Central Sensitization Explained: The Brain’s Role in Chronic Pain

1. Central Sensitization: When the Brain Becomes the Pain Generator

One of the most discussed explanations in current literature is central sensitization—a condition in which the central nervous system becomes hypersensitive to stimuli. Think of it as a volume knob on pain perception that’s been turned up… and broken off.

In central sensitization, even non-noxious inputs can be perceived as painful (allodynia), and painful stimuli can feel disproportionately intense (hyperalgesia). There’s increasing evidence that changes in pain modulation pathways in the brainstem and spinal cord play a central role.

Key conditions where this is commonly seen:

• Fibromyalgia
• Irritable bowel syndrome
• Chronic fatigue syndrome
• Tension headaches

Neuroimaging studies show altered activation patterns in pain-processing areas in these patients, even in the absence of tissue damage. But because this dysfunction isn’t visible on traditional scans, it’s often dismissed—much to the patient’s despair.

2. Neuroinflammation: The Invisible Fire in the Brain

Microglia—the immune cells of the CNS—are not supposed to stay chronically activated. Yet in many chronic pain syndromes, they do. This “smoldering” neuroinflammation doesn’t cause fever or show up on CRPs, but it wreaks havoc on pain thresholds and mood regulation.

Emerging studies suggest links between chronic pain and elevated pro-inflammatory cytokines in the brain and spinal cord—even without a clear systemic infection or autoimmune disease. It’s a silent storm, one that damages neuronal circuits subtly over time.

3. Maladaptive Neuroplasticity: When Healing Goes Wrong

The nervous system is plastic—it adapts. But sometimes, it adapts in the wrong direction. After an injury (surgical or traumatic), nerve pathways may heal in a distorted way, reinforcing pain circuits even after the original insult is gone. This is seen in conditions like:

• Phantom limb pain
• Postherpetic neuralgia
• Complex regional pain syndrome

The phenomenon of “learned pain” suggests that the body can retain pain even in the absence of the original nociceptive signal. It’s not psychological—it’s a rewired neurobiological reality.

4. The Role of Hidden Trauma: Psychosomatic Is Not Pseudoscience

The term “psychosomatic” has been unfortunately stigmatized. But countless studies show that early-life trauma, adverse childhood experiences (ACEs), and untreated PTSD can alter the stress response system and pain perception networks.

The hypothalamic-pituitary-adrenal (HPA) axis, when repeatedly activated due to trauma, can result in dysregulated cortisol levels, heightened sympathetic tone, and increased inflammation—all contributors to chronic pain without visible pathology.

In many cases, the body becomes the storybook of unprocessed trauma.

This doesn’t mean the pain is “psychological.” It means the nervous system has been biologically shaped by emotional injury in a way that medicine is only beginning to understand.

5. Subclinical Infections and Dysbiosis: The Gut-Brain-Pain Axis

The microbiome’s role in chronic pain syndromes is now under intense scrutiny. In conditions like fibromyalgia and chronic pelvic pain, researchers are finding altered gut flora and increased intestinal permeability (aka “leaky gut”), which may lead to systemic inflammation and altered pain processing.

Similarly, post-viral syndromes (e.g., post-COVID chronic pain or fatigue) have highlighted the possibility that subclinical infections may persist and subtly alter immune and neural pathways without triggering classic diagnostic markers.

6. Small Fiber Neuropathy: Invisible but Impactful

Standard nerve conduction studies examine large fibers. But small fiber neuropathy (SFN) affects unmyelinated C-fibers and thinly myelinated Aδ fibers, which are responsible for pain and temperature sensation.

Patients often report burning, tingling, and pain, but their EMGs and MRIs return normal. Diagnosis requires skin biopsy or specialized testing, which many clinics do not routinely offer.

SFN can be idiopathic or associated with conditions like diabetes, sarcoidosis, Sjögren's, or even gluten sensitivity.

7. Mitochondrial Dysfunction and Chronic Pain

While not classically considered in pain syndromes, mitochondrial energy failure may contribute to muscle pain, fatigue, and lactic acid buildup, especially in syndromes like chronic fatigue or fibromyalgia.

Low cellular energy availability impairs tissue repair and increases pain susceptibility. Some researchers speculate that mitochondrial dysfunction may be a unifying mechanism behind several unexplained pain syndromes.

8. Endocrine and Hormonal Contributors

Subtle imbalances in thyroid hormones, adrenal function (especially low cortisol), and even sex hormones can modulate pain perception. Hypothyroidism, for instance, can mimic fibromyalgia. Low estrogen levels in postmenopausal women often correlate with increased joint and muscle pain.

Yet many patients with borderline lab results get dismissed as “normal.” What’s “normal” for labs may not be optimal for function—and certainly not for pain control.

9. Genetic and Epigenetic Susceptibility

Some individuals are genetically predisposed to experience more intense or prolonged pain. Variants in genes like COMT, GCH1, and SCN9A influence pain thresholds, response to opioids, and vulnerability to chronic pain.

Even more compelling is the role of epigenetics—how environmental stressors modify gene expression over time, influencing the development of chronic pain conditions without visible lesions.

This may explain why two patients with identical injuries can have drastically different pain trajectories.

10. Sleep, Circadian Disruption, and Pain Amplification

Sleep disorders and chronic pain are deeply interwoven. Poor sleep reduces pain tolerance. Pain causes fragmented sleep. It becomes a vicious cycle.

Disruptions in circadian rhythms affect inflammatory cytokine production and nociceptive signaling. It’s not uncommon for patients to report pain flares after poor sleep, travel, or night-shift work.

Optimizing sleep hygiene, and in some cases melatonin regulation, is a non-pharmacologic cornerstone often overlooked in pain management.

11. Overmedicalization and the Diagnostic Limbo

Paradoxically, the more specialists a patient sees, the less likely they are to receive an answer. Tests pile up. Labels like “possible lupus,” “rule out MS,” or “somatoform disorder” may appear in charts without context.

The pressure to label often leads to diagnostic inflation, while the real issue—centralized pain without a peripheral cause—is missed entirely.

A better approach may be to focus on function, coping, and rehabilitation rather than exhaustive investigations that only compound anxiety.

12. The Role of Health Anxiety and Secondary Gain—Cautiously Navigated

Yes, in rare cases, secondary gain or health anxiety can amplify symptoms. But these must be approached with nuance, empathy, and nonjudgment.

Labeling patients as “somatizers” too early often breaks trust and leads to fragmented care. Instead, trauma-informed communication and interdisciplinary involvement—including psychiatry and pain psychology—should be prioritized.

The truth is: even patients with health anxiety feel real pain. Our job isn’t to dismiss it—it’s to help them regain control over it.

13. The Danger of Disbelief: When Clinicians Unknowingly Harm

The most damaging phrase a patient in pain can hear is: “All your tests are normal. There’s nothing wrong.” That phrase shuts down the therapeutic alliance. It converts an invisible pain into a medical orphan.

Doctors are trained to find abnormalities, but we must also be comfortable with functional disorders—real conditions with dysfunctional physiology rather than structural pathology.

Educating ourselves, and patients, about central pain syndromes, neuroplasticity, and the role of lifestyle modulation (exercise, stress reduction, sleep, nutrition) may be more healing than any prescription.

14. The Multidisciplinary, Empathy-Driven Approach

The management of chronic pain without a clear cause is not about finding “the one” diagnosis—it’s about shifting from a disease-centered model to a patient-centered one. Multidisciplinary pain clinics often see the best outcomes when combining:

• Pain psychology
• Physical therapy
• Pharmacology (e.g., low-dose naltrexone, tricyclics, SNRIs)
• Occupational therapy
• Lifestyle medicine

This model views pain not just as a symptom, but as a biopsychosocial experience deserving of validation, exploration, and compassion.