This overview summarizes the current clinical state of knowledge in the field of adenosinemediated pain reduction, also including a condensed experimental background of relevance for clinical implementation. Clinical investigations have been systematically performed and include experimental pain models in volunteers, as well as studies in acute perioperative pain and in chronic neuropathic pain. Adenosine has been administered as a low-dose intravenous infusion and as an intrathecal injection. Effects on pain and on signs of hyperexcitability in the nervous system have been investigated, both after administration of adenosine alone and in combination with well-known analgesic agents. The different modes of adenosine administration demonstrate reduced pain, primarily in modalities that involve mechanisms of hyperexcitability of the central nervous system, i.e., central sensitization. Because this phenomenon is an important factor in chronic pain conditions, the promising results of pain relief in patients with neuropathic pain suggest that this is especially relevant for future development and research. In addition, the potential use of adenosine in combination with other pain-modulating agents deserves further evaluation. Drug Dev.