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Habituation to repetitive painful stimulation may represent an important protection mechanism against the development of chronic pain states. However, the exact neurobiological mechanisms of this phenomenon remain unclear. In this study we (i) explore the somatotopic specificity of pain attenuation over time and (ii) investigate the role of the endogenous opioid system in its development. We investigated 24 healthy volunteers with a paradigm of daily painful stimulation of the left volar forearm for 1 week. Habituation was assessed by comparing pain-related responses (ratings and thresholds) between days 1 and 8. To test whether a repetition-dependent attenuation of pain is restricted to the site of stimulus application or induces additional systemic effects indicative of a central mechanism, we also measured pain-related responses at the contralateral arm and the left leg. To assess the role of the endogenous opioid system in this mechanism, we used the opioid-receptor antagonist naloxone in a double-blind design. Repetitive painful stimulation over several days resulted in a significant habituation to pain at the site of daily stimulation. In addition, we also observed significant pain attenuation at the non-stimulated limbs. This effect was less pronounced at the untreated arm compared to the treated arm and even weaker in the leg, displaying a significant Stimulation-Site × Time interaction. The development of pain habituation was unaffected by the opioid antagonist naloxone. Taken together, these results strongly support the role of central components in the mechanism of pain habituation that do not directly involve the endogenous opioid system.