(ĐTĐ-Anatomy of Pain) - Knowledge of the peripheral anatomy of the human body is essential in evaluating the complex problems found in a patient with pain. The clinical problem is often reduced to the simple question, “Is the pain in an area supplied by a single nerve root, a single peripheral nerve, or a branch of a peripheral nerve?” A physical examination to evaluate pain, weakness, and their distribution often leads the clinician to better localize the nerves involved in the patient’s report of pain.

FIGURE 49-3. The connections and interchanges of the funiculi in the brachial plexus.

Somatic Innervation

A difficulty encountered in the diagnosis of pain is secondary to the overlap of cutaneous fields of segmental and peripheral nerves, as well as the overlapping innervation of muscle and bone. Single cutaneous nerves innervate sharply defined regions with little overlap, but these fibers regroup in the peripheral nerve and are again redistributed in the brachial or lumbosacral plexus. This makes it impossible to follow individual fibers from the dorsal roots to the areas innervated by the individual cutaneous nerve. Adjacent cutaneous nerves may be supplied by fibers from more than one spinal nerve (Fig. 49-3) (95). Anatomists and physicians have attempted to define areas of the skin, muscle, and bone that are of the exclusive domain of a single spinal cord root, as well as the areas of overlap. The size of these areas varies from nerve to nerve and from individual to individual. As with all knowledge of the human body, anatomy of sensation and pain rests on a foundation of original work performed by investigators too numerous to list. The figures in this chapter have taken some of the best work in the field and compiled it into a comprehensive review (Figs. 49-4 through 49-17). In delving into the literature in this area of anatomy, one cannot help but feel that he or she is standing on the shoulders of giants without whose work the figures in this chapter would be impossible.

FIGURE-4. Dermatome, myotome, and sclerotome distribution for C3. Dermatome: neck. Myotome: paraspinals, trapezius, and diaphragm. Sclerotome: bones–vertebra and periosteum; joints–facet; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-5. Dermatome, myotome,and sclerotome distribution for C4. Dermatome: shoulder. Myotome:paraspinals, trapezius, diaphragm, scapular abductors. Sclerotome: bones–vertebra, periosteum, and clavical; joints–facet; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-6. Dermatome, myotome, and sclerotome distribution for C5. Dermatome: lateral shoulder and lateral arm. Myotome: paraspinals, scapular abductors, scapular elevators, shoulder extensors, shoulder rotators, and elbow flexors. Sclerotome: bones–vertebra and periosteum, scapula, and humerus; joints–facet; ligaments–rotator cuff, longitudinal, ligamentum flavum, and interspinous.

FIGURE-7. Dermatome, myotome, and sclerotome distribution for C6. Dermatome: lateral arm, lateral forearm, and lateral hand. Myotome: paraspinals, shoulder adductors, elbow flexors, forearm pronators, forearm supinators, and wrist flexors. Sclerotome: bones–scapula, humerus, radius, and lateral fingers; joints–facet, shoulder, and elbow; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-8. Dermatome, myotome, and sclerotome distribution for C7. Dermatome: midhand and middle finger. Myotome: paraspinals, elbow extensors, forearm pronators, and wrist extensors. Sclerotome: bones– scapula, humerus, radius, ulna, and middle fingers; joints–facet and wrist; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-9. Dermatome, myotome, and sclerotome distribution for C8. Dermatome: medial forearm and medial hand. Myotome: paraspinals, elbow extensors, wrist flexors, grip, finger abduction, finger flexion, finger adduction, finger opposition, and finger extension. Sclerotome: bones– vertebra and periosteum, ulna, and medial fingers; joints–facet and wrist; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-10. Dermatome, myotome, and sclerotome distribution for T1. Dermatome: medial arm and medial forearm. Myotome: paraspinals, finger adduction, finger flexion, finger abduction, finger opposition, and finger extension. Sclerotome: bones–vertebra and periosteum, ulna, and medial fingers; joints–facet; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-11. Dermatome, myotome, and sclerotome distribution for L1. Dermatome: groin and flank. Myotome: paraspinals, hip flexors, spine extensors, and spine rotators. Sclerotome: bones–vertebra and periosteum; joints–facet; ligaments– longitudinal, ligamentum flavum, interspinous. Serosal surface: abdominal wall. Viscera: large intestine, kidney, ureter, suprarenal, prostate, and uterus.

FIGURE-12. Dermatome, myotome, and sclerotome distribution for L2. Dermatome: thigh and upper buttock. Myotome: paraspinals, hip flexors, and hip adductors. Sclerotome: bones–vertebra and periosteum, iliac crest, and medial femur; joints–facet; ligaments–longitudinal, ligamentum flavum, and interspinous. Serosal surface: posterior abdominal wall, descending large intestine, ureter, bladder, and abdominal aorta.

FIGURE-13. Dermatome, myotome, and sclerotome distribution for L3. Dermatome: upper buttock, medial thigh, knee, and medial calf. Myotome: paraspinals, hip flexors, hip adductors, and knee extensors. Sclerotome: bones–iliac crest, ischium, femur, patella, and proximal tibia; joints–facet, hip, and knee; ligaments–longitudinal, ligamentum flavum, and interspinous. Serosal surface: posterior abdominal wall. Viscera: abdominal aorta.

FIGURE-14. Dermatome, myotome, and sclerotome distribution for L4. Dermatome: knee, anterior lower leg, and medial foot. Myotome: hip adductors, hip extensors, knee extensors, ankle dorsiflexors, and ankle invertors. Sclerotome: bones– vertebra and periosteum, iliac wing, femur, tibia, and medial foot; joints–facet, hip, and knee; ligaments–longitudinal, ligamentum flavum, and interspinous. Serosal surface: posterior abdominal wall. Viscera: abdominal aorta.

FIGURE-15. Dermatome, myotome, and sclerotome distribution for L5. Dermatome: lateral lower leg, medial foot. Myotome: paraspinals, hip extension, knee flexion, ankle eversion, ankle inversion, and big toe extension. Sclerotome: bones– vertebra and periosteum, iliac wing, femur, tibia, proximal fibula, and medial foot; joints–facet, sacroiliac, hip, knee, ankle, and large toe; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-16. Dermatome, myotome, and sclerotome distribution for S1. Dermatome: posterior lower leg, lateral lower leg, and lateral foot. Myotome: hip extensors, hip abductors, knee flexors, ankle evertors, ankle plantar flexors, and toe dorsiflexors. Sclerotome: bones–vertebra and periosteum, sacrum, ischium, femur, tibia, and mid-foot; joints– sacroiliac, hip, knee, ankle, and large toe; ligaments–longitudinal, ligamentum flavum, and interspinous.

FIGURE-17. Dermatome, myotome, and sclerotome distribution for S2. Dermatome: posterior upper leg and posterior lower leg. Myotome: knee flexors, ankle plantar flexors, toe dorsiflexors, toe abduction, and toe adduction. Sclerotome: bones– sacrum, coccyx, distal fibula and lateral foot; joints–sacroiliac, ankle, and toes; ligaments–longitudinal, ligamentum flavum, and interspinous.

Dermatomes

Different techniques were used in determining the site and extent of innervation. Foerster’s (96) data were based on remaining sensibility of the skin innervated by an intact posterior root isolated by severing several nerve roots above and below. In determining the field of unaltered sensation, Foerster demonstrated considerable overlap of contiguous nerve roots. Similar techniques were used by Bing (97), the Armed Forces Institute of Pathology, and Haymaker and Woodhall (98). Keagan and Garrett (99) used hyposensitivity to pin scratch in cases of herniated intervertebral discs, which resulted in the most extensive dermatome map. Keagan and Garrett contended that no sensory overlap exists between dermatomes, which is contrary to most investigators’ experiences. Richter and Woodruff used the electrical skin resistance method (100,101) over sympathectomized areas of the skin. It is noted that dermatomes of almost all cutaneous nerves are beyond the anatomic boundaries noted on gross dissection. Clinical data suggest that areas of sensory deficit extend further proximally than mapped by Foerster, but not as far proximally as suggested by Keagan and Garrett. For this reason, the dermatomes used in the figures are derived from an interpolation of areas determined by personal experience and multiple other authors (96–104).

Myotomes

The determination of muscular innervation is the result of the analysis by many observers of traumatic and surgical outcomes evaluated during the postoperative and recovery periods (98,104,105). The results of these analyses are provided in detail in Tables 49-1 and 49-2. The myotomes used in these drawings are derived from the experience of multiple clinicians.

TABLE 1 Upper Extremity Muscle Innervation
Muscle Peripheral Nerve Spinal Segment
Levator scapulae Trapezius C3, C4
Serratus anterior Long thoracic nerve C3, C4, C5, C6, C7
Rhomboid major/minor Dorsal scapular (C4), C5
Supraspinatus Suprascapular C5, C6
Infraspinatus Suprascapular C5, C6
Latissimus dorsi Thoracodorsal C6, C7, C8
Teres major Lower subscapular C5, C6, C7
Teres minor Axillary C5, C6
Pectoralis major (clavicular) Lateral pectoral C5, C6, C7
Pectoralis major (sternal) Lateral/medial pectoral C6, C7, C8, T1
Deltoid Axillary C5, C6
Coracobachialis Musculocutaneous C6, C7
Biceps brachii Musculocutaneous C5, C6
Brachialis Musculocutaneousa C5, C6
Triceps Radial C6, C7, C8
Anconeus Radial C6, C7, C8
Brachioradialis Radial C5, C6
Extensor carpi radialis longus Radial C6, C7
Supinator Radial C5, C6, (C7)
Extensor digitorum communis Radial C7, C8
Extensor digiti minimi Radial C7, C8
Extensor carpi ulnaris Radial C7, C8
Abductor pollicis longus Radial C7, C8
Extensor pollicis brevis Radial C7, C8
Extensor pollicis longus Radial C7, C8
Extensor indicis Radial C7, C8
Pronator teres Median C6, C7
Flexor carpi radialis Median C6, C7, C8
Palmaris longus Median C7, C8, T1
Flexor digitorum superficialis Median C7, C8, T1
Flexor digitorum profundus I and II Median C7, C8, T1
Flexor pollicus brevis Median
Flexor pollicis longus Median C7, C8, T1
Pronator quadratus Median C8, T1
Abductor pollicis brevis Median C8, T1
Opponens pollicis Median C8, T1
Lumbrical I and II Median C8, T1
Flexor carpi ulnaris Ulnar C7, C8, T1
Flexor digitorum profundus III and IV Ulnar C7, C8, T1
Abductor digiti minimi Ulnar C8, T1
Palmar/dorsal interossei Ulnar C8, T1
Lumbrical III and IV Ulnar C8, T1
Adductor pollicis Ulnar C8, T1
Spinal segments in parentheses signify those that are occasionally present; those in boldface are the major segments supplying the muscle designated. Segments not in boldface are usually present but to a minor degree. a The small branch from the radial nerve also innervates the brachialis muscle.

Sclerotomes

Areas of segmental innervation of bone (sclerotomes) are closely linked with muscle innervation. Injury to bone, ligament, tendon, fascia, and other mesodermal structures of the body may result in pain referred in a sclerotomal distribution (98,106). Notable references for peripheral nerve innervation of the skeleton include Haymaker and Woodhall (98), Dejerine (107), Foerster (108), and Brash (109). The peripheral nervous system of the skeleton is closely linked to muscle innervation. Most of the bones of the skeleton receive their innervation from nerve twigs of the attached muscles. Some parts of the skeleton, especially the joints, receive branches directly from nerve trunks (99).

TABLE 2 Lower Extremity Muscle Innervation
Muscle Peripheral Nerve Spinal Segment
Psoas major Lumbar plexus L1, L2, L3
Illiacus Femoral L2, L3, L4
Sartorius Femoral L2, L3, L4
Quadriceps femoris Femoral L2, L3, L4
Adductor longus Obturator L2, L3, L4
Adductor brevis Obturator L2, L3, L4
Gracilis Obturator L2, L3, L4
Adductor magnus Obturator and sciatic L2, L3, L4, L5, S1
Gluteus medius Superior gluteal (L4), L5, S1
Gluteus minimus Superior gluteal (L4), L5, S1
Tensor fascia lata Superior gluteal (L4), L5, S1
Gluteus maximus Inferior gluteal L5, S1, S2
Biceps femoris (long head) Sciatic (tibial division) L5, S1, S2
Semitendinosus Sciatic (tibial division) L5, S1, S2
Semimembranosus Sciatic (tibial division) L4, L5, S1, S2
Biceps femoris (short head) Sciatic (peroneal division) L5, S1, S2
Tibialis anterior Peroneal L4, L5, S1
Extensor hallucis longus Peroneal L4, L5, S1
Extensor digitorum longus Peroneal L4, L5, S1
Peroneus tertius Peroneal L4, L5, S1
Extensor digitorum brevis Peroneal L5, S1
Peroneus longus Peroneal (L4), L5, S1
Peroneus brevis Peroneal L4, L5, S1
Gastrocnemius (medial head) Tibial L5, S1, S2
Gastrocnemius (lateral head) Tibial L5, S1
Soleus Tibial (L5), S1, S2
Tibialis posterior Tibial (L4), L5, S1
Flexor digitorum longus Tibial L5, S1
Flexor hallucis longus Tibial L5, S1, S2
Abductor hallucis Tibial (L5), S1, S2
Abductor digiti minimi Tibial S1, S2
Plantar/dorsal interossei Tibial S1, S2
Spinal segments in parentheses signify those that are occasionally present; those in boldface are the major segments supplying the muscle designated. Segments not in boldface are usually present but to a minor degree.

Autonomic Innervation

The peripheral component of the autonomic nervous system is concerned with innervation of visceral glands, blood vessels, and nonstriated muscle. The relationship to pain has been confined to the visceral components in this section (104,105,110–112).

 

REFERENCES

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

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

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

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

Effects of the inflammatory mediators

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

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

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

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

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

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

The Complex interaction of Inflammatory Mediators

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

Interleukin-1 beta

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

Interleukin-6

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

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

Interleukin – 8

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

Interleukin –10

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

Prostaglandins

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

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

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

Tumor necrosis factor alpha

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

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

Nitric Oxide

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

Substance P (sP)

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

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

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

Natural suppression of the inflammatory response and Gate Control

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

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

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

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

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

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

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

DISCUSSION

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

  1. Inflammation can exist without structural damage that is visible with our current imaging technology.
  2. Structural damage will result in inflammation and the inflammatory response
  3. Inflammation and the inflammatory response will produce structural damage Classification and treatment of pain syndromes should depend on the complex inflammatory profile and should not be based alone on symptomatology, structural pathology, genetic markers or presence of autoantibodies.
Table 1 - Inflammatory Mediator Profile of Pain Syndromes.
PAIN SYNDROME INFLAMMATORY PROFILE
Arthritis IL-1 Beta, IL-6, TNF-alpha
Back/Neck Pain (Herniated Disk) Prostaglandin, TNF-alpha, IL-1 Beta
Bursitis / Tendonitis Prostaglandin, IL-1 Beta
Fibromyalgia Substance P, IL-1 Beta, IL-6
Neuropathic Pain Substance P, Prostaglandin, IL-1 Beta, IL-6, TNF-alpha, Glutamate
Migraine Serotonin, Substance P
Osteoporosis IL-6, TNF-alpha
RSD/CRPS Substance P, IL-1 Beta, IL-6, TNF-alpha,Glutamate
Note that these mediators as well as other mediators may be present in varying quantities at varying times in any pain syndrome.

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

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

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

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

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

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

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

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

Principles for Treatment of Pain Syndromes

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

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

CONCLUSION

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

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

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

REFERENCES

(ĐTĐ) - The gate control theory of pain was developed by Melzack and Wall to account for mechanisms by which other cutaneous stimuli and emotional states alter the level of pain.

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They suggested that within the substantia gelatinosa of the dorsal horn, there are interneurons that presynaptically inhibit transmission of nociceptive information to the ascending tracts. These interneurons are activated by large-diameter afferents and inhibited by small-diameter afferents. In addition, they suggested that the brain exerts descending control on this system, relying on the fact that cognitive factors are known to influence pain behavior.

Several studies have failed to provide support for the gate control theory. It remains significant, although incorrect in detail, in hypothesizing that nociceptive pain undergoes dynamic integration and modulation. The gate control theory of pain has altered the concept of pain as solely an afferent sensory experience, broadening the concept to include the affective and motivational factors involved in the human pain experience. The gate control theory has been modified extensively during the past 40 years. It still represents the first attempt to describe a pain-modulating system that responds to input by noxious stimuli, innocuous afferent impulses, and descending control.

Gate Control Pain Theory explains why thoughts and emotions influence pain perception, Ronald Melzack and Patrick Wall proposed that a gating mechanism exists within the dorsal horn of the spinal cord. Small nerve fibers (pain receptors) and large nerve fibers ("normal" receptors) synapse on projection cells (P), which go up the spinothalamic tract to the brain, and inhibitory interneurons (I) within the dorsal horn.

The interplay among these connections determines when painful stimuli go to the brain:

  1. When no input comes in, the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed).
  2. Normal somatosensory input happens when there is more large-fiber stimulation (or only large-fiber stimulation). Both the inhibitory neuron and the projection neuron are stimulated, but the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed).
  3. Nociception (pain reception) happens when there is more small-fiber stimulation or only small-fiber stimulation. This inactivates the inhibitory neuron, and the projection neuron sends signals to the brain informing it of pain (gate is open).

Descending pathways from the brain close the gate by inhibiting the projector neurons and diminishing pain perception.

This theory doesn't tell us everything about pain perception, but it does explain some things. If you rub or shake your hand after you bang your finger, you stimulate normal somatosensory input to the projector neurons. This closes the gate and reduces the perception of pain.

Law of Pain: The Prior Theories - We are proposing a unifying theory or law of pain, which states: The origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters.
 

Abstract

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

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

At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization.

Keywords: inflammation, cytokine, interleukin 1 beta, tumor necrosis factor alpha, sympathetic nerve block, sympathectomy, lumbar block, stellate ganglion, non-steroidal anti-inflammatory drugs (NSAIDs), Steroid, Etanercept, Anakinra, Oxcarbazepine, Ketamine, arthritis, migraine, Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD), back pain, neck pain, herniated disks, migraine, Fibromyalgia, Interstitial cystitis, Neuropathic pain, Post-stroke pain

Description of the Prior Theories

The prior theories do not contain any unifying Law of Pain. Each disease entity e.g. fibromyalgia, Complex Regional Pain Syndrome/Reflex Sympathetic Dystrophy (RSD/CRPS), carpal tunnel syndrome, rheumatoid arthritis and ankylosing spondylitis is considered distinct from the other entities and is classified in terms of symptomatology, structural pathology, genetic markers, presence of autoantibodies e.t.c. The prior theories assign a different mechanism to nociceptive and neuropathic pain, a different mechanism to acute and chronic pain, and a different mechanism to peripheral and central pain. The prior theories result in a treatment of pain syndromes that focuses mainly on structural pathology. Where present, treatment of inflammation in these disease entities has hitherto addressed one biochemical mediator of inflammation at a time (mostly focused on prostaglandin), instead of addressing the inflammatory soup of biochemical mediators that are present in all pain syndromes.

Four centuries ago Descartes described pain in terms of an alarm bell ringing in a bell tower. In 1898, in his landmark work, The Integrative Action of the Nervous System[1], the British physiologist, Sir Charles Scott Sherrington, proposed the key concept of nociception: pain as the evolved response to a potentially harmful, "noxious" stimulus.. Livingston wrote in his Pain Mechanisms [2]: "I believe that the concept of 'specificity' in the narrow sense in which it is sometimes used has led away from a true perspective. Pain is a sensory experience that is subjective and inpidual; it frequently exceeds its protective function and becomes destructive. The impulses, which subserve it, are not pain, but merely a part of its underlying and alterable physical mechanisms. The specificity of function of neuron units cannot be safely transposed into terms of sensory experience. A chronic irritation of sensory nerves may initiate clinical states that are characterized by pain and a spreading disturbance of function in both somatic and visceral structures. If such disturbances are permitted to continue, profound and perhaps unalterable organic changes may result in the affected part. A vicious circle is thus created[3].

In 1942 Paul Sudeck suggested that the signs and symptoms of RSD/CRPS including sympathetic hyperactivity might be provoked by an exaggerated inflammatory response to injury or operation of an extremity. His theory found no followers, as many doctors incorrectly believe that RSD/CRPS is solely initiated by a hyperactive sympathetic system.

In 1965, collaboration between Canadian psychologist Ronald Melzack and British physiologist Patrick Wall produced the gate control theory. Their paper, "Pain Mechanisms: A New Theory,[4] has previously been described as "the most influential ever written in the field of pain. " Melzack and Wall suggested a gating mechanism within the spinal cord (substantia gelatinosa of the dorsal horns) that closed in response to normal stimulation of the fast conducting A-beta "touch" nerve fibers; but opened when the slow conducting C "pain" fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers. By opening or closing in varying degrees, the neural gate modulates incoming pain signals before they reach the brain. The opening and closing of the gate is determined by the amount of activity in the pain fibers, the amount of activity in other peripheral fibers, activity of descending inhibitory pathways from neurons in the brainstem and cortex. In summary, the Gate Theory proposed that small (C) fibres activated excitatory systems that excited output cells—these latter cells had their activity controlled by the balance of large-fibre (A-beta) mediated inhibitions and were under the control of descending systems. Wall went on to add to and refine the theory to include changes in afferents, prolonged central excitability, and changes in these systems after nerve damage. The concepts of convergence and modulation espoused by the Gate Control Theory reduced the emphasis on destruction of pathways and led to the idea that pain could be controlled by modulation—reduce excitation or increase inhibition. The Gate Control Theory explains why massage or applying heat reduces some pain and why people who are hypnotized or distracted may not notice pain. However, in a 1965 article, Melzack himself stated that the gate control theory is not able to explain several chronic pain problems[5]. The Gate Control theory does not provide an explanation of the biochemical and molecular mechanism of neuronal activation and transmission, does not explain the pathophysiology of pain syndromes and does not provide a road map for treatment of all pain syndromes.

More recently, Pain is currently defined by the International Association for the Study of Pain (IASP) as 'an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage'. This definition was adapted in 1979, and published in the paper 'Pain terms; a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy', in the journal Pain in 1979[6]. This definition was subsequently considered elusive, and the following statement was added in order to make the position more clear: 'Pain is always subjective. Each inpidual learns the application of the word through experiences related to injury in early life. It is unquestionably a sensation in a part of the body but it is also unpleasant and therefore also an emotional experience. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is no way to distinguish their experience from that due to tissue damage, if we take the subjective report. If they regard their experience as pain and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. This definition avoids tying pain to the stimulus…’

Pain is also currently classified as being peripheral or central in origin. Peripheral pain originates in muscles, tendons, etc., or in the peripheral nerves. Pain originating in the peripheral nerves, i.e. via trauma to the nerves, is classified as neurogenic pain. Central pain is currently thought to arise from central nervous system pathology: a "primary" CNS dysfunction. Some of this has been thought to arise due to maladaptive thought processes, true "psychogenic" pain[7]. But most of it has been thought to be due to structural changes in the CNS, e.g., spinal cord injury, multiple sclerosis, stroke and epilepsy (Boivie, 1996)[8] [9].

Another current classification, that distinguishes between normally functioning nerves and nerves whose function has been altered by pathology is as follows: Nociceptive pain is pain in which normal nerves transmit information to the central nervous system about trauma to tissues. Neuropathic pain is pain in which there are structural and/or functional nervous system adaptations secondary to injury, that take place either centrally or peripherally (Jensen, 1996)[10]. The IASP defines central pain as "pain initiated or caused by a primary lesion or dysfunction in the central nervous system" (Merskey, and Bogduk, 1994)[11].

Current theories of Pain state that physiological pain arises from damage to tissue (inflammatory pain), whereas neuropathic pain results from changes in damaged nerves[12]. When tissue is damaged, peripheral chemicals sensitize the sensory endings and after neuropathic pain, excitability changes occur within the nerve itself. These peripheral changes then alter activity in central systems[13]. The current theories further state that inflammation will produce peripheral sensitization[14] in that the system will be driven harder for a given stimulus. Ongoing ectopic activity in damaged peripheral nerves will continually produce transmitter release into the spinal cord, and this will cause subsequent neuronal activity[13].[15] [16] After tissue and nerve injury, there are increases in the activity of calcium channels within the spinal cord responsible for both presynaptic transmitter release and postsynaptic neuronal excitability. Current theories on wind-up and central sensitization explain central pain on the basis of augmented transmitter release, an increased release of glutamate and enhanced activation of the glutamate receptors for glutamate, especially the N-methyl-D-aspartate (NMDA) receptor.[13] Central sensitization is said to occur when peripheral sensory neuron activity drives central spinal systems that amplify and prolong the incoming sensory messages.

The variations in the current treatment of pain syndromes reflect a lack of a unifying theory of pain. Depending on the physician, a patient with severe back pain and an MRI showing a 4 mm herniated disc may be given heat or cold therapy, trigger point injections, epidural steroid injections, radiofrequency (RF) neurotomy, cryotherapy of the lumbar facet medial branch nerve, heating of the intervertebral disk with intradiscal electro-thermal therapy (IDET), spinal cord stimulation, implantation of an intrathecal infusion pump, surgical laminectomy or surgical fusion. This demonstrates significant differences in understanding of the pathophysiology and treatment of pain syndromes. 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 osteoarthritis or herniated disk on MRI scans get operated upon often times needlessly and end up with more joint, back or neck pain. Patients with severe pain who do not have structural abnormalities on MRI scans e.g. patients with fibromyalgia are referred for psychiatric intervention. The fallacy of this approach has been confirmed in numerous published studies. In one of these studies[17], the authors performed magnetic resonance imaging on sixty-seven inpiduals 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[18], 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[19], which tracked the natural history of inpiduals with asymptomatic disc abnormalities in magnetic resonance imaging the authors stated that the high rate of lumbar disc alterations recently detected in asymptomatic inpiduals by magnetic resonance imaging demands reconsideration of a pathomorphology-based explanation of low back pain and sciatica. . In another controlled trial of arthroscopic surgery for osteoarthritis of the knee[20], 180 patients with osteoarthritis of the knee were randomly assigned to receive arthroscopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment-group assignment. Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores — three on scales for pain and two on scales for function — and one objective test of walking and stair climbing. A total of 165 patients completed the trial. The study results were astounding. At no point did either of the intervention groups report less pain or better function than the placebo group. For example, mean (±SD) scores on the Knee-Specific Pain Scale (range, 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and débridement groups: 48.9±21.9, 54.8±19.8, and 51.7±22.4, respectively, at one year (P=0.14 for the comparison between placebo and lavage; P=0.51 for the comparison between placebo and débridement) and 51.6±23.7, 53.7±23.7, and 51.4±23.2, respectively, at two years (P=0.64 and P=0.96, respectively). Furthermore, the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinically meaningful difference. The authors concluded that in this controlled trial involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure. This is further confirmation of the fallacy of a structure-based approach to the treatment of pain.

Medical treatment of pain syndromes has vastly improved with a greater recognition of the need to effectively control pain through the use of a variety of medications including NSAIDs, Corticosteroids, Opioids, Anti-seizure drugs, Antidepressants e.t.c. However the vast majority of physicians have no experience in the utilization of inflammatory mediator blockers in the treatment of pain syndromes.

REFERENCES

(ĐTĐ) - Pain is a central perception of multiple primary sensory modalities. This interpretive function is complex, involving psychological, neuroanatomic, neurochemical, and neurophysiologic factors of both the pain stimulus and the memory of past pain experiences.

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The peripheral mechanisms for sensing and modulating pain have been extensively studied during the past 30 years. The pathways for pain sensation, from the initial stimulus of the nociceptors to the central nervous system, are summarized in Figure-1. There appear to be several descending systems that play a role in control of the modification of the ascending pain pathways, which are summarized in Figure-2.

FIGURE-1. Central nervous system structures that modify ascending pain pathways. H, hypothalamus; IL, intralaminar thalamic nuclei; L, limbic system.

Polymodal nociceptors respond to stimuli that damage tissue. This stimulation results in impulses ascending in the A-delta or C fibers to the marginal layers of the dorsal horn of the spinal cord. The A-delta fibers primarily synapse in laminae I and V, whereas C fibers synapse primarily in lamina II. Deeper regions of the dorsal horn may be polysynaptically involved in the processing of noxious stimuli.

FIGURE-2. Ascending pathways for pain sensation from nociceptors to the central nervous system. H, hypothalamus; IL, intralaminar thalamic nuclei; L, limbic system; PT, posterior thalamic nuclei; VPL, ventral posterolateral thalamic nuclei.

The major ascending nociceptive pathways are the spinothalamic and spinoreticular tracts, which involve both oligosynaptic and polysynaptic neurons. These oligosynaptic pathways are fast conducting, with discrete somatotopic organization resulting in rapid transmission of nociceptive information regarding site, intensity, and duration of stimulus. Further, the oligosynaptic tracts provide somatic information by way of the posterior ventral nuclei of the thalamus to the postcentral cortex. The sensory discriminatory characteristics are delineated from the neospinothalamic portion of the lateral spinothalamic tract and the nonproprioceptive portion of the dorsal columns.

Polysynaptic pathways are slow conducting, with a lack of somatotopic organization resulting in poor localization as well as dull aching and burning sensations. The nociceptive impulses transmitted through this system result in suprasegmental reflex responses related to ventilation, circulation, and endocrine function. Pathways contributing to this slowconducting system are the paleospinothalamic tract, spinoreticular, spinocollicular, and the dorsal intercornual, as well as the spinomesencephalic tracts. The polysynaptic tracts form the brain stem reticular activating system with projections to the medial and interlaminar nuclei of the thalamus. From these nuclei, diffuse radiation occurs to the cerebral cortex, limbic system, and basal ganglia.

There are multiple levels of processing and convergence of nociceptive information in its ascending transmission to the cerebral cortex. In addition, there appear to be several descending pain control systems that play a role in the control and modification of the ascending pain pathways. The most complete studies have been of the periaqueductal gray (PAG) region of the midbrain. Stimulation of the PAG neurons and the subsequent descending impulses result in release of endogenous opioids at the nucleus raphe magnus (NRM) and nucleus locus ceruleus (NLC). Endogenous opioids activate the serotonergic cells in the NRM and norepinergic neurons in the NLC. The axons of both of these monoaminergic neurons descend in the dorsolateral tract to interneurons, predominantly in laminae I, II, and V. These monoamines activate opioid-secreting interneurons. The morphine-like transmitter released may vary, depending on what type of receptor in the periphery has been activated. Both A-delta and C afferent fibers are inhibited by descending influences in the dorsal horn. The opioid inhibitory interneurons may be influenced by intersegmental and descending pathways, but the intersegmental and segmental mechanisms have not been established. These interneurons may function either by presynaptic inhibition on the terminals with the primary nociceptive afferents preventing the release of substance P or by postsynaptic inhibition on second-order neurons. Cells in the raphe magnus are activated by ascending sensory pathways transmitted to the reticular formation as well as by descending input from cells in the PAG region.

Other descending monoamine systems include locus ceruleus to the dorsal horn interneurons, nucleus reticularis, magnicellularis to the dorsal horn interneurons, and the mesencephalic lateral reticular formation to the dorsal horn interneurons. It has been suggested that monoamines are involved with supraspinal and spinal nociceptive mechanisms. Hormonally based descending pathways have been described but are poorly understood.

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