  (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 should not be used together with MAOIs.[5] How it works is unclear.[5] In any case, it is known to inhibit serotonin and norepinephrine reuptake and to block serotonin, adrenergic, histamine, and muscarinic acetylcholine receptors.[6][7] Chemically, it is very similar to tricyclic antidepressants like amitriptyline.[6]

Cyclobenzaprine was approved for medical use in the United States in 1977.[5] It is available by prescription as a generic medication.[5] In 2022, it was the 45th most commonly prescribed medication in the United States, with more than 13 million prescriptions.[8][9] It was not available in the United Kingdom as of 2012.[10]

Medical uses

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Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.[11] 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.[12] It decreases pain in the first two weeks,[13][14] peaking in the first few days, but has no proven benefit after two weeks.[13][15] Since no benefit is proven beyond that, therapy should not be continued long-term.[12] It is the best-studied muscle relaxer.[13] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[12][16] It may also be used along with other treatments for tetanus.[17]

Comparison to other medications

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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.[18] However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice.[medical citation needed] Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.[medical citation needed]

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.[19]

Side effects

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Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).[15] Drowsiness and dry mouth appear to intensify with increasing dose.[20] The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors.[medical citation needed]

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.[21][22] 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.[23]

Dysphagia, a life-threatening side-effect, may rarely occur.[24] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[25]

Overdose

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The most common effects of overdose are drowsiness and tachycardia.[12] Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome.[12] Life-threatening overdose is rare,[12] however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats.[12] The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes other drugs.[12]

Interactions

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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.[26]

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.[27]

Pharmacology

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Pharmacodynamics

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Cyclobenzaprine (and metabolite)[6][7][28]
Site CBP NCBP Action
SERTTooltip Serotonin transporter 108 ND Inhibitor
NETTooltip Norepinephrine transporter 36 ND Inhibitor
DATTooltip Dopamine transporter 5489 ND Inhibitor
5-HT1A 5300 3200 Agonist
5-HT2A 5.2–29 13 Antagonist
5-HT2B 100–154 ND Antagonist
5-HT2C 5.2–57 43 Antagonist
5-HT6 145 ND Antagonist
5-HT7 151 ND 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 Antagonist
M1 7.9 30 Antagonist
M2 High ND Antagonist
M3 High ND Antagonist
M4 Negligible ND –
M5 Negligible ND –
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Cyclobenzaprine is a centrally acting muscle relaxant with a chemical structure that is very similar to those of tricyclic antidepressants like amitriptyline and imipramine.[29][6]

Its known actions include serotonin–norepinephrine reuptake inhibition, serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptor antagonism, α1- and α2-adrenergic receptor antagonism, histamine H1 receptor noncompetitive antagonism, and muscarinic acetylcholine receptor antagonism.[6][7][30] In terms of its antimuscarinic activity, it is said to be an antagonist of the muscarinic acetylcholine M1, M2, and M3 receptors, but not of the muscarinic acetylcholine M4 or M5 receptor.[28]

The mechanism of action of cyclobenzaprine as a muscle relaxant is unknown.[30] However, it may work through modulating the serotonergic and noradrenergic systems.[30][31] The antihistamine activity of cyclobenzaprine is thought to play a major role in its sedative effects.[30] Similarly to tricyclic antidepressants, cyclobenzaprine shows antidepressant-like effects in animals.[32]

Pharmacokinetics

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Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. Its metabolite norcyclobenzaprine (NCBP) is active.[7] The elimination half-life of cyclobenzaprine is 18 hours and it has a clearance of 0.7 L/min.[29][33][34]

Chemistry

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Cyclobenzaprine is a tricyclic compound of the dibenzocycloheptene group. It is very similar in chemical structure to tricyclic antidepressants like amitriptyline and imipramine, which are likewise dibenzocycloheptenes.[6] Cyclobenzaprine differs from amitriptyline in structure only by the presence of a single double bond within the tricyclic ring system.[6]

Society and culture

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Formulations

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Cyclobenzaprine 10mg tablets

By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprine, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[35] Cyclobenzaprine is also used by compounding pharmacies in topical creams.[citation needed]

Research

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Fibromyalgia

[edit]

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.[36] A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.[37]

Two Phase 3 clinical trials reported that an experimental sublingual formulation of cyclobenzaprine, TNX-102 SL, was able to reduce pain and improve sleep quality in patients with fibromyalgia. The RESILIENT trial reported significant reductions in daily pain and improvements in various fibromyalgia symptoms, including fatigue and depressive symptoms, compared to placebo.[38][39] A separate Phase 3 clinical trial evaluated TNX-102 SL in patients with military-related post-traumatic stress disorder (PTSD) and reported the drug did not provide a sustained, significant improvement in overall PTSD severity, but it did demonstrate improvements in sleep quality during the 12-week trial.[40]

References

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  1. ^ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
  2. ^ "Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only". nih.gov. Retrieved 1 October 2016.
  3. ^ a b Teva Pharmaceuticals USA, Inc (May 2016). "AMR40470 (Amrix) Prescribing Information" (PDF).
  4. ^ U.S. Food and Drug Administration. "NDA 17-821/S-045 Flexeril (Cyclobenzaprine HCl) Tablets" (PDF).
  5. ^ a b c d e f g h i j "Cyclobenzaprine Monograph for Professionals". Drugs.com. AHFS. Retrieved 22 December 2018.
  6. ^ a b c d e f g Mestres J, Seifert SA, Oprea TI (November 2011). "Linking pharmacology to clinical reports: cyclobenzaprine and its possible association with serotonin syndrome". Clin Pharmacol Ther. 90 (5): 662–665. doi:10.1038/clpt.2011.177. PMC 3809033. PMID 21975349.
  7. ^ a b c d Daugherty B, Gershell L, Lederman S (October 2012). "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". Arthritis and Rheumatism. 64 (10): S416–S416. In vitro, CBP and nCBP exhibited high affinity binding (Ki) to receptors: 5HT2a (5.2 and 13 nM, respectively) and 5HT2c (5.2 and 43 nM), adrenergic α-1A (5.6 and 34 nM), α-2B (Ki = 21 and 150 nM) and α-2C (Ki = 21 and 48 nM,); H1 (1.3 and 5.6 nM); and M1 (7.9 and 30 nM). Like CBP, nCBP is a functional antagonist at 5HT2a (IC50 = 92 nM) by Ca+ mobilization. CBP is also an antagonist on 5HT2b (IC50 = 100 nM). CBP and nCBP are functional antagonists on 5HT2c (IC50 = 0.44 and 1.22 μM) and on α-2A (IC50 = 4.3 and 6.4 μM). In contrast, both CBP and nCBP are functional agonists on 5HT1a (EC50= 5.3 and 3.2 μM). [...] CPB and nCBP are potent antagonists of 5HT2a, 5HT2b, H-1, adrenergic α-1A, α-2B and α-2C receptors.
  8. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
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  17. ^ Smith BT (2014). Pharmacology for Nurses. Jones & Bartlett Publishers. p. 122. ISBN 9781449689407.
  18. ^ "Medscape: Medscape Access". medscape.com. Retrieved 1 October 2016.
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  20. ^ "Flexeril: Side effects". RxList.com. Archived from the original on 12 September 2008. Retrieved 22 February 2010.
  21. ^ "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. PMID 25763449.
  22. ^ Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. Archived 12 August 2015 at the Wayback Machine [1]
  23. ^ "High risk medications" (PDF). National Committee for Quality Assurance. Archived from the original (PDF) on 1 February 2010. Retrieved 22 February 2010.
  24. ^ "MEDICATIONS AND DYSPHAGIA/ SWALLOWING RISKS" (PDF).
  25. ^ Chabria SB (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.
  26. ^ Keegan MT, Brown DR, Rabinstein AA (December 2006). "Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs". Anesthesia and Analgesia. 103 (6): 1466–8. doi:10.1213/01.ane.0000247699.81580.eb. PMID 17122225.
  27. ^ Medical Practice of William H. Gorman, M.D. (18 February 2014). "Medications to Avoid, Continue, or Stop - Before & After Surgery". Archived from the original on 1 December 2017. Retrieved 2 February 2017.
  28. ^ a b Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM (January 2023). "A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity". Pharmaceutics. 15 (1): 230. doi:10.3390/pharmaceutics15010230. PMC 9863833. PMID 36678858.
  29. ^ a b "Cyclobenzaprine". www.drugbank.ca.
  30. ^ a b c d Singh K, Senatorov IS, Cheshmehkani A, Karmokar PF, Moniri NH (March 2022). "The Skeletal Muscle Relaxer Cyclobenzaprine Is a Potent Non-Competitive Antagonist of Histamine H1 Receptors". J Pharmacol Exp Ther. 380 (3): 202–209. doi:10.1124/jpet.121.000998. PMID 34992159.
  31. ^ Kobayashi H, Hasegawa Y, Ono H (September 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.
  32. ^ Zhang TT, Xue R, Wang X, Zhao SW, An L, Li YF, et al. (October 2018). "Network-based drug repositioning: A novel strategy for discovering potential antidepressants and their mode of action". Eur Neuropsychopharmacol. 28 (10): 1137–1150. doi:10.1016/j.euroneuro.2018.07.096. PMID 30087074.
  33. ^ "Cyclobenzaprine". pubchem.ncbi.nlm.nih.gov.
  34. ^ Winchell GA, King JD, Chavez-Eng CM, Constanzer ML, Korn SH (January 2002). "Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency". Journal of Clinical Pharmacology. 42 (1): 61–9. doi:10.1177/0091270002042001007. PMID 11808825. S2CID 7749001.
  35. ^ "Patient Web site for Amrix (Cyclobenzaprine Hydrochloride Extended-Release Capsules)". amrix.com. Retrieved 1 October 2016.
  36. ^ Tofferi JK, Jackson JL, O'Malley PG (February 2004). "Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis". Arthritis and Rheumatism. 51 (1): 9–13. doi:10.1002/art.20076. PMID 14872449.
  37. ^ Leite FM, Atallah AN, El Dib R, Grossmann E, Januzzi E, Andriolo RB, et al. (July 2009). "Cyclobenzaprine for the treatment of myofascial pain in adults". The Cochrane Database of Systematic Reviews. 2009 (3): CD006830. doi:10.1002/14651858.CD006830.pub3. PMC 6481902. PMID 19588406.
  38. ^ Derman C (17 June 2024). "TNX-102 SL Significantly Reduces Daily Pain, Improves Fibromyalgia Symptoms". HCP Live. Retrieved 20 September 2024.
  39. ^ Lederman S, Arnold LM, Vaughn B, Kelley M, Sullivan GM (November 2023). "Efficacy and Safety of Sublingual Cyclobenzaprine for the Treatment of Fibromyalgia: Results From a Randomized, Double-Blind, Placebo-Controlled Trial". Arthritis Care & Research. 75 (11): 2359–2368. doi:10.1002/acr.25142. PMID 37165930.
  40. ^ Parmenter ME, Lederman S, Weathers FW, Davis LL, Vaughn B, Engels J, et al. (April 2024). "A phase 3, randomized, placebo-controlled, trial to evaluate the efficacy and safety of bedtime sublingual cyclobenzaprine (TNX-102 SL) in military-related posttraumatic stress disorder". Psychiatry Research. 334: 115764. doi:10.1016/j.psychres.2024.115764. PMID 38350291.
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