The biochemical origin of pain – Proposing a new law of pain part1 of 3

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The biochemical origin of pain Proposing a newlaw of pain: The origin of all pain is inflammationand the inflammatory response. Part 1 of 3 Aunifying law of pain q

Sota Omoigui *

Division of Inflammation and Pain Research, L.A Pain Clinic, 4019 W. Rosecrans Avenue, Los Angeles,

CA 90250, United States

Received 13 November 2006; accepted 17 November 2006

Summary We are proposing a unifying theory or law of pain, which states: the origin of all pain is inflammation andthe inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growthfactors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or centralpain, 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 onecontinuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it issharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatoryresponse. 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 thepain syndrome; 2. Inhibition or suppression of production of the appropriate inflammatory mediators, e.g. withinflammatory mediator blockers or surgical intervention where appropriate; 3. Inhibition or suppression of neuronalafferent and efferent (motor) transmission, e.g. with anti-seizure drugs or local anesthetic blocks; 4. Modulation ofneuronal transmission, e.g. with opioid medication.

At theL.A. PainClinic, we have successfullytreated a varietyof pain syndromesby utilizingtheseprinciples.Thistheoryof the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of themechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and centralsensitization.

c 2006 Elsevier Ltd. All rights reserved.

0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2006.11.028

q The paper is not under consideration elsewhere and none of the papers contents have been previously published. All authors haveread and approved the manuscript. Work was done at the L.A. Pain Clinic. The study was not supported by any grant. There is noconflict of interest.

* Tel.: +1 310 675 9121; fax: +1 310 675 7989.E-mail address: [email protected]

Medical Hypotheses (2007) 69, 7082

http://intl.elsevierhealth.com/journals/mehy
mailto:[email protected]:[email protected]


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Description of the prior theories

Prior theories The prior theories do not containany unifying Law of Pain. Each disease entity,e.g. fibromyalgia, Complex Regional Pain Syn-drome/Reflex Sympathetic Dystrophy (RSD/CRPS),carpal tunnel syndrome, rheumatoid arthritis and

ankylosing spondylitis is considered distinct fromthe other entities and is classified in terms of symp-tomatology, structural pathology, genetic markers,presence of autoantibodies, etc. The prior theoriesassign a different mechanism to nociceptive andneuropathic pain, a different mechanism to acuteand chronic pain, and a different mechanism toperipheral and central pain. The prior theories re-sult in a treatment of pain syndromes that focusesmainly on structural pathology. Where present,treatment of inflammation in these disease entitieshas hitherto addressed one biochemical mediatorof inflammation at a time (mostly focused on pros-taglandin), instead of addressing the inflammatorysoup of biochemical mediators that are present inall pain syndromes.

Four centuries ago Descartes described pain interms of an alarm bell ringing in a bell tower. In1898, in his landmark work, The Integrative Actionof the Nervous System [1], the British physiologist,Sir Charles Scott Sherrington, proposed the keyconcept of nociception: pain as the evolved re-sponse to a potentially harmful, noxious stimu-lus. Livingston wrote in his Pain Mechanisms [2]:I believe that the concept of specificity in the

narrow sense in which it is sometimes used hasled away from a true perspective. Pain is a sensoryexperience that is subjective and individual; it fre-quently exceeds its protective function and be-comes destructive. The impulses, which subserveit, are not pain, but merely a part of its underlyingand alterable physical mechanisms. The specificityof function of neuron units cannot be safely trans-posed into terms of sensory experience. A chronicirritation of sensory nerves may initiate clinicalstates that are characterized by pain and a spread-ing disturbance of function in both somatic and vis-

ceral structures. If such disturbances are permittedto continue, profound and perhaps unalterable or-ganic changes may result in the affected part. A vi-cious circle is thus created [3].

In 1942 Paul Sudeck suggested that the signs andsymptoms of RSD/CRPS including sympathetichyperactivity might be provoked by an exaggeratedinflammatory response to injury or operation of anextremity. His theory found no followers, as manydoctors incorrectly believe that RSD/CRPS is solelyinitiated by a hyperactive sympathetic system.

In 1965, collaboration between Canadian psy-chologist Ronald Melzack and British physiologistPatrick Wall produced the gate control theory.Their paper, Pain Mechanisms: A New Theory[4], has previously been described as the mostinfluential ever written in the field of pain. Mel-zack and Wall suggested a gating mechanism within

the spinal cord (substantia gelatinosa of the dorsalhorns) that closed in response to normal stimula-tion of the fast conducting A-b touch nerve fi-bers; but opened when the slow conducting Cpain fibers transmitted a high volume and inten-sity of sensory signals. The gate could be closedagain if these signals were countered by renewedstimulation of the large fibers. By opening or clos-ing in varying degrees, the neural gate modulatesincoming pain signals before they reach the brain.The opening and closing of the gate is determinedby the amount of activity in the pain fibers, theamount of activity in other peripheral fibers, activ-

ity of descending inhibitory pathways from neuronsin the brainstem and cortex. In summary, the GateTheory proposed that small (C) fibers activatedexcitatory systems that excited output cells these latter cells had their activity controlled bythe balance of large-fiber (A-b) mediated inhibi-tions and were under the control of descending sys-tems. Wall went on to add to and refine the theoryto include changes in afferents, prolonged centralexcitability, and changes in these systems afternerve damage. The concepts of convergence andmodulation espoused by the gate control theory re-

duced the emphasis on destruction of pathways andled to the idea that pain could be controlled bymodulation reduce excitation or increase inhibi-tion. The gate control theory explains why massageor applying heat reduces some pain and why peoplewho are hypnotized or distracted may not noticepain. However, in a 1965 article, Melzack himselfstated that the gate control theory is not able toexplain several chronic pain problems [5]. The gatecontrol theory does not provide an explanation ofthe biochemical and molecular mechanism of neu-ronal activation and transmission, does not explainthe pathophysiology of pain syndromes and doesnot provide a road map for treatment of all painsyndromes.

More recently, Pain is currently defined by theInternational Association for the Study of Pain(IASP) as an unpleasant sensory or emotional expe-rience associated with actual or potential tissuedamage, or described in terms of such damage.This definition was adapted in 1979, and publishedin the paper Pain terms; a list with definitions andnotes on usage. Recommended by the IASP

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Subcommittee on Taxonomy, in the journal Pain in1979 [6]. This definition was subsequently consid-ered elusive, and the following statement wasadded in order to make the position more clear:Pain is always subjective. Each individual learnsthe application of the word through experiencesrelated to injury in early life. It is unquestionably

a sensation in a part of the body but it is alsounpleasant and therefore also an emotional experi-ence. Many people report pain in the absence oftissue damage or any likely pathophysiologicalcause; usually this happens for psychological rea-sons. There is no way to distinguish their experi-ence from that due to tissue damage, if we takethe subjective report. If they regard their experi-ence as pain and if they report it in the same waysas pain caused by tissue damage, it should be ac-cepted as pain. This definition avoids tying painto the stimulus. . .

Pain is also currently classified as being periphe-

ral or central in origin. Peripheral pain originates inmuscles, tendons, etc., or in the peripheral nerves.Pain originating in the peripheral nerves, i.e. viatrauma to the nerves, is classified as neurogenicpain. Central pain is currently thought to arise fromcentral nervous system pathology: a primaryCNS dysfunction. Some of this has been thoughtto arise due to maladaptive thought processes, truepsychogenic pain [7]. But most of it has beenthought to be due to structural changes in theCNS, e.g. spinal cord injury, multiple sclerosis,stroke and epilepsy [8,9].

Another current classification, that distinguishesbetween normally functioning nerves and nerveswhose function has been altered by pathology isas follows: Nociceptive pain is pain in which normalnerves transmit information to the central nervoussystem about trauma to tissues. Neuropathic pain ispain in which there are structural and/or func-tional nervous system adaptations secondary to in-jury, that take place either centrally orperipherally [10]. The IASP defines central pain aspain initiated or caused by a primary lesion ordysfunction in the central nervous system [11].

Current theories of Pain state that physiologicalpain arises from damage to tissue (inflammatorypain), whereas neuropathic pain results fromchanges in damaged nerves [12]. When tissue isdamaged, peripheral chemicals sensitize the sen-sory endings and after neuropathic pain, excitabilitychanges occur within the nerve itself. These periph-eral changes then alter activity in central systems[13]. The current theories further state that inflam-mation will produce peripheral sensitization [14] inthat the system will be driven harder for a givenstimulus. Ongoing ectopic activity in damaged

peripheral nerves will continually produce transmit-ter release into the spinal cord, and this will causesubsequent neuronal activity [13,15,16]. After tis-sue and nerve injury, there are increases in theactivity of calcium channels within the spinal cordresponsible for both presynaptic transmitter releaseand postsynaptic neuronal excitability. Current the-

ories on wind-up and central sensitization explaincentral pain on the basis of augmented transmitterrelease, an increased release of glutamate and en-hanced activation of the glutamate receptors forglutamate, especially the N-methyl-D-aspartate(NMDA) receptor [13]. Central sensitization is saidto occur when peripheral sensory neuron activitydrives central spinal systems that amplify and pro-long the incoming sensory messages.

The variations in the current treatment of painsyndromes reflect a lack of a unifying theory ofpain. Depending on the physician, a patient withsevere back pain and an magnetic resonance imag-

ing (MRI) showing a 4 mm herniated disc may be gi-ven heat or cold therapy, trigger point injections,epidural steroid injections, radiofrequency (RF)neurotomy, cryotherapy of the lumbar facet med-ial branch nerve, heating of the intervertebral diskwith intradiscal electro-thermal therapy (IDET),spinal cord stimulation, implantation of an intra-thecal infusion pump, surgical laminectomy or sur-gical fusion. This demonstrates significantdifferences in understanding of the pathophysiol-ogy and treatment of pain syndromes. Currentmedical theories place an over reliance on struc-

tural abnormalities to explain pain syndromes. Thisis not surprising because our current imaging tech-nologies are structure based. Physicians are com-fortable treating what they see. Patients whohave structural abnormalities such as an osteoar-thritis or herniated disk on MRI scans get operatedupon often times needlessly and end up with morejoint, back or neck pain. Patients with severe painwho do not have structural abnormalities on MRIscans, e.g. patients with fibromyalgia are referredfor psychiatric intervention. The fallacy of this ap-proach has been confirmed in numerous publishedstudies. In one of these studies [17], the authorsperformed magnetic resonance imaging on 67 indi-viduals who had never had low-back pain, sciatica,or neurogenic claudication. The scans were inter-preted independently by three neuro-radiologistswho had no knowledge about the presence or ab-sence of clinical symptoms in the subjects. Aboutone-third of the subjects were found to have a sub-stantial abnormality. Of those who were less than60 years old, 20% had a herniated nucleus pulposusand one had spinal stenosis. In the group that was60 years old or older, the findings were abnormal

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on about 57% of the scans: 36% of the subjects hada herniated nucleus pulposus and 21% had spinalstenosis. There was degeneration or bulging of adisc at least one lumbar level in 35% of the subjectsbetween 20 and 39 years old and in all but one ofthe 60- to 80-year-old subjects. In view of thesefindings in asymptomatic subjects, the authors con-

cluded that abnormalities on magnetic resonanceimages must be strictly correlated with age andany clinical signs and symptoms before operativetreatment is contemplated. In another study [18],the authors examined the prevalence of abnormalfindings on MRI scans of the lumbar spine in peoplewithout back pain. 52% of the asymptomatic sub-jects were found to have a bulge at least at one le-vel, 27% had a protrusion, and 1% had an extrusion.Thirty-eight percent had an abnormality of morethan one intervertebral disk. The prevalence ofbulges, but not of protrusions, increased withage. The most common nonintervertebral disk

abnormalities were Schmorls nodes (herniation ofthe disk into the vertebral-body end plate), foundin 19% of the subjects; annular defects (disruptionof the outer fibrous ring of the disk), in 14%; and fa-cet arthropathy (degenerative disease of the pos-terior articular processes of the vertebrae), in 8%.The findings were similar in men and women. Theauthors concluded that on MRI examination of thelumbar spine, many people without back pain havedisk bulges or protrusions but not extrusions. Theauthors went further to state that given the highprevalence of these findings and of back pain, the

discovery by MRI of bulges or protrusions in peoplewith low back pain may frequently be coincidental.In another study [19], which tracked the naturalhistory of individuals with asymptomatic discabnormalities in magnetic resonance imaging theauthors stated that the high rate of lumbar discalterations recently detected in asymptomaticindividuals by magnetic resonance imaging de-mands reconsideration of a pathomorphology-based explanation of low back pain and sciatica.In another controlled trial of arthroscopic surgeryfor osteoarthritis of the knee [20], 180 patientswith osteoarthritis of the knee were randomly as-signed to receive arthroscopic debridement,arthroscopic lavage, or placebo surgery. Patientsin the placebo group received skin incisions andunderwent a simulated debridement without inser-tion of the arthroscope. Patients and assessors ofoutcome were blinded to the treatment-groupassignment. Outcomes were assessed at multiplepoints over a 24-month period with the use of fiveself-reported scores three on scales for pain andtwo on scales for function and one objective testof walking and stair climbing. A total of 165

patients completed the trial. The study resultswere astounding. At no point did either of theintervention groups report less pain or better func-tion than the placebo group. For example, mean(SD) scores on the Knee-Specific Pain Scale(range, 0 to 100, with higher scores indicating moresevere pain) were similar in the placebo, lavage,

and debridement groups: 48.9 21.9, 54.8 19.8,and 51.7 22.4, respectively, at 1 year (P= 0.14for the comparison between placebo and lavage;P= 0.51 for the comparison between placebo anddebridement) and 51.6 23.7, 53.7 23.7, and51.4 23.2, respectively, at 2 years (P= 0.64and P= 0.96, respectively). Furthermore, the 95%confidence intervals for the differences betweenthe placebo group and the intervention groups ex-clude any clinically meaningful difference. Theauthors concluded that in this controlled trialinvolving patients with osteoarthritis of the knee,the outcomes after arthroscopic lavage or arthro-

scopic debridement were no better than thoseafter a placebo procedure. This is further confirma-tion of the fallacy of a structure-based approach tothe treatment of pain.

Medical treatment of pain syndromes has vastlyimproved with a greater recognition of the needto effectively control pain through the use of avariety of medications including NSAIDs, Cortico-steroids, Opioids, Anti-seizure drugs, Antidepres-sants, etc. However, the vast majority ofphysicians have no experience in the utilization ofinflammatory mediator blockers in the treatment

of pain syndromes.

The biochemical origin of pain theory

We propose a Law of Pain which states that: Theorigin of all pain is inflammation and the inflamma-tory response [21]. This law unifies all painsyndromes as sharing a common origin of inflamma-tion and the inflammatory response. It is our theorythat nociceptive and neuropathic pain, acute andchronic pain, peripheral and central pain includingwindup, neuroplasticity and central sensitizationare a continuum of inflammation and the inflamma-tory response.

In all organisms, the cellular response to injury,infection and the aging process is inflammation andthe inflammatory response. Tissue injury may arisefrom a physical, chemical or biological trauma orirritation. Degeneration of tissue subsequent toaging or previous injury can also lead to inflamma-tion. Injured tissues can be muscle, ligament,disks, joints or nerves. A variety of mediators(cytokines, neuropeptides, growth factors and neu-rotransmitters) are generated by tissue injury and



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inflammation. These include substances producedby damaged tissue, substances of vascular originas well as substances released by nerve fibersthemselves, sympathetic fibers and various im-mune cells [22]. The biochemical mediators pro-duced by the immune cells include prostaglandin,nitric oxide, tumor necrosis factor a, interleukin

1-a, interleukin 1-b, interleukin-4, interleukin-6and interleukin-8, histamine, serotonin. The bio-chemical mediators produced by the nerve cellsinclude inflammatory protein Substance P, gluta-mate, calcitonin gene-related peptide (CGRP) neu-rokinin A and vasoactive intestinal peptide.

Cell enzymes that catalyze reaction pathwaysand generate these biochemical mediators ofinflammation include cyclooxygenase (COX),lipoxygenase (LOX). A cell enzyme that is activatedby inflammatory mediators such as TNF-a andinterleukin-1 is Gelatinase B or Matrix Metallo-Pro-teinase 9 (MMP-9). Once activated MMP-9 helps im-

mune cells migrate through the blood vessels toinflammatory sites or to metastatic sites. Acti-vated, MMP-9 can also degrade collagen in the ex-tra cellular matrix of articular bone and cartilageand is associated with joint inflammation and bonyerosions [23].

There are three phases of an inflammatory re-sponse: initiation, maintenance and termination.Upon tissue injury or painful stimulation, special-ized blood cells in the area such as basophils, mastcells and platelets release inflammatory mediatorsserotonin, histamine and nitric oxide. Subsequent

to the binding of serotonin to its receptor, thereis inflammation of the adjacent nerves and thenerve endings release short-lived inflammatorypeptide proteins such as substance P, calcitoningene-related peptide (CGRP). In addition, clottingfactors in the blood produce and activate potentinflammatory mediator peptide proteins calledneurokinin A, bradykinin, kallidin and T-kinin. Allof these proteins increase blood flow to the areaof injury, stimulate arachidonic acid metabolismto generate inflammatory mediators prostaglandinsand attract specialized immune cells to the area.The first immune cells to the area are tissue macro-phages, which provide the front line defenseagainst bacterial infection. Macrophages releasepowerful enzymes to digest any bacteria that arepresent and produce potent inflammatory chemicalmediators (called cytokines) to attract and acti-vate other cells of the immune system. Shortlythereafter the area of bacterial invasion or tissueinjury is invaded by the other immune cells, whichinclude white blood cells such as T helper cells,lymphocytes, neutrophils, eosinophils, and othercells such as fibroblasts and endothelial cells.

These immune cells respond to the chemical medi-ators, release destructive enzymes to kill anyinvading organism and release more chemicalmediators to attract more immune cells. A conse-quence of this immune response is tissue damage,pain and spasm. In a sense the initial immune reac-tion ignites a cascade of immune reactions and

generates an inflammatory soup of chemical medi-ators. These chemical mediators produced by theimmune cells include prostaglandin, nitric oxide,tumor necrosis factor a, interleukin 1-a, interleu-kin 1-b, interleukin-4, interleukin-6 and interleu-kin-8, histamine, serotonin. In the area of injuryand subsequently in the spinal cord, enzymes suchas cyclooxygenase increase the production of theseinflammatory mediators. These chemical media-tors attract tissue macrophages and white bloodcells to localize in an area to engulf (phagocytize)and destroy foreign substances. The chemicalmediators released during the inflammatory re-

sponse give rise to the typical findings associatedwith inflammation.

Effects of the inflammatory mediators

The inflammatory mediators activate local painreceptors and nerve terminals and produce hyper-sensitivity in the area of injury. Activity of themediators results in excitation of pain receptorsin the skin, ligaments, muscle, nerves and joints.Excitation of these pain receptors stimulate thespecialized nerves, e.g. C fibers and A-d fibers that

carry pain impulses to the spinal cord and brain.Subsequent to tissue injury, the expression of so-dium channels in nerve fibers is altered signifi-cantly thus leading to abnormal excitability in thesensory neurons. Nerve impulses arriving in thespinal cord stimulate the release of inflammatoryprotein Substance P. The presence of substance Pand other inflammatory proteins such as calcitoningene-related peptide (CGRP) neurokinin A andvasoactive intestinal peptide removes magnesiuminduced inhibition and enables excitatory inflam-matory proteins such as glutamate and aspartateto activate specialized spinal cord NMDA receptors.These results in magnification of all nerve trafficand pain stimuli that arrive in the spinal cord fromthe periphery. Activation of motor nerves that tra-vel from the spinal cord to the muscles results inexcessive muscle tension. More inflammatorymediators are released which then excite addi-tional pain receptors in muscles, tendons and jointsgenerating more nerve traffic and increased musclespasm. Persistent abnormal spinal reflex transmis-sion due to local injury or even inappropriate pos-tural habits may then result in a vicious circle

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between muscle hypertension and pain [24]. Sepa-rately, constant C-fiber nerve stimulation to trans-mission pathways in the spinal cord resulting ineven more release of inflammatory mediators butthis time within the spinal cord. The transcriptionfactor, nuclear factor-jB (NF-jB), plays a pivotalrole in regulating the production of inflammatory

cytokines [25]. Inflammation causes increased pro-duction of the enzyme cyclooxygenase-2 (Cox-2),leading to the release of chemical mediators bothin the area of injury and in the spinal cord. Wide-spread induction of Cox-2 expression in spinal cordneurons and in other regions of the central nervoussystem elevates inflammatory mediator prostaglan-din E2 (PGE2) levels in the cerebrospinal fluid. Themajor inducer of central Cox-2 upregulation isinflammatory mediator interleukin-1 in the CNS[26]. Basal levels of the enzyme phospholipase A2activity in the CNS do not change with peripheralinflammation. The central nervous system response

to pain can keep increasing even though the painfulstimulus from the injured tissue remains steady.This wind-up phenomenon in deep dorsal neu-rons can dramatically increase the injured personssensitivity to the pain.

Tissue injury with local release of inflammatorymediators produces an acute discharge in the sen-sory afferents innervating the injured or inflamedtissue. Activation of the polymodal nociceptiveafferents (C fibers) depolarizes populations of dor-sal horn wide dynamic range (WDR) neurons thatproject supraspinally. This output in turn evokes

a supraspinally organized escape behavior. Thehot plate test (thermal stimulus to the paw) orthe local injection of an irritant such as formalinor capsaicin where the unconditioned stimulusevokes a somatotopically directed behavior (e.g.withdrawal or licking) are behavioral paradigmsbelieved to reflect this underlying mechanism[27].

Electrophysiological studies have shown that thepersistent activation of spinal WDR neurons bysmall, but not large, afferents, will lead to a pro-gressive enhancement of the WDR response to eachsubsequent input, and an increase in the dimen-sions of the peripheral receptive field to whichthe spinal neuron will respond [28].

The neurotrophins are a family of growthpromoting proteins that are essential for the gener-ation and survival of nerve cells during develop-ment, neurotrophins promote growth of smallsensory neurons and stimulate the regeneration ofdamaged nerve fibers They consist of four mem-bers, nerve growth factor (NGF), brain derived neu-rotrophic factor (BDNF), neurotrophin-3 (NT-3) andneurotrophin 4/5 (NT-4/5).

Nerve growth factor and brain-derived neurotro-phic factor modulate the activity of a sodium chan-nel (NaN) that is preferentially expressed in painsignaling neurons that innervate the body (spinalcord dorsal root ganglion neurons) and face (tri-geminal neurons). Transection of a nerve fiber(axotomy) results in an increased production of

inflammatory cytokines and induces markedchanges in the expression of sodium channels with-in the sensory neurons [29]. Following axotomy thedensity of slow (tetrodotoxin-resistant) sodiumcurrents decrease and a rapidly repriming sodiumcurrent appears. The altered expression ofsodium channels leads to abnormal excitability inthe sensory neurons [30]. Studies have shown thatthese changes in sodium channel expression follow-ing axotomy may be attributed at least in part tothe loss of retrogradely transported nerve growthfactor [31].

In addition to effects on sodium channels, there

is a large reduction in potassium current subtypesfollowing nerve transection and neuroma forma-tion. Studies have shown that direct applicationof nerve growth factor to the injured nerve canprevent these changes [32].

Abnormal development of sensory-sympatheticconnections follow nerve injury, and contributeto the hyperalgesia (abnormally severe pain) andallodynia (pain due to normally innocuous stimuli).These abnormal connections between sympatheticand sensory neurons arise in part due to sproutingof sympathetic axons. Studies have shown that

sympathetic axons invade spinal cord dorsal rootganglia (DRG) following nerve injury, and activityin the resulting pericellular axonal baskets mayunderlie painful sympathetic-sensory coupling[33]. Sympathetic sprouting into the DRG may bestimulated by neurotrophins such as nerve growthfactor (NGF), brain derived neurotrophic factor(BDNF), neurotrophin-3 (NT-3) and neurotrophin4/5 (NT-4/5). Local tissue inflammation can alsoresult in pain hypersensitivity in neighboring unin-jured tissue (secondary hyperalgesia) by spreadand diffusion of the excess inflammatory mediatorsthat have been produced as well as by an increasein nerve excitability in the spinal cord (central sen-sitization). This can result in a syndrome compris-ing diffuse muscle pain and spasm, joint pain,fever, lethargy and anorexia.

The complex interaction of inflammatorymediators

The inflammatory mediators interact in a complexway to induce, enhance and propagate persistentpain. There are also natural anti-inflammatory



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mediators produced by the body to simmer downinflammation and the inflammatory response.

Interleukin-1b

This is a potent pain-generating mediator. Interleu-kin-1 b stimulates inflammatory mediators prosta-

glandin E2 (PGE2), cyclooxygenase-2 (COX-2) andmatrix metalloproteases (MMPs) production[34,35] interleukin-1 b is a significant catalyst incartilage damage. It induces the loss of proteogly-cans, prevents the formation of the cartilage ma-trix [36] and prevents the proper maintenance ofcartilage. Interleukin-1 b is a significant catalystin bone resorption. It stimulates osteoclasts cellsinvolved in the resorption and removal of bone[34,37,36].

Interleukin-6

This is another potent pain-generating inflamma-tory mediator. IL-6 is one of a family of cytokinescollectively termed the interleukin-6-type cyto-kines. The cytokines which make up this familyare IL-6, leukemia inhibitory factor (LIF), oncosta-tin-M (OSM), ciliary neurotrophic factor (CNTF),cardiotrophin-1 (CT-1), and interleukin-11 [38,39]. IL-6 is involved in a myriad of biologic pro-cesses, perhaps explaining its long list of synonyms(B-cell stimulatory factor-2, B cell differentiationfactor, T cell-replacing factor, interferon-b2, 26-kDa protein, hybridoma growth factor, interleukin

hybridoma plasmacytoma factor 1, plasmacytomagrowth factor, hepatocyte-stimulating factor,macrophage granulocyte-inducing factor 2, cyto-toxic T cell differentiation factor, thrombopoietin)[40]. Among its many functions, IL-6 plays an activerole in inflammation, immunology, bone metabo-lism, reproduction, arthritis, neoplasia, and aging.IL-6 expression is regulated by a variety of factors,including steroidal hormones, at both the tran-scriptional and post-transcriptional levels. IL-6 ap-pears to play an important role in bone metabolismthrough induction of osteoclastogenesis and osteo-clast activity [41,42]. In rodents, inhibition of IL-6gene expression is in part responsible for estro-gens ability to inhibit osteoclast activation [4346]. These findings are further supported by theobservation that IL-6 gene knockout mice are pro-tected from cancellous bone loss associated withovariectomy. IL-6 neutralizing antibody also blocksbone resorption induced by a variety of agentsincluding TNF [47]. In addition to increasing osteo-clast numbers, IL-6 has been shown to stimulatebone resorption in rat long bones [48] and fetalmouse metacarpi [49], calvaria [50], and bone

resorption pit assays [51,52]. Although it is notclear that IL-6 alone is sufficient to mediate theseactivities [53], these data demonstrate the impor-tance of IL-6 in enhancing osteoclastic activity thusproviding a mechanism for IL-6 promoting osteopo-rosis. IL-1 b may induce IL-6 production in humanosteoblasts (MG-63 cells) by the following sequence

of steps: IL-1 b-induced COX-2 activation, prosta-glandin E(2) production, and PGE receptor-1 (EP-1receptor) signaling prior to IL-6 production [54].IL-6 functions in a wide variety of other systemsincluding the reproductive system by participatingin the menstrual cycle [55] and spermatogenesis,skin proliferation, megakaryocytopoiesis, macro-phage differentiation, and neural cell differentia-tion and proliferation [56]. A significant amountof interleukin-6 is produced in the rat spinal cordfollowing peripheral nerve injury that results inpain behaviors suggestive of neuropathic pain.These spinal IL-6 levels correlated directly with

the mechanical allodynia intensity following nerveinjury [57]. During times of stress or inflammationIL-6 levels are increased. Inflammatory joint dis-ease, particularly rheumatoid arthritis [58], is asso-ciated with increased synovial fluid levels of IL-6[59].

Interleukin-6 is the primary chemical mediatorinvolved in bone inflammation and bone pain.Interleukin-6 increases the activity of the osteo-clasts and leads to excessive breakdown of bone,leakage of calcium into the blood, loss of bone den-sity and bone inflammation, which is associated

with bone pain. Interleukin-6 production is in-creased by interleukin-1b and tumor necrosis fac-tor a. Patients with rheumatoid arthritis (RA)develop both generalized and periarticular osteo-porosis. Both of them are believed to be associatedwith increased production of inflammatory cyto-kines (TNF-a, IL-1 b, IL-6) and increased formationand activation of osteoclasts [60].

Interleukin-8

This is a pain-generating inflammatory mediator. Inone study of patients with post-herpetic neuralgia,the patients who received methylprednisolone, hadinterleukin-8 concentrations decrease by 50%, andthis decrease correlated with the duration of neu-ralgia and with the extent of global pain relief[61] (P< 0.001 for both comparisons).

Interleukin-10

This is one of the natural anti-inflammatory cyto-kines, which also include Interleukin-1 receptorantagonist (IL-1ra), interleukin-4, interleukin-13

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and transforming growth factor-b1 (TGF-b1). inter-leukin-10 (IL-10) is made by immune cells calledmacrophages during the shut-off stage of theimmune response. Interleukin-10 is a potent anti-inflammatory agent, which acts partly by decreas-ing the production of inflammatory cytokinesinterleukin-1 b (interleukin-1 b), tumor necrosis

factor-a (TNF-a) and inducible nitric oxide synthe-tase (iNOS), by injured nerves and activated whiteblood cells, thus decreasing the amount of spinalcord and peripheral nerve damage [62,63]. In ratswith spinal cord injury (SCI), a single injection ofIL-10 within half an hour resulted in 49% less spinalcord tissue loss than in untreated rats. Theresearchers observed nerve fibers traveling straightthrough the spared tissue regions, across the zoneof injury. They also reported a decrease in theinflammatory mediator TNF-a, which rises signifi-cantly after SCI.

Prostaglandins

These are inflammatory mediators that are re-leased during allergic and inflammatory processes.Phospholipase A2 enzyme, which is present in cellmembranes, is stimulated or activated by tissue in-jury or microbial products. Activation of phospholi-pase A2 causes the release of arachidonic acid fromthe cell membrane phospholipid. From here thereare two reaction pathways that are catalyzed bythe enzymes cyclooxygenase (COX) and lipoxyge-nase (LOX). These two enzyme pathways compete

with one another. The cyclooxygenase enzymepathway results in the formation of inflammatorymediator prostaglandins and thromboxane. Thelipoxygenase enzyme pathway results in the forma-tion of inflammatory mediator leukotriene. Be-cause they are lipid soluble these mediators caneasily pass out through cell membranes.

In the cyclooxygenase pathway, the prostaglan-dins D, E and F plus thromboxane and prostacyclinare made. Thromboxanes are made in platelets andcause constriction of vascular smooth muscle andplatelet aggregation. Prostacyclins, produced byblood vessel walls, are antagonistic to thrombox-anes as they inhibit platelet aggregation.

Prostaglandins have diverse actions dependenton cell type but are known to generally causesmooth muscle contraction. Prostaglandins sensi-tize peripheral nociceptor terminals and producelocalized pain hypersensitivity. Peripheral inflam-mation also generates pain hypersensitivity inneighboring uninjured tissue (secondary hyperalge-sia), because of increased neuronal excitability inthe spinal cord (central sensitization) [64]. Prosta-glandins are very potent but are inactivated rapidly

in the systemic circulation. Leukotrienes are madein leukocytes and macrophages via the lipoxyge-nase pathway. They are potent constrictors of thebronchial airways. They are also important ininflammation and hypersensitivity reactions asthey increase vascular permeability and attractleukocytes.

Tumor necrosis factor a

Subsequent to tissue injury, this inflammatorymediator is released by macrophages as well asnerve cells. During an inflammatory response,nerve cells communicate with each other by releas-ing neuro-transmitter glutamate. This process fol-lows activation of a nerve cell receptor calledCXCR4 by the inflammatory mediator stromal cell-derived factor 1 (SDF-1). An extraordinary featureof the nerve cell communication is the rapid re-lease of inflammatory mediator tumor necrosis fac-

tor-a (TNF-a). Subsequent to release of TNF-a,there is an increase in the formation of inflamma-tory mediator prostaglandin. Excessive prostaglan-din release results in an increased production ofneurotransmitter glutamate and an increase innerve cell communication resulting in a vicious cy-cle of inflammation. There is excitation of painreceptors and stimulation of the specializednerves, e.g. C fibers and A-d fibers that carry painimpulses to the spinal cord and brain.

Studies have established that herniated disk tis-sue (nucleus pulposus) produces a profound inflam-

matory reaction with release of inflammatorychemical mediators. Disk tissue applied to nervesmay induce a characteristic nerve sheath injury[6567] increased blood vessel permeability, andblood coagulation. The primary inflammatorymediator implicated in this nerve injury is Tumornecrosis factor-a but other mediators includinginterleukin 1-b, matrix metalloproteinase, nitricoxide, prostaglandin E2, and interleukin-6 may alsoparticipate in the inflammatory reaction. Recentstudies have also shown that local application ofnucleus pulposus may induce pain-related behaviorin rats, particularly hypersensitivity to heat andother features of a neuropathic pain syndrome.

Nitric oxide

This inflammatory mediator is released by macro-phages. Other mediators of inflammation such asreactive oxygen products and cytokines, consider-ably contribute to inflammation and inflammatorypain by causing an increased local production ofcyclooxygenase enzyme. The cyclooxygenase en-zyme pathway results in the formation of inflamma-



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tory mediator prostaglandins and thromboxane.Concurrently to the increased production of thecyclooxygenase-2 (COX-2) gene, there is increasedproduction of the gene for the enzyme inducible ni-tric oxide synthetase (iNOS), leading to increasedlevels of nitric oxide (NO) in inflamed tissues. Inthese tissues, NO has been shown to contribute to

swelling, hyperalgesia (heightened reaction topain) and pain. NO localized in high amounts in in-flamed tissues has been shown to induce pain lo-cally and enhances central as well as peripheralstimuli. Inflammatory NO is thought to be synthe-sized by the inducible isoform of nitric oxide syn-thetase (iNOS).

Substance P (sP)

An important early event in the induction of neuro-pathic pain states is the release of Substance P frominjured nerves which then increases local Tumor

Necrosis Factor a (TNF-a) production. Substance Pand TNF-a then attract and activate immune mono-cytes and macrophages, and can activate macro-phages directly. Substance P effects are selectiveand Substance P does not stimulate production ofinterleukin-1, interleukin-3, or interleukin-6. Sub-stance P and the associated increased productionof TNF-a has been shown to be critically involvedin the pathogenesis of neuropathic pain states.TNF protein and message are then further increasedby activated immune macrophages recruited to theinjury site several days after the primary injury.

TNF-a can evoke spontaneous electrical activity insensory C and A-d nerve fibers that results in low-grade pain signal input contributing to central sen-sitization. Inhibition of macrophage recruitment tothe nerve injury site, or pharmacologic interfer-ence with TNF-a production has been shown to re-duce both the neuropathologic and behavioralmanifestations of neuropathic pain states [68].

Gelatinase B or matrix metallo-proteinase 9(MMP-9)

This enzyme is one of a group of metalloprotein-ases (which includes collagenase and stromelysin)that are involved in connective tissue breakdown.Normal cells produce MMP-9 in an inactive, or la-tent form. The enzyme is activated by inflamma-tory mediators such as TNF-a and interleukin-1that are released by cells of the immune system(mainly neutrophils but also macrophages and lym-phocytes) and transformed cells [69,70]. MMP-9helps these cells migrate through the blood vesselsto inflammatory sites or to metastatic sites. Acti-vated, MMP-9 can also degrade collagen in the

extra cellular matrix of articular bone and cartilageand is associated with joint inflammation and bonyerosions [71]. Consequently, MMP-9 plays a majorrole in acute and chronic inflammation, in cardio-vascular and skin pathologies as well as in cancermetastasis.

Natural suppression of the inflammatoryresponse and gate control

How does the inflammatory response end?Immune cells produce anti-inflammatory cyto-

kine mediators that help to suppress the inflamma-tory response and suppress the production ofpro-inflammatory cytokines. The natural anti-inflammatory cytokines are Interleukin-1 receptorantagonist (IL-1ra), interleukin-10, interleukin-4,interleukin-13 and transforming growth factor-b1(TGF-b1). Research has shown that administrationof these anti-inflammatory cytokines prevents the

development of painful nerve pain that is producedby a naturally occurring irritant protein calledDynorphin A [72].

Under normal circumstances, the inflammatoryresponse should only last for as long as the infec-tion or the tissue injury exists. Once the threat ofinfection has passed or the injury has healed, thearea should return to normal existence.

One of the ways that the inflammatory responseends is by a phenomenon known as Apoptosis.

Most of the time, cells of the body die by beingirreparably damaged or by being deprived of nutri-

ents. This is known as Necrotic death. However,cells can also be killed in another way, i.e. bycommitting suicide. On receipt of a certainchemical signal, most cells of the body can destroythemselves. This is known as Apoptotic death.There are two main ways in which cells can commitApoptosis. (1) By receiving an Apoptosis signal.When a chemical signal is received that indicatesthat the cell should kill itself, it does so. (2) Bynot receiving a stay-alive signal. Certain cells,once they reach an activated state, are primed tokill themselves automatically within a certain per-iod of time, i.e. to commit Apoptosis, unless in-structed otherwise. However, there may be othercells that supply them with a stay-alive signal,which delays the Apoptosis of the cell. It is onlywhen 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 re-sponse, once they become activated, are primed tocommit Apoptosis. Helper T cells emit the stay-alive signal, and keep emitting the signal for aslong as they recognize foreign antigens or a state

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of injury in the body, thus prolonging the inflamma-tory response. It is only when the infection or in-jury has been eradicated, and there is no moreforeign antigen that the helper T cells stop emit-ting the stay-alive signal, thus allowing the cells in-volved 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 Tcells do not recognize that fact, or if the immunecells receive the stay-alive signal from anothersource, then chronic inflammation may develop.

The final pathway for the natural suppression ofthe inflammatory response is in the spinal cordwhere there is a complex network of inhibitory neu-rons (gate control) that is driven by descendingprojections from brain stem sites. These inhibitoryneurons act to dampen and counteract the spinalcord hyper excitability produced by tissue or nerveinjury. Thus, peripherally evoked pain impulsespass through a filtering process involving inhibitory

transmitters c-aminobutyric acid (GABA), glycineand enkephalins. The activity of these substancesin the spinal cord usually attenuates and limitsthe duration of pain. In the case of persistent pain,there is evidence of pathological reduction of thesupraspinal inhibitory actions in combination withectopic afferent input in damaged nerves [73].

Discussion

The various biochemical mediators of inflammation

(cytokines, neuropeptides, growth factors and neu-rotransmitters) are present in differing amounts inall pain syndromes and are responsible for the painexperience. Every pain syndrome has a uniqueinflammatory profile with a predominance of cer-tain inflammatory mediators (see Table 1 whichlists the biochemical mediators for which drugsare currently available). This inflammatory profileis not static but dynamic and variable in the samepatient and from one patient to another. Theinflammatory profile is derived from the original in-jury or trauma and modified by ongoing injuries andaggravations including iatrogenic interventions. Itis important to understand that:

1. Inflammation can exist without structural dam-age that is visible with our current imagingtechnology.

2. Structural damage will result in inflammationand the inflammatory response.

3. Inflammation and the inflammatory responsewill produce structural damage. Classificationand treatment of pain syndromes should dependon the complex inflammatory profile and should

not be based alone on symptomatology, struc-tural pathology, genetic markers or presenceof autoantibodies.

We believe the Sudeck started on the right pathwhen in 1942, he suggested that the signs andsymptoms of RSD/CRPS including sympathetic

hyperactivity might be provoked by an exaggeratedinflammatory response. However, inflammationand the inflammatory response do not just provokethe signs and symptoms of sympathetic hyperactiv-ity. It is our unifying theory that inflammation andthe inflammatory response are the biochemical ori-gin of pain.

Our Unifying Theory of Pain encompasses theGate Theory, provides an explanation for the bio-chemical origin of Pain and a road map for thetreatment of all pain syndromes.

We believe that the definition of Pain by the IASPSubcommittee on Taxonomy is incorrect and

wrongly places a focus on the presence of visible tis-sue damage or a structural pathophysiologicalcause. The biochemical mediators of inflammationare not visible on MRI or X-rays but can now be mea-sured in the serum and CSF and in the future, we willbe able to image the mediators by MRI spectroscopy.

Our theory of Pain explains the biochemical ori-gin of pain that hitherto was unfortunately classi-fied as psychogenic or due to maladaptivethought processes.

The classification of Pain as being peripheral orcentral in origin is incorrect. Central pain may arise

from peripheral injury. This is well documented inpatients with neuropathic pain or RSD/CRPS.

The current theories that we are replacing havefailed to realize that the mechanisms for wind-up,central sensitization and neuroplasticity are but anintegral part of inflammation and the inflammatoryprocess.

Our theory explains that peripheral and centralpain including windup and central sensitizationare a continuum of inflammation and the inflamma-tory response. The current theories mentioninflammation as a component of the peripheralpain mechanism. None expand on the role of thebiochemical mediators in the inflammatory re-sponse and none of these theories provide any rolefor inflammatory mediator blockers or immunemodulators in the treatment of pain syndromes.The cellular response to injury is inflammationand the inflammatory response. In our theory,inflammation and the inflammatory response arethe biochemical origin and a therapeutic target ofboth peripheral and central pain.

Every drug that is currently used in the treat-ment of pain has a mechanism of action that is



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compatible with the principles we hereby outline inour 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. withinflammatory mediator blockers or surgicalintervention where appropriate.

3. Inhibition or suppression of neuronal afferentand efferent (motor) transmission, e.g. withanti-seizure drugs or local anesthetic blocks.

4. Modulation of neuronal transmission, e.g. withopioid medication.

Pain syndromes may be treated medically or sur-gically. The goal is inhibition or suppression of pro-duction of the inflammatory mediators. Asuccessful outcome is one that results in lessinflammation and thus less pain.

Conclusion

In accordance with our Law of Pain, the origin of allpain is inflammation and the inflammatory re-sponse. The biochemical mediators of inflamma-tion include cytokines, neuropeptides, growthfactors and neurotransmitters. Irrespective of thetype of pain whether it is acute or chronic pain,peripheral or central pain, nociceptive or neuro-pathic pain, the underlying origin is inflammationand the inflammatory response. Activation of painreceptors, transmission and modulation of pain sig-nals, neuro plasticity and central sensitization areall one continuum of inflammation and the inflam-matory response. Irrespective of the characteristicof the pain, whether it is sharp, dull, aching, burn-ing, stabbing, numbing or tingling, all pain arisefrom inflammation and the inflammatory response.We are proposing a re-classification and treatment

of pain syndromes based upon their inflammatoryprofile. Treatment of pain syndromes should bebased on these principles:

1. Determination of the inflammatory profile of thepain syndrome.

2. Inhibition or suppression of production of theappropriate inflammatory mediators, e.g. withinflammatory mediator blockers or surgicalintervention where appropriate.

3. Inhibition or suppression of neuronal afferentand efferent (motor) transmission, e.g. withanti-seizure drugs or local anesthetic blocks.

4. Modulation of neuronal transmission, e.g. withopioid medication.

At the L.A. Pain Clinic, we have successfullytreated a variety of pain syndromes by utilizingthese principles. This unifying theory of the bio-

chemical origin of pain is compatible with, inclu-sive of, and unifies existing theories andknowledge of the mechanism of pain includingthe gate control theory, and theories of pre-emp-tive analgesia, windup and central sensitization.Our current knowledge is rudimentary and but abeachhead in the vast frontier of inflammationand the inflammatory response. We have medica-tions for only a few of these mediators. More re-search is needed to understand and develop newdrugs and interventions to treat inflammationand the inflammatory response and thus to con-

quer pain.

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Table 1 Inflammatory mediator profile of pain syndromes

Pain syndrome Inflammatory profile

Arthritis IL-1 b, IL-6, TNF-aBack/neck pain (herniated disk) Prostaglandin, TNF-a, IL-1 bBursitis/tendonitis Prostaglandin, IL-1 bFibromyalgia Substance P, IL-1 b, IL-6Neuropathic pain Substance P, Prostaglandin, IL-1 b, IL-6, TNF-a, glutamateMigraine Serotonin, substance POsteoporosis IL-6, TNF-aRSD/CRPS Substance P, IL-1 b, IL-6, TNF-a, glutamate

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