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

Key Points Question Can a psychological treatment based on the reappraisal of primary chronic back pain as due to nondangerous central nervous system processes provide substantial and durable pain relief? Findings In this randomized clinical trial, 33 of 50 participants (66%) randomized to 4 weeks of pain reprocessing therapy were pain-free or nearly pain-free at posttreatment, compared with 10 of 51 participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual care, with gains largely maintained through 1-year follow-up. Treatment effects on pain were mediated by reduced beliefs that pain indicates tissue damage, and longitudinal functional magnetic resonance imaging showed reduced prefrontal responses to evoked back pain and increased resting prefrontal-somatosensory connectivity in patients randomized to treatment relative to patients randomized to placebo or usual care. Meaning Psychological treatment focused on changing beliefs about the causes and threat value of primary chronic back pain may provide substantial and durable pain relief.


C
hronic pain affects 20% of people in the US, with an estimated annual cost of more than $600 billion. 1,2he most common type is chronic back pain (CBP).][10] Although these treatments can improve functioning, reductions in pain intensity are limited 11,12 and better treatments are needed.
Advances in the neurosc ience of pain 1 3 -1 7 and interoception [18][19][20][21] suggest new directions for treatment development.3][24][25][26] Fearful appraisals of tissue damage can cause innocuous somatosensory input to be interpreted and experienced as painful. 22,24,27,28][39] We developed pain reprocessing therapy (PRT) based on this understanding of primary chronic pain.Leading psychological interventions for pain typically present the causes of pain as multifaceted and aim primarily to improve functioning and secondarily to reduce pain.PRT emphasizes that the brain actively constructs primary chronic pain in the absence of tissue damage and that reappraising the causes and threat value of pain can reduce or eliminate it.
In this study, we conducted the first test of PRT.In a randomized clinical trial with 1-year follow-up, we compared PRT with both open-label placebo and usual care control conditions.We tested hypothesized mechanisms of PRT with mediation analyses and longitudinal functional magnetic resonance imaging (fMRI) during spontaneously occurring and evoked back pain.fMRI provided objective correlates of treatment effects and identified potential neurobiological treatment mechanisms.

Participants and Trial Design
The trial was preregistered on ClinicalTrials.gov(Identifier: NCT03294148) and conducted from August 2017 to November 2018, with 1-year follow-up completed by November 2019.Clinical and fMRI data were analyzed from January 2019 to August 2020, after data collection at each follow-up timepoint was complete.Participants aged 21 to 70 years with back pain for at least half the days of the last 6 months and 1-week average pain intensity score of 4 of 10 or greater at screening were recruited from the community in Boulder, Colorado.We targeted primary CBP, excluding patients with leg pain worse than back pain (eMethods in Supplement 2).Power analysis targeted 80% power (α = .05)to detect a medium effect (d = 0.62) on pain intensity at the primary end point (eMethods in Supplement 2).Participants provided written informed consent as approved by the University of Colorado Institutional Review Board.The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for social and psychological intervention trials.
Participants completed an eligibility and consent session, followed by a baseline assessment session with fMRI.They were subsequently randomized to PRT, placebo, or usual care with equal probability, balancing on age, sex, baseline pain, and opioid use using an imbalanceminimization algorithm 40 (eMethods in Supplement 2).The primary end point (posttreatment fMRI session) occurred 1 month after the baseline fMRI.Participants completed online follow-up assessments at 1, 2, 3, 6, and 12 months after the primary end point (Figure 1).

Interventions
PRT 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 pain [41][42][43][44][45][46][47][48] and with the cognitive behavioral treatment of panic disorder. 66articipants completed a 1-hour telehealth evaluation and education session with a physician (H.S.) assessing likely centralized vs peripheral contributions to pain, including a review of available preexisting spinal imaging.Assessment find-

Key Points
Question Can a psychological treatment based on the reappraisal of primary chronic back pain as due to nondangerous central nervous system processes provide substantial and durable pain relief?
Findings In this randomized clinical trial, 33 of 50 participants (66%) randomized to 4 weeks of pain reprocessing therapy were pain-free or nearly pain-free at posttreatment, compared with 10 of 51 participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual care, with gains largely maintained through 1-year follow-up.Treatment effects on pain were mediated by reduced beliefs that pain indicates tissue damage, and longitudinal functional magnetic resonance imaging showed reduced prefrontal responses to evoked back pain and increased resting prefrontal-somatosensory connectivity in patients randomized to treatment relative to patients randomized to placebo or usual care.
Meaning Psychological treatment focused on changing beliefs about the causes and threat value of primary chronic back pain may provide substantial and durable pain relief.
ings and centralized pain education were shared with the patient (eAppendix 1 in Supplement 2).
Participants then completed 8 individual 1-hour therapy sessions with a therapist with extensive PRT experience (A.G. or C.U.) twice weekly for 4 weeks.Techniques included (1) providing personalized evidence for centralized pain; (2) guided reappraisal of pain sensations while seated and while engaging in feared postures or movements; (3) techniques addressing psychosocial threats (eg, difficult emotions) potentially amplifying pain; and (4) techniques to increase positive emotions and self-compassion.PRT followed the treatment protocol found in eAppendix 2 in Supplement 2.
Treatment fidelity was assessed by independent raters coding audiorecordings of PRT sessions (eMethods and eAppendix 3 in Supplement 2).A mean (SD) of 4.93 (0.87) of 6 PRT elements were present in each session, and all sessions included at least 3 elements, indicating high treatment fidelity.
Open-label Placebo Plus Usual Care Participants watched 2 videos describing how placebo treatments can powerfully relieve pain even when known to be inert (eg, they can automatically trigger the body's natural healing response). 49 subcutaneous injection described as saline was administered by a physician (K.K.) at the site of greatest back pain during an empathic, validating clinical encounter at an orthopedic medical center.1][52] Participants in this group were also asked to continue their ongoing care as usual and not start other new treatments until after the study period.

Usual Care
Participants in this group were given no additional treatment.They agreed to continue their ongoing care as usual and  not start new treatments before the posttreatment assessment.After the posttreatment assessment, they were given a chronic pain workbook 53 and access to http://www.unlearnyourpain.com.

Clinical Measures
The primary outcome was average pain over the last week on a numerical rating scale from 0 to 10 from the Brief Pain Inventory Short Form, assessed at the 1-month postbaseline session.We also calculated the proportion of participants reporting pain reduction of 30% or more, pain reduction of 50% or more, and a pain score of 0 or 1, indicating a pain-free or nearly pain-free state.Secondary outcomes included pain interference (Oswestry Disability Index); Patient-Reported Outcome Measurement Information System (PROMIS) short forms for depression, anxiety, anger, and sleep quality; and the Positive and Negative Affect Scale (measure details in the eMethods in Supplement 2).We considered 3 measures of pain beliefs as potential mediators: (1) the Tampa Scale of Kinesiophobia (TSK-11), assessing belief that pain indicates injury and fear of movement; (2) the Pain Catastrophizing Scale (PCS); and (3) the Survey of Pain Attitudes Emotion subscale (SOPA-Emotion), assessing beliefs that stress and negative emotion increase pain.Adverse events were recorded when participants spontaneously reported them to study personnel.Baseline pain was computed as the average score from 2 prerandomization assessments (eligibility session and pretreatment fMRI session).

Neuroimaging Measures
Structural T1 and multiband blood oxygenation leveldependent functional imaging was conducted on a 3-T Siemens Prisma Fit MRI scanner with standard fMRI preprocessing (eMethods in Supplement 2).During fMRI, participants completed (1) an evoked back pain task with a series of randomly ordered trials distending the back to 1 of 4 intensity levels and (2) a spontaneous pain scan in which participants rested and rated ongoing pain once per minute (design details in the eMethods in Supplement 2; fMRI data quality measures shown in eFigures 6 and 7 in Supplement 2).Participants rated pain during scanning on a visual analog scale from 0 (no pain) to 100 (worst pain imaginable).

Statistical Analyses
Intent-to-treat analyses (including all randomized patients) were performed for the primary outcome with a mixedeffects model (fitlme, MATLAB 2020a), including 2 group × time interactions (PRT vs placebo × posttreatment vs pretreatment and PRT vs usual care × posttreatment vs pretreatment), covariates for age and sex, and a random intercept per participant.Treatment response rates for 30% or greater reduction in pain, 50% or greater reduction in pain, and a painfree or nearly pain-free state at posttreatment and 1-year follow-up were based on all randomized patients; those missing data were considered nonresponders.For follow-up time points and secondary outcomes, we calculated Hedges g for the PRT vs placebo and PRT vs usual care comparisons.Follow-up time points were analyzed individually, testing group differences in change from baseline to each time points.The placebo vs usual care comparison will be reported elsewhere.
To investigate psychological treatment mechanisms, we (1) correlated pretreatment to posttreatment changes in pain intensity with pretreatment to posttreatment changes in pain beliefs (TSK-11, PCS, and SOPA-Emotion) within each group and (2) tested pretreatment to posttreatment changes in pain beliefs as mediators of treatment effects on pain at follow-up timepoints (1 through 12 months posttreatment), controlling for baseline pain.PRT vs placebo and PRT vs usual care were tested in separate models.We also tested the reverse: whether pretreatment to posttreatment pain reductions mediated treatment effects on pain beliefs at follow-up, controlling for baseline pain beliefs (eMethods in Supplement 2).Correlational and mediation analyses were not prespecified in the trial protocol.

Evoked Back Pain Analyses
An evoked back pain localizer identified brain regions positively associated with evoked back pain intensity at baseline.The localizer was conducted within a mask of regions of interest (medial prefrontal, posteromedial, insula, cingulate, and somatosensory cortices; amygdala; and nucleus accumbens; eMethods and eFigure 1 in Supplement 2; localizer task design in eFigure 8 in Supplement 2).We tested for treatment effects (group × time interactions) in the average activity of clusters positively associated with evoked back pain using a mixedeffects (random-effects) model, applying a 1-tailed threshold of P < .05owing to directional hypotheses that PRT would reduce activity in pain-positive clusters.

Spontaneous Pain Connectivity Analyses
Evoked pain analyses identified group × time interactions in the anterior insula, anterior midcingulate (aMCC), and a prefrontal region.We submitted these 3 regions as seeds to connectivity analyses in the spontaneous pain scan.We conducted permutation tests (threshold-free clusterenhancement; eMethods in Supplement 2) testing for group × time interactions in connectivity between these seed regions and 2 areas most often demonstrating altered connectivity in chronic pain: (1) the midline default mode network, including the medial prefrontal and posteromedial cortex, and (2) primary somatosensory cortex (S1) 36,54-59 (masks in eFigure 2 in Supplement 2).
Of 50 participants randomized to PRT, 44 (88%) completed all treatment sessions and the posttreatment assess-ment.Five participants dropped out prior to initiating PRT and 1 had an unrelated medical emergency.Of 51 participants randomized to placebo, 44 (86%) received the treatment, all of whom completed the posttreatment assessment.Of the 50 participants randomized to usual care, 47 (94%) completed the posttreatment assessment (Figure 1).
Twenty patients in the PRT group had preexisting spinal imaging, all of which showed at least 1 spinal anomaly (median of 4 findings per patient; eTable 1 in Supplement 2) assessed by a physician (H.S.) as not causal of pain (eMethods and eAppendix 1 in Supplement 2). 61

Clinical Outcomes
Patients randomized to PRT reported substantial reductions in pain intensity at posttreatment compared with both control groups, 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 (Figure 2; Table 2).Patients in the PRT group reported a pain reduction of 1.79 (on the 0 to 10 numerical rating scale) relative to placebo (t 137.63 = 6.06;P < .001;g, −1.14; 95% CI, −1.65 to −0.71) and reported a pain reduction of 2.40 relative to the usual care group (t 135.69 = 8.13; P < .001;g, −1.74; 95% CI, −2.28 to −1.32).A total of 33 of 50 patients randomized to PRT (66%), corresponding to 73% of the 45 patients who initiated PRT, were pain-free or nearly pain-free at posttreatment, compared with 10 of 51 patients (20%) in the placebo group and 5 of 50 patients (10%) in the usual care group.At 1-year followup, effects of PRT on pain remained large relative to both control groups, 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)(Table 2; treatment response rates in eTable 2 in Supple- Analyses of secondary outcomes at posttreatment revealed significant reductions in disability and anger for PRT vs both controls (g, −0.62 to −1.7; P < .005)and improvements in sleep (g, −0.56; P = .009)and depression (g, −0.63; P = .003)relative to usual care (Table 2).Treatment gains on secondary outcomes were largely maintained at 1-year follow-up (Table 2).Significant PRT vs control effects were observed at posttreatment for positive affect (Positive and Negative Affect Schedule; g for PRT vs placebo, 0.63, g for PRT vs usual care, 0.59; P < .005;eTable 3 in Supplement 2) but not for negative affect or alcohol, cannabis, or opioid use (eTable 3 in Supplement 2).Treatment satisfaction was high among participants in the PRT group (eTable 4 in Supplement 2).

Mediation Analyses
Pretreatment to posttreatment reductions in TSK-11 and pain intensity scores were correlated among participants in the PRT group (r 42 = 0.44; P = .003;eFigure 4 in Supplement 2).This correlation was not significant for the placebo condition (r 42 = 0.16; P = .29)or usual care condition (r 45 = 0.27; P = .07).Pretreatment to posttreatment changes in PCS and SOPA-Emotion scores did not correlate with pain reductions within any group.
Pretreatment to posttreatment reductions in TSK-11 scores mediated PRT vs placebo and PRT vs usual care effects on pain intensity at most follow-up time points (eFigure 4 and eTables 5 and 6 in Supplement 2).The reverse was also true: pretreatment to posttreatment pain reductions mediated PRT vs placebo and PRT vs usual care effects on TSK-11 at follow-up.Pretreatment to posttreatment changes in PCS and SOPA-Emotion did not mediate PRT vs control effects at any follow-up time point.Treatment effects on TSK-11 were very large at posttreatment (g for PRT vs placebo, −1.90; g for PRT vs usual care,−1.67;P < .001).
Neither age nor sex moderated the treatment effect on pain intensity (eMethods in Supplement 2).No adverse events were reported for PRT.
We submitted the aMCC, aPFC, and aIns regions exhibiting treatment effects in evoked pain analyses as connectivity seed regions in the spontaneous pain task.Within S1, PRT vs placebo and PRT vs usual care led to increased aPFC-and

Discussion
PRT yielded large reductions in CBP intensity relative to openlabel placebo and usual care control conditions in a community sample, with nearly two-thirds of randomized patients and 73% of those initiating PRT reporting they were pain-free or nearly pain-free at posttreatment.Large effects of PRT on pain continued at 1-year follow-up.PRT also reduced experimentally evoked back pain and spontaneous pain during fMRI with large effect sizes, and several secondary outcomes (eg, disability and anger) also improved for PRT relative to the control groups.
PRT targets primary (nociplastic) pain by shifting patients' beliefs about the causes and threat value of pain.3][24][25][26][27] PRT builds on and extends existing psychological treatment models.Cognitive-behavioral, acceptance-based, and mindfulnessbased interventions typically aim to improve functioning by decreasing pain catastrophizing, enhancing pain coping or acceptance, and promoting engagement in valued life activities. 41,44,46,48,62Exposure-based treatments share with PRT an emphasis that painful activities are not injurious, 42,63-65 but do not emphasize reappraising pain sensations and reattributing the causes of pain.Some pain neuroscience education interventions present pain in a similar way as PRT, 43 though they typically lack guided exposure and reappraisal exercises.
Large reductions in pain are rarely observed in CBP psychological treatment trials. 11,12Relatively unique components of PRT potentially contributing to the observed effects include (1) an in-depth medical and psychological assessment generating personalized evidence for centralized pain; (2) reattribution of pain to reversible learning-and affect-related brain processes rather than bodily injury; and (3) a unique combination of cognitive, somatic, and exposure-based techniques supporting pain reappraisal (eDiscussion in Supplement 2).
Correlational and mediational analysis results support changes in fear-inducing pain beliefs as a potential PRT mechanism.Effects of PRT on pain beliefs were also mediated by pain intensity reductions, perhaps because pain reductions promote beliefs in pain modifiability (eDiscussion in Supplement 2).Changes in pain beliefs are not unique to PRT, but PRT may more strongly change these beliefs compared with existing therapies (eTable 6 in Supplement 2).
These hypothesized mechanisms are consistent with extinction-based treatment approaches to anxiety disorders. 42,65or example, 85% of patients became free of panic symptoms following treatment focused on reappraising somatic symptoms as caused by nondangerous central nervous system processes (eg, false alarms). 66RT reduced evoked pain-related activity in aPFC, aMCC, and aIns.The aPFC and adjacent dorsolateral prefrontal cortex (dlPFC) are implicated in the detection and inhibition of pain. 67aPFC reductions following PRT suggest a potential reduction of painrelated signals or decreased prioritization of pain control.9][70] Cognitive pain regulation strategies, including mindful acceptance 38,39 and placebo analgesia, 24,25,28 have been found to reduce aMCC and aIns responses to pain, demonstrating parallels between experimental findings and our clinical findings.The aIns reductions in our study were not specific to PRT vs placebo and may reflect processes common to both these interventions.
PRT also increased aPFC and aIns connectivity to S1, aligning with previous findings that cognitive behavioral therapy for fibromyalgia 57 and acupuncture for CBP 55 increased aIns-S1 connectivity.Increased aPFC and aIns connectivity to S1 may reflect increased attention to somatosensory input in constructing pain. 71This is congruent with mindfulness-based treatments promoting nonreactive attention to bodily sensations, reducing catastrophizing. 38,39,48,71Yet, increased S1 connectivity has also been associated with increased clinical pain, 72 and the role of S1 connectivity remains unclear. 55PRT vs usual care also increased aMCC-precuneus connectivity, with intermediate effects observed in participants receiving placebo treatment.Altered default mode connectivity has often been reported in chronic pain, although typically with heightened connectivity for patients vs controls (eDiscussion in Supplement 2). 36,54,56,58,59mitations This study has limitations.The study sample was relatively well educated and active and reported long-standing low to moderate pain and disability at baseline.The physician and therapists were experts in the treatment model.Future studies should test generalizability to other patient populations, therapists, and treatment contexts (eDiscussion in Supplement 2).The fMRI effect sizes were modest, with some results not surviving whole-brain correction (eMethods in Supplement 2).Future trials should test PRT efficacy relative to leading psychological and medical treatments (eDiscussion in Supplement 2).

Conclusions
Overall, our findings raise key possibilities about the nature and treatment of primary CBP.Changing fear-and avoidance-inducing beliefs about the causes and threat value of pain may provide substantial, durable pain relief for people with primary CBP.

Figure 3 .
Figure 3. Effects of Treatment on Evoked and Spontaneous Back Pain and Related Brain Function Evoked back pain-related activation B Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research jamapsychiatry.com(Reprinted) JAMA Psychiatry January 2022 Volume 79, Number 1

Table 2 .
Primary and Secondary Clinical Outcomes Effect sizes show the group difference in change from baseline (group × time interaction), including all available data at the follow-up time point and corresponding baseline data for effect size computation.b Hedges g and SE estimated with bootstrapping procedure.Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain Original Investigation Research a jamapsychiatry.com(Reprinted) JAMA Psychiatry January 2022 Volume 79, Number 1 A,Errorbarsshowstandarderror.B,Coordinatesandstatisticsforactivationsprovided in eTable 7 in Supplement 2; analyses conducted within a mask of regions of interest; eFigure 1 in Supplement 2. C, Decreased evoked pain-related activity was observed in anterior midcingulate (aMCC) and anterior prefrontal regions for PRT vs placebo and left anterior insula for PRT vs usual care.D, Error bars show standard error.E, PRT vs control conditions increased aPFC-seeded (red clusters) and aIns-seeded (green clusters) connectivity with primary somatosensory cortex (permutation test, P < .05).Inset shows seed regions, derived from evoked pain analyses; magenta outlines, PRT vs placebo; black outlines, PRT vs usual care.F, PRT vs usual care increased connectivity between an aMCC seed (yellow; derived from evoked back pain analyses) and the precuneus (orange).Connectivity analyses were conducted within primary somatosensory cortex and medial default mode network masks.-seededconnectivity to 4 distinct S1 subregions (permutation test COPE-MAX, 3.55-3.91;P<.05).Within the medial default mode network, PRT vs usual care increased aMCCprecuneus connectivity (permutation test COPE-MAX, 4.23; P = .01;Figure3E;cluster coordinates and statistics in eTable 8 in Supplement 2).No group × time interactions were found for aPFC-or aIns-seeded connectivity to default mode network regions or for aMCC-seeded connectivity to S1.