ArticlesLearning potentiates neurophysiological and behavioral placebo analgesic responsesColloca, Luanaa,*,1; Tinazzi, Micheleb,1; Recchia, Serenab; Le Pera, Domenicac; Fiaschi, Antoniob; Benedetti, Fabrizioa; Valeriani, Massimilianod Author Information aDepartment of Neuroscience, University of Turin Medical School, and National Institute of Neuroscience, Turin, Italy bDepartment of Vision and Neurological Sciences, University of Verona, Verona, Italy cMotor Rehabilitation, IRCSS San Raffaele, Rome, Italy dDivision of Neurology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy *Corresponding author. Address: Dipartimento di Neuroscienze, Università di Torino, Corso Raffello 30, 10125 Turin, Italy. Tel.: +39 011 6707701; fax: +39 011 6708174. E-mail: [email protected] 1These authors have equally contributed. Submitted December 7, 2007; revised April 21, 2008; accepted April 24, 2008. Pain 139(2):p 306-314, October 15, 2008. | DOI: 10.1016/j.pain.2008.04.021 Buy Metrics Abstract Expectation and conditioning are supposed to be the two main psychological mechanisms for inducing a placebo response. Here, we further investigate the effects of both expectation, which was induced by verbal suggestion alone, and conditioning at the level of N1 and N2–P2 components of CO2 laser-evoked potentials (LEPs) and subjective pain reports. Forty-four healthy volunteers were pseudorandomly assigned to one of three experimental groups: Group 1 was tested with verbal suggestion alone, Group 2 was tested with a conditioning procedure, whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the volunteers believe that the treatment was effective, Group 3 was a control group that allowed us to rule out phenomena of sensitization and/or habituation. Pain perception was assessed according to a Numerical Rating Scale (NRS) ranging from 0 = no pain sensation to 10 = maximum imaginable pain. Both verbal suggestions (Group 1) and conditioning (Group 2) modified the N2–P2 complex, but not the N1 component of LEPs. However, the suggestion-induced LEP changes occurred without subjective perception of pain decrease. Conversely, the N2–P2 amplitude changes that were induced by the conditioning procedure were associated with the subjective perception of pain reduction. Compared to natural history, conditioning produced more robust reductions of LEP amplitudes than verbal suggestions alone. Overall, these findings indicate that prior positive experience plays a key role in maximizing both behavioral and neurophysiological placebo responses, emphasizing that the placebo effect is a learning phenomenon which affects the early central nociceptive processing. © 2008 Lippincott Williams & Wilkins, Inc.