CHAPTER 1

SOTA OMOIGUI’S LAW OF PAIN

The origin of all pain is inflammation and the inflammatory response.

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, back or neck pain from herniated disks, RSD/CRPS pain, Fibromyalgia, Interstitial cystitis, Neuropathic pain, Post-stroke pain etc, the underlying basis is 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.

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. Current medical theories place an over reliance on structural abnormalities to explain pain syndromes. This is not surprising because our current imaging technologies are structure based. Physicians are comfortable treating what they see. Patients who have structural abnormalities such as a herniated disk on MRI scans get operated upon often times needlessly and end up with more back or neck pain. Patients with severe pain who do not have structural abnormalities on MRI scans are dismissed as psychiatric cases. The fallacy of this approach has been confirmed in numerous published studies. In one of these studies [2] [1], the authors performed magnetic resonance imaging on sixty-seven individuals who had never had low-back pain, sciatica, or neurogenic claudication. The scans were interpreted independently by three neuro-radiologists who had no knowledge about the presence or absence of clinical symptoms in the subjects. About one-third of the subjects were found to have a substantial abnormality. Of those who were less than sixty years old, 20 per cent had a herniated nucleus pulposus and one had spinal stenosis. In the group that was sixty years old or older, the findings were abnormal on about 57 per cent of the scans: 36 per cent of the subjects had a herniated nucleus pulposus and 21 per cent had spinal stenosis. There was degeneration or bulging of a disc at least one lumbar level in 35 per cent of the subjects between twenty and thirty-nine years old and in all but one of the sixty to eighty-year-old subjects. In view of these findings in asymptomatic subjects, the authors concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated. In another study [3] [2], the authors examined the prevalence of abnormal findings on magnetic resonance imaging (MRI) scans of the lumbar spine in people without back pain. 52 percent of the asymptomatic subjects were found to have a bulge at least at one level, 27 percent had a protrusion, and 1 percent had an extrusion. Thirty-eight percent had an abnormality of more than one intervertebral disk. The prevalence of bulges, but not of protrusions, increased with age. The most common nonintervertebral disk abnormalities were Schmorl's nodes (herniation of the disk into the vertebral-body end plate), found in 19 percent of the subjects; annular defects (disruption of the outer fibrous ring of the disk), in 14 percent; and facet arthropathy (degenerative disease of the posterior articular processes of the vertebrae), in 8 percent.. The findings were similar in men and women. The authors concluded that on MRI examination of the lumbar spine, many people without back pain have disk bulges or protrusions but not extrusions. The authors went further to state that given the high prevalence of these findings and of back pain, the discovery by MRI of bulges or protrusions in people with low back pain may frequently be coincidental. In another study [4] [3], which tracked the natural history of individuals with asymptomatic disc abnormalities in magnetic resonance imaging the authors stated that the high rate of lumbar disc alterations recently detected in asymptomatic individuals by magnetic resonance imaging demands reconsideration of a pathomorphology-based explanation of low back pain and sciatica.

The origins of pain are the biochemical mediators of inflammation and the inflammatory response. To treat pain, we must block these mediators and block the signals they send up through the nerve cells. We can now measure many of these inflammatory mediators in the blood and spinal fluid. However, our current technology does not allow us to image these mediators. Hopefully sometime in the future we will be able to do so.

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 [5] [4]. 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 neutrophils then monocytes and macrophages. These are the same cells that provide the body’s front line defense against bacterial infection. These immune cells release powerful enzymes that can digest any bacteria that have invaded the site of injury. The cells also release 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.

Molecules called selectins cause the circulating immune leukocytes to slow their flow and roll along the inner blood vessel wall [6] . Inflammatory mediators such as Il-1 and TNF-alpha produced by cells at the injured or infected site then stimulate the endothelial cells that form blood vessels to produce other chemical mediators such as interleukin-8 (IL-8). The mediators are held on the inner surface of the endothelial cells where they interact with receptors on the surface of the rolling leukocytes. This interaction, in turn, triggers the activation of molecules called integrin on the surface of the leukocytes.  Activation of these integrins by inflammatory mediators enables the slowly rolling leukocytes to strongly bind to adhesion molecules such as ICAMs (intercellular adhesion molecules) and VCAMs (vascular cell adhesion molecules) on the inner surface of the vascular endothelial cells.  Macrophage-produced mediators such as Interleukin-1 and TNF-alpha stimulate the production of these adhesion molecules on the vascular endothelium. Once bound to the endothelial cells, the leukocytes then flatten and squeeze between the endothelial cells to leave the blood vessels and enter the tissue. The leukocytes are then chemically attracted to the injured site by the inflammatory mediators. The chemical mediators released during the inflammatory response give rise to the typical findings associated with inflammation

CHAPTER 2

EFFECTS OF THE INFLAMMATORY RESPONSE

The primary physical effect of the inflammatory response is for blood circulation to increase around the affected area. Blood vessels around the site of inflammation dilate, allowing increased blood flow to the area. Gaps appear in the cell walls surrounding the area, allowing the larger cells of the blood, i.e. the immune cells, to pass through. As a result of the increased blood flow, the immune presence is increased. All of the different types of cells that constitute the immune system congregate at the site of inflammation, along with a large supply of chemical mediators, which fuel the immune response. There is an increase in local or body heat. The main symptoms of the inflammatory response are as follows.

1.      The tissues in the area are red and warm, as a result of the large amount of blood reaching the site.

2.      The tissues in the area are swollen, again due to the increased amount of blood and proteins that are present.

3.      The tissues in the area are painful, due to the presence of the inflammatory mediators and due to the expansion of tissues, causing mechanical pressure on nerve cells.

CHAPTER 3

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 [7] [5]. 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. Inflammation causes increased production of the enzyme cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-LOX), leading to the release of chemical mediators both in the area of injury and in the spinal cord.  Lipoxygenases (LOX) and cyclooxygenase (COX) enzymes can insert oxygen into the molecule of arachidonic acid and thereby synthesize inflammatory mediators leukotrienes [due to 5-lipoxygenase (5-LOX) activity] and prostaglandins (via COX activity) [8] . 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 in the CNS [9] [6]. Basal levels of the enzyme phospholipase A₂ activity in the CNS do not change with peripheral inflammation.. 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 [10] . 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.

CHAPTER 4

THE COMPLEX INTERACTION OF INFLAMMATORY MEDIATORS 

We will now review the main inflammatory mediators and their complex interaction in induction, enhancement and propagation of persistent pain. We will also review some of the 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) [11] [7].   Effects of Interleukin-1 beta include:

. Interleukin-1 beta stimulates inflammatory mediators prostaglandin E₂ (PGE₂), cyclooxygenase-2 (COX-2)  and matrix metalloproteases (MMPs) production [12] ^{, [13]} Interleukin-1 is a significant catalyst in cartilage damage. It induces the loss of proteoglycans, prevents the formation of the cartilage matrix [14] and prevents the proper maintenance of cartilage. Interleukin –1 is a significant catalyst in bone resorption^.  It stimulates osteoclasts cells involved in the resorption and removal of bone [15] [16] [17]

Interleukin-6

This 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 [18] . 

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 [19] [8] (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 [20] [21] . 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 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

This inflammatory mediator 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 [22] [9](24, 38, 41, 42), [23] [10] [24] [11] increased blood vessel permeability (9), and blood coagulation (24, 36). 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 (23, 40).

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 [19, 20] 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 [21]. In these tissues, NO has been shown to contribute to swelling, hyperalgesia (heightened reaction to pain) and pain [20, 22]. NO localized in high amounts in inflamed tissues has been shown to induce pain locally [59, 60] and enhances central as well as peripheral stimuli [61]. 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-alpha 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 [25] [12].

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 [26] [27] . 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 [28] . 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 [29] .

CHAPTER 5

NATURAL SUPPRESSION OF THE INFLAMMATORY RESPONSE

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 [30] [13] 

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 an 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 [31] .

CHAPTER 6

Arthritis means 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 [32] [20]. 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 [33] [34] . Inhibition of IL-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 [35] .

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 [36] [15]. 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 [37] [16] [38] [17]. 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 [39] [18]. 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 [40] [19]. 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 and 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 [41] [31]. In fact, there is some evidence that fibromyalgia is accompanied by some signs of immunosuppression [42] [32]. 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) [43] [33] [44] [34] [45] [35]. The levels of platelet serotonin are also abnormal [46] [36].  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) [47] [37].  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 [48] [38].

INTERSTITIAL CYSTITIS 

Interstitial cystitis is a severe debilitating bladder disease characterized by unrelenting pelvic pain and urinary frequency. This sterile painful bladder disorder is associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells.  Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory mediators in response to immunoglobulin E (IgE) and specific antigen.  Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses [49] . SP-containing nerve fibres are increased in the submucosa of the urinary bladder of interstitial cystitis (IC) patients and are frequently seen in juxtaposition to Mast cells [50] [51] . There is enhanced sympathetic innervation of the bladder in the submucosa and detrusor muscle. In interstitial cystitis the number of neurons positive for inflammatory mediator vasoactive intestinal polypeptide and neuropeptide Y is higher [52] . Substance P (SP) and bradykinin (BK) influence the excitatory motor innervation of the urinary bladder. These peptides potentiate the responses to the purinergic component of the neurogenic stimulation (that part of the contractile response that remains after treatment with atropine) and potentiate the responses to exogenously applied adenosine triphosphate (ATP) [53] . Significant elevations in Interleuken-2, Interleukin-6, and Interleukin-8 have also been found in the urine of subjects with active interstitial cystitis compared with subjects with interstitial cystitis in remission and control subjects [54] [39]

Migraine headache is caused by activation of trigeminal sensory fibers by known and unknown migraine triggers. There is subsequent release of inflammatory mediators from the trigeminal nerve. This leads to distention of the large meningeal blood vessels in the skull and brain and the development of a central sensitization within the trigeminal nucleus caudalis (TNC). Genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual [55] .

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) [56] . 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 [57] . 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) [58] . 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 autonomic and sensory 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 noradrenaline ( 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 [59] . 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) [60] [14]. 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. SP, on the other hand, 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 (e.g. carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, 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 pain of 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 pain receptors, 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 [61] . This is a finding commonly observed in patients where a minor injury results in severe pain that is out of proportion to the injury. Getting back 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 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 [62] . 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. [63] 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 [64] .  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 [65] 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 [66] . 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 [67] .

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 [68] [5]. 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 [69] . 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 in the CNS [70] [6]. 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.  

Neurotrophic factors are a family of growth promoting proteins that are essential for the generation and survival of nerve cells during development. Neurotrophic factors promote growth of small sensory neurons and stimulate the regeneration of damaged nerve fibers. The neurotrophins are a polypeptide family within this broad class of factors that bind and activate tropomyosin receptor kinase (Trk), a transmembrane receptor tyrosine kinase. 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). Other neurotrophic factor families include the fibroblast growth factor (FGF) family, the insulin-like growth factors I and II, the ciliary neurotrophic factor (CNTF) family and the glial cell line derived neurotrophic factor (GDNF) family. All of these factors have survival and nerve outgrowth-promoting effects and some have been shown to have neuroprotective actions. Nerve growth factor and glial-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 [71] . 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 [72] . 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 [73] .

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 [74] .

REFLEX SYMPATHETIC DYSTROPHY / CHRONIC REGIONAL PAIN SYNDROME (RSD/CRPS)

Vulvar vestibulitis syndrome is a major subtype of vulvodynia. It is a constellation of symptoms and findings involving and limited to the vulvar vestibule that consists of: (1) severe pain on vestibular touch to attempted vaginal entry, (2) tenderness to pressure localized within the vulvar vestibule, and (3) physical findings confined to vulvar erythema of various degrees. The syndrome has been seen in association with subclinical human papillomavirus, chronic recurrent candidiasis, chronic recurrent bacterial vaginosis, chronic alteration of vaginal pH, and the use of chemical and destructive therapeutic agents [87] . In a study of VVS cases and asymptomatic controls, median tissue levels of inflammatory cytokines: IL-1 b and TNF-a, from selected regions of the vulva,, vestibule, and vagina were 2.3-fold and 1.8-fold elevated, respectively, in women with VVS compared to pain-free women. Analysis revealed a significant 2.2-fold higher median level of TNF alpha at the vulvar site compared to the vestibule. Cytokine elevations correlated poorly with inflammatory cell infiltrate and suggested cytokine production from another cell source. The study authors concluded that inflammatory cytokine elevation may contribute to the pathophysiology of mucocutaneous hyperalgesia [88]

CHAPTER 7

CURRENT TREATMENT FOR PERSISTENT PAIN 

ANTI-INFLAMMATORY MEDICATIONS

Non-steroidal anti-inflammatories, such as aspirin, tolmetin sodium, indomethacin and ibuprofen, inhibit the enzyme cyclooxygenase and therefore decrease prostaglandin synthesis. 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 and lipoxygenase. The cyclooxygenase enzyme pathway results in the formation of inflammatory mediator prostaglandins and thromboxane.

New generation Non-steroidal anti-inflammatories, such as Licofelone inhibit both enzymes cyclooxygenase and lipoxygenase therefore decreasing prostaglandin and leukotriene synthesis.

CORTICOSTEROID e.g. Solumedrol, Decadron, Triamcinolone

Glucocorticoids are naturally occurring hormones that prevent or suppress inflammation and immune responses when administered at pharmacological doses. At the molecular level, unbound glucocorticoids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding induces a response by modifying transcription and, ultimately, protein synthesis to achieve the steroid's intended action. Such actions can include: inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. Some of the net effects include reduction in edema or scar tissue and a general suppression in immune response. The degree of clinical effect is normally related to the dose administered. The anti-inflammatory corticosteroids inhibit the activation of phospholipase A₂ by causing the synthesis of an inhibitory protein called lipocortin. It is lipocortin that inhibits the activity of phospholipases and therefore limits the production of potent mediators of inflammation such as prostaglandins and leukotriene.

Corticosteroids are also effective for some types of neuropathic pain and complex regional pain syndromes. One study examined the effects of systemic methylprednisolone on acute pain and pain hypersensitivity in normal and neuropathic rats.. In this study, when systemic methylprednisolone was started immediately after sciatic and saphenous nerve injury, there was a dose-dependent reduction in autotomy behavior. Substance P is an inflammatory mediator of neuropathic pain and edema. Single dose methylprednisolone (12 mg/kg) slightly reduced the substance P mediated inflammation induced with electrical stimulation of the saphenous nerve. Chronic methylprednisolone (3.4 mg/kg per day for 28 days) severely reduced the neurogenic inflammation induced with saphenous nerve stimulation.. Rats with sciatic nerve injury developed hind paw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with methylprednisolone (3.4 mg/kg per day). The study results demonstrate that corticosteroids did not affect pain thresholds in normal or neuropathic rats. However, chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema [89] [40]. 

OPIOID PAIN MEDICATION e.g. Methadone, Morphine 

Opioid medication such as Methadone, Oxycodone, Morphine, Demerol and Vicodin produce pain relief by binding and activating specialized opioid receptors at the site of tissue injury and in an area of the spinal cord called the substantia gelatinosa. Once activated, the opioid receptors inhibit the release of inflammatory mediators such as bradykinin at site of tissue injury and Substance P from pain transmitting C nerve fibers. The pain receptors that were previously excited are now suppressed. There is also suppression of the signal traffic in the specialized nerves e.g. C fibers and A-delta fibers that carry pain impulses to the spinal cord and brain.  Morphine and other opioids also alter emotional processing of painful input by acting on opioid receptors in the limbic and cortical area of the brain. In addition, new research now shows that morphine and other opioids have additional anti-inflammatory effects. These effects include:

1.      Inhibition of Interleukin-1 beta converting enzyme (ICE), a proteolytic enzyme that converts the inactive precursor of interleukin-1 beta (Interleukin-1 beta) to its mature active form [90] [41]

2.       Inhibit inflammatory cytokine mediators interferon-alpha IFN (IFN-alpha) and interferon-beta (IFN-beta) production by lymphocytes and fibroblast cells [91] [42]

3.       Inhibits tumor necrosis factor-alpha (TNF-alpha) production by activated macrophages [92] [43]

4.     Induces the suicidal cell death (apoptosis) of immune cell lymphocytes.

5.     Increases the release of anti-inflammatory cytokines such as transforming growth factor-beta1 (TGF-beta1) and Interleuken-10 [93] [44].

Morphine and other opioids are also effective anti-migraine agents.  In electrophysiological studies morphine significantly attenuated brainstem neuronal activity in response to electrical stimulation of the dura by 65%. Morphine also inhibited the trigeminal nucleus caudalis (TNC) neuronal sensitization following calcitonin gene-related peptide (CGRP)-evoked dilation. Studies have demonstrated that opioids block the nociceptive neurotransmission within the trigeminal nucleus caudalis and in addition inhibit neurogenic dural vasodilation via an action on mu-opioid receptors located on trigeminal sensory fibres innervating dural blood vessels [94] . These peripheral and central actions could account for the anti-migraine actions of opioids.

CHAPTER 8

REASONS WHY CURRENT TREATMENTS MAY NOT RELIEVE PERSISTENT PAIN

The only inflammatory mediators that are addressed in the old ways of treatment are the prostaglandins and leukotrienes, which are produced by the cyclooxygenase and lipoxygenase pathways. Failure to address the other major inflammatory mediators such as interleukin-1 beta and tumor necrosis factor alpha will result in treatment failure in patients whose pain is derived from inflammatory mediators that are not being treated. Physicians who do not understand this new law of pain will continue to blame patients for chronic pain and recommend psychiatric help. Over-reliance on structural imaging studies such as MRI and CT-scans to explain chronic pain should stop. Structural imaging studies cannot provide any information on the biochemical mediators causing soft tissue pain. Presence of a structural defect cannot predict pain and neither can the absence do the same. A landmark study has shown that one-third of perfectly healthy persons who have no pain will have a herniated disk present on an MRI scan. Should any of these persons have a slip and fall injury and present in the Emergency Room, the disk will be blamed for the pain and they have a high probability of getting unneeded surgery. On the other hand, persons with severe pain such as Fibromyalgia who do not have any structural abnormalities will be labeled as malingerers and drug seekers and sent for urgent psychiatric counseling. There is an urgent need for doctors and patients to understand Sota Omoigui’s Law of Pain and for development of biochemical functional scans that will provide information on the biochemical mediators that are responsible for persistent pain in areas of injury as well as neighboring uninjured areas.

CHAPTER 9

NEW BREAKTHROUGH TREATMENT OPTIONS FOR PERSISTENT PAIN

Anti-Spasm Medications

BOTULINUM TOXINS (BOTOX, MYOBLOC)

Botulinum toxins are potent nerve toxins, which bind to transport proteins in nerve cells and block the release of nerve transmitters from nerve endings. One of these transmitters called acetylcholine is released by nerve cells and transported into muscle cells to signal the muscle to contract. Blockade of this transmitter by Botulinum toxin can produce a long lasting relief of muscle spasms. By interfering with transport proteins in nerve cells, studies have shown that Botulinum toxin may also inhibit the release of excitatory nerve transmitter glutamate [95] and inflammatory mediators such as Arachidonic acid (AA) [96] , vasoactive intestinal peptide (VIP) and Neuropeptide Y (NPY) [97] .  Botulinum toxins also inhibits the release of tumor necrosis factor alpha [98] [45]  (TNF-alpha) from immune cells and thus can alleviate pain and spasm produced by the inflammatory response..  

Tumor Necrosis Factor Alpha Blocker Medications

The central role in inflammatory responses have InterLeukin-1 and TNF-alpha because the administration of their antagonists, such as IL-1ra (Interleukin-1 receptor antagonist), soluble fragment of Interleukin-1 receptor, or monoclonal antibodies to TNF-alpha and soluble TNF receptor, all block various acute and chronic responses in animal models of inflammatory diseases.

ETANERCEPT (ENBREL)

Etanercept is a fusion protein produced by recombinant DNA technology. Etanercept binds to and inactivates Tumor Necrosis Factor (TNF-alpha) but does not affect TNF-alpha production or serum levels. Etanercept may also modulate other biologic responses that are induced or regulated by TNF-alpha such as production of adhesion molecules, other inflammatory cytokines and matrix metalloproteinase-3 (MMP-3 or stromelysin). Patients with rheumatoid arthritis have increased levels of TNF-alpha in their joint fluid. The introduction of Etanercept transformed the treatment of rheumatoid arthritis.  Etanercept decreases the inflammation and inhibits the progression of structural damage in patients with moderately to severely active rheumatoid arthritis. When Etanercept was added in patients who had persistent disease despite receiving Methotrexate, rapid and sustained improvement was noted. Etanercept has been used successfully in the treatment of other inflammatory disorders. In one study, TNF-alpha blockade with Etanercept was markedly effective in controlling the clinical manifestations of inflammatory back pain located in the cervical spine, lumbar spine and sacro-iliac joints [99] [67]. In another study, Etanercept was found to reduce pain and hyperalgesia in an animal model of painful neuropathy. Treatment with Etanercept by local near-nerve injection to the injured nerve or by systemic application significantly reduced thermal hyperalgesia and mechanical hypersensitivity to pain. The effect of Etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hypersensitivity to pain was already present. The authors conclude that the results suggest the potential of Etanercept as a treatment option for patients with neuropathic pain [100] [68]. In another research study, two tumor necrosis factor-alpha inhibitors (Etanercept and Infliximab) prevented the reduction of nerve conduction velocity and nerve fiber injury produced by application of disk tissue (nucleus pulposus) to a nerve [101] [69].

INFLIXIMAB (REMICADE)

Infliximab is a monoclonal antibody targeted against tumor necrosis factor-alpha (TNF-alpha). Infliximab neutralizes the biological activity of the cytokine tumor necrosis factor-alpha (TNF-alpha). Infliximab binds to high affinity soluble and transmembrane forms of TNF-alpha and inhibits the binding of TNF-alpha with its receptors. Infliximab does not neutralize TNF-beta, a related cytokine that utilizes the same receptors as TNF-alpha. Biological activities attributed to TNF-alpha include induction of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6; enhancement of leukocyte migration by increasing endothelial layer permeability; expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; fibroblast proliferation; synthesis of prostaglandins; and induction of acute phase and other liver proteins. In patients with rheumatoid arthritis, infliximab substantially improves clinical symptoms when given in combination with Methotrexate. In patients with rheumatoid arthritis, infliximab treatment reduces inflammatory cell infiltration into inflamed areas of the joint and reduces the expression of molecules mediating adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vacular adhesion molecule-1 (VCAM-1)], chemoattraction (monocyte chemotactic protein (MCP-1 and IL-8), and tissue degradation (matrix metalloproteinase (MMP) 1 and 3). In patients with Crohn's disease, infliximab reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas of the intestine. In addition, the proportion of mononuclear cells from the lamina propria able to express TNF-alpha and interferon gamma is reduced. After treatment with infliximab, patients with Crohn's disease or rheumatoid arthritis have decreased concentrations of IL-6 and C-reactive protein as compared to baseline.

ANAKINRA (KINERET)

Anakinra is a form of the human interleukin-1 receptor antagonist (IL-1Ra) produced by recombinant DNA technology. Anakinra differs from the naturally occurring native human IL-1Ra in that it has an additional methionine residue at its amino terminus. Anakinra acts similarly to the naturally occurring interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra blocks effects of Interleukin-1 by competitively inhibiting binding of this cytokine, specifically IL-alpha and IL-beta, to the interleukin-1 type 1 receptor (IL-1R1), which is produced in a wide variety of tissues. Il-1Ra is part of the feedback loop that is designed to balance the effects of inflammatory cytokines. During clinical trials, rheumatoid arthritis patients treated with Anakinra experienced clinical responses, including improvement in swollen and painful joints within 4 weeks, and most by 13 weeks, of therapy. After 6 months of therapy, 38% of patients treated with Anakinra, alone or in combination with Methotrexate, achieved a 20% improvement in the American College of Rheumatology criteria.

LEFLUNOMIDE (ARAVA)

Leflunomide interferes with RNA and protein synthesis in immune T and B-lymphocytes. T and B cell collaborative actions are interrupted and antibody production is suppressed.  Leflunomide is the first agent for rheumatoid arthritis that is indicated for both symptomatic improvement and retardation of structural joint damage. Leflunomide may also have anti-inflammatory properties secondary to reduction of histamine release, and inhibition of induction of cyclooxygenase-2 enzyme (COX-2). Leflunomide may decrease proliferation, aggregation and adhesion of peripheral and joint fluid mononuclear cells.  Decrease in the activity of immune lymphocytes leads to reduced cytokine and antibody-mediated destruction of joints and attenuation of the inflammatory process.

PENTOXIFYLLINE

Pentoxifylline is a phosphodiesterase inhibitor, which is used as a blood thinner medication in persons who have poor peripheral circulation. However the drug has another unique effect. It suppresses inflammatory cytokine production by T cells and macrophages [102] [46]. Some of the anti-inflammatory effects occur by blocking nitric oxide (NO) production by macrophages. Pentoxifylline also blocks the production of Tumor Necrosis Factor Alpha. In one study, Pentoxifylline prevented nerve root injury and swelling (dorsal root ganglion compartment syndrome) caused by topical application of disk tissue (nucleus pulposus) [103] [47]

CLARITHROMYCIN (BIAXIN)

Studies have shown that injured joint cells produce cytokine inflammatory mediators including IL-1beta, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF. Clarithromycin significantly inhibits the production of these cytokines and also suppresses the proliferation of immune T cells [104] [48].

TETRACYCLINES (DOXYCYCLINE, MINOCYCLINE)

Tetracyclines such as doxycycline and minocycline may block a number of cytokines including Interleukin-1 [105] [49] [106] [50], IFNg [107] [51], NO-synthetases, and metalloproteinases [108] [52]. Interleukin -1 and IFN-.gamma act synergistically with TNF-alpha and are known to be toxic to nerve tissue [109] [53] [110] [54] [111] [55] [112] [56] [113] [57]. One study showed that oral administration of doxycycline prevented the breakdown of cartilage in subjects with osteoarthritis [114] [58]. In another study, a patient with rheumatoid arthritis who did not respond to other arthritis medications had marked improvement with Minocycline [115] [59]. In another study, minocycline-treated patients were more likely to have gone in remission and discontinued treatment with prednisone at 2 years than patients who were treated with other standard rheumatoid arthritis medications [116] [60]. Tetracyclines may also block the inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-alpha). 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 [117] [61]. In one study, treatment with doxycycline significantly blocked the nucleus-pulposus-induced reduction of conduction velocity [118] [62]

ANTI-NAUSEA SEROTONIN (5-HT3) BLOCKERS

ONDANSETRON (ZOFRAN)

In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists such as Tropisetron in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favorable treatment results with 5-HT3-receptor antagonists in fibromyalgia [119] [63].

A scavenger of oxygen radicals, topical DMSO inhibits nerve conduction and decreases inflammatory swelling. DMSO local anti-inflammatory effects provide symptomatic relief when the solution is applied in the bladder (intra-vesically) in patients with interstitial cystitis. A crossover study was performed for patients with RSD/CRPS to evaluate the therapeutic efficacy of the hydroxyl radical scavenger DMSO. All patients were given DMSO locally 5 times a day during one week, and a placebo during one week. Before and after each treatment, both the patient and the examiner performed subjective evaluation of the clinical activity of RSD/CRPS. Measurement was then performed of the range of motion (ROM) of all joints in the affected extremity. DMSO was the most effective treatment as to improvement of ROM (p = 0.035) and as to overall improvement (p = 0.001). The authors concluded that the efficacy of the hydroxyl radical scavenger DMSO indicates that RSD/CRPS primarily involves an inflammatory process rather than a sympathetic reflex. The authors further stated that during the last 20 years no single report was published studying RSD in terms of inflammation. The authors then suggested that such studies are urgently needed to elucidate the real nature of RSD/CRPS [120] [64]

ALENDRONATE, PAMIDRONATE (FOSAMAX, AREDIA)

Bisphosphonates originally were used to soften hard water. This class of drugs reduces bone turnover and bone loss. 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) [121] [65]. 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.   Bisphosphonates are used in the treatment of bone pain due to Paget's disease, postmenopausal osteoporosis, bone metastasis in patients with advanced cancer and in the treatment of elevated calcium levels associated with cancer. In one study, the efficacy and the safety of Pamidronate was assessed in patients in various stages of recalcitrant reflex sympathetic dystrophy (RSD/CRPS). Some patients had more than one site involved. Mean duration of the disease was 15 months. About half of the patients have been previously treated unsuccessfully by sympathetic blockades. Pamidronate was administered intravenously for 1- 3 consecutive. Efficacy was assessed by a decrease of pain.  A significant decrease of pain was observed. These results suggest an efficacy of Pamidronate in recalcitrant RSD [122] [66].

Solid cancers metastasize to bone by a multi-step process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production. The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Drugs such as the new-generation bisphosphonates can inhibit osteoclasts; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone. In experimental situations, this has clearly been shown to affect not only morbidity but also survival. The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates such as ibandronate, pamidronate, and risedronate have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone [123] . In conclusion, Bisphosphonates not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis [124] .

 ANTI-DEPRESSANT MEDICATIONS

PROTRIPTYLINE (VIVACTIL) 

2000 years ago, St John’s wort, a herbal anti-depressant was used to treat sciatic and nerve pain. Studies have shown that it is only the older tricyclic class anti-depressants like protriptyline or desipramine that are effective in the treatment of persistent pain. Newer SSRI class anti-depressants like Prozac and Paxil are not effective. The analgesic effects of Protriptyline and other cyclic type antidepressants may occur partly through the alleviation of depression, which may be responsible for increased pain suffering, but also by mechanisms that are independent of mood effects. Current research suggests that the pain-relieving effect of antidepressants is due to their blockade of reuptake of chemical transmitters norepinephrine and serotonin. The resulting increase in the levels of these chemical transmitters enhances the activation of pain inhibiting pathways that descend from the brain to the spinal cord.  Activation of these pathways decreases the transmission of pain impulses from injured or inflamed nerves to the spinal cord dorsal horn wherein the impulses are transmitted to the brain.  Amitriptyline and other cyclic antidepressants may also enhance the analgesic effect of opioid medication by increasing their efficacy of binding to opioid receptors. Protriptyline (and other cyclic antidepressants) may have a blocking effect on spinal N-methyl-D-aspartate (NMDA) receptors, and inhibit NMDA receptor activation-induced neuroplasticity [125] [70]. Spinal NMDA receptor activation is believed to be central to the generation and maintenance of persistent hyperalgesic pain.  Anti-depressant medication may also have effects on inflammatory mediators. In one study, four weeks of prolonged administration of amitriptyline and desipramine resulted in a significant increase in the secretion of the anti-inflammatory cytokine Interleukin-10 [126] [71].

ANTI-SEIZURE MEDICATIONS

OXCARBAZEPINE (TRILEPTAL)

Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly thus leading to abnormal excitability in the sensory neurons.  Studies have shown that the inflammatory mediators interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthetase are significantly increased when there is excessive nerve traffic as occurs during seizures or persistent pain [127] [72].  Anti-seizure medications such as Trileptal or Zonegran decrease pain by reducing the rate of continuing discharge of injured and inflamed nerve fibers. Blockade of sodium channels in nerve cells leads to a decrease in electrical activity and a subsequent reduction in release of the excitatory nerve transmitter glutamate. Anti-seizure drugs also inhibit the initiation and propagation of painful nerve impulses by inhibiting Nitric Oxide Synthetase activity [128] [73]. Nitric Oxide Synthetase is the enzyme responsible for the production of the inflammatory mediator Nitric Oxide. Anti-seizure drugs may also protect nerve cells from free radical damage by Nitric Oxide and/or hydroxyl radicals (OH*) [129] [74] . In one study, the anti-seizure drug Sodium valproate was shown to significantly inhibit immune cell production of TNF-alpha and Interleuken-6 [130] [75].  Sodium valproate suppresses TNF-alpha and IL-6 production via inhibition of activation of the nuclear transcription factor kappa B (NF-kappaB). In immune cells and human nerve cells, NF-kappaB is essential to the expression of inflammatory cytokines. 

In addition anti- seizure medications reduce painful muscle spasm. Spasticity from different causes is associated with a deficiency of inhibitory nerve transmitters like gamma aminobutyric acid or an excess of excitatory nerve transmitters such as glutamate. Anti-seizure drugs enhance the inhibition of nerve-muscle activity by gamma aminobutyric acid in the spinal cord [131] [76].

THALIDOMIDE AND THALIDOMIDE ANALOGUES

 Thalidomide and analogues mainly inhibit tumor necrosis factor alpha (TNF-alpha) synthesis but the drugs also have effects on other cytokines. Thalidomides increase the production of the anti-inflammatory cytokine interleukin-10 (IL-10) in lesioned sciatic nerves. In addition, Thalidomides stimulate the release of the pain relieving natural opioid peptide methionine-enkephalin in the dorsal horn of the spinal cord [132] .

In a recent case report, a 43-year-old woman had injured her hand and developed a severe case of RSD/CRPS that confined her to bed or a wheelchair most of the time. Three years after developing RSD/CRPS, the woman was diagnosed with multiple myeloma. She was started on thalidomide, which has shown promise for treating multiple myeloma. The change in the woman's condition was "astounding," as reported by the authors. Within a month, the woman experienced an unexpected improvement in RSD/CRPS symptoms, which nearly disappeared [133]

 NERVE BLOCKADE

The role of neural or nerve blocks with local anesthetics with or without anti-inflammatory agents in the treatment and relief of persistent pain is well defined. A nerve fiber is a long cylinder surrounded by a semi permeable (allows only some substances to pass) membrane. This membrane is made up of proteins and lipids (fats). Some of the proteins act as channels, or pores, for the passage of sodium and potassium ions through the membrane.

The conduction of nerve impulses along a nerve fiber is associated with a change in the permeability of the membrane. The channels widen, and sodium ions (Na+) move to the inside of the fiber. At the same time, potassium ions (K+) diffuse out through other channels. As these electrolytes change positions, an electrical charge is set up and the impulses will travel down the nerve fiber. This process is called depolarization. Once the nerve impulse has passed, the channels become smaller. Sodium ions (Na+) are now "pumped" out of the fiber and potassium ions (K+) are pumped back in. The nerve membrane is now repolarized and ready to conduct another impulse.

Local anesthetic agents stabilize nerve membrane by inhibiting the sodium influx required for the initiation and conduction of impulses. The local anesthetic effect of numbness lasts as long as the agent maintains a certain critical concentration in the nerve membrane.

Subsequent to tissue injury, the expression of sodium channels in nerve fibers is altered significantly thus leading to abnormal excitability in the sensory neurons.  Studies have shown that the inflammatory mediators interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthetase are significantly increased when there is excessive nerve traffic as occurs during seizures or persistent pain [134] [72].  Local anesthetic agents like anti-epileptic medications decrease pain by reducing the rate of continuing discharge of injured and inflamed nerve fibers. Blockade of sodium channels in nerve cells leads to a decrease in electrical activity and a subsequent reduction in release of the excitatory nerve transmitter glutamate.  

Researchers have found that preemptive analgesia -- delivering pain medication to patients before or just after surgery -- results in significant pain reduction long afterward – for a period that significantly exceeds the duration of action of the local anesthetic or analgesic medication. Beginning pain treatment before or immediately after surgery can vastly decrease post-operative pain [135] [136] [137] .

SURGERY

The role of surgery is uncontested when there is an underlying surgical condition such as a fracture or perforated appendix that produces a continuous aggravation and ongoing production of inflammatory mediators that cannot be controlled by medical intervention. Surgery should not be performed just to treat a structural abnormality and will often be counter productive if a persistent pain condition is amenable to biochemical intervention as described in this book.

CHAPTER 10

Mr. M. H.

A 27- year old male presented with an 11-year history of low back pain following a motor vehicle accident. Injuries sustained during the accident included burst fracture of the lumber spine at the L2 and L3 levels, and a fractured pelvic bone. The patient had a history of repeated surgeries in the spine with multiple fusions, the placement of a Harrington Rod which was later removed and the use of pedicle screws. On presentation, low back pain was a severe constant aching, graded nine on a pain scale of one to ten. Pain was radiating to both lower extremities experienced as a burning, with numbness and tingling on both thighs and legs.

Physical examination revealed a scar over the lumber spine in the midline. There was marked tenderness from the thoracic spine T9 to the sacrum S1. In addition, there was moderate spasm of the lumber paraspinal muscles. Range of motion was reduced to thirty degrees of flexion at the lumber spine; extension was limited to five degrees. Sensory perception of a pinprick was significantly reduced in both right and left L2 to L4 dermatomes. However, the motor strength was normal globally.

Initial treatment consisted of a refill of Oxycodone SR 40mg, 2-3 tabs P.O. q 12hrs. Other medications prescribed were Roxicodone 15mg, 1 tab P.O. q 4-6 hrs, Tizanidine 2mg P.O. bid, 4mg P.O. q hs, Oxcarbazepine 300mg P.O bid and Tolmetin DS 400mg P.O tid with meals. The patient was subsequently scheduled for a chemodenervation procedure with Botulinum toxin. Two months later chemodenervation of the lumber paraspinal muscles with Botulinum toxin was carried out. This resulted in a drop in pain score from nine to five within five days of the procedure. More relief was noted in the aching pain and spasms in the lower back following the procedure compared to the burning pain felt in the lower extremities. Two additional chemodenervation procedures were done over a period of six months. Each time after the procedures, the pain score in the lower back would drop further than before. The most dramatic pain relief was observed after Anakinra injection 100mg was given subcutaneous; the pain score dropped from a score of ten to two in twenty minutes. The Anakinra injection was repeated three weeks later with similar result.

Ms. R.B

39- year old female presented with a twenty-month history of aching and burning pain on the entire left side of the body. Onset of pain was preceded by a cerebro-vascular accident resulting in paralysis and paresthesia of the left side of the body.. The pain felt by the patient was constant and severe; graded ten on a scale of one to ten. There was also muscle spasms associated with her pain.

The patient was diagnosed to have hypertension at the age of eighteen years, had coronary angioplasty for recurrent angina at the age of thirty-five years. Blood work done before surgery revealed a deficiency in Protein S. A family history of hypertension, Protein S deficiency and Lupus was also noted. She was on Warfarin, Atenolol, Amlodipine, Acetaminophen 300mg/ codeine 30mg, Carisoprodol and Amitriptyline. Physical examination showed hyperesthesia and hyperpathia on the left side of the body. Also noted were increased motor tone, spasticity and hyperreflexia on the left upper and lower limbs. A working diagnosis of neuropathic pain and spastic hemi paresis, post CVA was made.

The patient was commenced on Tizanidine 2mg P.O bid, 4mg P.O qhs, acetaminophen 2.5mg / Oxycodone 325mg 1 tab P.O q 6hr, prn pain, and Oxcarbazepine 300mg P.O two times daily. She was told to discontinue Carisoprodol and amitriptyline that she had been taking. A two- week appointment was made for review and to receive Etanercept injection.

On re-evaluation two weeks later, her pain score had dropped to six on the pain scale. Subsequently, she was given Etanercept 25 mg injection subcutaneous in her left arm. She was re-evaluated one week later and she gave the information that her pain score dropped from six to two within six hours of receiving the Enbrel injection.

Mr. C.N.

45-year-old male presented with sixteen-year-old history of low back pain and four year old history of neck pain. Pain started gradually without an immediate preceding trauma. However he had several falls on his previous construction jobs. His pain was constant, severe, radiates to both upper and lower extremities with associated numbness and tingling. The radicular symptoms were felt in the left leg and toes, right and left third to fifth fingers. He also complained of muscle spasms in the lower back and thighs, and in the shoulders.

Previous MRIs done had showed multiple- level disc bulges and degenerative changes in both the cervical and lumbar spine. He has had several surgical procedures done prior to presentation. These procedures included lumbar laminectomy (L3 - L5), diskectomies and nerve root blocks in the cervical and lumbar spine. All these only afforded him temporary pain relief.

Moderate tenderness was noted in the cervical spine and cervical paraspinal muscles on examination, with moderate reduction in range of motion. He also had mild tenderness in the muscles around the right and left shoulders. Moderate tenderness was also noted in the lumbosacral spine with spasms and stiffness in the lumbar paraspinal muscles. The range of motion, however, was full. Neurological examination revealed decreased sensory perception of the pinprick on both right and left C8 dermatome. A diagnosis of post laminectomy lumbar syndrome, lumbar and cervical facet arthropathy with radiculopathy was made.

Subsequently, chemodenervation of the peripheral nerves and paraspinal muscles was done using Botulinum toxin. In addition, the patient was injected with Anakinra 100mg subcutaneously. On re-evaluation one week later, the patient gave the information that his pain dropped significantly. His back and neck pain score dropped from a value of nine to three within one hour of receiving the injections. His radicular symptoms improved one day after the procedures.

Mr. S .P

43-year-old male was being treated for chronic low back pain when he complained of severe, and constant burning pain and hypersensitivity in his skin and joints throughout the entire body, worse in the extremities. No information was given at this initial presentation about any precipitating factor. There was no history of fever or malaise. Prior to presentation, he was being treated with Clarithromycin after a diagnosis of phlebitis and toxic neuropathy. He did not comply with the antibiotic treatment despite obtaining some relief. Physical examination showed the patient was in moderate distress, but alert and oriented. Body temperature and blood pressure were within normal range. Chest examination was normal. The skin was erythematous, especially overlying the veins, with generalized hyperesthesia and allodynia. He also had mild to moderate tenderness in the bilateral shoulder, elbow, wrist and knee joints without joint swelling or heat.

 A diagnosis of neurogenic inflammation to rule out Rheumatoid arthritis and phlebitis was made. The patient was told to complete the course of antibiotics. And he was to continue pain medications and therapy while awaiting blood test results from work up performed. On re evaluation one week later, he was still having severe burning pain, which was made worse after bathing in a warm Jacuzzi. Blood work results were still pending. The patient then gave the information that he had injected himself with adulterated cocaine prior to the onset of his burning pain. He had gone to see a Toxicologist who analyzed the remaining sample of the drug that was injected. The injected cocaine was found to be adulterated with chlormezanone (Trancopal). Subsequently, he was placed on Leflunomide 100mg P.O once daily for three days, then 20mg P.O once daily and Methadone 10mg P.O q 6hrs. On re-evaluation one week later, his burning pain had improved tremendously with the pain score dropping to 2/10 from an initial score of 6/10.

Mr. C.N.

45-year-old male presented with complaints of severe pain in his right shoulder after falling on the shoulder from a height of about three feet. His pain was constant and severe, with associated difficulty abducting the joint. Patient had been seen by an orthopedic surgeon who had ordered an MRI of the right shoulder. The MRI revealed a complete rotator cuff tear involving the anterior aspect of the supraspinatus tendon adjacent to the intertuberous sulcus. The patient was advised to get immediate surgical repair of his rotator cuff. When the patient presented in our clinic he was in a lot of pain. Examination revealed severe tenderness to palpation of the right rotator cuff. His range of motion examination showed a severe limitation of abduction at 20 / 180 degrees. Mr. C.N. was placed on Tolmetin sodium 400mg P.O. three times daily with meal and Oxycodone 5mg 1-2 tabs P.O. q 4hr. He had only a slight improvement on the medications. He was subsequently given Anakinra 100mg subcutaneously. Within two minutes of administration of the Anakinra, patient was able to fully raise his right shoulder to 180 / 180 degrees and was quite surprised. On re-evaluation one week later, he gave the information that his pain dropped from a score of 9/10 to 3/10 within five minutes of receiving the Anakinra injection. The duration of pain relief lasted for one month. He was given a second injection of Anakinra 100 mg SC that has given sustained pain relief for five months till the time of publication.

Mrs. M. H..

53-year-old female with a five-year history of generalized body pain involving the joints and soft tissue. She has been receiving specialist pain management following a diagnosis of fibromyalgia, myofascial pain and osteoarthritis. She also had a four-year history of intermittent abdominal pain, worse in the lower abdominal regions, passage of loose stool with occasional bloodstains. After undergoing endoscopy with biopsy, her abdominal condition was diagnosed to be ulcerative colitis by a Gastroenterologist.  As part of her chronic pain management, she was given Anakinra 100mg subcutaneously. This resulted in relief of her joint and soft tissue pain and remission of her ulcerative colitis as evidenced by resolution of abdominal pain within two days of the injection. This remission lasted for six months up till the time of publication. The remission was accompanied by an increase in appetite and a slight gain in weight.  

Mrs. V.C.

40-year-old female presented with a fourteen-year history of generalized body pain. Pain was described as severe, constant aching, aggravated by activity, relieved slightly and transiently by pain medications. She also had insomnia, extreme fatigue, and a history of Irritable Bowel Disease. Her primary care physician had diagnosed her to have Fibromyalgia. She has also had several tender point injections with local anesthetic before her referral for pain management. On examination, the patient could only walk with the aid of a walker due to severe pain and weakness. She had eighteen out of eighteen Fibromyalgia tender points detected by mild digital pressure, muscle spasms in the cervical and lumbar paraspinal muscles and spasms in both shoulders. Subsequently she was placed on Oxycodone 20 mg P.O. q8-12hrs, acetaminophen 750/ Hydrocodone 7.5mg, 1-2 Tabs P.O. q 4hr, prn pain, and Baclofen 10mg, ½ tab P.O., tid. In the following months she had trigger point injections using local anesthetics and steroid, and also denervation of peripheral nerves and muscles in spasms using Botulinum toxin. After each of these procedures the patient’s pain score would drop from a score of 10/10 to 4-5/10 within three days. The relief would persist for several weeks before pain will gradually increase to a score of 10/10. During an exacerbation of the patient’s condition, she was treated with intra-venous infusion of methylprednisolone succinate 125mg. This resulted in a dramatic pain relief with associated resolution of fatigue. The pain dropped to a score of 2/10 as never before, and muscle spasms were mild and infrequent.    

Mrs. J.B.

64-year-old female presented with a fifteen-year history of low back pain and severe pain in the tailbone, which started after a slip and fall on the buttocks. Examination of the spine revealed marked tenderness in the lumbar spinous processes and paraspinal muscles as well as the coccyx. MRIs of the lumbar spine, sacrum and coccyx were ordered.  These revealed multiple-level diffuse disc bulge in the lumbar spine measuring 3-4mm with displacement of the posterior longitudinal ligament, neural foramina narrowing and disk desiccations. However, there were no signs of fracture in the lumbar spine, sacrum and coccyx. She has had two lumbar spine epidurals, several trigger point injections using local anesthetic and steroid, in addition to hydromorphone 4mg, 1-2 tabs P.O. q4hr, prn pain, morphine SR 60 mg P.O q12hr, and Rofecoxib 50mg P.O. qd. These treatments only resulted in moderate and transient pain relief in the lumbar region. The pain over the coccyx persisted until the patient was given Etanercept injection 25mg subcutaneously. Within two days, the patient had significant relief of pain in the tailbone and lower back. Her requirement for oral hydromorphone 4mg decreased from six tablets daily with three tablets of morphine SR 60 mg to just one tablet of hydromorphone 4mg.  The pain relief was significant and lasted one month before gradually increasing to the pre-Etanercept injection levels. 

CONCLUSION

This is the conclusion of this book and the beginning of a new dawn in our understanding and treatment of Persistent Pain by the application of Sota Omoigui’s Law of Pain which states: The origin of all pain is inflammation and the inflammatory response.

Sota Omoigui MD

Hawthorne, California

April 11^th, 2002

ABOUT THE AUTHOR

Sota Omoigui M.D. is Medical Director of the L.A. Pain Clinic in Hawthorne, California.  Dr. Sota Omoigui is author of Sota Omoigui's Anesthesia Drug Handbook (Blackwell Scientific Publishers, 1999), Sota Omoigui's Pain Drug Handbook (Blackwell Scientific Publishers, 1999) The Anesthesia Drug Handbook (Mosby Yearbook Publishers, 1995), The Pain Drug Handbook (Mosby Yearbook Publishers, 1996), Pain Relief - The L.A. Pain Clinic Guide (State-of-the-Art Technologies, 1998), The Universal Drug Infusion Ruler (State-of-the-Art Technologies, 1995) It’s a Jungle out there – 163 Business Lessons from the Animal Kingdom (State-of-the-Art Technologies, 2001) and co-author of The Nigerian National Anthem (1978). Dr Sota Omoigui's drug handbooks are used worldwide and have been published in five other languages (Italian, Japanese, Malaysian, Polish and Portuguese). Dr Sota Omoigui’s research focus is on the biochemical origin of Pain, and development of biochemical interventions for relief of persistent pain. Dr Sota Omoigui pioneered the technique of audio-capnometry and holds a United States patent for the audio-capnometer monitor and a patent for the process of continuous non-invasive hemometry (measurement of hemoglobin).

On April 11th, 2002, Dr Sota Omoigui published his Law of Pain which states: - The origin of all pain is inflammation and the inflammatory response. This is the most significant advance in our understanding of Pain since the 1965 publication of the Gate Theory of Pain by Ronald Melzack and Patrick Wall.  

ABOUT THE BOOK

What happens between injury and our perception of pain? This book is about the first unifying law of Pain that explains the origin of all types of pain: from Arthritis to Fibromyalgia and from Migraine to Sciatica. Sota Omoigui’s Law of Pain states that: The origin of all pain is inflammation and the inflammatory response. This is the most significant advance in our understanding of Pain in the last century. With this understanding and new drugs we have significantly advanced our ability to treat persistent pain. The knowledge in this book will help everyone who has ever suffered from pain. This book and Sota Omoigui’s Law of Pain will endure as a significant milestone in the age-old quest of mankind to conquer pain.

Copyright 2002. Sota Omoigui, M.D. All rights reserved.