The effect of ceruletide (CRL), a synthetic decapeptide analogue of cholecystokinin, on rest pain and arterial blood flow was evaluated in 8 patients with advanced, occlusive atherosclerosis of the lower extremities. CRL 1, 2, or 4 ng kg-1 or placebo were infused intravenously in random order, and in a double-blind fashion. Pain relief, assessed by a scoring system, was significantly better (p less than 0.01) following the 2 and 4 ng kg-1 doses of CRL (2.71 and 2.66, respectively) than following placebo (0.75). Arterial blood flow was not affected by either CRL in any dose or by placebo. Pretreatment with naloxone, a pure opioid antagonist, abolished the analgesic effect of CRL. Following the 2 ng dose of CRL, beta-endorphin levels were significantly elevated from a basal value of 125 +/- 15 pg/ml to 191 +/- 35 pg/ml 5 h after CRL administration (p less than 0.05). Circulating levels of ACTH, prolactin and GH were not affected by CRL. It is concluded that CRL was effective in relieving ischaemic rest pain, and that the mechanism was related to the release of endogenous opioids.