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There is some accumulation of tramadol with chronic administration; peak plasma levels of tramadol with the maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100 mg dose.[77] Positron emission tomography imaging studies have reportedly found that tramadol levels are at least 4-fold higher in the brain than in plasma.[73][79] Conversely, brain levels of desmetramadol “only slowly approach those in plasma”.[73] The plasma protein binding of tramadol is only 4 to 20%; hence, almost all tramadol in circulation is free and thus bioactive.[80][81][82]
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