β endorphin (β-EP) is an important modulator of central pain pathways. To examine whether changes in central production of β-EP contribute to the pathogenesis of diabetic neuropathic pain, we compared the cerebrospinal fluid (CSF) levels of β-EP and its precursor proopiomelanocortin (POMC) between 15 diabetic patients with chronic painful diabetic polyneuropathy, eight patients with severe painless diabetic neuropathy, and ten nondiabetic controls. Both peptides were measured by specific monoclonal antibody-based two-site immunoradiometric assays (IRMAs). In the diabetic patients with painful neuropathy, mean ± SD CSF β-EP concentrations (5.7 ± 2.2 pmol/L) were comparable to those of the diabetic patients with painless neuropathy (6.0 ± 2.3 pmol/L) and did not correlate with the severity of neuropathic pain. CSF β-EP, but not POMC, concentrations were lower in the diabetic neuropathic patients overall (5.8 ± 1.9 pmol/L) compared to the control subjects (7.6 ± 2.2 pmol/L) (p < 0.05). CSF POMC showed no intergroup differences. However, POMC levels were 80-fold higher than those of β-EP and should always be considered when interpreting immunoreactive β-EP or other derivative peptide levels in CSF. We conclude that CSF β-EP levels appear to be reduced in diabetic polyneuropathy but they do not relate to the presence of neuropathic pain. This might explain why opioid analgesics are of little, if any, help in alleviating diabetic neuropathic pain.