Severe, chronic pain is postulated to produce an extended stress state with overstimulation of the autonomic nervous system and hypothalamus-pituitary-adrenal axis (HPA). To determine if this postulate is valid, we studied 60 patients who were consecutively admitted to ambulatory treatment for severe, chronic pain. All had chronic pain for over one year and characterized their pain as being constantly present, interfering with sleep, and debilitating to the point of being bed-or house-bound without opioid treatment. All were referred after failing multiple pain treatments, and all were being treated with low dosages of various oral opioids which reported to be inadequate. To evaluate these patients, pressure and pulse rates were determined at monthly intervals for four consecutive months. A morning blood specimen was taken to determine serum concentrations of the adrenal hormones, cortisol, pregnenolone, dehydroepiandrosterone, and androstenedione. Fifty-five (91.7%) subjects demonstrated hypertension above 130/90 mmHg and/or tachycardia above 84 beats per minute. Fifty-one (85.0%) demonstrated one or more abnormalities of serum adrenal hormone concentrations. All 60 subjects (100%) demonstrated at least one cardiovascular or adrenal hormone abnormality. This study suggests that severe, chronic pain may be associated with a neuroendocrine syndrome that may, itself, have clinical complications, and adequate pain control should be such that identified neuroendocrine abnormalities are normalized.