Opioid receptors are localised in multiple sites in the brain, spinal cord and peripheral tissue. The primary mechanism through which opioids act supraspinally to produce antinociception is through activation of central nociceptive modulatory network that exert a net inhibitory effect on spinal nociceptive processing. In spinal cord opioid receptors are localised in dorsal horn both pre- and postsynaptically. Spinal opioids exert their action mostly by a very complicated modulation of presynaptic release of different neurotransmitters. Apart from this, particularly in inflammation, peripheral opioid receptors have been shown to mediate analgesic effect when activated by exogenous opioids. Due to differencies in physicochemical properties, opioids may act in different way. Independently on the route of administration, lipophilic opioids, like fentanyl, act in the brain and produce analgesia via supraspinal mechanism. Morphine and other hydrophylic opioids, after systemic administration, produce analgesia via supraspinal and peripheral mechanisms, and to a much less degree, spinal mechanism. Probably only hydrophylic opioids reach dorsal horn after spinal administration and show the spinal mechanism of analgesia. The synergistic interactions among supraspinal and spinal opioid-sensitive sites are likely to be crucial in the analgesic effects of systemically administered opioids. The lack of this synergistic interaction is responsible for relative unresposiveness of neuropathic pain with allodynia to a monotherapy with opioids.