Continuing Education Activity

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. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cyclobenzaprine, for members of the interprofessional team who will potentially prescribe or encounter patients taking cyclobenzaprine.


  • Identify the mechanism of action of cyclobenzaprine.
  • Review the FDA approved indications for cyclobenzaprine.
  • Explain the importance of monitoring regarding toxicity and adverse events with cyclobenzaprine.
  • Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients for whom cyclobenzaprine is a therapeutic option.


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 further be in a subgroup of 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 also became recognized. This fact, in part, contributed to a shift, 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 associated effects of reducing muscle hyperactivity. It has FDA-approval 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 administration is via the oral route. 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 patient should rinse their mouth to ensure that they have swallowed all the contents.

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 receptors, which 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 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 have monitoring performed for signs and symptoms of serotonin syndrome, especially patients who are taking other serotonergic drugs. In two case reports, the authors described 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 should pose similar toxicities to tricyclic antidepressants; however, retrospective studies that have looked at reported cyclobenzaprine overdoses are conflicting.  Among the most feared toxicities associated with cyclical antidepressants, overdoses are 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 period. The authors, therefore, concluded that despite being a tricyclic antidepressant in its structure, cyclobenzaprine correlates 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 reportedly pure cyclobenzaprine ingestions, and 121 were multidrug overdoses. No one case exceeded 1000 mg of cyclobenzaprine in the ingested dose. The chart reviews reported no seizure activity. 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, there were two reported cases of overdoses 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 deaths. 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 other clinicians should educate the patient about the adverse effects. Also, the patient should understand not to combine this agent with other CNS acting medications, alcohol, or any sedatives. Finally, the patient should receive instructions not to drive or operate heavy machinery when using this agent.

Article Details

Article Author

Imran Khan

Article Editor:

Chadi Kahwaji


8/10/2020 4:22:01 PM

PubMed Link:




Cyclobenzaprine 2006;     [PubMed PMID: 30000455]


Fischoff D,Spivakovsky S, Are pharmacological treatments for oro-facial pain effective? Evidence-based dentistry. 2018 Mar 23;     [PubMed PMID: 29568025]


Yang YW,Macdonald JB,Nelson SA,Sekulic A, Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review. Journal of the American Academy of Dermatology. 2017 Dec;     [PubMed PMID: 29132849]


Häuser W,Ablin J,Perrot S,Fitzcharles MA, Management of fibromyalgia: practical guides from recent evidence-based guidelines. Polish archives of internal medicine. 2017 Jan 4;     [PubMed PMID: 28075425]


Morgan DJ,Dhruva SS,Wright SM,Korenstein D, 2016 Update on Medical Overuse: A Systematic Review. JAMA internal medicine. 2016 Nov 1;     [PubMed PMID: 27654002]


Macfarlane GJ,Kronisch C,Dean LE,Atzeni F,Häuser W,Fluß E,Choy E,Kosek E,Amris K,Branco J,Dincer F,Leino-Arjas P,Longley K,McCarthy GM,Makri S,Perrot S,Sarzi-Puttini P,Taylor A,Jones GT, EULAR revised recommendations for the management of fibromyalgia. Annals of the rheumatic diseases. 2017 Feb;     [PubMed PMID: 27377815]


Chaffee DM, Cyclobenzaprine in the Treatment of Low Back Pain. American family physician. 2016 Feb 1;     [PubMed PMID: 26926618]


Kraus MB,Wie CS,Gorlin AW,Wisenbaugh ES,Rosenfeld DM, Painful Ejaculation with Cyclobenzaprine: A Case Report and Literature Review. Sexual medicine. 2015 Dec;     [PubMed PMID: 26797071]


Braschi E,Garrison S,Allan GM, Cyclobenzaprine for acute back pain. Canadian family physician Medecin de famille canadien. 2015 Dec;     [PubMed PMID: 26668287]