Medications for treating pain come from varying classes. Most uses of pain medication are off label, i.e. physicians have used medications approved for other types of treatment, in order to treat pain. These off label medications include anti-inflammatories, antidepressants, anxiolytics, anticonvulsants, cardiovascular agents, local anesthetics, and general anestetics. Pain presents a complex picture of multiple alterations to the peripheral and central nervous system, with loss of normal symmetry between the spinal cord and the brain. The general rule of treating acute pain with one or two agents is reasonable, but chronic pain must usually be treated with an approach of rational polypharmacology. Coordinating this with psychotherapy, social interventions, non-invasive approaches, interventional invasive approaches and surgery may be necessary to control severe chronic pain states.