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Enhancing the Placebo Response: Functional Magnetic Resonance Imaging Evidence of Memory and Semantic Processing in Placebo Analgesia

Published:January 13, 2014DOI:https://doi.org/10.1016/j.jpain.2013.12.009

      Abstract

      Two groups of patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension (20 seconds, 7 stimuli). Group 1 was tested under baseline (natural history [NH]) and a verbally induced placebo condition, whereas Group 2 was tested under baseline and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group 2. Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects.

      Perspective

      Expectations for pain can be verbally manipulated to produce placebo analgesia. Placebo analgesia is accompanied by decreased brain activity related to processing pain and increased brain activity that generates placebo analgesia, including semantic and memory regions. Placebo suggestions may enhance placebo analgesia by engaging a feedback mechanism triggered by the painful stimulus itself and related to brain mechanisms involved in memory and semantic processing.

      Key words

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      References

        • Amanzio M.
        • Benedetti F.
        Neuropharmacological dissection of placebo analgesia: Expectation-activated opioid systems versus conditioning-activated specific subsystems.
        J Neurosci. 1999; 19: 484-494
        • Atlas L.Y.
        • Wager T.D.
        How expectations shape pain.
        Neurosci Lett. 2012; 520: 140-148
        • Bar M.
        • Aminoff E.
        • Mason M.
        • Fenske M.
        The units of thought.
        Hippocampus. 2007; 17: 420-428
        • Benedetti F.
        • Amanzio M.
        Mechanisms of the placebo response.
        Pulm Pharmacol Ther. 2013; 26: 520-523
        • Bjorkedal E.
        • Flaten M.A.
        Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females.
        J Pain Res. 2012; 5: 289-300
        • Colloca L.
        • Benedetti F.
        Placebos and painkillers: Is mind as real as matter?.
        Nat Rev Neurosci. 2005; 6: 545-552
        • Colloca L.
        • Benedetti F.
        How prior experience shapes placebo analgesia.
        Pain. 2006; 124: 126-133
        • Craggs J.G.
        • Price D.D.
        • Perlstein W.M.
        • Verne G.N.
        • Robinson M.E.
        Using fMRI to examine the efficacy of placebo in irritable bowel syndrome patients (IBS): Insights into novel intervention strategies.
        J Pain. 2006; 7: S16
        • Craggs J.G.
        • Price D.D.
        • Perlstein W.M.
        • Verne G.N.
        • Robinson M.E.
        The dynamic mechanisms of placebo induced analgesia: Evidence of sustained and transient regional involvement.
        Pain. 2008; 139: 660-669
        • Craggs J.G.
        • Price D.D.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia.
        Neuroimage. 2007; 38: 720-729
        • Goebel R.
        • Esposito F.
        • Formisano E.
        Analysis of functional image analysis contest (FIAC) data with brainvoyager QX: From single-subject to cortically aligned group general linear model analysis and self-organizing group independent component analysis.
        Hum Brain Mapp. 2006; 27: 392-401
        • Kellow J.E.
        • Delvaux M.
        • Azpiroz F.
        • Camilleri M.
        • Quigley E.M.
        • Thompson D.G.
        Principles of applied neurogastroenterology: Physiology/motility-sensation.
        Gut. 1999; 45: II17-II24
        • Mertz H.
        • Naliboff B.
        • Munakata J.
        • Niazi N.
        • Mayer E.A.
        Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
        Gastroenterology. 1995; 109: 40-52
        • Montgomery G.H.
        • Kirsch I.
        Classical conditioning and the placebo effect.
        Pain. 1997; 72: 107-113
        • Naliboff B.D.
        • Munakata J.
        • Fullerton S.
        • Gracely R.H.
        • Kodner A.
        • Harraf F.
        • Mayer E.A.
        Evidence for two distinct perceptual alterations in irritable bowel syndrome.
        Gut. 1997; 41: 505-512
        • Petrovic P.
        • Kalso E.
        • Petersson K.M.
        • Ingvar M.
        Placebo and opioid analgesia—Imaging a shared neuronal network.
        Science. 2002; 295: 1737-1740
        • Price D.D.
        • Craggs J.G.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients.
        Pain. 2007; 127: 63-72
        • Price D.D.
        • Craggs J.G.
        • Zhou Q.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging.
        Neuroimage. 2009; 47: 995-1001
        • Price D.D.
        • Finniss D.G.
        • Benedetti F.
        A comprehensive review of the placebo effect: Recent advances and current thought.
        Annu Rev Psychol. 2008; 59: 565-590
        • Rankin K.P.
        • Salazar A.
        • Gorno-Tempini M.L.
        • Sollberger M.
        • Wilson S.M.
        • Pavlic D.
        • Stanley C.M.
        • Glenn S.
        • Weiner M.W.
        • Miller B.L.
        Detecting sarcasm from paralinguistic cues: Anatomic and cognitive correlates in neurodegenerative disease.
        Neuroimage. 2009; 47: 2005-2015
        • Rose J.P.
        • Geers A.L.
        • Rasinski H.M.
        • Fowler S.L.
        Choice and placebo expectation effects in the context of pain analgesia.
        J Behav Med. 2012; 35: 462-470
        • Smith C.N.
        • Squire L.R.
        Medial temporal lobe activity during retrieval of semantic memory is related to the age of the memory.
        J Neurosci. 2009; 29: 930-938
        • Talairach J.
        • Tournoux P.
        Co-Planar Stereotaxic Atlas of the Human Brain.
        Thieme Publishers Inc, New York1988
        • Vase L.
        • Robinson M.E.
        • Verne G.N.
        • Price D.D.
        The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation.
        Pain. 2003; 105: 17-25
        • Vase L.
        • Robinson M.E.
        • Verne G.N.
        • Price D.D.
        Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms.
        Pain. 2005; 115: 338-347
        • Verne G.N.
        • Himes N.C.
        • Robinson M.E.
        • Gopinath K.S.
        • Briggs R.W.
        • Crosson B.
        • Price D.D.
        Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome.
        Pain. 2003; 103: 99-110
        • Verne G.N.
        • Robinson M.E.
        • Price D.D.
        Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome.
        Pain. 2001; 93: 7-14
        • Verne G.N.
        • Robinson M.E.
        • Vase L.
        • Price D.D.
        Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients.
        Pain. 2003; 105: 223-230
        • Verne G.N.
        • Sen A.
        • Price D.D.
        Intrarectal lidocaine is an effective treatment for abdominal pain associated with diarrhea-predominant irritable bowel syndrome.
        J Pain. 2005; 6: 493-496
        • Voudouris N.J.
        • Peck C.L.
        • Coleman G.
        The role of conditioning and verbal expectancy in the placebo response.
        Pain. 1990; 43: 121-128
        • Whitehead W.E.
        • Holtkotter B.
        • Enck P.
        • Hoelzl R.
        • Holmes K.D.
        • Anthony J.
        • Shabsin H.S.
        • Schuster M.M.
        Tolerance for rectosigmoid distention in irritable bowel syndrome.
        Gastroenterology. 1990; 98: 1187-1192
        • Zubieta J.K.
        • Smith Y.R.
        • Bueller J.A.
        • Xu Y.
        • Kilbourn M.R.
        • Jewett D.M.
        • Meyer C.R.
        • Koeppe R.A.
        • Stohler C.S.
        Regional mu opioid receptor regulation of sensory and affective dimensions of pain.
        Science. 2001; 293: 311-315