The study also reviewed 83 impaired driving cases over this period in which tramadol was detected, so as to establish a nonlethal blood tramadol concentration reference range. Tramadol is a centrally acting synthetic opioid-receptor agonist that inhibits the re-uptake of serotonin and norepinephrine. It is the most widely sold opioid analgesic in the world, and has been used in the United States since 1995 to treat moderate to severe pain. Study methods involved analytical toxicology and the collection of data from the death investigations. In almost all of the cases examined, tramadol was present in the subject along with at least one other drug. There were four cases in which death was attributed exclusively to tramadol; in all of these cases, tramadol was present with other drugs. There were other cases in which tramadol was clearly the underlying cause of death, but other drugs present contributed to death as well. There is potential for potentially fatal drug interaction with tramadol on three levels. First, drugs may increase serotonergic activity; second, they may inhibit the metabolism of tramadol; and third, they may cause additional CNS depression. The findings indicate that when certifying deaths in which tramadol is present, drug interactions should be considered. Regarding impaired driving, the data did not permit determining a minimum concentration at which a subject will be predictably impaired; however, driving after excessive dosing, shortly after beginning a course of therapy with tramadol, or after combining it with other CNS depressant medication will increase the risk for impaired driving. 3 tables and 13 references