Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon where opioid therapy, intended to relieve pain, may increase pain sensitivity and worsen preexisting pain. This systematic review summarizes current research on OIH, highlighting its mechanisms, clinical implications, and potential future research directions. Opioids are widely used for moderate to severe pain, but concerns about side effects, dependence, and addiction have led to growing interest in OIH. Recent studies suggest that opioids may cause OIH, which involves increased sensitivity to pain and may be linked to upregulation of compensatory pronociceptive pathways. OIH has been observed in various settings, including maintenance therapy, withdrawal, high or escalating doses, and ultra-low doses. Human studies show that former opioid addicts on methadone are more sensitive to cold pressor pain than controls, and OIH has been documented in surgical patients and human volunteers. Animal studies indicate that OIH can occur after opioid administration, with mechanisms involving the activation of NMDA receptors, dynorphin release, and changes in spinal cord signaling. The review also discusses the distinction between OIH and opioid tolerance, noting that while both may require dose escalation, they have different underlying mechanisms. The review highlights the need for further research to clarify the mechanisms of OIH and its clinical implications. It emphasizes the importance of understanding OIH to improve pain management strategies and avoid adverse effects of opioid therapy. The findings suggest that OIH may be a significant consequence of opioid use, and alternative pain control methods may be necessary to mitigate its effects. Overall, the review provides a comprehensive overview of OIH, its potential mechanisms, and its relevance to clinical practice.Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon where opioid therapy, intended to relieve pain, may increase pain sensitivity and worsen preexisting pain. This systematic review summarizes current research on OIH, highlighting its mechanisms, clinical implications, and potential future research directions. Opioids are widely used for moderate to severe pain, but concerns about side effects, dependence, and addiction have led to growing interest in OIH. Recent studies suggest that opioids may cause OIH, which involves increased sensitivity to pain and may be linked to upregulation of compensatory pronociceptive pathways. OIH has been observed in various settings, including maintenance therapy, withdrawal, high or escalating doses, and ultra-low doses. Human studies show that former opioid addicts on methadone are more sensitive to cold pressor pain than controls, and OIH has been documented in surgical patients and human volunteers. Animal studies indicate that OIH can occur after opioid administration, with mechanisms involving the activation of NMDA receptors, dynorphin release, and changes in spinal cord signaling. The review also discusses the distinction between OIH and opioid tolerance, noting that while both may require dose escalation, they have different underlying mechanisms. The review highlights the need for further research to clarify the mechanisms of OIH and its clinical implications. It emphasizes the importance of understanding OIH to improve pain management strategies and avoid adverse effects of opioid therapy. The findings suggest that OIH may be a significant consequence of opioid use, and alternative pain control methods may be necessary to mitigate its effects. Overall, the review provides a comprehensive overview of OIH, its potential mechanisms, and its relevance to clinical practice.