Instituut voor Neuropathische Pijn

In Patent literature sometimes great insights can be found about how to proceed in pain treatment, such as in this patent,  and we enclose here the introductrion and a part of the summary. Pain clearly is especially influenced by non-neuronal cells, is the thesis of this patent.

The current theories and treatment options for persistent pain are not satisfactory. The population of patients with chronic pain and disrupted lives grows constantly. According to the American Pain Foundation, there are 75 million Americans who have chronic pain. Pain is the second most common reason for doctor visits. Unless we can understand how pain is generated, we cannot provide a solution. Our understanding of pain has not advanced since the 1965 publication of the gate theory of pain by Canadian psychologist Ronald Meizack and British physiologist Patrick Wall. In their paper titled “Pain Mechanisms: A New Theory,” Melzack and Wall suggested a gating mechanism within the spinal cord that closed in response to normal stimulation of the fast conducting “touch” nerve fibers; but opened when the slow conducting “pain” fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers.

A recent model, known as Sota Omoigui's Law, proposes that the origin of all pain is inflammation and the inflammatory response. This model is a dramatic and revolutionary shift from a focus on structural pathology to an understanding of the biochemical origin of Pain.

The biochemical and physiologic changes (inflammatory mediators) that occur along the “pain pathway” (nociceptors, peripheral nerve, dorsal root ganglion, dorsal root, neurons in the spinal cord) may sensitize one or all these sites along the pain pathway and hence lead to chronicpain. Deagle's Law of the Multilevel Pain Gate states, “Changes at one level of the multilevel gate cause pathway and molecular facilitative neurotransmitter and inflammatory mediator changes at all other levels of the gated neural network from the Langerhans complex in the skin to the cortical levels.” Pain is a neurologic signal disease and may or may not be associated with tissue inflammation. Thus lack of structural disease or tissue inflammation in conditions such as fibromyalgia or other non-inflammatory pain disorders such as non-inflammatory neuropathy, are primarily due to molecular increased pain signal transmission. Irrespective of the type of pain, whether it is acute pain as in a sprain, sports injury or eurochange jellyfish sting, or whether it is chronic pain as in arthritis, migraine pain, back or neck pain from herniated disks, RSD/CRPS pain, migraine, fibromyalgia, interstitial cystitis, neuropathic pain, post-stroke pain etc, the underlying basis is the opening of the pain gate to allow the transmission of the pain signal from the primary or higher gates to the cortex at gate levels six and seven, where higher receptive, motor and behavioral responses occur.

A portion of the model known as Deagle's Law of the Multilevel Pain Gate states, “Any change in inflammatory or faciliatory gene and molecular mediators at one level of the neural multilevel pain gate, causes upregulation of the gate at all other levels from the Langerhans complexes in the skin to the highest cortical gating neural processes.” The present invention provides a method to blockade the pain gate at multiple levels, for acute and persistent chronic pain. Pharmaceuticals, immunopharmaceuticals, and gene control methodologies are provided to close the pain gate at any of the seven broad levels, which include the entire range of neural processing for the pain experience.

Thus, all pain is gated at the Langerhans complex in the skin, the dorsal root ganglion (DRG), the substantia gelatinosa, spinothalamic tracts, thalamic and other nuclei, receptive parietal-temporal cortex and motor-behavioral frontal cortex. Hence, each of these seven levels offers a specific opportunity to treat pain in a person in need of such treatment. For example, pain originating at a specific Langerhans complex can be treated at that specific, first level Langerhans complex in the skin. The successful treatment is applied only to this first level site, and the treatment may consist of a small dose of a suitable inhibitor, rather than a larger dose as might be required to inhibit pain by generalized treatment. The patient need not be broadly drugged, such as at the frontal cortex of the seventh level, to treat the first level source of pain.

The invention contemplates that acute or persistent pain disorder is best treated after evaluation of the origin. Treatment can be applied to any chosen level of the pain gate pathway. The chosen level may be selected as the lowest level where treatment appears practical. The chosen level may be selected according to the best available treatment, such a treatment directed to facilitator molecules of the chosen level. The treatment may employ one or more site-specific methodologies.

Molecules that close the gate can be considered primarily inflammatory or excitatory such as aspartate or glutamate, that operate via increasing nerve transmission, receptor density for NMDA and Na channels, and other excitatory neurotransmitters and peptides. This occurs by nerve and glial cell activation to upregulate and open the pain gate at the glial cell levels throughout the nervous system.

This model differs substantially from the model that inflammation is the sole cause of pain and that other molecular modulators of pain signal transmission or inhibition are not primary in the cause of chronic or acute pain disorders. This process involves pain gate facilitatory molecules. In other tissues and circumstances, these may be proinflammatory, or neutral or anti-inflammatory. Pain gate neuromodulatory signal facilatory and inhibitory as well as inflammatory molecular mediators of the gate include leukotrienes, prostaglandins, nitric oxide and the free radical NO, tumor necrosis factor alpha (TNF-Alpha), interleukin 1-alpha (IL1-Alpha), interleukin 1-beta (IL1-Beta), interleukin-4 (IL4), Interleukin-6 (IL-6) and interleukin-8 (IL-8), granulocyte inhibition factor (GIF), histamine and serotonin, substance P, matrix metalloproteinase, calcitonin gene-related peptide, vasoactive intestinal peptide (VIP), and the neuromodulatory inflammatory mediator peptide proteins neurokinin A, bradykinin, kallidin and T-kinin, and nitric oxide (NO) as well as the aspartate and glutamate via the N-Methyl D-Aspartate (NMDA) receptor or the AMPA or catecholamine receptors. These mediators alter pain transmission and inhibiton at one or more of the integrated vertical pain gates of the neural array. Thus pain is a signal and neural informational disorder resulting in increase pain nociceptive signal to the brain, and resulting in the brain and spinal cord sending increased vasconstrictive and muscular tonic spastic neurologic input to the blood vessels and muscles. Thus pain is efferent at seven levels to the cortex and afferent to the blood vessels and muscles as well as all levels of the gate.

Deagle's Law of the Multilevel Pain Gate states, “Changes at one level of the multilevel gate cause pathway and molecular neurotransmitter and inflammatory mediator changes at all other levels.” Pain can arise at any level of the gating process, with different molecules responsible, and different genetic, pharmaceutical, immunopharmaceutical and technical challenges to block the gate mediators. Pain of all types arises through the multilevel gate, with changes in molecular upregulation at all other continuous levels. Thus levels of molecules that open the gate in the skin are increased in fibromyalgia and skin levels of cytokines and excitatory neurotransmitters are increased in the brain and skin in spinal cord and peripheral nerve injuries.

Pain is a neurologic signal disease and may or may not be associated with tissue inflammation. Lack of structural disease or tissue inflammation in conditions such as fibromyalgia or other non-inflammatory pain disorders such as non-inflammatory neuropathy, are primarily due to molecular increased pain signal transmission. Irrespective of the type of pain, whether it is acute pain as in a sprain, sports injury or eurochange jellyfish sting, or whether it is chronic pain as in arthritis, migraine pain, back or neck pain from herniated disks, RSD/CRPS pain, migraine, fibromyalgia, interstitial cystitis, neuropathic pain, post-stroke pain, etc., the underlying basis is the opening of the pain gate to allow the transmission of the pain signal from the primary or higher gates to the cortex at gate levels six and seven, where higher receptive, motor and behavioral responses occur. This model differs substantially from the model that inflammation is the sole cause of pain and that other molecular modulators of pain signal transmission or inhibition are not primary in the cause of chronic or acute pain disorders.

In fibromyalgia, non-inflammatory neuromodulatory molecules are increased in the skin as well as in other disorders at the pain gates inflammatory molecules and profacilatory pain signal modulators are increased. Receptor density on the nerve fibers increases due to increased nerve traffic transmitting painful stimuli. Blockade of faciliative neurotransmitters and inflammatory gate controlling molecules narrows the twelve-lane superhighway facilitated for pain in the chronic pain state down to a two lane normal pathway, and reduces the receptor density for neurotransmitters as well.

This process involves pain gate facilitatory molecules. In other tissues and circumstances, these may be proinflammatory, or neutral, or anti-inflammatory. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all painarises with the allowance of increased signal of pain at one of the seven pain gate levels at the specific site of the structures that comprise the gates. In the skin this structure is the Langerhans dermal structures, next the dorsal root ganglion, the dorsal horn substantia gelatinosa, ascending spinothalamic tracts, subthalamic nuclei, sensory receptive cortex, and anterior motor and behavioral response cortex. Pain gate facilatatory molecules such as in the condition of fibromyalgia can be identified in the skin with increased frequency in this condition. Lack ofpain gate inhibitory molecules may also be identified at all seven levels of the gate, with upregulation of genes, proteins, enzymes and glial cell transformation to open the gate in pain and down-regulation of genes, proteins, enzymes and blockade of glial cell transformation molecules in the pain state. Thus pain can be viewed as a signal disease and a neurological informational disorder, with excessive transmission to higher levels from one gate to another gate of pain signal increasingly processed, with lack of signal inhibition until there is a cortical response.

According to a study on neuropharmaceutical multilevel neural pain gate and transduction-transmission blockades, the neural process of painrequires multilevel hierarchical integrated gating and requires the pain gate to be opened by inflammatory molecules. These include interleukin 1 Beta, IL1B; necrosis factor alpha, TNF-Alpha; interleukin 6, IL6; interleukin 8, IL8; interleukin 2, IL2; and vanilloid receptor 1, VR1; and granulocyte inhibitor factor, GIF; iNO, glial cell activation, and free radical molecules such as hydroxyl OH, and nitric oxide or nitroperoxyl radicals NO, and NOOH.

These may be blocked with pharmaceuticals that bind to the receptor. Amgen has made Anakinra or Kineret to block IL1 Beta, and Etanercept and Enbrel to block TNF-Alpha.

Pain may be present in inflammatory or non-inflammatory conditions and therefore the presence of molecules that are found to cause or propagate pain if these molecules are not found at the pain gate. Non-inflammatory conditions such as fibromyalgia, myofascial pain, and non-inflammatory metabolic neuritic pain syndromes are excellent examples.

The invention proposes not only the use of PF, of preservative free forms for spinal and nerve blocks of these pharmaceuticals, but additional newer technologies, that would result in longer or permanent blockade of the pain pathways. The two-lane bicycle pathway of pain has been widened to a twelve lane concrete superhighway, and must be made to return to the normal appropriate physiology of the two lane bicycle pathway.

These new pharmaceutical and immunopharmaceutical technologies and uses include:

1. Monoclonal antibodies to the receptors would bind and make the receptor temporarily or permanently inactivated and unable to keep thepain gate open.

2. Soluble receptor blockade would bind free cytokines in paragraph one, and prevent interaction with the receptors.

3. Antibodies to the cytokines would bind them on site—this is much more temporary. The best and most permanent neuropharmaceutical would be #1.

4. Antisense RNA would block gene transcription for the making of more cytokines—This could be injected at the specific nerve cord peripheral levels, and turns off the ability of the body to make excessive local cytokines that keep the pain gate open.

5. Glial cell activation blockade—A large number of current drugs blocks the supporting and nourishing glial cells around the nerves of the body, spinal cord and brain. These cells are the primary generators of inflammatory cytokine molecules that keep the pain gate open. Changes in the cellular metabolism are known to be blocked by many older drugs, and newer more permanent blocking drugs or immunopharmaceuticals, antisense-RNA blockade, etc. will render glial cells incapable of transformation or reverse these changes back to the non-open state. Drugs currently known to perform this action with published electron microscopic and immunologic verification include Propentofylline, Minocycline, Tetracycline, Doxycycline, and Lefluonomide and its active metabolite A77 1726.

6. Lipoxygenase and cycloxygenase blockade with local NSAIDS, non steroidal antiinflammatory molecules, antisense RNA blockade, and monoclonal antibodies to the glial cell enzyme receptors that regulate these enzymes.

7. Inducible NO, nitrous oxide synthase—The production of NO, or nitrous oxide, is pro-inflammatory. Blocking excessive induction with iNO blocking drugs known now, and future enzyme blockade with monoclonal antibodies or antisense RNA blockade or other means of gene transcription blockade in the endoplasmic reticulum, will down-regulate over activity demonstrated with increased pain, inflammation and eventual nerve cell death or apoptosis.

8. Anti-inflammatory cytokine—Anti-inflammatory cytokine analogues made with recombinant DNA could produce pharmaceutical molecular equivalents of Interleukin 10 (IL10), the most powerful anti-inflammatory cytokine, with properties that would last many times longer than the natural molecule. This would act synergist with other blockade types. IL2 has also been demonstrated to have antinoceptive properties. Gene insertion and manipulation to increase these anti-inflammatory factors are prime targets for interventional therapies with directed neuropharmaceuticals based on gene control, which would be very effective in reduction of pain. These pain gate inhibitory molecules close the molecular transmission of pain signal. Thus pain can be viewed as a signal disease and an neurological informational disorder, with excessive transmission to higher levels from one to another gate of pain signal increasing processed, with lack of signal inhibition until there is a cortical response.

Free Radical blockade—DMSO is know to topically stop CRP1 pain or RSD, pain syndromes by blocking free hydroxyl (OH), and thus to stoppain. It also works in fibromyalgia, where in about 30 percent of these patients' elevations in skin cytokine levels can be demonstrated. Thus I have developed a topical with DMSO, 2% DL-Phenylalanine to block the opoid receptor, 2% Anakinra to block Interleukin1, 2% Trental or pentoxyphylline to block TNF-Alpha. The invention includes other free radical scavengersds and newer gene regulators such as antisense RNA and other pharmaceuticals and immunopharmaceuticals that block specific genes that allow free radical generation.

The acid-sensing ion channel family (ASIC) comprises six discrete ASIC subunits (ASIC1A, ASIC1B, ASIC2A, ASIC2B, ASIC3, ASIC4) that detect tissue acidosis (i.e. a decrease in pH), a hallmark response to tissue injury, pain and inflammation. Like many ion channels, ASICs are multimeric protein complexes, with four or more ASIC proteins physically associating to form the functional ion channel. The individual ASIC subunits can be all identical (“homomers”) or different (“heteromers”). A correlation between pain intensity/discomfort and the degree of local acidification is well established as exemplified by the intense pain associated with muscle cramps, resulting from lactic acid accumulation in muscle tissue. Tissue acidosis also occurs in many chronic pain conditions including angina, stroke, ischemic heart disease, arthritis, cancer, infections, and traumatic injuries.

All six ASIC receptor subtypes are located within sensory neurons, with ASIC1B and AISC3 showing the highest degree of selectivity for sensory neurons. When expressed in vitro in cultured cell lines, ASICs can be activated by acid solutions (low pH) and generate depolarizing currents similar to the native currents recorded from intact sensory neurons. ASIC1 channels activate and inactivate very rapidly even when the medium remains acidic. In contrast, ASIC3 channels display biphasic currents with a sustained phase during which channels remain open as long as the pH is low, making this receptor a key mediator of pain during sustained acidosis. The ASIC3 channel has also been linked to ischemic heart pain and inflammatory bowel disease. Data from ASIC3 knockout mice have also confirmed that the ASIC3 channel is an important component of the acid-sensing pain response.

Amiloride is the only known compound that blocks ASICs. However, the effect is not potent and not selective as indicated by amiloride's potent blockade of other receptor targets, which precludes its clinical use as an ASIC antagonist.

Neurotrophins are a family of structurally similar proteins that regulate the growth, differentiation, function, survival and plasticity of nerve cells. These proteins are expressed in greatest abundance within the nervous system, including target tissues for sensory nerve endings. Neurotrophins produce their effects in responsive cells by interacting with two classes of cell surface receptors: the selective trk receptors (trkA, trkB and trkC) and the non-selective p75NGF receptors, which do not discriminate between the various neurotrophin proteins. Nerve Growth Factor (NGF) is the prototypic member of the neurotrophin family, having been discovered over 40 years ago. The dysfunction of NGF-mediated signaling has been implicated in disorders such as chronic pain, ALS, Parkinson's disease and stroke.

There is now extensive evidence that neurotrophins alter the functions of nerve cells that recognize painful stimuli (nociceptors). Specifically, NGF binding to trkA/p75NGF has been shown to have both acute and long-term effects on nociceptor function. Tissue damage or inflammation induces high levels of NGF secretion. The acute effect of NGF is to stimulate the release of naturally occurring chemicals that increase the sensitivity of nociceptors to pain (e.g. substance P, CGRP, histamine). After this initial phase, the over-stimulation of NGF receptors leads to a remodeling of pain pathways with an increase in the number of nociceptive fibers and pain receptors, such as ion channels. These acute and long term changes in the processing of pain signals and reorganization of the neuronal networks mediated by NGF underlie the chronic painmechanisms induced by nerve damage or disease.

Another study has found that a polypharmaceutical approach is superior and a multilevel blockade is superior. Polypharmaceutical approaches are additive and multiplicative in action. Thus current studies with IL1 and TNF-Alpha blockade in the cerebrospinal fluid are additive and thus would result in much more efficacious and profound blockades that last many times longer. Blockades with multiple pharmaceuticals and at multiple levels are much more effective than with single agents and at single levels. This invention contemplates the use of current immunopharmaceuticals that block cytokines, pharmaceuticals that block numerous receptors that allow pain transmission, and future technologies for anti-sense RNA, gene insertion to block pain gate faciliatory molecules or gene manipulation to increase pain gate inhibitory molecules.

The origins of pain are the biochemical mediators pain signal facilitation and may also include some mediator molecules that have the property of inflammation and the inflammatory response. Modulators thus may not have any affect directly or indirectly on inflammation in non-inflammatory pain syndromes, or in part of the processes that are facilitated that are non-inflammatory in situations where some of the molecular factors perpetuating the pain are inflammatory. This model is thus more inclusive of all modulatory molecules, both non-inflammatory and inflammatory. Nociceptors in the skin, ligaments, periosteum, nerve sheath and capsules of internal organs are some of the sources of pain signals. The pain gate is opened by the presence of inflammatory molecules. Closing the pain gate stops the transmission from local structures initiating the pain signal.

The new Multilevel Cytokine Pain Gate Theory of Deagle proposes that the first gate is the Langerhans structures in a grid-like pattern at the dermal-epidermal junction. Autonomic, sensory and microvascular and local cytokine microorganelle structures are the first step at which inflammatory mediators such as LOX and COX leukotrienes, protaglandins, and cytokines, NO nitric oxide, free radical inflammatory molecules as well as neurotransmitters, especially NMDA N-Methyl D-Aspartate, and others, locally modulate the pain signal.

The next pain gate integrated is the dorsal root ganglion (DRG). The spinothalamic tracks and interneurons at the substantia gelatinosa. Spinal recruitement of pain at this level connects to gates at levels above and below the levels at which pain signal enters. At each level, thepain can be primarily perpetuated, meaning that a pain signal does not require a peripheral stimulus to perpetuate, explaining the presence ofpain without significant pathology, such as normal MRI or x-ray study.

Inflammation occurs when there is infection or tissue injury. 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 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. 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 and 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, and 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. The inflammatory mediators produce several effects. Excitation of these pain nociceptive 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.

Separately, constant C-fiber nerve stimulation to transmission pathways in the spinal cord result in even more release of inflammatory mediators, but this time within the spinal cord. 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 E. (PGE) levels in the cerebrospinal fluid.

The major inducer of central Cox-2 upregulation is inflammatory mediator interleukin-1 beta in the CNS. Basal levels of the enzyme phospholipase A activity in the CNS do not change with peripheral inflammation.

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. 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).

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. 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 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 cool down inflammation and the inflammatory response. Interleukin-1 beta is a potent pain-generating mediator. Two pain producing pathways have been identified: Inflammatory stimuli or injury to soft tissue induces the production of mediator Bradykinin, which stimulates the release of mediator Tumor necrosis factor alpha. The TNF-alpha induces production of (i) Interleukin-6 and Interleukin-1-Beta which stimulate the production of cyclooxygenase enzyme products, and (ii) Inflammatory mediator Interleukin-8, which stimulates production of sympathomimetics (sympathetic hyperalgesia). Effects of Interleukin-1 beta include: Interleukin-1 beta stimulates inflammatory mediators prostaglandin E (PGE), cyclooxygenase-2 (COX-2) and matrix metalloproteases (MMPs) production. Interleukin-1 beta is a significant catalyst in cartilage damage. It induces the loss of proteoglycans, prevents the formation of the cartilage matrix, 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. Interleukin-6 is another potent pain-generating inflammatory mediator. 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.

Interleukin-8 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. (p<0.001 for both comparisons).

Interleukin-10 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-betaI (TGF-betaI). 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.

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. Rresearchers 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 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 diverse actions dependent on cell type but are known to generally cause smooth muscle contraction. They 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 is an inflammatory mediator that is released by macrophages as well as nerve cells. Very importantly, TNF-alpha is released from injured or herniated disks.

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, 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 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 is an inflammatory mediator that 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) is an important early event in the induction of neuropathic pain states. It 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.

Gelatinase B or matrix metallo-proteinase 9 (MMP-9) is an enzyme that 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. 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. Consequently, MMP-9 plays a major role in acute and chronic inflammation, in cardiovascular and skin pathologies as well as in cancer metastasis. MMP-9 can also degrade a protein called beta amyloid. Normal cells produce MMP-9 in an inactive, or latent form, converting it to active enzyme when it is needed. But when normal brain cells producing MMP-9 fail to activate the enzyme, insoluble amyloid-b could accumulate in brain tissue. Previous research has shown that the undegraded form of amyloid-beta accumulates in the brain as senile “plaques” that signal the presence of Alzheimer's disease.

The inflammatory response ends by immune cells producing 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-betaI (TGF-betaI). 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. 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. The first is by receiving an apoptosis signal. When a chemical signal is received that indicates that the cell should kill itself, it does so. The second is 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.

Arthritis is an inflammatory pain syndrome involving inflammation of the joints. People of all ages including children and young adults can develop arthritis. The symptoms are intermittent pain, swelling, redness and stiffness in the joints. There are many different types of arthritis, some of which are rheumatoid arthritis, osteoarthritis, infectious arthritis and spondylitis. In rheumatoid arthritis, and other autoimmune diseases like systemic lupus erythematosus (SLE), the joints are destroyed by the immune system. In osteoarthritis, the biggest risk factor is a previous injury to the joint, ligament or cartilage. Injuries that seem to heal perfectly well appear to set up a process of deterioration that can produce severe pain and disability decades later. The injury need not be sustained in one episode. Long term or repeated trauma can have the same effect.

TNF-alpha and interleukin 1-beta play an important role in rheumatoid arthritis by mediating cytokines that cause inflammation and joint destruction. TNF-alpha, interleukin 1-beta and substance P are elevated in the joint fluids in patients with rheumatoid arthritis. These inflammatory mediators are also elevated in the joint fluid in patients with osteoarthritis albeit to a far less extent. Along with mechanical factors, growth factors and cytokines such as TGF beta 1, IL-1 alpha, IL-1 beta and TNF-alpha may be involved in the formation and growth of osteophytes, since these molecules can induce growth and differentiation of mesenchymal cells. The incidence and size of osteophytes may be decreased by inhibition of direct or indirect effects of these cytokines and growth factors on osteoid deposition in treated animals. Inhibition of interleukin-1 receptor also decreases the production of metalloproteinase enzymes collagenase-1 and stomelysin-1 in the synovial membrane and cartilage. These enzymes are involved in connective tissue breakdown.

Back and neck pain most commonly results from injury to the muscle, disk, nerve, ligament or facet joints with subsequent inflammation and spasm. Degeneration of the disks or joints produces the same symptoms and occurs subsequent to aging, previous injury or excessive mechanical stresses that this region is subjected to because of its proximity to the sacrum in the lower back. Herniated disk tissue (nucleus pulposus) produces a profound inflammatory reaction with release of inflammatory chemical mediators most especially tumor necrosis factor alpha. Subsequent to release of TNF-alpha, there is an increase in the formation of inflammatory mediator prostaglandin and nitric oxide.

It is now known that tumor necrosis factor alpha is released by herniated disk tissue (nucleus pulposus), and is primarily responsible for the nerve injury and behavioral manifestations of experimental sciatica associated with herniated lumbar discs. This has been confirmed by numerous animal studies and research wherein application of disk tissue (nucleus pulposus) to a nerve results in nerve fiber injury, with reduction of nerve conduction velocity, intracapillary thrombus formation, and the intraneural edema formation. One study demonstrated that disk tissue (nucleus pulposus) increases inducible nitric oxide synthetase activity in spinal nerve roots and that nitric oxide synthetase inhibition reduces nucleus pulposus-induced swelling and prevents reduction of nerve-conduction velocity. According to the authors, the results suggest that nitric oxide is involved in the pathophysiological effects of disk tissue (nucleus pulposus) in disc herniation.

Tumor necrosis factor alpha and other inflammatory mediators induce phospholipase A2 activation. High levels of phospholipase A2 previously have been demonstrated in a small number of patients undergoing lumbar disc surgery. Phospholipase A2 is the enzyme responsible for the liberation of arachidonic acid from cell membranes at the site of inflammation and is considered to be the limiting agent in the production of inflammatory mediator prostaglandins and leukotrienes.

Subsequent to the release of inflammatory mediators, activation of motor nerves that travel from the spinal cord to the muscles results in excessive muscle tension, spasm and pain. The vast majority of herniated disk pain is inflammatory in origin, can be treated medically and does not require surgery. Surgery is only indicated when there is compression of the nerve roots producing significant muscle weakness or urinary or bowel incontinence.

Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Other syndromes commonly associated with fibromyalgia include irritable bowel syndrome, interstitial cystitis, migraine headaches, temporomandibular joint dysfunction, dysequilibrium including nerve mediated hypotension, sicca syndrome, and growth hormone deficiency. Fibromyalgia is accompanied by activation of the inflammatory response system, without immune activation. In fact, there is some evidence that fibromyalgia is accompanied by some signs of immunosuppression. Several studies have shown that there are increased levels of the inflammatory transmitter substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal fluid of patients with fibromyalgia syndrome (FMS). The levels of platelet serotonin are also abnormal. Furthermore, in patients with fibromyalgia, the level of pain intensity is related to the spinal fluid level of arginine, which is a precursor to the inflammatory mediator nitric oxide (NO). Another study found increases over time in blood levels of cytokines interleukin-6, interleukin-8 and interleukin-1R antibody (IL-1Ra) whose release is stimulated by substance P. The study authors concluded that because interleukin-8 promotes sympathetic pain and interleukin-6 induces hypersensitivity to pain, fatigue and depression, both cytokines play a role in producing FM symptoms.

The painful neurogenic vasodilation of meningeal blood vessels is a key component of the inflammatory process during migraine headache. The cerebral circulation is supplied with two vasodilator systems: the parasympathetic system storing vasoactive intestinal peptide, peptide histidine isoleucine, acetylcholine and in a subpopulation of nerves neuropeptide Y, and the sensory system, mainly originating in the trigeminal ganglion, storing inflammatory mediator substance P, neurokinin A and calcitonin gene-related peptide (CGRP). A clear association between migraine and the release of inflammatory mediator calcitonin gene-related peptide (CGRP) and substance P (SP) has been demonstrated. Jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) have been shown to be elevated in migraine headache. CGRP-mediated neurogenic dural vasodilation is blocked by anti-migraine drug dihydroergotamine, triptans, and opioids. In cluster headache and in chronic paroxysmal hemicrania, there is additional release of inflammatory mediator vasoactive intestinal peptide (VIP) in association with facial symptoms (nasal congestion, runny nose).

Immunocytochemical studies have revealed that cerebral blood vessels are invested with nerve fibers containing inflammatory mediator neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP). In addition, there are studies reporting the occurrence of putative neurotransmitters such as cholecystokinin, dynorphin B, galanin, gastrin releasing peptide, vasopressin, neurotensin, and somatostatin. The nerves occur as a longitudinally oriented network around large cerebral arteries. There is often a richer supply of nerve fibers around arteries than veins. The origin of these nerve fibers has been studied by retrograde tracing and denervation experiments. These techniques, in combination with immunocytochemistry, have revealed a rather extensive innervation pattern. Several ganglia, such as the superior cervical ganglion, the sphenopalatine ganglion, the otic ganglion, and small local ganglia at the base of the skull, contribute to the innervation. Sensory fibers seem to derive from the trigeminal ganglion, the jugular-nodose ganglionic complex, and from dorsal root ganglia at the cervical spine level C2. The noradrenergic and most of the NPY fibers derive from the superior cervical ganglion. A minor population of the NPY-containing fibers contains vasoactive intestinal peptide (VIP), instead of NA and emanates from the sphenopalatine ganglion. The cholinergic and the vasoactive intestinal peptide (VIP)-containing fibers derive from the sphenopalatine ganglion, the otic ganglion, and from small local ganglia at the base of the skull. Most of the substance P (SP-), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP)-containing fibers derive from the trigeminal ganglion. Minor contributions may emanate from the jugular-nodose ganglionic complex and from the spinal dorsal root ganglia. Neuropeptide Y (NPY), is a potent vasoconstrictor in vitro and in situ. Vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) act via different mechanisms to induce cerebrovascular dilatation.

Meningeal blood vessels are involved in the generation of migraine pain and other headaches. Classical experiments have shown that blood vessels of the cranial dura mater are the most pain-sensitive intracranial structures. Dural blood vessels are supplied by trigeminal nerve fibers, and dilate in response to activation of the trigeminal nerves and release of neuropeptide cytokines such as substance P (SP) and calcitonin gene-related peptide (CGRP). CGRP can be released experimentally from dural nerve fibers, and there is evidence that this occurs also during migraine attacks. Stimulation of dural nerve fibers causes vasodilatation and an increase in dural arterial flow, which depends on the release of CGRP but not SP. On the other hand, SP is known to mediate plasma leakage (extravasation) from small veins in the dura mater. The dural arterial flow depends also on the formation of cell wall nitric oxide. The introduction of serotonin (5-HT1) receptor agonists such as sumatriptan changed the treatment strategies for migraine. Sumatriptan and other triptans may inhibit the release of inflammatory mediators from the trigeminal nerve. Sumatriptan has been shown to block the release of vasoactive cytokines from trigeminal nerves that surround the blood vessels in the dura mater during migraine. Sumatriptan blocks nerve fiber induced plasma extravasation but has only minor effects on nerve fiber mediated vasodilatation and dural arterial flow.

Foods like cheese, beer, and wine can also induce migraine in some people because they contain the mediator histamine and/or mediator-like compounds that cause blood vessels to expand. Women tend to react to histamine-containing foods more frequently than men do, on account of a deficiency in an enzyme (diamine oxidase) that breaks histamine down. Taking supplemental B6 has been shown to be helpful in migraine, as it can increase diamine oxidase activity.

Nerve (Neuropathic) pain syndromes include carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, and phantom limb pain. Nociceptive pain is mediated by receptors on A-delta and C nerve fibers, which are located in skin, bone, connective tissue, muscle and viscera. These receptors serve a biologically useful role at localizing noxious chemical, thermal and mechanical stimuli. Nociceptive pain can be somatic or visceral in nature. Somatic pain tends to be well-localized, constant pain that is described as sharp, aching, throbbing, or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, spasmodic in nature and is usually described as deep, aching, squeezing and colicky in nature. Examples of nociceptive pain include: post-operative pain, pain associated with trauma, and the chronic painof arthritis. Neuropathic pain, in contrast to nociceptive pain, is described as “burning”, “electric”, “tingling”, and “shooting” in nature. It can be continuous or paroxysmal in presentation. Whereas nociceptive pain is caused by the stimulation of peripheral A-delta and C-polymodal painreceptors, by inflammatory mediators, (e.g., histamine bradykinin, substance P, etc.) neuropathic pain is produced by injury or damage to peripheral nerves or the central nervous system. The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia. Allodynia is defined as pain resulting from a stimulus that ordinarily does not elicit a painful response (e.g. light touch). Hyperalgesia is defined as an increased sensitivity to normally painful stimuli. Examples of neuropathic pain include carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies. Subsequent to nerve injury, there is increase in nerve traffic. Expression of sodium channels is altered significantly in response to injury 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, 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.

In one study, monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly produced in nerve-injured rats. Interestingly, ED-1-, TNF-alpha- and interLeukin-6-positive cells increased more markedly in allodynic rats than in non-allodynic ones. The magnitude of the inflammatory response was not related to the extent of damage to the nerve fibers because rats with complete transection of the nerves displayed much lower production of inflammatory cytokines than rats with partial transection of the nerve. This is a finding commonly observed in patients where a minor injury results in severe pain that is out of proportion to the injury. Referring again to the study, the authors determined that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of interleukin-6 and TNF-alpha. This may relate to the generation of touch allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and interleukin-6-positive cells and the degree of allodynia.

Abnormal development of sensory-sympathetic connections follows nerve injury, and contributes 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. 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).

In another study, animals exhibiting heat hyperalgesia as a sign of neuropathic pain seven days after loose ligation of the sciatic nerve exhibited a significant increase in the concentration of brain derived neurotrophic factor (BDNF) in their lumbar spinal dorsal horn. Administration of nerve growth factor to rodents has resulted in the rapid onset of hyperalgesia. In clinical trials with nerve growth factor for the treatment of Alzheimer disease and peripheral neuropathy, induction of pain has been the major adverse event.

In one study, the use of trkA-IgG, an inhibitor of nerve growth factor (NGF) reduced neuroma formation and neuropathic pain in rats with peripheral nerve injury. In another study, the systemic administration of anti-nerve growth factor (NGF) antibodies significantly reduced the severity of autotomy (self mutilating behavior induced by nerve damage) and prevented the spread of collateral sprouting from the saphenous nerve into the sciatic innervation territory.

Activity in sympathetic fibers is associated with excessive sweating, temperature instability of the extremities and can induce further activity in sensitized pain receptors and, therefore, enhance pain and allodynia (sympathetically maintained pain). This pathologic interaction acts via noradrenaline released from sympathetic terminals and newly expressed receptors on the afferent neuron membrane. 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.

Separately, constant C-fiber nerve stimulation to transmission pathways in the spinal cord results 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.

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.supβ Din the CNS87. 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. 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. 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. 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. 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.

Reflex sympathetic dystrophy (RSD) syndrome, also called chronic regional pain syndrome (CRPS), has been recognized clinically for many years. It is most often initiated by trauma to a nerve, neural plexus, or soft tissue. Diagnostic criteria are the presence of regional pain and other sensory changes following a painful injury. The pain is associated with changes in skin color, skin temperature, abnormal sweating, tissue swelling. With time, tissue atrophy may occur as well as involuntary movements, muscle spasms, or pseudoparalysis. Like other organs with a blood supply, the bones also react to the disturbances in permeability caused by various inflammatory mediators. There is fluid accumulation in the bones and loss of bone density (osteoporosis). In addition, the inflammatory mediators accelerate the rate at which bone is broken down. The bone loss is further aggravated by decreased use of the affected body part due to pain. Complex regional pain syndrome, type I (reflex sympathetic dystrophy; CRPS-I/RSD) can spread from the initial site of presentation.

In one study of 27 CRPS-I/RSD patients who experienced a significant spread of pain, three patterns of spread were identified. Contiguous spread (CS) was noted in all 27 cases and was characterized by a gradual and significant enlargement of the area affected initially. Independent spread (IS) was noted in 19 patients (70%) and was characterized by the appearance of CRPS-I in a location that was distant and non-contiguous with the initial site (e.g. CRPS-I/RSD appearing first in a foot, then in a hand). Mirror-image spread (MS) was noted in four patients (15%) and was characterized by the appearance of symptoms on the opposite side in an area that closely matched in size and location the site of initial presentation. Only five patients (19%) suffered from CS alone; 70% also had IS, 11% also had MS, and one patient had all three kinds of spread.

In 1942 Paul Sudeck suggested that the signs and symptoms of RSD/CRPS including sympathetic hyperactivity might be provoked by an exaggerated inflammatory response to injury or operation of an extremity. His theory found no followers, as most doctors incorrectly believe that RSD/CRPS is solely initiated by a hyperactive sympathetic system. Recent research and studies including various clinical and experimental investigations now provide support to the theory of Paul Sudeck. As we now understand, soft tissue or nerve injury causes excitation of sensory nerve fibers. Reverse (antidromic) firing of these sensory nerves causes release of the inflammatory neuropeptides at the peripheral endings of these fibers. These neuropeptides may induce vasodilation, increase vascular permeability, attract other immune cells such as T helper cells and excite surrounding sensory nerve fibers—a phenomenon referred to as neurogenic inflammation.

While true inflammation is not present, this is a very good example of neuromodulatory molecules that are essentially non-inflammatory consistent with the “Deagle's Multilevel Pain Gate Model” where input stimuli above or below the subject gate structures increases pain signal transmission by modulating the pain gate at that level. At the level of the central nervous system, the increased input from peripheral painreceptors alters the central processing mechanisms. Sympathetic dysfunction, which often has been purported to play a pivotal role in RSD/CRPS, has been suggested to consist of an increased rate of outgoing (efferent) sympathetic nerve impulses towards the involved extremity induced by increased firing of the sensory nerves. However, the results of several experimental studies suggest that sympathetic dysfunction also consists of super sensitivity to catecholamines induced by nerve injury (autonomic denervation). Part of this occurs due to injured sensory nerves and immune cells developing receptors for the chemical transmitter norepinephrine and epinephrine (catecholamines), which are normally released by sympathetic nerves and also circulate in the blood. Stimulation of these receptors by locally released or circulating catecholamines produces sympathetic effects such as sweating, excessive hair growth and narrowing of blood vessels. In addition and under certain conditions, catecholamines may boost regional immune responses, through increased release of interleukin-1, tumor necrosis factor-alpha, and interleukin-8 production. In several studies, patients with RSD/CRPS showed a markedly increased level of the inflammatory peptide bradykinin as well as calcitonin gene-related peptide. The levels of bradykinin were four times as high as the controls. A few showed increased levels of the other inflammatory chemical mediators.

Two pain producing pathways have been identified: inflammatory stimuli induce the production of bradykinin, which stimulates the release of TNF-alpha. The TNF-alpha induces production of (i) interleukin-6 and interleukin-1b, which stimulate the production of cyclooxygenase products, and (ii) interLeuken-8, which stimulates production of sympathomimetics (sympathetic hyperalgesia). 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. This can be induced by neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5).

The foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly all suitable modifications and equivalents may be regarded as falling within the scope of the invention as defined by the claims that follow.