When Pain Is Real but the Injury Is Gone: Understanding Neuroplastic and Nociplastic Pain

When Pain Persists Longer Than the Injury

Patients with persistent pain often find themselves in an uncomfortable part of medicine. They know what they feel, yet imaging, laboratory testing, or the expected timeline of tissue healing may not provide a satisfying explanation for why the pain continues. One clinician may focus on an abnormality seen on imaging while another considers the finding incidental. Treatments directed at the presumed injury may help temporarily, fail altogether, or leave the patient with more questions than answers. After enough time, the uncertainty itself can become exhausting.

Active disease remains an important part of the differential diagnosis. Structural injury, inflammatory disease, autoimmune conditions, infection, peripheral nerve injury, neurologic disease, medication effects, endocrine abnormalities, poor sleep, metabolic dysfunction, and other medical problems can all contribute to persistent pain. The history, examination, symptom pattern, and appropriate testing still matter because a nervous-system explanation should never be used simply because an initial workup was unrevealing.

There are also patients in whom the original injury or inflammatory event has resolved while pain continues well beyond the expected period of healing. Others have symptoms whose intensity, distribution, or variability is difficult to reconcile with the structural findings. Pain science increasingly recognizes that altered processing within the nervous system can contribute to these presentations.

Nociplastic Pain and the Nervous System

The International Association for the Study of Pain defines nociplastic pain as pain arising from altered nociception despite no clear evidence that actual or threatened tissue damage activating peripheral nociceptors, or a disease or lesion of the somatosensory system, adequately explains the pain. Importantly, the IASP also notes that nociplastic pain can coexist with other forms of pain. A patient does not have to fit neatly into one mechanism.

The term neuroplastic pain is commonly used in clinical education to describe persistent pain in which learned nervous-system responses and altered perceptions of threat appear to play an important role. Neuroplasticity itself is not pathological. It is the normal ability of the brain and nervous system to change with experience, which is how we learn skills, form memories, adapt to repeated circumstances, and recover after certain injuries. The same capacity for adaptation can also reinforce protective responses.

Pain is one of those protective responses. Signals from the body are interpreted within a nervous system that is continuously using previous experience, context, attention, expectation, and perceived threat to decide what requires protection. After a severe episode of back pain, for example, bending may remain associated with danger long after tissue healing. A patient who has experienced repeated painful flares during particular activities may begin anticipating pain before the activity has meaningfully stressed the tissue. As these associations are repeated, the nervous system can become increasingly efficient at producing a protective response.

None of this requires the patient to consciously expect pain or to be unusually anxious. Learning within the nervous system occurs largely outside conscious awareness, just as many other physiologic responses do. The resulting pain remains a real sensory experience regardless of whether ongoing tissue injury is responsible for generating it.

The Diagnosis Requires Clinical Discipline

Recognizing nociplastic or neuroplastic features requires more care than simply noting that an MRI is normal. New neurologic deficits, progressive weakness, unexplained weight loss, fever, inflammatory findings, persistent night pain, new severe headache, chest pain, abdominal or pelvic pain, evidence of infection, malignancy, fracture, vascular disease, or a changing clinical picture may require additional evaluation. The appropriate workup depends on the patient's history and presentation.

The same caution applies when imaging does reveal abnormalities. Degenerative changes are common with aging and may or may not account for symptoms, but it would be equally inappropriate to assume that every structural finding is irrelevant. Patients frequently have mixed presentations in which structural disease, inflammation, sleep disruption, hormonal changes, psychological stress, physical deconditioning, central sensitization, and altered pain processing contribute in different proportions.

Patterns can sometimes suggest that altered nervous-system processing deserves consideration. Pain may move or fluctuate considerably, become more intense during periods of stress, persist after expected healing, appear in several locations over time, or change markedly according to attention and context. Those observations can inform the assessment, although none of them establishes a neuroplastic mechanism on its own.

Howard Schubiner and Unlearn Your Pain

Howard Schubiner, MD, has spent years working with patients whose chronic pain and other persistent symptoms cannot be adequately explained by continuing tissue injury. His book Unlearn Your Pain and subsequent educational work describe pain through the interaction of nervous-system processing, previous experience, emotional stress, fear, attention, and learned associations with danger.

Dr. Kathryn Retzler and Daniel Soule have both read or listened to Schubiner's work, and Dr. Retzler has pursued approved continuing medical education in this area. One reason his work has been of interest to us is that it provides a more clinically useful framework than the vague language often associated with “mind-body” medicine. The body does not disappear from the explanation. Instead, the nervous system is treated as part of the body's physiology and as a system capable of learning protective responses that may persist after circumstances change.

Schubiner has applied these ideas to chronic back pain and has discussed their potential relevance to conditions that may include nociplastic or centrally mediated components, including migraine, fibromyalgia, irritable bowel syndrome, pelvic pain, and some other persistent symptom syndromes. These conditions are heterogeneous, however, and the presence of a possible neuroplastic component does not establish that it is the principal cause of an individual patient's symptoms.

Pain Reprocessing Therapy and Chronic Back Pain

One of the better-known clinical studies in this field evaluated Pain Reprocessing Therapy (PRT) in 151 adults with primary chronic back pain. Published in JAMA Psychiatry, the randomized clinical trial compared four weeks of PRT with an open-label placebo intervention and usual care. PRT was designed to help participants reinterpret pain as arising from nondangerous central nervous system processes while reducing fear associated with movement and bodily sensations.

At the end of treatment, 33 of 50 participants assigned to PRT, or 66%, were pain-free or nearly pain-free. The corresponding figures were 20% in the placebo group and 10% among participants receiving usual care. Improvements were largely maintained through the original one-year follow-up, and the investigators found that reductions in beliefs that pain indicated tissue damage helped mediate the treatment effect.

The research became more interesting when five-year follow-up data were published in JAMA Psychiatry in 2025. Of the 151 original participants, 113 provided five-year data. Among respondents, 55% of those originally assigned to PRT were nearly or completely pain-free, compared with 26% in the placebo group and 36% in the usual-care group. Participants in the PRT group also showed persistent improvements in pain interference and beliefs about bodily harm.

Those results support the possibility of durable improvement in appropriately selected patients, although the study has boundaries that should remain visible when discussing it. The original participants had primary chronic back pain of generally low to moderate severity, and the trial does not establish PRT as an appropriate treatment for every cause of back pain or for chronic pain as a whole. Structural disease, inflammatory disorders, fracture, malignancy, infection, neurologic compromise, and other medical causes remain separate clinical problems requiring appropriate management.

Fibromyalgia and Emotional Awareness and Expression Therapy

Related research has explored Emotional Awareness and Expression Therapy (EAET) in fibromyalgia. A randomized trial led by Mark Lumley and colleagues compared EAET with cognitive behavioral therapy and an education intervention. The approach focused on emotional awareness, interpersonal experiences, and the relationship between stress and pain processing rather than treating fibromyalgia as a purely psychological disorder.

The trial found improvements on several outcomes and led the investigators to describe EAET as an additional treatment option for fibromyalgia. As with PRT, this evidence is most useful when it broadens the therapeutic discussion rather than being used to replace medical care. Fibromyalgia is clinically complex, and patients commonly have sleep disorders, migraine, mood symptoms, metabolic issues, autonomic complaints, gastrointestinal symptoms, hormonal changes, or other conditions that may require attention alongside pain-directed therapy.

Long COVID Requires a More Cautious Discussion

Long COVID illustrates why persistent symptoms should not be placed casually into a neuroplastic framework. The condition can involve post-exertional malaise, dysautonomia, cardiopulmonary symptoms, sleep disruption, cognitive problems, pain, and other manifestations with potentially different underlying mechanisms. Current CDC clinical guidance specifically recognizes post-exertional malaise, in which even minor physical or mental exertion may produce delayed worsening of symptoms that can last for days or weeks.

That matters because a patient with post-exertional malaise should not automatically be encouraged to push through symptoms on the assumption that activity avoidance reflects fear or learned danger. Management has to account for the physiologic response to exertion and the individual's clinical presentation.

At the same time, an acute infection is a significant physiologic event, and persistent illness can affect autonomic regulation, sleep, pain processing, threat perception, physical conditioning, and the way bodily sensations are interpreted. Neuroplastic or sensitization mechanisms may therefore contribute to symptoms in some patients without providing a complete explanation for Long COVID itself. Keeping those possibilities separate allows clinicians to consider nervous-system mechanisms without reducing a complex post-infectious illness to them.

How HormoneSynergy® Thinks About Persistent Symptoms

HormoneSynergy® approaches chronic symptoms from the evaluation side of medicine. Thyroid physiology, menopause and hormone changes, glucose regulation, inflammation, sleep, cardiovascular health, body composition, cognition, medications, nutritional status, and other clinical variables can materially affect how someone feels. When one of those problems is present and treatable, it belongs in the medical plan.

This broader evaluation is also why nociplastic and neuroplastic pain deserve a place in the discussion. Persistent symptoms frequently emerge from several influences rather than a single isolated diagnosis. A patient can have an orthopedic injury that has healed while sleep deprivation continues to increase pain sensitivity. Menopause can alter sleep, migraine patterns, mood, musculoskeletal symptoms, and pain perception. A post-infectious illness can coexist with autonomic symptoms and central sensitization. Someone can have genuine structural disease and an exaggerated protective response from the nervous system at the same time.

Clinical care becomes more useful when these mechanisms are evaluated on their own merits instead of being forced into a choice between structural disease and psychology. Treatable disease should be treated. Appropriate rehabilitation should restore capacity where possible. Sleep, metabolic health, hormonal physiology, and other contributors should be addressed when relevant. When the remaining symptom pattern suggests altered nervous-system processing, treatment can also include approaches intended to reduce fear, change learned associations with danger, and restore confidence in ordinary movement and sensation.

Used carefully, this framework may help some patients avoid repeated procedures, unnecessary restrictions, and years of searching for structural damage that no longer explains their pain. Used carelessly, it can become another way of dismissing symptoms that have not been adequately evaluated. The quality of the medical assessment determines the difference.

Editorial Transparency

Dr. Kathryn Retzler and Daniel Soule have both read or listened to the work of Howard Schubiner, MD, including Unlearn Your Pain. Dr. Retzler has pursued approved CME training related to this clinical approach. HormoneSynergy® has no financial relationship with Dr. Schubiner. Our interest in this area reflects the potential clinical value of neuroplastic and nociplastic pain concepts when they are considered alongside, rather than in place of, appropriate medical evaluation.

Related HormoneSynergy® Resources

• Longevity Medicine Resource Library
• Bioidentical Hormone Therapy for Women and Men
• DEXA Bone Density & Body Composition Testing
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References

• Ashar YK, Gordon A, Schubiner H, et al. Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain. JAMA Psychiatry. 2022.
• Ashar YK, Low EL, Knight K, et al. Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: 5-Year Follow-Up of a Randomized Clinical Trial. JAMA Psychiatry. 2025.
• Lumley MA, Schubiner H, Lockhart NA, et al. Emotional Awareness and Expression Therapy, Cognitive Behavioral Therapy, and Education for Fibromyalgia. Pain. 2017.
• International Association for the Study of Pain. IASP Terminology: Nociplastic Pain.
• Centers for Disease Control and Prevention. Long COVID Clinical Guidance.