This qualitative systematic review by Angst and Clark explores the phenomenon of opioid-induced hyperalgesia (OIH), a condition where opioid therapy, intended to alleviate pain, paradoxically increases patients' sensitivity to pain. The review provides a comprehensive summary of basic and clinical research, outlines the current state of knowledge, and discusses potential clinical implications and future research directions. OIH has been observed in various settings, including maintenance therapy, withdrawal, and at both very high and ultra-low opioid doses. Human studies have shown that former opioid addicts maintained on methadone exhibit increased sensitivity to cold pressor pain, while patients undergoing surgery or in experimental pain paradigms also experience aggravated pain despite increased opioid consumption. Animal studies have demonstrated that chronic opioid administration can lead to hyperalgesia, with the spinal cord playing a crucial role in this process. Mechanisms underlying OIH include enhanced descending facilitation of nociceptive signal transmission, increased production and release of nociceptive neurotransmitters, and changes in signaling systems such as the excitatory amino acid (EAA) system and NMDA receptors. The review also discusses the distinction between OIH and tolerance, noting that both phenomena can result in dose escalation but have distinct pharmacological and mechanistic characteristics. Tolerance involves desensitization of antinociceptive pathways, while OIH involves sensitization of pronociceptive pathways. The authors emphasize the need to consider OIH as a significant consequence of opioid therapy, as it may limit the usefulness of opioids in pain management. They recommend further research to better understand the mechanisms and clinical implications of OIH, particularly in the context of high-dose opioid use.This qualitative systematic review by Angst and Clark explores the phenomenon of opioid-induced hyperalgesia (OIH), a condition where opioid therapy, intended to alleviate pain, paradoxically increases patients' sensitivity to pain. The review provides a comprehensive summary of basic and clinical research, outlines the current state of knowledge, and discusses potential clinical implications and future research directions. OIH has been observed in various settings, including maintenance therapy, withdrawal, and at both very high and ultra-low opioid doses. Human studies have shown that former opioid addicts maintained on methadone exhibit increased sensitivity to cold pressor pain, while patients undergoing surgery or in experimental pain paradigms also experience aggravated pain despite increased opioid consumption. Animal studies have demonstrated that chronic opioid administration can lead to hyperalgesia, with the spinal cord playing a crucial role in this process. Mechanisms underlying OIH include enhanced descending facilitation of nociceptive signal transmission, increased production and release of nociceptive neurotransmitters, and changes in signaling systems such as the excitatory amino acid (EAA) system and NMDA receptors. The review also discusses the distinction between OIH and tolerance, noting that both phenomena can result in dose escalation but have distinct pharmacological and mechanistic characteristics. Tolerance involves desensitization of antinociceptive pathways, while OIH involves sensitization of pronociceptive pathways. The authors emphasize the need to consider OIH as a significant consequence of opioid therapy, as it may limit the usefulness of opioids in pain management. They recommend further research to better understand the mechanisms and clinical implications of OIH, particularly in the context of high-dose opioid use.