Case Presentation: Immediately after completing a drug rehabilitation program, the patient relapsed and used fentanyl. That morning, he was evaluated in an emergency department (ED) for opioid overdose and first-time generalized tonic-clonic movements. He returned to baseline during observation, and the symptoms were considered secondary to fentanyl induced hypoxia. He was discharged home with suboxone. Over the next 24 hours, the family found the patient to have persistent weakness, tremor, and cognitive slowing, so he was brought to our ED for re-evaluation. He did not take suboxone during the interim time. He was tachycardic, hypertensive, afebrile, and maintained adequate oxygenation, and corroborated the above information. Non-contrast head CT and chest radiograph were unremarkable. Examination revealed tongue fasciculations, mild bilateral resting tremor, inducible clonus and slowed, depressed speech. Laboratory evaluation showed marked rhabdomyolysis (creatine phosphokinase >40,000) and leukocytosis. Empiric therapy for possible central nervous system infection was initiated; however cerebrospinal fluid and infectious studies were unremarkable. The patient met Hunter’s criteria by having received a serotonergic agent (fentanyl) and presenting with tremor and inducible clonus. The patient’s symptoms improved with benzodiazepine taper, cyproheptadine, aggressive hydration, and electrolyte repletion.
Discussion: Serotonin syndrome (SS) results from serotonin receptor overstimulation or excess serotonin due to drug interactions, overdose, or therapeutic dosing. Fentanyl in combination with serotonergic agents is a rarely reported cause. Clinical features commonly include tachycardia, diaphoresis, hyperthermia, clonus, agitation, and hypervigilance. Severe cases may progress to shock with marked rigidity and hypertonicity, leading to rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation. This case illustrates fentanyl-induced SS and highlights the need for clinician awareness of the serotonergic potential of commonly used opioids.The most frequently implicated combinations involve selective serotonin or serotonin–norepinephrine reuptake inhibitors with monoamine oxidase inhibitors. Analgesics including meperidine, tramadol, and, less commonly, fentanyl have been associated with SS. In a large retrospective study on patients who received both fentanyl and a serotonergic agent, only 0.09% met criteria for SS. Meperidine and tramadol inhibit serotonin reuptake at the neuromuscular junction, whereas fentanyl, though not a serotonin transporter inhibitor, may directly activate 5-HT₁A and 5-HT₂A receptors, causing widespread serotonergic stimulation. The broad clinical spectrum of SS complicates diagnosis, as its manifestations often obscure underlying mechanisms and overlap with other syndromes. When initiating pharmacologic therapy, it is essential to assess potential drug–drug interactions and risks associated with polypharmacy.
Conclusions: Early recognition of serotonergic toxicity from opioids is critical, especially in patients with opioid use disorder, as it may be mistaken for withdrawal. Shared features such as tremor, agitation, and hyperreflexia complicate diagnosis. This case emphasizes the need for heightened suspicion when neuropsychiatric or autonomic symptoms occur following opioid changes. Prompt identification and discontinuation of serotonergic agents remain key to recovery.