Acute tramadol enhances brain activity associated with reward anticipation in the nucleus accumbens

Yuki Asari, Yumiko Ikeda, Amane Tateno, Yoshiro Okubo, Takehiko Iijima, Hidenori Suzuki

Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence. A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo. Tramadol significantly reduced anxiety (Z = - 2.513, p = 0.012) and enhanced vigor (Z = - 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z = - 2.316, p = 0.021), relaxed (Z = - 2.236, p = 0.025), and amicable feelings (Z = - 2.015, p = 0.044) as well as increased alertness (Z = - 1.972, p = 0.049) and contentedness domains (Z = - 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +¥500 cue significantly more than the placebo (Z = - 2.295, p = 0.022). Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.