Cyclobenzaprine
Encyclopedia
Cyclobenzaprine is a muscle relaxant
medication used to relieve skeletal muscle
spasm
s and associated pain in acute
musculoskeletal conditions. It is the most well-studied drug for this application, and it also has been used off-label
for fibromyalgia
treatment.
for cyclobenzaprine is unclear. Studies from the 1980s in rat
s indicate that cyclobenzaprine activates the locus ceruleus
in the brain stem
, leading to an increased release of norepinephrine
in the ventral horn of the spinal cord
and the subsequent inhibitory action of norepinephrine on alpha motor neuron
s.
Cyclobenzaprine has been considered structurally related to the first-generation tricyclic antidepressant
s. Such tricyclics, including amitriptyline
, act to inhibit the uptake of norepinephrine, resulting in increased transynaptic norepinephrine
concentration. They have been shown to exert analgesic effects in chronic nerve and muscle pain. Cyclobenzaprine may have a similar effect.
Others contend that the structure is more closely related to cyproheptadine
, an antagonist
at histamine H1 receptors, muscarinic acetylcholine receptor
s, and 5-HT2A serotonin receptor
s. Corroborating studies show that cyclobenzaprine causes inhibition of descending serotonergic
systems in the spinal cord by blocking 5-HT2A and 5-HT2C
receptors. This action is thought to have an inhibitory effect on the alpha motor neurons in the ventral horn of the spinal cord, thereby resulting in decreased firing of alpha-motor neurons and a reduction in spinal mono- and polysynaptic reflexes.
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 not useful for spasticity
due to neurologic conditions such as cerebral palsy
.
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). Like other tricyclic antidepressants, it is also prescribed off-label as a sleep-aid
.
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.
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
. Drowsiness and dry mouth appear to intensify with increasing dose.
Other side effects are not significantly more common than they are in patients taking placebo
. Some of these include blurred vision, fatigue, nausea, and headache. 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. There is one case report
of overdose causing rhabdomyolysis
(muscle breakdown). Treatment protocols and support should follow the same as for any tricyclic antidepressant.
. Rare but potentially critical complications are cardiac arrest
, cardiac dysrhythmia
s, severe hypotension
, seizure
s, and neuroleptic malignant syndrome
. Life-threatening overdose is rare, however, as the median lethal dose is approximately 338 mg/kg 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.
when cyclobenzaprine was taken with the serotonergic drugs duloxetine
or phenelzine
.
The following substances may interact with cyclobenzaprine:
of the resulting carbinol in acidic conditions into cyclobenzaprine.
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
medication used to relieve skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
spasm
Spasm
In medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
s and associated pain in acute
Acute (medicine)
In medicine, an acute disease is a disease with either or both of:# a rapid onset, as in acute infection# a short course ....
musculoskeletal conditions. It is the most well-studied drug for this application, and it also has been used off-label
Off-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
for fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
treatment.
Mechanism of action
The mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
for cyclobenzaprine is unclear. Studies from the 1980s in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s indicate that cyclobenzaprine activates the locus ceruleus
Locus ceruleus
The locus coeruleus , is a nucleus in the brainstem involved with physiological responses to stress and panic. It was discovered in the 18th century by Félix Vicq-d'Azyr....
in the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, leading to an increased release of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
in the ventral horn of the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
and the subsequent inhibitory action of norepinephrine on alpha motor neuron
Alpha motor neuron
Alpha motor neurons are large lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their contraction...
s.
Cyclobenzaprine has been considered structurally related to the first-generation tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s. Such tricyclics, including amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
, act to inhibit the uptake of norepinephrine, resulting in increased transynaptic norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
concentration. They have been shown to exert analgesic effects in chronic nerve and muscle pain. Cyclobenzaprine may have a similar effect.
Others contend that the structure is more closely related to cyproheptadine
Cyproheptadine
Cyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
, an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
at histamine H1 receptors, muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s, and 5-HT2A serotonin receptor
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
s. Corroborating studies show that cyclobenzaprine causes inhibition of descending serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
systems in the spinal cord by blocking 5-HT2A and 5-HT2C
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
receptors. This action is thought to have an inhibitory effect on the alpha motor neurons in the ventral horn of the spinal cord, thereby resulting in decreased firing of alpha-motor neurons and a reduction in spinal mono- and polysynaptic reflexes.
Use
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 spasm 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 not useful for spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
due to neurologic conditions such as cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
.
Cyclobenzaprine has also shown effectiveness in the treatment of fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
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). Like other tricyclic antidepressants, it is also prescribed off-label as a sleep-aid
Tranquilizer
A tranquilizer, or tranquilliser , is a drug that induces tranquility in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
.
Formulations and dosages
Cyclobenzaprine is marketed as Apo-Cyclobenzaprine (10 mg tablets), Flexeril (5 and 10 mg tablets) and Fexmid (7.5 mg tablet). Both Flexeril and Fexmid are available in generic form. A once-a-day extended-release formulation Amrix is available in 15- and 30-mg capsules.Cyclobenzaprine is regulated in the U.S. for prescription
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
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.
Side effects
Meta-analysisMeta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
studies have found significantly increased rates of drowsiness (38% of patients), dry mouth (24%), dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
(10%), and adverse events of any kind in patients taking cyclobenzaprine versus placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. Drowsiness and dry mouth appear to intensify with increasing dose.
Other side effects are not significantly more common than they are in patients taking placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. Some of these include blurred vision, fatigue, nausea, and headache. 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
National Committee for Quality Assurance
The National Committee for Quality Assurance is an independent 501 non-profit organization in the United States designed to improve health care quality. It was established in 1990 with support from the Robert Wood Johnson Foundation. NCQA manages voluntary accreditation programs for individual...
recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects. There is one case report
Case report
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence....
of overdose causing rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
(muscle breakdown). Treatment protocols and support should follow the same as for any tricyclic antidepressant.
Overdose
The most common effects of overdose are drowsiness and tachycardiaTachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
. Rare but potentially critical complications are cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
, cardiac dysrhythmia
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
s, severe hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, and neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
. Life-threatening overdose is rare, however, as the median lethal dose is approximately 338 mg/kg in mice and 425 mg/kg in rats,. The potential harm is increased when central nervous system depressants
Depressant
A depressant, or central depressant, is a drug or endogenous compound that depresses the function or activity of a specific part of the brain...
and antidepressants are also used; deliberate overdose often includes alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
among other drugs.
Interactions
Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndromeSerotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
when cyclobenzaprine was taken with the serotonergic drugs duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
or phenelzine
Phenelzine
Phenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
.
The following substances may interact with cyclobenzaprine:
- AlcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
- Central nervous system (CNS) depressants (medicines that cause drowsiness)
- Tricyclic antidepressantTricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s may increase the chance of side-effects - Monoamine oxidase inhibitorMonoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s taken within 2 weeks of cyclobenzaprine may result in serious, life-threatening side-effects
Chemistry
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 dehydrationDehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
of the resulting carbinol in acidic conditions into cyclobenzaprine.
- H.La Roche, (1961).
- F.J. Villani, C.A. Ellis, C. Teihman, C. Biges, J. Med. Pharm. Chem., 5, 373 (1962).