Ashar et al. · JAMA Psychiatry, 2021 · Randomized Controlled Trial (n=151)

Key Finding: A four-week neuroplastic intervention produced large and durable reductions in chronic back pain, with 66% of participants pain-free or nearly pain-free after treatment.

In 151 adults with chronic back pain (average duration ~10 years), mean pain decreased from 4.10/10 at baseline to 1.18/10 post-treatment in the PRT group, compared to 2.84 in placebo and 3.13 in usual care. At post-treatment, 66% of PRT participants were pain-free or nearly pain-free (vs 20% placebo, 10% usual care). Benefits remained significant at 1-year follow-up. fMRI showed reduced activation in anterior midcingulate and insula regions and increased prefrontal–somatosensory connectivity.

This landmark study demonstrates that changing pain-related beliefs and threat appraisal can substantially alter both subjective pain and brain function, supporting neuroplastic models of chronic pain recovery.

Ashar et al. · 5-Year Follow-Up Study · Randomized Trial Extension (n=151; 75% retained)

Key Finding: Over half of patients receiving Pain Reprocessing Therapy remained pain-free or nearly pain-free five years later.

At 5-year follow-up, 55% of participants originally assigned to PRT reported pain scores of 0–1/10, compared to 26% in placebo and 36% in usual care. Mean pain intensity remained significantly lower in PRT (1.87) versus placebo (3.10) and usual care (2.53). Reductions in harm beliefs and activity avoidance persisted, along with increased mind–brain attributions of pain.

In the five-year follow-up to the above landmark study, the authors provide rare long-term evidence that chronic back pain remission is durable when patients shift from structural damage beliefs to brain-based interpretations of pain.

Lumley et al. · PAIN, 2017 · Cluster Randomized Controlled Trial (n=230)

Key Finding: An emotion-focused therapy targeting trauma and conflict improved fibromyalgia symptoms and produced higher rates of substantial pain reduction than CBT or education.

In this 230-patient cluster RCT, EAET was compared to CBT and fibromyalgia education across 8 sessions. While EAET did not significantly outperform education on the primary pain severity measure, it led to greater improvements in overall symptoms, widespread pain, physical functioning, depression, and anxiety (effect sizes d≈0.29–0.45). Notably, 22.5% of EAET patients achieved ≥50% pain reduction compared to 8.3% in CBT. At 6-month follow-up, 34.8% of EAET participants reported being “much” or “very much” improved versus 15.4% in education.

This trial shows that directly addressing avoided emotions and unresolved trauma can meaningfully reduce centralized pain. It supports the model that fibromyalgia symptoms are maintained by CNS amplification processes that can be modified through corrective emotional experiences.

Yarns et al. · Pain Medicine, 2020 · Randomized Clinical Trial (n=53)

Key Finding: EAET produced significantly greater reductions in pain severity than CBT, with 42% achieving clinically significant improvement (≥30% reduction) compared to 4% in CBT.

In this randomized clinical trial of older veterans (mean age 73.5) with chronic musculoskeletal pain, participants received one individual session and eight group sessions of either EAET or CBT. EAET resulted in significantly lower pain severity at post-treatment and at 3-month follow-up. At post-treatment, 42% of EAET participants achieved ≥30% pain reduction compared to 4% in CBT; 29% achieved ≥50% reduction versus 0% in CBT. EAET also showed advantages over CBT on measures of pain interference and anxiety. Effect sizes for pain reduction were in the moderate-to-large range.

This trial demonstrated that emotionally focused, trauma-informed therapy can outperform traditional cognitive-behavioral coping approaches for chronic pain in older adults. The findings support the role of unresolved emotional conflict and stress in maintaining neuroplastic pain and suggest that directly processing avoided emotions may yield stronger and more durable symptom reduction than skills-based coping strategies alone.

Yarns et al. · JAMA Network Open, 2024 · Randomized Clinical Trial (n=126)

Key Finding: EAET was superior to CBT for reducing pain severity, with 63% of EAET participants achieving clinically significant (≥30%) pain reduction versus 17% in CBT at posttreatment.

In this randomized clinical trial of older veterans (mean age 71.9) with chronic musculoskeletal pain, participants received one 90-minute individual session plus eight 90-minute group sessions of either EAET or CBT. EAET produced significantly greater reductions in pain severity from baseline to the primary endpoint at week 10 and maintained superiority at six-month follow-up. At posttreatment, 63% of participants in EAET achieved at least a 30% pain reduction compared to 17% in CBT; 35% of EAET participants achieved ≥50% reduction versus 7% in CBT. EAET also yielded greater improvements than CBT in anxiety, depression, general life satisfaction, PTSD symptoms, and patient global impression of change, with higher baseline emotional distress moderating stronger response to EAET.

This large and diverse RCT provides strong evidence that targeting emotional awareness and expression — especially in populations with significant psychiatric comorbidity — can produce more robust pain relief and broader psychological benefits than standard CBT for chronic pain. The results support integrating trauma-informed, emotion-focused therapeutic principles into mainstream chronic pain treatment.

Donnino et al. · PAIN Reports, 2021 · Pilot Randomized Controlled Trial (n=35)

Key Finding: A 12-week psychophysiologic intervention produced significant reductions in disability and pain, with nearly two-thirds of participants pain-free at 6 months.

In this three-arm pilot RCT, adults with nonspecific chronic back pain were randomized to PSRT, mindfulness-based stress reduction (MBSR), or usual care. Roland–Morris Disability scores in the PSRT group decreased from 9.5 to 3.3 at 26 weeks (P=0.04 vs. MBSR; P=0.03 vs. usual care). At 26 weeks, 63.6% of PSRT participants reported being completely pain-free, compared with 25.0% in MBSR and 16.7% in usual care. Pain-related anxiety and bothersomeness also improved significantly.

This study supports the hypothesis that many cases of chronic back pain are centrally mediated and reversible. Addressing conditioned pain responses and emotional stressors produced clinically meaningful recovery beyond mindfulness alone.

Sturgeon et al. · Regional Anesthesia & Pain Medicine, 2025 · Pilot Open-Label Trial (n=35)

Key Finding: A 3-session telehealth version of Pain Reprocessing Therapy produced meaningful reductions in fibromyalgia pain and interference.

In this pilot study, 35 adults with fibromyalgia completed a 3-session Brief Pain Reprocessing Therapy protocol delivered via telehealth. Completion rate was 94%. Participants showed significant reductions in pain intensity (d=0.56 at 1 month; d=0.89 at 3 months), pain interference (d=1.06 at 3 months), and pain-related fear. At 3 months, 42.3% reported being “much” or “very much” improved.

These findings suggest that targeting threat processing and learned pain responses can reduce fibromyalgia symptoms — even with a brief, scalable intervention. This strengthens evidence that centralized pain is modifiable through neuroplastic retraining.

Donnino et al. · Mayo Clinic Proceedings: Innovations, Quality & Outcomes, 2023 · Interventional Cohort Study (n=23)

Key Finding: A 13-week psychophysiologic program significantly reduced long-COVID symptom burden, with large improvements across fatigue, dyspnea, and pain.

In adults with persistent PASC symptoms and no organ injury, Somatic Symptom Scale-8 scores decreased by 10.9 points at 13 weeks (P<.001). Median symptom duration before enrollment was 267 days. Significant improvements were also observed in fatigue, dyspnea, pain intensity, and functional limitations. Participants received ~44 hours of PSRT delivered virtually.

These findings extend neuroplastic models beyond back pain to complex multisystem symptoms. Even in long-COVID, centrally mediated symptom processes appear modifiable through targeted mind–body intervention.

Kohns et al. · 2020 · Randomized Controlled Trial

Key Finding: A brief, internet-based pain neuroscience intervention significantly reduced pain-related distress and maladaptive beliefs about pain.

In this randomized trial, participants with chronic pain completed an online self-guided intervention focused on pain neuroscience education and psychological contributors to chronic pain. Compared to control conditions, the intervention group showed significant reductions in pain catastrophizing, fear-avoidance beliefs, and pain-related distress. Improvements were associated with increased understanding of neuroplastic pain mechanisms.

This study demonstrates that educating patients about brain-based pain mechanisms can meaningfully reduce maladaptive pain beliefs — even without intensive therapy — supporting the importance of cognitive reframing in chronic pain recovery.

Fitzcharles et al. · The Lancet, 2021 · Narrative Review

Key Finding: Many common chronic pain conditions reflect altered central pain processing (nociplastic pain), not ongoing tissue damage.

This Lancet review introduces nociplastic pain as a third mechanistic category distinct from nociceptive and neuropathic pain. The authors describe amplified CNS processing, altered descending inhibition, widespread hyperalgesia, and comorbid symptoms such as fatigue, sleep disturbance, and cognitive dysfunction. Epidemiologic estimates suggest 5–15% of the general population may have nociplastic pain conditions, including fibromyalgia, IBS, and chronic primary musculoskeletal pain.

The nociplastic framework provides scientific validation for brain-based chronic pain and explains why many patients have severe symptoms despite minimal structural findings. It directly supports neuroplastic treatment approaches targeting central processing rather than peripheral tissue.

Lumley & Schubiner · Psychosomatic Medicine, 2019 · Clinical Model Review

Key Finding: Centralized pain can often be substantially reduced — and sometimes eliminated — by targeting cognitive, emotional, and interpersonal drivers.

This integrative treatment model distinguishes centralized (nociplastic) pain from peripheral nociceptive pain and outlines a stepped intervention approach: pain neuroscience education, cognitive and behavioral exposure, emotional processing of trauma and conflict, and adaptive communication strategies. The authors review evidence suggesting modest effects for CBT alone (d ≈ .2–.4) and argue that incorporating emotional processing yields stronger outcomes.

This model reframes chronic pain as a reversible brain-generated process in many patients. It expands treatment beyond symptom management toward addressing emotional and relational triggers that perpetuate pain signaling.

Schubiner et al. · The Journal of Pain, 2024 · Clinical Study (n=222)

Key Finding: Using a structured diagnostic approach, 88% of chronic back/neck pain patients were classified as having primary (nociplastic) pain despite near-universal spinal imaging abnormalities.

In this physiatry clinic study of 222 patients with chronic back or neck pain, 97.7% showed at least one spinal anomaly on imaging. However, applying a structured rule-out/rule-in diagnostic framework, 88.3% were diagnosed with primary (nociplastic) pain, 5% secondary pain, and 6.8% mixed pain. Primary pain patients were more likely to show spreading pain, light-touch sensitivity, stress-related exacerbation, and central sensitization features.

This study demonstrates how often imaging findings are incidental and supports the clinical reality that most chronic back pain is centrally mediated. Accurate diagnosis can redirect patients toward education and neuroplastic treatments rather than structural interventions.

Kaptchuk, Hemond & Miller · BMJ, 2020 · State-of-the-Art Review

Key Finding: Placebo effects in chronic pain are real, biologically mediated, and can account for 50–75% of observed treatment responses in many trials.

Reviewing large meta-analyses across osteoarthritis, fibromyalgia, IBS, migraine, and neuropathic pain, placebo response rates commonly ranged from 30–50%, sometimes accounting for up to 75% of total treatment effect. The authors argue that predictive coding and Bayesian brain models help explain how expectations and contextual cues shape symptom perception. Open-label placebo studies also demonstrate symptom improvement without deception.

This review reframes placebo effects as evidence of the brain’s role in symptom generation and relief. It supports the legitimacy of harnessing expectation, context, and therapeutic alliance in treating chronic pain.

Ongaro & Kaptchuk · PAIN, 2019 · Topical Review

Key Finding: The brain constructs symptoms through predictive processes; pain reflects the brain’s best inference about bodily state, not a direct readout of tissue damage.

This review applies Bayesian predictive coding models to symptom perception. The brain continuously generates top-down predictions about bodily states and updates them based on incoming sensory input. When predictions of threat or danger are assigned high “precision,” pain can persist even without structural pathology. Relief occurs when predictions are revised and threat inference decreases.

This framework provides a neurocomputational explanation for neuroplastic pain recovery. Changing beliefs, expectations, and contextual cues can recalibrate predictive models and reduce chronic pain.

Van den Bergh et al. · Neuroscience & Biobehavioral Reviews, 2017 · Theoretical Review

Key Finding: Symptom perception is shaped by predictive brain processes that integrate expectations, prior learning, and bodily signals.

This review proposes that many physical symptoms arise from inferential brain processes rather than direct tissue damage. Predictive coding models suggest the brain generates symptom experiences based on prior beliefs, context, and learned associations. When expectations are strong, top-down predictions can dominate sensory input, leading to persistent symptoms even in the absence of ongoing pathology.

Offers a cognitive-neuroscientific framework explaining how chronic pain can persist through learned neural predictions. Supports the rationale for therapies that update threat beliefs and alter symptom expectations.

Barrett & Simmons · Nature Reviews Neuroscience, 2015 · Theoretical Neuroscience Model

Key Finding: The brain actively predicts bodily sensations; perception reflects top-down predictions constrained by sensory input rather than passive stimulus response.

The Embodied Predictive Interoception Coding (EPIC) model proposes that agranular visceromotor cortices generate predictions about bodily states, while sensory cortices compute prediction error. Perception, including pain, emerges from minimizing discrepancies between prediction and incoming sensory signals. Disruptions in predictive regulation may contribute to both mental and physical illness.

Provides a neuroscientific framework explaining how chronic pain can persist without tissue damage: the brain’s predictive models can maintain pain through learned threat expectations.

Lumley et al. · PAIN, 2022 · Topical Review

Key Finding: Trauma-focused interventions reduce PTSD symptoms and can meaningfully reduce chronic pain — particularly in centralized pain conditions.

This review examines trials targeting trauma in individuals with chronic pain. Meta-analytic findings show large reductions in PTSD symptoms (≈0.79 SD) and moderate reductions in pain intensity (≈0.51 SD) following trauma-focused therapies. Interventions such as EMDR and short-term psychodynamic therapy demonstrated clinically meaningful pain reductions, especially in centralized pain syndromes.

The review highlights trauma and adversity as key drivers of chronic pain in many patients. Addressing unresolved trauma may reduce pain by decreasing nervous system sensitization and emotional threat signaling.

Aaron & Lumley et al. · 2020 · Clinical Review / Theoretical Model

Key Finding: Difficulties in emotion regulation may underlie both chronic pain persistence and problematic opioid use.

This paper proposes that impaired emotional processing and avoidance amplify pain-related distress and increase reliance on opioids for affect regulation. The authors review evidence linking alexithymia, trauma exposure, and emotion suppression to greater pain severity and opioid misuse risk. Interventions targeting emotional awareness and expression are proposed as mechanisms to reduce both pain and opioid dependence vulnerability.

Suggests that chronic pain is not solely sensory but intertwined with emotional processing systems, reinforcing the importance of addressing fear, avoidance, and unresolved emotion in neuroplastic pain treatment.

Schubiner et al. · Journal of General Internal Medicine, 2023 · Theoretical & Empirical Review

Key Finding: Chronic exposure to racism-related stress may activate brain-based danger signaling and contribute to persistent pain.

This article synthesizes research showing that Black Americans experience higher rates of chronic pain and greater pain-related disability. Studies estimate that millions of adults may experience chronic pain linked to discrimination-related stress. The authors integrate predictive processing models of pain, arguing that repeated exposure to racial stressors can amplify central threat responses and sustain nociplastic pain.

This work extends neuroplastic pain models to sociocultural stress. It highlights that chronic pain can emerge not only from physical injury but from persistent psychosocial threat — reinforcing the importance of addressing trauma and stress in treatment.

Yarns et al. · Neuroscience & Biobehavioral Reviews, 2022 · Theoretical Mini-Review

Key Finding: Anger regulation and nociplastic pain show opposing patterns of activation in the medial prefrontal cortex and amygdala, suggesting a shared brain-based mechanism.

This review synthesizes behavioral and neuroimaging research linking anger and maladaptive anger regulation to nociplastic pain conditions (e.g., chronic back pain, fibromyalgia). Nociplastic pain is associated with altered activation and connectivity in affective brain regions including the mPFC and amygdala. Healthy anger regulation appears to normalize activity in these same regions. The authors propose the Anger, Brain, and Nociplastic Pain (AB-NP) model integrating emotional regulation, brain plasticity, and chronic pain mechanisms.

Provides neuroscientific grounding for emotion-focused and expressive therapies in chronic pain. Suggests that improving anger regulation may directly modify brain circuits involved in pain persistence.

Kross et al. · PNAS, 2011 · Experimental fMRI Study (n=40)

Key Finding: Social rejection activates brain regions associated with the sensory components of physical pain.

In this fMRI study of 40 individuals recently experiencing romantic rejection, participants viewed photos of their ex-partners while undergoing scanning. Social rejection activated the secondary somatosensory cortex (S2) and dorsal posterior insula — regions typically associated with physical pain processing — overlapping with neural activation during thermal pain stimulation. Activation patterns showed significant convergence between social and physical pain networks.

These findings provide neurological evidence that emotional pain is processed in overlapping brain regions with physical pain. This supports the view that social threat, loss, and rejection can directly activate pain circuitry — reinforcing neuroplastic models of chronic pain maintenance.

Schubiner, Schwartz & Siegel · Psychotherapy Networker, 2021 · Clinical Feature Article

Key Finding: Chronic pain can function as a protective response to unresolved emotional burdens, and working compassionately with internal “parts” may reduce pain.

This clinical article integrates Internal Family Systems (IFS) therapy with psychophysiologic pain concepts. The authors describe how “protector” parts may generate or amplify pain to shield vulnerable emotional “exiles.” Clinical examples illustrate how reducing fear, addressing trauma, and restoring internal safety can diminish chronic pain symptoms—even when imaging shows only normal age-related findings.

The article provides a therapeutic framework explaining how fear, avoidance, and unresolved emotional injury reinforce pain pathways. It offers a structured method for working directly with the psychological drivers of centrally maintained pain.

Sam Scott · Stanford Magazine, December 2022 · Research Feature on Alia Crum’s Work

Key Finding: Expectations and beliefs measurably influence physiology, pain perception, immune response, and treatment outcomes.

The article summarizes experiments from Alia Crum’s lab showing biological effects of mindset. Hotel housekeepers informed their work met exercise guidelines showed reductions in weight and blood pressure without behavioral change. Identical milkshakes labeled “indulgent” vs “sensible” produced different ghrelin responses. In pediatric immunotherapy, children encouraged to view symptoms as signs of healing showed improved antibody responses and less anxiety.

Demonstrates that beliefs function as biological inputs. Interpretation of symptoms and treatment meaning can alter physiological outcomes — a foundational principle in neuroplastic approaches to chronic pain recovery.