Case Presentation: A 66-year-old man with history of atrial fibrillation, heart failure, hepatocellular carcinoma (HCC), bipolar disorder, and gout presented with lightheadedness and a syncopal episode with tremulousness and confusion. His reported medications included apixaban, carvedilol, risperidone, and allopurinol. Vitals were notable for tachycardia but otherwise normal. Physical exam was notable for irregularly irregular heart rate in the 110s, diaphoresis, diffuse tremors and restlessness, pinpoint pupils, and increased tone and rigidity in all extremities without myoclonus or hyperreflexia. He was alert and oriented x3, though occasionally gave inappropriate answers to questions. Labs were notable for an elevated creatine phosphokinase >80,000 U/L, creatinine >3 mg/dL, anion gap metabolic acidosis, and blood in urine. Upon further questioning, patient reported that he had stopped taking risperidone 4 months ago but had been taking tramadol every 6 hours for the past two weeks for gout pain. Toxicology was consulted with concern for serotonin syndrome due to tramadol use with resulting rhabdomyolysis. Patient received IV hydration, cyproheptadine, and lorazepam as needed for tremulousness. His diaphoresis, confusion, tremors and rigidity resolved, and his labs improved. His tramadol was discontinued and he was provided strict instructions to stop taking it on discharge.
Discussion: Serotonin syndrome is associated with excessive serotonergic activity in the central nervous system, and is characterized by the triad of autonomic instability, mental status changes, and neuromuscular hyperactivity. While the syndrome is classically associated with concurrent use of two serotonergic agents, it can also occur with initiation or increase in dose of a single serotonergic agent. The most common medications associated with serotonin syndrome are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) or monoamine oxidase (MAO) inhibitors; however, it can also occur more rarely with tramadol, an opiate agonist and a serotonin and norepinephrine reuptake inhibitor. Serotonin syndrome can present similarly as neuroleptic malignant syndrome (NMS), though NMS usually has a longer onset over days-weeks and is associated with a sluggish neuromuscular response rather than neuromuscular hyperactivity. Patients with serotonin syndrome can develop complications such as rhabdomyolysis, renal failure, or acute respiratory distress syndrome, with severe cases causing seizures or death. Therapy include discontinuation of all serotonergic agents, supportive care, and administration of cyproheptadine – a histamine and serotonin antagonist – as well as benzodiazepine for sedation and agitation control. This case illustrates an example of serotonin syndrome, later found to be due to tramadol use. In addition to his recent increased tramadol use for pain control, our patient also had a history of HCC which may have contributed to decreased tramadol metabolism by the liver. With prompt recognition and treatment, he had complete resolution of his symptoms.
Conclusions: Hospitalists frequently prescribe tramadol as an analgesic as it is perceived to be less harmful than other opioids. However, recognizing its potential to cause serotonin syndrome – as well as prompt discontinuation, supportive care and other treatments – is crucial.