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Multiple lines of evidence suggest that endogenous opioids are involved in the pathogenesis of non-suicidal self-injury (NSSI). Evidence for such a role is based on the partial success of opioid antagonist treatment to ameliorate NSSI, reports of altered pain sensitivity during episodes of NSSI, and findings of altered endogenous opioid levels in individuals with NSSI. While suicidal behavior (SB) and NSSI are distinct behaviors, NSSI is a significant risk factor for suicide attempts and suicide. The high co-occurrence of SB and NSSI suggests that they may share a common biology. Available data indicate that endogenous opioids may be involved in the pathophysiology of SB. Future studies of the role of opioids in the biological mechanisms of NSSI and SB are merited and may lead to the development of new treatment modalities.