Group Title: BMC Musculoskeletal Disorders
Title: The Influence of expectation on spinal manipulation induced hypoalgesia : An experimental study in normal subjects
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Title: The Influence of expectation on spinal manipulation induced hypoalgesia : An experimental study in normal subjects
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Language: English
Creator: Bialosky, Joel
Bishop, Mark
Robinson, Michael
Barabas, Josh
George, Steven
Publisher: BMC Musculoskeletal Disorders
Publication Date: 2008
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Abstract: BACKGROUND:The mechanisms thorough which spinal manipulative therapy (SMT) exerts clinical effects are not established. A prior study has suggested a dorsal horn modulated effect; however, the role of subject expectation was not considered. The purpose of the current study was to determine the effect of subject expectation on hypoalgesia associated with SMT.METHODS:Sixty healthy subjects agreed to participate and underwent quantitative sensory testing (QST) to their leg and low back. Next, participants were randomly assigned to receive a positive, negative, or neutral expectation instructional set regarding the effects of a specific SMT technique on pain perception. Following the instructional set, all subjects received SMT and underwent repeat QST.RESULTS:No interaction (p = 0.38) between group assignment and pain response was present in the lower extremity following SMT; however, a main effect (p < 0.01) for hypoalgesia was present. A significant interaction was present between change in pain perception and group assignment in the low back (p = 0.01) with participants receiving a negative expectation instructional set demonstrating significant hyperalgesia (p < 0.01).CONCLUSION:The current study replicates prior findings of c- fiber mediated hypoalgesia in the lower extremity following SMT and this occurred regardless of expectation. A significant increase in pain perception occurred following SMT in the low back of participants receiving negative expectation suggesting a potential influence of expectation on SMT induced hypoalgesia in the body area to which the expectation is directed.
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Research article

The influence of expectation on spinal manipulation induced
hypoalgesia: An experimental study in normal subjects
Joel E Bialosky*I, Mark D Bishop', Michael E Robinson2, Josh A Barabas'
and Steven Z George*I


Address: 'University of Florida Department of Physical Therapy, Gainesville, Florida, USA and 2University of Florida Department of Clinical and
Health Psychology, Gainesville, Florida, USA
Email: Joel E Bialosky* bialosky@phhp.ufl.edu; Mark D Bishop bish@phhp.ufl.edu; Michael E Robinson merobin@ufl.edu;
Josh A Barabas barabas@phhp.ufl.edu; Steven Z George* sgeorge@phhp.ufl.edu
* Corresponding authors


Published: I I February 2008
BMC Musculoskeletal Disorders 2008, 9:19 doi: 10.1 186/1471-2474-9-19


Received: 3 October 2007
Accepted: I I February 2008


This article is available from: http://www.biomedcentral.com/1471-2474/9/19
2008 Bialosky et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.ore/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: The mechanisms thorough which spinal manipulative therapy (SMT) exerts clinical
effects are not established. A prior study has suggested a dorsal horn modulated effect; however,
the role of subject expectation was not considered. The purpose of the current study was to
determine the effect of subject expectation on hypoalgesia associated with SMT.
Methods: Sixty healthy subjects agreed to participate and underwent quantitative sensory testing
(QST) to their leg and low back. Next, participants were randomly assigned to receive a positive,
negative, or neutral expectation instructional set regarding the effects of a specific SMT technique
on pain perception. Following the instructional set, all subjects received SMT and underwent repeat
QST.
Results: No interaction (p = 0.38) between group assignment and pain response was present in
the lower extremity following SMT; however, a main effect (p < 0.01) for hypoalgesia was present.
A significant interaction was present between change in pain perception and group assignment in
the low back (p = 0.01) with participants receiving a negative expectation instructional set
demonstrating significant hyperalgesia (p < 0.01).
Conclusion: The current study replicates prior findings of c- fiber mediated hypoalgesia in the
lower extremity following SMT and this occurred regardless of expectation. A significant increase
in pain perception occurred following SMT in the low back of participants receiving negative
expectation suggesting a potential influence of expectation on SMT induced hypoalgesia in the body
area to which the expectation is directed.


Background
A growing body of evidence supports spinal manipulative
therapy (SMT) as an effective treatment for low back pain
[1-6]. Furthermore, the evidence is particularly strong
when patients are classified into subgroups by patterns


suggesting the likelihood of a favorable response [2,3,6].
Despite the positive findings of clinical trials, the mecha-
nisms through which SMT acts are not established.


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Hypoalgesia has been associated with SMT and has a pos-
tulated involvement in the clinical effectiveness [7-16].
For example, Vicenzino et al [14] observed greater pain
free grip and pain pressure threshold in the forearm fol-
lowing SMT to the cervical spine. A prior study by our
group found hypoalgesia of c- fiber mediated pain as
measured by lessening of temporal summation in the
lower extremity following SMT to the lumbar spine [7].
Temporal summation results from multiple painful stim-
uli of the same intensity applied at a frequency of less than
3 seconds and has been observed in both healthy subjects
[17-19] and those experiencing chronic pain [20,21]. Acti-
vation of the dorsal horn of the spinal cord has been
directly observed with temporal summation in animal
studies [22-25]. Subsequently, we interpreted our prior
findings of hypoalgesia of temporal summation following
SMT in healthy participants as indicative of a pain inhib-
iting effect occurring at the dorsal horn.

A criticism of prior studies of SMT is a lack of considera-
tion for the influence of non- specific effects such as pla-
cebo and expectation [26-28]. The failure to account for
non- specific effects may be significant as expectation has
demonstrated a robust influence in the general pain liter-
ature [29-40]. Specific to manual therapy, Kalauokalani et
al [39] report on a secondary analysis of subjects with low
back pain who were randomly assigned to receive either
acupuncture or massage treatments. Subjects with higher
expectations for the effectiveness of their assigned treat-
ments demonstrated greater improvement in function. In
our prior study, we attributed hypoalgesia of c- fiber medi-
ated pain in response to SMT to a local spinal cord effect.
However, a limitation of our prior study was the failure to
account for the potential influence of non- specific effects.
Therefore, the purpose of this study was to determine how
subjects' expectation about the effect of SMT would influ-
ence hypoalgesia. Similar to prior studies [7-15], we
expected a hypoalgesic effect in response to SMT, however
we hypothesized this effect would be greater in subjects
receiving positive expectation regarding the SMT proce-
dure as compared to those receiving neutral or negative
expectation.

Methods
Subjects
The University Institutional Review Board approved the
current study. Subjects were recruited from the University
Health Science Center community by flyer and word of
mouth. Potential participants were made aware of the
methodology of the study and screened for appropriate-
ness by a study representative. Subjects wishing to partici-
pate then signed an informed consent form. Inclusion
criterion was ages eighteen to sixty and exclusion criteria
were non-English speaking, systemic medical conditions
(e.g. diabetes, hypertension), current use of psychiatric


medication, pregnancy, regular use of prescription medi-
cation for management of pain, presently experiencing
low back pain, or history of surgery to the low back. We
elected to limit the current study to pain free participants
for several reasons. First, we were primarily interested in
the effect of SMT on a pain protocol known to produce
temporal summation. While not as robust as observed in
pain conditions [20,21,41], temporal summation is
observed in healthy subjects [17,19,42]. Second, we were
attempting to both replicate the findings of our prior
study in which we used pain free participants [7] and to
observe the effect of expectation on those findings. Third,
use of healthy subjects eliminated confounding of the
hypoalgesic response from clinical pain conditions and
pain medications.

Procedures
Demographic information, psychological questionnaires,
baseline expectation for pain, and thermal pain sensitivity
measures were collected prior to random assignment of
the studied intervention.

Thermal Pain Sensitivity
Quantitative sensory testing (QST) was performed using
the Medoc Neurosensory Analyzer (TSA- 2001, Ramat
Yishai, Israel) with hand- held peltier- element- based
stimulator. Participants first underwent a practice session
in order to familiarize themselves with the pain testing
protocol. Participants then underwent the full QST fol-
lowing a previously established protocol to measure c-
fiber mediated pain [43,44]. Briefly, c-fiber mediated pain
was assessed on the plantar surface of the non- dominant
foot using a train of ten consecutive heat pulses of less
than one second duration at an inter- stimulus frequently
of .33 Hz (temporal summation). The baseline tempera-
ture of each pulse was 35 C and temperature peaked at
51 C. Subjects were asked to rate their delayed (second)
pain using a NRS. We used the same protocol to assess
pain perception in the low back with the stimulator
placed above the posterior superior iliac spine on the non-
dominant side; however, in a previous pilot study, we
found that subjects were unable to differentiate A6 and c-
fiber mediated pain in the low back [7]. Subsequently,
while allowing inferences regarding pain perception fol-
lowing SMT, we are unable to attribute the findings in the
low back specifically to c- fiber mediated pain. We chose
to investigate both the lower extremity and the low back
in this study due to prior studies having noted a region
specific influence of non- specific effects. For example, a
placebo provided with expectation of relieving experi-
mental pain in the hand has been found to exert an effect
localized to that hand, without change in pain perception
in the other hand or either foot [45]. Our instructional set
and the SMT used in this study were specific to the low
back. We felt the region specific nature of the instructional


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set and the SMT technique might localize the influence of
non- specific effects associated with SMT to the low back.
Including both anatomical areas in our QST protocol
allowed us to test the specificity of our instruction set in
our data analysis.

Expectation Intervention
Immediately following the practice session, participants
were asked to quantify the amount of pain they expected
to feel during the QST in both their back and lower
extremity using separate numeric rating scales (NRS).
These ratings served as the baseline expectation for pain.
Following initial QST, participants were randomly
assigned to receive a positive, a negative, or a neutral
expectation instructional set.

Participants in the positive expectation group were told
the SMT; "is a very effective form of manipulation used to treat
low back pain and we expect it to reduce your perception of heat
pain."

Participants in the negative expectation group were told
the SMT; "is an ineffective form of manipulation used to treat
low back pain and we expect it to temporarily worsen your per-
ception of heat pain."

Participants in the neutral expectation group were told the
SMT; "is a form of manipulation used to treat low back pain
that has unknown effects on perception of heat pain."

Additional interactions with study personnel and partici-
pants were minimized in order to avoid bias.

After receiving the expectation instructional set, partici-
pants were asked to quantify the amount of pain they
expected to feel with the QST following SMT. Specifically,
subjects were asked to rate the amount of pain they
expected to feel in their low back, and leg respectively uti-
lizing separate NRSs. We expected subjects receiving a
negative expectation instructional set to have lower base-
line NRS of pain expectations than the NRS of pain expec-
tation obtained following the instructional set.
Conversely, we expected subjects receiving a positive
expectation instructional set to have higher baseline NRS
of pain expectation than the NRS of pain expectation
obtained following the instructional set. Subjects then
received SMT to their low back.

SMT intervention
The SMT technique was used in our prior study [7] and
has been shown to be effective in the treatment of low
back pain in subjects meeting a clinical prediction rule
[2,6]. We wished to minimize any expectation of SMT
resulting from the wording of the consent form. Subjects
were shown a picture of the technique and received the


following written instruction, "You will lie on your back
and the researcher will place you in a standard position
that involves twisting. Then, a gentle force will be applied
to your lumbar spine by pushing on your pelvis." Similar
to the protocols used in prior studies, we performed the
technique two times on each side. Similar to our prior
study, this was done to all subjects regardless of whether a
cavitation was experienced during the procedure. Imme-
diately following the SMT, the same quantitative sensory
testing protocol was performed.

Measures
Numeric Rating Scale (NRS)
NRSs were used as a measure of expected and perceived
pain. Participants were asked to quantify their experi-
enced and expected pain using a numeric rating scale
anchored by "0" (no pain at all) and "100" (worst imagi-
nable pain). The NRS is frequently used as a measure of
both clinical and experimental pain and has demon-
strated sound psychometric properties in previous studies
[46-49].

Psychological Questionnaires
Psychological questionnaires with known influences on
experimental pain [50-53] were chosen and used to eval-
uate for post-randomization differences that could affect
reporting of experimental pain sensitivity.

Pain Catastrophizing Scale (PCS)
The PCS consists of 13 items specific to individual coping
styles with pain which are each quantified with a five
point ordinal scale. Higher scores indicate greater levels of
catastrophizing. The score may be taken as a whole or as
individual factors of rumination, helplessness, and mag-
nification. Prior studies have validated the factor structure
and found good internal consistency reliability and valid-
ity of the PCS [54-57].

Fear of Pain Questionnaire-Ill (FPQ-1l1)
The FPQ-III [58] consists of 30 items, each scored on a 5-
point adjectival scale, which measures fear of normally
painful situations. Higher scores indicate greater pain
related fear. The FPQ has demonstrated sound psycho-
metric properties in both experimental and clinical pain
studies [59-61].

Anxiety Visual Analog Scale (VAS)
Anxiety was measured through a 10 cm VAS. Subjects were
asked to indicate along the VAS anchored with none and
most severe anxiety imaginable the amount of anxiety
they were currently feeling regarding the experimental
pain task they were about to experience. VASs have been
used to measure anxiety in other studies and have demon-
strated sound psychometric properties [62-65].



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Data analysis
Descriptive statistics were generated for continuous and
categorical measures. Univariate ANOVA was used to
assess post-randomization differences in continuous vari-
ables of demographic, psychological, and baseline ther-
mal testing measures. Chi- square analysis was used to
assess post-randomization differences in categorical
demographic variables.

Next, we analyzed the effect of our instructional set on
expectation for pain in response to QST following SMT
and whether this was influenced by body region. A 2 x 2
x 3 repeated measure ANOVA was used to investigate
whether change in pre- instructional set and post- instruc-
tional set NRS of expected pain differed by body region,
time, and group assignment. Pre and post instructional set
measures of expectation for both the low back and lower
extremity served as the within subject factors while group
assignment was the between subject factor. Post hoc test-
ing was performed as necessary by repeated measure
ANOVA models.

Finally, we analyzed the effect of SMT on pain perception
and whether this was influenced by instructional set or
body region. First, we sought to determine whether a dif-
ference existed by body region and time in response to


SMT between the different expectation groups. A 2 x 2 x 3
repeated measure ANOVA was used to investigate this
question with pre and post SMT pain measures in both the
back and the lower extremity as the within subject factors
and group assignment as the between subject factor. The
dependent variable in this model was response to the c-
fiber mediated pain protocol as our previous findings
found the effects of SMT to be specific to these fibers in the
lower extremity [7]. Post hoc testing was performed as
indicated by repeated measure ANOVA models.

Results
Sixty subjects responded to the recruiting efforts and agreed
to participate. No baseline differences were observed in
demographic findings, responses to psychological ques-
tionnaires, or baseline pain measures (Table 1).

Effect of instructional set on expected pain
Our original plan was to use pre and post instructional set
measures of expectation for pain associated with QST in
our analysis of the effect of the instructional set. Following
data collection, we were concerned that several factors
influenced the integrity of this plan. First, we recruited
pain-free subjects that were naive to the sensory testing
protocol that we used. Second, the participant's frames of
reference may have been different for the two expectation


Table I: Descriptive information for the sample


Positive


Sex: Male: 5
Female: 15
Age in years (sd) 22.95 (2.06)
Race: Caucasian: 18
African
American: I
Other: I
Education (years 16.20 (1.32)
(sd))
History of LBP: Yes: 5
No: 14
Missing: I
Pain Threshold
Temperature (sd) 42.42 (5.25)
NRS Rating (sd) 13.89 ( 1.72)
Baseline Pain
Testing
Lower Extremity NRS 34.92 (23.24)
(sd)
Low Back NRS (sd) 46.22 (24.08)
Psychological
Questionnaires
PCS (sd) 15.15 (9.15)
FPQ (sd) 72.25 (13.47)
Anxiety VAS (sd) 23.20 (17.60)


Neutral

4
16
23.10 (3.49)
14

I
5
16.21 (1.51)


42.99 (2.89)
19.63 (20.33)


34.01 (28.1 1)

52.99 (27.05)


17.30 (9.53)
81.1 (19.43)
21.89 (23.96)


Negative

7
13
23.20 (3.66)
16

I
3
16.03 (1.26)


41.98 (3.12)
17.40 (18.16)


27.62 (20.93)

43.86 (26.18)


14.75 (8.43)
76.65 (14.81)
24.30 (19.76)


Total Sample


16
44
23.08 (3.10)
48

3
9
16.14 (1.35)


42.46 (3.86)
16.97 (17.01)


32.10 (24.02)

47.76 (25.64)


15.73 (8.96)
76.67 (16.24)
23.15 (20.21)


Sample demographic, baseline pain perception, and psychological characteristics. Variables were all obtained prior to randomization. Significance set
at p < 0.05. Temperature measures are in degrees Celsius. Pain ratings obtained through 0 to 100 numeric rating scale (NRS). PCS = Pain
Catastrophizing Scale. FPQ = Fear of Pain Questionnaire. VAS = Visual Analog Scale.


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NRSs. Specifically, the baseline NRS was obtained follow-
ing a brief practice session in which the participants expe-
rienced only four thermal stimuli to their lower extremity.
The post instructional set expectation NRS was obtained
following ten thermal stimuli to both the low back and
lower extremity. Our concern was that our practice session
was insufficient to allow a baseline rating of pain expecta-
tion for valid comparison to the rating provided following
the full QST protocol. We were particularly concerned that
the healthy sample in our study would not be adequately
able to determine expectation for transient, experimental
pain based upon limited exposure. Subsequently, we
chose to analyze the effectiveness of our instructional set
with pre- SMT average pain ratings of the ten c- fiber medi-
ated thermal stimuli protocol as our baseline rating for
comparison to the post instructional set expectation rating.
We think the average pain rating of baseline testing better
represents each participant's frame of reference for the
quantitative sensory testing. Consequently, the average
pain rating of the ten pre- SMT c- fiber mediated heat
impulses served as the first level within subject factor. The
post instructional set NRS in which participants were
asked to quantify the amount of pain they expected to
experience with quantitative sensory testing following the
SMT served as the second level within subject factor.
Group assignment served as the between subject factor.

A three way interaction was not present between expecta-
tion of pain by body area and group assignment (Wilks'
Lambda = 0.92, F(2,53) = 2.47, p = 0.09, partial r12 = 0.09).
A 2 x 3 ANOVA of change in expectation was significant for
an interaction in the low back (Wilks' Lambda = 0.85,
F(2,53) = 4.55, p = 0.02, partial 12= 0.15), indicating a differ-
ential effect of the instructional set for the low back. Post
hoc testing of the low back indicated a significant decrease
in expected pain in the positive expectation group (mean
difference +7.70, sd = 14.9, p = 0.03, effect size = 0.52), a
significant increase in expected pain in the negative expec-
tation group (mean difference -6.98, sd = 15.30, p = 0.05,
effect size = 0.46), and no change in the neutral expecta-
tion group (mean difference +2.18, sd = 14.91, p = 0.53,
effect size = 0.15). (Figure 1) A 2 x 3 ANOVA of change in
expectation was not significant for the lower extremity
(Wilks' Lambda = 0.95, F(2,53) = 1.42, p = 0.25, partial r12=
0.05), indicating a main effect of the instructional set for
the lower extremity. Pairwise comparison in the lower
extremity indicated a mean increase in expected pain of
12.01 (sd = 12.14, p < 0.01, effect size = 0.99).

Influence of SMT on pain perception in the lower extremity
and back by group assignment
A three way interaction existed suggesting change in pain
perception differed by body area and group assignment
(Wilks' Lambda = 0.88, F(2,53) = 3.80, p = 0.03, partial r2 =
0.13).


15






-5

-10
0

-15
Positive Expectation* Neutral Expectation Negative Expectation*

Figure I
Effect of Instructional Set on Expected Pain in the
Low Back. Change in expected pain in the low back follow-
ing instructional set. Positive values indicate expectation of
less pain. A statistical interaction occurred with participants
receiving a positive expectation instructional set reporting
expectations for less pain with quantitative sensory testing
(QST) following spinal manipulative therapy (SMT) and those
receiving a negative expectation instructional set reporting
expectations for greater pain. Error bars represent I stand-
ard error of the mean (SEM). indicates significant change at
p <: 0.05.



Influence of SMT on pain perception in the lower extremity
No interaction between instructional set and pain percep-
tion was noted in the lower extremity (Wilks' Lambda =
0.97, F (2,54) = 0.99, p = 0.38, partial r2 = 0.04) suggest-
ing the expectation instructional set did not influence SMT
associated hypoalgesia in the lower extremity. A significant
main effect (Wilks' Lambda = 0.85, F (1,54) = 9.22, p < 0.01,
partial r12 = 0.15) was found. Paired t- test determined a
mean difference of 4.83 (sd = 12.05) between pre and post
SMT pain ratings with post SMT rating being smaller indi-
cating hypoalgesia in the lower extremity after SMT. This
difference corresponded to a small effect size of 0.21.

Influence of SMT on pain perception in the low back by
group assignment
A significant interaction was present between change in
pain perception and group assignment in the low back
(Wilks' Lambda = 0.84, F(2,56) = 5.35, p = 0.01, partial r2 =
0.16) suggesting a response dependent upon group assign-
ment. Post hoc testing revealed no change in pain percep-
tion following SMT in participants receiving the positive
expectation instructional set (mean difference +1.66, sd =
13.10, p = 0.57, effect size = 0.13) and the neutral expecta-
tion instructional set (mean difference +4.17, sd = 13.10, p
= 0.16, effect size = 0.32). Subjects receiving the negative
expectation instructional set exhibited a significant
increase in pain perception of moderate magnitude fol-




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lowing the SMT (mean difference -8.81, sd = 13.42, p <
0.01, effect size = 0.66). (Figure 2)

Discussion
The current study suggests that hypoalgesia associated
with SMT may be influenced by expectation and that this
outcome varies by anatomical location in a way that is
consistent with the instructional set. Specifically, a
hypoalgesic effect was observed in the lower extremity
regardless of the provided expectation. Conversely, hyper-
algesia was present following SMT in the low back in sub-
jects provided with a negative expectation. This finding is
comparable to prior studies which have noted a region
specific effect of placebo [45].

A hypoalgesic response to c- fiber mediated pain in the
lower extremity of healthy subjects following SMT is con-
sistent with our prior work [7]. Furthermore, the current
study suggests that this finding is independent of expecta-
tion of pain relief in the low back. Hypoalgesia is sugges-
tive of a mechanism of action of SMT upon neural
plasticity. Central sensitization is characterized by percep-


O Low Back
O Lower Extremity


1 15
- 10
10
.2
g 5
0
w o
I -5
a-
o10
-15
5-


Y


Positive Neutral Negative
Expectation Expectation Expectation*


Figure 2
Change in Pain Perception in the Low Back and
Lower Extremity by Expectation Instructional Set.
Change in pain perception in the low back and lower
extremity following spinal manipulative therapy (SMT). Posi-
tive numbers indicate hypoalgesia, while negative numbers
indicate hyperalgesia. A significant interaction was present in
the low back suggesting that post SMT pain perception was
dependent upon the group to which the participant was ran-
domly assigned. Follow up pairwise comparison indicated a
significant increase in pain perception in subjects receiving a
negative expectation instructional set. No interaction was
observed in the lower extremity of participants; however, a
significant main effect occurred suggesting hypoalgesia
regardless of group assignment. Error bars represent I
standard error of the mean (SEM). indicates a statistically
significant change in pain perception in the low back following
SMT at p < 0.05.


tion of pain to previously non- painful stimuli (allodynia)
and perception of worsening pain to previously painful
stimuli (hyperalgesia). Moreover, central sensitization is
hypothesized to be instrumental in the progression of
acute to chronic pain and in the maintenance of chronic
pain conditions [66]. Subsequently, interventions which
inhibit central sensitization may be useful in the preven-
tion of chronic musculoskeletal pain. In fact, others have
theorized that the effects of SMT may be due to direct
mediation upon the neuroplastic changes which occur
with central sensitization [67]. Our repeated finding of c-
fiber mediated hypoalgesia in healthy participants suggests
that SMT may have a role in the reduction or prevention of
neuroplastic changes associated with central sensitization.

Pain perception in the low back following SMT was
dependent upon the provided expectation. Specifically,
subjects receiving a negative expectation instructional set
demonstrated a hyperalgesic response. A role for non- spe-
cific effects such as expectation in the outcomes associated
with SMT is suggested by this finding. This relationship
has not been studied extensively so we have little from the
literature with which to compare our findings. However,
similar to SMT, acupuncture is an alternative and comple-
mentary therapy often used for pain. Non- specific effects
have been studied more extensively in the acupuncture lit-
erature and this body of work may have applicability to
SMT. Functional imaging studies of acupuncture have
noted significant overlap in brain activity between actual
acupuncture and placebo acupuncture in which subjects
believe they are receiving real acupuncture [68]. In con-
trast, brain activity is dissimilar during placebo acupunc-
ture in which subjects do not believe they are receiving
actual treatment [68]. Furthermore, clinical outcomes in
acupuncture studies may depend upon the subject's expec-
tations [39,69]. For example, one study noted no differ-
ence between actual and placebo acupuncture in analgesic
effect; however, subjects who believed they had received
the actual acupuncture treatment experienced significantly
less pain than those believing they had received the pla-
cebo [69]. These studies underscore the significant influ-
ence of non- specific effects on clinical outcomes
following acupuncture and may have applicability to SMT.
Collectively, the findings of our study and the acupunc-
ture literature suggest further investigation into their role
in outcomes associated with SMT is warranted.

Limitations of the present study include the use of a
healthy sample and a single session of SMT. We do not
know individual expectations for pain relief when expec-
tation is not provided and expectation for pain relief from
SMT may be different in individuals who seek treatment
for musculoskeletal pain. Furthermore, the pre- existing
expectations of a sample experiencing clinical pain could
be quite different from a healthy sample exposed to tran-


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,I







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sient, experimental pain. Our decision to include a single
experimental session rather than multiple sessions is sim-
ilar to prior studies which have emphasized the immedi-
ate hypoalgesic effect of SMT [16], however we
acknowledge that the outcomes we observed may differ
over repeated sessions. Specifically, patient expectation
may change in response to treatment occurring over mul-
tiple sessions in the clinical settings, and our methodol-
ogy did not account for this type of scenario.

Although speculative, and despite these limitations, we
think the current study suggests expectation may have a
greater influence on pain outcomes in a clinical popula-
tion for several reasons. First, desire for pain relief has
been shown to have a significant effect on placebo analge-
sia [32,33]. Participants experiencing clinical pain may
have greater desire for pain relief with subsequent greater
expectations for the benefits of SMT. Our healthy sample
may have likely had lower desire for pain relief due to
their asymptomatic status and the transient nature of the
pain experienced for the purpose of this study. Second,
placebo has been shown to have an additive effect and
placebo analgesia strengthens with repetition [33]. Conse-
quently, we think that the finding of significant influences
of non- specific effects on the outcomes immediately asso-
ciated with one session of SMT in healthy participants is
suggestive of the potential for a much larger effect in indi-
viduals seeking treatment for musculoskeletal pain that
occurs over multiple sessions. Finally, placebo analgesia is
strengthened by expectation. In fact, the magnitude of the
placebo effect is heightened in experimental pain studies
if the painful stimulus is surreptitiously reduced immedi-
ately following the suggestion of pain relief [35]. The
influence of expectation on the outcomes associated with
SMT may strengthen over multiple sessions as immediate
hypoalgesia during an individual session may enhance
the effect of expectation over multiple sessions. Future
studies of non- specific effects of SMT may wish to account
for desire for pain relief and include multiple sessions in
order to observe immediate changes in pain perception
and their affect on subsequent sessions.

A further limitation of the current study is the lack of a
control group not receiving SMT. Such a study design
would allow the calculation of the magnitude of the effect
in comparison to natural history rather than to other
groups receiving SMT. However, we feel our study design
is sound for two reasons. First, we controlled for expecta-
tion by direct manipulation in both a positive and nega-
tive direction. Second, a true control group would be
difficult in this type of study, as participants would enter
with preconceived expectations. Subsequently, a study
design in which a control group was included would
require measurement of pre- existing expectation and
then controlling for these statistically. As a result, we do


not think that the lack of a control group invalidates the
findings of the present study.

Despite these limitations, we feel the current study pro-
vides preliminary support for the influence of non- spe-
cific effects on the outcomes associated with a single
session of SMT in normal subjects and that this finding is
worthy of further investigation over longer duration and
in clinical settings.

Conclusion
This study provides preliminary evidence for the influence
of a non- specific effect (expectation) on the hypoalgesia
associated with a single session of SMT in normal subjects.
We replicated our previous findings of hypoalgesia in the
lower extremity associated with SMT to the low back.
Additionally, the resultant hypoalgesia in the lower
extremity was independent of an expectation instructional
set directed at the low back. Conversely, participants
receiving a negative expectation instructional set demon-
strated hyperalgesia in the low back following SMT which
was not observed in those receiving a positive or neutral
instructional set.

Competing interests
The authors) declare that they have no competing inter-
ests.

Authors' contributions
All authors read, edited, and approved the final version of
the manuscript.

JEB was responsible for the initial conception of the
research question, supervising the protocol, data analysis,
and manuscript preparation. SZG was responsible for the
initial conception of the research question, modifying the
research question, supervising the protocol, securing
funding, and critically reviewing earlier versions of the
manuscript. MDB was responsible for the initial concep-
tion of the research question, modifying the research
question, and critically reviewing earlier versions of the
manuscript. MER was responsible for modifying the
research question and critically reviewing earlier versions
of the manuscript. JAB was responsible for administering
the protocol and critically reviewing earlier versions of the
manuscript.

Acknowledgements
The project was supported by Grant Number R-21 AT002796-01 from the
National Institutes of Health National Center for Complimentary and
Alternative Medicine (SZG, MDB, MER).

JEB received support from the National Institutes of Health T-32 Neural
Plasticity Research Training Fellowship (T32HD043730).

Valdora Martelli and Lauren Gates assisted with the data collection.


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