An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment
Introduction
It is well known that expectation can significantly modulate pain perception (Benedetti, 2008, Benedetti et al., 2006, Kong et al., 2007c). Recent advances in brain imaging have contributed to our mechanistic understanding of how expectancy (combined with placebo/sham treatment) can produce placebo analgesia and nocebo hyperalgesia effects (Bingel et al., 2006, Colloca et al., 2008, Craggs et al., 2007, Kong et al., 2008, Kong et al., 2006a, Lieberman et al., 2004, Petrovic et al., 2002, Price et al., 2007, Scott et al., 2007, Scott et al., 2008, Wager et al., 2004, Wager et al., 2007, Zubieta et al., 2005). However, the interaction between expectancy and genuine treatment has rarely been studied.
In one of the few studies on this topic performed in human subjects, Volkow et al. investigated how expectation can influence response to the stimulant drug methylphenidate in both cocaine abusers (Volkow et al., 2003) and non abusers (Volkow et al., 2006). They found that expectation significantly modified both subjective report (Volkow et al., 2003) and pattern of brain activation in response to a challenge dose of methylphenidate (Volkow et al., 2006, Volkow et al., 2003).
To date, acupuncture has been studied in almost one thousand different randomized controlled trials (RCTs) (Ernst, 2006, Kaptchuk, 2000, Linde et al., 2001). In these trials, it is not uncommon for “placebo/sham acupuncture/minimal acupuncture” controls to induce positive therapeutic effects on the same order of magnitude as verum (genuine) acupuncture, with verum and sham groups usually demonstrating superiority and clinical benefits over wait list or standard of care controls (Brinkhaus et al., 2006, Haake et al., 2007, Kaptchuk, 2000, Kaptchuk, 2002, Leibing et al., 2002, Linde et al., 2005, Melchart et al., 2005). In an attempt to find predictors of acupuncture response, Linde et al. (2007) reanalyzed the results from several RCTs of acupuncture treatment for chronic pain and found that expectation of relief was the only factor that correctly predicted outcome. Thus, it is important to elucidate the interaction between expectancy and acupuncture treatment in a well-controlled experimental setting.
One difficulty in studying expectancy is its large heterogeneity among healthy volunteers in part due to past treatment experience or knowledge that can condition responses. To overcome this challenge we have modified an expectancy/conditioning manipulation model used in other studies (De Pascalis et al., 2002, Kong et al., 2008, Kong et al., 2006a, Montgomery and Kirsch, 1997, Price et al., 1999, Voudouris et al., 1990, Wager et al., 2004) and applied it to a treatment that is relatively novel in this culture, acupuncture. Our group's previous studies (Kong et al., 2008, Kong et al., 2006a) that employ this paradigm demonstrate successful alteration of subjects' expectancies for acupuncture analgesia following experimental pain in a relatively short period of time.
In the current study, we combined the same expectancy/conditioning manipulation model and fMRI to investigate how expectancy can modulate acupuncture analgesia to calibrated noxious stimuli. In this experiment, subjects were randomized into four groups, receiving verum or sham acupuncture paired with either a high or low expectancy/conditioning manipulation. Then analgesic response to experimental heat pain applied on the right forearm was tested. In each group, we also included a within-subject control. Subjects were told that if they responded to the acupuncture treatment they would experience analgesia only on the treated (meridian) side of their arm, but not on the untreated (non-meridian) side of their arm (Fig. 1). Forty-eight subjects (12 in each group) completed the experiment. In this manuscript, we will focus on the data from the two real (verum) acupuncture groups (High and Low Expectancy) to investigate the mechanism of how expectancy can modulate treatment effects using within-subject and between-subject comparisons. To facilitate the understanding of the data, we will also include results from the other groups as secondary endpoints of this study. Data from other groups have also been presented in a separate manuscript (Kong et al., 2009) with additional analyses still underway.
Section snippets
Subjects
Seventy-seven healthy, right-handed subjects enrolled in this experiment, which was said to be a study of acupuncture analgesia. All subjects were naive to acupuncture. Experiments were conducted with the written consent of each subject and approval by the Massachusetts General Hospital's Institutional Review Board. All subjects were debriefed at the end of the experiment.
Procedures for the delivery and assessment of noxious thermal stimuli
Subjects were recruited to participate in two behavioral testing sessions and one fMRI scanning session. Each session was
Subjects
Forty-eight of seventy-seven consenting volunteers completed the study and were used for data analysis (average age 26.4 ± 4.9; 24 males). Twelve subjects did not fit the criteria for continued inclusion in the study (average ratings for HIGH pain were not greater than average ratings for LOW pain, or IP ratings on the radial and ulnar sides of their right arm were not approximately equivalent), eleven voluntarily withdrew, two could not tolerate the heat pain in Session 1, one could not tolerate
Discussion
In this study, we combined an expectancy manipulation procedure and fMRI to investigate how expectancy can influence the analgesia effect produced by verum acupuncture. Our results showed that although electroacupuncture treatment in VH and VL groups both received identical electroacupuncture treatment and produced comparable magnitudes of acupuncture sensations as measured by MASS, analgesia effect was significantly modulated by expectancy. Positive expectation can significantly enhance
Acknowledgments
This work was supported by PO1-AT002048 to Bruce Rosen from National Center for Complimentary and Alternative Medicine (NCCAM), R21AT00949 to Randy Gollub from NCCAM, KO1AT003883 to Jian Kong from NCCAM, K24AT004095 to Ted Kaptchuk from NCCAM, M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR and the MIND Institute.
References (69)
- et al.
Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network
Pain
(2006) - et al.
Identifying biological markers of activity in human nociceptive pathways to facilitate analgesic drug development
Pain
(2008) - et al.
Learning potentiates neurophysiological and behavioral placebo analgesic responses
Pain
(2008) - et al.
Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia
Neuroimage
(2007) - et al.
The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting
Pain
(2002) - et al.
A combined [11C]diprenorphine PET study and fMRI study of acupuncture analgesia
Behav. Brain Res.
(2008) - et al.
Ratio scales of sensory and affective verbal pain descriptors
Pain
(1978) - et al.
Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam
Pain
(1978) Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies
Trends Neurosci.
(2003)- et al.
Randomised clinical trial comparing the effects of acupuncture and a newly designed placebo needle in rotator cuff tendinitis
Pain
(1999)
Psychophysical outcomes from a randomized pilot study of manual, electro, and sham acupuncture treatment on experimentally induced thermal pain
J. Pain.
Expectancy and treatment interactions: a dissociation between acupuncture analgesia and expectancy evoked placebo analgesia
Neuroimage
Acupuncture treatment of chronic low-back pain — a randomized, blinded, placebo-controlled trial with 9-month follow-up
Pain
The neural correlates of placebo effects: a disruption account
Neuroimage
The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain
Pain
Classical conditioning and the placebo effect
Pain
Imaging cognitive modulation of pain processing
Pain
An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm
Pain
Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients
Pain
Individual differences in reward responding explain placebo-induced expectations and effects
Neuron
Introducing a placebo needle into acupuncture research
Lancet
Effects of expectation on the brain metabolic responses to methylphenidate and to its placebo in non-drug abusing subjects
Neuroimage
The role of conditioning and verbal expectancy in the placebo response
Pain
The placebo needle, is it a valid and convincing placebo for use in acupuncture trials? A randomised, single-blind, cross-over pilot trial
Pain
Relations between brain network activation and analgesic effect induced by low vs. high frequency electrical acupoint stimulation in different subjects: a functional magnetic resonance imaging study
Brain Res.
Mechanisms of placebo and placebo-related effects across diseases and treatments
Annu. Rev. Pharmacol. Toxicol.
Somatotopic activation of opioid systems by target-directed expectations of analgesia
J. Neurosci.
Neurobiological mechanisms of the placebo effect
J. Neurosci.
The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect
J. Neurosci.
Acupuncture in patients with chronic low back pain: a randomized controlled trial
Arch. Intern. Med.
The human cortex responds to an interoceptive challenge
Proc. Natl. Acad. Sci. U. S. A.
The placebo effect in pain reduction: the influence of conditioning experiences and response expectancies
Int. J. Behav. Med.
Acupuncture—a critical analysis
J. Intern. Med.
The effect of a placebo on the perception of painful radiant heat stimuli
Psychosom. Med.
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