Serotonin and Norepinephrine Transporter Occupancy of Tramadol in Nonhuman Primate Using Positron Emission Tomography

BACKGROUND: Tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin transporter and norepinephrine transporter in addition to μ-opioid receptor. Based on this characteristic, tramadol is expected to have an antidepressant effect. METHODS: Positron emission tomography measurements with [(11)C]MADAM and [(18)F]FMeNER-D(2) were performed at baseline and after i.v. administration of 3 different doses (1, 2, and 4 mg/kg) of tramadol using 6 cynomolgus monkeys. The relationship between dose and occupancy for serotonin transporter and norepinephrine transporter was estimated. RESULTS: Tramadol occupied similarly both serotonin transporter (40%–72%) and norepinephrine transporter (7%–73%) in a dose-dependent manner. The K(d) was 2.2 mg/kg and 2.0 mg/kg for serotonin transporter and norepinephrine transporter, respectively. CONCLUSIONS: Both serotonin transporter and norepinephrine transporter of in vivo brain were blocked at >70% at a clinically relevant high dose of tramadol. This study suggests tramadol has potential antidepressant effects through the inhibition of serotonin transporter and norepinephrine transporter in the brain.