Article Author:
Imran Khan
Article Editor:
Chadi Kahwaji
10/1/2019 1:52:49 PM
PubMed Link:


Cyclobenzaprine is FDA-approved as an adjunct to rest for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. Cyclobenzaprine is a part of a group of medications referred to as cyclical antidepressants. These cyclical antidepressants have roles in the treatment of depression, neuropathic pain, migraine prophylaxis, attention deficit hyperactive disorder as well as potential muscle relaxation properties. Cyclical antidepressants can be further grouped into tricyclic antidepressants which were first described chemically in 1889. These tricyclic antidepressants were first used for the treatment of agitation and psychosis at the turn of the 19th century when they were incidentally discovered to have a potential role in the treatment of depression. Tricyclic antidepressants eventually emerged as the mainstay pharmacotherapy for depression from the 1960s until the 1980s. During this time, however, their toxicities and adverse effects were also recognized. This in part contributed to a shift that took place, making selective serotonin reuptake inhibitors (SSRI) the main class of medications in the treatment of depression. There remained, however, various other indications for the use of cyclical antidepressants such as chronic pain. For this reason, although the prescribing patterns for cyclical antidepressants evolved, the recognition of their adverse events and potential for lethality in overdose remains critical as they continue to cause a significant number of deaths and hospitalizations.[1][2][3]

Mechanism of Action

Cyclobenzaprine is a tricyclic amine salt that works in the central nervous system (CNS) as a depressant and sedative and has been associated with reducing muscle hyperactivity. It is FDA-approved as an adjunct to rest for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. Cyclobenzaprine is a centrally-acting muscle relaxant that reduces tonic somatic motor activity, which may influence alpha and gamma motor neurons at the level of the spinal cord.    [4][5][6]


Cyclobenzaprine is administered orally. It is available in immediate release tablets of 5 milligrams, 7.5 milligrams, and 10 milligrams and extended-release capsules of 15 milligrams and 30 milligrams. The maximum recommended dose per day is 30 milligrams. The extended-release formulation should be administered at the same time each day. The capsule may be swallowed whole, but its contents also may be sprinkled onto a tablespoon of applesauce for immediate consumption without chewing the granules. The mouth should be rinsed to ensure that all the contents have been swallowed.

Adverse Effects

The primary, adverse effects of cyclobenzaprine include dizziness, xerostomia, drowsiness, fatigue, headache, nervousness, and confusion. Like other cyclical antidepressants, cyclobenzaprine antagonizes the muscarinic receptor. This may produce undesired side effects such as xerostomia, ileus, tachycardia, mydriasis, confusion, and hallucinations. Additionally, like other cyclical antidepressants, cyclobenzaprine antagonizes the alpha1 adrenergic receptor, causing a vasodilatory effect, and may contribute further to a reflex tachycardia. The most common adverse effects seen with cyclobenzaprine are somnolence, dry mucous membranes, dizziness, and confusion.[7][8][9]


Cyclobenzaprine is contraindicated in patients with hyperthyroidism, arrhythmias, heart failure, heart block or conduction disturbances, during the acute recovery phase of myocardial infarction, or within 14 days of taking a monoamine oxidase inhibitor (MAOI). 


Patients taking cyclobenzaprine should be monitored for signs and symptoms of serotonin syndrome, especially patients who are taking other serotonergic drugs. In two reported cases, the authors report patients who quickly developed serotonin syndrome after initiating cyclobenzaprine in the short term. In both cases, the patients were found to be on serotonergic medications (phenelzine and duloxetine) prior to the initiation of cyclobenzaprine.


Cyclobenzaprine is structurally similar to amitriptyline, and only differs in a double bond in the central amine ring. Due to its structure, cyclobenzaprine is structurally and pharmacologically related to the tricyclic antidepressants. In theory,  it is thought to pose similar toxicities to tricyclic antidepressants; however, retrospective studies that have looked at reported cyclobenzaprine overdoses are conflicting.  Amongst the most feared toxicities associated with cyclical antidepressant overdoses is their effects on fast-acting sodium channels in the cardiac conduction system. Cyclical antidepressants block the cardiac sodium channel and cause prolongation of cardiac depolarization which manifests as QRS widening on electrocardiograms. There is also evidence that cyclical antidepressants may decrease the seizure threshold by interfering with chloride conductance on the GABA receptor.

Some case reports show that cyclobenzaprine overdoses have fatal tendencies. Other retrospective studies show that their toxicities may manifest slightly differently than other tricyclic antidepressant medications. These particular studies indicate the theoretical risks that are associated with traditional tricyclic antidepressants, such as cardiac dysrhythmias from a widening of the QRS complex due to sodium channel blockade, and seizures may not apply to cyclobenzaprine toxicity despite their similarities in chemical structures.

In one retrospective review comparing isolated ingestions of cyclobenzaprine to its sister drug amitryptiline, the authors found that the cyclobenzaprine overdoses resulted in no deaths, no ventricular dysrhythmias, and reduced numbers of seizures as compared to the cases of amitryptiline overdoses in the same time period. The authors therefore concluded that cyclobenzaprine, despite being a tricyclic antidepressant in its structure, is associated with less incidence of tricyclic antidepressant-like complications when compared to amitryptiline. 

One study retrospectively looked at 750 charts at five regional poison centers between the years of 1989 to 1993. Out of the 750 charts, 523 had sufficient data for review. Out of these, 402 were said to be pure cyclobenzaprine ingestions, and 121 were shown to be multidrug overdoses. No one case exceeded 1000 mg of cyclobenzoprine in the ingested dose. In the chart reviews, no seizure activity was reported. Dysrhythmias beyond sinus tachycardia were infrequent, and none were found to be life threatening. No deaths occurred. These findings are different from the theoretical neurotoxic and cardiotoxic effects seen with traditional tricyclic antidepressant overdoses in which seizures and dysrhythmias are often life threatening. The authors concluded that based on their retrospective study, cyclobenzaprine in toxic doses less than 1000 mg does not appear to produce the life threatening neurotoxicity and cardiotoxic dysrhythmias associated with traditional tricyclic antidepressants.

Other case reports however have implicated cyclobenzaprine in acute overdose as the culprit leading to fatalities. In one case report, two cases of overdoses are reported in which elevated levels of cyclobenzaprine were found in postmortem evaluations of the patients. Although it is unknown the exact mechanism by which the fatalities occurred (i.e., dysrhythmias, seizure activity) blood samples revealed elevated levels in both patients that suffered fatalities. Estimates by the author put these levels equivalent to approximately 800 mg of cyclobenzaprine. The authors therefore document an association linking elevated cyclobenzaprine levels with two examples of presumed fatal overdoses.

Enhancing Healthcare Team Outcomes

Cyclobenzaprine is a rarely used medication to manage muscle spasms. While the drug is effective, it does have many adverse effects. The primary care provider, nurse practitioner, pharmacist and the internist should educate the patient on the adverse effects. In addition, the patient should be urged not to combine this agent with other CNS acting medications, alcohol or any sedatives. Finally, the patient should be instructed not to drive or operate heavy machinery when using this agent.


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