Significance Empathy is of major importance for everyday social interaction. Recent neuroscientific models suggest that pain empathy relies on the activation of brain areas that are also engaged during the first-hand experience of pain. These models rely on rather unspecific and correlational evidence. Here, we show that inducing pain analgesia also reduces pain empathy, and that this is associated with decreased activation of empathy-related brain areas. We then document that blocking placebo analgesia via an opioid antagonist also blocks placebo analgesia effects on pain empathy. This finding suggests that pain empathy is grounded in neural responses and neurotransmitter activity related to first-hand pain.