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.

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.