ABSTRACT
Tramadol hydrochloride, (1RS, 2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol HCl (tramadol) (Fig. 1), is a centrally acting synthetic analgesic widely used throughout the world. Tramadol appears to produce its analgesic effect through two mechanisms (1-6). One mechanism relates to weak affinity for µ-opioid receptors (about 6000-fold less than morphine, 100-fold less than d-propoxyphene, and about the same as dextromethorphan). An active metabolite (O-desmethyltramadol) binds to opioid receptors with greater affinity than the parent compound and might contribute to this component (7). In most animal tests and in human clinical trials (8-10), the analgesic effect of tramadol is only partially blocked (50%) by the opioid antagonist naloxone, suggesting a significant nonopioid mechanism. The nonopioid mechanism appears related to tramadol’s ability to enhance synaptic levels of the neurotransmitters 5-hydroxytryptamine (5-HT; serotonin) and norepinephrine (NE). Several lines of evidence suggest that the two mechanisms combine in a complementary fashion and sometimes greater-thanadditive (synergistic) manner to produce antinociception, but only in an additive, or less than additive, manner in several side effect measures (10). This proposed duality in mechanism of action is consistent with, and forms the basis for understanding, tramadol’s clinical attributes. Analogues of tramadol have been designed that emphasize one or the other of tramadol’s mechanisms of action.
