#home PLOS ONE: New Articles

   Advertisement

   IFRAME: a3ac9da4

     * plos.org
     * create account
     * sign in

   PLOS ONE
     * Subject Areas
     * For Authors

Submit your Manuscript
          + Fair, rigorous peer review
          + Broad scope and wide reach
       get started
          + Why Publish with PLOS ONE
          + Publication Criteria
          + Editorial Policies
          + Preparing A Manuscript
          + Figure and Table Guidelines
          + Supporting Information Guidelines
          + Submitting a Manuscript
     * About Us
          + Journal Information
          + Editorial Board
          + Reviewer Guidelines
          + Article-Level Metrics
          + Open-Access License
          + Media Downloads
          + Guidelines for Comments and Corrections
          + Help Using this Site
          + Contact Us

   Search

   Search
   ____________________ SEARCH

   advanced search

   Open Access Peer-Reviewed
   Research Article

Are All Placebo Effects Equal? Placebo Pills, Sham Acupuncture, Cue
Conditioning and Their Association

     * Jian Kong mail,
       * E-mail: kongj@nmr.mgh.harvard.edu
       Affiliation: Psychiatry Department, Massachusetts General Hospital
       and Harvard Medical School, Charlestown, Massachusetts, United
       States of America
       X
     * Rosa Spaeth,
       Affiliation: Psychiatry Department, Massachusetts General Hospital
       and Harvard Medical School, Charlestown, Massachusetts, United
       States of America
       X
     * Amanda Cook,
       Affiliation: Psychiatry Department, Massachusetts General Hospital
       and Harvard Medical School, Charlestown, Massachusetts, United
       States of America
       X
     * Irving Kirsch,
       Affiliations: Program in Placebo Studies, Beth Israel Deaconess
       Medical Center, Harvard Medical School, Boston, Massachusetts,
       United States of America, School of Psychology, Plymouth
       University, Plymouth, United Kingdom
       X
     * Brian Claggett,
       Affiliations: Division of Cardiovascular Medicine, Harvard Medical
       School, Boston, Massachusetts, United States of America,
       Biostatistics Department, Harvard School of Public Health, Boston,
       Massachusetts, United States of America
       X
     * Mark Vangel,
       Affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for
       Biomedical Imaging, Charlestown, Massachusetts, United States of
       America
       X
     * Randy L. Gollub,
       Affiliation: Psychiatry Department, Massachusetts General Hospital
       and Harvard Medical School, Charlestown, Massachusetts, United
       States of America
       X
     * Jordan W. Smoller,
       Affiliation: Psychiatry Department, Massachusetts General Hospital
       and Harvard Medical School, Charlestown, Massachusetts, United
       States of America
       X
     * Ted J. Kaptchuk
       Affiliation: Program in Placebo Studies, Beth Israel Deaconess
       Medical Center, Harvard Medical School, Boston, Massachusetts,
       United States of America
       X

     * Published: July 31, 2013
     * DOI: 10.1371/journal.pone.0067485

     * Article
     * About the Authors
     * Metrics
     * Comments
     * Related Content

     * Reader Comments (1)
     * Figures

Abstract

   Placebo treatments and healing rituals have been used to treat pain
   throughout history. The present within-subject crossover study examines
   the variability in individual responses to placebo treatment with
   verbal suggestion and visual cue conditioning by investigating whether
   responses to different types of placebo treatment, as well as
   conditioning responses, correlate with one another. Secondarily, this
   study also examines whether responses to sham acupuncture correlate
   with responses to genuine acupuncture. Healthy subjects were recruited
   to participate in two sequential experiments. Experiment one is a
   five-session crossover study. In each session, subjects received one of
   four treatments: placebo pills (described as Tylenol), sham
   acupuncture, genuine acupuncture, or no treatment rest control
   condition. Before and after each treatment, paired with a verbal
   suggestion of positive effect, each subject's pain threshold, pain
   tolerance, and pain ratings to calibrated heat pain were measured. At
   least 14 days after completing experiment one, all subjects were
   invited to participate in experiment two, during which their analgesic
   responses to conditioned visual cues were tested. Forty-eight healthy
   subjects completed experiment one, and 45 completed experiment two. The
   results showed significantly different effects of genuine acupuncture,
   placebo pill and rest control on pain threshold. There was no
   significant association between placebo pills, sham acupuncture and cue
   conditioning effects, indicating that individuals may respond to unique
   healing rituals in different ways. This outcome suggests that placebo
   response may be a complex behavioral phenomenon that has properties
   that comprise a state, rather than a trait characteristic. This could
   explain the difficulty of detecting a signature for “placebo
   responders.” However, a significant association was found between the
   genuine and sham acupuncture treatments, implying that the non-specific
   effects of acupuncture may contribute to the analgesic effect observed
   in genuine acupuncture analgesia.

   Citation: Kong J, Spaeth R, Cook A, Kirsch I, Claggett B, et al. (2013)
   Are All Placebo Effects Equal? Placebo Pills, Sham Acupuncture, Cue
   Conditioning and Their Association. PLoS ONE 8(7): e67485.
   doi:10.1371/journal.pone.0067485

   Editor: Sam Eldabe, The James Cook University Hospital, United Kingdom

   Received: February 17, 2013; Accepted: May 18, 2013; Published: July
   31, 2013

   Copyright: © 2013 Kong et al. This is an open-access article
   distributed under the terms of the Creative Commons Attribution
   License, which permits unrestricted use, distribution, and reproduction
   in any medium, provided the original author and source are credited.

   Funding: This work was supported by KO1AT003883 (NCCAM), R21AT004497
   (NCCAM), R03AT218317 (NIDA), and R01AT006364 (NCCAM) to Jian Kong;
   R01AT005280 (NCCAM) to Randy Gollub; K24AT004095 (NCCAM) to Ted
   Kaptchuk; K24MH094614 (NIMH) to Jordan W. Smoller, and P01 AT006663
   (NCCAM) to Bruce Rosen. The funders had no role in study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.

   Competing interests: The authors have declared that no competing
   interests exist.

Introduction

   Placebo treatments and healing rituals have been used since the
   beginning of human history [1], [2]. The systematic study of placebo
   and ritual is still in its infancy [3], [4]. Whether all placebo
   treatments, or medical rituals, have equivalent effects remains
   unknown. This raises the question: Do patients who respond to one
   placebo intervention also tend to respond to other placebo
   interventions?

   In a previous clinical trial [5] of chronic pain patients, we found
   that sham acupuncture reduced pain significantly more over time than
   did placebo pills, while placebo pills offered more short-term benefits
   of improving pain-disturbed sleep over sham acupuncture. Thus it showed
   that not all placebo treatments are equal. However, this clinical trial
   involved multiple, concurrent experimental arms and was not designed to
   answer the question of whether individuals who tend to respond to sham
   acupuncture also tend to respond to placebo pills.

   In another study [6], Colloca and colleagues compared the placebo
   effects of verbal suggestion and conditioning to a control condition
   and found that verbal suggestion alone could not produce significant
   differences in subjective pain ratings. Conditioning, on the other
   hand, could significantly reduce subjective pain ratings. The
   between-subject design of this study prevents the authors from
   elucidating the association between verbal suggestion and conditioning
   effects.

   Elucidating the relationship between different placebo modalities
   paired with verbal suggestion (suggestion-evoked placebo effects) as
   well as understanding their association with conditioning-evoked
   placebo effects will enhance our understanding of the variability
   observed in the placebo response. We are particularly interested in
   whether placebo responses can be characterized by the involvement of
   relatively stable traits or states, depending on particular
   circumstances.

   Acupuncture has been used to relieve pain in East Asia for two thousand
   years [7]. Recent clinical trials investigating acupuncture's effects
   on chronic pain have shown contradictory results and often fail to show
   superiority over sham acupuncture [8]. This ambiguity may be the result
   of acupuncture's sizeable placebo effects as well as large
   inter-individual variability in response to acupuncture treatment [5],
   [8]–[11]. It is well known that some patients respond well to placebo
   and acupuncture treatments while others do not [5], [9]. Thus, as a
   secondary aim, this paper also addresses whether individuals who
   respond to sham acupuncture also respond to genuine acupuncture.

   In this study, all subjects participated in two experiments
   sequentially. The first experiment was a multi-session crossover study
   [12] designed to test the analgesic effects of placebo Tylenol (pill),
   sham acupuncture, and genuine acupuncture (electroacupuncture) as
   compared to a no treatment (rest control). Subjects also participated
   in experiment two, in which we investigated how visual cues could
   modulate pain perception. These two experiments allow us to investigate
   the relationship between the analgesia evoked by different treatments
   as well as the analgesic effect evoked by conditioning cues.

Methods

Experiment one

Subjects.

   Seventy-one healthy, acupuncture-naïve subjects were recruited from the
   community, using flyers and postings, and enrolled in the study. The
   Institutional Review Board at Massachusetts General Hospital approved
   the study and all subjects gave written informed consent before
   commencing experiment one. All subjects were told that if they
   completed experiment one, they would also be invited to participate in
   experiment two. Subjects were debriefed at the end of experiment two
   and investigators explained the rationale for deception during the
   experiments. All subjects found study procedures acceptable and agreed
   to have their data used for analysis.

Outcome measurements.

   The outcome measures for this study include heat pain threshold and
   tolerance and subjective pain ratings of calibrated heat pain. All pain
   assessments were appliedusing a TSA-2001 Thermal Sensory Analyzer with
   a 3×3 cm probe (Medoc Advanced Medical Systems, RimatYishai, Israel)
   running proprietary computerized visual analog scale software (COVAS).

   Subjects' thresholds and tolerances to pain were assessed on the dorsal
   portion of the hand using an ascending method of limits paradigm with a
   rate of rise of 0.5°C/sec from a baseline of 32°C. The 3 cm X 3 cm
   thermode was held lightly in place on the skin by a member of the study
   staff blinded to treatment mode.Subjects pressed a button in front of
   them to indicate when the heat “first becomes painful”to indicate pain
   threshold and when the heat “becomes too painful to tolerate” to
   indicate tolerance. Three trials of pain threshold and tolerance
   assessments were performed. The thermode was repositioned between each
   trial.

   Calibrated heat pain stimuli were applied on the volar side of the
   forearms. All stimuli were delivered in 10-secondsegments (including an
   approximate 2.5 second ramp up and down from baseline) with a minimum
   inter-stimulus interval of 24 seconds. After each stimulus, the
   subjects were asked to rate the pain using the Gracely Sensory Scale
   (0–20) [13], [14].

Experimental procedure.

   The first experiment was a crossover study that involved five study
   visits, including one training session and4experimental sessions
   (Figure 1). Each session was separated by at least 3 days to avoid
   sensitization to the repeated application of the noxious stimuli and to
   allow for full recovery of the subjects' skin. Similar methods have
   been used in our previous studies and no damage or lesions have been
   observed [12], [15]–[17].
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Figure 1. Experimental design.
   doi:10.1371/journal.pone.0067485.g001

   The first session was used to introduce the study procedures, determine
   appropriate stimulus intensities for each subject, minimize
   anticipatory anxiety to pain and acupuncture, and to control for rating
   strategy and learning effects.

   At the beginning of the training session (Session 1),subjects were told
   that in the subsequent 4 sessions, they would receive each of the 4
   experimental conditions in a randomized order, i.e. two different modes
   of acupuncture treatment(electroacupuncture and manual acupuncture),
   one painkiller (Tylenol), and one control condition. Subjects were also
   told that before and after each treatment condition and the control
   condition, trained study staff would test their pain sensations to
   investigate the analgesic effect of different treatments on
   experimental pain applied to the forearm.

   In reality, the manual acupuncture was sham acupuncture and the Tylenol
   painkiller was a placebo pill. In addition, subjects were explicitly
   informed that the control condition was a baseline control for the
   study and, thus, no treatment effects were expected. To maintain
   uniform expectancy across treatment sessions, subjects were also told
   that the effects of the two types of acupuncture (electroacupuncture
   and manual acupuncture) and Tylenol treatments could work via different
   mechanisms, and that the efficacy of one treatment would not influence
   the efficacy of the others.

   The subjects were then trained to assess their pain threshold and
   tolerance. The heat stimuli were applied to the back of their hand in
   three separate locations for both threshold and tolerance measures.
   After that, they were instructed how to use the Gracely Sensory and
   Affective Scales [13], to rate calibrated heat pain with methods used
   in our previous studies [12], [15]–[17]. In order to identify the
   individually calibrated heat pain stimuli, a training set of ascending
   heat pain stimuli was administered starting from 38°C and increasing by
   one degree for each stimulus. From the subject's ratings of this
   initial series of stimuli, two heat pain intensities were determined
   for each subject: one to elicit responses in the strong range (“High
   pain”; 14–17 on the Sensory Scale) and one to elicit responses in the
   mild to moderate range (“Low pain”; 8–11 on the Sensory Scale).
   Sequences of the subject-specific High and Low stimuli were then
   applied in random order to separate areas of skin on the right volar
   forearm to further test the reliability of these ratings. Each random
   sequence consisted of six stimuli:3 Low pain stimuli and 3 High pain
   stimuli. The high and low temperatures were adjusted as necessary to
   reliably elicit a High or Low rating from a subject. Following these
   adjustments, the temperatures would remain fixed for all subsequent
   sessions.

   Next, acupuncture was administered for 2 minutes to introduce subjects
   to the acupuncture experience. As several previous studies [18]–[20]
   have suggested that optimism is associated with placebo effects, all
   subjects were asked to complete the Life Orientation Test (LOT) to
   assess individual differences in generalized optimism versus pessimism.

   Study sessions 2–5 were experimental test sessions. In each
   experimental session, a predetermined set of experimental heat pain
   tests was administered before and after treatment/conditioning in the
   following order: 1) pain threshold (3 times) on the dorsal portion of
   the right hand; 2) a pseudorandom noxious thermal stimuli sequence
   consisting of the 3 High and 3 Low pain stimuli on the volar side of
   right forearm; and 3) heat pain tolerance on the dorsal portion of the
   right hand. The dorsal portion of the hand was chosen due to its
   proximity to the acupuncture point used in this study. Heat pain was
   applied to separate areas of skin on the volar forearm in order to
   avoid the potential influence of one sequence of calibrated pain on
   each subsequent sequence. This predetermined set of tests was repeated
   during each experimental session. The only difference among the
   sessions was the treatment condition: electroacupuncture, sham
   acupuncture, placebo Tylenol, or rest control condition. The order in
   which subjects received the 4 experimental conditions was randomized
   prior to study proceedings using a computerized random number
   generator. Sequentially numbered method was applied for allocation
   concealment.

   To ensure that all subjects could consistently rate the discrete levels
   of heat pain, only subjects who demonstrated the ability to distinguish
   different pain intensities during Session 2 (i.e., on average, rating
   the High pain stimuli higher than the Low pain stimuli after
   application of the random noxious stimuli sequence) were selected to
   proceed in the study.

   Studies have shown that expectation can significantly influence an
   individual's perception of pain [15]–[17],[21]–[28]. Thus, all subjects
   were asked to complete the Expectations for Relief Scale (ERS) to
   indicate how much pain relief they expected from each particular
   treatment after receiving the treatment but prior to the post-treatment
   pain testing. The ERS is a ten-point scale (0–10) where 0 indicates a
   very negative expectation of “does not work at all” and 10 indicates a
   very positive expectation of “complete pain relief.”For the three
   treatment conditions, the subjects were told prior to treatment that
   they were about to receive a treatment that the investigators believed
   would have an analgesic effect on their entire body, including the arm.
   This served as verbal suggestion for the subjects in the treatment
   groups. For the control condition (30-minute rest period), subjects
   were still required to use ERS to rate how they expected their pain
   sensitivity would change after a 30-minute break, although they
   received no treatment.

Interventions.

   Placebo Tylenol Pill: Subjects were informed that the goal of the
   session was to test the analgesic effect of a non-opioid analgesia
   pill, acetaminophen (Tylenol by brand), on experimental pain. They were
   also told that the pill would begin to take effect approximately half
   an hour after administration and that previous research has suggested
   that Tylenol can produce a general analgesic effect on the whole body,
   including the experimental pain applied to the forearms. After orally
   ingesting the pill (in reality an inert placebo pill), subjects waited
   about half an hour prior to the beginning of the post-treatment pain
   assessment.

   Sham (Placebo) Acupuncture: Sham acupuncture was performed using the
   validated Streitberger sham acupuncture device [12], . A small plastic
   ring was covered by an opaque, thin covering and then placed
   over2non-acupoints after the acupuncturist disinfected the area with
   isopropyl alcohol. A placebo needle, which was visually
   indistinguishable from genuine acupuncture needles, was inserted into
   the center of the ring and held in place by the tape. Because the
   Streitberger placebo needle has a blunt tip and a retractable shaft,
   the needle did not actually penetrate the skin; however the subjects
   felt a sensation similar to that of a pinprick or a scratch. After
   insertion, the needles were kept in place for 25 minutes.

   Two sham acupoints (sham large Intestine 4 and 3 (LI 4 and LI 3) were
   chosen [32].Sham acupoint LI 4 is located on the dorsum of the right
   hand, between the 1st and 2nd metacarpal bones, approximately in the
   middle of the 1st metacarpal bone on the ulnar side. Sham acupoint LI 3
   is about one half cm above the metacarpal bones. Both needles were
   rotated until the subject reported some level of sensation. Then, all
   needles were left alone for the remainder of the procedure (about 23
   minutes) without further manipulation. The subject was told that these
   proceedings constituted the manual acupuncture treatment.

   Genuine Acupuncture: The acupoints LI 4 and LI 3 on the right hand were
   used for the genuine acupuncture treatment. These points have
   well-documented analgesic effects in laboratory experiments [12], [33],
   [34]. After the acupuncturist located the acupoint and disinfected it
   with isopropyl alcohol, a small plastic ring was placed over the
   acupoint and secured with a thin strip of sterile plastic tape. This
   covering was used to maintain subject blinding to genuine and sham
   acupuncture conditions.

   A small alligator-type conducting clamp was then attached to each
   needle to create a circuit using an electroacupuncture device (OMS
   Medical Supplies IC-1107). A current was passed through the electrode
   at a continuous frequency of 2 Hz. The intensity of the stimulation was
   gradually increased to the highest level subjects could tolerate
   without the sensation of sharp pain. The electroacupuncture was applied
   for approximately 23 minutes. Immediately following each acupuncture
   treatment (genuine and sham acupuncture treatment), subjects quantified
   the sensations they felt around the stimulated acupoint using the MGH
   Acupuncture Sensation Scale (MASS) [12], [35].

   No treatment rest control: The subjects in this group were told that
   the no-treatment condition was used as a within-subject control for the
   treatment conditions. Following the initial pain assessments, subjects
   were told to simply sit and relax for 30 minutes and wait for the
   post-treatment pain assessment to begin. Again, the subjects were asked
   to rate how much they thought the half hour rest period would change
   their sensitivity to pain during the second set of pain assessments.

Experiment two

   All subjects who completed experiment one were invited to return to our
   lab at least 2 weeks after completion of experiment one to participate
   a one-session fMRI study to investigate the conditioning effects of
   visual cues. Please see original publication for more details on
   experimental procedures and fMRI results [36]. The present manuscript
   only focuses on the analysis of the association between the placebo
   effects evoked by suggestion in experiment one and the visual cue
   conditioning effects in experiment two. This analysis has not been
   included in previous reports.

   In brief, at the beginning of the experiment, subjects were told that
   the aim of experiment two was to investigate the brain's response to
   different levels of thermal pain. Subjects were then familiarized with
   the visual presentation paradigm, including a pre-stimulus cue, a pain
   stimulus symbol, and a post-stimulus rating scale. In addition,
   subjects were told that the pre-stimulus cue (text saying either “HIGH”
   or “LOW”) would indicate the level of the subsequent pain stimulus.

   Based on experiment one, temperatures that elicited subjective
   intensity ratings in the strong range (“High pain”; 14–17 on the
   Sensory Scale) and one to elicit responses in the mild to moderate
   range (“Low pain”;8–11 on the Sensory Scale)were selected for each
   subject and used in experiment 2 (MRI study). Immediately prior to the
   fMRI scan, a brief pain sensitivity test was performed to further
   confirm that the subjective ratings in response to the high and low
   temperature stimuli elicited were within the targeted range for the
   study and necessary adjustments were made.

   During fMRI scanning, 3 different series of pseudo-randomized pain
   sequences were applied to the distal portion of the right forearm above
   the wrist. Subjects were instructed to focus on a small black fixation
   cross in the center of the screen in front of them. The first scan was
   a contextual conditioning/learning scan where subjects were presented
   with a pre-stimulus cue, indicating (without deception) whether they
   would be administered a LOW or HIGH pain stimulus. The duration of the
   pain stimulus was 12 seconds and the intensity of the stimulus for this
   first sequence always corresponded to the pre-stimulus cue. After each
   pain stimulus, the Sensory Box Scale was displayed on the screen for 8
   seconds, and subjects rated the intensity of their subjective pain by
   moving a cursor along the scale. In total, this learning sequence
   included 4 LOW and 4 HIGH pain stimuli.

   The initial conditioning scan was followed by 2 test pain sequences in
   which the LOW cue (LC) was sometimes followed by the HIGH pain stimulus
   (HP) (the LC condition), representing a condition where subjects were
   expected to report less pain in response to a suggested low stimulus,
   and sometimes followed by the LOW pain stimulus. Both test scans
   included nine stimuli, where 3 of the stimuli were cued as HIGH pain
   and six were cued as LOW pain. Following all HIGH cues (HC), a high
   pain stimulus was delivered (the HC condition). However, following 3 of
   the six LOW cues, a HIGH pain stimulus was delivered (the LC condition)
   instead of a LOW pain stimulus. All other timing aspects of the 2 test
   scans were identical to the first contextual learning/conditioning
   scan. The subjective pain ratings evoked by the different cues (LC or
   HC with identical HIGH heat pain stimuli) in runs 2 and 3 were used to
   calculate the conditioned cue effect. The cue effect was used to
   investigate the association between the analgesic effect of treatment
   observed in experiment one and the analgesic effect of visual cue
   conditioning.

Analysis

Experiment one

   The primary outcomes for experiment one were post-treatment measures of
   pain threshold, pain tolerance, and pain ratings (for high pain and low
   pain). Because each subject was evaluated under all 4 of the
   experimental conditions, the data were analyzed using repeated measures
   analysis of covariance (ANCOVA) with the corresponding baseline
   measures as the covariate and treatment as the factor of interest. A
   separate ANCOVA model was fit for each of the 3outcomes. In these
   ANCOVA models, session order and subject ID were also included as
   factors, eliminating the need to further control for subject-level
   covariates such as age and gender.

   For each subject outcome, the distribution of residuals from the ANCOVA
   model was visually inspected. In the event that noticeable
   non-normality was detected, a robust analysis rank ANCOVA was
   performed, replacing both outcomes and baseline scores with their
   respective ranked values [37]. If both normal-theory and robust
   analyses produced similar results, we concluded that the results were
   not likely to be sensitive to the normality assumption.

   For outcomes in which a significant difference among treatments was
   detected, regression analyses were used to investigate whether
   subject-level outcomes (including subject response to other treatments)
   were useful predictors of response to genuine acupuncture. Robust
   regression using M-estimation was employed to minimize the effect of
   outliers [38].All analyses were conducted using Stata (version 11).
   P-values of ≤0.05 were considered to be statistically significant.

Experiment two

   The primary outcome for experiment two was the subjective pain ratings
   evoked by the different visual cues (Low Cue or High Cue with identical
   HIGH heat pain stimuli) in the 2 test pain sequences. We explored the
   association between the analgesic effect evoked by different treatments
   in experiment one (genuine acupuncture, sham acupuncture and placebo
   pills compared with rest condition, separately) and visual cue effects
   in experiment two by applying non-parametric Spearman correlations
   separately. For this analysis, we used the primary outcomes of
   experiment one (changes in pain threshold, pain ratings of calibrated
   pain stimuli and pain tolerance), and the primary outcome in experiment
   two (conditioning cue effects as indicated by subjective pain rating
   changes to identical pain stimuli).

Results

Experiment one

   Of the 71 healthy subjects who participated the study, 48 subjects (19
   males, 34 white, 4 black, 6 Asian, 3 more than one race and 1 unknown)
   ages 21–37 (mean: 26.23, SE: 0.48) completed experiment one with data
   for analysis. One subject who completed experiment one was not included
   in data analysis due to missing data. Twenty-two subjects did not
   complete the study. The reasons for dropped subjects included
   scheduling difficulties (11), unstable pain ratings (6), inability to
   tolerate testing conditions (acupuncture or heat) (3), inability to
   understand nuances of pain rating scales (1), and voluntary withdrawal
   (1). The average intervals between treatments (baseline and each of the
   four conditions) were 8 days, 7.7 days, 7.5 days and 8.2 days.

   A summary of pain threshold and tolerance values and pain ratings of
   calibrated heat pain stimuli are shown in Table 1 and Figure 2. The
   ANCOVA (Table 2) showed that pain threshold post-treatment scores were
   significantly dependent on the mode of treatment (F = 3.57; df = 3,
   137; p = 0.016). The distribution of the post-treatment scores, as well
   as the residual values from the ANCOVA model, was found to include
   outliers, which could potentially impact the results of the ANCOVA
   model. However, the sensitivity analysis conducted using rank data
   found a similar result (F = 3.63; df = 3, 137; p = 0.015). Post hoc
   analysis among the 4 experimental conditions showed that both genuine
   acupuncture and placebo pills produced significant post-treatment pain
   threshold increases (+0.79, 95% CI:[+0.25, +1.33], p = 0.004; and
   +0.74,95%CI: [+0.19, +0.1.29], p = 0.008 respectively) relative to rest
   control. No other significant differences between treatments were
   detected with respect to pain threshold (Table 3).
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Figure 2. Summary of pain measurement difference (post- minus
   pre-treatment, mean ± SE) on pain threshold, pain tolerance, and pain
   rating across different groups.

   EA, electroacupuncture group; PA, placebo acupuncture group; PT,
   placebo Tylenol group; RS, resting control group.
   doi:10.1371/journal.pone.0067485.g002
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 1. Pre- and post-treatment pain threshold (centigrade), tolerance
   (centigrade), and pain ratings (intensity rating of high and low pain
   stimuli using the 0–20 GracelyScale) across different conditions
   (mean±SE).
   doi:10.1371/journal.pone.0067485.t001
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 2. Treatment effects across different measurements of pain
   sensation.
   doi:10.1371/journal.pone.0067485.t002
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 3. Post-hoc analysis of pain threshold: effect of treatment
   relative to rest control.
   doi:10.1371/journal.pone.0067485.t003

   For pain ratings of calibrated heat pain stimulation and pain
   tolerance, no significant treatment effects were detected (Table 2).
   While the null hypothesis of global F-test for the effect of treatment
   on the pain tolerance outcome could not be rejected, it should be noted
   that an exploratory post-hoc analysis using a test for detecting trends
   across the treatment groups did reveal a significant progression in the
   strength of treatment effects when the treatments were ordered as rest
   control condition<placebo Tylenol = sham acupuncture
   <electroacupuncture. In this analysis, the effect of treatment was
   estimated, with the rest condition coded as 0, each of the two placebo
   treatments coded as 1, and the genuine acupuncture coded as 2. Using
   the same ANCOVA models as mentioned above, the effects of treatment
   were found to be significant with p-values of 0.012 and 0.007
   corresponding to the original and ranked data, respectively.

   Because only the pain threshold outcome showed significant differences
   among the experimental conditions, further analyses focused only on
   this outcome. In an attempt to determine whether responses to placebo
   Tylenol were significantly related to each subject's response to sham
   acupuncture, we investigated the relationship between post-treatment
   placebo Tylenol pain threshold and the following predictors,
   controlling for pre-treatment placebo Tylenol pain threshold: pre- and
   post-sham acupuncture pain threshold change, pre- and
   post-electroacupuncture pain threshold change, pre- and post- rest
   control pain threshold change, expectancy ratings for each of the4
   conditions(placebo Tylenol, sham acupuncture, genuine acupuncture, and
   rest control), age, gender, and optimism measured by the LOT scale.

   We assessed these relationships via univariate and multivariate
   regression models. The results (Table 4) show the estimated regression
   coefficients and associated p-values. In the left column, each variable
   is considered one at a time, controlling only for baseline placebo
   Tylenol pain threshold and the session number in which placebo Tylenol
   was received. In the right column, all variables appear together in a
   single multivariate model. In both settings, there is no significant
   association between post-treatment placebo Tylenol pain threshold and
   the sham acupuncture pain threshold change, suggesting the 2 placebo
   modalities are not associated. No other predictors were found to be
   significantly related to placebo Tylenol pain threshold in either
   univariate or multivariate models.
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 4. Potential predictors of placebo Tylenol response using pain
   threshold as outcome.
   doi:10.1371/journal.pone.0067485.t004

   Similarly, in an attempt to determine whether any individual
   characteristics were significantly related to subject response to
   electroacupuncture, we investigated the relationship between
   post-treatment electroacupuncture pain threshold and the following
   predictors, controlling for pre-treatment electroacupuncture pain
   threshold as well as the session number in which electroacupuncture was
   received: pre- and post- sham acupuncture pain threshold change, pre-
   and post-placebo Tylenol pain threshold change, pre- and post- rest
   control pain threshold change, expectancy ratings for each of the 4
   conditions(genuine acupuncture, sham acupuncture, placebo Tylenol, and
   rest control), age, gender, and optimism measures using the LOT scale.

   The results (Table 5) show the estimated regression coefficients and
   associated p-values. In both settings, the sham acupuncture pain
   threshold change was significantly and positively correlated to post-
   electroacupuncture pain threshold (β = 0.41, p = 0.005 in univariate
   model; β = 0.41, p = 0.03 in multivariate model).
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 5. Potential predictors of electro-acupuncture response using
   pain threshold as outcome.
   doi:10.1371/journal.pone.0067485.t005

   After each treatment, the expectancy for that particular treatment was
   also measured using the ERS. The average expectancy ratings (avg ± SE)
   for each of the 4 experimental conditions are: 4.4±0.3 for the genuine
   acupuncture condition, 4.1±0.4 for the sham acupuncture condition,
   5.3±0.3 for the placebo Tylenol condition, and 0.6±0.2 for the rest
   control condition. The ANOVA showed that there was a significant
   difference in expectancy ratings across the 4 experimental conditions
   (F(3,137) = 79.6, p<0.0001), and post hoc analysis showed that
   expectancy rating in all 3 treatment groups were significantly greater
   than the rest control condition (p<0.001 for each). Expectancy ratings
   in the placebo Tylenol condition were also greater than both the sham
   acupuncture condition (p = 0.001) and the genuine acupuncture condition
   (p = 0.003).

   To further test the association between the pre- and post-treatment
   pain measurement differences and expectancy ratings, we regressed all
   post-treatment pain measurements on expectancy scores, controlling for
   pre-treatment measurements, session order, and subject ID. The results
   indicated that the expectancy level was significantly correlated with
   pain threshold (beta = 0.17, p<0.001) and pain tolerance (beta = 0.07,
   p = 0.003), but not significantly associated with low and high pain
   ratings.

   We also measured the sensations evoked by electro-acupuncture and sham
   acupuncture treatment using the MASS. A summary of the results is shown
   in Table 6. There was a significant difference in the average MASS
   sensation between electro-acupuncture (2.2±1.5) and sham acupuncture
   (0.5 ±0.6) conditions (p<0.001). Correlation analysis did not find
   significant correlations between the MASS rating and outcome
   measurements (pain threshold, pain tolerance and pain rating changes).
   thumbnail
   Download:
     * PPT
       PowerPoint slide
     * PNG
       larger image ()
     * TIFF
       original image ()

   Table 6. Average MASS scores (mean ± SE) across electro-acupuncture and
   sham acupuncture conditions.
   doi:10.1371/journal.pone.0067485.t006

Experiment two

   Of the 48 datasets that were included in analyses from experiment one,
   data from 46 subjects were included in data analysis for experiment
   two. One subject was not able to complete experiment due to scheduling
   conflicts, and the other subject did not complete experiment two (fMRI
   scan session) due to a suspected abnormal brain scan. Subsequent follow
   up with a physician determined that the abnormality was not clinically
   significant.

   Behavioral data of experiment two showed that the pain ratings (mean±
   SE) for the low-cue low pain condition averaged 5.3±0.3, the low-cue
   high pain condition (LC) averaged 11.3±0.4, and the high-cue high pain
   condition (HC) averaged 14.2±0.3.The cue effect (LC condition minus HC
   condition) ranged from −0.5 to 7.6 (median = 3.0). A one-way mixed
   model was applied with mean pain ratings as the response, the result
   showed that the contrasts HC and LC condition was highly significant
   (p<0.0001).

   To explore the association between the analgesic effects observed from
   experiment one and the conditioning cue effects observed in experiment
   two, we applied a Spearman correlation between the analgesic effect of
   different treatments (treatment (pre-post) – control (pre-post) and cue
   effects respectively. The results showed that that there was no
   association between the conditioning cue effect and any
   treatment-evoked analgesic effect (p-values ranged from 0.13–0.99).

Discussion

   In this study, we investigated the analgesic effects produced by
   placebo Tylenol, sham acupuncture, genuine acupuncture and a rest
   control condition, as well as the association between the effects of
   verbal suggestion on evoked placebo treatments (placebo Tylenol and
   sham acupuncture), electroacupuncture, and conditioning cue effects.
   The results showed that genuine acupuncture and placebo pills could
   significantly increase subjects' pain threshold compared with rest
   control condition. Regression analysis showed that there were no
   significant associations between individuals' responses to placebo
   pills, sham acupuncture, electroacupuncture and conditioning cue
   effects; however, subjects' responses to sham acupuncture correlated
   significantly with their response to genuine acupuncture.

   To the best of our knowledge, the question of whether individuals are
   likely to respond to different placebo routes of administration in a
   similar or different manner was an explicit topic of research in
   several experiments performed between 1956 and 1965 and each concluded
   that sham injections were more powerful than placebo pills
   [39]–[42].Further supporting this belief, a relatively old
   meta-analysis that included 35 RCTs for treatment of acute migraine
   extracted the placebo responses of trials that utilized an oral placebo
   and compared those responses with placebo responses in trials that used
   an injected placebo. The analysis showed that the injected placebo was
   statistically and clinically superior to the oral placebo [43].

   Our team performed an RCT comparing placebo pills and sham acupuncture
   across 270 patients with chronic arm pain. The results showed that sham
   acupuncture was statistically and clinically superior to placebo pills
   over time, while placebo pills were more beneficial in the short-term
   for improving sleep disturbances due to the pain condition [5]. A
   recent Cochrane meta-analysis of placebo effects [44] revisited this
   question of pill placebos versus device placebos and found that RCTs (n
   = 61) with “physical placebos” (which included sham acupuncture and
   such devices as sham electrotherapy and ultrasound) produced larger
   placebo effects than studies with “pharmacological” pill controls. In a
   separate study, Linde and colleagues [10] re-analyzed this
   meta-analysis [44] to investigate whether effects associated with sham
   acupuncture differed from those of other 'physical placebos'. They
   found pooled standardized mean differences were −0.41 (95% CI(−0.56,
   −0.24)) between sham acupuncture and no treatment, and −0.26 (95% CI
   −0.37, −0.15) between other physical placebos and no treatment,
   implying a larger effect of acupuncture treatment. In another
   meta-analysis from the same group [8], the authors also found that sham
   acupuncture interventions are often associated with moderately large
   nonspecific effects.

   In our present study, we did not find any differences between the sham
   acupuncture treatment and placebo pills in the measurement of pain
   threshold, tolerance, and pain ratings. Additionally, there was no
   significant association between any of the pain measurement changes
   after the 2 modes of placebo treatments (placebo pill and sham
   acupuncture) in both univariate analysis and after adjusting for
   expectancy and optimism, suggesting a lack of consistency in placebo
   response across different modes of placebo treatments. This result is
   consistent with the findings from a recent study, in which Whalley and
   colleagues [45] found that placebo effects across trials were highly
   correlated when placebo creams bore the same name but were not
   significantly correlated when placebo creams had different names.

   We did not find any significant sham acupuncture effects compared to
   the rest control. Additionally, analgesic effects across all treatment
   modes were, in general, mild. This is consistent with previous findings
   that indicate that placebo effects evoked by verbal suggestion alone
   are weak in healthy subjects compared to patients [6], [46], [47],
   particularly considering that acupuncture treatment is a novel
   treatment method in the United States [15].The fact that sham
   acupuncture had significantly lower expectancy ratings than placebo
   Tylenol further supports this view.

   Interestingly, we found that response to genuine acupuncture is
   significantly and positively correlated with response to sham
   acupuncture. This finding suggests that a non-specific effect of
   acupuncture treatment may play a significant role in the analgesic
   effect evoked by genuine acupuncture, which is consistent with the
   conclusion from a recent meta analysis on acupuncture treatment of
   chronic pain [11]. Nevertheless, our results do not indicate that the
   two are necessarily the same. We found that although the explicit
   conscious expectancy for genuine acupuncture is lower than the
   expectancy for placebo pills, the analgesic effect (as measured by pain
   threshold and tolerance) produced by genuine electroacupuncture trends
   is higher than the effect produced by placebo pills. This dissociation
   suggests that the specific effect of acupuncture may significantly
   contribute to the analgesic effect of electroacupuncture, which is
   consistent with previous neuroimaging studies that found different
   brain activation patterns associated with placebo and acupuncture
   analgesia [16], [17].

   In a previous study [6], Colloca and colleagues investigated 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. They found
   that both verbal suggestions (placebo cream) and conditioning modified
   the N2–P2 complex. Verbal suggestion in combination with the
   application of placebo cream could not produce subjective pain rating
   differences as compared with control condition, while conditioning with
   placebo cream produced more robust reductions of LEP amplitudes and
   subjective pain rating decreases. Our results are consistent with their
   findings of weak placebo effects with verbal suggestion alone and
   robust effects using a conditioning paradigm. Although we cannot
   perform a direct comparison, in our results the p-value of the
   conditioned visual cue effect was more significant compared to the
   placebo effect observed with verbal suggestion alone. More importantly,
   our results extend their findings showing that there is no association
   between the placebo analgesia observed with verbal suggestion and the
   effects of visual cue conditioning, suggesting that each may be
   associated with different mechanisms.

   In this study, the most significant findings were pain threshold
   changes, but not pain tolerance or pain rating changes. Previous
   studies have suggested that different pain sensation measurements (pain
   threshold, pain tolerance, and pain rating) may represent different
   aspects of pain sensation [48], [49]. One potential explanation is the
   order effect of the pain measurements obtained. In this study, we
   collected pain threshold, then pain rating to calibrated heat pain, and
   finally the pain tolerance measurements. Since pain threshold is always
   measured first, this may partly explain why the greatest analgesia
   effect is observed in the pain threshold measurement. However, further
   study is warranted.

   Although our study is based on an experimental model in healthy
   volunteers, it may have implications for clinical care and research.
   Until now it has been understoodthat aggregate placebo responses in
   RCTs and experiments are variable [50]. Our study may suggest a new
   dimension of variability in placebo effects: responses may differ
   within individual subjects according to route of administration (pills
   vs. sham acupuncture) as well as environmental cues and learning
   processes (e.g., verbal suggestion and conditioning). This finding
   implies that placebo responses may not be dependent on stable
   individual traits but rather are more a characteristic of the state
   circumstances of individuals or combination of both trait and state.
   This result may help explain the difficulty of detecting reliable and
   consistent placebo responders [51]. Furthermore, the fact that people
   have unique responses to different routes of administration suggests
   that, for some, pills may work better than injections or vice versa.
   Moreover, the significant correlation between genuine and sham
   acupuncture on subjective outcomes suggests that elucidating whether
   acupuncture is more than a placebo effect will be difficult.

   The potential limitations of the study include the following: 1) the
   crossover design may have resulted in carryover effects and order
   effects from one study visit to the next. However, since the treatment
   sessions were separated by at least 3 days, we did not expect any
   residual effect of the previous treatment on the subsequent session.
   Additionally, each treatment session included pre-treatment
   measurements, which were used as covariates in our analysis. This
   should adjust for any residual effect from a previous treatment as well
   as other potential confounding factors, such as hyperalgesia due to
   repeated pain application; 2) The placebo effect of sham acupuncture
   was not statistically superior to no-treatment control. It is possible
   that had we had a larger placebo effect, we might have found a
   correlation between pill and sham device; 3) The study was performed on
   healthy subjects in a relatively small sample size and thus it is
   unclear whether or not similar results could be repeated in patient
   populations. These results warrant further investigation of this topic.

   In summary, in this crossover study, we found that individuals respond
   differently to different types of verbally suggested placebo treatments
   and cue conditioning. In addition, we found a significant association
   between genuine and sham acupuncture treatments, which implies that
   non-specific effects may significantly contribute to the analgesic
   effect observed in acupuncture analgesia.

Author Contributions

   Conceived and designed the experiments: JK TK IK RG JS. Performed the
   experiments: JK RS. Analyzed the data: BC IK MV AC. Wrote the paper: JK
   AC RS TK JS.

References

    1. 1. Shapiro AK, Shapiro E (1997) The Powerful Placebo: From Ancient
       Priest to Modern Physician. Baltimore: The Johns Hopkins University
       Press.
    2. 2. Kaptchuk TJ (2011) Placebo studies and ritual theory: a
       comparative analysis of Navajo, acupuncture and biomedical healing.
       Philos Trans R Soc Lond B Biol Sci 366: 1849–1858. doi:
       10.1098/rstb.2010.0385
          + View Article
          + PubMed/NCBI
          + Google Scholar
    3. 3. Brody H, Miller FG (2011) Lessons from recent research about the
       placebo effect – from art to science. Jama 306: 2612–2613. doi:
       10.1001/jama.2011.1850
          + View Article
          + PubMed/NCBI
          + Google Scholar
    4. 4. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010)
       Biological, clinical, and ethical advances of placebo effects.
       Lancet 375: 686–695. doi: 10.1016/S0140-6736(09)61706-2
          + View Article
          + PubMed/NCBI
          + Google Scholar
    5. 5. Kaptchuk TJ, Stason WB, Davis RB, Legedza AR, Schnyer RN, et al.
       (2006) Sham device v inert pill: randomised controlled trial of two
       placebo treatments. Bmj 332: 391–397. doi:
       10.1136/bmj.38726.603310.55
          + View Article
          + PubMed/NCBI
          + Google Scholar
    6. 6. Colloca L, Tinazzi M, Recchia S, Le Pera D, Fiaschi A, et al.
       (2008) Learning potentiates neurophysiological and behavioral
       placebo analgesic responses. Pain 139: 306–314. doi:
       10.1016/j.pain.2008.04.021
          + View Article
          + PubMed/NCBI
          + Google Scholar
    7. 7. Kaptchuk TJ (2002) Acupuncture: theory, efficacy, and practice.
       Ann Intern Med 136: 374–383. doi:
       10.7326/0003-4819-136-5-200203050-00010
          + View Article
          + PubMed/NCBI
          + Google Scholar
    8. 8. Linde K, Niemann K, Schneider A, Meissner K (2010) How large are
       the nonspecific effects of acupuncture? A meta-analysis of
       randomized controlled trials. BMC Med 8: 75. doi:
       10.1186/1741-7015-8-75
          + View Article
          + PubMed/NCBI
          + Google Scholar
    9. 9. Kaptchuk TJ, Goldman P, Stone DA, Stason WB (2000) Do medical
       devices have enhanced placebo effects? J Clin Epidemiol 53:
       786–792. doi: 10.1016/S0895-4356(00)00206-7
          + View Article
          + PubMed/NCBI
          + Google Scholar
   10. 10. Linde K, Niemann K, Meissner K (2010) Are sham acupuncture
       interventions more effective than (other) placebos? A re-analysis
       of data from the Cochrane review on placebo effects. Forsch
       Komplementmed 17: 259–264. doi: 10.1159/000320374
          + View Article
          + PubMed/NCBI
          + Google Scholar
   11. 11. Vickers AJ, Cronin AM, Maschino AC, Lewith G, Macpherson H, et
       al.. (2012) Acupuncture for Chronic Pain: Individual Patient Data
       Meta-analysis. Arch Intern Med: 1–10.
   12. 12. Kong J, Fufa DT, Gerber AJ, Rosman IS, Vangel MG, et al. (2005)
       Psychophysical outcomes from a randomized pilot study of manual,
       electro, and sham acupuncture treatment on experimentally induced
       thermal pain. J Pain 6: 55–64. doi: 10.1016/j.jpain.2004.10.005
          + View Article
          + PubMed/NCBI
          + Google Scholar
   13. 13. Gracely RH, McGrath PA, Dubner R (1978) Ratio scales of sensory
       and affective verbal pain descriptors. Pain 5: 5–18. doi:
       10.1016/0304-3959(78)90020-9
          + View Article
          + PubMed/NCBI
          + Google Scholar
   14. 14. Gracely RH, McGrath PA, Dubner R (1978) Validity and
       sensitivity of ratio scales of sensory and affective verbal pain
       descriptors: manipulation of affect by diazepam. Pain 5: 19–29.
       doi: 10.1016/0304-3959(78)90021-0
          + View Article
          + PubMed/NCBI
          + Google Scholar
   15. 15. Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, et al. (2006)
       Brain activity associated with expectancy-enhanced placebo
       analgesia as measured by functional magnetic resonance imaging. J
       Neurosci 26: 381–388. doi: 10.1523/JNEUROSCI.3556-05.2006
          + View Article
          + PubMed/NCBI
          + Google Scholar
   16. 16. Kong J, Kaptachuk TJ, Polich G, Kirsch IV, Angel M, et al..
       (2009) Expectancy and treatment interactions: A dissociation
       between acupuncture analgesia and expectancy evoked placebo
       analgesia. Neuroimage 45: 940–949 PMID: 19159691
   17. 17. Kong J, Kaptchuk TJ, Polich G, Kirsch I, Vangel M, et al..
       (2009) An fMRI study on the interaction and dissociation between
       expectation of pain relief and acupuncture treatment. Neuroimage
       47: 1066–1076 PMID: 19501656.
   18. 18. Geers AL, Helfer SG, Kosbab K, Weiland PE, Landry SJ (2005)
       Reconsidering the role of personality in placebo effects:
       dispositional optimism, situational expectations, and the placebo
       response. J Psychosom Res 58: 121–127. doi:
       10.1016/j.jpsychores.2004.08.011
          + View Article
          + PubMed/NCBI
          + Google Scholar
   19. 19. Geers AL, Wellman JA, Fowler SL, Helfer SG, France CR (2010)
       Dispositional optimism predicts placebo analgesia. J Pain 11:
       1165–1171. doi: 10.1016/j.jpain.2010.02.014
          + View Article
          + PubMed/NCBI
          + Google Scholar
   20. 20. Morton DL, Watson A, El-Deredy W, Jones AK (2009)
       Reproducibility of placebo analgesia: Effect of dispositional
       optimism. Pain 146: 194–198. doi: 10.1016/j.pain.2009.07.026
          + View Article
          + PubMed/NCBI
          + Google Scholar
   21. 21. Voudouris NJ, Peck CL, Coleman G (1990) The role of
       conditioning and verbal expectancy in the placebo response. Pain
       43: 121–128. doi: 10.1016/0304-3959(90)90057-K
          + View Article
          + PubMed/NCBI
          + Google Scholar
   22. 22. Montgomery GH, Kirsch I (1997) Classical conditioning and the
       placebo effect. Pain 72: 107–113. doi:
       10.1016/S0304-3959(97)00016-X
          + View Article
          + PubMed/NCBI
          + Google Scholar
   23. 23. Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, et al.
       (1999) An analysis of factors that contribute to the magnitude of
       placebo analgesia in an experimental paradigm. Pain 83: 147–156.
       doi: 10.1016/S0304-3959(99)00081-0
          + View Article
          + PubMed/NCBI
          + Google Scholar
   24. 24. De Pascalis V, Chiaradia C, Carotenuto E (2002) The
       contribution of suggestibility and expectation to placebo analgesia
       phenomenon in an experimental setting. Pain 96: 393–402. doi:
       10.1016/S0304-3959(01)00485-7
          + View Article
          + PubMed/NCBI
          + Google Scholar
   25. 25. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, et al.
       (2004) Placebo-induced changes in FMRI in the anticipation and
       experience of pain. Science 303: 1162–1167. doi:
       10.1126/science.1093065
          + View Article
          + PubMed/NCBI
          + Google Scholar
   26. 26. Kong J, Gollub RL, Polich G, Kirsch I, Laviolette P, et al..
       (2008) A functional magnetic resonance imaging study on the neural
       mechanisms of hyperalgesic nocebo effect. J Neurosci 28:
       13354–13362 PMCID: PMC2649754.
   27. 27. Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C (2006)
       Mechanisms of placebo analgesia: rACC recruitment of a subcortical
       antinociceptive network. Pain 120: 8–15. doi:
       10.1016/j.pain.2005.08.027
          + View Article
          + PubMed/NCBI
          + Google Scholar
   28. 28. Bingel U, Wanigasekera V, Wiech K, Mhuircheartaigh RN, Lee MC,
       et al. (2011) The effect of treatment expectation on drug efficacy:
       Imaging the analgesic benefit of the opioid remifentanil. Sci
       Transl Med 3: 70ra14. doi: 10.1126/scitranslmed.3001244
          + View Article
          + PubMed/NCBI
          + Google Scholar
   29. 29. Kleinhenz J, Streitberger K, Windeler J, Gussbacher A, Mavridis
       G, et al. (1999) Randomised clinical trial comparing the effects of
       acupuncture and a newly designed placebo needle in rotator cuff
       tendinitis. Pain 83: 235–241. doi: 10.1016/S0304-3959(99)00107-4
          + View Article
          + PubMed/NCBI
          + Google Scholar
   30. 30. Streitberger K, Kleinhenz J (1998) Introducing a placebo needle
       into acupuncture research. Lancet 352: 364–365. doi:
       10.1016/S0140-6736(97)10471-8
          + View Article
          + PubMed/NCBI
          + Google Scholar
   31. 31. White P, Lewith G, Hopwood V, Prescott P (2003) The placebo
       needle, is it a valid and convincing placebo for use in acupuncture
       trials? A randomised, single-blind, cross-over pilot trial. Pain
       106: 401–409. doi: 10.1016/j.pain.2003.08.013
          + View Article
          + PubMed/NCBI
          + Google Scholar
   32. 32. Wasan AD, Kong J, Pham LD, Kaptchuk TJ, Edwards R, et al.
       (2010) The Impact of Placebo, Psychopathology, and Expectations on
       the Response to Acupuncture Needling in Patients With Chronic Low
       Back Pain. J Pain 11: 555–563. doi: 10.1016/j.jpain.2009.09.013
          + View Article
          + PubMed/NCBI
          + Google Scholar
   33. 33. Cheng XN (1987) Chinese acupuncture and moxibustion. Beijing:
       Foreign Language Press. 513–523 p.
   34. 34. Stux G (1997) Channels, Organs, and Points. In: Stux G,
       Pomeranz B, editors. Basics of Acupuncture. Berlin:
       Springer-Verlag. 110.
   35. 35. Kong J, Gollub R, Huang T, Polich G, Napadow V, et al. (2007)
       Acupuncture de qi, from qualitative history to quantitative
       measurement. J Altern Complement Med 13: 1059–1070. doi:
       10.1089/acm.2007.0524
          + View Article
          + PubMed/NCBI
          + Google Scholar
   36. 36. Kong J, Jensen K, Loiotile R, Cheetham A, Wey HY, et al. (2013)
       Functional connectivity of frontoparietal network predicts
       cognitive modulation of pain. Pain 154: 459–467. doi:
       10.1016/j.pain.2012.12.004
          + View Article
          + PubMed/NCBI
          + Google Scholar
   37. 37. Conover WJ, Iman RL (1982) Analysis of covariance using the
       rank transformation. Biometrics 38: 715–724. doi: 10.2307/2530051
          + View Article
          + PubMed/NCBI
          + Google Scholar
   38. 38. Huber P (1973) Robust Regression: Asymptotics, Conjectures and
       Monte Carlo. Ann Statist 1: 799–821. doi: 10.1214/aos/1176342503
          + View Article
          + PubMed/NCBI
          + Google Scholar
   39. 39. Passarelli EW, Traut EF (1956) Study in the controlled therapy
       of degenerative arthritis. AMA Arch Intern Med 98: 181–186. doi:
       10.1001/archinte.1956.00250260055007
          + View Article
          + PubMed/NCBI
          + Google Scholar
   40. 40. Traut EF, Passarelli EW (1957) Placebos in the treatment of
       rheumatoid arthritis and other rheumatic conditions. Ann Rheum Dis
       16: 18–22. doi: 10.1136/ard.16.1.18
          + View Article
          + PubMed/NCBI
          + Google Scholar
   41. 41. Grenfell RF, Briggs AH, Holland WC (1961) A double-blind study
       of the treatment of hypertension. Jama 176: 124–128. doi:
       10.1001/jama.1961.03040150040010
          + View Article
          + PubMed/NCBI
          + Google Scholar
   42. 42. Goldman AR, Witton K, Scherer JM (1965) The Drug-Giving Ritual,
       Verbal Instructions and Schizophrenics Ward Activity Levels. J Nerv
       Ment Dis 140: 272–279. doi: 10.1097/00005053-196504000-00003
          + View Article
          + PubMed/NCBI
          + Google Scholar
   43. 43. de Craen AJ, Tijssen JG, de Gans J, Kleijnen J (2000) Placebo
       effect in the acute treatment of migraine: subcutaneous placebos
       are better than oral placebos. J Neurol 247: 183–188. doi:
       10.1007/s004150050560
          + View Article
          + PubMed/NCBI
          + Google Scholar
   44. 44. Hrobjartsson A, Gotzsche PC (2010) Placebo interventions for
       all clinical conditions. Cochrane Database Syst Rev: CD003974.
   45. 45. Whalley B, Hyland ME, Kirsch I (2008) Consistency of the
       placebo effect. J Psychosom Res 64: 537–541. doi:
       10.1016/j.jpsychores.2007.11.007
          + View Article
          + PubMed/NCBI
          + Google Scholar
   46. 46. Roberts AH, Kewman DG, Mercier L, Hovell M (1993) The power of
       nonspecific effects in healing implication for psychosocial and
       bioligical treatments. Clin psycho rev 13: 375–391. doi:
       10.1016/0272-7358(93)90010-j
          + View Article
          + PubMed/NCBI
          + Google Scholar
   47. 47. Charron J, Rainville P, Marchand S (2006) Direct comparison of
       placebo effects on clinical and experimental pain. Clin J Pain 22:
       204–211. doi: 10.1097/01.ajp.0000161526.25374.e5
          + View Article
          + PubMed/NCBI
          + Google Scholar
   48. 48. Gracely RH (1994) Studies of pain in normal man. In: Wall PD,
       Melzack R, editors. Textbook of Pain. 3rd ed. Edinbourgh: Churchill
       Livingstone. 315–336.
   49. 49. Gelfand S (1964) The Relationship of Experimental Pain
       Tolerance to Pain Threshold. Can J Psychol 18: 36–42. doi:
       10.1037/h0083283
          + View Article
          + PubMed/NCBI
          + Google Scholar
   50. 50. Hrobjartsson A, Gotzsche PC (2001) Is the placebo powerless? An
       analysis of clinical trials comparing placebo with no treatment. N
       Engl J Med 344: 1594–1602. doi: 10.1056/NEJM200105243442106
          + View Article
          + PubMed/NCBI
          + Google Scholar
   51. 51. Kaptchuk TJ, Kelley JM, Deykin A, Wayne PM, Lasagna LC, et al.
       (2008) Do “placebo responders” exist? Contemp Clin Trials 29:
       587–595. doi: 10.1016/j.cct.2008.02.002
          + View Article
          + PubMed/NCBI
          + Google Scholar

   Download PDF

     * Citation
     * XML

   Print
     * Print article
     * EzReprint

   Share
     * Reddit Reddit
     * Google+ Google+
     * StumbleUpon StumbleUpon
     * Facebook Facebook
     * Mendeley LinkedIn
     * CiteULike CiteULike
     * Mendeley Mendeley
     * PubChase PubChase

     Twitter Twitter

     Email Email

Subject Areas

   info
   [button_info.png]

   We want your feedback. Do these subject areas make sense for this
   article? If not, click the flag next to the incorrect subject area and
   we will review it. Thanks for your help!
     * Acupuncture
     * Analgesia
     * Analgesics
     * Behavioral conditioning
     * Conditioned response
     * Instrument calibration
     * Pain sensation
     * Sensory perception

   Advertisement

   IFRAME: a0852f54

Comments

   Media coverage of this article
   Posted by PLoS_ONE_Group

   PLOS Logo

   Ambra 2.9.2 Managed Colocation provided
   by Internet Systems Consortium.

   Privacy Policy | Terms of Use | Advertise | Media Inquiries

   Publications
     * PLOS Biology
     * PLOS Medicine
     * PLOS Computational Biology
     * PLOS Currents
     * PLOS Genetics
     * PLOS Pathogens
     * PLOS ONE
     * PLOS Neglected Tropical Diseases

   plos.org

   Blogs

   Collections

   Send us feedback