Accurate Education – Central Sensitization

Central Sensitization


Understanding Central Sensitization:


Neurobiology of Pain

Neuropathic (Nerve) Pain

Mast Cell Activation Disease (MCAD)


Treating Central Sensitization:

Medications for Pain

Complementary and Alternative Medicine (CAM)

Nutrition and Supplements

Diet & Fasting

Antioxidants and Oxidative Stress


Curcumin (Meriva)

Minocycline (coming soon)

Naltrexone (coming 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

Central and Peripheral Sensitization

To understand the process and impact of sensitization in the nervous system it may be helpful to quickly review the signaling pathways associated with the perception and experience of pain.


Processing the Pain Experience

When a pain-inducing stimulus such as tissue injury occurs, it initially triggers a specialized nerve: a pain receptor (nociceptor), the entry point for pain perception. There are different types of pain receptors – some react to mechanical trauma, some to temperature etc. These receptors are located “peripherally,” or outside the central nervous system (spinal cord and brain) and have long axons that bundle with other receptor nerves to form a peripheral sensory nerve (termed a primary afferent nerve) that extends into the spinal cord. When activated, these receptors trigger an electrical response that travels to the dorsal horn area of the spinal cord.


The dorsal horn of the spinal cord is where there are connections (synapses) between the peripheral sensory nerves and other nerves that interact with one another and engage various nerve pathways. Some of these pathways ascend up the cord to the brain, other pathways descend downward from the brain. Different areas in the brain are involved in the processing of the pain experience including the emotional centers in the limbic system of the midbrain, sensory areas in the somatosensory cortex and consciousness and alertness centers in the reticular activating system of the brainstem. The interaction of these brain areas with the pain pathways extending into the spinal cord impact the pain experience. The final pain experience is determined by the interactions amongst these pathways and brain areas, where activity may enhance or suppress the pain experience.



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 that occurs in primary afferent nerves, those nerves  carrying sensory information from the peripheral nervous system to the central nervous system, the spinal cord and brain is termed 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 that occurs in higher-order nerves in the central nervous system, including the spinal cord and brain is termed central sensitization. Sensitization, both peripheral and central, 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

The Evolution of Peripheral Sensitization

Nociceptive pain is caused by activation of peripheral nociceptors (pain receptors) and associated neural pathways in response to damaging or potentially damaging stimuli to body tissue such as occurs with chemical or mechanical trauma including surgical and traumatic tissue injury and burns. Nociceptive pain normally diminishes once the peripheral driving force is removed and tissue damage repaired.


Acute nociceptive pain arises from damage to peripheral tissue and activation of nociceptors causing the release of numerous biochemical mediators including cytokines, prostaglandins and neurotrophins (see below). These biochemical mediators trigger increased spontaneous firing of nerves and alterations in nerve conduction and neurochemical sensitivity. A phenomenon known as neurogenic inflammation also occurs, whereby inflammatory products are released by activated nociceptors, leading to a cascade of changes including ion channel permeability and increased density of receptors on the nerve cell membranes. When these conditions persist, these changes increase the responsiveness and excitability of the nerves leading to the condition of peripheral sensitization, manifest by nociceptors being activated by lower levels of stimulation including innocuous stimulation that would ordinarily not be painful. And, in turn, this heightened condition of peripheral sensitization leads to central sensitization within the central nervous system.


Central Sensitization (CS)

Central Sensitization (CS) is a process that accompanies many chronic pain syndromes, contributing to increased pain and suffering. CS is a 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 and signal transmission as well as reduced inhibition from higher levels in the brain changes in nerve firing patterns. 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 increase or amplification of pain perception. Because central sensitization results from changes in the properties of nerves in the central nervous system,  pain is no longer coupled to the presence, intensity, or duration of the original cause of pain. In other words, the pain experience takes on a life of its own and may persist even after the original injury that created the pain has healed. Instead, sensitization produces pain hypersensitivity by changing the sensory response elicited even by normal inputs, including those that usually evoke innocuous sensations.


How Does Sensitization Manifest?

The result of both peripheral and, especially, central sensitization is that a person with these conditions will experience a magnification of their pain when a painful event occurs. For example, when a patient with chronic pain accompanied by sensitization has a new traumatic injury, they will experience their pain associated with the new injury as more painful then the same experience would have been if they had never had their chronic pain condition in the first place.


For example, it is not uncommon for post-operative pain to be experienced more severely in chronic pain patients, even when the surgery is unrelated to the chronic pain condition. In this example, the magnified pain may require higher than expected doses of opioids to manage, even more than predicted by the patient’s established opioid analgesic tolerance. Unfortunately, this situation may lead the managing clinician to misinterpret the need for higher doses as drug seeking behavior and lead to restriction of opioid management rather than providing adequate doses to control the pain.


It should be emphasized that the development of CS is not simply a ‘yes’ or ‘no’ but CS evolves at different degrees over a continuum, from a little to a lot, mild to severe.

See: YouTube explanation of Peripheral and Central Sensitization


The Evolution of Central Sensitization

Central sensitization occurs when the nervous system goes through a process called “wind-up,” which is when chronic, repetitve stimulation of peripheral pain receptors (nociceptors) leads to ongoing repetitive impulses into the central nervous system (the spinal cord and brain), especially the dorsal horn neurons in the spinal cord.  This creates a persistent state of high reactivity or hypersensitivity in these nerves even after the original pain stimulus is resolved.  As a result, sensory experience becomes amplified so that that a pain patient becomes hypersensitive to sensory stimulation, especially mechanical stimulation such as touch or pressure. Central sensitization may also spread sensitivity to areas 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. 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 also develop emotional sensitivity and become more impacted by anxiety and stress. This combination of magnified physical and emotional experiences associated with CS can impact one’s quality of life.


At least two pathways are proposed for central sensitization. The first is the chronic neurologic processing of pain which causes changes in the nerve receptors and nerve pathways which progress to central sensitization. The second pathway is psychologically centered and also contributes to magnification of the pain experience.  This pathway is characterized by elevated levels of chronic stress and includes elements of anxiety, emotional distress, impaired social interaction and disruption of sleep. 


Stress and Central Sensitization

The role of stress in the chronification of pain cannot be over-emphasized. In addition to the psychological and emotional components of experiencing stress that magnify the pain experience there are important neuro-chemical changes associated with stress that impact the neurobiology of pain. The HPA axis (hypothalamus – pituitary – adrenal glands) is the primary regulator of the stress response. Under normal conditions, an acute stressor signal the paraventricular nucleus (PVN) of the hypothalamus to release corticotropin-releasing factor (CRF) and vasopressin which cause the pituitary gland to release adrenocorticotrophic hormone (ACTH), which in turn signals the adrenal cortex to release cortisol, the stress hormone. Cortisol has many systemic effects including raising blood sugar and reducing inflammation. Chronic stress however is associated with long term effects from cortisol that are detrimental.


The CRF released with HPA axis activation has peripheral effects including activating mast cells which  release cytokines and growth factors that interact with pain receptors in the brain and the dorsal horn of the spinal cord. Mast cells are a critical part of the immune system and are highly responsive to activation of the HPA axis. They are found most predominantly in areas with direct contact to the environment: skin, airway, gastrointestinal and urinary tracts.


Mast cells are filled with granules that contain histamine, heparin, tryptase, and other enzymes and cytokines including endogenous neuropeptides such as nerve growth factor (NGF) and substance P. The release of these neuropeptides cause hypersensitivity reactions and contribute to the peripheral anzd central sensitization process. Mast cells are responsible for the increased pain associated with changes in weather.

See: Mast Cell Activation Disease


The Central Sensitization Syndrome

Both of these pathways actively contribute to the central sensitization syndrome, (also described as “Central Pain Syndrome”) which is characterized by magnified pain experience, widespread pain, poor pain control, disruption of emotional stability, fataigue, impaired coping ability, cognitive difficulties and reduced quality of life. The central sensitization syndrome is the archetypal example of a chronic biopsychosocial pain disorder.


Neurobiology of Peripheral Sensitization

Sensitization of pain receptors (nociceptors) in the skin and other tissues is caused by numerous factors that result in lower neuronal thresholds of activation and nociceptor hyperexcitability. Factors that promote this peripheral sensitization (PS) include the exposure to biochemical mediators and inflammatory agents that are released from nociceptor nerve terminals. These biochemical mediators include cytokines, prostaglandins, neuropeptides, chemokines, interleukins,  and growth factors:


  1. Cytokines – Tumour necrosis factor alpha ((TNFa): interact with pain receptors to release more biochemical mediators to amplify pain signalling
  2. Prostaglandins – Prostaglandin E2 (PGE): sensitize pain receptors
  3. Neuropeptides – CGRP (Calcitonin gene-related peptide), Substance P: increase pain signalling
  4. Chemokines – Chemokine ligand 2: proteins that signal immune cells, recruiting them to sites of inflammation or injury
  5. Interleukins – Interleukin 6 & 1-Beta (IL-6 & IL1B): upregulate inflammatory responses
  6. Growth Factors – Brain derived nerve growth factor (BDNF) and Nerve growth factor (NGF): regulate neuronal activity, excitability and function

These agents promote vascular permeability and leakage, which causes local swelling (edema) and the release of additional biochemical mediators. The consequence of these events is peripheral nociceptor hyperexcitability, contributing to peripheral sensitization. Injured nociceptive neurons can become so “sensitized” that they may activate even in the absence of any stimulation, another manifestation of peripheral sensitization. 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.


Neurobiology of Central Sensitization

For those interested in the neurobiology of CS, this hypersensitive response to stimulation 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, neuro-inflammation and neuro-endocrine dysfunction, NMDA dysregulation (NMDA is a receptor involved in pain pathways – see Education – Pain), sympatho-afferent coupling; and altered serotonin and norepinephrine production and utilization.


CS reflects not only spinal cord sensitization but also enhanced activity of pain descending facilitation pathways and impairment of descending pain suppressive pathways and activation of collateral synapses. These changes 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/utilization. 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 nerve pathways, immune cells and various biochemical 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. As with peripheral sensitization, 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.


Management of Central Sensitivity

Understanding these concepts and the two pathways proposed for the evolution of CS allows for three categorical approaches to limiting the development of CS and reducing it’s impact on one’s experience. First is a neurochemical approach with the use of medications and/or supplements such as nutriceuticals to impact the nervous system to suppress or reverse the changes associated with sensitization. Second is a non-pharmacologic approach with electrical stimulation and third is a behavioral approach to address the psychological and behavioral aspects of chronic pain that are associated with central sensitization.


Neurochemical Treatment of Central Sensitivity

Anti-epileptic Medications

The neurochemical approach can be directed at various components of the nervous system that contribute to CS. One of the most common and most useful class of medications used to manage CS are the anti-epileptic class of drugs that act directly on nerves. These anti-epileptic drugs include gabapentin (Neurontin), pregabalin (Lyrica) and topiramate (Topamax).


Medications that act on the descending inhibitory nerve pathways

Important pathways in the nervous system involved in pain modification and central sensitivity are the descending nerve pathways from the brain to the dorsal horn of the spinal cord. These pathways have an inhibitory function on pain signaling and medications that promote activity of these pathways are helpful in the treatment of pain. Medications that impact the descending pathways include the SNRI anti-depressants duloxetine (Cymbalta), venlafaxine (Effexor) and milnacaprin (Savella).


While opioids that interact solely via opioid receptors do not appear to offer value for the treatment of CS, some opioids have secondary mechanisms of action on the descending inhibitory pathways that  offer therapeutic benefit. These opioids include tapentadol (Nucynta) and tramadol (Ultram).


For more information about agents effect for  central sensitization and neuropathic pain, see Neuropathic Pain.


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)


Non-Pharmacologic Approaches to the Management of Central Sensitization

Electrical Stimulation

Non-pharmacological forms of treatment with the use of electrical stimulation is effective for management of pain, including central sensitization. Trans-cutaneous electrical nerve stimulation (TENS) which provides electrical current through the skin to treat pain is effective in inflammatory, neuropathic, and non-inflammatory pain conditions associated with CS.  Spinal cord stimulation (SCS), which also delivers electrical current to the dorsal columns through implanted electrodes, is commonly used for the treatment of neuropathic pain. Both TENS and SCS provide pain relief via similar mechanisms including the release of inhibitory neurotransmitters gamma-aminobutyric acid (GABA), serotonin, and endorphins in the central nervous system, as well as a reduction of central neuron sensitization.


TENS and SCS have been shown to suppress central neuron sensitization and glial cell activity to reduce pain perception, allodynia and hyperalgesia. Electrical stimulation alters the membrane potential of neurons and thereby alter the electrochemical properties of the the neurons. It is believed that peripheral stimulation with TENS induces electrical activity which inhibits the brain’s perception of pain by regulating the flow of pain signalling in the ascending and descending pathways between the brain and dorsal horn of the spinal cord.



Although still controversial as to its effectiveness in chronic pain, acupuncture is proposed to provide its analgesic benefits through activation of both peripheral and central mechanisms, including the activation of the descending inhibitory pain pathways. Additionally, acupuncture has been shown to have a direct effect on the immune system by increasing the release of the anti-inflammatory cytokine interleukin (IL)-10 to reduce inflammatory cell infiltration, vascular permeability, neutrophilic activity, and edema, all contributing factors to peripheral and central sensitization.



Behavioral Approaches to the Management of Central Sensitization

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.



Exercise has been shown to relieve stress and reduce depression and anxiety and is successful in reducing the pain associated with the pain disorders most associated with central sensitization including chronic pelvic pain (including interstitial cystitis, irritable bowe syndrome etc. ), migraine and fibromyalgia. The reverse is also true: people who are more physically active have
been shown to have less chance of developing chronic pain disorders.


Chronic pain is associated with dysfunction of the descending inhibitory pathways from the brain to the spinal cord that suppress pain signaling. Exercise appears to support these pathways as a mechanism for the benefits of exercise in pain.



Exercise can include a wide range of activities such as walking, aerobic strength training, yoga, pilates, or swimming. Variety is important so that a patient can find an activity that they enjoy and therefore they are more likely to engage exercise as a long-term life style change rather than a quick fix treatment.


It is important to understand that the length of an exercise protocol, as well as the intensity of exercise, has been shown to have influence the pain benefit outcomes. High-intensity exercise tends to be more stressful and therefore does not have as beneficial effects that low-intensity exercise does. There appears to be a narrow ‘‘therapeutic window’’ for the use of exercise in chronic pain treatment, whereby low or moderate levels may be successul when minimal levels or more intense levels are counter-productive.


Therefore exercise regimens should be initiated slowly and engaged in a manner that de-emphasizes vigorous achievement and reduce the stress associated with high pressures to perform. In the cases where exercise has detrimental effects on chronic pain symptoms, it is likely due to improper application of the exercise regimen. Studies that have shown that combining exercise and CBT significantly reduces pain, anxiety, depression, and fatigue as well as improving physical functioning in chronic pain patients.



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
  4. What is different about spinal 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
  3. CGRP-Based Migraine Therapeutics – How Might They Work, Why So Safe, and What Next? – 2019
  4. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine – 2017
  5. Targeted CGRP Small Molecule Antagonists for Acute Migraine Therapy – 2018


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?
  4. Evidence for central sensitization in patients with osteoarthritis pain – A systematic literature review – 2014


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 – TENS (Transcutaneous Electrical Nerve Stimulation)

  1. Transcutaneous electrical nerve stimulation, acupuncture, and spinal cord stimulation on neuropathic, inflammatory and, non-inflammatory pain in rat models – 2020
  2. Transcutaneous electrical nerve stimulation and heat to reduce pain in a chronic low back pain population – a randomized controlled clinical trial – 2020

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.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


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