Residency · Residency · Physical Medicine Rehabilitation

Central Sensitization and Nociplastic Pain

Overview

Central sensitization: amplification of neural signaling within the CNS leading to pain hypersensitivity. Nociplastic pain: third mechanistic descriptor alongside nociceptive and neuropathic pain (IASP, 2017). Defined as pain arising from altered nociception despite no clear evidence of tissue damage or somatosensory nerve lesion. Relevant to many conditions seen in PM&R: fibromyalgia, chronic low back pain, chronic whiplash, chronic widespread pain, CRPS, post-surgical pain. Understanding these mechanisms changes treatment approach from tissue-focused to CNS-focused.

Mechanisms of Central Sensitization

Spinal Cord Level

Wind-up: progressive increase in dorsal horn neuron firing with repeated C-fiber stimulation. NMDA receptor activation: glutamate-mediated excitotoxicity and calcium influx. Long-term potentiation (LTP): strengthening of synaptic connections in pain pathways. Loss of inhibitory interneurons: reduced GABAergic and glycinergic inhibition.

Microglial activation: release of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, BDNF). Astrocyte activation: altered glutamate reuptake, maintained excitation.

Supraspinal/Brain Level

Descending facilitation: enhanced facilitation from rostral ventromedial medulla (RVM). Impaired descending inhibition: reduced serotonergic and noradrenergic inhibition from PAG/RVM. Cortical reorganization: altered somatosensory cortex representation. Altered default mode network connectivity.

Thalamic and insular cortex changes: amplified pain processing. Amygdala and prefrontal cortex: emotional-cognitive amplification of pain.

Peripheral Contributions

Peripheral sensitization often initiates the process. Ongoing peripheral input may maintain central sensitization. Neurogenic inflammation: substance P, CGRP release. Transition from acute to chronic pain involves both peripheral and central mechanisms.

<image>Mechanisms of central sensitization at spinal cord and brain levels showing ascending and descending pathways</image>

Nociplastic Pain - The Third Descriptor

Definition (IASP 2017)

"Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain". Fills the gap between nociceptive and neuropathic pain categories. Can coexist with nociceptive and/or neuropathic pain.

Conditions Associated with Nociplastic Pain

Primary nociplastic conditions: fibromyalgia, chronic primary pain, irritable bowel syndrome, chronic tension-type headache, temporomandibular disorder. Secondary nociplastic features: chronic low back pain, osteoarthritis with central sensitization, chronic post-surgical pain, chronic whiplash, CRPS (central component). Many rehabilitation patients have mixed pain presentations.

Clinical Features Suggesting Nociplastic Pain

Pain distribution inconsistent with specific tissue or nerve pathology. Widespread or multifocal pain. Heightened sensitivity to non-painful stimuli (light, sound, odors, temperature). Associated fatigue, sleep disturbance, cognitive difficulties ("fibro fog").

Emotional distress amplifying pain experience. Pain that spreads over time or migrates. Disproportionate pain relative to identifiable pathology. Poor response to peripheral treatments (surgery, injections, NSAIDs).

Clinical Assessment

History

Pain characteristics: diffuse, burning, aching, associated with sensory sensitivity. Temporal pattern: often constant with fluctuations, worsened by stress and poor sleep. Associated symptoms: fatigue, sleep disturbance, cognitive complaints, mood changes. History of multiple pain sites or diagnoses. Central sensitization may be suspected when "everything hurts".

Screening Tools

Central Sensitization Inventory (CSI): 25-item self-report questionnaire. Score ≥ 40/100 suggests central sensitization. Assesses somatic and emotional symptoms associated with CSS.

Part B identifies previously diagnosed central sensitivity syndromes. Pain Sensitivity Questionnaire (PSQ). painDETECT: originally for neuropathic pain, captures some nociplastic features.

Physical Examination Findings

Widespread hyperalgesia: enhanced pain to noxious stimuli in areas beyond primary pain site. Allodynia: pain from normally non-painful stimuli (light touch, clothing). Temporal summation: progressive increase in pain with repeated identical stimuli. After-sensations: pain persists long after stimulus removed.

Conditioned pain modulation (CPM) deficit: reduced "pain inhibits pain" response. Test: apply noxious stimulus to one site, measure whether it reduces pain at a remote site. Impaired CPM = deficient descending inhibition.

Quantitative Sensory Testing (QST)

Standardized psychophysical testing of somatosensory function. Pressure pain thresholds: lowered in central sensitization. Thermal detection and pain thresholds. Temporal summation testing. Primarily a research tool but increasingly used clinically.

<image>Central Sensitization Inventory screening tool and quantitative sensory testing setup for clinical assessment</image>

Treatment Implications

Paradigm Shift

Tissue-focused treatments (surgery, injections, NSAIDs) are less effective when central sensitization dominates. CNS-directed treatments become primary. Multimodal, biopsychosocial approach is essential. Patient education about pain mechanisms is itself therapeutic.

Pain Neuroscience Education (PNE)

Teaching patients about the neurobiology of pain. Reconceptualizing pain as a protective output of the brain, not a measure of tissue damage. Reduces pain catastrophizing and fear-avoidance. Improves treatment engagement.

Evidence: reduces pain intensity, disability, and healthcare utilization. Can be delivered in individual or group format.

Exercise Therapy

Exercise-induced hypoalgesia (EIH): normal response is reduced pain sensitivity after exercise. In central sensitization, EIH may be impaired or reversed initially. Graded exercise exposure starting well below symptom exacerbation threshold. Aerobic exercise: strongest evidence for normalizing central pain processing.

Gradually progressive to moderate intensity (goal: 150 min/week). Resistance training: additional benefits for self-efficacy. Aquatic therapy: may be better tolerated initially.

Cognitive-Behavioral Therapy (CBT)

Addresses maladaptive cognitions: catastrophizing, fear-avoidance, helplessness. Targets central mechanisms: cortical processing, descending modulation. Components: cognitive restructuring, graded activity, relaxation training, pacing. Evidence: Level 1 for chronic pain, fibromyalgia. Benefits persist beyond treatment period.

Acceptance and Commitment Therapy (ACT)

Focuses on psychological flexibility rather than symptom elimination. Acceptance of pain rather than avoidance. Values-directed activity engagement despite pain. Growing evidence base for chronic pain.

Mindfulness-Based Stress Reduction (MBSR)

8-week structured program of meditation and body awareness. Reduces pain-related distress and catastrophizing. May modulate default mode network connectivity. Evidence for fibromyalgia, chronic low back pain.

Pharmacologic Management

Target central mechanisms rather than peripheral inflammation.

First-Line

SNRIs: duloxetine 60-120 mg/day, milnacipran 50-100 mg BID. Enhance descending serotonergic and noradrenergic inhibition. FDA approved for fibromyalgia (duloxetine, milnacipran). Gabapentinoids: pregabalin 150-450 mg/day (FDA approved for fibromyalgia).

Modulate calcium channels, reduce excitatory neurotransmitter release. TCAs: amitriptyline 10-75 mg, nortriptyline. Enhance descending inhibition, improve sleep.

Second-Line

Tramadol: weak mu-agonist + SNRI; use cautiously. Low-dose naltrexone (LDN): 1.5-4.5 mg/day. Anti-neuroinflammatory (glial cell modulation). Emerging evidence in fibromyalgia. Cyclobenzaprine: low-dose (5-10 mg at bedtime) for sleep and muscle relaxation.

Generally Ineffective

NSAIDs (peripheral mechanism, minimal central effect). Acetaminophen alone. Opioids (may worsen central sensitization through opioid-induced hyperalgesia). Corticosteroids.

Sleep Optimization

Sleep disruption both causes and perpetuates central sensitization. CBT for insomnia (CBT-I) is first-line for chronic insomnia. Low-dose amitriptyline or trazodone. Melatonin for circadian regulation. Sleep hygiene education. Evaluate for comorbid sleep disorders (sleep apnea).

<image>Treatment algorithm for nociplastic pain showing CNS-directed multimodal approach</image>

Relevance to Specific PM&R Conditions

Chronic Low Back Pain

Central sensitization present in 20-30% of chronic LBP patients. Explains why imaging findings poorly correlate with pain. Explains failure of repeated spinal injections/surgery. CSI screening can identify these patients.

Chronic Whiplash

Central sensitization documented with QST in chronic whiplash. Widespread hyperalgesia beyond cervical region. Impaired conditioned pain modulation. Predicts poor prognosis.

Post-Surgical Pain

Central sensitization may persist after technically successful surgery. Pre-operative central sensitization predicts chronic post-surgical pain. Pre-habilitation with PNE and exercise may be protective.

Osteoarthritis

Many OA patients have central sensitization component. Explains why joint replacement sometimes fails to relieve pain. CSI or QST screening may identify patients less likely to benefit from surgery.

Clinical Pearls

When a patient has diffuse pain disproportionate to imaging or physical findings, think central sensitization/nociplastic pain rather than dismissing symptoms. The Central Sensitization Inventory (CSI ≥ 40) is a practical screening tool that takes 5 minutes and can redirect treatment approach. Pain neuroscience education is an evidence-based treatment intervention, not just patient counseling - it can change pain processing. Opioids are counterproductive in nociplastic pain as they may worsen central sensitization through opioid-induced hyperalgesia. Identifying nociplastic pain BEFORE surgery can prevent unnecessary procedures and predict patients who need perioperative CNS-directed treatment.

References

• Nijs J, et al. Nociplastic pain criteria or recognition of central sensitization? Pain phenotyping in the past, present and future. J Clin Med. 2021;10(15):3203.
• Kosek E, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382-1386.
• Mayer TG, et al. The development and psychometric validation of the Central Sensitization Inventory. Pain Pract. 2012;12(4):276-285.
• Nijs J, et al. Treatment of central sensitization in patients with chronic pain: time for change? Expert Opin Pharmacother. 2019;20(16):1961-1970.
• Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-S15.

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