indian j physiol pharmacol 2003; 47 (3) : 247–269 review ... · casey (6) developed a model of...

Indian J Physiol Pharmacol 2003; 47 (3) : 247–269

†Corresponding Author

REVIEW ARTICLE

NEUROPHYSIOLOGY OF PAIN : INSIGHT TO OROFACIAL PAIN

O. P. TANDON*†, V. MALHOTRA*, S. TANDON** AND I. D’SILVA

*Department of Physiology,University College of Medical Sciences & Guru Teg Bahadur Hospital,Dilshad Garden, Delhi – 110 095

and**Department of Periodontia,

Nair Hospital Dental College,Mumbai – 400 008

((((( Received on January 22, 2003Received on January 22, 2003Received on January 22, 2003Received on January 22, 2003Received on January 22, 2003 )))))

Abstract :Abstract :Abstract :Abstract :Abstract : This is a very exciting time in the field of pain research. Majoradvances are made at every level of analysis from development to neuralplasticity in the adult and from the transduction of a noxious stimulus ina primary afferent neuron to the impact of this stimulus on cortical circuitry.The molecular identity of nociceptors, their stimulus transduction processesand the ion channels involved in the generation, modulation andpropagation of action potentials along the axons in which these nociceptorsare present are being vigorously perused. Similarly tremendous progresshas occurred in the identification of the receptors, transmitters, secondmessenger systems, transcription factors, and signaling moleculesunderlying the neural plasticity observed in the spinal cord and brainstemafter tissue or nerve injury. With recent insight into the pharmacology ofdifferent neural circuits, the importance of descending modulatory systemsin the response of the nervous system to persistent pain after injury isbeing reevaluated. Finally, imaging studies revealed that information abouttissue damage is distributed at multiple forebrain sites involved inattentional, motivational, and cognitive aspects of the pain experience.

Key words :Key words :Key words :Key words :Key words : pain pathways evaluation pain relieforofacial pain evoked potentials TSEPs

INTRODUCTION

Pain : the Internat ional perspect ivePain : the Internat ional perspect ivePain : the Internat ional perspect ivePain : the Internat ional perspect ivePain : the Internat ional perspect ive

A Committee o f the Internat ional

Association for the study of pain has definedpain as an unpleasant sensory and emotionalexperience associated with actual or potentialtissue damage (1). It is mostly accompaniedby the desire to stop and to avoid stimuli

248 Tandon et al Indian J Physiol Pharmacol 2003; 47(3)

causing it. It is linked with a feeling ofaversion (2). Throughout most of recordedhistory, pain was characterised as anef fect ive fee l ing state rather than asensation (3). Emotions play a key role inpainful experience. Aristotle described painas a “passion of soul”, distinct from theclassic five senses (4).

Melzack and Wall (5) and Melzack andCasey (6) developed a model of pain in whicht issue damage concurrent ly act ivatessensory, discriminative, cognitive-evaluativeand affective-motivational components ofpain.

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Receptors of pain

Sensory receptors for pain, nociceptors,are naked nerve endings that terminate inthe skin and most other tissues of the body.However, their distribution is not uniformthroughout organs of the body. As a generalrule, deep visceral organs of the body arenot well supplied with nociceptors. Thesereceptors are generally classified accordingto the type to which they respond:

1. Mechanosensitive pain receptors respondto mechanical damage.

2. Thermosensitive pain receptors respondto respond to temperature extremes.

3. Chemosensitive pain receptors respond tochemicals that occur with damagedt issues example hypertonic sa l ine ,potass ium chlor ide , acety lchol ine ,5-Hydroxytryptamine, h istamine,bradykinin and substance P. Vasoactiveamines are released just after injury bythe basophils, platelets and mast cells.

As these receptors signal either actualor potential damage to tissues, pain hassurvival value to the organism. Consequentlypain receptors generally do not adapt to

Fig. 1 : Pathway by which Fast Pain is conveyed tothe Central Nervous.I–VI : Laminae of the Dorsal Horn of the

Spinal Cord.

Indian J Physiol Pharmacol 2003; 47(3) Neurophysiology of Pain : Insight of Orofacial Pain 249

evidence for the existence of cutaneousmyelinated Aδ and unmyelinated C fiberswas provided by Zottermann (8-10), whointerpreted his observations as strongsupport for Bell’s and Mullers theory ofspecificity (11,12). It is known that noxiousstimulation exciting somatic and dental Aδafferents may exert a masking or inhibitoryeffect on C-fiber related sensations. TablesI to III describe the peripheral mechanismand recent developments in ion channels,neural transmission and transduction forpain sensation.

Molecules invo lved in pain transmiss ionMolecules invo lved in pain transmiss ionMolecules invo lved in pain transmiss ionMolecules invo lved in pain transmiss ionMolecules invo lved in pain transmiss ion

The role of trophic factors and cytokinesin the development and maintenance of painin response to various forms of tissue injuryis an area of research that has virtuallyexploded in the last several years.

In addition to its role in development,NGF and other growth factors, and cytokineshave been shown to mediate pain andhyperalgesia associated with tissue injury.

Lorne Mendell (20) the first to describethe l ink between NGF mechanismsunderlying the initial hyperalgesic responseto NGF. The initial hyperalgesia in responseto systemic or peripherally administeredNGF depends on indirect mechanisms,specifically mast cell degranulation.

Linda Watkins (21) described additionalpathways through which activation of theimmune system results in changes inmultiple sites throughout the nervoussystem. Watkins described the moleculesinvolved in the signaling pathways as well

prolonged stimulation. In fact pain sensationmay intensify as pain thresholds becomelowered through continued stimulation (7).

From the peripheral receptor to thecerebral cortex, specialised neural pathwaystermed the nociceptive system processnoxious st imuli . Peripheral ly , noxiousst imul i act ivate spec i f i c receptors(nociceptors) of thinly myelinated Aδ andunmyelinated C fibers terminating in thespinal cord dorsal horn. Neurophysiological

Fig. 2 : Pathway by which slow pain is conveyed tothe Central Nervous System.

THALAMUS


TABLE II : Recent developments on Ion channels & nociception in the peripheral nerve.

S.No. Scientist/Researcher Work

1. Steve Waxman (13) Indicated Dynamic changes of expression of TTX-sensitive sodiumchannel contributing to hyperexcitable nociceptors after injury

2. Michael Gold (14) Role of Modulation of TTX-resistant sodium currents by PGE2, 5HT,and adenosine modifies mechanical induced hyperalgesia duringinflammation.

3. Daniel Weinrech (15) Role of Ca++ dependent K+ current in controlling excitability of vagalafferents.

4. Peter McNaughton (16) Presented evidence implicating activation of Protein Kinase heatactivated channel by bradykinin

Note: These mechanisms explain the ionic basis of increase in hyperexcitability in presence of nociception.

TABLE I : Characteristics of fast and slow fibers (7).

Fast (Diagram 1) Slow (Diagram 2)

Carried by Aδ By C fibersSharp, pricking sensation Dull, aching, burningEasily localised Poorly localisedOccurs first Occurs second; persist for longer time, more unpleasantOccurs on stimulation of mechanical and thermal receptors Occurs on stimulation of polymodal receptors

TABLE III : Transduction transmission and modulation of nociceptive information.

S.No. Scientist/Researcher Work

1. Amy Mac Dermott (17) Experiments on the role of presynaptic non-NMDA & kainate receptorsin dorsal root ganglion neurons. Activation of these receptors appearsto influence glutamate release from the sensory neuron & thereforeactivation of dorsal horn neurons.

2. Edwin McCleskey (17) Using Electrophysiology, single-cell PCR and reverse transcriptionPCR reactions determined the number of mRNA copies encoding theµ-opiod receptor in a single cell. Their results explained perplexingaspects of opiod analgesia.

3. Michael Salter (18) Provided evidence-supporting development of long-term potentiationin the hippocampus and by analogy, central sensitisation of spinalcord dorsal horn neurons after tissue injury.

4. Edward Perl (19) Pointed changes in α -adrenergic receptors present in sensory neuronsafter injury. Expression of the receptors involved in transmission ofnociceptive stimuli contributes pathophysiology of pain.

Note: Researchers on receptors involving the transduction, transmission, and modulation of nociceptiveinformation is clearly one of the most exciting and rapidly advancing involved in the transmission ofnociceptive stimuli as well as the cellular elements necessary for synaptic transmission. Researchershave begun to collect together the essential elements for the first steps ultimately leading to theperception of pain.


as how activation of this system results inchanges in behavior.

Steve McMohan (22) summarised thegrowing body of data implicating a criticalrole for brain derived neurotrophic factor inthe altered nociceptive processing observedin the presence of inflammation.

Brain derived neurotrophic factor appearsto funct ion as a neurotransmitter /Neuromodulator in the dorsal horn of thespinal cord, where it is released from thecentral terminals of small-caliber afferentsand increases the excitability of dorsal hornneurons.

Spinal integrat ing mechanism of painSpinal integrat ing mechanism of painSpinal integrat ing mechanism of painSpinal integrat ing mechanism of painSpinal integrat ing mechanism of pain

From the pain receptors, pain impulsesare carried to the CNS by two fiber systems:the large myelinated fibres (A-delta) conductimpulses rapidly (15.25 m/sec), the smallunmyelinated fibres (C-fibres) conduct at aslower rate (<1 m/sec). Both types of fibresoccur in peripheral nerves and connect painreceptors to the spinal cord. Within the cord,these fibres synapse in the dorsal graymatter and the substantial gelatinosa (SG).The SG cells are thought to serve as anintegration centre and relay system for painsensations, although their exact role in painprocess is not known. However, this area ofspinal cord has many interconnections withother gray matter neurons and it has a largenumber of opiate receptors and an abundanceof substance P. Substance P is aneurotransmitter that is apparently uniqueto pain fibers of spinal cord. Cells of thecordal gray matter send axons across themidl ine to ascend in the lateral

spinothalamic fibres synapse with relayneurons of the thalamus, which projectupwards to the postcentral gyrus of thecortex to complete pain pathways.

Besides, spinal integrating mechanism,diencephalic and brainstem, analgesic-descending influences impinge upon SG tointegrate pain sensation at the cord level.

Gate-contro l theory for pain re l ie fGate-contro l theory for pain re l ie fGate-contro l theory for pain re l ie fGate-contro l theory for pain re l ie fGate-contro l theory for pain re l ie f

This theory proposes a physiological basisfor reduction of perceived pain by gentletactile stimulation over the affected site (e.g.abdominal pain is subjectively reduced bylightly stroking the skin over the abdomen).A network of “t-cells” (cells propagating painfrom slow fibres) and interneurons that caninhibit the t-cells is postulated to form agate within the dorsal horn spinal cord. Thefaster propagated f ibres that carryinformation about light touch, thus inhibiting“t-cells” and decreasing the transmission ofpain impulse actuate the interneurons.Although the exact site of gate network isnot known the principles of the theory havebeen accepted and applied clinically. Tactilestimulation that is used to “close the gate”can be replaced by electrical stimulation ofthe pathways o f l ight touch throughelectrodes placed on the skin, as is done inTrancutaneous electrical nerve stimulationTENS or electroacupuncture.

Natural endogenous a lges ic and analges icNatural endogenous a lges ic and analges icNatural endogenous a lges ic and analges icNatural endogenous a lges ic and analges icNatural endogenous a lges ic and analges icmechanism (Fig . 3 )mechanism (Fig . 3 )mechanism (Fig . 3 )mechanism (Fig . 3 )mechanism (Fig . 3 )

Opium was determined to be “ God’s ownmedicine” for pain. Not only does opiumproduce definite analgesic effects, but it also


Consequent ly , natural ly occurr ing(Endogenous) opiate compounds were found.These compounds are collectively called asEndorphins. Three-endorphin compounds-met (methionine) enkephaline, leu (leucine)encephalin and beta endorphins are knownto play a role in natural pain suppressingmechanisms. These are produced at differentlevels o f CNS as a result o f painfulst imulation. They serve to raise painthreshold and reduce pain.

Phantom l imb and p last i c i tyPhantom l imb and p last i c i tyPhantom l imb and p last i c i tyPhantom l imb and p last i c i tyPhantom l imb and p last i c i ty

Amputation of limb is often followed bythe feeling that limb is still present. Thisphenomenon is termed as phantom limb andenhances our understanding o f painpathways. The phantom area graduallyshrinks and may completely disappear. Butin 5 to 10% amputees; there is a persistentand severe pain apparently from the absentregion. The pain is thought to be of centralor ig in. On sect ioning of contralateralspinothalamic tracts pain may be relievedfor long periods by a prolonged or severestimulus to the stump; although in othersthe stump may be reamputated oranaesthetised without any relief.

“Fooling the brain” may relieve pain. Amirror is applied in between the amputatedlimb and the normal limb. The patient isasked to look in the mirror and move hisnormal limb. Visual stimuli of movement ofnormal limb make the individual feel as ifhis amputated limb is moving. This bringsback a surge of plasticity changes in thecortex , which are l inked to surge o femotional changes that relieve the limb fromits “ locked” pos i t ion at the t ime o famputation (7).

eliminated fear, anxiety and suffering. Theopiate receptors are part of the naturallyoccurr ing or endogenous , analges icmechanism within the human nervoussystem. Analgesics relieve pain and the mostpotent analges ic i s the morphine . I tcomplexes with opiate receptors associatedwith synaptic terminals of the substantialge lat inosa and the gray matter thatsurrounds the third ventricle of the brainstem (periaqueductal gray). Morphine whencomplexed with opiate receptors, reduces oreliminates pain.

With discovery of opiate receptors,came a search for their natural function.

Fig. 3 : Endogenous Pain Relief System.


increased rigidity “guarding” helps inlocalising the possible source of pain inparticular viscera. Gall bladder pain isreferred to right shoulder tip and cardiacpain to left shoulder and upper arm. Suchreferred pain thus helps in making correctdiagnosis of the diseased viscera.

Subcort i ca l mechanismsSubcort i ca l mechanismsSubcort i ca l mechanismsSubcort i ca l mechanismsSubcort i ca l mechanisms

Pituitary mechanisms

Melzack R. postulated the existence of apain neuromatrix in which the experience ofpain is produced by multiple influences andcomprises of a widely distributed neuralnetwork with input from the body’s stress-regulation systems, including HypothalamicPituitary axis (HPA) and opioid systems.Facial pain itself may act, on the other handas a strong activator of the HPA. (25)

Cerebral cort i ca l mechanismsCerebral cort i ca l mechanismsCerebral cort i ca l mechanismsCerebral cort i ca l mechanismsCerebral cort i ca l mechanisms

The current knowledge of pain perceptionis quite fragmentary. The role played by thecerebral cortex in pain is not c learlyunderstood. I f the post central gyrus(somatosensory area) i s e lectr ica l lystimulated, very few patients report asensation of pain. The cortex is thought toaid in the appreciation of pain, but theresponses to painful stimuli persist evenwhen the cortex is surgically removed. Agreat deal o f evidence impl icates thethalamus in the perception of pain.

Newer concepts o f understanding cort i ca lNewer concepts o f understanding cort i ca lNewer concepts o f understanding cort i ca lNewer concepts o f understanding cort i ca lNewer concepts o f understanding cort i ca lm e c h a n i s m sm e c h a n i s m sm e c h a n i s m sm e c h a n i s m sm e c h a n i s m s

A considerable amount of evidencesuggest that Primary Somatosensory cortex

Marie Fitzgerald (23) reported changesin the neonatal spinal cord that areincomplete versions of what occurs in theadult. Central sensitisation occurs in theresponse to electrical stimulation of A βfibers whereas activity – induced plasticityin the adult spinal cord takes place only inresponse to C fiber strength stimulatingunless the dorsal horn is primed by previousperipheral injury. NMDA receptors aredistributed in higher density in the neonatalcord.

Cl i f ford Wool f (24) provided anoutstanding, concise and up to date reviewof activity-induced and signal inducedplasticity in sensory neurons after tissueinjury.

Referred pain : I ts s igni f i canceReferred pain : I ts s igni f i canceReferred pain : I ts s igni f i canceReferred pain : I ts s igni f i canceReferred pain : I ts s igni f i cance

The pain originating from viscera isgenerally of slow, aching type, which isdifficult to localise. Frequently visceral painmay be referred to other parts of the bodysupplied by the same spinal nerve (thedermatomal rule) known as referred pain.When pain is referred to another part of thebody, the site of referral is usually a part ofthe body that develops from the sameembryological segment or dermatome, as theaffected source of the pain. The sameperipheral nerves supply these commonregions of the body. For example, the heartand arm are der ived from the samedermatome, and the kidney, ureter andtestes are all derived from another commondermatome.

Clinical significance of classical referredpain lies in diagnosis. Usually visceral painof the abdomen may cause over ly ing,abdominal muscles to contract . This


(SI ) has a p ivotal ro le in sensorydiscriminative aspects of pain such as spatialdiscrimination (26) and intensity coding (27).

Cognitive factors can alter the perceivedintensity of pain and accordingly, canmodulate SI activity in functional imagingstudies . Physio logical ly , inhibi t ion o fnociceptive neurons and neurons withnon sensory d iscr iminat ive responsecharacteristics may be involved in thiscognitive modulation and in interaction ofpain and touch in SI area.

Neurophysiologic and functional imagingdata clearly indicate participation of SIIin human pain processing. Preserved,direct thalamic access o f noc icept iveinformation to SII, supported by anatomicthalamocortical connections and by parallelact ivat ion o f somatosensory cort ices ,suggests a particular relevance of this areain pain processing.

Functionally, SII may be involved inrecognition, learning and memory of painfulevents (26,28-32)

Numerous functional imaging studiesindicate participation of anterior insularcortex in human pain processing. Recentfindings indicate a dedicated pain andtemperature pathway to the insula need tobe integrated with functional imaging data.Functionally the insula may be involved inautomatic reactions to noxious stimuli andin pain-related memory and learning (33-35).

Clinical reports that patients withcingulotomies sometimes still feel pain butreport it as less distressing along withfindings that high level of opioid binding

occurs in the Anterior cingulate cortex(ACC). Pain affect (i.e. unpleasantness ofpain) is encoded in the ACC.

By using hypnosis, Rainville et al (36)selectively altered unpleasantness of noxiousthermal st imuli without changing theperceived pain intensity.

Analysis of cerebral activation pattern asmeasured by PET revealed that themodulation of pain affect was paralleled byactivation changes in the ACC but not inthe other brain tissues.

Along with these and other studies theproximity of the nociceptive, motor andcognitive regions of the ACC suggestspossible local interconnections that mayallow the output of the ACC pain area tocommand immediate behavioral reactions(37-40)

Grading /Evaluat ion o f painGrading /Evaluat ion o f painGrading /Evaluat ion o f painGrading /Evaluat ion o f painGrading /Evaluat ion o f pain

Pain is a complex physio logical -behavioral puzzle that requires assessmenton different levels.

At the same time the measures of painshould be reliable and valid, other wise theywi l l be o f l i t t le use to c l in ic ians orresearchers (41). An ideal pain measure (42)should provide sensitive measurement freeof bias, provide immediate information aboutaccuracy and reliability. The measurementshould a lso separate the sensory-discriminative aspects of pain from itshedonic qualities assess experimental andclinical pain with the same scale and provideabsolute scales that allow assessment of painbetween groups and within groups over time.


The pain threshold can be determinedby the classical methods. Simple categoryscales such As four-point “none, mild,moderate and severe” (verbal categoricalscale) or 1-10 numerical scale can be scoredin several ways. The simplest, the methodof equal appearing intervals ass ignssuccessive integers to verbal categoriesdirectly (43). The three most frequentlyconsidered aspects of pain are the subjective(Measured by self-report), the behavioral(measured by sampling of physiological orelectric potentials and assaying body fluidsor other biological responses.) Self-reportmeasures, when they can be obtained, shouldbe regarded as the “ Gold standard”. Indeed,the International Association for the studyof pain emphasises that pain is alwayssubjective.

Fortunately , techniques for thepsychological assessment of the pain patientshave improved to the extent that emotionalstress such as anxiety, depression anddefensive personality styles can now beidentified. People experiencing pain are ableto report separately on the sensory andaffective dimensions and emotional qualitiesdiffer dramatically across different forms ofclinical pain and within individuals overtime (44). Currently evidence indicatesthat pharmaceutical and psychologicalinterventions have different effects on ethersensory, affective or both qualities of theexperience.

Subject ive pain assessmentSubject ive pain assessmentSubject ive pain assessmentSubject ive pain assessmentSubject ive pain assessment

A Visual Analogue Scale (VAS) is a simplemeasure of subjective pain. It consists of a10-cm horizontal or vertical line with twoend points labeled “no pain” and “worst painever”.

The subject is required to place a markon the 10-cm l ine at a po int , whichcorresponds to the level of pain intensitythe subject presently feels. The distance incm from the lower end of the VAS to thepatients mark is used as a numerical indexof the severity of pain. (45,46)

The VAS is sensitive to pharmacologicaland non-pharmacological procedures thatalter the experience of pain (47) andcorrelates highly with pain measured onverbal and numerical rating scales (48,49).The ease of administration and scoring hascontributed to the popularity of this method.A major advantage of the VAS as a measureof sensory pain intensity is its ratio scaleproperties (50), minimal intrusiveness andconceptual simplicity (51).

The traditional view that the cerebralcortex is not involved in pain processing hasbeen abandoned during the past decade basedon anatomic and physiologic studies, lesionalstudies , funct ional neuroimaging andneurophysiologic studies in humans.

The use of techniques such as micro-recordings of the unitary or multiunitaryactivity of the nerves or nuclei, intracranialevoked potent ia ls , noc icept ive evokedpotentials, reflexology, polysomnography andtopography together with techniques such aspercutaneous objective localisation of deepnerves, allows quantitative evaluation pre-intra and postoperatively (52).

Evoked Potent ia lsEvoked Potent ia lsEvoked Potent ia lsEvoked Potent ia lsEvoked Potent ia ls

Specific stimulation at periphery causesnerve impulses to be conveyed to the brainsensory areas producing at the cerebral


cortex an electrical potential change calledthe Cortical Evoked Response. This potentialchange cannot be recorded as a singleresponse because it is too small to show upagainst the normal var iabi l i ty o f theelectroencephalogram (EEG). However, if aconsiderable number (say 50 or more) ofevoked responses are produced and the EEGtracings are analysed by a suitable computer,the average response becomes apparent afterdue amplification.

Evoked potent ia ls are a complexsummation of graded potentials alongafferent pathways and at the cortex byperipheral volleys. (53)

It is tempting to regard this evokedpotential response as an indicator that theneural impulses initiated by the stimulushave reached consciousness, and that it is aphysical indicator of perception, but twofactors are not necessarily coincident. (54)

Pain and cognit ionPain and cognit ionPain and cognit ionPain and cognit ionPain and cognit ion

Event Related Potentials (ERP) arevaluable and useful parameters for assessinga variety of cognitive abilities (55) andpsychological processes including expectancy,attention, search, discrimination, decision –making and memory. P 300 is a valuabletool and our preliminary work have shownthat it can evaluate the cognitive andaffective components of pain (56-59)

A significant increase in P 300 latencyin patents suffering from pain as comparedto age and sex matched controls. Our findingsuggest that there are cognitive changes inchronic pain states. This cognitive blunting

is reversible with analgesic intervention.(60). Contingent Negative Variation (CNV)is a surface –negat ive s low potent ia lrecorded from human subjects during a fixedforeperiod of a warned reaction time task.(61).

The electrical phenomenon of the brain,has drawn the interest o f manypsychophysiologists because it reflects somepsychological processes such as expectancy,motivate attention and arousal. The CNVwaveform depends primarily on psychologicaland to a lesser extent on physical proportionof the stimulus.

CNV can be used to evaluate theaffective-emotional components of pain. It isstill unclear how brain processes emotionalityand pain, and what are the interactionmechanisms of emotion and pain.

Slow brain potentials in the contingentnegative variation (CNV) are found to belarger in the pain condition than that of thecontrol (62-64). When patients with chronicpain were studied in The CNV paradigm, theappearance of CNV response was moremarked. It was concluded that slow evokedpotentials are sensitive to anxiety level andto pain perception. Rizzo (65) have shownthe usefulness of this measure in theinvestigation of pain as a complex sensation.A number of recent studies have assessedthe influence of baseline or induced moodon subjective and psychological responses toexperimental stimulation. Baseline (66) andinduced (67) anxiety have been shown toincrease pain ratings to thermal or pressurepain ratings, while an experimentallyinduced depress ive mood ( induced by


stimulus intensity and painfulness andinitiation of motor movements.

Further analysis by Chen et al (70) onthe consistency and reliability of the pain-related sources revealed that two painrelated components are consistently found anegativity at 145 msec. and a positivity at225 msec. The initial components correlatewith stimulus intensity and appear to codeinformation about intensity of the externalstimulation. The latter components areclosely related to the subjective estimationof pain intensity and seem to ref lectassociation processes involved in evaluationof noxious stimulus.

Chen et al findings suggest that the latecomponents of the EP waveform may reflectthe cognit ive aspects o f dental painperception in laboratory models.

When analges ic intervent ions areintroduced subject ive reports o f painintensity is reduced and EP componentsdiminish accordingly.

Zelansky et al (71) suggested that thepain–EP reflects the emotional-motivationalresponse to pain rather than the sensory-discriminative components.

Somatosensory evoked potent ia lsSomatosensory evoked potent ia lsSomatosensory evoked potent ia lsSomatosensory evoked potent ia lsSomatosensory evoked potent ia ls

Following stimulation of sensory receptors,a series of electrical events ensues in theafferent pathway and in the brain, and thisactivity may be measured non-invasivelyfrom s i tes on the body surface . Thewaveform is known a Somatosensory EvokedPotential.

presentation of text with depressive themes)decreased tolerance to cold pressor pain (68).Pain memory processes have beeninvestigated using experimental painfulstimulation (69). These studies provideexperimental examples of how the experienceof chronic pain can exert subtle influenceon cognitive processes and mood. Pain itselfcan also impair cognitive and psychomotorperformance.

Pain evoked potent ia lsPain evoked potent ia lsPain evoked potent ia lsPain evoked potent ia lsPain evoked potent ia ls

Evoked Potentials (EPs) are stimulus orevent related electrical signals of brainactivity that may be recorded from the scalpwhen precisely controlled discrete stimuliare delivered.

Significant correlation exists between lateEP components by experimental pain stimuliand the induced pain sensation.

EPs can serve as indicators of perceptionat multiple levels . Pain related brainevoked potentials are recognised as anobjective and quantitative test for evaluationof peripheral and central spinothalamic tract,thalamocortical projections and cortico-cortical circuit for pain processing.

Chen et al (70) identified the currentsource dipoles in noxious informationprocessing.

The pain related components late andultra late are distributed bilaterally in bothhemispheres exhibit maximum amplitude inthe vertex. Th late components are assumedto re f lect secondary mechanisms o finformation processing, such as stimulusrecognition, localisation, estimation of


The evaluation of somatosensory evokedpotentials is mainly related to assessmentof a particular nerve to central nervoussystem pathway.

Results in our studies have demonstratedthat there is a change in the absolute peaklatency of N19 in patients with chronic pain.

Imaging : MRI and SPECTImaging : MRI and SPECTImaging : MRI and SPECTImaging : MRI and SPECTImaging : MRI and SPECT

During the last decade, advances infunctional brain imaging techniques have ledto identification of neuroanatomic substratesof pain perception. Human lesion studiesusing computer tomography and MRI,and funct ional neuroimaging studiesusing Single-Photon Emission ComputedTomography (SPECT), positron emissiontomography (PET) and functionally (fMRI).

Ken Casey (72) described the role of forbrain mechanisms of pain in imaging inhumans and reviewed convincing evidencethat the perceived intensity of unilateral painevoked by different input as correlates withincreases in regional cerebral blood flow inprimarily five structures. Bilaterally in thethalamus, the contralateral insula, thebilateral premotor cortex, the contralateralanterior cingulate and cerebral vermis.

The combined use o f psychosoc ia ldimension and imaging in humans shouldhelp reveal the functional role of differentforebrain structures that have d irectcorticofugal projections to the thalamus,brain stem, and spinal cord, and therebymodulate the pain experience at those levels.

These studies non-invasively demonstratedinvolvement of distributed cerebral areas in

human pain processing involves a variety ofsubcortical and cortical regions. Morerecent ly , topographic aspects o f painrepresentations in the cerebral cortex havebeen extended to the temporal domain byresults of neurophysiologic studies usingwhole scalp magnetoencephlography (MEG)and EEG (73).

Thus it may be concluded that pain is apersonal, subjective experience influenced bycultural learning, the meaning of thesituation, attention and other psychologicalvariables. Approaches to measurement ofpain include verbal and numeric self-ratingscales, behavioral observation scales andphysiological responses. The complex natureof the experience of pain suggests thatmeasurements from these domains may notalways show high concordance. Furtherdevelopment and re f inement o f painmeasurement techniques will be able to meetthe challenge and lead to increasinglyaccurate tools with greater predictive powers.

Orofac ia l and dental painOrofac ia l and dental painOrofac ia l and dental painOrofac ia l and dental painOrofac ia l and dental pain

Introduction to dental pain

Face is considered as a mirror of mind-Inward events, emotions, behaviors arereflected on facial expressions. The cortexis also a mirror image to the body. Itreflects the body image and perceives whatthe body exper iences . The cort ica lhomunculus o f the body has widerrepresentation for orofacial area as comparedto other parts. This is elucidated below indetail along with the clinical significance.

When a patient comes to the dentist andcomplains of pain, the dentist is not dealing


with a simple sensory phenomenon involvingthe peripheral neural events elicited bypainful stimuli. Pain in dentistry has asensory –discr iminative dimension. I tprovides information about the noxiousstimuli-characterised by quality, intensity,location and duration, pain from otherregions may not reflect that, where

Pain has multidimensional emphasis,involves affective, motivational and cognitivecomponents. In orofacial pain for examplethe patient’s last visit to the dentist, andongoing sensory experiences of stress andanxiety during the current v is i t maymodulate the pain experience. (73,74).

Sensory disturbances of the face and oralcavity can occur in number of situations thatare of particular interest to the oral andmaxillofacial surgeon. These include nervelesions during removal of mandibular cysts,third molars, osteotomies of the facialskeleton and maxillofacial trauma.

Temporo Mandibular Disorders (TMD)comprise by far the most common cause ofchronic facial pain conditions with a higherprevalence in women as compared to men(75). TMD are a complex heterogeneousgroup of conditions, involving masticatorymuscles and/ or temporomandibular joints,charaterised by chronic facial pain andrepresent ing cause o f physical andpsychological debility in a large segment ofpopulation.

Accompaniments o f pa inAccompaniments o f pa inAccompaniments o f pa inAccompaniments o f pa inAccompaniments o f pa in

Sensory-discriminative system (76)

Under ordinary conditions, a noxiousstimulus can quickly be localised in time and

place. Somatosensory and dorsolateralspinal cord are so organised that thisspat iotemporal information is rapidlytransmitted. The dorsal column nucleus istopographically organised so that cellsresponding to stimulation from a smallarea of the body are clustered togetherand are physical ly adjacent to theneurons that receive input from contiguousareas of the body. This system allowsidentification of pain duration and its exactlocation.

A secondary input into the posterolateraland ventral posterolateral thalamic nucleiis from direct spinothalamic tract input bymeans o f f ibres that ascend in theventrolateral spinal cord-the classic painpathway. These rapidly conducting neuronsform an alternate pathway for discriminativesomatosensory functions.

Mot ivat ional -a f fect ive system (76)Mot ivat ional -a f fect ive system (76)Mot ivat ional -a f fect ive system (76)Mot ivat ional -a f fect ive system (76)Mot ivat ional -a f fect ive system (76)

The paleo spinothalamic system consists offibers of the ventrolateral system thatsynapse in the reticular formation of thebrain stem, where neurons form a complexnetwork with extensive connections toascending and descending systems.

This complex system may provide theneural pathways for the avers ive-motivational component of pain-the sufferingaspects o f ten assoc iated with painfulexperiences. In addition to interactions withthe limbic system and the hypothalamus, thesystem projects to periaqueductal graymatter, where it interacts with descendingimpulses that ul t imately a id in themodulation of impulse transmission withinthe spinal cord.


Many drugs , part icular ly narcot icanalges ics , can a l ter the avers ive-motivational aspects of the pain experience.That is, these agents reduce fear and anxietyand can eliminate the suffering aspectsassociated with pain. Indifference to noxiousstimulus is brought about in this manner.Patients may state that the pain has notdecreased in intensity but they are no longerbothered by it. Drugs create this indifferenceto pain.

Act ivat ion o f motor mechanisms (76)Act ivat ion o f motor mechanisms (76)Act ivat ion o f motor mechanisms (76)Act ivat ion o f motor mechanisms (76)Act ivat ion o f motor mechanisms (76)

Motor mechanisms that are responsible formany of the overt reactions to pain areinterrelated with spatio-temporal analysisand affective aspects of the experience ofpain. Once integrated within the centralnervous system, the impulse triggers asequence of responses characterised in theindividual by:

1) Startle response

2) Flexion response

3) Postural readjustment

4) Vocalisation

5) Orientation of the head and eyes toexamine the damaged area,

6) Evocation of past experience in similarsituations,

7) Prediction of the consequence of thestimulation, and

8) Many other patterns of behavior aimedat diminishing the sensory and affectivecomponents of the entire experience.

Facial grimacing, clenching the teeth,crying and other manifestations of the

experience may occur. Change in vitalsigns may also occur. Sympathetic nervoussystem function is generally enhanced aswell.

Thus the pain center, as postulated bythe specificity theory, has been replaced bythe encompassing global concept of an actionsystem. The system is not only responsiblefor identification, appreciation, recognition,and reaction to the unpleasantness impulsesarriving from the periphery, but it is alsointimately involved with the modulation ofimpulse transmission at spinal cord (ortrigeminal nucleus) levels.

How di f ferent i s th is pain f rom generalHow di f ferent i s th is pain f rom generalHow di f ferent i s th is pain f rom generalHow di f ferent i s th is pain f rom generalHow di f ferent i s th is pain f rom generalpain? : pecul iar i t ies o f dental painpain? : pecul iar i t ies o f dental painpain? : pecul iar i t ies o f dental painpain? : pecul iar i t ies o f dental painpain? : pecul iar i t ies o f dental pain

The tooth pulp has many attractivefeatures for the study of peripheral painmechanisms because of its rich innervation,its unique distribution of nerve fibers andits general disposition to give rise to painupon stimulation (76-84). In the last century,three theor ies explaining the exactmechanism of sensitivity of dentin, thisseemingly inert s tructure has beenelucidated:

1. Pain is a direct result of stimulation ofsensory nerve endings in the dentin. Themost sensitive area of the tissue is nearthe dentoenamel junction.

2. Odontoblasts are sensory cells. Theyreceive and transfer stimuli to nerveendings in the pulp.

3. Hydrodynamic theory: Dental sensitivityis a result of mechanical stimulation offree endings in the pulp caused by rapid


fluid flow in the dental tubules wherethe dentin is stimulated.

Orofacial pain can be as severe as anypain experienced and includes cases ofintractable pain as well as acute pain.Moreover personal, family and social cost ofthis is enormous, not just in terms offinancial loss and cost of treatment but alsoin the risk of drug addiction, multipleoperations and even suicide. These featuresare peculiar to orofacial pain. The mostfrequent source of orofacial pain is dentaldisorders and it has been estimated thattoothache is suffered for upto five milliondays, and one million nights sleep lost as aresult of it, in one year, in Britain alone(85). This article helps the reader develophis understanding of orofacial pain inparticular, with an object of exploring thenewer techniques and procedures thatimprove his diagnostic ability for bettertreatment.

Psychology o f dental painPsychology o f dental painPsychology o f dental painPsychology o f dental painPsychology o f dental pain

Perhaps the most important factoraffecting reaction to pain is basic emotion offear. A pain in the leg might well elicit lessof a reaction than a pain of equal intensityin the chest because the latter might appearto the sufferer to signify heart disease. Painin the head (including the face) are alsoregarded with greater apprehension sincethey might appear to threaten the innermostbeing including mind and thought processingin the cortex. Pain distorts this normal innerimage causing a feeling of revulsion. Theclinician attempts to see this picture todetermine its attributes, characteristics. Thisarticle in further is a step in this directionanalysing newer methods of electrophysiology

to understand this “blurred” image in orderto improve the diagnost ic abi l i ty andtreatment.

Pathways o f oro fac ia l pain : neuroanatomyPathways o f oro fac ia l pain : neuroanatomyPathways o f oro fac ia l pain : neuroanatomyPathways o f oro fac ia l pain : neuroanatomyPathways o f oro fac ia l pain : neuroanatomy(Diagram 4)(Diagram 4)(Diagram 4)(Diagram 4)(Diagram 4)

Sensory input from peripheral receptorsis carried along the trigeminal pathway tothe somatic sensory areas of the cerebralcortex via a 3-neurone chain. The cell bodiesfrom the Trigeminal (Gasserian) Ganglionand this main nerve bundle then enter thebrainstem at the level of the pons. Thesefibers synapse for the first time at the mainsensory nucleus o f the Vth nerve(discriminative tactile senses, light touch andpressure) or alternatively at descendingspinal tract nuclei, the N. caudalis (pain,temperature and crude touch), N. oralis(cutaneous sensation of oral mucosa) and N.interpolaris (tooth pulp pain). Second orderfibers arising from these sites then crossthe midline and ascend to synapse at thethalamus, from which thalamocort icalprojections then pass to those cortical areasconcerned with oro-facial sensation and itsappreciation. (86-89)

Neurophysio log ica l techniques for recordingNeurophysio log ica l techniques for recordingNeurophysio log ica l techniques for recordingNeurophysio log ica l techniques for recordingNeurophysio log ica l techniques for recordingorofac ia l pa inoro fac ia l pa inoro fac ia l pa inoro fac ia l pa inoro fac ia l pa in

Somatosensory evoked potentials (SEP)

The trigeminal SEP (TSEP) waveform :

The essential features of TSEP are thefollowing sequence of waves. N13, P20 andN27. Some studies have also observed muchearlier events, denoting N5 and P9 (90-92).The peak event at 20 ms has been noted asthe most consistently obtained and the most


clinically used (93,94). The P20 wave is thefirst consistent sign of concerted corticalact ivat ion. Beyond 30 ms the Evokedpotential, is subject to other influences suchas efferent and limbic activity and memoryrecall, making the behavior and morphologyof the wave form more complex to interpret.

These studies have shown that TSEP canbe recorded by stimulation of peripheralbranches of the trigeminal nerve. The siteof stimulation is usually the oral cavity. Themost favored being the lips or gums becauseof their relatively large sensory receptorrepresentation in the cortex. The infraorbitalnerve at the infraorbital foramen or thementalis nerve as it emerges from themandibular foramen is the other sites. These

however may show muscle artifacts onstimulation and may require the nerve to bepierced by a needle. Certain areas of scalp,which overl ie the central gyrus, havebeen shown to be good recording sitesfor detecting TSEP. Reference electrodesare placed in the mid frontal position(Fpz). Positions C5 and C6 that overliethe facial area of somatosensory cortex arethe most popular sites for active electrode(95).

Pain induced changes in TSEP could beobserved on stimulation of tooth pulp. Thesepain-induced changes could further bestudied in different diseased conditions,metabolic disorders in patients.

Cl in ica l appl i cat ions o f TSEPCl inica l appl i cat ions o f TSEPCl inica l appl i cat ions o f TSEPCl inica l appl i cat ions o f TSEPCl inica l appl i cat ions o f TSEP

There is still much to be elucidatedabout some features of the trigeminalsomatosensory evoked potentials (TSEP),particularly the early events. However,there are a number of instances where theyhave proved to be valuable in the assessmentof certain conditions. Their use and furtherexploration is advocated in these conditions(96-98)

For example a significant increase in thelatency of the P20 event has been taken toindicate a compressive lesion in trigeminalneuralgia, and this feature distinguishesthose patients most likely to benefit fromsurgical correction. (99).

The abolition of peaks N5 and P9 andthe normalisation of the latency of the N13peak has been taken to indicate the successof the treatment by thermocoagulation of thetrigeminal ganglion. (100).

Fig. 4 : Summary of the central connections ofthe Trigeminal Nerve.


Similarly, preservation and improvementof tactile sensibility following surgicalprocedures may be monitored using TSEP.Impairment of sensibility may be indicatedby reduction in amplitude, latency delays andeven abolition of the response (101).

A condit ion in which a pat ientexperiences an exaggerated response tonoxious stimuli is termed as Anaesthesiadolorosa (AD). It usually occurs postdentalsurgeries, in trigeminal tumors and post-herpetic neuralgias. Increased amplitudes ofTSEP beyond 50ms in AD is a diagnosticindicator.

This is an example where the subjectivepain sensation may be objectively assessedby the dental clinician using TSEPs.

Physio log ica l bas is o f pain re l ie f : c l in ica lPhysio log ica l bas is o f pain re l ie f : c l in ica lPhysio log ica l bas is o f pain re l ie f : c l in ica lPhysio log ica l bas is o f pain re l ie f : c l in ica lPhysio log ica l bas is o f pain re l ie f : c l in ica la p p l i c a t i o n sa p p l i c a t i o n sa p p l i c a t i o n sa p p l i c a t i o n sa p p l i c a t i o n s

Control of pain

One of the most important aspects of practiceof dentistry is the control or elimination ofpain. Pain has been so closely associatedwith dentistry that pain and dentistry havebecome almost synonymous. (76)

Fol lowing are the methods of paincontrol:

1) Removing the cause

2) Blocking the pathway of painful impulsese.g. Local anaesthetics

3) Raising the pain threshold e.g. aspirinand other pharmacological agents.

4) Preventing pain reaction by corticaldepression e.g. general anaesthesia

5) Using psychosomatic methods e .g .hypnosis, faith healing.

The f i rst two methods af fect painperception, the last two affect pain reaction,the third affects both.

Previous /o ld techniquesPrevious /o ld techniquesPrevious /o ld techniquesPrevious /o ld techniquesPrevious /o ld techniques

Across studies results suggested thatacupuncture, biofeedback and relaxationwere comparable to conservative treatment(for example an intraoral appliance) andwarranted further study. There were nostudies found that conducted randomisedclinical trials that tested the effects ofhomeopathy, naturopathy, chiropractic,massage , meditat ion, yoga or herbalmedicines for chronic facial pain. Significantgaps in the scientific basis limit the accuracywith which dental professionals can guidetheir patients regarding Complementaryalternative medicine approaches used totreat chronic facial pain (101).

A c u p u n c t u r eA c u p u n c t u r eA c u p u n c t u r eA c u p u n c t u r eA c u p u n c t u r e

In Classical Chinese Medicine it ispostulated that a vital force or life energy(chi) flows through the body in channels ormeridians.

Disease is associated with disturbance ofthis flow, but fortunately, the fault can becorrected by inserting one or more needlesinto the meridians concerned.

Scient i f i c bas is : mechanisms o f AcupunctureSc ient i f i c bas is : mechanisms o f AcupunctureSc ient i f i c bas is : mechanisms o f AcupunctureSc ient i f i c bas is : mechanisms o f AcupunctureSc ient i f i c bas is : mechanisms o f Acupuncture

Electropuncture has been found toproduce analgesia in various chronic painsyndromes of musculoskeletal origin (102).


This effect is due to activation of theperi-aqueductal matter which is connectedto the descending inhibitory pathways of thelower brainstem. (103)

This activation of the per-aqueductal greymatter releases endogenous opiod peptideson their binding sites, resulting in aninhibition of the inhibitory neurons and asubsequent disinhibition of the outputneurons to the nucleus raphe magnusand nucleus raphe dorsal is . Fromthese raphe nuclei of the lower pons andmedulla, one pathway spreads down to thedorsal horn o f the spinal cord whereincoming pain signals are inhibited andanother spreads upwards and releases 5-HTin forebrain structures . Thus . , withelectropuncture both descending andascending inhibitory pathways are involvedin pain control (104)

In the study group for electropuncture,ster i l i sed acupuncture needles areintroduced into the points selected accordingto tradit ional Chinese channels andcollaterals. (105,106)

Acute pain is sometimes proportional tothe extent of injury, but the contribution ofpsychological factors reveal complexrelationships that are profoundly influencedby fear, anxiety, cultural background and themeaning of the situation to the person (107).Various workers using evoked potential havereported electrophysiological correlates ofacupuncture (41). These analgesia studiessuggest interaction of other sensory afferentswith speci f ic pain pathways in brain,relieving pain.

Recent deve lopmentsRecent deve lopmentsRecent deve lopmentsRecent deve lopmentsRecent deve lopments

Some workers have reported that theapplication of electrical stimulation to thepituitary gland (PG) has produced dramaticrelief of intractable pain caused by advancedcancer (108,109). Electrical stimulation of thepituitary gland was followed by suppressionof tooth pulp evoked potentials (110). ThePituitary Inhibitory system is an entirelynew picture of the mechanism by whichelectrical stimulation of the PG results inpain relief and consists of rendering thehypophyseal system hyperactive, which inturn antidromically exerts an inhibitoryinfluence on the pain pathway in the brain(111).

Pharmacology and pharmacotherapeut icsPharmacology and pharmacotherapeut icsPharmacology and pharmacotherapeut icsPharmacology and pharmacotherapeut icsPharmacology and pharmacotherapeut ics

The narcot ic Fentanyl reduces thesensory intensity but not the unpleasantnessof painful pulp sensation (112). In contrast,anxiolyt ics such as Diazepam reducesaffective discomfort rather than sensory-intensi ty qual i t ies o f the exper ience .Similarly placebo medication has an impacton unpleasantness rather than on sensoryqualities of painful events.

There is also sufficient evidence ofefficacy of carbamazepine in trigeminalneuralgia, also for baclofen and lamotrigine.In Temporomandibular disorders (TMD),there is evidence of a moderate effect ofmuscle relaxants/ tranquilisers (113).

Recent advances in knowledge of theneural processes underlying pain in the faceand mouth reveal a remarkable degree of


plasticity following injury or inflammationof cranio fac ia l t i ssue . Ins ights intomechanisms involved in the transmission andmodulation of nociceptive signals in thebrainstem hold promise of the developmentof new or improved therapeutic proceduresfor the relief of pain (114).

Future trends and future therapeut icFuture trends and future therapeut icFuture trends and future therapeut icFuture trends and future therapeut icFuture trends and future therapeut icd i r e c t i o n sd i r e c t i o n sd i r e c t i o n sd i r e c t i o n sd i r e c t i o n s

A promis ing approach is the useof cort icotrophin-re leas ing hormoneantagonists . This is based on severalundergoing trials on chronic facial painpatients with antidepressants (115,116). It hasbeen postulated that hyperactivity of theHPA axis in-patients with fibromyalgiacorrelates with depression.

This leads us on to the hypothesis thatperhaps facial pain occurs in susceptibleindiv iduals who have an underly ingabnormality of stress hormone responseresulting in higher cortisol levels. Recentdata indicate very high anytime cortisollevels in patients with facial pain indicatingpathology in the hypothalamic Pituitary axis(HPA) (117).

As yet, there are no data available on

whether high cortisol levels persist in facialpain patients treated with antidepressantsand the mechanism of antidepressants tomodulate the Hypothalamic Pituitary axisactivity and increase glucorticoid is stillunknown. (118)

Tackling pain at the sourceTackling pain at the sourceTackling pain at the sourceTackling pain at the sourceTackling pain at the source : new ideas about: new ideas about: new ideas about: new ideas about: new ideas aboutn o c i c e p t o r sn o c i c e p t o r sn o c i c e p t o r sn o c i c e p t o r sn o c i c e p t o r s

P2X receptors are a family of ligand gatedion channels responsive to ATP, and seensubtypes that form homometr ic orheterometric channels have been identified(119) . In the spinal cord ATP actspresynaptically to regulate transmitterre lease and involves NMDA receptormechanism. (120-123)

Recent studies have provided evidence ofP2X mechanisms influencing nociceptivetransmission in the trigeminal system.(119,124). These research studies indicateappl icat ion o f se lect ive antagonistfor example TNP-ATP (2 ′ - (or 3 ′ - ) O-trinitrophenyl-ATP) may reversibly attenuatethe perception of nociceptive stimuli to thetooth pulp. On application there is a decreasein neuronal mechanoreceptor field andresponses to innocuous and noxiousmechanical stimuli (120,125).

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