The complexity of chronic pain demands interdisciplinary treatment approaches, however, complex analgesic regimens pose risks for potential adverse drug interactions. Effective management of chronic pain is further complicated by the presence of associated comorbidities, especially depression. As a result, is common for these patients to be prescribed opioid analgesics with antidepressant medications. The first ones may significantly affect serotonin kinetics in the presence of other serotoninergic agents, increasing intrasynaptic serotonin levels. Serotonin syndrome (SS) is a rare and potentially life-threatening iatrogenic complication of serotoninergic polypharmacy. It typically appears after initiation or dose escalation of the offending agent to a regimen that generally includes other serotoninergic agents (like antidepressants drugs and opioids) and all drugs that directly or indirectly increase central serotonin neurotransmission at postsynaptic 5-HT1A and 5-HT2A receptors can produce serotonin syndrome. Individual vulnerability appears to play a role in the development of this complication.