This case report presents a rare and complex presentation of serotonin syndrome (SS) in a 60-year-old immunocompromised male, highlighting the role of atypical medication interactions in SS development, specifically focusing on oxycodone and a combination HIV medication that includes CYP2D6 and CYP3A4 inhibitor, cobicistat.

We describe an instance of SS involving fentanyl, oxycodone, venlafaxine, meperidine, and fluconazole, exacerbated by the CYP2D6 and CYP3A4 inhibitor, cobicistat. While cobicistat itself does not directly increase serotonin levels, its interaction with other serotonergic medications can potentiate SS. Oxycodone, though not typically considered a primary causative agent for SS, may contribute to SS when co-administered with other serotonergic drugs. 

We conducted an extensive literature review and reviewed the clinical presentation, diagnostic criteria, and treatment approaches for an original SS case.

The patient presented with altered mental status, lethargy, and respiratory distress, leading to intubation. Lab results showed metabolic acidosis and positive urine toxicology for oxycodone. Despite treatment for aspiration pneumonia, the patient's condition deteriorated, exhibiting hyperthermia, hyperreflexia, and tremulousness. SS was eventually suspected and confirmed based on clinical criteria. Discontinuation of serotonergic medications, including cobicistat in the patient’s HIV medication and oxycodone, led to significant improvement in the patient's condition.

This case underscores the importance of recognizing the diverse range of agents that can contribute to SS, including CYP2D6 and CYP3A4 inhibitors like cobicistat, and the need for more specific diagnostic criteria. It emphasizes the potential underdiagnosis of SS in patients taking HIV combination antivirals with multiple drug interactions. Clinicians should remain vigilant and consider SS when patients present with compatible symptoms, even when the causative agents are not traditionally associated with SS. This report sheds light on the complexity of SS diagnosis and the necessity of increased awareness, ultimately aiming to improve patient outcomes in the face of this rare and potentially life-threatening condition.