Cyclobenzaprine

Template:Short description Template:Distinguish Template:Use American English Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

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| _other_data=3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-propan-1-amine

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| _datapage = Cyclobenzaprine (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=Rx-onlyRx-only | _ATC_prefix_supplemental=M03 | _has_EMA_link = | CAS_number=303-53-7 | PubChem=2895 | ChemSpiderID=2792 | ChEBI=3996 | ChEMBL=669 | DrugBank=DB00924 | KEGG=D07758 | _hasInChI_or_Key={{#if: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,7,15H2,1-2H3JURKNVYFZMSNLP-UHFFFAOYSA-N |yes}} | UNII=69O5WQQ5TI | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields= |verifiedrevid=460109805}} Cyclobenzaprine, sold under several brand names including, historically, Flexeril, is a muscle relaxer used for muscle spasms from musculoskeletal conditions of sudden onset.<ref name=AHFS2018/> It is not useful in cerebral palsy.<ref name=AHFS2018/> It is taken by mouth.<ref name=AHFS2018>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include headache, feeling tired, dizziness, and dry mouth.<ref name=AHFS2018/> Serious side effects may include an irregular heartbeat.<ref name=AHFS2018/> There is no evidence of harm in pregnancy, but it has not been well studied in this population.<ref name=AHFS2018/> It should not be used together with MAOIs.<ref name=AHFS2018/> How it works is unclear.<ref name=AHFS2018/> In any case, it is known to inhibit serotonin and norepinephrine reuptake and to block serotonin, adrenergic, histamine, and muscarinic acetylcholine receptors.<ref name="MestresSeifertOprea2011" /><ref name="DaughertyGershellLederman2012" /> Chemically, it is very similar to tricyclic antidepressants like amitriptyline.<ref name="MestresSeifertOprea2011" />

Cyclobenzaprine was approved for medical use in the United States in 1977.<ref name=AHFS2018/> It is available by prescription as a generic medication.<ref name=AHFS2018/> In 2022, it was the 45th most commonly prescribed medication in the United States, with more than 13Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was not available in the United Kingdom as of 2012.<ref>Template:Cite journal</ref>

Medical uses

Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.<ref>Template:Cite journal</ref> 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.<ref name="Cyclobenzaprine FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It decreases pain in the first two weeks,<ref name = chou>Template:Cite journal</ref><ref>Template:Cite journal</ref> peaking in the first few days, but has no proven benefit after two weeks.<ref name = chou /><ref name = browning>Template:Cite journal</ref> Since no benefit is proven beyond that, therapy should not be continued long-term.<ref name="Cyclobenzaprine FDA label" /> It is the best-studied muscle relaxer.<ref name = chou /> It is not useful for spasticity due to neurologic conditions such as cerebral palsy.<ref name="Cyclobenzaprine FDA label" /><ref>Template:Cite journal</ref> It may also be used along with other treatments for tetanus.<ref>Template:Cite book</ref>

Comparison to other medications

Cyclobenzaprine has been found not to be 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice.Template:Medcn Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.Template:Medcn

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.<ref>Template:Cite journal</ref>

Side effects

Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).<ref name = browning /> Drowsiness and dry mouth appear to intensify with increasing dose.<ref name=rxlist>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Agitation is a common side effect observed, especially in the elderly. Some expertsTemplate:Who believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment.<ref>Template:Cite book</ref><ref>Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. Template:Webarchive [1]</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Dysphagia, a life-threatening side-effect, may rarely occur.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.<ref name="chabria">Template:Cite journal</ref>

Overdose

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

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.<ref>Template:Cite journal</ref>

These substances may interact with cyclobenzaprine:

• Central nervous system depressants (e.g. alcohol, opioids, benzodiazepines, nonbenzodiazepines, phenothiazines, carbamates, barbiturates, major tranquilizers)
• Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.<ref name="Cyclobenzaprine FDA label" />

Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pharmacology

Pharmacodynamics

Cyclobenzaprine (and metabolite)<ref name="MestresSeifertOprea2011" /><ref name="DaughertyGershellLederman2012" /><ref name="LavradorCabralVeríssimo2023" />

Site	Template:Abbr	Template:Abbr	Action
Template:Abbrlink	108	Template:Abbr	Inhibitor
Template:Abbrlink	36	Template:Abbr	Inhibitor
Template:Abbrlink	5489	Template:Abbr	Inhibitor
5-HT1A	5300	3200	Agonist
5-HT2A	5.2–29	13	Antagonist
5-HT2B	100–154	Template:Abbr	Antagonist
5-HT2C	5.2–57	43	Antagonist
5-HT6	145	Template:Abbr	Antagonist
5-HT7	151	Template:Abbr	Antagonist
α1A	5.6	34	Template:Abbr
α2A	4.3	6.4	Antagonist
α2B	21	150	Template:Abbr
α2C	21	48	Template:Abbr
H1	1.3	5.6	Antagonist
M1	7.9	30	Antagonist
M2	High	Template:Abbr	Antagonist
M3	High	Template:Abbr	Antagonist
M4	Negligible	Template:Abbr	–
M5	Negligible	Template:Abbr	–
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.<ref name="Cyclobenzaprine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="MestresSeifertOprea2011">Template:Cite journal</ref>

Its known actions include serotonin–norepinephrine reuptake inhibition, serotonin 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₆, and 5-HT₇ receptor antagonism, α₁- and α₂-adrenergic receptor antagonism, histamine H₁ receptor noncompetitive antagonism, and muscarinic acetylcholine receptor antagonism.<ref name="MestresSeifertOprea2011" /><ref name="DaughertyGershellLederman2012">Template:Cite journal</ref><ref name="SinghSenatorovCheshmehkani2022">Template:Cite journal</ref> 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.<ref name="LavradorCabralVeríssimo2023">Template:Cite journal</ref>

The mechanism of action of cyclobenzaprine as a muscle relaxant is unknown.<ref name="SinghSenatorovCheshmehkani2022" /> However, it may work through modulating the serotonergic and noradrenergic systems.<ref name="SinghSenatorovCheshmehkani2022" /><ref name="KobayashiHasegawaOno1996">Template:Cite journal</ref> The antihistamine activity of cyclobenzaprine is thought to play a major role in its sedative effects.<ref name="SinghSenatorovCheshmehkani2022" /> Similarly to tricyclic antidepressants, cyclobenzaprine shows antidepressant-like effects in animals.<ref name="ZhangXueWang2018">Template:Cite journal</ref>

Pharmacokinetics

Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. Its metabolite norcyclobenzaprine (NCBP) is active.<ref name="DaughertyGershellLederman2012" /> The elimination half-life of cyclobenzaprine is 18Template:Nbsphours and it has a clearance of 0.7Template:NbspL/min.<ref name="Cyclobenzaprine"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

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.<ref name="MestresSeifertOprea2011" /> Cyclobenzaprine differs from amitriptyline in structure only by the presence of a single double bond within the tricyclic ring system.<ref name="MestresSeifertOprea2011" />

Society and culture

Formulations

File: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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Cyclobenzaprine is also used by compounding pharmacies in topical creams.Template:Cn

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.<ref name = tofferi>Template:Cite journal</ref> A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.<ref>Template:Cite journal</ref>

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.<ref name="Derman 2024">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid37165930">Template:Cite journal</ref> 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.<ref name="pmid38350291">Template:Cite journal</ref>