Research

JAMA Psychiatry | Original Investigation

Effect of Pain Reprocessing Therapy vs Placebo

and Usual Care for Patients With Chronic Back Pain
A Randomized Clinical Trial
Yoni K. Ashar, PhD; Alan Gordon, LCSW; Howard Schubiner, MD; Christie Uipi, LCSW; Karen Knight, MD; Zachary Anderson, BS; Judith Carlisle, MA;
Laurie Polisky, BA; Stephan Geuter, PhD; Thomas F. Flood, MD, PhD; Philip A. Kragel, PhD; Sona Dimidjian, PhD; Mark A. Lumley, PhD; Tor D. Wager, PhD

Visual Abstract
IMPORTANCE Chronic back pain (CBP) is a leading cause of disability, and treatment is often Supplemental content
ineffective. Approximately 85% of cases are primary CBP, for which peripheral etiology
cannot be identified, and maintenance factors include fear, avoidance, and beliefs that pain
indicates injury.
OBJECTIVE To test whether a psychological treatment (pain reprocessing therapy [PRT])
aiming to shift patients’ beliefs about the causes and threat value of pain provides substantial
and durable pain relief from primary CBP and to investigate treatment mechanisms.
DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial with longitudinal
functional magnetic resonance imaging (fMRI) and 1-year follow-up assessment was
conducted in a university research setting from November 2017 to August 2018, with 1-year
follow-up completed by November 2019. Clinical and fMRI data were analyzed from January
2019 to August 2020. The study compared PRT with an open-label placebo treatment and
with usual care in a community sample.
INTERVENTIONS Participants randomized to PRT participated in 1 telehealth session with
a physician and 8 psychological treatment sessions over 4 weeks. Treatment aimed to help
patients reconceptualize their pain as due to nondangerous brain activity rather than peripheral
tissue injury, using a combination of cognitive, somatic, and exposure-based techniques.
Participants randomized to placebo received an open-label subcutaneous saline injection
in the back; participants randomized to usual care continued their routine, ongoing care.
MAIN OUTCOMES AND MEASURES One-week mean back pain intensity score (0 to 10) at
posttreatment, pain beliefs, and fMRI measures of evoked pain and resting connectivity.
RESULTS At baseline, 151 adults (54% female; mean [SD] age, 41.1 [15.6] years) reported mean
(SD) pain of low to moderate severity (mean [SD] pain intensity, 4.10 [1.26] of 10; mean [SD]
disability, 23.34 [10.12] of 100) and mean (SD) pain duration of 10.0 (8.9) years. Large group
differences in pain were observed at posttreatment, with a mean (SD) pain score of 1.18 (1.24)
in the PRT group, 2.84 (1.64) in the placebo group, and 3.13 (1.45) in the usual care group.
Hedges g was −1.14 for PRT vs placebo and −1.74 for PRT vs usual care (P < .001). Of 151 total
participants, 33 of 50 participants (66%) randomized to PRT were pain-free or nearly pain-free
at posttreatment (reporting a pain intensity score of 0 or 1 of 10), compared with 10 of 51
participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual
care. Treatment effects were maintained at 1-year follow-up, with a mean (SD) pain score of
1.51 (1.59) in the PRT group, 2.79 (1.78) in the placebo group, and 3.00 (1.77) in the usual care
group. Hedges g was −0.70 for PRT vs placebo (P = .001) and −1.05 for PRT vs usual care
(P < .001) at 1-year follow-up. Longitudinal fMRI showed (1) reduced responses to evoked
back pain in the anterior midcingulate and the anterior prefrontal cortex for PRT vs placebo;
(2) reduced responses in the anterior insula for PRT vs usual care; (3) increased resting Author Affiliations: Author
connectivity from the anterior prefrontal cortex and the anterior insula to the primary affiliations are listed at the end of this
article.
somatosensory cortex for PRT vs both control groups; and (4) increased connectivity from
the anterior midcingulate to the precuneus for PRT vs usual care. Corresponding Author: Tor D.
Wager, PhD, Department of
CONCLUSIONS AND RELEVANCE Psychological treatment centered on changing patients’ Psychological and Brain Sciences,
Dartmouth College, 352 Moore Hall,
beliefs about the causes and threat value of pain may provide substantial and durable pain
HB 6207, Hanover, New Hampshire
relief for people with CBP. 03755 (tor.d.wager@dartmouth.
edu); Yoni K. Ashar, PhD, Department
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03294148.
of Psychiatry, Weill Cornell Medical
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2021.2669 College, 1300 York Ave, New York, NY
Published online September 29, 2021. 10065 ([email protected]).

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 Research Original Investigation Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

C
hronic pain affects 20% of people in the US, with an
estimated annual cost of more than $600 billion.1,2 Key Points
The most common type is chronic back pain (CBP).
Question Can a psychological treatment based on the
In approximately 85% of cases, definitive peripheral causes of reappraisal of primary chronic back pain as due to nondangerous
CBP cannot be identified, and central nervous system pro- central nervous system processes provide substantial and
cesses are thought to maintain pain.3-7 For people with this durable pain relief?
type of CBP— often referred to as primary, nonspecific, noci-
Findings In this randomized clinical trial, 33 of 50 participants
plastic, or centralized pain—psychological and behavioral treat- (66%) randomized to 4 weeks of pain reprocessing therapy were
ments are recommended. 8-10 Although these treatments pain-free or nearly pain-free at posttreatment, compared with
can improve functioning, reductions in pain intensity are 10 of 51 participants (20%) randomized to placebo and 5 of 50
limited11,12 and better treatments are needed. participants (10%) randomized to usual care, with gains largely
Ad v a n c e s i n t h e n e u ro s c i e n c e o f p a i n 1 3 - 1 7 a n d maintained through 1-year follow-up. Treatment effects on pain
were mediated by reduced beliefs that pain indicates tissue
interoception18-21 suggest new directions for treatment devel-
damage, and longitudinal functional magnetic resonance imaging
opment. In constructionist and active inference models, pain showed reduced prefrontal responses to evoked back pain and
is a prediction about bodily harm, shaped by sensory input increased resting prefrontal-somatosensory connectivity in
and context-based predictions.18,19,22-26 Fearful appraisals patients randomized to treatment relative to patients randomized
of tissue damage can cause innocuous somatosensory input to placebo or usual care.
to be interpreted and experienced as painful.22,24,27,28 Such Meaning Psychological treatment focused on changing beliefs
constructed perceptions can become self-reinforcing: threat about the causes and threat value of primary chronic back pain
appraisals enhance pain, which is in turn threatening, creat- may provide substantial and durable pain relief.
ing positive feedback loops that maintain pain after initial
injuries have healed.27,29-31
As pain becomes chronic, it is increasingly associated point was complete. Participants aged 21 to 70 years with back
with activity in the affective and motivational systems tied pain for at least half the days of the last 6 months and 1-week
to avoidance and less closely tied to systems encoding noci- average pain intensity score of 4 of 10 or greater at screening
ceptive input.14,32-34 Accordingly, brain regions serving allo- were recruited from the community in Boulder, Colorado. We
stasis and predictive control18,23—including the default mode targeted primary CBP, excluding patients with leg pain worse
network, somatosensory and insular cortices, amygdala, than back pain (eMethods in Supplement 2). Power analysis
and nucleus accumbens—have been implicated in animal targeted 80% power (α = .05) to detect a medium effect
models13-17 and human studies of chronic pain22,25,32,33,35,36 (d = 0.62) on pain intensity at the primary end point (eMethods
and pain modulation.24,25,28,37-39 in Supplement 2). Participants provided written informed
We developed pain reprocessing therapy (PRT) based on consent as approved by the University of Colorado Institu-
this understanding of primary chronic pain. Leading psycho- tional Review Board. The study followed the Consolidated
logical interventions for pain typically present the causes of Standards of Reporting Trials (CONSORT) reporting guideline
pain as multifaceted and aim primarily to improve function- for social and psychological intervention trials.
ing and secondarily to reduce pain. PRT emphasizes that the Participants completed an eligibility and consent ses-
brain actively constructs primary chronic pain in the absence sion, followed by a baseline assessment session with fMRI.
of tissue damage and that reappraising the causes and threat They were subsequently randomized to PRT, placebo, or usual
value of pain can reduce or eliminate it. care with equal probability, balancing on age, sex, baseline pain,
In this study, we conducted the first test of PRT. In a and opioid use using an imbalance-minimization algorithm40
randomized clinical trial with 1-year follow-up, we compared (eMethods in Supplement 2). The primary end point (post-
PRT with both open-label placebo and usual care control treatment fMRI session) occurred 1 month after the baseline
conditions. We tested hypothesized mechanisms of PRT fMRI. Participants completed online follow-up assessments at
with mediation analyses and longitudinal functional mag- 1, 2, 3, 6, and 12 months after the primary end point (Figure 1).
netic resonance imaging (fMRI) during spontaneously occur-
ring and evoked back pain. fMRI provided objective correlates Interventions
of treatment effects and identified potential neurobiological PRT
treatment mechanisms. PRT seeks to promote patients’ reconceptualization of primary
(nociplastic) chronic pain as a brain-generated false alarm. PRT
shares some concepts and techniques with existing treatments
for pain41-48 and with the cognitive behavioral treatment of panic
Methods disorder.66
Participants and Trial Design Participants completed a 1-hour telehealth evaluation and
The trial was preregistered on ClinicalTrials.gov (Identifier: education session with a physician (H.S.) assessing likely cen-
NCT03294148) and conducted from August 2017 to Novem- tralized vs peripheral contributions to pain, including a re-
ber 2018, with 1-year follow-up completed by November 2019. view of available preexisting spinal imaging. Assessment find-
Clinical and fMRI data were analyzed from January 2019 to ings and centralized pain education were shared with the
August 2020, after data collection at each follow-up time- patient (eAppendix 1 in Supplement 2).

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 Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research

Figure 1. CONSORT Participant Flow Diagram

Online
1321 Assessed for eligibility

668 Did not meet inclusion criteria

192 Pain score <4 of 10
128 Other reasons
101 Leg pain > back pain
96 Pain < half the days in past 6 mo
88 Ineligible for MRI
25 Autoimmune conditions
19 History of metastatic cancer
19 Age out of range
435 Potentially eligible but did not respond

In person
218 Assessed for eligibility

66 Excluded
24 Pain score <4 of 10
24 Hypersensitive/hyposensitive to back bladder
9 Declined to participate
9 Ineligible for MRI

152 Completed pretreatment assessment

1 Excluded
No longer interested in participation

151 Randomized

50 PRT 51 Placebo 50 Usual care

45 Initiated treatment 4 Lost to follow-up
44 Completed treatment 3 Withdrew
1 Dropped out (medical 44 Received treatment
emergency)
5 Did not initiate treatment

44 Monitored at posttreatment 44 Monitored at posttreatment 47 Monitored at posttreatment

38 Monitored at 1 mo 44 Monitored at 1 mo 41 Monitored at 1 mo
37 Monitored at 2 mo 35 Monitored at 2 mo 38 Monitored at 2 mo
37 Monitored at 3 mo 38 Monitored at 3 mo 37 Monitored at 3 mo
41 Monitored at 6 mo 37 Monitored at 6 mo 38 Monitored at 6 mo
45 Monitored at 12 mo 43 Monitored at 12 mo 36 Monitored at 12 mo

All available data included in All available data included in All available data included in
analysis analysis analysis
MRI indicates magnetic resonance
imaging.

Participants then completed 8 individual 1-hour therapy Open-label Placebo Plus Usual Care
sessions with a therapist with extensive PRT experience Participants watched 2 videos describing how placebo treatments
(A.G. or C.U.) twice weekly for 4 weeks. Techniques can powerfully relieve pain even when known to be inert (eg, they
included (1) providing personalized evidence for centralized can automatically trigger the body’s natural healing response).49
pain; (2) guided reappraisal of pain sensations while seated A subcutaneous injection described as saline was administered
and while engaging in feared postures or movements; by a physician (K.K.) at the site of greatest back pain during
(3) techniques addressing psychosocial threats (eg, difficult an empathic, validating clinical encounter at an orthopedic
emotions) potentially amplifying pain; and (4) techniques medical center. Open-label placebo treatments are as effective
to increase positive emotions and self-compassion. PRT fol- or nearly as effective as traditional (deceptive) placebos for CBP
lowed the treatment protocol found in eAppendix 2 in and other chronic symptoms when administered in this man-
Supplement 2. ner (eMethods in Supplement 2).50-52 Participants in this group
Treatment fidelity was assessed by independent raters were also asked to continue their ongoing care as usual and not
coding audiorecordings of PRT sessions (eMethods and eAp- start other new treatments until after the study period.
pendix 3 in Supplement 2). A mean (SD) of 4.93 (0.87) of
6 PRT elements were present in each session, and all ses- Usual Care
sions included at least 3 elements, indicating high treatment Participants in this group were given no additional treat-
fidelity. ment. They agreed to continue their ongoing care as usual

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 Research Original Investigation Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

and not start new treatments before the posttreatment points were analyzed individually, testing group differences
assessment. After the posttreatment assessment, they were in change from baseline to each time points. The placebo vs
given a chronic pain workbook53 and access to http://www. usual care comparison will be reported elsewhere.
unlearnyourpain.com. To investigate psychological treatment mechanisms, we
(1) correlated pretreatment to posttreatment changes in pain
Clinical Measures intensity with pretreatment to posttreatment changes in
The primary outcome was average pain over the last week pain beliefs (TSK-11, PCS, and SOPA-Emotion) within each
on a numerical rating scale from 0 to 10 from the Brief Pain group and (2) tested pretreatment to posttreatment changes
Inventory Short Form, assessed at the 1-month postbaseline in pain beliefs as mediators of treatment effects on pain at
session. We also calculated the proportion of participants re- follow-up timepoints (1 through 12 months posttreatment),
porting pain reduction of 30% or more, pain reduction of 50% controlling for baseline pain. PRT vs placebo and PRT vs
or more, and a pain score of 0 or 1, indicating a pain-free or usual care were tested in separate models. We also tested the
nearly pain-free state. Secondary outcomes included pain reverse: whether pretreatment to posttreatment pain reduc-
interference (Oswestry Disability Index); Patient-Reported tions mediated treatment effects on pain beliefs at follow-
Outcome Measurement Information System (PROMIS) short up, controlling for baseline pain beliefs (eMethods in Supple-
forms for depression, anxiety, anger, and sleep quality; and ment 2). Correlational and mediation analyses were not
the Positive and Negative Affect Scale (measure details in the prespecified in the trial protocol.
eMethods in Supplement 2).
We considered 3 measures of pain beliefs as potential me- Evoked Back Pain Analyses
diators: (1) the Tampa Scale of Kinesiophobia (TSK-11), assess- An evoked back pain localizer identified brain regions posi-
ing belief that pain indicates injury and fear of movement; tively associated with evoked back pain intensity at baseline.
(2) the Pain Catastrophizing Scale (PCS); and (3) the Survey of The localizer was conducted within a mask of regions of in-
Pain Attitudes Emotion subscale (SOPA-Emotion), assessing terest (medial prefrontal, posteromedial, insula, cingulate, and
beliefs that stress and negative emotion increase pain. Ad- somatosensory cortices; amygdala; and nucleus accumbens;
verse events were recorded when participants spontane- eMethods and eFigure 1 in Supplement 2; localizer task de-
ously reported them to study personnel. Baseline pain was sign in eFigure 8 in Supplement 2). We tested for treatment
computed as the average score from 2 prerandomization effects (group × time interactions) in the average activity of
assessments (eligibility session and pretreatment fMRI clusters positively associated with evoked back pain using
session). a mixed-effects (random-effects) model, applying a 1-tailed
threshold of P < .05 owing to directional hypotheses that PRT
Neuroimaging Measures would reduce activity in pain-positive clusters.
Structural T1 and multiband blood oxygenation level–
dependent functional imaging was conducted on a 3-T Spontaneous Pain Connectivity Analyses
Siemens Prisma Fit MRI scanner with standard fMRI prepro- Evoked pain analyses identified group × time interactions in
cessing (eMethods in Supplement 2). During fMRI, partici- the anterior insula, anterior midcingulate (aMCC), and a pre-
pants completed (1) an evoked back pain task with a series of frontal region. We submitted these 3 regions as seeds to con-
randomly ordered trials distending the back to 1 of 4 intensity nectivity analyses in the spontaneous pain scan. We con-
levels and (2) a spontaneous pain scan in which participants ducted permutation tests (threshold-free cluster-enhancement;
rested and rated ongoing pain once per minute (design de- eMethods in Supplement 2) testing for group × time interac-
tails in the eMethods in Supplement 2; fMRI data quality mea- tions in connectivity between these seed regions and 2 areas
sures shown in eFigures 6 and 7 in Supplement 2). Partici- most often demonstrating altered connectivity in chronic pain:
pants rated pain during scanning on a visual analog scale from (1) the midline default mode network, including the medial pre-
0 (no pain) to 100 (worst pain imaginable). frontal and posteromedial cortex, and (2) primary somatosen-
sory cortex (S1)36,54-59 (masks in eFigure 2 in Supplement 2).
Statistical Analyses
Intent-to-treat analyses (including all randomized patients)
were performed for the primary outcome with a mixed-
effects model (fitlme, MATLAB 2020a), including 2 group ×
Results
time interactions (PRT vs placebo × posttreatment vs pretreat- We randomized 151 participants (54% female; mean [SD] age,
ment and PRT vs usual care × posttreatment vs pretreat- 41.1 [15.6] years; mean [SD] CBP duration, 10.0 [8.9] years). At
ment), covariates for age and sex, and a random intercept per baseline, patients reported low to moderate pain intensity
participant. Treatment response rates for 30% or greater re- scores (mean [SD], 4.10 [1.26]) to 4.41 [1.29]) and disability
duction in pain, 50% or greater reduction in pain, and a pain- (mean [SD], 23.34 [10.12] on the Oswestry Disability Index),
free or nearly pain-free state at posttreatment and 1-year fol- with similar pain and demographic characteristics across
low-up were based on all randomized patients; those missing groups (Table 1).
data were considered nonresponders. For follow-up time points Of 50 participants randomized to PRT, 44 (88%) com-
and secondary outcomes, we calculated Hedges g for the PRT pleted all treatment sessions and the posttreatment assess-
vs placebo and PRT vs usual care comparisons. Follow-up time ment. Five participants dropped out prior to initiating PRT and

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 Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research

Table 1. Baseline Patient Characteristics

No. (%)
Pain reprocessing Usual
Characteristic therapy Placebo care
Demographic characteristics
Age, mean (SD), y 42.6 (16.2) 39.4 (14.9) 41.3 (15.9)
Sex
Female 29 (58) 25 (49) 27 (54)
Male 21 (42) 26 (51) 23 (46)
Education
High school or less 0 0 0
Some college 11 (22) 15 (29) 15 (30)
College graduate 39 (78) 36 (71) 35 (70)
Married 26 (52) 25 (49) 30 (60)
Racea
American Indian or Alaskan Native 0 0 1 (2)
Asian/Pacific Islander 3 (6) 2 (4) 0
Black (not of Hispanic origin) 0 2 (4) 1 (2)
White (not of Hispanic origin) 46 (92) 45 (88) 43 (86)
Other or unknown 1 (2) 2 (4) 5 (10)
Hispanic ethnicity 0 2 (4) 2 (4)
Employment status
Full-time (>30 h/wk) 33 (66) 26 (51) 28 (56)
Part-time (5-30 h/wk) 10 (20) 12 (24) 13 (26)
Unemployed/lightly employed (<5 h/wk) 7 (14) 13 (25) 9 (18)
Subjective socioeconomic status, mean (SD), 1-1060 6.8 (1.8) 6.4 (2.0) 6.7 (1.6)
Exercise
Almost none 6 (12) 1 (2) 4 (8)
1 h/wk 4 (8) 7 (14) 9 (18)
3 h/wk 17 (34) 23 (45) 14 (28)
7 h/wk 19 (38) 18 (35) 21 (42)
≥14 h/wk 4 (8) 2 (4) 2 (4)
Pain-related characteristics
Pain duration, mean (SD), y 10.7 (9.7) 8.9 (8.2) 10.5 (8.9)
Current opioid use (yes/no) 5 (10) 2 (4) 2 (4)
Pain in body sites besides back?
None 5 (10) 9 (18) 4 (8)
A little 29 (58) 24 (47) 28 (56) a
Race and ethnicity were collected
A moderate amount 11 (22) 15 (29) 16 (32) in accord with National Institutes of
Health guidelines by multiple choice
A lot 5 (10) 3 (6) 2 (4)
self-report.

1 had an unrelated medical emergency. Of 51 participants ran- PRT group, 2.84 (1.64) in the placebo group, and 3.13 (1.45) in
domized to placebo, 44 (86%) received the treatment, all of the usual care group (Figure 2; Table 2). Patients in the PRT
whom completed the posttreatment assessment. Of the 50 par- group reported a pain reduction of 1.79 (on the 0 to 10 numeri-
ticipants randomized to usual care, 47 (94%) completed the cal rating scale) relative to placebo (t137.63 = 6.06; P < .001;
posttreatment assessment (Figure 1). g, −1.14; 95% CI, −1.65 to −0.71) and reported a pain reduction
Twenty patients in the PRT group had preexisting spinal of 2.40 relative to the usual care group (t135.69 = 8.13; P < .001;
imaging, all of which showed at least 1 spinal anomaly (me- g, −1.74; 95% CI, −2.28 to −1.32). A total of 33 of 50 patients ran-
dian of 4 findings per patient; eTable 1 in Supplement 2) as- domized to PRT (66%), corresponding to 73% of the 45 pa-
sessed by a physician (H.S.) as not causal of pain (eMethods tients who initiated PRT, were pain-free or nearly pain-free at
and eAppendix 1 in Supplement 2).61 posttreatment, compared with 10 of 51 patients (20%) in the
placebo group and 5 of 50 patients (10%) in the usual care
Clinical Outcomes group. At 1-year follow-up, effects of PRT on pain remained
Patients randomized to PRT reported substantial reductions large relative to both control groups, with a mean (SD) pain
in pain intensity at posttreatment compared with both con- score of 1.51 (1.59) in the PRT group, 2.79 (1.78) in the placebo
trol groups, with a mean (SD) pain score of 1.18 (1.24) in the group, and 3.00 (1.77) in the usual care group. Hedges g was

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 Research Original Investigation Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

Figure 2. Clinical Outcomes

A Pain intensity B Percent change in pain intensity from baseline to C Patients reporting a pain-free or
PRT posttreatment nearly-pain-free state
5 100 100
Placebo

Randomized with pain ≤1, %

Change in pain intensity, %
Usual care
4 50
75
Pain intensity

3 0
50
2 –50

25
1 –100

0 –150 0
1 mo 2 mo 3 mo 6 mo 12 mo PRT Placebo Usual care Posttreatment 1-y follow-up
ttr line

t
en
tm
se
Ba

ea
s
Po

A, Shading indicates standard error. B, Dots represent individual participants; thick lines represent the group mean. C, Percentage of patients reporting pain scores
of 0 or 1 of 10 (ie, pain-free or nearly pain-free) at posttreatment and at 1-year follow-up. PRT indicates pain reprocessing therapy.

−0.70 for PRT vs placebo (P = .001) and −1.05 for PRT vs usual Neither age nor sex moderated the treatment effect on pain
care (P < .001) (Table 2; treatment response rates in eTable 2 intensity (eMethods in Supplement 2). No adverse events were
in Supplement 2; individual patient pain trajectories in reported for PRT.
eFigure 3 in Supplement 2).
Analyses of secondary outcomes at posttreatment re- Neuroimaging Outcomes
vealed significant reductions in disability and anger for PRT Evoked Back Pain
vs both controls (g, −0.62 to −1.7; P < .005) and improve- At baseline, increased back distention led to increased pain
ments in sleep (g, −0.56; P = .009) and depression (g, −0.63; (mean [SD] for distention level 1, 32.15 [18.57]; distention level
P = .003) relative to usual care (Table 2). Treatment gains on 2, 37.91 [20.30]; distention level 3, 46.70 [21.71]; distention
secondary outcomes were largely maintained at 1-year fol- level 4, 52.73 [21.78]). There was a significant effect of disten-
low-up (Table 2). Significant PRT vs control effects were ob- tion level on pain (mean [SD] β for inflation, 7.05 [5.06];
served at posttreatment for positive affect (Positive and Nega- t95 = 13.64; P < .001. Individual patient-evoked pain data are
tive Affect Schedule; g for PRT vs placebo, 0.63, g for PRT vs shown in eFigure 5 in Supplement 2.
usual care, 0.59; P < .005; eTable 3 in Supplement 2) but not Patients receiving PRT reported significant pretreatment
for negative affect or alcohol, cannabis, or opioid use (eTable 3 to posttreatment reductions in evoked back pain relative to
in Supplement 2). Treatment satisfaction was high among placebo (β, −13.05 on a 101-point visual analog scale;
participants in the PRT group (eTable 4 in Supplement 2). t122.85 = −2.82; P = .006; g, −0.60; 95% CI, −1.06 to −0.16) and
relative to usual care (β, −19.61; t79.52 = −4.03; P < .001; g, −0.99;
Mediation Analyses 95% CI, −1.50 to −0.55; Figure 3A). Among patients in the PRT
Pretreatment to posttreatment reductions in TSK-11 and pain group, pretreatment to posttreatment reductions in evoked
intensity scores were correlated among participants in the PRT back pain and 1-week average back pain intensity were corre-
group (r42 = 0.44; P = .003; eFigure 4 in Supplement 2). This lated (r32 = 0.47; P = .005).
correlation was not significant for the placebo condition Localizer analyses identified 16 regions within the mask of
(r42 = 0.16; P = .29) or usual care condition (r45 = 0.27; P = .07). interest positively associated with evoked pain intensity, includ-
Pretreatment to posttreatment changes in PCS and SOPA- ing bilateral insula, cingulate, bilateral somatotopic back areas
Emotion scores did not correlate with pain reductions within S1 and secondary somatosensory cortex, and prefrontal regions
any group. (Figure 3B; eFigure 1 and eTable 7 in Supplement 2). Relative to
Pretreatment to posttreatment reductions in TSK-11 scores placebo, PRT reduced pain-related activity in aMCC (t133.48 = −1.73;
mediated PRT vs placebo and PRT vs usual care effects on pain P = .04) and the anterior prefrontal cortex (aPFC; t133.48 = −1.85;
intensity at most follow-up time points (eFigure 4 and eTables 5 P = .03). Relative to usual care, PRT reduced pain-related activ-
and 6 in Supplement 2). The reverse was also true: pretreat- ity in the left anterior insula (aIns; t120.1 = −2.34; P = .01; Figure 3C).
ment to posttreatment pain reductions mediated PRT vs pla-
cebo and PRT vs usual care effects on TSK-11 at follow-up. Spontaneous Pain
Pretreatment to posttreatment changes in PCS and SOPA- Patients receiving PRT reported reductions in spontaneous pain
Emotion did not mediate PRT vs control effects at any fol- relative to placebo (β, −18.24 on a 101-point visual analog scale;
low-up time point. Treatment effects on TSK-11 were very large t140.66 = −4.59; P < .001; g, −0.92; 95% CI, −1.44 to −0.47)
at posttreatment (g for PRT vs placebo, −1.90; g for PRT vs usual and relative to usual care (β, −21.53; t79 = −5.26; P < .001;
care,−1.67; P < .001). g, −1.11; 95% CI, −1.66 to −0.66; Figure 3D).

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 Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research

Table 2. Primary and Secondary Clinical Outcomes

Mean (SD) PRT vs PRT vs

placebo, usual care,
a
Between-group differences PRT Placebo Usual care g (SE)b P value g (SE)b P value
Primary outcome
Pain intensity (0-10)
Baseline 4.22 (1.21) 4.16 (1.33) 3.91 (1.24) NA NA NA NA
Posttreatment 1.18 (1.24) 2.84 (1.64) 3.13 (1.45) −1.14 (0.24) <.001 −1.75 (0.24) <.001
At 1 mo 1.26 (1.77) 2.91 (1.97) 3.07 (1.63) −0.83 (0.27) <.001 −1.24 (0.29) <.001
At 2 mo 1.59 (1.92) 3.06 (1.89) 3.00 (1.86) −0.84 (0.28) .001 −1.03 (0.28) <.001
At 3 mo 1.54 (1.68) 3.21 (2.02) 3.27 (1.95) −0.93 (0.23) <.001 −1.35 (0.25) <.001
At 6 mo 1.39 (1.48) 2.68 (2.08) 2.95 (1.93) −0.74 (0.23) .001 −1.14 (0.26) <.001
At 12 mo 1.51 (1.59) 2.79 (1.78) 3.00 (1.77) −0.70 (0.21) .001 −1.05 (0.24) <.001
Secondary outcome
Oswestry Disability Index (0-100)
Baseline 23.70 (10.70) 23.06 (10.14) 23.26 (9.67) NA NA NA NA
Posttreatment 10.14 (10.63) 19.00 (11.07) 20.68 (10.68) −1.30 (0.28) <.001 −1.70 (0.26) <.001
At 1 mo 10.58 (14.26) 18.68 (11.95) 20.30 (9.04) −1.04 (0.25) <.001 −1.61 (0.27) <.001
At 2 mo 9.57 (12.86) 19.43 (11.84) 21.37 (11.07) −1.30 (0.29) <.001 −1.55 (0.23) <.001
At 3 mo 9.68 (13.39) 21.42 (14.32) 23.57 (13.36) −1.26 (0.28) <.001 −1.61 (0.25) <.001
At 6 mo 9.80 (11.94) 18.50 (13.43) 20.84 (11.57) −0.96 (0.26) <.001 −1.3 (0.28) <.001
At 12 mo 11.16 (13.13) 18.52 (12.60) 18.78 (12.59) −0.23 <.001 −0.83 (0.24) <.001
PROMIS depression, raw score (8-32)
Baseline 14.66 (4.39) 13.17 (4.67) 12.85 (4.74) NA NA NA NA
Posttreatment 12.23 (4.94) 11.75 (4.05) 11.81 (4.45) −0.35 (0.24) .099 −0.56 (0.24) .009
At 1 mo 12.87 (5.23) 10.64 (3.57) 11.57 (4.61) 0.13 (0.23) .555 −0.54 (0.25) .019
At 2 mo 12.51 (4.88) 11.11 (4.95) 11.76 (5.17) −0.08 (0.24) .723 −0.51 (0.24) .028
At 3 mo 11.47 (4.64) 12.45 (6.09) 12.30 (4.51) −0.57 (0.24) .015 −0.90 (0.22) <.001
At 6 mo 12.90 (5.28) 10.97 (4.00) 11.84 (4.65) −0.09 (0.24) .701 −0.47 (0.23) 0.40
At 12 mo 12.53 (5.12) 11.95 (5.86) 12.75 (4.50) −0.20 (0.23) .360 −0.62 (0.24) .007
PROMIS anger, raw score (5-25)
Baseline 12.46 (3.73) 10.97 (3.18) 11.17 (3.18) NA NA NA NA
Posttreatment 9.52 (3.91) 9.89 (3.81) 10.45 (3.86) −0.62 (0.21) .004 −0.78 (0.21) <.001
At 1 mo 9.50 (4.40) 8.84 (3.27) 10.55 (3.19) −0.23 (0.25) .291 −0.91 (0.25) <.001
At 2 mo 10.70 (4.68) 9.37 (3.30) 10.00 (3.92) −0.11 (0.23) .652 −0.28 (0.25) .231
At 3 mo 9.31 (4.06) 9.87 (4.78) 10.49 (3.52) −0.52 (0.21) .027 −0.92 (0.25) <.001
At 6 mo 9.83 (4.49) 9.31 (2.96) 10.51 (3.44) −0.38 (0.25) .099 −0.90 (0.23) <.001
At 12 mo 10.49 (4.15) 9.64 (3.55) 10.89 (3.38) −0.16 (0.21) .454 −0.61 (0.22) .008
PROMIS anxiety, raw scores (8-40)
Baseline 16.37 (5.88) 15.52 (5.83) 15.11 (6.40) NA NA NA NA
Posttreatment 15.02 (6.16) 13.89 (5.78) 14.11 (6.99) 0 (0.22) 1.00 −0.21 (0.21) .318
At 1 mo 14.58 (6.45) 12.25 (4.81) 13.75 (6.78) 0.36 (0.20) .109 −0.29 (0.21) .203
At 2 mo 14.14 (7.07) 13.23 (6.74) 13.58 (6.75) 0.02 (0.24) .923 −0.22 (0.25) .348
At 3 mo 13.75 (6.45) 14.50 (7.42) 14.08 (6.42) −0.34 (0.23) .147 −0.62 (0.21) .009
At 6 mo 14.88 (7.12) 13.00 (5.14) 14.59 (6.90) 0.03 (0.24) .907 −0.50 (0.24) .028
At 12 mo 14.09 (6.79) 14.07 (7.51) 14.81 (6.94) −0.20 (0.22) .362 −0.56 (0.23) .014
PROMIS sleep, raw score (8-40)
Baseline 22.21 (6.54) 22.65 (6.38) 22.63 (6.26) NA NA NA NA
Posttreatment 17.73 (6.75) 20.50 (6.17) 20.89 (6.02) −0.41 (0.23) .056 −0.63 (0.22) .003
At 1 mo 17.18 (6.38) 21.02 (6.34) 21.62 (6.45) −0.46 (0.25) .039 −0.89 (0.27) <.001
At 2 mo 17.08 (6.71) 19.71 (6.72) 21.74 (7.19) −0.38 (0.24) .112 −0.84 (0.27) <.001
At 3 mo 16.67 (6.67) 20.16 (7.05) 21.73 (6.26) −0.44 (0.24) .061 −1.08 (0.24) <.001
At 6 mo 17.85 (7.24) 19.42 (6.22) 21.38 (6.03) −0.29 (0.23) .198 −0.85 (0.23) <.001
At 12 mo 18.11 (7.36) 19.95 (5.79) 21.19 (6.73) −0.23 (0.22) .272 −0.60 (0.25) .009
Abbreviations: NA, not applicable; PROMIS, Patient-Reported Outcome interaction), including all available data at the follow-up time point and
Measurement Information System; PRT, pain reprocessing therapy. corresponding baseline data for effect size computation.
a b
Effect sizes show the group difference in change from baseline (group × time Hedges g and SE estimated with bootstrapping procedure.

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 Research Original Investigation Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

Figure 3. Effects of Treatment on Evoked and Spontaneous Back Pain and Related Brain Function

A Reductions in evoked pain B Evoked back pain-related activation

50
Mean spontaneous pain, 0-100 a Usual
care
40

Placebo
30
PRT
z=0 z = 24 z = 48
20

10

0
Baseline Posttreatment
x=4

C Decreased evoked pain-related activity D Reductions in spontaneous pain

40

35

Mean spontaneous pain, 0-100

a
Usual
30 care
25
x=2 Placebo
20
y = 52
z = 24 z=2
15
parameter esteimate

b b b PRT
0.10 0.10 0.10 10
Δ Evoked pain

0.05 0.05 0.05 5

0 0 0
0
–0.05 –0.05 –0.05 Baseline Posttreatment
–0.10 –0.10 –0.10
ua o

ua o

ua o
e
e

e
Pl RT

Pl RT

Pl RT

ar
Us ceb

Us ceb

Us ceb
ar

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lc
P

P
lc

lc
a

E Increased connectivity from aPFC and aIns to F Increased connectivity between an aMCC
somatosensory cortex seed and the precuneus
1 2
1 2
4 5
3
3

x = –6
y = –18 x = –52 x = 46

1 4 1 4

2
3
z=2
z = 24 z = 46 z = 54

1 2 3 4 5
b b b
0.10 0.10 b 0.10 b 0.10 0.10
Δ Pearson r

0.05 0.05 0.05 0.05 0.05

0 0 0 0 0
–0.05 –0.05 –0.05 –0.05 –0.05
–0.10 –0.10 –0.10 –0.10 –0.10
ua o

ua o

ua o

Pl RT
ua o
e

Pl RT
ua o
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e

e
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ar

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a

A,Errorbarsshowstandarderror.B,Coordinatesandstatisticsforactivationsprovided Inset shows seed regions, derived from evoked pain analyses; magenta outlines,
in eTable 7 in Supplement 2; analyses conducted within a mask of regions of interest; PRT vs placebo; black outlines, PRT vs usual care. F, PRT vs usual care increased
eFigure 1 in Supplement 2. C, Decreased evoked pain-related activity was observed connectivitybetweenanaMCCseed(yellow;derivedfromevokedbackpainanalyses)
inanteriormidcingulate(aMCC)andanteriorprefrontalregionsforPRTvsplaceboand and the precuneus (orange). Connectivity analyses were conducted within primary
left anterior insula for PRT vs usual care. D, Error bars show standard error. E, PRT somatosensory cortex and medial default mode network masks.
a
vs control conditions increased aPFC-seeded (red clusters) and aIns-seeded (green P < .001.
b
clusters) connectivity with primary somatosensory cortex (permutation test,P < .05). P < .05.

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 Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research

We submitted the aMCC, aPFC, and aIns regions exhibit- may more strongly change these beliefs compared with exist-
ing treatment effects in evoked pain analyses as connectivity ing therapies (eTable 6 in Supplement 2).
seed regions in the spontaneous pain task. Within S1, PRT These hypothesized mechanisms are consistent with ex-
vs placebo and PRT vs usual care led to increased aPFC- and tinction-based treatment approaches to anxiety disorders.42,65
aIns-seeded connectivity to 4 distinct S1 subregions (permu- For example, 85% of patients became free of panic symptoms
tation test COPE-MAX, 3.55-3.91; P < .05). Within the medial following treatment focused on reappraising somatic symp-
default mode network, PRT vs usual care increased aMCC- toms as caused by nondangerous central nervous system
precuneus connectivity (permutation test COPE-MAX, 4.23; processes (eg, false alarms).66
P = .01; Figure 3E; cluster coordinates and statistics in eTable 8 PRT reduced evoked pain-related activity in aPFC, aMCC,
in Supplement 2). No group × time interactions were found and aIns. The aPFC and adjacent dorsolateral prefrontal cor-
for aPFC- or aIns-seeded connectivity to default mode net- tex (dlPFC) are implicated in the detection and inhibition of
work regions or for aMCC-seeded connectivity to S1. pain.67 aPFC reductions following PRT suggest a potential
reduction of pain-related signals or decreased prioritization
of pain control. The aMCC and aIns are cortical convergence
zones in the construction of negative affect in pain and other
Discussion domains.20,68-70 Cognitive pain regulation strategies, includ-
PRT yielded large reductions in CBP intensity relative to open- ing mindful acceptance38,39 and placebo analgesia,24,25,28 have
label placebo and usual care control conditions in a commu- been found to reduce aMCC and aIns responses to pain, dem-
nity sample, with nearly two-thirds of randomized patients and onstrating parallels between experimental findings and our
73% of those initiating PRT reporting they were pain-free or clinical findings. The aIns reductions in our study were not spe-
nearly pain-free at posttreatment. Large effects of PRT on pain cific to PRT vs placebo and may reflect processes common
continued at 1-year follow-up. PRT also reduced experimen- to both these interventions.
tally evoked back pain and spontaneous pain during fMRI PRT also increased aPFC and aIns connectivity to S1, align-
with large effect sizes, and several secondary outcomes (eg, ing with previous findings that cognitive behavioral therapy for
disability and anger) also improved for PRT relative to the fibromyalgia57 and acupuncture for CBP55 increased aIns-S1 con-
control groups. nectivity. Increased aPFC and aIns connectivity to S1 may reflect
PRT targets primary (nociplastic) pain by shifting patients’ increased attention to somatosensory input in constructing
beliefs about the causes and threat value of pain. It presents pain pain.71 This is congruent with mindfulness-based treatments pro-
as a reversible, brain-generated phenomenon not indicative of moting nonreactive attention to bodily sensations, reducing
peripheral pathology, consistent with active inference and con- catastrophizing.38,39,48,71 Yet, increased S1 connectivity has also
structionist accounts of interoception and pain.18,19,22-27 PRT been associated with increased clinical pain,72 and the role of S1
builds on and extends existing psychological treatment mod- connectivity remains unclear.55 PRT vs usual care also increased
els. Cognitive-behavioral, acceptance-based, and mindfulness- aMCC-precuneus connectivity, with intermediate effects ob-
based interventions typically aim to improve functioning served in participants receiving placebo treatment. Altered de-
by decreasing pain catastrophizing, enhancing pain coping fault mode connectivity has often been reported in chronic pain,
or acceptance, and promoting engagement in valued life although typically with heightened connectivity for patients vs
activities.41,44,46,48,62 Exposure-based treatments share with controls (eDiscussion in Supplement 2).36,54,56,58,59
PRT an emphasis that painful activities are not injurious,42,63-65
but do not emphasize reappraising pain sensations and reat- Limitations
tributing the causes of pain. Some pain neuroscience educa- This study has limitations. The study sample was relatively well
tion interventions present pain in a similar way as PRT,43 though educated and active and reported long-standing low to mod-
they typically lack guided exposure and reappraisal exercises. erate pain and disability at baseline. The physician and thera-
Large reductions in pain are rarely observed in CBP psy- pists were experts in the treatment model. Future studies
chological treatment trials.11,12 Relatively unique compo- should test generalizability to other patient populations, thera-
nents of PRT potentially contributing to the observed effects pists, and treatment contexts (eDiscussion in Supplement 2).
include (1) an in-depth medical and psychological assess- The fMRI effect sizes were modest, with some results not sur-
ment generating personalized evidence for centralized pain; viving whole-brain correction (eMethods in Supplement 2). Fu-
(2) reattribution of pain to reversible learning- and affect- ture trials should test PRT efficacy relative to leading psycho-
related brain processes rather than bodily injury; and (3) a logical and medical treatments (eDiscussion in Supplement 2).
unique combination of cognitive, somatic, and exposure-
based techniques supporting pain reappraisal (eDiscussion in
Supplement 2).
Correlational and mediational analysis results support
Conclusions
changes in fear-inducing pain beliefs as a potential PRT mecha- Overall, our findings raise key possibilities about the nature
nism. Effects of PRT on pain beliefs were also mediated by pain and treatment of primary CBP. Changing fear- and avoidance-
intensity reductions, perhaps because pain reductions pro- inducing beliefs about the causes and threat value of pain may
mote beliefs in pain modifiability (eDiscussion in Supple- provide substantial, durable pain relief for people with pri-
ment 2). Changes in pain beliefs are not unique to PRT, but PRT mary CBP.

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 Research Original Investigation Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain

ARTICLE INFORMATION royalties for Unlearn Your Pain, Unlearn Your pathology in patients presenting to primary care
Accepted for Publication: July 27, 2021. Anxiety and Depression and Hidden From View; settings with acute low back pain. Arthritis
serves as a consultant with UnitedHealth Group, Rheum. 2009;60(10):3072-3080. doi:10.1002/art.
Published Online: September 29, 2021. Karuna Labs, and Curable Health; and receives 24853
doi:10.1001/jamapsychiatry.2021.2669 personal fees from OVID Dx outside the submitted 7. Deyo RA, Weinstein JN. Low back pain. N Engl J
Open Access: This is an open access article work. Mrs Uipi serves as a consultant for Med. 2001;344(5):363-370. doi:10.1056/
distributed under the terms of the CC-BY License. UnitedHealth Group. Dr Dimidjian reports being NEJM200102013440508
© 2021 Ashar YK et al. JAMA Psychiatry. a co-founder of Mindful Noggin, Inc, and received
royalties from Guilford Press and Wolters Kluwer 8. Karshikoff B, Jensen KB, Kosek E, et al Why
Author Affiliations: Department of Psychiatry, sickness hurts: a central mechanism for pain
Weill Cornell Medical College, New York City, as well as funding from The National Institutes of
Health. Dr Lumley reports personal fees from induced by peripheral inflammation. Brain Behav
New York (Ashar); Department of Psychology and Immun. 2016;57:38-46. doi:10.1016/j.bbi.2016.
Neuroscience, University of Colorado, Boulder CognifiSense, Inc, outside the submitted work.
Dr Wager reports grants from the National 04.001
(Ashar, Anderson, Carlisle, Polisky, Geuter, Kragel,
Dimidjian, Wager); Institute of Cognitive Science, Institutes of Health and the Foundation for the 9. Nicholas M, Vlaeyen JWS, Rief W, et al;
University of Colorado, Boulder (Ashar, Anderson, Study of the Therapeutic Encounter, and funding IASP Taskforce for the Classification of Chronic Pain.
Carlisle, Polisky, Geuter, Kragel, Wager); Pain to support trainees from the Radiological Society The IASP classification of chronic pain for ICD-11:
Psychology Center, Los Angeles, California (Gordon, of North America and the German Research chronic primary pain. Pain. 2019;160(1):28-37.
Uipi); Ascension Providence Hospital, Southfield, Foundation; he is on the Scientific Advisory Board doi:10.1097/j.pain.0000000000001390
Michigan (Schubiner); Michigan State University of Curable Health. No other disclosures were 10. Clauw DJ. Diagnosing and treating chronic
College of Human Medicine, East Lansing reported. musculoskeletal pain based on the underlying
(Schubiner); Panorama Orthopedics and Spine Funding and Support: This study was funded by mechanism(s). Best Pract Res Clin Rheumatol.
Center, Golden, Colorado (Knight); Department of National Institutes of Health grants R01 DA035484 2015;29(1):6-19. doi:10.1016/j.berh.2015.
Psychology, Northwestern University, Evanston, (Dr Wager), R01 MH076136 (Dr Wager), National 04.024
Illinois (Anderson); Department of Philosophy, Center for Advancing Translational Sciences grant 11. Williams ACC, Fisher E, Hearn L, Eccleston C.
Washington University in Saint Louis, Saint Louis, TL1-TR-002386 (Dr Ashar), Radiological Society Psychological therapies for the management of
Missouri (Carlisle); Johns Hopkins University of North America (Dr Flood), German Research chronic pain (excluding headache) in adults.
Department of Biostatistics, Baltimore, Maryland Foundation grant GE 2774/1-1 (Dr Geuter), the Cochrane Database Syst Rev. 2020;8(8):CD007407.
(Geuter); Department of Radiology, Brigham and Psychophysiologic Disorders Association, the doi:10.1002/14651858.CD007407.pub4
Women’s Hospital, Boston, Massachusetts (Flood); Foundation for the Study of the Therapeutic
Department of Psychology, Emory University, Encounter, and community donations. 12. Chou R, Deyo R, Friedly J, et al.
Atlanta, Georgia (Kragel); Renée Crown Wellness Nonpharmacologic therapies for low back pain:
Role of the Funder/Sponsor: The funders had no a systematic review for an American College of
Institute, University of Colorado, Boulder role in the design and conduct of the study;
(Dimidjian); Department of Psychology, Wayne physicians clinical practice guideline. Ann Intern Med.
collection, management, analysis, and 2017;166(7):493-505. doi:10.7326/M16-2459
State University, Detroit, Michigan (Lumley); interpretation of the data; preparation, review, or
Department of Psychological and Brain Sciences, approval of the manuscript; and decision to submit 13. Woolf CJ. Central sensitization: implications
Dartmouth College, Hanover, New Hampshire the manuscript for publication. for the diagnosis and treatment of pain. Pain. 2011;
(Wager). 152(3)(suppl):S2-S15. doi:10.1016/j.pain.2010.
Data Sharing Statement: See Supplement 3. 09.030
Author Contributions: Drs Ashar and Wager had
full access to all the data in the study and take Additional Information: Deidentified demographic 14. Kuner R, Flor H. Structural plasticity and
responsibility for the integrity of the data and and clinical outcomes data and subject-level reorganisation in chronic pain. Nat Rev Neurosci.
the accuracy of the data analysis. functional magnetic resonance imaging statistical 2016;18(1):20-30. doi:10.1038/nrn.2016.162
Concept and design: Ashar, Gordon, Schubiner, parameter maps for evoked pain and seed
connectivity are provided here: https://figshare. 15. Corder G, Ahanonu B, Grewe BF, Wang D,
Uipi, Knight, Geuter, Dimidjian, Wager. Schnitzer MJ, Scherrer G. An amygdalar neural
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ensemble that encodes the unpleasantness of pain.
Ashar, Gordon, Schubiner, Uipi, Knight, Anderson, Science. 2019;363(6424):276-281. doi:10.1126/
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