“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 – Central and Peripheral

Central and peripheral sensitization are very common but under-addressed processes that afflict a large portion of chronic pain patients who suffer from chronic neck or back pain, migraine headaches, fibromyalgia and visceral organ pain (like pancreas or liver). These sensitization processes also impact conditions not specifically related to pain including anxiety, panic attacks and restless legs syndrome.

There are many manifestations of peripheral sensitization (PS) and central sensitization (CS) but most importantly they contribute to an enhanced or magnified experience of pain in which a stimulis that is ordinarily painless or only mildly painful becomes moderately or severely painful.

Additionally, central and peripheral sensitization contribute to the transition of acute to chronic pain, whereby the  pain from an acute injury becomes chronic, despite resolution of the original injury initially triggering pain.

Knowledge of PS and CS is important to anyone that suffers from chronic pain. Understanding them will provide insights as to why pain becomes so severe but more importantly, understanding CS in particular may allow one to reduce further development of CS and possibly reduce the severity of existing central sensitivity.

 

Understanding Central Sensitization:

 

Treating Central Sensitization:

 

Terms:

Pain

Pain is defined as:

“an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

 

Allodynia

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

 

Hyperalgesia

Hyperalgesia is a magnified painful response to a stimulus which is normally painful. 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 of allodynia in contrast to hyperalgesia has been debated since its existence.

 

Nociception

Nociception is the process of detecting noxious stimuli, such as painful, irritating or other aversive stimulation. The term also includes the neural responses of encoding and processing noxious stimuli. Nociception is a protective process that helps prevent injury by generating both a reflex withdrawal from the stimulus and providing a sensation so unpleasant that it results in complex behavioral strategies to avoid further contact with such stimuli.

 

Nociceptive Pain

Nociceptive pain is by far the most common type of pain. It is defined by the IASP as “pain that arises from actual or threatened damage to non-neural tissue and is due to activation of peripheral nerve endings (nociceptors) in response to noxious stimulation. The term nociceptive pain includes pain associated with active inflammation and is designed to contrast with neuropathic pain.

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.  It is usually described as a sharp, aching, or throbbing pain. Nociceptive pain is further divided into “visceral” pain, originating from the organs inside the body,  and “somatic” pain, originating from muscles, bone and skin. Visceral pain is often vague, difficult to describe and hard to localize. Nocicptive pain is usually a symptom of a disease process.

 

Neuropathic pain (“Nerve Pain”)

The International Association for the Study of Pain (IASP)’s 1994 definition of neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”proved debatable, specifically related to the term “dysfunction” which was considered to be too broad and imprecise. The IASP Special Interest Group on Neuropathic Pain (NeuPSIG) subsequently proposed a new definition of neuropathic pain in 2008, as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” This was later modified to include  “neuropathic pain is a clinical description (and not a diagnosis).

Nerve pain is usually perceived as burning, electric, shock-like, tingling or sharp and may start at one location and shoot, or “radiate” to another location (like sciatica). Neuropathic pain can be “peripheral,”  (outside the central nervous system),”  like carpal tunnel pain or “central,” originating in the spinal cord or brain.  Neuropathic pain is often a disease process, not simply the symptom of one.

 

 Definitions and Terms Related to Pain

Key to Links:

  • Grey text – handout
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Central Sensitization Overview

Central sensitization of pain occurs when a patient’s nervous system is persistently in a high pain activity state. When this happens, even if the peripheral nervous system sends limited signals of painful stimulation, the central nervous system responds as if there has been a high level of input, which results in amplification of pain signals to the brain and consciousness. So patients become hypersensitive to pain. Ordinary touch may be perceived as painful (allodynia), or a painful stimulus is perceived as magnified (hyperalgesia). Because of central sensitization, pain can be made even worse by cold temperatures and changes in an emotional state.

Central sensitization is also known as centralized pain, central pain, central pain syndrome, and widespread or diffuse pain. It is relatively common and has genetic and environmental influences that may predispose its development in patients. Patients with multiple chronic disease states that experience local pain can develop centralized pain. For example, centralized pain often occurs in patients with fibromyalgia and other chronic pain syndromes (migraine headaches, back pain, arthritis etc.) and it also occurs following neurological injuries such as a stroke or a spinal cord injury.

Centralized pain is associated with memory loss and worsening anxiety. The treatment of central sensitization is different from pain arising from pain receptors in tissues. Traditional pain relievers, such as NSAIDs and opioids, are often not adequate. Medications including antidepressants (Cymbalta/duloxetine) and anticonvulsants (Neurontin/gabapentin and Lyrica/pregabalin) to augment pain relief. 

Central sensitization can result in widespread generalized pain which can be disabling and cause significant impact on a patient’s quality of life. Widespread generalized pain affects up to one-fifth of adult patients.

 

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) which is the entry point for pain perception. There are different types of pain receptors – some react to mechanical trauma, some to temperature and some to chemical injury etc. These receptors are located “peripherally,” or outside the central nervous system (spinal cord and brain) and have long tail-like 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 by injury, these receptors trigger an electrical response that travels to the dorsal horn area in 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 with 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

Tissue damage leads to increased spontaneous firing and alterations in the the conduction and neurochemical sensitivity of nociceptors and afferent nerve pathways sending pain signals to the spinal cord. A phenomenon known as neurogenic inflammation also occurs, whereby inflammatory products are released by activated nociceptors, leading to a cascade of events involving enhanced ion channel permeability, gene expression, and receptor and channel density on the cell membrane. The consequence of these events is peripheral nociceptor hyperexcitability, termed ‘peripheral sensitization, defined as “Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to
 the stimulation of their receptive fields.”

 

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 (PS). This sensory information may be related to  physical stimulation (mechanical damage or trauma, distention, contraction etc.), chemical stimulation or thermal (hot or cold) stimulation. Of interest is that PS appears to play a greater role in altered heat but not mechanical sensitivity, which is a more of a  feature of central sensitization.

 

 

The sensitization process that occurs in higher-order nerves in the central nervous system, including the spinal cord and brain is termed central sensitization (CS). 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

Acute nociceptive pain is that physiological sensation of hurt that results from the activation of pain receptors (nociceptors) and their associated pain pathways (nociceptive pathways) by peripheral stimulation of sufficient intensity in response to damaging or potentially damaging stimuli to body tissue (referred to as noxious stimuli) such as occurs with chemical or mechanical trauma including surgical and traumatic tissue injury and burns.

Damage to peripheral tissue and activation of nociceptors causes 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 lead to peripheral sensitization (PS), manifest by nociceptors being activated by lower levels of stimulation including innocuous stimulation that would ordinarily not be painful.

Viewed from an evolutionary perspective, this nociceptor-induced sensitization of the somatosensory system is adaptive in that it makes the system hyperalert in conditions in which the risk of further damage is high, for example, immediately after exposure to an intense or damaging stimulus. In other words, when an injury results in pain and further mechanical stimulation (trauma) would threaten to worsen the injuy, having a greater painful response to further trauma would be protective by limiting further injurious behavior. A common example of periperal sensitization is the magnified perception of heat-induced pain that occurs when a sunburn is exposed to a hot shower – even warm water application to the burn is perceived as painfully hot and avoided.

Peripheral sensitization is limited to the site of tissue injury and requires ongoing activity of the neural pathways to be sustained. Once tissue damage is repaired, this state of heightened sensitivity returns over time  to the normal baseline, where high- intensity stimuli are again required to initiate nociceptive pain; the phenomenon may be long lasting but it is not permanent. The nociceptor-induced sensitization of the somatosensory system is adaptive in that it makes the system hyperalert in conditions in which a risk of further damage is high, for example, immediately after exposure to an intense or damaging stimulus.

 

The development of PS often leads to central sensitization (CS) within the central nervous system, although it is not a required prerequisite for CS to evolve such as the case of migraine headaches commonly associated with CS that is generated 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, arthritis, musculoskeletal disorders with generalized pain hypersensitivity, temporomandibular joint (TMJ) disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders, interstitial cystitis, irritable bowel syndrome (IBS) and postsurgical pain (to name a few…) . In fact, CS is potentially a contributing factor to almost any type of chronic pain. Unfortunately, there is no definitive method of diagnosing or directly measuring CS currently available. Researchers commonly incorporate a questionnaire, the Central Sensitization Inventory (CSI), that quantitatively reflects the severity of symptoms often associated with CS and can allow for a means of assessing a persons subjective experience of CS symptoms.

 

Peripheral vs Central Sensitization

Although it may appear that central sensitization is comparable to peripheral sensitization (PS), it differs substantially, both in terms of the molecular mechanisms responsible and how it manifests. Peripheral sensitization is characterized by a reduction in threshold and an amplification in the responsiveness of nociceptors that occurs when the peripheral terminals of these normally high-threshold primary sensory neurons are exposed to inflammatory mediators associated with damaged tissue. Peripheral sensitization is restricted to the site of tissue injury. Although PS certainly contributes to the sensitization of the nociceptive system and thereby the hypersensitivity to inflammatory pain at inflamed sites (primary hyperalgesia), it actually represents a form of pain triggered by activation of nociceptors,which, due to the increased peripheral transduction sensitivity, converts normally high threshold pain receptors to low threshold.

In other words, pain receptors that normally require a strong stimulus to be perceived are converted so that it only requires a weak stimulus to trigger a painful response, which makes pain much more easily perceived. This conversion to low threshold requires ongoing signalling from pain receptors to be maintained so that over time, as a result of tissue healing, the reduction of pain signalling from the receptors allows the low threshold status to return to its normal high threshold status.

As noted above, PS appears to play a major role in altered heat but not mechanical sensitivity, which is a major feature of central sensitization. This can be easily noticed when after one sustains a burn, even a sunburn, exposing the burned tissue to heat, such as hot water, that heat is poorly tolerated because of increased sensitivity to the heat.

Central sensitization (CS), in contrast to peripheral sensitization, co-opts, or repurposes, inputs to nociceptive pathways including those that do not normally drive them, such as large low-threshold mechanoreceptor myelinated fibers to produce Aβ fiber–mediated pain. It also produces pain hypersensitivity in non-inflamed tissue by changing the sensory response triggered by normal inputs by increasing pain sensitivity long after the initiating injury may have resolved and no peripheral pathology remains.

Because CS results from changes in the properties of nerves in the central nervous system (CNS), the pain is no longer coupled, as acute pain is, to the presence, intensity, or duration of the peripheral stimulation from injured tissues. Instead, CS represents an abnormal state of enhanced responsiveness of the nociceptive system. Pain is effectively generated as a consequence of changes within the CNS that alters how it responds to sensory inputs, rather than specifically reflecting the presence of peripheral noxious stimuli.

In this respect, CS represents a major functional shift in the somatosensory system from high-threshold nociception to low-threshold pain hypersensitivity. We all perceive pain as arising from somewhere, and consequently experience it to be actually triggered by noxious stimuli where we feel the pain. Central sensitization changes this, however, so that in many cases the perceived pain localization is a sensory illusion. In other words, specific CS changes in the CNS can result in painful sensations perceived in the absence of either peripheral pathology or noxious stimulation.  As such, once CS is etablished, the target for treatment in CS pain must be the CNS not the periphery because as noted above, PS generally resolves as an injury heals and pain signalling tapers down and off.

 

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

 

For example, it is not uncommon for post-operative or post-traumatic pain to be experienced more severely in chronic pain patients, even when the surgery or trauma is unrelated to the patient’s underlying chronic pain condition. In this example, the magnified pain may require higher than expected doses of opioids to be effective, even more than might be 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 higher doses to adequately 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 temporal summation or  “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.

 

To induce central sensitization, the noxious stimulus must be intense, repeated, and sustained. Input from many fibers is required over tens of seconds; a single stimulus, such as a pinch, is insufficient. Peripheral tissue injury is not necessary, although the degree of noxious stimulation that produces significant tissue injury almost always induces central sensitization, so that the phenomenon is very prominent after post-traumatic or surgical injury. Interestingly, nerves innervating muscles or joints produce a longer-lasting central sensitization than those that innervate skin.

 

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 and central sensitization process. Mast cells are responsible for the increased pain associated with changes in weather. The stabilization of mast cells to suppress inappropriate or excessive release of these neuropeptides offers one mechanism of treating central sensitivity.

See: Mast Cell Activation Disease

 

The Central Sensitization Syndrome

Both of these pathways, excessive neurologic processing and psychologic influences, 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, fatigue, 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.

 

Activation of NMDA receptors (N-Methyl-D-Aspartate) on nerves is an essential step in initiating and maintaining the sensitization. The NMDA receptor binds with glutamate, the most common excitatory neurotransmitter in the nervous system. It plays a crucial role in regulating a wide variety of neurological functions, including breathing, movement, learning, memory formation and especially neuroplasticity (forming and reorganizing connections between nerves in response to learning or following injury).

 

Structural and/or functional impairment of the NMDA receptor can lead to neuropathic pain as well as neurodegenerative and cognitive disorders such as Alzheimer’s disease, Parkinson’s disease and psychiatric disorders. Under normal circumstances this receptor channel is blocked by magnesium (Mg) ions. With continued pain, the sustained release by nociceptors of the neurotransmitters glutamate, substance P and CGRP leads to nerve depolarization, forcing Mg off NMDA receptors which activates intracellular pathways and maintains sensitization. This is why the use of NMDA antagonists may be useful in preventing or reducing peripheral and central sensitization (see below).

 

Management of Peripheral Sensitization

Anti-inflammatory medications are theorized to target inflammatory markers, thereby interfering with neurogenic inflammation, and suppressing peripheral sensitization. Prospective studies of anti-inflammatory medications for the prevention of chronic pain however, are lacking.  Other treatments targeting peripheral sensitization include antidepressants, cannabinoids, local anesthetics, and topical agents.

Neurobiology of Central Sensitization

As pain signals are transmitted from the peripheral nervous system when pain receptors are stimulated, the signals converge in the spinal cord at the dorsal horn areas along the length of the spinal cord. The dorsal horn serves as the interface between peripheral and central pain reception (nociception) where the complex mechanisms that enhance (excitatory) or suppress (inhibitory) pain converge. These mechanisms involve various cell types including interneurons that communicate between nerves and glial cells that surround and share the cellular matrix of the nervous system. Pain signalling can be modified, or modulated, via the biochemical mediators listed above. Nerve pathways that descend from the brain down to the dorsal horn called the descending pathways act to either facilitate or suppress pain signaling. The severity and duration of pain is determined in part by these descending pathways and the influence of brain areas such as the periaqueductal gray (PAG), rostroventral medulla (RVM), and nucleus caudalis.

 

It is in the dorsal horn that central sensitization and the resultant hyperalgesia and allodynia appear to be initiated. This hypersensitive response to stimulation is thought to initiate 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, sympatho-afferent coupling; and altered serotonin and norepinephrine production and utilization. 

 

Two mechanisms contributing to the over-bombardment of pain signals that play significant roles in central sensitization are temporal summation and spatial summation.

 

Temporal Summation

Temporal summation is a important manifestation of central sensitization. Temporal summation, also referred to as “wind-up,” occurs when a painful stimulus is continuously repeated lasting more than 10 seconds, the pain will integrate and become more painful by increasing pain intensity at the end of the stimulus train. Temporal summation is a measure of increased central nervous system pain and an important mechanism related to central sensitization. It is an important contributor to the degree of severity of knee pain associated with arthritis.

 

Difficult to block with conventional analgesics or anaesthetic procedures, it is a very powerful pain mechanism associated with repetitive activation of C nerve fibers and dorsal horn wide-dynamic range neurons. Temporal summation can be elicited with mechanical or thermal stimulation in the skin, musculoskeletal structures, and viscera. In clinical bedside testing, temporal cutaneous summation can be assessed by tapping the skin with a nylon filament.

 

Spatial Summation

Painful stimulation does not only integrate temporally, but also spatially. Spatial summation is an increase in pain intensity when the size of the stimulated area is expanded, for example if the number of stimulation points delivering a painful stimulus is increased, the perceived severity of that pain is disproportionately magnified. Spatial integration relies on central networks and the general sensitization status. Painful stimuli suceptible to spatial summation include heat, mechanical and pressure. Spatial summation is facilitated in various pain conditions, such as fibromyalgia, OA  and lateral epicondylitis.

 

Central sensitization reflects not only spinal cord sensitization but also enhanced activity of descending pain facilitation pathways and impairment of descending pain suppressive pathways along with  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

 

Treatment of Temporal Summation

The NMDA receptor plays a key role in temporal summation, but is very difficult to block even when using general anaesthesia or epidural analgesia. Many animal studies have shown that wind-up and temporal summation in dorsal horn neurons are inhibited by NMDA receptor antagonists as well as by antagonists of the glycine site in the NMDA receptor channel complex. Temporal summation in chronic pain patients can be inhibited by NMDA receptor antagonists in patients with surgical incisions, postherpetic neuralgia, phantom limb pain, chronic postsurgical neuropathic pain and fibromyalgia.

Drugs showing an inhibitory effect on temporal summation include dextromethorphan (Delsym), ketamine, amantadine, imipramine, gabapentin (Neurontin) and venlafaxine (Effexor).

 

 Anti-epileptic Medications (Anticonvulsant) – AEDs

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 (AEDs) that act directly on nerves. AEDs act as  membrane stabilizers and share a common mechanism of ion channel blockade, thus interfering with peripheral sensitization.These anti-epileptic drugs include gabapentin (Neurontin), pregabalin (Lyrica) and topiramate (Topamax).

 

Medications that act on the descending inhibitory nerve pathways

Important nerve pathways 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 may  act to inhibit or to facilitate pain signaling from the spinal cord to the brain. The descending pain control network is important for the chronification of pain when impaired descending pain modulatory pathways and particularly the facilitatory pathways may contribute to development and maintenance of CS.

 

Impairment of the descending pain modulatory pathways is associated with many pain conditions, such as chronic low back pain, whiplash, temporomandibular joint pain (TMJ), myofascial pain, fibromyalgia, knee arthritis, chronic tension-type and migraine headaches, interstitial cystitis, irritable bowel syndrome (IBS), neuropathy, and chronic pancreatitis. Studies indicate that impaired descending pain modulation is more common in females which may explain the greater frequency of conditions such as fibromyalgia and headaches identified in females.

 

Descending pain inhibition is largely mediated by noradrenaline release in the spinal cord. Noradrenaline acts at the α2-adrenoceptors which inhibit the release of excitatory neurotransmitters which facilitate pain signals. Medications that promote activity of these inhibitory 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). Multiple studies have concluded that traditional opioids acting on opioid receptors have no benefit with descending pain inhibition.

 

While traditional 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.

 

 Acupuncture

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

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.

 

CoQ10

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

 

 

Resources

You Tube videos:

  1. Dr. Sletten Discussing Central Sensitization Syndrome (CSS)
  2. Peripheral and central sensitisation

 

Reference Articles

Central Sensitization – New Articles

  1. Psychosocial Factors and Central Sensitivity Syndromes – 2015
  2. Centralization in patients with sciatica – are pain responses to repeated movement and positioning associated with outcome or types of disc lesions? – 2012
  3. Central Sensitization-Based Classification for Temporomandibular Disorders – A Pathogenetic Hypothesis – 2017
  4. Central sensitization is a risk factor for wound complications after primary total knee arthroplasty – PubMed – 2019
  5. Phenotypic Features of Central Sensitization – 2018
  6. The Mediating Effect of Central Sensitization on the Relation between Pain Intensity and Psychological Factors – A Cross-Sectional Study with Mediation Analysis – 2019
  7. Difference in the impact of central sensitization on pain-related symptoms between patients with chronic low back pain and knee osteoarthritis – 2019
  8. Diagnostic accuracy of the clinical indicators to identify central sensitization pain in patients with musculoskeletal pain – 2021
  9. The Discriminative Validity of “Nociceptive,” “Peripheral Neuropathic,” and “Central Sensitization” as Mechanisms-based Classifications of Musculoskeletal Pain – 2011
  10. An Integrative Neuroscience Framework for the Treatment of Chronic Pain – From Cellular Alterations to Behavior – 2018
  11. Central Sensitivity Is Associated with Poor Recovery of Pain – Prediction, Cluster, and Decision Tree Analyses – 2020
  12. Lack of Evidence for Central Sensitization in Idiopathic, Non-Traumatic Neck Pain – A Systematic Review – 2015
  13. Psychological Distress and Widespread Pain Contribute to the Variance of the Central Sensitization Inventory A Cross-Sectional Study in Patients with Chronic Pain – PubMed – 2018
  14. Use of the Central Sensitization Inventory (CSI) as a treatment outcome measure for patients with chronic spinal pain disorder in a functional restoration program – PubMed – 2017
  15. Psychological Therapy for Centralized Pain – An Integrative Assessment and Treatment Model – 2019
  16. Posttraumatic Stress Symptoms Mediate the Effects of Trauma Exposure on Clinical Indicators of Central Sensitization in Patients with Chronic Pain – 2019
  17. Central Sensitisation and functioning in patients with chronic low back pain – protocol for a cross-sectional and cohort study – 2020
  18. Nociplastic Pain Criteria or Recognition of Central Sensitization? Pain Phenotyping in the Past, Present and Future – 2021
  19. Opioid-Induced Hyperalgesia and Allodynia Causes and Treatments – 2020
  20. Increased Experimental Pain Sensitivity in Chronic Pain Patients Who Developed Opioid Use Disorder – PubMed – 2021
  21. Measures of central sensitization and their measurement properties in musculoskeletal trauma A systematic review – PubMed – 2021
  22. Measures of central sensitisation and their measurement properties in the adult musculoskeletal trauma population – a protocol for a systematic review and data synthesis – 2019
  23. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers – 2007
  24. An Integrative Neuroscience Framework for the Treatment of Chronic Pain – From Cellular Alterations to Behavior – 2018
  25. Assessment and manifestation of central sensitisation across different chronic pain conditions – 2018
  26. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain – 2018
  27. Peripheral inflammatory pain sensitisation is independent of mast cell activation in male mice – 2017
  28. Applying Modern Pain Neuroscience in Clinical Practice – Criteria for the Classification of Central Sensitization Pain – 2014
  29. Mechanisms of Dexmedetomidine in Neuropathic Pain – 2020
  30. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine
  31. Cognitive Performance Is Related to Central Sensitization and Health-related Quality of Life in Patients with Chronic Whiplash-Associated Disorders and Fibromyalgia – 2015
  32. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  33. Interaction of Fentanyl and Buprenorphine in an Experimental Model of Pain and Central Sensitization in Human Volunteers | Request PDF – 2012
  34. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. – 2014
  35. Amitriptyline for musculoskeletal complaints – a systematic review – 2017
  36. Pain inhibition is not affected by exercise-induced pain – 2020
  37. The Interexaminer Reproducibility and Prevalence of Lumbar and Gluteal Myofascial Trigger Points in Patients With Radiating Low Back Pain – 2020
  38. Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain – a case–control study – 2015
  39. Diffuse central sensitization in low back patients – 2020
  40. A Subgroup of Chronic Low Back Pain Patients with Central Sensitization – 2019
  41. Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers – PubMed – 2005
  42. Does central sensitization help explain idiopathic overactive bladder? – 2016
  43. Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and above with knee osteoarthritis – ethnic differences – 2014
  44. Tapentadol treatment results in long-term pain relief in patients with chronic low back pain and associates with reduced segmental sensitization – 2020
  45. Oxycodone alters temporal summation but not conditioned pain modulation preclinical findings and possible relations to mechanisms of opioid analgesia – PubMed – 2013
  46. The Effect of Hydromorphone Therapy on Psychophysical Measurements of the Descending Inhibitory Pain Systems in Patients with Chronic Radicular Pain – 2015
  47. Fibromyalgia-The-Unifying-Concept-of-Central-Sensitivity-Syndromes Signaling Pathways in Sensitization – Toward a Nociceptor Cell Biology – 2007
  48. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. – 2014
  49. Pain inhibition is not affected by exercise-induced pain – 2020 Neurophysiologic-evidence-for-a-central-sensitization-in-patients-with-fibromyalgia-2003
  50. Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain – a case–control study – 2015
  51. Diffuse central sensitization in low back patients – 2020
  52. A Subgroup of Chronic Low Back Pain Patients with Central Sensitization – 2019
  53. Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers – PubMed – 2005
  54. Does central sensitization help explain idiopathic overactive bladder? – 2016
  55. Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and above with knee osteoarthritis – ethnic differences – 2014
  56. Tapentadol treatment results in long-term pain relief in patients with chronic low back pain and associates with reduced segmental sensitization – 2020
  57. Oxycodone alters temporal summation but not conditioned pain modulation preclinical findings and possible relations to mechanisms of opioid analgesia – PubMed – 2013
  58. The Noradrenergic Locus Coeruleus as a Chronic Pain Generator – 2017
  59. The link between chronic pain and Alzheimer’s disease – 2019
  60. Gabapentin loses efficacy over time after nerve injury in rats – Role of glutamate transporter-1 in the locus coeruleus – 2016
  61. Advances in Pain Research – Mechanisms and Modulation of Chronic Pain – 2018 Book
  62. Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System – 2019
  63. Descending Noradrenergic Inhibition An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain – PubMed – 2018
  64. Pharmacological rationale for tapentadol therapy – a review of new evidence – 2019
  65. Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System – 2019
  66. Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain – Focus on Microglia Activation – 2019
  67. The proportion of women with central sensitivity syndrome in gynecology outpatient clinics (GOPDs) – PubMed – 2019
  68. Metabolomics in Central Sensitivity Syndromes – 2020

 

 

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 – Central Sensitization Inventory (CSI)

  1. Ability of the central sensitization inventory to identify central sensitivity syndromes in an outpatient chronic pain sample – PubMed 2015
  2. Use of the Central Sensitization Inventory (CSI) as a treatment outcome measure for patients with chronic spinal pain disorder in a functional restoration program – PubMed – 2017
  3. Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory – PubMed – 2017
  4. Additional evidence supporting the central sensitization inventory (CSI) as an outcome measure among chronic pain patients in functional restoration program care – The Spine Journal – 2017
  5. Inventory A Cross-Sectional Study in Patients with Chronic Pain – PubMed – 2018

 

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

  1. Palmitoylethanolamide counteracts autistic-like behaviours – Contribution of central and peripheral mechanisms – 2018

 

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

CS Treatment – CGRP

  1. Utilizing CGRP Antagonists for Non-Migraine Indications – 2021
  2. Calcitonin gene-related peptide and pain- a systematic review – 2017
  3. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine – 2017
  4. Anti-calcitonin gene-related peptide monoclonal antibodies for neuropathic pain in patients with migraine headache – PubMed – 2021
  5. Serum Calcitonin Gene-Related Peptide and Receptor Protein Levels in Patients With Fibromyalgia Syndrome- A Cross-Sectional Study – 2020
  6. Targeted CGRP Small Molecule Antagonists for Acute Migraine Therapy – 2018
  7. Calcitonin gene-related peptide (CGRP)- Role in migraine pathophysiology and therapeutic targeting – 2021
  8. CGRP-and-Brain-Functioning-Borkum-2019 Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice – 2020

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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