This study investigates the mechanisms underlying placebo analgesia by examining the activation of endogenous opioids. Using a model of human experimental ischemic arm pain, different types of placebo analgesic responses were induced through cognitive expectation cues, drug conditioning, or a combination of both. The study found that expectation cues produced placebo responses blocked by the opioid antagonist naloxone, while morphine conditioning alone induced a naloxone-reversible placebo effect. In contrast, ketorolac conditioning with expectation cues elicited a placebo effect partially blocked by naloxone, and ketorolac conditioning alone produced naloxone-insensitive placebo responses. These findings suggest that cognitive factors and conditioning balance in different ways in placebo analgesia, with expectation triggering endogenous opioid systems and conditioning activating specific subsystems. The study concludes that placebo analgesia can be dissected into opioid and nonopioid components, depending on the procedure used to evoke the placebo response.This study investigates the mechanisms underlying placebo analgesia by examining the activation of endogenous opioids. Using a model of human experimental ischemic arm pain, different types of placebo analgesic responses were induced through cognitive expectation cues, drug conditioning, or a combination of both. The study found that expectation cues produced placebo responses blocked by the opioid antagonist naloxone, while morphine conditioning alone induced a naloxone-reversible placebo effect. In contrast, ketorolac conditioning with expectation cues elicited a placebo effect partially blocked by naloxone, and ketorolac conditioning alone produced naloxone-insensitive placebo responses. These findings suggest that cognitive factors and conditioning balance in different ways in placebo analgesia, with expectation triggering endogenous opioid systems and conditioning activating specific subsystems. The study concludes that placebo analgesia can be dissected into opioid and nonopioid components, depending on the procedure used to evoke the placebo response.