Dehydroepandrosterone (DHEA)-dehydroepiandrosterone sulfate (DHEAS) deficiency often produces fatigue, depression, weakness, and sexual dysfunction, which improve during replacement therapy. DHEAS deficiency is a sensitive marker for generalized adrenal insufficiency, but it has not been related to opioid ingestion. DHEAS values were determined in 34 male and 32 female opioid-consuming outpatients aged 35-78 years, in stable health, and in 33 male and 53 female nonopioid-consuming control subjects. No subjects used anticonvulsants or corticosteriod medications, and none had malignant, collagen-vascular, or endocrine disease other than menopause or opioid-induced androgen deficiency. Adrenocorticotropic hormone (ACTH) values were measured in 94 of 152 subjects. DHEAS levels were lower in opioid consumers than in control subjects in a dose-related pattern (P < .01), were below age-specific norms in 67% of opioid consumers and 8% of controls (P < .001), and were below our laboratory's lowest detection limit (15 mug/dL) in 29% of opioid users and 1% of controls (P < .001). DHEAS values were also lower in opioid-consuming nonsmokers than in smokers (P < .05) and were unrelated to body mass index or concurrent hormonal replacement therapy. ACTH levels were normal and unrelated to opioid use. The combination of subnormal DHEAS levels in the presence of normal ACTH values in most opioid-consuming patients suggests that these low levels result from factors other than diminished adrenal ACTH stimulation. The study documents a dose-related DHEAS deficiency in a majority of nonhospitalized adults who are chronically consuming sustained-action oral or transdermal opioids for control of nonmalignant pain. This deficiency in these patients has not previously been recognized and is probably symptomatic. Evaluation of replacement therapy should receive high priority.