Naltrexone doses of 0.5, 1.0, 1.5, and 2.0 mg/kg were administered in randomized orders to four participants with developmental disabilities and severe chronic self-injurious behavior (SIB) in a double-blind, placebo-controlled repeated reversal procedure. A nonspecific generalized attenuation of SIB was found, with different dosages in different individuals showing statistical, but not clinical, reductive significance in some cases, and “paradoxical” increases in others. Independent measurement of pressure pain thresholds with an algometer procedure disclosed no parallel correlations in pain sensitivity with SIB changes. Biochemistry assays showed expected neuroendocrine stimulatory or inhibitory effects of naltrexone, including a reduction of beta-endorphins, although the latter was overal low in all subjects. Post-hoc analyses suggested that SIB and beta-endorphin levels tended to covary in the same direction, but not in causal relation to each other. The results do not confirm a pain-system mediation of SIB, but do suggest that non-opiate mechanisms of naltrexone action merit clinical research.