Common migraine (CM) is an evolutive disease characterized by a progressive increase in the number of attacks and a consequent reduction in the free periods, eventually reaching a state of continuous migraine with interparoxysmal headache (MIH). To evaluate the role of central pro-opiocortin-related peptides in the pathogenesis of the disease, cerebrospinal fluid (CSF) levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP) and ACTH were measured in two groups of migraine sufferers with increasing severity of the disease (CM and MIH), and in healthy controls. ACTH values were similar in the 3 groups, while beta-LPH levels were significantly lower (P less than 0.005) in patients affected by MIH (10.4 +/- 8.6 fmol/ml) than in patients with CM (35.7 +/- 8.3) and in controls (32.9 +/- 15.33). beta-EP levels were closely correlated with the severity of the disease: they decreased significantly from those found in healthy controls (86.1 +/- 37 fmol/ml) to those of CM sufferers (38.5 +/- 3.5; P less than 0.005) and showed a further significant fall (P less than 0.01) to the lowest levels which were found in MIH patients (14.8 +/- 9.8). These data showing that the progressive evolution of migraine is concomitant with a progressive impairment in the CSF levels of beta-EP, sustain the concept that non-organic central pain is related to a reduced activity of the neurons responsible for the CSF content of beta-EP.