How does Flexeril (Cyclobenzaprine) cause muscle relaxation by acting on the Central Nervous System (CNS)?

From the Guidelines

Flexeril (cyclobenzaprine) causes muscle relaxation by acting on the central nervous system (CNS) as a 5-HT2 receptor antagonist, which is supported by the most recent evidence from 2021 1.

Mechanism of Action

The medication works by blocking nerve impulses or pain sensations that are sent to the brain, and it is structurally similar to tricyclic antidepressants.

• It functions primarily by reducing tonic somatic motor activity at the level of the brainstem, rather than directly affecting skeletal muscle.
• Cyclobenzaprine appears to reduce muscle spasm through modulation of gamma and alpha motor neurons within the CNS, decreasing muscle hyperactivity without affecting normal muscle function.
• The medication achieves this by enhancing the effects of norepinephrine in the CNS and possibly by affecting serotonin receptors as well.

Clinical Use

This central action interrupts the pain-spasm-pain cycle, allowing muscles to relax without directly affecting the muscle tissue itself.

• Flexeril is typically prescribed at 5-10 mg doses taken three times daily, with treatment usually limited to 2-3 weeks to avoid dependence and minimize side effects like drowsiness, dry mouth, and dizziness.
• According to the evidence, cyclobenzaprine has the potential to interact with sedatives and anesthetic agents and can cause adverse anticholinergic effects, including hallucinations, confusion, drowsiness, constipation, urinary retention, and dry mouth 1.

Important Considerations

It is essential to note that with long-term use, patients can experience withdrawal symptoms of malaise, nausea, and headache for 2 to 4 days after discontinuation, although these symptoms are not life-threatening 1.

• Tapering cyclobenzaprine over 2 to 3 weeks can help prevent withdrawal symptoms.
• Concomitant use of cyclobenzaprine with monoamine oxidase inhibitors may increase the potential for serotonin syndrome 1.

From the FDA Drug Label

Cyclobenzaprine HCl relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease. Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that cyclobenzaprine acts primarily within the central nervous system at brain stem as opposed to spinal cord levels, although its action on the latter may contribute to its overall skeletal muscle relaxant activity Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems

Cyclobenzaprine causes muscle relaxation by acting on the Central Nervous System (CNS), specifically at the brain stem level, and to a lesser extent at the spinal cord level. It reduces tonic somatic motor activity by influencing both gamma (γ) and alpha (α) motor systems. This results in a reduction of skeletal muscle hyperactivity, leading to muscle relaxation. 2

From the Research

Mechanism of Action

• Cyclobenzaprine is a tricyclic pharmacologic agent that acts on the Central Nervous System (CNS) to produce muscle relaxation 3.
• The exact mechanism of action is not fully understood, but it is thought to influence the α and γ motor neurons in the CNS, leading to the attenuation of muscle spasm 4.
• Cyclobenzaprine may also mediate its effects centrally via inhibition of tonic somatic motor function, likely through modulation of noradrenergic and serotonergic systems 5.

Effects on the CNS

• Higher orders of the CNS are affected by cyclobenzaprine, contributing to its side effects, which are largely anticholinergic in nature 3.
• Cyclobenzaprine has been shown to exhibit low nanomolar affinity for the cloned human H1R, as well as that expressed in both rat and mouse brain, and binds to the H1R in a noncompetitive manner 5.
• The noncompetitive antagonism of H1R by cyclobenzaprine may facilitate the significant sedative effect of this agent seen in patients 5.

Clinical Evidence

• Clinical studies have provided supportive evidence for the use of cyclobenzaprine in the short-term management of acute neck and back pain, and fibromyalgia 3.
• Cyclobenzaprine has been shown to be effective in improving muscle spasm, reducing local pain and tenderness, and increasing range of motion in acute, painful musculoskeletal conditions 6.
• A case study reported the successful treatment of levator ani syndrome with cyclobenzaprine, suggesting its potential as a first-line treatment option for this condition 4.