Case: A 66-year-old male with chronic pain on tramadol (200 mg daily) presents to the ED with symptoms of restlessness and shaking concerning for seizures. After decades of opiate use for chronic pain, he decided to abruptly discontinue his tramadol. That evening he developed tremulousness, insomnia, confusion, hallucinations, and worsening gait instability. On presentation to the ED he had tachycardia, increased lacrimation/rhinorrhea, hyperreflexia, and marked akathisia.  Labs and neuroimaging were unremarkable. Neurology and psychiatry were consulted. Initially treated symptomatically for opiate withdrawal with minimal improvement. Given atypical presentation with predominate neurologic features and SNRI effects of tramadol, concern arose for a component of SNRI discontinuation syndrome. He was started on a venlafaxine taper with rapid amelioration of symptoms. 

Tramadol has both weak opiate and SNRI mechanisms of action. The proportion of opiate vs SNRI effect is unpredictable and affected by variations in CYP metabolism/inhibition. The unpredictable mechanism of action has important implications for the efficacy of tramadol in pain management and in the manifestations and treatment of withdrawal. SNRI discontinuation syndrome should be considered in patients with refractory or atypical symptoms in tramadol withdrawal, with SNRI taper considered as adjuvant treatment.