Cyclobenzaprine

Cyclobenzaprine, also known by the brand name Flexeril is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions.^[3] It is the most well-studied drug for this application,^[4] and it also has been used off-label for fibromyalgia treatment.^[5]

Mechanism of action

The mechanism of action for cyclobenzaprine is unclear. Studies from the 1980s in rats 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 neurons.^[6]

Cyclobenzaprine has been considered structurally related to the first-generation tricyclic antidepressants.^[7] 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,^[8][9] an antagonist at histamine H₁ receptors, muscarinic acetylcholine receptors, and 5-HT_2A serotonin receptors. Corroborating studies show that cyclobenzaprine causes inhibition of descending serotonergic systems in the spinal cord by blocking 5-HT_2A and 5-HT_2C receptors.^[10] 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.^[11]

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.^[3] It decreases pain in the first two weeks,^[4][12] peaking in the first few days, but has no proven benefit after two weeks.^[4][13] Since no benefit is proven beyond that, therapy should not be continued long-term.^[14] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.^[14][15]

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).^[16] Like other tricyclic antidepressants, it is also prescribed off-label as a sleep-aid.

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.^[17]

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.

Side effects

Meta-analysis 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.^[13] Drowsiness and dry mouth appear to intensify with increasing dose.^[18]

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.^[18] 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.^[19] There is one case report of overdose causing rhabdomyolysis (muscle breakdown).^[20] Treatment protocols and support should follow the same as for any tricyclic antidepressant.^[20]

Overdose

The most common effects of overdose are drowsiness and tachycardia.^[3] Rare but potentially critical complications are cardiac arrest, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.^[3] Life-threatening overdose is rare,^[3] however, as the median lethal dose is approximately 338 mg/kg in mice and 425 mg/kg in rats,^[3]. The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.^[3]

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.^[21]

The following substances may interact with cyclobenzaprine:

• Alcohol
• Central nervous system (CNS) depressants (medicines that cause drowsiness)
• Tricyclic antidepressants may increase the chance of side-effects
• Monoamine oxidase inhibitors taken within 2 weeks of cyclobenzaprine may result in serious, life-threatening side-effects^[14]

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 dehydration of the resulting carbinol in acidic conditions into cyclobenzaprine.

• H.La Roche, GB 858187  (1961).
• F.J. Villani, C.A. Ellis, C. Teihman, C. Biges, J. Med. Pharm. Chem., 5, 373 (1962).
• Winthrop, S. O.; Davis, M. A.; Myers, G. S.; Gavin, J. G.; Thomas, R.; Barber, R. (1962). "New Psychotropic Agents. Derivatives of Dibenzo[a,d]-1,4-cycloheptadiene". The Journal of Organic Chemistry 27: 230. doi:10.1021/jo01048a057.  edit

Notes