Accurate Education – Central Sensitization

Central Sensitization


Understanding Central Sensitization:


Neurobiology of Pain

Neuropathic (Nerve) Pain


Treating Central Sensitization:

Medications for Pain

Complementary and Alternative Medicine (CAM)

Nutrition and Supplements

Diet & Fasting

Antioxidants and Oxidative Stress


Curcumin (Meriva)

Minocycline (comng soon)

Naltrexone (comng soon)

PEA (Palmitoylethanolamide)

Fibromyalgia – Overview

Fibromyalgia – CAM Treatment




Hyperalgesia is an increased response to a stimulus which is normally painful.



Allodynia is a term that describes the experience of pain arising from a stimulus which does not normally provoke pain.


Hyperalgesia has been frequently reserved for ‘nociceptor-mediated’ stimulus-evoked pain, whereas allodynia was regarded to be stimulus-evoked pain, mediated by receptors other than nociceptors. The usefulness of the concept allodynia in contrast to hyperalgesia has been debated since its existence.



 Definitions and Terms Related to Pain

Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication


“You’d think a guy who has broken 35 bones in his body would have a high pain threshold, but mine is pretty low. I got hit in the shin with a golf ball once, and it almost brought tears to my eyes. I’ve had broken bones that didn’t hurt as bad.”
 – Evel Knievel


Sensitization is a process where nerves become more responsive to stimulation, both painful and non-painful. It may be due to a number of changes individually or in combination including a decrease in threshold necessary for a response, an increase in magnitude of response, expansion of a receptive field and/or the emergence of spontaneous activity. The sensitization process occurs in primary afferent neurons, those nerves  carrying sensory information from outside the central nervous system into the spinal cord and brain (peripheral sensitization). This sensory information may be related to  physical stimulation (mechanical damage or trauma, distention, contraction etc.), chemical stimulation or thermal (hot or cold) stimulation.


The sensitization process also occur in higher-order neurons within the central nervous system, including the spinal cord and brain (central sensitization). Sensitization is believed to play a role in transformation of acute pain to chronic pain, including the evolution of episodic headaches to chronic daily or near-daily migraine headaches. Research currently suggests that while both peripheral and central sensitization are significant in the chronification of pain, central sensitization is likely the dominant factor.


Peripheral Sensitization

Sensitization of pain receptors (nociceptors) in the skin and other tissues can be caused by numerous factors which effectively lower neuronal thresholds of action potentials and promote peripheral sensitization. These factors include exposure to inflammatory agents that are released from nociceptive nerve terminals, including substance P and the calcitonin gene-related peptide (CGRP). These agents promote vascular permeability and leakage, which causes local swelling (edema) and the release of growth factors, prostaglandins, cytokines, and bradykinin. It is thought that it is the multifactorial interplay of these various substances that produce nociceptive sensitization, which may explain why there is no single drug that is comprehensively effective to treat this condition.


Central Sensitization (CS)

Central Sensitization (CS) is a process that is yet to be fully understood but is thought to accompany many chronic pain syndromes, contributing to increased pain and suffering. CS is believe to be a potential complicating factor in chronic headaches, back pain, neck pain, fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders, interstitial cystitis, irritable bowel syndrome (IBS) and postsurgical pain. The list goes on.


In the quote above by Evel Knievel, it appears that his likely history of chronic pain related to his many injuries has led to this perfect description of hyperalgesia.


Understanding Central Sensitization

Understanding Central Sensitization and learning to recognize it’s manifestations is the first step in learning how to reduce it’s impact on quality of life.


Central sensitization represents an enhancement in the function of neurons and pain pathways caused by increases in nerve excitability as well as reduced inhibition from higher levels in the brain. It is a manifestation of the remarkable plasticity (ability to change and adapt) of the nervous system in response to activity, inflammation, and nerve injury. The overall effect of central sensitization is to generate an increased or amplification of pain perception. Central sensitization is responsible for many of the changes in pain sensitivity in chronic pain. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled to the presence, intensity, or duration of the original stimulus of pain. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.

See: YouTube explanation of Peripheral and Central Sensitization


The Evolution of Central Sensitization

Nociceptive pain is caused by activation of neural pathways in response to damaging or potentially damaging stimuli to body tissue such as occurs with chemical or mechanical trauma or burns. Acute pain arises from damage to peripheral tissue and nerves, as with surgical or traumatic tissue injury, leading to increased spontaneous firing and alterations in nerve conduction or neurochemical sensitivity. A phenomenon known as neurogenic inflammation also occurs, whereby inflammatory products are released by activated nociceptors (pain receptors), leading to a cascade of events involving enhanced ion channel permeability, gene expression, and receptor and channel density on the nerve cell membrane. The consequence of these events is peripheral nociceptor hyperexcitability, termed ‘peripheral sensitization.’


Nociceptive pain generally diminishes once the peripheral driving force is removed and tissue damage repaired. However, injured nociceptive neurons (pain receptors) can become “sensitized” (activated at a lower threshold) and may show activity in the absence of any stimulation, a condition called “peripheral sensitization.”


Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways (pathways in the central nervous system – the spinal cord and brain), the phenomenon of central sensitization.” Central sensitization occurs when the nervous system goes through a process called “wind-up,” which is when repetitve stimulation of peripheral pain receptors (nociceptors) leads to ongoing repetitive impulses into the central nervous system, especially the dorsal horn neurons in the spinal cord,  which leads to a persistent state of high reactivity or hypersensitivity. Central sensitization is associated with the development and maintenance of chronic pain. In other words, even after the original stimulus is gone, the nerves keeps signalling the central nervous system in the brain. As a result, sensory experience becomes amplified in such that a pain patient becomes hypersensitive to sensory stimulation most commonly including mechanical stimulation such as touch or pressure. Central sensitization may also include the spread of sensitivity beyond the original peripheral site of injury.


As a consequence, stimuli that previously would have been perceived as slightly painful now become moderately painful (hyperalgesia). Or being touched lightly or gently squeezed or hugged, normally not painful at all become painful (allodynia). These experiences are the hallmark of peripheral and central sensitivity. And such hypersensitivity is not limited to mechanical sensory stimuli but may extend into the other senses resulting in increased sensitivity or intolerance of heat or cold, light or sound and even smell. People may even develop emotional sensitivity becoming more impacted by anxiety and stress. One can begin to see the impact that CS can have on quality of life.


At least two pathways are proposed for central sensitization. The first is chronic processing of pain which causes changes in the nerves and peripheral nerve pathways which progress to central sensitization and the resulting clinical pain. The second, more psychologically centered pathway, is proposed as an alternative to the transformation of pain. This alternate pathway begins with elevated levels of chronic stress, and includes elements of anxiety, sleep disruption, decreased pain thresholds, and dysautonomia (dysfunction of the autonomic nervous system, see References below). It is common to find both proposed pathways actively involved in central sensitization syndrome. Central sensitization syndromes can be thought of as archetypal examples of a chronic biopsychosocial pain disorder.


Neurobiology of Central Sensitization

For those interested in the neurobiology of CS, this hypersensitive response to stimuli is thought to occur as a result of the over-bombardment of pain signals to the central nervous system which induces a number of pathophysiologic changes including neuro-immune dysfunction and neuro-inflammation, neuro-endocrine dysfunction, NMDA dysregulation (NMDA a receptor involved in pain pathways – see Education – Pain), sympatho-afferent coupling; and altered serotonin and norepinephrine production and utilization. These events are thought to occur predominantly in the mid-brain and associated structures and are influenced by elements of the neuromatrix (the overall collection of nerves and neural pathways that make up the experience of pain including the psychological response to the experience). These pathophysiologic changes are associated with decreased descending inhibition, dysautonomia, and altered serotonin production/utilzation. The resulting depression, anxiety, sleep fragmentation, allodynia, and hyperalgesia characterize a number of chronic pain disorders.


From a neurochemical perspective, central sensitization involves many mechanisms involving multiple pathways and chemical agents. Some of the primary players in central sensitization are the microglia, immune cells in the nervous system  that contribute to neuroinflammation when activated by specific conditions including persistent pain. Activated microglia release reactive oxidative species (ROS), inflammatory cytokines, neurotrophic factors, and prostaglandins that excite nociceptive neurons and contribute to the persistence of chronic pain.


Treating Central Sensitivity

Understanding these concepts and the two pathways proposed for the evolution of CS allows for the two basic approaches to limiting the development of CS and reducing it’s impact on one’s experience.


Treating the Central Sensitization Pain

While central sensitization is associated with all types of pain including inflammatory pain, the medications that appear to be most useful belong to the anti-epileptic class of drugs including gabapentin (Neurontin), pregabalin (Lyrica) and topiramate (Topamax) which act on nerves and the SNRI anti-depressants including duloxetine (Cymbalta), venlafaxine (Effexor) and milnacaprin (Savella) which act on the descending inhibitory nerve pathways from the brain.


NMDA Receptor Antagonists

Medications that block the NMDA receptors involved in pain pathways (see Education – Pain) are also believed to reduce or suppress CS. Medications that block NMDA receptors include ketamine, commonly used topically though current research is looking at use of intravenous ketamine. Methadone is thought to possibly provide some NMDA blocking activity which may contribute to it’s effectiveness in treating CS pain. Levorphanol, an older opioid recently re-introduced offers signiificant NMDA blocking activity and is likely the most effective opioid for the treatment of CS pain.


There is also recent research that suggest buprenorphine (Butrans, Belbuca, Suboxone, Zubsolv, Bunivail) also has NMDA blocking activity that contributes to it’s effectiveness in treating chronic CS pain ( see Buprenorphine). Additionally, both levorphanol and buprenorphine are thought to have activity on the descending inhibitory pathways from the brain to the spinal cord as contributing mechanisms of their effectiveness for CS.


Medications with NMDA Antagonism, Possibly Effective for Central Sensitization:

  1. Dextromethorphan (Delsym)
  2. Ketamine
  3. Levorphanol
  4. Methadone
  5. Orphenadrine (Norflex)
  6. Buprenorphine (Belbuca, Butrans and Suboxone, Zubsolv, Bunivail)


Treating the CS Process

Underscoring the role of stress, anxiety and sleep deprivation in the evolution of central sensitivity, behavioral approaches to CS have been shown to be effective. Foremost along these lines are mindful exercises including meditation, deep relaxation techniques, yoga, tai chi, music therapy and hypnosis. Cognitive Behavior Training (CBT) has also been shown to be effective. Amongst the mechanisms proposed to explain how these behavioral approaches impact CS include the enhancement of the descending inhibitory pathways from the brain to the spinal cord similar to the mechanisms of the SNRIs, levorphanol and buprenorphine.


New Research

Glia Cell Inhibitors

Recent research into the role of glial cells (non-neuronal cells that maintain and provide support and protection for neurons in the central and peripheral nervous system) suggests they play a significant role in central sensitization. When activated, glial cells produce many chemical agemts that contribute to the maintenance of chronic pain. It has been proposed that preventing glial cell activation through the use of glial cell inhibitors may suppress the development of CS and reduce the severity of symptoms. As of yet, no definitive glial cell inhibitors for the treatment for CS have been identified.  Howerver, there is growing research for the benefit of some proposed glial cell inhibitors. There is  very early, modest evidence that palmitoylethanolamide (PEA), a natural supplement, may offer benefit in neuropathic and CS via its inhibition of glial cells.


Minocycline, an antibiotic, also has preliminary evidece of benefit as a glial cell inhibitor and as a possible Toll-Like Receptor (TLR-4) antagonist and may offer benefit in the management of CS. Since its initial identification as an inhibitor of microglial activation, the mechanisms underlying minocycline’s inhibition of microglia remain unknown, but numerous additional effects including potent anti-inflammatory, immunomodulatory, and neuroprotective actions of minocycline have been documented.



Oxidative stress, mitochondrial dysfunction and neuroinflammation are all conditions thought to potentially benefit from supplementation with CoQ10,  an endogenous, vitamin-like antioxidant. A recent study published in 2015 suggest there may be a synergistic effect combining CoQ10 with minocycline in the treatment of neuroinflammation.

See CoQ10



Reference Articles

Central Sensitization – Overviews

  1. How to explain central sensitization to patients with ‘unexplained’ chronic musculoskeletal pain – Practice guidelines – 2011
  2. The efficacy of pain neuroscience education on musculoskeletal pain A systematic review of the literature
  3. The clinical application of teaching people about pain – 2016
  4. Central Sensitization – A Generator of Pain Hypersensitivity by Central Neural Plasticity
  5. Central sensitization – Implications for the diagnosis and treatment of pain
  6. The Discriminative Validity of “Nociceptive,” ” Peripheral Neuropathic,” and “Central Sensitization” as Mechanisms-based Classifications of Musculoskeletal Pain – 2011
  7. Spinal glial activation and oxidative stress are alleviated by treatment with curcumin or coenzyme Q in sickle mice
  8. Exploring the Neuroimmunopharmacology of Opioidsv- An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia – 2011
  9. Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions – 2018
  10. Central sensitization – Implications for the diagnosis and treatment of pain – 2010
  11. A possible neural mechanism for photosensitivity in chronic pain – 2017
  12. Central Sensitization – A Generator of Pain Hypersensitivity by Central Neural Plasticity – 2009
  13. The dark side of opioids in pain management – basic science explains clinical observation. – 2016


Central Sensitization – Back and Neck Pain

  1. Centralisation_phenomena_of_spinal_symptoms
  2. Evidence for central sensitization in chronic whiplash – A systematic literature review
  3. Central Sensitization in Low Back Pain – Mechanisms-based classifications of musculoskeletal pain – Part 1 of 3 – Symptoms and signs of central sensitisation in patients with low back (+:- leg) pain – 2012


Central Sensitization – Fibromyalgia

see also: Fibromyalgia

  1. Fibromyalgia – The Unifying Concept of Central Sensitivity Syndromes
  2. From acute musculoskeletal pain to chronic widespre… [Man Ther. 2009] – PubMed – NCBI
  3. Fibromyalgia patients show an abnormal dopamine response to pain. – PubMed – NCBI
  4. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia – 2003
  5. Fibromyalgia Syndrome- A Central Role for the Hippocampus—A Theoretical Construct
  6. What Fibromyalgia Teaches Us About Chronic Pain – 2013
  7. Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels 2012
  8. Central sensitization – a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome
  9. Current concepts in the treatment of fibromyalgia – 2013
  10. Innovative Approaches for the Complexity of Fibromyalgia – 2013



Central Sensitization – Headaches

  1. Central sensitization in photophobic and non-photophobic migraineurs
  2. Central sensitization in tension-type headache–possible pathophysi… – PubMed – NCBI


Central Sensitization – Musculoskeletal Pain

  1. Chronic whiplash and central sensitization; an evaluation of the role of a myofascial trigger points in pain modulation
  2. Peripheral and central sensitization in m… [Curr Rheumatol Rep. 2002] – PubMed – NCBI
  3. Myofascial Trigger Points – Peripheral or Central?


Central Sensitization (CS) Treatment

CS Treatment – CBT and Mindful Exercises

  1. CBT and Pain Management
  2. Accurate Clinic – Meditation Resources


CS Treatment – Buprenophine

CS Treatment – Levorphanol

CS Treatment – Melatonin

CS Treatment – Methadone

CS Treatment – Minocycline

  1. Minocycline, a Tetracycline Derivative, Is Neuroprotective against Excitotoxicity by Inhibiting Activation and Proliferation of Microglia – 2001
  2. Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes – 2015
  3. Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons – 2014
  4. A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. – PubMed – NCBI
  5. Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms. – PubMed – NCBI 2011
  6. Minocycline Provides Neuroprotection Against N-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia – 2001
  7. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia – 2008
  8. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia. – 2008
  9. Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons – 2014
  10. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression – 2009
  11. Microglia attenuate the opioid-induced depression of preBötzinger Complex (preBötC) inspiratory rhythm in vitro via a TLR4-independent pathway | The FASEB Journal
  12. Glial TLR4 signaling does not contribute to opioid-induced depression of respiration – 2014
  13. Microglial Inhibitory Mechanism of Coenzyme Q10 Against Aβ (1-42) Induced Cognitive Dysfunctions – Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations – 2016
  14. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation. 2007 – PubMed – NCBI
  15. Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor – 2016
  16. The “Toll” of Opioid-Induced Glial Activation – Improving the Clinical Efficacy of Opioids by Targeting Glia – 2009
  17. Toll-Like Receptors in Chronic Pain – 2012
  18. Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases – 2017
  19. Enhancement of antinociception by coadministration of minocycline and a non-steroidal anti-inflammatory drug indomethacin in naïve mice. – 2010
  20. Exploring the neuroimmunopharmacology of opioids – an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia – 2011
  21. Glial modulators – a novel pharmacological approach to altering the behavioral effects of abused substances – 2012
  22. Pathological pain and the neuroimmune interface – 2014
  23. The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica – 2012
  24. Minocycline – far beyond an antibiotic – 2013
  25. The brain’s best friend – microglial neurotoxicity revisited. – 2013
  26. Minocycline enhances the effectiveness of nociceptin:orphanin FQ during neuropathic pain – 2014
  27. Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration – 2015
  28. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic p… – PubMed – NCBI
  29. Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model – 2016
  30. Targeting the Microglial Signaling Pathways – New Insights in the Modulation of Neuropathic Pain. – 2016
  31. Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases – 2017
  32. Paradoxical effect of minocycline on established neuropathic pain in rat. – 2017
  33. Alternatives to Opioids in the Pharmacologic Management of Chronic Pain Syndromes: A Narrative Review of Randomized, Controlled, and Blinded Clinical Trials

CS Treatment – PEA

CS Treatment – Vitamin D

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


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