One of the main challenges in suicide prevention is the limited understanding of the biological mechanisms underlying suicide. Recent findings suggest impairments in pain processing in acutely suicidal patients. However, little is known about the biological factors that may drive these discrete physiological abnormalities. In this study, we examined plasma peptides involved in analgesic and inflammatory responses and physical pain threshold in acutely suicidal patients.Thirty-seven depressed patients of both sexes hospitalized for severe suicidal ideation or a recent suicide attempt were characterized clinically including history of suicidal ideation and behavior. Psychological and physical pain, and pressure pain threshold was also measured. Plasma levels of β-endorphin, neurotensin, agouti-related protein (AgRP), C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), and brain-derived neurotrophic factor (BDNF) were run in Milliplex multiplex assays.The number of lifetime suicide attempts was positively correlated with β-endorphin (r = 0.702; p = 0.007), and neurotensin (r = 0.728, p = 0.007) plasma levels. Higher pain threshold was measured in the suicide attempt group as compared to the suicidal ideation group. Pain threshold was strongly and negatively associated with CRP plasma levels (r = -0.548; p < 0.001). In patients reporting chronic pain, lower AgRP levels and lower pain threshold were observed (t = 4.472; p = 0.001).Our results suggest that abnormalities in the opioid and neurotensin systems may underlie the increase in pain threshold found in suicide attempters, and possibly risk for suicidal behavior. Targeting pain circuits and systems may provide therapeutic mechanisms for suicide prevention.