Placebo Analgesia persists PDF

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Titre: Conditioned Placebo Analgesia Persists When Subjects Know They Are Receiving a Placebo

Auteur: Scott M. Schafer

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The Journal of Pain, Vol 16, No 5 (May), 2015: pp 412-420
Available online at www.jpain.org and www.sciencedirect.com

Original Reports
Conditioned Placebo Analgesia Persists When Subjects Know
They Are Receiving a Placebo
Scott M. Schafer,* Luana Colloca,y and Tor D. Wager*
*Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
y
School of Nursing, Pain and Translational Symptom Science, University of Maryland Baltimore Center to Advance
Chronic Pain Research; and School of Medicine, Department of Anesthesiology, University of Maryland Baltimore,
Baltimore, Maryland.

Abstract: Belief in the effectiveness of a placebo treatment is widely thought to be critical for
placebo analgesia. Many types of placebo responses—even those that depend on conditioning—
appear to be mediated by expectations that are strengthened as treatment cues are reinforced
with positive outcomes. However, placebo effects may occur even when participants are aware
they are receiving a placebo. To address the question of whether conditioned placebo analgesia
can persist in the absence of expectations, we studied the effects of long (4 days) versus short
(1 day) conditioning to a placebo treatment. After an initial placebo test, a ‘‘reveal’’ manipulation
convincingly demonstrated to participants that they had never received an active drug. Placebo
analgesia persisted after the reveal in the long conditioning group only. These findings suggest
that reinforcing treatment cues with positive outcomes can create placebo effects that are
independent of reported expectations for pain relief.
Perspective: This article demonstrates a form of placebo analgesia that relies on prior conditioning
rather than current expected pain relief. This highlights the importance of prior experience on pain
relief and offers insight into the variability of placebo effects across individuals.
ª 2015 by the American Pain Society
Key words: Placebo, pain, conditioning, expectancy, reversal.

P

lacebo analgesia is pain relief observed following
administration of a treatment that is not directly
caused by pharmacological properties of that
treatment. Placebo analgesia is typically induced in the laboratory using a ‘‘response conditioning’’ paradigm, where
treatment cues (eg, a cream or injection) are paired with

Received September 18, 2014; Revised December 3, 2014; Accepted
December 29, 2014.
Research reported in this publication was supported by the National
Institute of Mental Health of the National Institutes of Health under
Award Number R01MH076136, by the National Institutes of Health under
Grant Number 5F31DA034516-03 and by the Intramural Program of the
National Institute of Mental Health under Grant Number Z99
AT999999. The content is solely the responsibility of the authors and
does not necessarily represent the official views of the National Institutes
of Health. The authors declare no conflicts of interest.
Supplementary data accompanying this article are available online at
www.jpain.org and www.sciencedirect.com.
Address reprint requests to Scott M. Schafer, MA, Department of
Psychology and Neuroscience, University of Colorado Boulder, 345 UCB,
Boulder, CO 80309-0345. E-mail: scott.schafer@colorado.edu
1526-5900/$36.00
ª 2015 by the American Pain Society
http://dx.doi.org/10.1016/j.jpain.2014.12.008

412

surreptitious reductions in the intensity of painful
stimuli.25,33 Afterward, painful stimuli are presented
under placebo (paired) and control (unpaired) conditions
to test for placebo effects. This procedure is a model
paradigm in the study of placebo analgesia and the
influence of expectations on pain and other affective,
perceptual, and physiological processes.24,31,35
Early studies concluded that the experience of pain relief was critical for reliably inducing placebo analgesia,33,34
but it is now generally understood that placebo
analgesia is directly mediated by expectations and
only indirectly relies on prior experiences.2,6,19,21,24
Manipulations of expectations produce pain relief,2,7
and greater expectancies are associated with greater
placebo analgesia.18,21,22,25,37 Even within conditioning
paradigms, expectancies appear to be critical: When
subjects attribute pain relief to sources other than a
placebo treatment, they do not acquire placebo
analgesia,21,38 and verbal suggestions of hyperalgesia
can block conditioned placebo analgesic effects.6,7,14

Schafer, Colloca, and Wager
These findings fit within a broader literature suggesting
that conditioning depends on the information value of
cues rather than associative pairing per se26 and may
reflect inferential rather that gradual learning processes.12
Expectancy theory implies that belief in the placebo is
critical for placebo analgesia. This expectation need not
be a belief in the chemical analgesic properties of the treatment but may instead be a more general belief that a
placebo treatment can relieve symptoms. This belief may
allow placebos to serve as either dose extenders for
chemically active treatments28,29 or effective treatments
on their own.17 However, expectancy theory is challenged
by demonstrations that placebo treatments can result in
analgesia even when participants are unaware they are
receiving a treatment.2,15 Other placebo manipulations
that generate expectancy-independent placebo effects
(eg, conditioned immunosuppression) generally use multiple conditioning sessions,1,6 and increasing the number of
conditioning sessions leads to placebo analgesia that is
both stronger and more resistant to extinction.10 A key
question is whether enhanced placebo analgesia following
multiple conditioning sessions also depends on expectancy.
If not, this suggests the existence of a class of placebo
analgesia that depends on conditioned associations3 and,
like conditioned immunosuppression, is independent of
expectations. These placebo effects should depend on
the duration of conditioning, be independent of reported
expectations, and persist when expectations are reversed.
In order to determine whether conditioned placebo
analgesia persists when subjects are made aware of a placebo treatment, pain response was tested both before and
after a complete and convincing disclosure of the placebo
manipulation (placebo reveal). To directly measure the
role of associative learning in ‘‘open-label’’ placebo effects, we varied the number of conditioning sessions and
tested whether postreveal placebo effects were greater
for participants who had experienced more conditioning
sessions. Critically, we measured expected pain relief
both before and after the placebo reveal, as nonconscious
cues may continue to elicit expectations for pain relief.15
We hypothesized that participants who experienced
more conditioning would engage mechanisms for
placebo analgesia that were independent of reported

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413

expectancies and would continue to show placebo analgesia even when aware that the treatment was a placebo.

Methods
Participants
Fifty-four participants (30 female, ages 18–55) were
recruited via online advertisements on a recruitment
website managed by the School of Medicine at the
University of Colorado Anschutz Medical Campus. Data
collection was planned to continue until 40 participants
met inclusion criteria and completed the study. Twelve
participants were excluded during an initial calibration
because they did not find the thermal stimuli sufficiently
painful (average pain rating below 30 on a 100-point
visual analog scale [VAS] for a 48 C stimulus), and 2
participants stopped participation midway through the
study because of discomfort from the heat. It was also
required that participants’ pain ratings increase with
higher stimulation temperatures during the initial
calibration (R2 > .40), but no participants were excluded
on the basis of low temperature discriminability. A total
of 40 participants were included in the final analysis, 20
in the long conditioning group (long; 13 female participants) and 20 in the short conditioning group (short;
14 female participants). All participants gave informed
consent to participate in a study of treatment effects
on pain relief and were fully debriefed at the conclusion
of the study. This study was approved by the University of
Colorado Boulder Institutional Review Board.

Materials and Procedures
Overview
Participants were informed that they were participating in a study to compare the analgesic effects of a
topical cream containing an active analgesic component
(placebo cream) to those of a topical cream containing
no active ingredients (control cream). Following the
initial calibration phase, subjects were randomized to
long or short conditioning groups and began the
conditioning phase of the study. Immediately following

Figure 1. Study design. (A) Participants in the long group had 4 sessions during the conditioning phase and participants in the short
group had a single session. (B) During the testing phase, the placebo reveal occurred after the first placebo run for half of all subjects
and after the second placebo run for the remaining subjects.

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the conditioning phase, placebo analgesia was
measured during the testing phase both before and
after subjects were told the treatment was a placebo
(placebo reveal) (Fig 1). Placebo analgesia was measured
as the difference in reported pain between placebo and
control stimulations at identical temperatures. All
thermal pain stimulations were delivered from a
16 16 mm thermode (Medoc, Ltd, Ramat Yishai, Israel)
and lasted for 20 seconds at peak temperature.32

Calibration Phase
During the initial calibration, participants received 16
thermal stimulations on their left forearm at 8 different
sites. Each site received 1 high-temperature stimulus
(45, 46, 47, or 48 C) and 1 low-temperature stimulus
(41, 42, 43, or 44 C). During stimulation, participants
were asked to continuously report how much pain they
were experiencing on a 100-point VAS, where 0 was
‘‘no pain experienced’’ and 100 was ‘‘the most pain
imaginable.’’ These continuous pain ratings were
averaged within each trial to create a single pain value
(equivalent to an area-under-the-curve measure up to
scaling) associated with each stimulation. The overall
ratings were regressed onto temperature, and the 4 sites
with the lowest residual errors were used for the
remainder of the experiment. The regression was used
to derive 6 temperatures for each participant to be
used in the remainder of the experiment: 2 low (ratings
from 10 to 20), 2 medium (ratings from 30 to 40), and 2
high (ratings from 50 to 60). This difference in pain level
between the low and high stimulations has been shown
to elicit strong placebo effects.24

Placebo Manipulation
Two creams were used in the study: a control cream
and a placebo cream. Both creams were an identical
petroleum-based jelly; the only difference between
them was the addition of blue food coloring to the
placebo cream. Participants were told that the placebo
cream contained an active analgesic and were instructed
on the nature of the analgesic, including its use,
warnings, and potential side effects. Following each
application of either cream, participants reported
whether they were experiencing any side effects
(eg, drowsiness, swelling, labored breathing) as a result
of the cream. During debriefing, all participants
indicated that they had believed that the placebo cream
contained an active analgesic prior to the experimenter’s
revealing otherwise.

Conditioning Phase
During conditioning, experience with the placebo
treatment was manipulated by adjusting how many
conditioning sessions each participant completed.
Subjects in the long group participated in 4 separate
conditioning sessions, whereas subjects in the short
group participated in only a single conditioning session.
Conditioning sessions given to participants in the long
group were each given on separate days, with a
maximum of 7 days of separation between sessions

(mean intervening time = 2.42 6 1.0 days). During each
conditioning session, placebo and control creams were
administered blockwise, with the order of the blocks
counterbalanced across participants such that half of
participants were first presented with control cream
blocks during conditioning (control first) whereas the
other half were first presented with placebo cream
blocks (placebo first), counterbalanced with conditioning group. Participants were fully aware of which cream
they had received at all times. Following each cream
application, participants rated their expectancies for
pain relief from that cream using a 0 to 100 VAS, where
0 was ‘‘no pain relief’’ and 100 was ‘‘the most pain relief
imaginable.’’ After a 5-minute waiting period, the cream
was cleaned off of the arm and the thermal stimulation
runs were initiated. Each run consisted of 2 stimulations
on each of 4 sites for a total of 8 trials per run. Placebo
stimulations used the 2 low temperatures, and control
stimulations used the 2 high temperatures. Conditioning
sessions on days 1 to 3 for the long group contained 2
runs within each cream block (16 trials total per cream).
However, on the final conditioning day (day 4 for long,
day 1 for short), there was only a single run of 8 stimulations in each cream block. This was designed to reduce
the likelihood of habituation during the subsequent
testing phase while still providing enough conditioning
to develop placebo analgesia in the short group.10

Testing Phase
The testing phase began 15 minutes after the end of
the conditioning phase and involved 5 runs of 8
medium-temperature stimulations each. The first and
last runs used the control cream (runs 1 and 5), whereas
the middle 3 runs used the placebo cream (runs 2–4).
Previously learned beliefs, such as those learned during
the conditioning phase, tend to persist even when
subjects are given subsequent information that those
beliefs may be inaccurate,27,30 so before each run,
participants were asked to rate how much pain relief
they expected from the cream using the same 0- to
100-point VAS discussed previously. Midway through
the placebo runs, the true nature of the treatment was
revealed, and subjects were informed that the placebo
treatment was not a pain-relieving cream. In order to
ensure that participants truly believed that both treatment creams were inert, the placebo reveal incorporated
both demonstration and verbal information, both of
which were designed to lead subjects to attribute their
previous pain relief to another source. Specifically,
participants were told that 1) both creams were identical
with the exception of blue food coloring, 2) the stimulation temperatures during conditioning had been
lowered for the placebo cream, and 3) neither cream
possessed active analgesic ingredients. Following the
reveal, a 15-minute waiting period was imposed before
resuming the experiment. During this time, the
experimenter demonstrated how the placebo cream
was made from the control cream to encourage belief
in the reveal. Control cream was removed from the
canister, mixed with blue food coloring, and then placed
into the placebo cream canister. All subjects reported

Schafer, Colloca, and Wager
being convinced by this demonstration during
debriefing. The placebo reveal and subsequent delay
occurred following either the first or second placebo
run (counterbalanced, overall testing run 2 or 3). There
was an additional 15-minute delay between the fourth
and fifth testing runs designed to reduce any potential
carryover analgesic effects from placebo to control
blocks (Fig 1B).
Although the manipulation of belief in the placebo
cannot be easily counterbalanced, several aspects of
this design mitigate the issue of convolving block order
with the reveal.2,16,23 Using the control cream during
the first and final blocks allows the test of whether
there is a habituation effect over the entirety of the
testing period. If there is no habituation effect, this
provides confidence that differences in pain reports
following the reveal are not due to simple habituation
mechanisms. Additionally, we controlled for any
extinction differences in placebo pain reports due to
simple repetition of thermal stimulations by adjusting
the timing of the reveal between participants. The
second placebo run occurs prereveal for half of the
participants and postreveal for the other half.
Comparing pain reports during the second placebo run
between subjects before and after the reveal allows
testing of whether the instructions were effective at
increasing placebo pain reports, controlling for the
total number of thermal stimulations.

Analysis
Differences in expected analgesia (Placebo Control)
were analyzed using a hierarchical mixed-effects
generalized linear model (GLM) over reveal state
(Prereveal Postreveal) and conditioning group (Long
Short). In addition to the hierarchical GLM, we
performed 2 planned, independent-samples t-tests. The
first was used to evaluate differences in prereveal
expected analgesia by conditioning group, and the
second was used to evaluate differences in postreveal
expected analgesia by conditioning group.
Placebo analgesia, calculated as (Placebo Control)
differences in pain, was analyzed using a mixed-effects
GLM: a 2-within (Placebo Control) (Postreveal
Prereveal) by 2-between (Long Short) (Control first
Placebo first) model, with temperature (2 mediumintensity values that varied by subject according to
their prior calibration) included as a covariate of
no interest. Planned contrasts included testing
placebo analgesia both prereveal and postreveal, the
interaction of analgesia with reveal state, and the
interaction of all of the above with conditioning group.
Given that these contrasts are not orthogonal to each
other, we ran 2 variants of the pain GLM. The first
variant was designed to implement a standard
analysis of variance design, estimating main effects for
each factor and all interactions between them. The
second variant was identical to the first, save that
prereveal and postreveal analgesia were estimated
separately in lieu of the (Placebo Control) main
effect and (Placebo Control) (Postreveal Prereveal)

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415

interaction, providing planned comparisons of placebo
effects prereveal and postreveal.
We also implemented tests in the hierarchical GLM for
short and long conditioning groups separately and
control first and placebo first groups separately.
Conditioning order effects (Control first Placebo first)
were not part of our planned contrasts and were
originally included in the model to control for order
effects. However, conditioning order was strongly
predictive of subsequent placebo analgesia, and so we
also report results from the (Placebo Control)
(Postreveal Prereveal) (Short vs Long conditioning)
model in the control first group, which showed the
strongest placebo analgesia.
We ran an additional mixed-effects GLM to test for
differences in placebo pain prereveal and postreveal,
controlling for the total number of stimulus
presentations. This model was a 3-between (Long
Short) (Control first Placebo first) (Postreveal
Prereveal) GLM. This model only used pain reports
collected from the third testing run, where half of the
participants were in the prereveal phase and the other
half were in the postreveal phase. The planned
contrasts for this model were whether placebo pain
was different prereveal compared to postreveal and
whether that difference varied by conditioning group
(Long Short). All mixed-effects models of pain were
fit using the lme4 package in R (R Foundation for
Statistical Computing, Vienna, Austria), allowing the
within-subject intercepts and slopes to vary as random
effects.4 When reporting statistics for mixed-effects
models, we report F statistics using the most
conservative estimates of degrees of freedom.
Finally, we tested whether placebo analgesia was
correlated with expected analgesia both prereveal and
postreveal and whether that correlation was different
between conditioning groups (long vs short).

Results
Habituation
During the testing phase, pain ratings for control
stimulations did not change following the placebo
reveal (F1,38 = .04, P = .84), and this effect was not
different between conditioning groups (F1,38 = .16,
P = .70). These results suggest an absence of overall
habituation or sensitization effects across time during
the testing phase.

Expectancy
VAS ratings of expected analgesia (Placebo Control)
were higher for the placebo cream compared to the
control cream prereveal (difference scores of
53.1 6 13.2 and 39.7 6 10.7 out of 100 points for long
and short groups, respectively) and were not different
between conditioning groups (t38 = 1.54, P = .13).
Differences in expected analgesia dropped 41 points on
average to near-zero levels (6.0 6 5.7 and 4.7 6 3.9 for
long and short groups, respectively) following the reveal
(F1,38 = 81.27, P < .001), and this decrease was not

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Conditioned Placebo Analgesia Persists

The Journal of Pain

(F1,36 = 4.07, P = .051). Overall, placebo analgesia
decreased marginally following the reveal (F1,36 = 3.69,
P = .063). This change was not different between
conditioning groups (F1,36 = .20, P = .66). Removing the
temperature covariate from the model had no effect
on the significance of these or other contrasts of placebo
analgesia, discussed below.

Placebo by Reveal State

Figure 2. Expectancy. Expected analgesia (Placebo Control)
significantly decreased following the reveal in both the long
and short conditioning groups, with no significant differences
between groups. The solid dark-gray and light-gray lines
represent the long and short groups, respectively. Data are
presented as means 6 standard errors of the mean.

significantly different between conditioning groups
(F1,38 = 1.79, P = .19). Postreveal expected analgesia was
not significantly different between conditioning groups
(t38 = .36, P = .72) (Fig 2). The reduction in expected
analgesia following the reveal was primarily driven by
changes in expectancy for the placebo cream
(F1,38 = 87.86, P < .001), with no significant changes in
expectancy for the control cream (F1,38 = .06, P = .81)
(Supplementary Fig 1).

Placebo Analgesia
The main effect of placebo analgesia (Placebo
Control) was significant (F1,36 = 5.30, P = .027) and
marginally greater within the long conditioning group

We found that the reveal resulted in increased pain
under placebo conditions by 1.9 points on average
(F1,36 = 11.30, P = .002). This increase was not significantly
different between long and short participants
(F1,36 = .05, P = .83).

Prereveal
Prereveal, placebo pain ratings were lower than
control pain ratings on average (F1,36 = 7.89, P = .008)
and were not significantly different between conditioning groups (F1,36 = 1.88, P = .18). However, prereveal
placebo analgesia was significant in the long group
(F1,36 = 8.74, P = .005) but not the short group
(F1,36 = 1.03, P = .32) (Figs 3A and 3B). A post hoc analysis
revealed that prereveal placebo analgesia was not
correlated with the time interval between conditioning
sessions in the long conditioning group (F1,35 = .03,
P = .88).

Postreveal
Postreveal, placebo analgesia was not significant on
average across both conditioning groups (F1,36 = .90,
P = .35). However, the long group demonstrated placebo
analgesia (F1,36 = 4.55, P = .040), and this analgesia was
significantly greater than that reported by the short

Figure 3. Placebo analgesia by conditioning group. (A) Average time course of prereveal placebo analgesia (Placebo Control)
during painful stimulation. Negative values indicate reduced pain with the placebo (analgesia), whereas positive values indicate
increased pain with the placebo (hyperalgesia). The solid dark-gray and light-gray lines represent the average of subjects within
the long and short conditioning groups, respectively. The dashed line shows the onset and termination of the painful stimulus and
the duration of peak temperature. (B) Mean prereveal placebo analgesia. Analgesia scores are generated by averaging over the
placebo effect (Placebo Control) time course for each subject. Long subjects had significant placebo analgesia prereveal, but short
subjects did not. Prereveal placebo analgesia was not different between groups. (C) Average time course of postreveal placebo
analgesia during painful stimulation. The lines are defined as in panel A. (D) Mean postreveal placebo analgesia. Long subjects
continued to demonstrate placebo analgesia postreveal and had significantly greater placebo analgesia than the short group. There
was no significant postreveal placebo effect in the short group. Error bars represent standard errors of the mean.

Schafer, Colloca, and Wager

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417

Conditioning Order

Figure 4. Placebo analgesia by expected analgesia. In both
conditioning groups, placebo analgesia (Placebo Control)
was not correlated with expected analgesia (Placebo Control)
either (A) prereveal or (B) postreveal. In both panels, the
dark-gray line represents the relationship between expected
and reported analgesia in the long group, with the dark-gray
circles representing individual subjects. Similarly, the light-gray
line represents the relationship between expected and reported
analgesia in the short group, with light-gray circles representing
individual subjects.
group (F1,36 = 4.27, P = .046), who did not have a
significant placebo response (F1,36 = .62, P = .44)
(Figs 3C and 3D). A post hoc analysis revealed that
postreveal placebo analgesia was not correlated with
the time interval between conditioning sessions in the
long conditioning group (F1,35 = .15, P = .70).

Placebo Analgesia by Expectancy
There was no relationship between expected analgesia
and placebo analgesia either prereveal (t38 = .14, P = .89)
or postreveal (t38 = .04, P = .96) (Fig 4).

Overall, subjects who were exposed to the control
cream (and high pain) before the placebo cream
(and low pain) during the initial conditioning sessions
(Control first Placebo first) demonstrated stronger
placebo effects than subjects with the reversed
conditioning order (F1,36 = 7.10, P = .011). This conditioning order effect was significantly greater prereveal
compared to postreveal (F1,36 = 4.78, P = .035).
Specifically, having a control first conditioning order
was associated with stronger prereveal placebo effects
on average (F1,36 = 10.44, P = .003) (Fig 5). Postreveal,
there was no effect of conditioning order on
placebo analgesia (F1,36 = 1.26, P = .27). These effects
were not different between conditioning groups either
prereveal (F1,36 = .50, P = .48) or postreveal (F1,36 < .01,
P = .96).
Subjects in the control first order demonstrated
significant prereveal placebo analgesia (F1,36 = 18.24,
P < .001) that did not vary by conditioning group
(F1,36 = 2.16, P = .15), whereas subjects in the placebo first
order had no prereveal placebo response (F1,36 = .09,
P = .77). Therefore, it was critical to conduct a secondary
post hoc test to examine how placebo analgesia changed
postreveal specifically among control first subjects.
Postreveal, within the control first order group, long
subjects continued to demonstrate placebo analgesia
(F1,36 = 4.19, P = .048), whereas short subjects did not
(F1,36 < .01, P = .98). There was no significant difference
between these groups (F1,36 = 2.04, P = .16). Within the
placebo first order, there was a nonsignificant trend of
postreveal hyperalgesia among the short conditioning
group (F1,36 = 1.30, P = .26) and no postreveal placebo
effect in the long subjects (F1,36 = .94, P = .34).

Figure 5. Placebo analgesia by conditioning order, conditioning group, and reveal state. (A) Average time course of prereveal

placebo analgesia (Placebo Control) during painful stimulation for subjects who received the control first order. Negative values
indicate reduced pain with the placebo (analgesia), whereas positive values indicate increased pain with the placebo (hyperalgesia).
The solid dark-gray and light-gray lines represent the average of subjects within the long and short conditioning groups, respectively.
The dashed line shows the onset and termination of the painful stimulus and the duration of peak temperature. On average, subjects
who received the control first order had significant placebo analgesia, and this effect was not significantly different between
conditioning groups (Long Short). (B) Average time course of postreveal placebo analgesia during painful stimulation for subjects
who received the control first order. The lines are defined as in panel A. Postreveal, long subjects, but not short subjects, who received
the control first order continued to demonstrate placebo analgesia. (C) Average time course of prereveal placebo analgesia during
painful stimulation for subjects who received the placebo first order. The lines are defined as in panel A. Prereveal, there was no
significant placebo effect for subjects who received the placebo first conditioning order. (D) Average time course of postreveal
placebo analgesia during painful stimulation for subjects who received the placebo first order. The lines are defined as in panel A.
Postreveal, placebo first subjects did not show significant analgesia or hyperalgesia on average.

418

The Journal of Pain

The effect of conditioning order on placebo analgesia
was not explainable in terms of habituation or other
adaptation effects as in previous studies,36 because
participants in both order conditions received the same
control–placebo–placebo–control sequence during the
test session. Similarly, expectancy (Placebo Control)
was not different based on conditioning order either
prereveal (t38 = 1.3, P = .20) or postreveal (t38 = 1.0,
P = .32) suggesting that the observed conditioning order
effects cannot be explained by differences in expected
analgesia.

Discussion
This study demonstrates that multiple sessions of
conditioning can lead to placebo analgesia that persists
even when the true nature of a placebo treatment is
convincingly revealed. Furthermore, there were no
detectable differences in postreveal expected analgesia
between the long and short groups, even though
postreveal placebo analgesia was significantly
greater in the long group. Together, these results
suggest that processes not explicitly associated with
reported expectancies can mediate conditioned placebo
analgesia.
These results parallel emerging evidence from other
studies demonstrating that placebo analgesia may occur
even when subjects know they have received a placebo.
In one study, placebo treatments reduced symptoms of
irritable bowel syndrome and measures of clinical
function even when participants were told the
medication was an inert placebo.17 In another case,
informing subjects that previous tests were performed
using a placebo did not inhibit subsequent placebo
analgesia when subjects were again told they were
receiving a real analgesic.8 However, in both of these
examples, subjects were encouraged to believe the
placebo to be effective by either imagining it to assist
their own healing processes or actually believing it to
be an active treatment. A critical difference between
the current study and previous studies is that in this
study, subjects knew the treatment was a placebo,
were explicitly told that it had no analgesic properties,
and were not led to expect relief from a placebo
treatment.
Other studies suggest that initial experiences create
persistent beliefs that are subsequently hard to
reverse,27,30 and such studies highlight the resistance of
placebo effects to potentially disconfirming information.
However, because most ‘‘open-label placebo’’ studies17
and studies demonstrating conditioned physiological
effects1,13 have not explicitly measured belief in the
placebo, these studies may demonstrate the persistence
of beliefs themselves. Our results provide new
information by demonstrating conditioned placebo
analgesia in response to a treatment that participants
believe to be ineffective.
The observed conditioning order effects are very
important with respect to future studies on conditioned
placebo analgesia, as the conditions under which
placebo effects are maximized are not well understood.

Conditioned Placebo Analgesia Persists
Previous work found that eliminating the association
between placebo cues and pain relief during the initial
conditioning session inhibited acquisition of the placebo
effect even when subsequent presentations of the
placebo cues were paired with pain relief.9 Here, we
found that even if the initial placebo cues are associated
with pain relief, subsequent placebo analgesia is
impaired if those cues are presented before receiving
the high pain stimulations experienced during control
blocks. In particular, subjects in the short conditioning
group who received the placebo first order appeared
to have a mild hyperalgesic response to the placebo.
Although not significant, this hyperalgesia likely
contributed to the finding that short subjects reported
less placebo analgesia than long subjects postreveal.
Critically, both long and short subjects in the control first
order reported analgesia prereveal, though only the
long subjects continued to experience analgesia
postreveal.
The mechanisms underlying the effect of conditioning
order on analgesia are unclear and deserve further
investigation at both the psychological and neural levels.
Acquisition of placebo analgesia may rely on a reduction
in stress that favors subsequent learning effects.20 The
feeling of relief when transitioning from the control
cream to the placebo cream could enhance placebo
analgesia,11 whereas the stress of transitioning from
the placebo cream condition to the more painful control
cream condition could inhibit acquisition of placebo
analgesia20 and even induce hyperalgesia.5 The reduced
placebo analgesia in the placebo first group may also
result from a relative judgment effect. Experiencing the
more painful control stimuli followed by less painful
placebo conditioning stimuli invites a relative
comparison that focuses on pain reduction with the
placebo, whereas beginning with the mildly painful
placebo stimulus instead highlights the painfulness of
the placebo stimulation absent the context of the more
painful control stimuli. Focus on the painfulness of the
placebo stimuli may inhibit acquisition of placebo
analgesia similar to when the pain is not reduced for
the placebo.9
There were several limitations to this study. Given that
participants had participated in all experimental sessions
with the same experimenter (S.M.S.), the experimenter
was never blinded to which conditioning group subjects
were in. This could be mitigated in the future by having a
separate experimenter conduct the conditioning portion
of the study. A second limitation is that there is no
titration of expectation in our manipulation as we
believed it was important for subjects to believe they
had received an analgesic during conditioning given
that certainty in a treatment typically leads to stronger
placebo analgesia than uncertainty.22 Future studies
could include subject groups who are told they ‘‘may
have’’ or ‘‘have not’’ received an analgesic during
conditioning sessions. There is some difficulty in
interpreting the relationship between expectancy and
analgesia postreveal, as expected analgesia was near
zero with little variance. Finally, subjects who received
the placebo first order did not acquire placebo analgesia

Schafer, Colloca, and Wager

The Journal of Pain

419

prereveal. Future studies aiming to condition placebo
analgesia should use a control first, as opposed to
placebo first, order.9
To our knowledge, this is the first study to
demonstrate reduced pain to a conditioned stimulus
in healthy subjects who are fully aware that they are
receiving an inert treatment without the use of any
pharmacologic agents. Here, we have demonstrated
that we can use different levels of conditioning to elicit
reliably different effects from an expectation reversal,
and demonstrate that conditioning can suppress the
effects of a reversal of beliefs even when no difference
in expectations is observed between conditioning
groups. This has several implications for medical
contexts. We speculate that some variant of the design
used in this study may be used to wean patients with
acute pain (eg, postoperative pain) off painkillers in a
way that could lower the potential for future addiction

by substituting a placebo for a chemically active treatment while simultaneously keeping pain reduced. We
suspect that the repeated administration of a (potentially nonopioid) analgesic2 combined with a subsequent enhancement of expected analgesia from a
placebo treatment17 would yield the strongest placebo
effects. In addition to differences in analgesia by conditioning group, differences by conditioning order may
explain why people experience either relief or symptom
worsening from a variety of medical treatments based
on differences in beliefs and prior learning, highlighting the importance of psychology in medicine.

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Supplementary Data
Supplementary data related to this article can be
found online at http://dx.doi.org/10.1016/j.jpain.2014.
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