Law of Pain: The Biochemical Origin of Pain Theory

Law of Pain: The Biochemical Origin of Pain Theory – We propose a Law of Pain which states that: The origin of all pain is inflammation and the inflammatory response^[21]. This Law unifies all pain syndromes as sharing a common origin of inflammation and the inflammatory response. It is our theory that nociceptive and neuropathic pain, acute and chronic pain, peripheral and central pain including windup, neuroplasticity and central sensitization are a continuum of inflammation and the inflammatory response.
 

In all organisms, the cellular response to injury, infection and the aging process is inflammation and the inflammatory response. Tissue injury may arise from a physical, chemical or biological trauma or irritation. Degeneration of tissue subsequent to aging or previous injury can also lead to inflammation. Injured tissues can be muscle, ligament, disks, joints or nerves. A variety of mediators (cytokines, neuropeptides, growth factors and neurotransmitters) are generated by tissue injury and inflammation. These include substances produced by damaged tissue, substances of vascular origin as well as substances released by nerve fibers themselves, sympathetic fibers and various immune cells^[22]. The biochemical mediators produced by the immune cells include prostaglandin, nitric oxide, tumor necrosis factor alpha, interleukin 1-alpha, interleukin 1-beta, interleukin-4, Interleukin-6 and interleukin-8, histamine, serotonin. The biochemical mediators produced by the nerve cells include inflammatory protein Substance P, glutamate, calcitonin gene-related peptide (CGRP) neurokinin A and vasoactive intestinal peptide.

Cell enzymes that catalyze reaction pathways and generate these biochemical mediators of inflammation include cyclooxygenase (COX), lipoxygenase (LOX). A cell enzyme that is activated by inflammatory mediators such as TNF-alpha and interleukin-1 is Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9). Once activated MMP-9 helps immune cells migrate through the blood vessels to inflammatory sites or to metastatic sites. Activated, MMP-9 can also degrade collagen in the extra cellular matrix of articular bone and cartilage and is associated with joint inflammation and bony erosions^[23].

There are three phases of an inflammatory response: initiation, maintenance and termination. Upon tissue injury or painful stimulation, specialized blood cells in the area such as basophils, mast cells and platelets release inflammatory mediators serotonin, histamine and nitric oxide. Subsequent to the binding of serotonin to its receptor, there is inflammation of the adjacent nerves and the nerve endings release short-lived inflammatory peptide proteins such as substance P, Calcitonin gene-related peptide (CGRP). In addition, clotting factors in the blood produce and activate potent inflammatory mediator peptide proteins called neurokinin A, bradykinin, kallidin and T-kinin. All of these proteins increase blood flow to the area of injury, stimulate arachidonic acid metabolism to generate inflammatory mediators prostaglandins and attract specialized immune cells to the area. The first immune cells to the area are tissue macrophages, which provide the front line defense against bacterial infection. Macrophages release powerful enzymes to digest any bacteria that are present and produce potent inflammatory chemical mediators (called cytokines) to attract and activate other cells of the immune system. Shortly thereafter the area of bacterial invasion or tissue injury is invaded by the other immune cells, which include white blood cells such as T helper cells, lymphocytes, neutrophils, eosinophils, and other cells such as fibroblasts and endothelial cells. These immune cells respond to the chemical mediators, release destructive enzymes to kill any invading organism and release more chemical mediators to attract more immune cells. A consequence of this immune response is tissue damage, pain and spasm. In a sense the initial immune reaction ignites a cascade of immune reactions and generates an inflammatory soup of chemical mediators. These chemical mediators produced by the immune cells include prostaglandin, nitric oxide, tumor necrosis factor alpha, interleukin 1-alpha, interleukin 1-beta, interleukin-4, Interleukin-6 and interleukin-8, histamine, serotonin, In the area of injury and subsequently in the spinal cord, enzymes such as cyclooxygenase increase the production of these inflammatory mediators. These chemical mediators attract tissue macrophages and white blood cells to localize in an area to engulf (phagocytize) and destroy foreign substances. The chemical mediators released during the inflammatory response give rise to the typical findings associated with inflammation.

Effects of the inflammatory mediators

The inflammatory mediators activate local pain receptors and nerve terminals and produce hypersensitivity in the area of injury. Activity of the mediators results in excitation of pain receptors in the skin, ligaments, muscle, nerves and joints. Excitation of these pain receptors stimulate the specialized nerves e.g. C fibers and A-delta fibers that carry pain impulses to the spinal cord and brain. Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly thus leading to abnormal excitability in the sensory neurons. Nerve impulses arriving in the spinal cord stimulate the release of inflammatory protein Substance P. The presence of Substance P and other inflammatory proteins such as calcitonin gene-related peptide (CGRP) neurokinin A and vasoactive intestinal peptide removes magnesium induced inhibition and enables excitatory inflammatory proteins such as glutamate and aspartate to activate specialized spinal cord NMDA receptors. This results in magnification of all nerve traffic and pain stimuli that arrive in the spinal cord from the periphery. Activation of motor nerves that travel from the spinal cord to the muscles results in excessive muscle tension. More inflammatory mediators are released which then excite additional pain receptors in muscles, tendons and joints generating more nerve traffic and increased muscle spasm. Persistent abnormal spinal reflex transmission due to local injury or even inappropriate postural habits may then result in a vicious circle between muscle hypertension and pain^[24]. Separately, constant C-fiber nerve stimulation to transmission pathways in the spinal cord resulting in even more release of inflammatory mediators but this time within the spinal cord. The transcription factor, nuclear factor-kappa B (NF-kappaB), plays a pivotal role in regulating the production of inflammatory cytokines^[25]. Inflammation causes increased production of the enzyme cyclooxygenase-2 (Cox-2), leading to the release of chemical mediators both in the area of injury and in the spinal cord. Widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the central nervous system elevates inflammatory mediator prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is inflammatory mediator interleukin-1 ^[β] in the CNS^[26]. Basal levels of the enzyme phospholipase A2 activity in the CNS do not change with peripheral inflammation. The central nervous system response to pain can keep increasing even though the painful stimulus from the injured tissue remains steady. This “wind-up” phenomenon in deep dorsal neurons can dramatically increase the injured person’s sensitivity to the pain. Tissue injury with local release of inflammatory mediators produces an acute discharge in the sensory afferents innervating the injured or inflamed tissue. Activation of the polymodal nociceptive afferents (C fibers) depolarizes populations of dorsal horn wide dynamic range (WDR) neurons that project supraspinally. This output in turn evokes a supraspinally organized escape behavior. The hot plate test (thermal stimulus to the paw) or the local injection of an irritant such as formalin or capsaicin where the unconditioned stimulus evokes a somatotopically directed behavior (e.g., withdrawal or licking) are behavioral paradigms believed to reflect this underlying mechanism^[27].

Electrophysiological studies have shown that the persistent activation of spinal WDR neurons by small, but not large, afferents, will lead to a progressive enhancement of the WDR response to each subsequent input, and an increase in the dimensions of the peripheral receptive field to which the spinal neuron will respond^[28]

The neurotrophins are a family of growth promoting proteins that are essential for the generation and survival of nerve cells during development, Neurotrophins promote growth of small sensory neurons and stimulate the regeneration of damaged nerve fibers

They consist of four members, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5).

Nerve growth factor and brain-derived neurotrophic factor modulate the activity of a sodium channel (NaN) that is preferentially expressed in pain signaling neurons that innervate the body (spinal cord dorsal root ganglion neurons) and face (trigeminal neurons). Transection of a nerve fiber (axotomy) results in an increased production of inflammatory cytokines and induces marked changes in the expression of sodium channels within the sensory neurons^[29]. Following axotomy the density of slow (tetrodotoxin-resistant) sodium currents decrease and a rapidly repriming sodium current appears. The altered expression of sodium channels leads to abnormal excitability in the sensory neurons^[30]. Studies have shown that these changes in sodium channel expression following axotomy may be attributed at least in part to the loss of retrogradely transported nerve growth factor^[31].

In addition to effects on sodium channels, there is a large reduction in potassium current subtypes following nerve transection and neuroma formation. Studies have shown that direct application of nerve growth factor to the injured nerve can prevent these changes^[32]. Abnormal development of sensory-sympathetic connections follow nerve injury, and contribute to the hyperalgesia (abnormally severe pain) and allodynia (pain due to normally innocuous stimuli). These abnormal connections between sympathetic and sensory neurons arise in part due to sprouting of sympathetic axons. Studies have shown that sympathetic axons invade spinal cord dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal ‘baskets’ may underlie painful sympathetic-sensory coupling^[33]. Sympathetic sprouting into the DRG may be stimulated by neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). Local tissue inflammation can also result in pain hypersensitivity in neighboring uninjured tissue (secondary hyperalgesia) by spread and diffusion of the excess inflammatory mediators that have been produced as well as by an increase in nerve excitability in the spinal cord (central sensitization). This can result in a syndrome comprising diffuse muscle pain and spasm, joint pain, fever, lethargy and anorexia.

The Complex interaction of Inflammatory Mediators

The inflammatory mediators interact in a complex way to induce, enhance and propagate persistent pain. There are also natural anti-inflammatory mediators produced by the body to simmer down inflammation and the inflammatory response.

Interleukin-1 beta

This is a potent pain-generating mediator. Interleukin-1 beta stimulates inflammatory mediators prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2) and matrix metalloproteases (MMPs) production ^{[34, 35]} Interleukin-1 beta is a significant catalyst in cartilage damage. It induces the loss of proteoglycans, prevents the formation of the cartilage matrix^[36] and prevents the proper maintenance of cartilage. Interleukin –1 beta is a significant catalyst in bone resorption. It stimulates osteoclasts cells involved in the resorption and removal of bone^[37,38,39]

Interleukin-6

This is another potent pain-generating inflammatory mediator. IL-6 is one of a family of cytokines collectively termed “the interleukin-6-type cytokines”. The cytokines which make up this family are IL-6, leukemia inhibitory factor (LIF), oncostatin-M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and interleukin-11 ^{[40] [41]}. IL-6 is involved in a myriad of biologic processes, perhaps explaining its long list of synonyms (B-cell stimulatory factor-2, B cell differentiation factor, T cell-replacing factor, interferon-β2, 26-kDa protein, hybridoma growth factor, interleukin hybridoma plasmacytoma factor 1, plasmacytoma growth factor, hepatocyte-stimulating factor, macrophage granulocyte-inducing factor 2, cytotoxic T cell differentiation factor, thrombopoietin)^[42]. Among its many functions, IL-6 plays an active role in inflammation, immunology, bone metabolism, reproduction, arthritis, neoplasia, and aging. IL-6 expression is regulated by a variety of factors, including steroidal hormones, at both the transcriptional and post-transcriptional levels. IL-6 appears to play an important role in bone metabolism through induction of osteoclastogenesis and osteoclast activity^[43,44]. In rodents, inhibition of IL-6 gene expression is in part responsible for estrogen’s ability to inhibit osteoclast activation^{[45,46,47,48]}. These findings are further supported by the observation that IL-6 gene knockout mice are protected from cancellous bone loss associated with ovariectomy. IL-6 neutralizing antibody also blocks bone resorption induced by a variety of agents including TNF^[49]. In addition to increasing osteoclast numbers, IL-6 has been shown to stimulate bone resorption in rat long bones^[50] and fetal mouse metacarpi^[51], calvaria^[52], and bone resorption pit assays^{[53] [54]}. Although it is not clear that IL-6 alone is sufficient to mediate these activities^[55], these data demonstrate the importance of IL-6 in enhancing osteoclastic activity thus providing a mechanism for IL-6 promoting osteoporosis. IL-1beta may induce IL-6 production in human osteoblasts (MG-63 cells) by the following sequence of steps: IL-1beta-induced COX-2 activation, prostaglandin E(2) production, and PGE receptor-1 (EP-1 receptor) signaling prior to IL-6 production^[56]. IL-6 functions in a wide variety of other systems including the reproductive system by participating in the menstrual cycle^[57] and spermatogenesis, skin proliferation, megakaryocytopoiesis, macrophage differentiation, and neural cell differentiation and proliferation^[58]. A significant amount of InterLeukin-6 is produced in the rat spinal cord following peripheral nerve injury that results in pain behaviors suggestive of neuropathic pain. These spinal IL-6 levels correlated directly with the mechanical allodynia intensity following nerve injury^[59]. During times of stress or inflammation IL-6 levels are increased. Inflammatory joint disease, particularly rheumatoid arthritis^[60], is associated with increased synovial fluid levels of IL-6^[61].

Interleukin-6 is the primary chemical mediator involved in bone inflammation and bone pain. Interleukin-6 increases the activity of the osteoclasts and leads to excessive breakdown of bone, leakage of calcium into the blood, loss of bone density and bone inflammation, which is associated with bone pain. Inteleukin-6 production is increased by Inteleukin-1 beta and Tumor necrosis Factor alpha. Patients with rheumatoid arthritis(RA) develop both generalized and periarticular osteoporosis. Both of them are believed to be associated with increased production of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6) and increased formation and activation of osteoclasts^[62].

Interleukin – 8

This is a pain-generating inflammatory mediator. In one study of patients with post herpetic neuralgia, the patients who received methylprednisolone, had interleukin-8 concentrations decrease by 50 percent, and this decrease correlated with the duration of neuralgia and with the extent of global pain relief^[63] (P<0.001 for both comparisons)

Interleukin –10

This is one of the natural anti-inflammatory cytokines, which also include Interleuken-1 receptor antagonist (IL-1ra), Interleukin –4, Interleukin –13 and transforming growth factor-beta1 (TGF-beta1). Interleukin-10 (IL-10) is made by immune cells called macrophages during the shut-off stage of the immune response. Interleukin-10 is a potent anti-inflammatory agent, which acts partly by decreasing the production of inflammatory cytokines interleukin-1 beta (Interleukin-1 beta), tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS), by injured nerves and activated white blood cells, thus decreasing the amount of spinal cord and peripheral nerve damage^[64,65]. In rats with spinal cord injury (SCI), a single injection of IL-10 within half an hour resulted in 49% less spinal cord tissue loss than in untreated rats. The researchers observed nerve fibers traveling straight through the spared tissue regions, across the zone of injury. They also reported a decrease in the inflammatory mediator TNF-alpha, which rises significantly after SCI.

Prostaglandins

These are inflammatory mediators that are released during allergic and inflammatory processes. Phospholipase A2 enzyme, which is present in cell membranes, is stimulated or activated by tissue injury or microbial products. Activation of phospholipase A2 causes the release of arachidonic acid from the cell membrane phospholipid. From here there are two reaction pathways that are catalyzed by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX). These two enzyme pathways compete with one another. The cyclooxygenase enzyme pathway results in the formation of inflammatory mediator prostaglandins and thromboxane. The lipoxygenase enzyme pathway results in the formation of inflammatory mediator leukotriene. Because they are lipid soluble these mediators can easily pass out through cell membranes.

In the cyclooxygenase pathway, the prostaglandins D, E and F plus thromboxane and prostacyclin are made. Thromboxanes are made in platelets and cause constriction of vascular smooth muscle and platelet aggregation. Prostacyclins, produced by blood vessel walls, are antagonistic to thromboxanes as they inhibit platelet aggregation.

Prostaglandins have perse actions dependent on cell type but are known to generally cause smooth muscle contraction. Prostaglandins sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighboring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization)^[66]. Prostaglandins are very potent but are inactivated rapidly in the systemic circulation. Leukotrienes are made in leukocytes and macrophages via the lipoxygenase pathway. They are potent constrictors of the bronchial airways. They are also important in inflammation and hypersensitivity reactions as they increase vascular permeability and attract leukocytes.

Tumor necrosis factor alpha

Subsequent to tissue injury, this inflammatory mediator is released by macrophages as well as nerve cells. During an inflammatory response, nerve cells communicate with each other by releasing neuro-transmitter glutamate. This process follows activation of a nerve cell receptor called CXCR4 by the inflammatory mediator stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the nerve cell communication is the rapid release of inflammatory mediator tumor necrosis factor-alpha (TNF alpha). Subsequent to release of TNF-alpha, there is an increase in the formation of inflammatory mediator prostaglandin. Excessive prostaglandin release results in an increased production of neurotransmitter glutamate and an increase in nerve cell communication resulting in a vicious cycle of inflammation. There is excitation of pain receptors and stimulation of the specialized nerves e.g. C fibers and A-delta fibers that carry pain impulses to the spinal cord and brain.

Studies have established that herniated disk tissue (nucleus pulposus) produces a profound inflammatory reaction with release of inflammatory chemical mediators. Disk tissue applied to nerves may induce a characteristic nerve sheath injury ^[67,68,69] increased blood vessel permeability, and blood coagulation. The primary inflammatory mediator implicated in this nerve injury is Tumor necrosis factor-alpha but other mediators including Interleukin 1-beta, matrix metalloproteinase, nitric oxide, prostaglandin E2, and interleukin-6 may also participate in the inflammatory reaction. Recent studies have also shown that that local application of nucleus pulposus may induce pain-related behavior in rats, particularly hypersensitivity to heat and other features of a neuropathic pain syndrome.

Nitric Oxide

This inflammatory mediator is released by macrophages. Other mediators of inflammation such as reactive oxygen products and cytokines, considerably contribute to inflammation and inflammatory pain by causing an increased local production of Cyclooxygenase enzyme. The cyclooxygenase enzyme pathway results in the formation of inflammatory mediator prostaglandins and thromboxane. Concurrently to the increased production of the Cyclooxygenase–2 (COX-2) gene, there is increased production of the gene for the enzyme inducible nitric oxide synthetase (iNOS), leading to increased levels of nitric oxide (NO) in inflamed tissues. In these tissues, NO has been shown to contribute to swelling, hyperalgesia (heightened reaction to pain) and pain. NO localized in high amounts in inflamed tissues has been shown to induce pain locally and enhances central as well as peripheral stimuli. Inflammatory NO is thought to be synthesized by the inducible isoform of nitric oxide synthetase (iNOS).

Substance P (sP)

An important early event in the induction of neuropathic pain states is the release of Substance P from injured nerves which then increases local Tumor Necrosis Factor alpha (TNF-alpha) production. Substance P and TNF-alpha then attract and activate immune monocytes and macrophages, and can activate macrophages directly. Substance P effects are selective and Substance P does not stimulate production of Interleukin-1, Interleukin – 3, or Interleukin -6. Substance P and the associated increased production of TNF-alpha has been shown to be critically involved in the pathogenesis of neuropathic pain states. TNF protein and message are then further increased by activated immune macrophages recruited to the injury site several days after the primary injury. TNF-alpha can evoke spontaneous electrical activity in sensory C and A-delta nerve fibers that results in low-grade pain signal input contributing to central sensitization. Inhibition of macrophage recruitment to the nerve injury site, or pharmacologic interference with TNF-alpha production has been shown to reduce both the neuropathologic and behavioral manifestations of neuropathic pain states^[70]

Gelatinase B or Matrix Metallo-Proteinase 9 (MMP-9)

This enzyme is one of a group of metalloproteinases (which includes collagenase and stromelysin) that are involved in connective tissue breakdown. Normal cells produce MMP-9 in an inactive, or latent form. The enzyme is activated by inflammatory mediators such as TNF-alpha and interleukin-1 that are released by cells of the immune system (mainly neutrophils but also macrophages and lymphocytes) and transformed cells^[71,72]. MMP-9 helps these cells migrate through the blood vessels to inflammatory sites or to metastatic sites. Activated, MMP-9 can also degrade collagen in the extra cellular matrix of articular bone and cartilage and is associated with joint inflammation and bony erosions^[73]. Consequently, MMP-9 plays a major role in acute and chronic inflammation, in cardiovascular and skin pathologies as well as in cancer metastasis.

Natural suppression of the inflammatory response and Gate Control

How does the inflammatory response end? Immune cells produce anti-inflammatory cytokine mediators that help to suppress the inflammatory response and suppress the production of pro-inflammatory cytokines. The natural anti- inflammatory cytokines are Interleuken-1 receptor antagonist (IL-1ra), Interleukin –10, Interleukin –4, Interleukin –13 and transforming growth factor-beta1 (TGF-beta1). Research has shown that administration of these anti-inflammatory cytokines prevents the development of painful nerve pain that is produced by a naturally occurring irritant protein called Dynorphin A^[74]

Under normal circumstances,, the inflammatory response should only last for as long as the infection or the tissue injury exists. Once the threat of infection has passed or the injury has healed, the area should return to normal existence.

One of the ways that the inflammatory response ends is by a phenomenon known as “Apoptosis”.

Most of the time, cells of the body die by being irreparably damaged or by being deprived of nutrients. This is known as Necrotic death. However, cells can also be killed in another way, i.e. by “committing suicide”. On receipt of a certain chemical signal, most cells of the body can destroy themselves. This is known as Apoptotic death. There are two main ways in which cells can commit Apoptosis. (1) By receiving an Apoptosis signal. When a chemical signal is received that indicates that the cell should kill itself, it does so. (2) By not receiving a “stay-alive” signal. Certain cells, once they reach an activated state, are primed to kill themselves automatically within a certain period of time, i.e. to commit Apoptosis, unless instructed otherwise. However, there may be other cells that supply them with a “stay-alive” signal, which delays the Apoptosis of the cell. It is only when the primed cell stops receiving this “stay-alive” signal that it kills itself.

The immune system employs method two above. The immune cells involved in the inflammatory response, once they become activated, are primed to commit Apoptosis. Helper T cells emit the stay-alive signal, and keep emitting the signal for as long as they recognize foreign antigens or a state of injury in the body, thus prolonging the inflammatory response. It is only when the infection or injury has been eradicated, and there is no more foreign antigen that the helper T cells stop emitting the stay-alive signal, thus allowing the cells involved in the inflammatory response to die off.

If foreign antigen is not eradicated from the body or the injury has not healed, or the helper T cells do not recognize that fact, or if the immune cells receive the stay-alive signal from another source, then chronic inflammation may develop.

The final pathway for the natural suppression of the inflammatory response is in the spinal cord where there is a complex network of inhibitory neurons (‘gate control’) that is driven by descending projections from brain stem sites. These inhibitory neurons act to dampen and counteract the spinal cord hyper excitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving inhibitory transmitters gamma-aminobutyric acid (GABA), glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal inhibitory actions in combination with ectopic afferent input in damaged nerves^[75].

DISCUSSION

The various biochemical mediators of inflammation (cytokines, neuropeptides, growth factors and neurotransmitters) are present in differing amounts in all pain syndromes and are responsible for the pain experience. Every pain syndrome has a unique inflammatory profile with a predominance of certain inflammatory mediators (see Table 1 which lists the biochemical mediators for which drugs are currently available). This inflammatory profile is not static but dynamic and variable in the same patient and from one patient to another. The inflammatory profile is derived from the original injury or trauma and modified by ongoing injuries and aggravations including iatrogenic interventions. It is important to understand that:

1. Inflammation can exist without structural damage that is visible with our current imaging technology.
2. Structural damage will result in inflammation and the inflammatory response
3. Inflammation and the inflammatory response will produce structural damage Classification and treatment of pain syndromes should depend on the complex inflammatory profile and should not be based alone on symptomatology, structural pathology, genetic markers or presence of autoantibodies.

Table 1 – Inflammatory Mediator Profile of Pain Syndromes.

Note that these mediators as well as other mediators may be present in varying quantities at varying times in any pain syndrome.

We believe the Sudeck started on the right path when in 1942, he suggested that the signs and symptoms of RSD/CRPS including sympathetic hyperactivity might be provoked by an exaggerated inflammatory response. However, inflammation and the inflammatory response do not just provoke the signs and symptoms of sympathetic hyperactivity. It is our unifying theory that inflammation and the inflammatory response are the biochemical origin of pain.

Our Unifying Theory of Pain encompasses the Gate Theory, provides an explanation for the biochemical origin of Pain and a road map for the treatment of all pain syndromes.

We believe that the definition of Pain by the IASP Subcommittee on Taxonomy is incorrect and wrongly places a focus on the presence of visible tissue damage or a structural pathophysiological cause. The biochemical mediators of inflammation are not visible on MRI or X-rays but can now be measured in the serum and CSF and in the future, we will be able to image the mediators by MRI Spectroscopy.

Our theory of Pain explains the biochemical origin of pain that hitherto was unfortunately classified as ‘ psychogenic’ or due to ‘maladaptive thought processes’

The classification of Pain as being peripheral or central in origin is incorrect. Central pain may arise from peripheral injury. This is well documented in patients with neuropathic pain or RSD/CRPS.

The current theories that we are replacing have failed to realize that the mechanisms for wind-up, central sensitization and neuroplasticity are but an integral part of inflammation and the inflammatory process.

Our theory explains that peripheral and central pain including windup and central sensitization are a continuum of inflammation and the inflammatory response. The current theories mention inflammation as a component of the peripheral pain mechanism. None expand on the role of the biochemical mediators in the inflammatory response and none of these theories provide any role for inflammatory mediator blockers or immune modulators in the treatment of pain syndromes. The cellular response to injury is inflammation and the inflammatory response. In our theory, inflammation and the inflammatory response are the biochemical origin and a therapeutic target of both peripheral and central pain.

Every drug that is currently used in the treatment of pain has a mechanism of action that is compatible with the principles we hereby outline in our unifying theory of pain.

Principles for Treatment of Pain Syndromes

1. Determination of the inflammatory profile of the pain syndrome
2. Inhibition or suppression of production of the appropriate inflammatory mediators e.g. with inflammatory mediator blockers or surgical intervention where appropriate
3. Inhibition or suppression of neuronal afferent and efferent (motor) transmission e.g. with anti-seizure drugs or local anesthetic blocks
4. Modulation of neuronal transmission e.g. with opioid medication.

Pain syndromes may be treated medically or surgically. The goal is inhibition or suppression of production of the inflammatory mediators. A successful outcome is one that results in less inflammation and thus less pain.

CONCLUSION

In accordance with our Law of Pain, the origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile. Treatment of pain syndromes should be based on these principles:

1. Determination of the inflammatory profile of the pain syndrome
2. Inhibition or suppression of production of the appropriate inflammatory mediators e.g. with inflammatory mediator blockers or surgical intervention where appropriate
3. Inhibition or suppression of neuronal afferent and efferent (motor) transmission e.g. with anti-seizure drugs or local anesthetic blocks
4. Modulation of neuronal transmission e.g. with opioid medication.

At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This unifying theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization. Our current knowledge is rudimentary and but a beachhead in the vast frontier of inflammation and the inflammatory response. We have medications for only a few of these mediators. More research is needed to understand and develop new drugs and interventions to treat inflammation and the inflammatory response and thus to conquer pain.

REFERENCES

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