Pain by Association? Experimental Modulation of Human Pain Thresholds Using Classical Conditioning

A classical conditioning framework is often used for clinical reasoning about pain that persists after tissue healing. However, experimental studies demonstrating classically conditioned pain in humans are lacking. The current study tested whether non-nociceptive somatosensory stimuli can come to modulate pain thresholds after being paired with painful nociceptive stimuli in healthy humans. We used a differential simultaneous conditioning paradigm in which one nonpainful vibrotactile conditioned stimulus (CS+ was simultaneously paired with an unconditioned painful laser stimulus, and another vibrotactile stimulus (CS-) was paired with a nonpainful laser stimulus. After acquisition; at pain-threshold laser stimuli were delivered simultaneously with a CS+ or CS- vibrotactile stimulus. The primary outcome was the percentage of at-threshold laser stimuli that were reported as painful. The results were as expected: after conditioning, at-threshold laser trials paired with the CS+ were reported as painful more often, as more intense, and as more unpleasant than those paired with the CS-. This study provides new evidence that pain thresholds can be modulated via classical conditioning, even when the stimulus used to test the threshold cannot be anticipated. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain. Perspective: This study provides new evidence that human pain thresholds can be influenced by non-nociceptive somatosensory stimuli, via a classical conditioning effect. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain.