This paper will review experimental and clinical studies investigating analgesic effects of opioids outside the central nervous system. The experimental data indicate that 1) opioids can produce antinociceptive effects in the periphery mediated by local opioid receptors, 2) three different receptor types (μ, δ, κ) can become active in peripheral tissue, 3) inflammatory hyperalgesic conditions are especially amenable to peripheral opioid actions and 4) the activation of opioid receptors located on primary afferent neurons is the most likely mechanism of action. The evidence from clinical studies is equivocal so far, partly because of methodological shortcomings. More extensive controlled studies investigating the effects of local application of opioids in the vicinity of peripheral nerve terminals or of compounds unable to cross the blood-brain barrier are warranted in view of the potential avoidance of central side effects such as respiratory depression, dependence, nausea or sedation.
