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Chronic Pain syndromes and Major Depressive Disorder account for two of the most costly and prevalent illnesses worldwide and are frequently comorbid and treatment resistant. In this review, we examine the current role of ketamine, a potent NMDA (N-methl-D-aspartic acid) receptor blocker, in treating chronic pain and major depression. The role of the NMDA receptor and glutamatergic system are increasingly being studied in mood disorders, and are known components in pain processing, opioid induced analgesic tolerance, and hyperalgesia. We propose a hypothetic therapeutic role of ketamine involving the opioidergic pathway in these patients with treatment resistant chronic pain and major depressive disorder.