Cyclobenzaprine

Last updated

Cyclobenzaprine
Cyclobenzaprine.svg
Clinical data
Trade names Flexeril, Amrix, others
AHFS/Drugs.com Monograph
MedlinePlus a682514
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 33–55% [1] [2]
Protein binding 93%
Metabolism major: CYP3A4, CYP1A2; minor: CYP2D6, N-demethylation [3]
Metabolites Norcyclobenzaprine
Elimination half-life 32 hours (extended-release, range 8–37 hours), [3] 18 hours (immediate release, range 8–37 hours) [4]
Excretion Kidney
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 InfoCard 100.005.588 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H21N
Molar mass 275.395 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 Yes check.svgY
  • Key:JURKNVYFZMSNLP-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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

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

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

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

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

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

Pharmacodynamics

Cyclobenzaprine (and metabolite) [6] [7] [28]
SiteCBPNCBPAction
SERT Tooltip Serotonin transporter108NDInhibitor
NET Tooltip Norepinephrine transporter36NDInhibitor
DAT Tooltip Dopamine transporter5489NDInhibitor
5-HT1A 53003200Agonist
5-HT2A 5.2–2913Antagonist
5-HT2B 100–154NDAntagonist
5-HT2C 5.2–5743Antagonist
5-HT6 145NDAntagonist
5-HT7 151NDAntagonist
α1A 5.634ND
α2A 4.36.4Antagonist
α2B 21150ND
α2C 2148ND
H1 1.35.6Antagonist
M1 7.930Antagonist
M2 HighNDAntagonist
M3 HighNDAntagonist
M4 NegligibleND–
M5 NegligibleND–
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

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

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

Formulations

Cyclobenzaprine 10mg tablets Cyclobenzaprine 10mg Tablets.jpg
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

Fibromyalgia

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]

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References

  1. ↑ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
  2. ↑ "Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only". nih.gov. Retrieved 1 October 2016.
  3. 1 2 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. 1 2 3 4 5 6 7 8 9 10 "Cyclobenzaprine Monograph for Professionals". Drugs.com. AHFS. Retrieved 22 December 2018.
  6. 1 2 3 4 5 6 7 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. 1 2 3 4 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. 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.
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  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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