DRUG PROFILE

CYCLOBENZAPRINE
HYDROCHLORIDE

[2]

IUPAC Name
N,N-dimethyl-3-(2-tricyclo[9.4.0.0]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)propan-
1-amine [2]

Molecular Formula
C20H22ClN [2]

Molecular Weight
311.8 [2]

Brand Names
Amrix, Fexmid, Flexeril [2]

Background
Cyclobenzaprine, a centrally-acting muscle relaxant, was first synthesized in 1961 and
has been available for human use since 1977.It was initially studied for use as
antidepressant given its structural similarity to tricyclic antidepressants - it differs from
Amitriptyline by only a single double bond.Since its approval, it has remained relatively
popular as an adjunctive, short-term treatment for acute skeletal muscle spasms
secondary to musculoskeletal injury.[1]

Indication
Cyclobenzaprine is indicated as a short-term (2-3 weeks) adjunct therapy, along with
rest and physical therapy, for relief of muscle spasm associated with acute, painful
musculoskeletal conditions. It has not been found effective in the treatment of
spasticity originating from cerebral or spinal cord disease, or spasticity in children with
cerebral palsy.Cyclobenzaprine is also occasionally used off-label for reducing pain and
sleep disturbances in patients with fibromyalgia.[1]

Associated Conditions
Muscle Spasms [1]

ABOUT
Cyclobenzaprine Hydrochloride is a centrally acting muscle relaxant, chemically similar
to amitriptyline hydrochloride with antidepressant activity. It primarily acts at the brain
stem to reduce tonic somatic motor activity, influencing both gamma and alpha motor
neurons. This leads to a reduction in muscle spasms.
Cyclobenzaprine hydrochloride is the hydrochloride salt of cyclobenzaprine. It is used in
the symptomatic treatment of painful muscle spasm. It derives from a hydride of a
[2]
dibenzo[a,d][7]annulene
Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle

spasms that occur because of acute musculoskeletal conditions. 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. It decreases
pain in the first two weeks, peaking in the first few days, but has no proven benefit
after two weeks.Since no benefit is proven beyond that, therapy should not be
continued long-term. It is the best-studied muscle relaxer.It is not useful for
spasticity due to neurologic conditions such as cerebral palsy.[6]

PHYSICAL AND CHEMICAL PROPERTIES

Physical Description
Solid[2]

Boiling Point
BP: 175-180 °C at 1 atm[2]

Melting Point
216 - 218 °C (hydrochloride salt)[2]

Solubility
It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and
insoluble in hydrocarbon solvents.

Vapor Pressure
2.29X10-6 mm Hg at 25 °C (est)[2]

LogP
5.2[2]

Henry's Law constant = 2.78X10-8 atm-cu m/mol at 25 °C (est)[2]

Stability/Shelf Life
Stable under recommended storage conditions.[2]

Decomposition
When heated to decomposition it emits toxic fumes of nitrogen oxides.[2]

UV Spectra UV max: 224, 289 nm [2]

CLASSIFICATION
Antidepressive Agents, Tricyclic; Muscle Relaxants, Central; Tranquilizing Agents
Muscle Relaxants, Central
A heterogeneous group of drugs used to produce muscle relaxation, excepting the
neuromuscular blocking agents. They have their primary clinical and therapeutic uses in
the treatment of muscle spasm and immobility associated with strains, sprains, and
injuries of the back and, to a lesser degree, injuries to the neck. They have been used
also for the treatment of a variety of clinical conditions that have in common only the
presence of skeletal muscle hyperactivity, for example, the muscle spasms that can

occur in MULTIPLE SCLEROSIS.[2]

Tranquilizing Agents
A traditional grouping of drugs said to have a soothing or calming effect on mood,
thought, or behavior. Included here are the ANTI-ANXIETY AGENTS (minor tranquilizers),
ANTIMANIC AGENTS, and the ANTIPSYCHOTIC AGENTS (major tranquilizers). These

drugs act by different mechanisms and are used for different therapeutic purposes. [2]
Antidepressive Agents, Tricyclic
Substances that contain a fused three-ring moiety and are used in the treatment of
depression. These drugs block the uptake of norepinephrine and serotonin into axon
terminals and may block some subtypes of serotonin, adrenergic, and histamine
receptors. However, the mechanism of their antidepressant effects is not clear because
the therapeutic effects usually take weeks to develop and may reflect compensatory

changes in the central nervous system.[2]

THERAPEUTIC USES
Cyclobenzaprine hydrochloride tablets are indicated as an adjunct to rest and physical
therapy for relief of muscle spasm associated with acute, painful musculoskeletal
conditions. Improvement is manifested by relief of muscle spasm and its associated
signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in
activities of daily living. Cyclobenzaprine hydrochloride should be used only for short
periods (up to two or three weeks) because adequate evidence of effectiveness for
more prolonged use is not available and because muscle spasm associated with acute,
painful musculoskeletal conditions is generally of short duration and specific therapy
for longer periods is seldom warranted. Cyclobenzaprine hydrochloride has not been
found effective in the treatment of spasticity associated with cerebral or spinal cord
[2]
disease, or in children with cerebral palsy.

Some data suggest that cyclobenzaprine may be useful for the treatment of fibrositis.
Cyclobenzaprine is ineffective in the treatment of spasticity associated with cerebral or
spinal disease or in children with cerebral palsy.
EXPL Tinnitus is defined as an intrinsic sound sensation that cannot be attributed to an
external sound source. Currently there are no standardized drug therapies for the
treatment of tinnitus. It was further demonstrated that particular subgroups, namely
pure tone tinnitus patients and unilateral tinnitus patients, respond better to
cyclobenzaprine. Our results indicate that cyclobenzaprine is a promising drug to treat
tinnitus particularly in certain subgroups. As there is a good risk-benefit ratio and there
are currently no well-established, specific treatments for tinnitus, cyclobenzaprine might

be worthwhile to further investigate. [2]

PHARMACOLOGY
Pharmacodynamics
Cyclobenzaprine is a skeletal muscle relaxant that works on areas of the brainstem to
reduce skeletal muscle spasm, though its exact pharmacodynamic behavior is currently
unclear.Despite its long half-life, it is relatively short-acting with a typical duration of
action of 4-6 hours.Cyclobenzaprine has been reported to contribute to the development
of serotonin syndrome when used in combination with other serotonergic
medications.Symptoms of serotonin syndrome may include autonomic instability,
changes to mental status, neuromuscular abnormalities, or gastrointestinal symptoms -
treatment with cyclobenzaprine should be discontinued immediately if any of these
reactions occur during therapy. [1]
Mechanism of action
The exact mechanism of action of cyclobenzaprine has not been fully elucidated in
humans, and much of the information available regarding its mechanism has been
ascertained from early animal studies. There is some evidence that cyclobenzaprine
exerts its effects at the supraspinal level, specifically within the locus coeruleus of the
brainstem, with little-to-no action at neuromuscular junctions or directly on skeletal
musculature. Action on the brainstem is thought to result in diminished activity of
efferent alpha and gamma motor neurons, likely mediated by inhibition of coeruleus-
spinal or reticulospinal pathways, and ultimately depressed spinal cord interneuron
activity. [1]

More recently it has been suggested that inhibition of descending serotonergic

pathways in the spinal cord via action on 5-HT2 receptors may contribute to
cyclobenzaprine’s observed effects. [1]

PHARMACOKINETICS
Absorption
The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and
0.55.Cmax is between 5-35 ng/mL and is achieved after 4 hours (T max). AUC over an 8
hour dosing interval was reported to be approximately 177 ng.hr/mL. [1]

Volume of distribution
The volume of distribution of cyclobenzaprine is approximately 146 L. The combination
of high plasma clearance despite a relatively long half-life observed with
cyclobenzaprine is suggestive of extensive tissue distribution. [1]

Protein binding
Cyclobenzaprine is approximately 93% protein bound in plasma. It has been identified
as specifically having a high affinity for human serum albumin. [1]
Metabolism
Cyclobenzaprine is extensively metabolized in the liver via both oxidative and
conjugative pathways.Oxidative metabolism, mainly N-demethylation, is catalyzed
primarily by CYP3A4 and CYP1A2 (with CYP2D6 implicated to a lesser extent) and is
responsible for the major metabolite desmethyl cyclobenzaprine . Cyclobenzaprine also
undergoes N-glucuronidation in the liver catalyzed by UGT1A4 and UGT2B10, and has
been shown to undergo enterohepatic circulation. [1]

Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides

via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-

demethylation, one of the oxidative pathways for cyclobenzaprine. [2]

Cyclobenzaprine is extensively metabolized by both oxidative and conjugative

pathways. Hepatic cytochrome P-450 (CYP) 3A4, 1A2, and (to a lesser extent) 2D6
isoenzymes are responsible for oxidative N-demethylation of the drug.Orally
administered cyclobenzaprine is excreted in urine principally as inactive glucuronide

metabolites; less than 1% of the drug is excreted renally as unchanged drug. [2]

Cyclobenzaprine has known human metabolites that include N-Desmethyl

Cyclobenzaprine. [2]

Route of elimination
After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity
was excreted in the urine while 14-15% was excreted in the feces. Cyclobenzaprine is
highly metabolized, with only approximately 1% of this same radio-labeled dose
recovered in the urine as unchanged drug.Metabolites excreted in the urine are likely
water-soluble glucuronide conjugates. [1]
Half-life
The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18
hours.These values are extended in the elderly and those with hepatic insufficiency, with
a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively. e
groups, respectively. [1]

Clearance
The approximate plasma clearance of cyclobenzaprine is 0.7 L/min.min. [1]
Cyclobenzaprine is widely distributed into body tissues. It is not known if
cyclobenzaprine crosses the placenta. The drug is extensively (about 93%) bound to
plasma protein.[2]

The absorption, distribution, excretion, and metabolism of 3-(5 H-

dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine (cyclobenzaprine) were
investigated in the rat, dog, rhesus monkey, and man. The drug was well absorbed in all
species after oral administration. The rat eliminated the drug primarily in the feces, but
urinary excretion was predominant in the dog, monkey, and man. The drug was rapidly
and widely distributed into rat tissues, highest concentrations being found in the small
intestine, lung, kidney, and liver. The drug was highly bound in human plasma. Extensive
biliary excretion of the labeled compound was observed in the rat. Major metabolites in
the rat were phenolic derivatives but in man the major metabolites were 10,11-hydroxy
nortriptyline and cyclobenzaprine glucuronide. Only minor amounts of unchanged drug
were present in the urine.
Orally administered cyclobenzaprine is well absorbed. Cyclobenzaprine undergoes
enterohepatic circulation, and appears to be metabolized during its first pass through
the GI tract and/or liver. Mean oral bioavailability of the drug is estimated to range from
33-55%. Following oral administration of a single 5- or 10-mg dose of cyclobenzaprine
hydrochloride, peak plasma concentrations of 4.3 or 8.5 ng/mL, respectively, are
attained in about 4 hours. When cyclobenzaprine is administered 3 times daily, steady-
state plasma concentrations are attained within 3-4 days that are about fourfold greater
than those after a single dose. In healthy individuals receiving the drug 3 times daily, a
mean steady-state peak plasma cyclobenzaprine concentration of 14.9 or 25.9 ng/mL
was achieved at 4 or 3.9 hours after administration of a 5 or 10 mg dose, respectively. [2]

Toxicity
The oral LD50 of cyclobenzaprine in mice and rats is 338 mg/kg and 425 mg/kg,
respectively. Signs of overdose may develop rapidly after ingestion and commonly
include significant drowsiness and tachycardia, with less common manifestations
including tremor, agitation, ataxia, GI upset, and other CNS effects such as confusion
and hallucinations. Potentially critical manifestations, though rare, include cardiac arrest
or dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

As the management of cyclobenzaprine overdose is complex and ever-changing, it is

recommended that a poison control center be consulted prior to treatment. Typical
management involves gastrointestinal decontamination, close cardiac monitoring, and
monitoring for signs of CNS or respiratory depression. As cyclobenzaprine exists in
relatively low concentrations in plasma, monitoring of drug plasma levels should not
guide management and dialysis is likely of no value.

Manifestations of toxicity may develop rapidly after a cyclobenzaprine overdose, and

rarely, death may occur. The most common toxic effects associated with
cyclobenzaprine overdose are drowsiness and tachycardia; less frequent
manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech,
confusion, dizziness, nausea, vomiting, and hallucinations. Rarely, potentially serious
effects may include cardiac arrest, chest pain, cardiac dysrhythmias, severe
hypotension, seizures, and neuroleptic malignant syndrome. Serotonin syndrome is
another potential side effect. Blood concentration of > or = 0.8 mg/L cyclobenzaprine
may be associated with a fatal outcome. In one case of accidental overdose, the victim
developed severe hypothermia and then developed cardiac arrest during transport. [2]
Side effects
Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and
dizziness (10%). Drowsiness and dry mouth appear to intensify with increasing dose.
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
believe that cyclobenzaprine should be avoided in elderly patients because it can cause
confusion, delirium, and cognitive impairment. 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.

Dysphagia, a life-threatening side-effect, may rarely occur. Treatment protocols and

support should follow the same as for any structurally related tricyclic, such as tricyclic

antidepressants. [6]

Overdose
The most common effects of overdose are drowsiness and tachycardia. Rare but
potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low
blood pressure, seizures, and neuroleptic malignant syndrome. Life-threatening
overdose is rare, however, as the median lethal dose is about 338 milligrams/kilogram in
mice and 425 mg/kg in rats. The potential harm is increased when central nervous
system depressants and antidepressants are also used; deliberate overdose often
includes alcohol among other drugs. [6]

● Drowsiness, dizziness, dry mouth, constipation, or tiredness may occur. If

any of these effects persist or worsen, tell your doctor or pharmacist
promptly.

● Remember that this medication has been prescribed because your doctor
has judged that the benefit to you is greater than the risk of side effects.
Many people using this medication do not have serious side effects.
 ● Tell your doctor right away if you have any serious side effects, including:
fast/irregular heartbeat, mental/mood changes (such as confusion,
hallucinations), trouble urinating.

● A very serious allergic reaction to this drug is rare. However, get medical
help right away if you notice any symptoms of a serious allergic reaction,
including: rash, itching/swelling (especially of the face/tongue/throat), severe
dizziness, trouble breathing.[3]

Food Interactions
● Avoid alcohol. Cyclobenzaprine is a central nervous system depressant which
may be potentiated by the co-administration of alcohol. [2]

Interactions
● Concomitant use of cyclobenzaprine with diflunisal or naproxen reportedly was
well tolerated and did not appear to result in any unexpected adverse effects.
However, concomitant use of cyclobenzaprine with naproxen has been
associated with an increased incidence of drowsiness. Plasma concentrations of
aspirin or cyclobenzaprine were unaffected when the drugs were administered
concomitantly. It has not been established whether combined therapy with
cyclobenzaprine and aspirin (or other analgesics) will result in enhanced clinical
efficacy.
● Cyclobenzaprine and structurally similar tricyclic antidepressants may block the
hypotensive effects of guanethidine and other similarly acting drugs.
● Cyclobenzaprine and structurally similar tricyclic antidepressants may enhance
the risk of seizures in patients receiving tramadol.
● Cyclobenzaprine may be additive with or may potentiate the action of other CNS
depressants (e.g., alcohol, barbiturates).
 ● Cyclobenzaprine, especially when used concomitantly with alcohol or other CNS
depressants, may impair the patient's ability to perform activities requiring
mental alertness or physical coordination (e.g., operating machinery, driving a
motor vehicle).[2]

Formulation
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. Cyclobenzaprine is also used by compounding

pharmacies in topical creams.[6]

Reference Links
1) Cyclobenzaprine: Uses, Interactions, Mechanism of Action | DrugBank Online
2) Cyclobenzaprine | C20H21N - PubChem (nih.gov)
3) https://go.drugbank.com/drugs/DB00924
4) Cyclobenzaprine Oral: Uses, Side Effects, Interactions, Pictures, Warnings &
Dosing - WebMD
5) Cyclobenzaprine: MedlinePlus Drug Information
6) Cyclobenzaprine - Wikipedia
7)