|Systematic (IUPAC) name|
|Trade names||Amrix (former Flexeril)|
|Pregnancy cat.||Category B|
|Legal status||℞ Prescription only|
|Bioavailability||33% to 55% |
|Half-life||18 hours (range 8–37 hours; n=18)|
|Mol. mass||275.387 g/mol|
|(what is this?)|
Cyclobenzaprine, brand names Amrix, Flexeril and Fexmid, is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. It is the best-studied drug for this application, it has also been used off-label for fibromyalgia treatment. A new bedtime formulation of cyclobenzaprine is under development for the management of fibromyalgia syndrome.
Mechanism of action
The mechanism of action for cyclobenzaprine is unclear. Studies from the 1980s in rats indicated cyclobenzaprine activates the locus ceruleus in the brain stem, leading to an increased release of noradrenaline (norepinephrine) in the ventral horn of the spinal cord, and the subsequent inhibitory action of noradrenaline on alpha motor neurons.
Cyclobenzaprine has been considered structurally related to the first-generation tricyclic antidepressants. Such tricyclics, including amitriptyline, act to inhibit the uptake of noradrenaline, resulting in increased transynaptic noradrenaline concentration. They have been shown to exert analgesic effects in chronic nerve and muscle pain. Cyclobenzaprine may have a similar effect.
Others contend the structure is more closely related to cyproheptadine, an antagonist at histamine H1 receptors, muscarinic acetylcholine receptors, and 5-HT2A serotonin receptors. Corroborating studies show 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.
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 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 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.
The range of dosages for the tablets is 5 to 10 mg of cyclobenzaprine taken 3 times a day. The capsules are taken either as a 15 or 30 mg capsule once a day or two 15 mg capsules twice a day. In elderly patients, cyclobenzaprine HCl may be started at a lower dose and titrated slowly upward. Cyclobenzaprine is recommended for use up to 3 weeks.
Formulations and dosages
Orally, cyclobenzaprine is marketed as Apo-Cyclobenzaprine (10 mg tablets), Flexeril (5 and 10 mg tablets), Fexmid (7.5 mg tablet), and Novo-Cycloprine (10 mg tablets). 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 also used by compounding pharmacies in topical creams to treat pain and muscle spasm / tightness.
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.
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. 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. 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 structurally related tricyclic, such as tricyclic antidepressants.
The most common effects of overdose are drowsiness and tachycardia. Rare but potentially critical complications are cardiac arrest, cardiac dysrhythmias, severe hypotension, seizures, 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.
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.
The following substances may interact with cyclobenzaprine:
- Central nervous system (CNS) depressants (eg. opioids, benzodiazepines, nonbenzodiazepines, phenothiazines, carbamates, barbiturates)
- Tricyclic antidepressants may increase the chance of side effects.
- Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.
If co-administered with opioids the dose of one or both medicines should be reduced accordingly. The patient should be monitored for excessive sedation.
A sublingual, very low dose formulation of cyclobenzaprine (TNX-102 SL) is being developed as a bedtime therapy for the management of fibromyalgia by Tonix Pharmaceuticals. TNX-102 SL is designed to provide benefit in fibromyalgia by improving sleep quality. In a randomized, double-blind, placebo-controlled Phase II clinical study in 36 patients, very low dose cyclobenzaprine given at nighttime was shown to significantly improve core fibromyalgia symptoms and was well tolerated. Reported clinical benefits include reductions in pain, fatigue, and depressed mood, superior to placebo. A 12-week Phase 2b/3 clinical trial of TNX-102 SL in fibromyalgia is currently open to patient enrollment.
Comparison to other medications
Cyclobenzaprine has been found to be non-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. However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advise. Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.
In a study on the treatment of musculoskeletal pain treatment with ibuprofen, cyclobenzaprine, and both, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day 7 of the treatment for all groups.
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.
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