Chronic Pain: Rewiring the Pain System

The Alarm That Will Not Stop

Acute pain is a gift. It tells you to pull your hand from the fire, to stop walking on a broken ankle, to rest after surgery. Acute pain is a faithful alarm system — it fires when there is danger, and it quiets when the danger resolves.

Chronic pain is a different animal entirely. Chronic pain is the alarm system itself malfunctioning — stuck in the ON position long after the original threat has passed, or firing in the absence of any threat at all. This is not acute pain that simply lasted too long. It is a fundamentally different neurological state involving structural and functional changes in the spinal cord, brainstem, and brain.

Here is the evidence that should reframe how you think about pain: the Brinjikji 2015 systematic review of spinal MRIs in asymptomatic people found disc degeneration in 37% of 20-year-olds, disc bulges in 30% of 20-year-olds, and herniated discs in nearly 60% of people over 50 — all with zero pain. Imaging findings often do not correlate with pain. The structure is not the whole story. The nervous system’s interpretation of that structure is the rest of the story.

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Central Sensitization: When the Nervous System Rewires Itself

In chronic pain, the dorsal horn neurons of the spinal cord become hyperexcitable. This is called central sensitization, and it involves measurable molecular changes:

• Wind-up: Repeated stimulation of C-fiber nociceptors causes progressive amplification of pain signals in the spinal cord. Each signal arrives louder than the last.
• NMDA receptor upregulation: Glutamate, the primary excitatory neurotransmitter, floods NMDA receptors in the dorsal horn. These receptors, once activated, maintain the sensitized state.
• Microglial activation: Microglia — the immune cells of the central nervous system — become chronically activated in the spinal cord and brain. They release pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) that further sensitize neurons. This is neuroinflammation.
• Substance P elevation: This neuropeptide amplifies pain signaling and is measurably elevated in the cerebrospinal fluid of chronic pain patients.

The clinical consequences of central sensitization are distinctive:

• Allodynia: Pain from stimuli that should not hurt — light touch, clothing against skin, gentle pressure
• Hyperalgesia: Amplified pain response — a minor bump produces disproportionate agony
• Expanded receptive fields: Pain spreads beyond the original injury site, sometimes to the opposite side of the body or to seemingly unrelated areas

This is not imagined pain. This is measurable, reproducible neurological dysfunction. And it explains why treatments targeting the periphery alone (surgery on a “damaged” disc, steroid injections at the original site) so often fail in chronic pain: the problem has migrated from the tissue to the nervous system itself.

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Root Causes: What Drives the Sensitization?

The IFM approach asks not merely “where does it hurt” but “why has your nervous system become sensitized?” The answer is almost always multifactorial.

Neuroinflammation

Activated microglia and astrocytes in the CNS maintain a pro-inflammatory milieu that keeps pain circuits firing. Peripheral inflammation — from the gut, from metabolic dysfunction, from chronic infection — sends inflammatory mediators across the blood-brain barrier that activate central microglia. This is why systemic inflammation amplifies pain even at sites far from the inflammatory source.

Testing: hs-CRP (systemic inflammation), ESR, cytokine panels (research settings), OAT (quinolinic acid — a neuroexcitotoxin produced in neuroinflammation, measurable in urine).

The Gut-Pain Axis

This connection surprises patients but should not surprise clinicians. Gut dysbiosis drives immune activation, which drives cytokine production, which drives neuroinflammation, which drives pain sensitization. The gut-brain axis is bidirectional — the vagus nerve carries information both ways.

Specific mechanisms: LPS (lipopolysaccharide from gram-negative bacteria) translocation through a permeable intestinal barrier activates TLR4 receptors on microglia — directly triggering neuroinflammation. SIBO has been found at elevated rates in fibromyalgia patients. Small intestinal fungal overgrowth (SIFO) produces metabolites that cross the blood-brain barrier. The gut is not a spectator in chronic pain — it is often a driver.

Sleep: The Pain Amplifier

The relationship between sleep and pain is one of the most vicious cycles in medicine. Poor sleep reduces endogenous opioid function — your body’s natural pain-dampening system weakens. Poor sleep increases inflammatory cytokines — IL-6 and TNF-alpha rise measurably after even one night of disrupted sleep. Poor sleep reduces descending pain inhibition — the brainstem pathways that normally dampen pain signals from below become less effective.

Meanwhile, pain disrupts sleep. The patient cannot get comfortable, wakes repeatedly, cannot achieve restorative slow-wave sleep. Less restorative sleep means more pain tomorrow. More pain means worse sleep tomorrow night. Breaking this cycle is often the highest-leverage intervention in chronic pain management.

Stress and Trauma

Adverse Childhood Experiences (ACEs) are one of the strongest predictors of chronic pain in adulthood. The ACE study (Felitti 1998) demonstrated a dose-response relationship: more ACEs, more chronic pain, more autoimmune disease, more everything destructive.

The mechanism: chronic stress or unresolved trauma keeps the autonomic nervous system locked in sympathetic overdrive (fight/flight) or dorsal vagal shutdown (freeze/collapse). Both states produce muscle tension, reduced blood flow to tissues, elevated cortisol (which is anti-inflammatory acutely but pro-inflammatory chronically), and neuroinflammation. The body that learned to brace for danger never unbraces.

Polyvagal theory (Stephen Porges) provides the framework: safe social engagement requires ventral vagal activation. Chronic pain patients are often stuck in sympathetic or dorsal vagal states where the body interprets its own sensations as threatening. The pain is real. The threat interpretation is the part that can change.

Nutrient Deficiencies

• Magnesium: A natural NMDA receptor antagonist and muscle relaxant. Deficiency removes the brake from excitatory neurotransmission and allows muscle hypertonicity. RBC magnesium is the better test (serum magnesium is maintained at the expense of intracellular stores until severely depleted).
• Vitamin D: The Al Faraj 2003 study found that 83% of chronic low back pain patients were vitamin D deficient, and supplementation produced significant improvement. Vitamin D receptors are present in pain-processing regions of the brain and spinal cord. Target: 50-70 ng/mL.
• Omega-3 fatty acids: EPA and DHA are precursors to resolvins and protectins — molecules that actively resolve inflammation rather than merely suppressing it. The omega-3 index (target 8-12%) predicts inflammatory status. Most Americans are at 3-4%.
• Vitamin B12: Deficiency causes peripheral neuropathy — numbness, tingling, burning pain in extremities. Methylmalonic acid (MMA) is the sensitive marker (rises before serum B12 falls). Common in vegans, elderly, metformin users, and those with low stomach acid.
• Vitamin B1 (Thiamine): Deficiency causes peripheral neuropathy and is far more common than recognized — alcohol use, diabetes, bariatric surgery, and chronic illness all deplete B1.

Metabolic Drivers

Insulin resistance is the silent accomplice of chronic pain. Elevated insulin and glucose damage peripheral nerves (diabetic neuropathy begins long before a diabetes diagnosis), impair tissue repair and regeneration, increase systemic inflammation through advanced glycation end products (AGEs), and reduce blood flow to injured tissues. Fasting insulin above 7-8 mIU/L warrants intervention. HbA1c above 5.5% signals impaired glucose control affecting tissue health.

Structural Considerations

Functional medicine does not dismiss structure — it contextualizes it. Surgical emergencies must be ruled out: cauda equina syndrome (saddle anesthesia, bowel/bladder dysfunction), spinal cord compression, progressive neurological deficit, joint instability requiring stabilization.

Beyond emergencies, structural contributors include: myofascial trigger points (the life work of Janet Travell — hyperirritable spots within taut bands of skeletal muscle that refer pain in predictable patterns), fascial restrictions (connective tissue adhesions that alter biomechanics and compress nerves), hypermobility/Ehlers-Danlos Syndrome (joints that sublux create chronic pain from tissue laxity, not inflammation — requires different management), and biomechanical dysfunction (leg length discrepancy, scoliosis, foot pronation affecting the entire kinetic chain).

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Testing: Map the Terrain

• hs-CRP: Systemic inflammation (target below 1.0)
• ESR: Inflammatory marker (elevated in autoimmune, infection)
• Vitamin D (25-OH): Target 50-70 ng/mL
• Magnesium RBC: Target 5.5-6.5 mg/dL (not serum magnesium)
• B12 and methylmalonic acid (MMA): Neuropathy screen
• Fasting insulin: Target below 7 mIU/L
• HbA1c: Target below 5.5%
• Full thyroid panel: Hypothyroid myalgias are common and overlooked
• Cortisol (DUTCH test): Diurnal pattern, free cortisol, cortisol metabolites — reveals HPA axis dysfunction
• Omega-3 index: Target 8-12%
• ANA: Autoimmune screen (lupus, Sjogren’s, and other connective tissue diseases present with widespread pain)
• GI-MAP: Gut health, dysbiosis, permeability markers
• OAT (Organic Acids Test): Quinolinic acid (neuroinflammation), mitochondrial markers, neurotransmitter metabolites
• Imaging: Only as clinically indicated. Avoid fishing expeditions — incidental findings (disc bulges, labral tears, degenerative changes) create nocebo effects that worsen pain through catastrophizing. If there is no red flag, imaging may do more harm than good.

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The Protocol: Multimodal by Necessity

No single intervention resolves chronic pain. The sensitized nervous system requires input from multiple directions simultaneously — reduce the inflammatory drivers, support nerve repair, optimize sleep, retrain the brain’s threat assessment, and move the body back toward safety.

Anti-Inflammatory and Neuroinflammation

• PEA (Palmitoylethanolamide): 600mg 2-3x/day. This is THE functional medicine pain supplement. PEA is an endogenous fatty acid amide that modulates the endocannabinoid system, downregulates mast cell and microglial activation, and produces analgesia through multiple mechanisms. Multiple randomized controlled trials support its use in sciatica (Guida 2010 — significant pain reduction at 21 days), neuropathic pain, chronic low back pain, and fibromyalgia. No drug interactions. No tolerance development. No withdrawal. Safe for long-term use.
• Omega-3 fatty acids: 3-4g/day EPA-dominant formulation. EPA is the precursor to resolvins and protectins — specialized pro-resolving mediators (SPMs) that actively clear inflammation and restore tissue homeostasis. This is not mere suppression; it is resolution.
• Curcumin: 1000-2000mg/day (liposomal or Meriva phytosome for absorption). Inhibits NF-kB and COX-2. Multiple head-to-head trials show comparable efficacy to NSAIDs for osteoarthritis pain without gastric side effects.
• SPMs (Specialized Pro-Resolving Mediators): Available as concentrated supplements derived from fish oil (Metagenics SPM Active, others). These are the downstream products — resolvins, protectins, maresins — that actively turn off the inflammatory process. For patients who do not adequately convert omega-3s to SPMs.
• NAC (N-Acetyl Cysteine): 1200mg/day. Glutathione precursor (master antioxidant), modulates glutamate (the excitatory neurotransmitter driving central sensitization via NMDA receptors), and reduces neuroinflammation. Also emerging evidence for reducing rumination and catastrophizing — the cognitive amplifiers of pain.
• LDN (Low-Dose Naltrexone): 1.5-4.5mg at bedtime. Mechanism: at low doses, briefly blocks opioid receptors, triggering a compensatory upregulation of endogenous endorphin production (rebound effect). Also directly inhibits microglial activation via TLR4 receptor antagonism. The Younger 2013 fibromyalgia study showed significant pain reduction versus placebo. The 2014 Crohn’s disease study (Smith) demonstrated mucosal healing. LDN is inexpensive, well-tolerated, and available from compounding pharmacies. Start at 1.5mg and titrate up by 0.5mg weekly to 4.5mg.

Nerve and Neuroplasticity Support

• Magnesium L-threonate: 1-2g/day (providing 144mg elemental magnesium per 2g). The only magnesium form shown to cross the blood-brain barrier and increase brain magnesium levels (Bhatt 2020). NMDA receptor modulation in the CNS, calms nerve excitability, supports synaptic plasticity. For body-wide magnesium, add glycinate or malate forms.
• B vitamins for neuropathy: Benfotiamine (fat-soluble B1) 150-300mg/day — protects nerves from glycation damage, particularly in diabetic neuropathy. Methylcobalamin (active B12) 5000mcg sublingual — nerve myelin repair. P5P (active B6) 50mg/day — neurotransmitter synthesis. Caution: B6 above 100mg/day chronically can paradoxically cause neuropathy.
• Alpha-lipoic acid: 600mg/day. The NATHAN trial (Neurological Assessment of Thioctic Acid in Diabetic Neuropathy) demonstrated significant improvement in neuropathic symptoms and deficits. Works as both a direct antioxidant and a regenerator of other antioxidants (glutathione, vitamin C, vitamin E). Also improves nerve blood flow.
• Lion’s mane mushroom (Hericium erinaceus): 1-2g/day. Unique among medicinal mushrooms for stimulating Nerve Growth Factor (NGF) production — the protein that promotes nerve regeneration and myelination. Mori 2009: improved cognitive function. Emerging evidence for peripheral neuropathy.
• Acetyl-L-carnitine: 1-2g/day. The Sima 2011 meta-analysis confirmed significant reduction in neuropathic pain. Mechanism: supports mitochondrial function in nerve cells, promotes nerve fiber regeneration, and has direct analgesic properties through modulation of glutamate neurotransmission.

Sleep Optimization

Sleep is not optional in a chronic pain protocol — it is foundational. Every night of poor sleep amplifies tomorrow’s pain.

• Magnesium glycinate: 400-600mg at bedtime. GABA modulation, muscle relaxation, parasympathetic activation.
• L-theanine: 200-400mg. Increases alpha brain waves (calm wakefulness → easier transition to sleep), modulates glutamate.
• Melatonin: 0.5-3mg (start low). Beyond sleep: melatonin is a potent anti-inflammatory and antioxidant with direct analgesic properties. It reduces neuroinflammation and has been shown to potentiate the effects of analgesic medications.
• Sleep apnea screening: Undiagnosed obstructive sleep apnea is epidemic and profoundly worsens chronic pain through fragmented sleep, hypoxia-driven inflammation, and sympathetic overdrive. Home sleep study or polysomnography.
• See dedicated sleep protocol for comprehensive approach.

Nervous System Reset

This is where chronic pain treatment diverges most dramatically from conventional approaches. The nervous system must be retrained — its threat assessment recalibrated.

• Vagal toning: The vagus nerve mediates the inflammatory reflex — Kevin Tracey’s groundbreaking discovery that vagal stimulation directly inhibits TNF-alpha and inflammatory cytokine production. Practical vagal activation: slow diaphragmatic breathing (exhale longer than inhale — 4 seconds in, 7-8 seconds out), cold water face immersion (triggers the dive reflex), humming and gargling (vibrate the vagal branches in the throat), singing. Daily practice, not occasional.
• Pain Neuroscience Education (PNE): Understanding pain science is itself therapeutic. The pioneering work of Lorimer Moseley and Adriaan Louw demonstrates that when patients understand that chronic pain reflects nervous system sensitization — not ongoing tissue damage — catastrophizing decreases, threat perception decreases, and pain itself decreases. The brain can amplify or dampen pain signals based on the meaning it assigns to those signals. Reconceptualizing pain from “damage signal” to “sensitivity signal” changes the brain’s output. This is not dismissive. This is empowering.
• Graded Motor Imagery (GMI): A three-stage neuroplasticity protocol developed by the NOI Group (Neuro Orthopaedic Institute) for conditions like CRPS, phantom limb pain, and chronic regional pain:
  1. Left/right discrimination training (identifying laterality of body part images — activates premotor cortex without movement)
  2. Imagined movements (mental rehearsal of the painful movement)
  3. Mirror therapy (watching the unaffected limb move in a mirror, creating the visual illusion of pain-free movement in the affected limb) Each stage progressively retrains cortical representation of the affected area.
• Mindfulness-Based Stress Reduction (MBSR): The 8-week standardized program developed by Jon Kabat-Zinn. Zeidan 2012 and 2015 neuroimaging studies demonstrated approximately 40% reduction in pain intensity and greater than 50% reduction in pain unpleasantness — through activation of pain-modulating brain regions (anterior cingulate, anterior insula) and deactivation of pain-amplifying regions. MBSR does not eliminate the sensory signal — it changes the brain’s relationship to it.
• Somatic Experiencing (Peter Levine): For trauma-driven pain. Works with the body’s held survival responses — the fight/flight/freeze energy that was never discharged. Gradual titrated release of this stored activation, tracked through bodily sensations (interoception). Particularly relevant when ACE scores are high.
• EMDR (Eye Movement Desensitization and Reprocessing): For pain with clear traumatic origin — motor vehicle accidents, surgical trauma, assault. Reprocesses the traumatic memory, reducing the emotional and somatic charge it carries.

Movement: The Fundamental Medicine

Movement must be graded, progressive, and framed as safe. The chronic pain patient’s nervous system has learned that movement equals threat. Forcing through pain (“no pain, no gain”) reinforces the threat interpretation and worsens sensitization.

Appropriate movement: walking (the most accessible starting point), swimming (buoyancy reduces joint load, warm water calms the nervous system), tai chi (multiple RCTs in chronic pain — meditative movement that retrains proprioception and reduces fear of movement), yoga (graduated, trauma-informed if needed). Progressive loading over weeks and months.

The biological benefits: exercise produces endogenous opioids (endorphins, endocannabinoids — the “runner’s high”), reduces neuroinflammation (BDNF release, microglial modulation), improves sleep quality, enhances descending pain inhibition, and produces anti-inflammatory myokines from contracting muscle. Exercise is an anti-inflammatory drug, an antidepressant, an analgesic, and a sleep aid — with no prescription required.

Manual Therapy

• Myofascial release: Sustained gentle pressure into fascial restrictions. Restores tissue mobility and breaks the pain-spasm-pain cycle.
• Trigger point therapy: Dry needling (fine needle into trigger point — produces a local twitch response and deactivation) or trigger point injection (lidocaine or saline). Based on Janet Travell’s trigger point maps.
• Craniosacral therapy: Gentle manipulation of cranial bones and sacrum. Particularly useful for headache, TMJ, and post-concussion pain.
• Visceral manipulation: Mobilization of internal organs and their fascial attachments. Useful when abdominal or pelvic adhesions contribute to pain referral patterns.
• Chiropractic: Specific adjustments for joint dysfunction, not just spinal manipulation. Neurological effects: joint manipulation activates mechanoreceptors that gate pain signals (gate control theory).

Advanced Interventions

For severe, refractory chronic pain:

• Frequency-Specific Microcurrent (FSM): Developed by Carolyn McMakin. Delivers specific frequencies of microcurrent (below sensory threshold) targeting specific tissue types and pathological states. Remarkable anecdotal and emerging research evidence for conditions like fibromyalgia, myofascial pain, and nerve pain. McMakin 2005: reduced fibromyalgia pain from mean 7.3 to 1.3 on VAS in a single treatment.
• Hyperbaric Oxygen Therapy (HBOT): Pressurized oxygen reduces neuroinflammation, promotes neuroplasticity, enhances tissue repair, and reduces microglial activation. Multiple studies in fibromyalgia (Efrati 2015 — significant improvement in all fibromyalgia symptoms, with corresponding changes on SPECT brain imaging showing normalized pain processing).
• IV Ketamine: NMDA receptor antagonist that can produce rapid neuroplasticity — essentially “rebooting” sensitized pain circuits. Used in specialized clinics for severe refractory chronic pain, CRPS, and treatment-resistant depression with pain. A series of 4-6 infusions over 2-3 weeks can produce lasting benefit. Not a first-line therapy, but transformative for the right patient.
• Stellate Ganglion Block: Injection of local anesthetic around the stellate ganglion (cervical sympathetic ganglion). Originally for CRPS, now investigated for PTSD-associated pain and sympathetically-maintained pain. Resets sympathetic overdrive.
• PRP (Platelet-Rich Plasma) and Prolotherapy: For joint, tendon, and ligament pain. PRP uses concentrated growth factors from the patient’s own blood. Prolotherapy uses dextrose injections to stimulate tissue repair. Both are regenerative — they promote healing rather than suppressing symptoms. Multiple studies in knee osteoarthritis, tennis elbow, Achilles tendinopathy.

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The Paradigm Shift

Chronic pain is not a sensation to be numbed. It is a state of the nervous system to be transformed. The opioid crisis demonstrated the catastrophic failure of treating chronic pain as if it were acute pain that simply needed more analgesic force. Chronic pain requires a fundamentally different framework — one that addresses why the alarm system malfunctioned, not just how to muffle the alarm.

Functional medicine brings root cause thinking to a field desperately in need of it. Reduce the inflammatory drivers. Heal the gut. Optimize the nutrients that nerve tissue requires. Restore sleep. Retrain the brain’s threat assessment through education, mindfulness, and graded exposure. Move the body back toward safety and capability. Address the trauma that lives in tissue.

The nervous system that learned to amplify can learn to quiet. Neuroplasticity works in both directions. The same mechanism that created the chronic pain state — experience-dependent neural change — is the mechanism that resolves it.