Cyclobenzaprine

Cyclobenzaprine, sold under several brand names including, historically, Flexeril, is a muscle relaxer used for muscle spasms from musculoskeletal conditions of sudden onset.

Common side effects include headache, tiredness, dizziness, and dry mouth. It was not available in the United Kingdom as of 2012.

Medical uses

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 may also be used along with other treatments for tetanus.

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. However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice. 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 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.

Side effects

Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).

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 tricyclics, such as tricyclic antidepressants.

Overdose

The most common effects of overdose are drowsiness and tachycardia.

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.

Pharmacology

Pharmacodynamics

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|+ Cyclobenzaprine (and metabolite)

Its known actions include serotonin–norepinephrine reuptake inhibition, serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptor antagonism, α1- and α2-adrenergic receptor antagonism, histamine H1 receptor noncompetitive antagonism, and muscarinic acetylcholine receptor antagonism. 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.

The mechanism of action of cyclobenzaprine as a muscle relaxant is unknown. The antihistamine activity of cyclobenzaprine is thought to play a major role in its sedative effects.

Pharmacokinetics

Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. Its metabolite norcyclobenzaprine (NCBP) is active.

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. Cyclobenzaprine is also used by compounding pharmacies in topical creams.

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. A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.

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. 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.

On August 15, 2025, the FDA approved TNX-102 SL under the name Tonmya.