Emergency Medicine Australasia (2005) 17, 65–72

Blackwell Science, LtdOxford, UKEMMEmergency Medicine Australasia1035-68512005 Blackwell Science Pty Ltd20051716572Original ArticleNeurophysiology of chronic painK Baker

Correspondence: Dr Kylie Baker, Ipswich Emergency Department, Ipswich General Hospital, Chelmsford Ave, Ipswich, QLD 4305, Australia. Email: Kylie_Baker@health.qld.gov.au

Kylie Baker, MBBS, Senior Medical Officer.

REVIEW ARTICLE

Recent advances in the neurophysiology of chronic painKylie BakerIpswich Emergency Department, Ipswich General Hospital, Ipswich, Queensland, Australia

Abstract

The chronic pain syndrome patient has become the ‘leper’ of emergency medicine. Thereare no emergency medicine guidelines and minimal research into managing this challeng-ing group of patients.

Objective: To summarize the recent advances in laboratory research into the development of chronicpain that have relevance to emergency management. When the level of supporting evi-dence is low, it is imperative that emergency physicians understand the physiology thatunderpins those expert opinions upon which they base their treatment strategies.

Methods: Literature was searched via Medline, Cochrane, Cinahl, and PsycINFO from 1996 to 2004,under ‘chronic pain and emergency management’. Medline from 1996 was searched for‘chronic pain and prevention’, ‘chronic pain and emergency’ and ‘chronic pain’. Bibliogra-phies were manually searched for older keynote articles.

Results: Advances in understanding the biochemical changes of chronic pain are paralleled bylesser known advances in delineation of the corticol processing.

Conclusions: Drug manipulation causes complex action and reaction in chronic pain. Emergency phy-sicians must also optimize cognitive and behavioural aspects of treatment to successfullymanage this systemic disease.

Key words: pain and chronic disease, neurophysiology.

Introduction

Current research indicates that chronic pain is not ‘allin the mind’, but a disease caused by maladaption ofpain pathways. It is well summarized by Carli:1

‘Repeated exposure to weak somatic stimuli leads to agradual decrease in response, i.e. habituation, whileexposure to potentially threatening or noxious stimuli

produces a progressive potentiation of the response, i.e.sensitization’.

Like most other body systems, the pain pathwaysdynamically remodel in response to ongoing stimula-tion. Roughly 10% of people seem to develop abnormalpain following injuries that may be minor.2–6

It is a mistake to consider pain purely as a sensoryinput. Pain pathways have complex efferent behav-

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ioural reflexes that generally operate at a subconsciouslevel.

This article follows the pain pathway from inputsignal to cortex and back-mentioning the various adap-tations that occur along the way. The complexities ofpharmacological management will become obvious, asdo further opportunities for intervention.

Mechanisms of chronic pain

The primary abnormality that presages chronic painremains a mystery. A myriad of cascading ligands,receptors, sodium channels, G-proteins, neurone tractsand receptor genes have been demonstrated, but exactinterrelationships are still under study. Correlatinglaboratory and animal studies with clinical human out-come remains difficult.7–9 However highly specific, use-dependent modifications have been identified at alllevels of the pain path.10–18 This dynamic response istermed neuroplasticity.1

Loeser identifies four broad categories of pain thatcan be used to divide the pain pathway both function-ally and anatomically.19

1. Nociception: — the purpose of the peripheral sensoryapparatus, and its local response

2. Perception of pain — the spinal interpretation andresponse to the initial input

3. Suffering — the product of midbrain, thalamic andlimbic modulation of input from both periphery andcortex. Provides focusing, autonomic and emotiveoutput, with reflexive behaviour.

4. Pain behaviour — the outcome of cortical analysisof all biopsychosocial input, current and past.

1.1 Nociception

Three types of sensory fibre can transmit pain sensa-tion. Namely, the slow, unmyelinated C fibre, the fastersmall myelinated A-delta and (after neuroplasticchange) the large myelinated A-beta fibres.7,20,21 TheseC, A-delta and A-beta fibres are bipolar, with cell bodiesin the dorsal root ganglion, and central terminals in thedorsal horn of the spinal cord. Their peripheral nerveendings, by tradition are said to lack a specific ‘nocice-ptive receptor’, however they have a multitude of otherreceptors designed to recognize the products of celldamage.7 Ligands for these receptors come from adja-cent nerves, nearby cells and the byproducts of damagesuch as protons and heat.21 Some receptors transmitcentrally to the dorsal horn, while others may fire anti-

dromically. Antidromic firing of the peripheral sectionof the nerve causes it to release its own barrage ofligands (e.g. Substance P, Calcitonin Gene RelatedProtein – CGRP and Neurokinin A) which enhance theinitial response.21,22 Mast cells degranulate and vascularendothelial cells generate nitric oxide (NO).7 The result-ant milieu has been called the ‘inflammatory soup’.19

The ‘soup’ causes peripheral sensitization in at leastthree ways.7,21,22

First, the number of nerve fibres deployed increasesusing recruitment of ‘sleeping’ A-delta and C fibres.21,22

Second, there is phenotypic change in the nerve fibresthemselves. For example, the A-beta fibres that trans-mit touch may start to express catecholamine receptorsand secrete substance P and glutamate.Third, theexcitability of the individual nerves change as calcium-initiated gene expression alters the N-methyl-D-aspartate (NMDA) receptors.7,21,22

Whether the information is transmitted furtherdepends partially on the intensity and duration of thestimulus, and partially on down-going modulation.14

Transient stimulus fires only the A-delta nerves and isusually self limited. Natural noxious stimuli cause anon-synchronous, irregular discharge in a fraction ofthe nociceptive nerve fibres.10 Significant injury, suchas surgical incision, favours localized peripheral sensi-tization which recruits further nociceptors. Localizedperipheral sensitization results in ‘primary hyperalge-sia’ or enhanced pain sensitivity at the site of injury.7,10,20

This primary response can be modulated peripher-ally. Certain systems, such as the opioid,15 the cannab-inoid,23 and gamma-aminobutyric acid (GABA)20,22

circuits are known to inhibit the response of the periph-eral nerve, often by hyperpolarizing it. If the stimulusis intense or prolonged the local response is more usu-ally amplified. Peripheral inputs summate in the dorsalhorn. This integration in the dorsal horn may eitherinhibit or maintain the peripheral sensitization, fordays, weeks or even years.10,12,22

1.2 Perception of pain

Peripheral sensory afferents synapse in the dorsal hornlamina of the spinal cord. Messages relevant to pain arerelayed in many tracts7,20 — predominantly via thespinothalamic tracts, but also in dorsal column tracts.20

The strength of the ongoing relay is influenced bydescending pathways which likewise synapse in thelamina. The message can thus be amplified or sup-pressed, due to either ‘central sensitization’ or ‘descend-ing noxious inhibition’.20,21,24,25 Stimuli that excite A-beta

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and A-delta but not C fibres, tend to cause pain sup-pression — hence the efficacy of counterirritationtechniques.10

Peripheral afferents that terminate in lamina I tendto synapse with nociception specific neurones, whichconvey information that aids discrimination and local-ization.20 The deeper laminas contain wide dynamicrange neurones (WDR). Several types of afferent fibremay converge on WDR neurones, giving informationthat is both somatic and visceral, noxious and non-noxious. The WDR neurones summate the input andtransmit information used in affective and motivationalresponse to the stimulus.21,22 Other neurone types areinhibitory, such as the interneurones of lamina II (thesubstantia gelatinosa).12

One of the most ubiquitous and best established pro-cesses is that by which synaptic transmission is rapidlystrengthened, and then durably up-regulated. Ituses glutamate reinforced by Substance P andNeurokinins7,20,22,25 (Fig. 1). Transient ‘wind-up’ can thusbe converted to ‘long-term potentiation’ with alteredgene expression.13,21

The outcomes of spinal sensitization are similar tothose of peripheral sensitization. There is increasedresponsiveness of second order neurones, due tochanges in sodium channel expression resulting in astronger action potential fired despite weaker initialstimuli.10,26 New and possibly abnormal circuits form,such as the sprouting of A-beta fibres into Lamina II.Furthermore, the size of peripheral receptor fields canincrease.11,22

The clinically relevant result of spinal sensitizationis termed ‘secondary hyperalgesia’, and describes theafferent changes in areas adjacent to the injury.10,11

These areas demonstrate hyperalgesia and allodynia.Allodynia is the feeling of pain with non-noxious stim-uli. Secondary hyperalgesia is more susceptible tonarcotic analgesia, and can spread to contralateral anddistant sites.10,11,22

1.3 Suffering — the midbrain, thalamus and limbic connections

The thalamus receives the majority of sensory informa-tion, and relays this through the hypothalamus, limbicnuclei and sensorimotor cortices.20 Bromm has mappedfour pathways that ascend from the spinothalamictract.27 He describes two medial paths that pass throughthe anterior or posterior cingulate gyrus. The anteriorcingulate gyrus transmits on to the thalamus, limbicnuclei and the primary somatosensory cortex (S1). This

is presumed to assign motivation and affect to a stim-ulus. The tract through the posterior cingulate gyrusrelays on to the secondary somatosensory cortex (SII)and the insula. This appears to appoint significance anddirect the appropriate amount of attention to a stimulus.Two lateral spinothalamic paths ascend directly tothe primary and secondary somatosensory cortices. Theformer is somatotopic and discriminative, while thelatter simply recognizes a stimulus as ‘pain’. The sen-sitivity of the medial tracts depends on the importanceattached to the stimulus, while the lateral tracts dependmerely on the arousal status of the patient.16,20,27

Complex processing presumably results in messagesfrom these cortical nuclei descending to the periaque-ductal grey (PAG) of the midbrain, where furtherintegration and production of a defence response takesplace.15 Current research has plotted several efferentpathways from the PAG.25

Initially considered the source of endogenous analge-sia, the PAG is now known to contain at least twoopposing pathways.14,25

Intense phasic pain is more likely to result indescending inhibition, while stimuli of lesser intensityinvoke facilitation.9 The path descending to dorsal hornlamina via the dorsolateral funiculus is analgesic, beingresponsible for ‘descending noxious inhibitory control’.This pathway is not somatotopic. For example stimula-tion in the trigeminal nerve area can cause increasedanalgesic neurotransmitters detectable in the lumbarspinal cord.21 This first analgesic pathway can be fur-ther divided into two separate actions. The lateral PAGinitiates flight or fight responses while the ventrolateralPAG enforces rest and immobilization.25

The second pathway from the PAG involves nervesdescending in the ventrolateral funiculus. In contrast tothe dorsolateral pathway, this tract involves differentneuromodulators and leads to facilitation of nociceptionin the periphery9,25 (Fig. 2). Facilitation is somatotopicinitially, thought to contribute significantly to centralsensitization, and opioid tolerance.28–30 Both antinocice-ption and nociception can be triggered by opioids in thePAG, or by electrical stimulation.25 It is thought that theinitial analgesic effect of narcotics is due to the morerapid firing of the dorsolateral pathway from the PAG,which is subsequently cancelled out as the slowerventrolateral pathway switches on the nociceptivefacilitation function. This results in a rebound localhypersensitivity to the painful stimulus. These oppos-ing systems also allow considerable margin for adapta-tion to pharmacological agents, resulting in a demandfor rapid escalation of drug doses.31

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Figure 1. Neuroplastic changes with ongoing noxious stimulus. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;NMDA, N-methyl-D-aspartate .

Step 1. Summation ofaction potentials in C fibres causes co-release ofSUBSTANCE P and GLUTAMATE.

Step 2. SUBSTANCE P AND GLUTAMATE act in concert on postsynaptic receptors causing increase in postsynaptic intracellular CALCIUM.

Step 4. High intracellular CALCIUM triggers several intracellular cascades.

Nitric oxide is madeand back-diffuses tofurther potentiateinflammatoryprocesses.

Prostaglandins are generated and backdiffuse to increaseinflammatoryprocesses.

Early immediate geneexpression alters, withdevelopment of new nerve phenotype egdifferent receptors,and different transmitters.

Step 3. NMDA and AMPA receptors upregulated byincreased calcium and transport further CALCIUM into the cell.

Early Wind-up

Long termPotentiation

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Figure 2. Descending modulation via the periaqueductal gray (PAG). GABA, gamma-aminobutyric acid; RVM, rostral ventromedialmedulla.

Ventrolateral PAG –results in analgesia, rest, immobilization probably in response tohypothalamic opioid.

Lateral PAG – results in flight or fight behaviour and analgesia, opioids hyperpolarize GABA, switching offinhibition in RVM.

Dorsolateral funiculus

Secretion of Seratonin, opioids,cholecystokinin into dorsal horn.

Ventrolateral funiculus

Rostral ventromedialmedulla

Locus Ceruleus provides noradrenalin

Raphe and Kolliker-Fuse nuclei provide glycine and serotonin.

Secretion of Noradrenalin, Acetylcholine, Seratonin, Glycine in dorsal horn.

DESCENDING NOXIOUSINHIBITON

DESCENDINGFACILITATION

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So why do several key transmitters act in both noci-ceptive and antinociceptive pathways with seeminglyparadoxical effects? One rationale for this action is sug-gested by Kerr who studied the triphasic response togalanin.32 Galanin is tonically secreted in very low dosesin the spinal cord where it acts to inhibit nociception.With moderate levels of noxious insult, higher levels ofgalanin sensitize nociceptive pathways and increaseavoidance behaviours. With severe noxious insult, veryhigh levels of galanin again inhibit the pain pathways.This provision in the dorsal horn allows a wide rangeof noxious insults to be summated and transmuted to aneurotransmitter concentration, with a concentration-dependent protective response ensuing from the dorsalhorn itself.

Mention must be made of visceral pain. It is consid-ered a separate entity by investigators33 and hasreceived less attention. Within the limitations of thisreview, similarities outweigh differences, which can bebriefly summarized. Visceral pain is poorly localized, isreceived by a different pattern of lamina in the dorsalhorn, is associated with more intense motor and auto-nomic reactions and does not exhibit short-term wind-up. Conditions such as irritable bowel syndrome dem-onstrate a hypervigilance pattern, with PET scans sup-porting an abnormal cortical processing pattern.18,33

1.4 Pain behaviour

Chronic pain is differentiated from acute pain by thebody’s inability to restore its original physiologicalhomeostasis.19 The body’s rapidity in adapting to druginterventions suggest that the abnormality involves thesetting of homeostasis itself. Loeser and Melzack pro-pose a ‘neuromatrix’, a cortical template of the bodywherein reside the blueprints of normality.19 Earlyresearch supports this idea, as do the modest successesof cognitive and behavioural therapies.16,34

Flor et al. identify a possible ‘neuromatrix’ in theprimary somatosensory cortex (SI), just medial to theinsula.16 This area is separate from the sensoridiscrim-inative areas within SI. It receives the contralateralbody input. Flor and co-workers believe it to be dedi-cated specifically to pain, mapped with body parts likeother organizations within the brain. They have dem-onstrated that chronic pain leads to an expansion of theSI cortical representation zone related to that particu-lar nociceptive source. Following deafferentation (forexample, amputation) Flor has demonstrated that thearea previously serving the amputated limb, can be‘taken over’ by adjacent inputs, in their study non-

nociceptive afferent input from the mouth can causeexcitation in the SI previously devoted to the amputatedlimb. They hypothesize that non-painful sensory inputfrom the mouth is interpreted as pain in the phantomlimb. Wilder-Smith has extended this work investigat-ing the effects of pre-amputation analgesia.8

While Flor investigates subconscious pain per-ception,16 Hasenbring and colleagues have studiedconscious processing of painful stimuli, using neu-ropsychological testing, and subjective pain ratings incooperative patients.5 How one perceives pain effectssubsequent modulation.

Hasenbring showed that more or less attention paidto both acute and chronic pains, led to greater or lesserrating of its severity.5 Furthermore, initial consciousprocessing techniques of a new acute pain stimulusdictated the extent to which the body up-regulated thepain pathways. Conscious processing techniquesdepended more on the patient’s mood state at the time,than on underlying chronic propensity. Verbal rein-forcement also enhances early cortical nociceptive pro-cessing.16 Hasenbring showed that patients who reactedto acute pain with ‘catastrophising’ — focusing on itsmost serious, fearful outcome, were the people mostlikely to progress to chronic pain.5 The best outcomeswere experienced by people who used sensory monitor-ing — periodically attending to the pain but withoutemotive connections. Presumably, the safe direction ofattention is vital in avoiding corticolimbic activationand hence central sensitization.

Chronic pain results in spreading hyperalgesia, allo-dynia and the exaggerated avoidance behaviours thatwe stigmatize as histrionic.11 Another aberrant behav-iour is termed ‘pseudoaddiction’. This term is used todescribe behaviour very similar to that of the drug-seeker, but which disappears with appropriate manage-ment of the pain — narcotic or otherwise.35,36

There remains the argument that chronic pain iscaused by an initial psychiatric abnormality — such asdepression. Certainly the overlap with psychiatric dis-ease is impressive, but most researchers lean away frompsychiatric disease as the major factor. Carli points outthat there is a population of pain patients who have nodiscernable psychiatric disease, and still display plasticchanges in the nociceptive system.1

Conclusions

In summary, chronic pain syndrome is a spectrum ofsystemic disease. Behaviours that we loosely term

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‘abnormal’ are expected outcomes of central sensitiza-tion to a painful stimulus. The stimulus may be longgone but the circuitry remains, for a reason not yetdiscovered. In the same way as cranial nerve examina-tion localizes brainstem injury, so do the various pat-terns of pain indicate abnormalities along the pathwaysdescribed in this paper.

Pain behaviour patterns are predictable and repeti-tive. The pervasiveness of an acute exacerbation ofchronic pain is reminiscent of a seizure disorder, ormore simplistically, a cardiac re-entrant dysrhythmia.The treatment modalities overlap substantially yet ourattitudes diverge.

Emergency physicians should recognize the chronicpain syndrome as a dynamic response and any dynamicresponse can be influenced. Chronic pain patients do notstay confined to pain clinics, their disease is a ‘24/7’condition and the ED is often the only ‘24/7’ serviceavailable. Therefore uniform, non-judgemental and evi-dence-based ED guidelines are required. Bearing inmind that chronic pain is exquisitely sensitive to cogni-tive and verbal reinforcement, it is imperative that wemonitor our own approach to these patients.

It will require conscious effort to break this viciouscycle.

Acknowledgements

I would like to thank librarians Ms Elisabeth Cash andMs Lyn Bogaarts for exceptional patience and assis-tance. Also Dr Nigel Roberts and Dr Stephen Brierleyfor editing suggestions.

This paper has been written with the support ofIpswich General Hospital in the form of study leave,library assistance and use of the information systems.

Competing interests

None declared.

Accepted 20 September 2004

References

1. Carli G. Neuroplasticity and clinical pain. In: Sandkuhler J,Bromm B, Gebhart GF (eds). Nervous system plasticity andchronic pain. Prog. Brain Res. Amsterdam: Elsevier, 2000; 129:325–30.

2. Callesen T, Bech K, Kehlet H. Prospective study of chronic painafter groin hernia repair. Br. J. Surg. 1999; 86: 1528–31.

3. Hubbard J, Tracy J, Morgan S, McKinney R. Outcome measuresof a chronic pain program: a prospective statistical study. Clin.J. Pain 1996; 12: 330–7.

4. Stanton-Hicks M, Burton A, Bruehl S et al. An updated interdis-ciplinary clinical pathway for CRPS: report of an expert panel.Pain Practice 2002; 2: 1–16.

5. Hasenbring M. Attentional control of pain and the process ofchronification. In: Sandkuhler J, Bromm B, Gebhart GF (eds).Nervous system plasticity and chronic pain. Prog. Brain Res.Amsterdam: Elsevier, 2000; 129: 525–34.

6. Nielson W, Mior S. Prevention of chronic pain: the unexploredfrontier. Clin. J. Pain. 2001; 17 (Suppl. 4): S68–9.

7. Besson J. The neurobiology of pain. Lancet 1999; 353: 1610–15.

8. Wilder-Smith O. Preemptive analgesia and surgical pain. In:Sandkuhler J, Bromm B, Gebhart GF (eds). Nervous system plas-ticity and chronic pain. Prog. Brain Res. Amsterdam: Elsevier,2000; 129: 505–24.

9. Boureau F, Luu M, Doubrere J. Study of experimental pain mea-sures and nociceptive reflex in chronic pain patients and normalsubjects. Pain 1991; 44: 131–8.

10. Sandkuhler J, Benrath J, Brechtel C, Ruscheweyh R, Heinke B.Synaptic mechanisms of hyperalgesia. In: Sandkuhler J, BrommB, Gebhart GF (eds). Nervous system plasticity and chronic pain.Prog. Brain Res. Amsterdam: Elsevier, 2000; 129: 81–100.

11. Treede RD, Magerl W. Multiple mechanism of secondary hype-ralgesia. In: Sandkuhler J, Bromm B, Gebhart GF (eds). Nervoussystem plasticity and chronic pain. Prog. Brain Res. Amsterdam:Elsevier, 2000; 129: 331–42.

12. Moore KA, Baba H, Woolf CJ. Synaptic transmission and plas-ticity in the superficial dorsal horn. In: Sandkuhler J, Bromm B,Gebhart GF (eds). Nervous system plasticity and chronic pain.Prog. Brain Res. Amsterdam: Elsevier, 2000; 129: 63–80.

13. Gerber G, Youn DH, Hsu CH, Isaev D, Randic M. Spinal dorsalhorn synaptic plasticity: involvement of Group 1 metaboltrophicglutamate receptors. In: Sandkuhler J, Bromm B, Gebhart GF(eds). Nervous system plasticity and chronic pain. Prog. BrainRes. Amsterdam: Elsevier, 2000; 129: 115–36.

14. Pertovaara A. Plasticity in descending pain modulatory systems.In: Sandkuhler J, Bromm B, Gebhart GF (eds). Nervous systemplasticity and chronic pain. Prog. Brain Res. Amsterdam:Elsevier, 2000; 129: 231–42.

15. Ingram SL. Cellular and molecular mechanism of opioid action.In: Sandkuhler J, Bromm B, Gebhart GF (eds). Nervous systemplasticity and chronic pain. Prog. Brain Res. Amsterdam:Elsevier, 2000; 129: 483–92.

16. Flor H. The functional organisation of the brain in chronic pain.In: Sandkuhler J, Bromm B, Gebhart GF (eds). Nervous systemplasticity and chronic pain. Prog. Brain Res. Amsterdam:Elsevier, 2000; 129: 313–24.

17. Lenz FA, Lee JI, Garonzik IM, Rowland LH, Dougherty PM, HuaSE. Plasticity of pain-related neuronal activity in the humanthalamus. In: Sandkuhler J, Bromm B, Gebhart GF (eds). Nervoussystem plasticity and chronic pain. Prog. Brain Res. Amsterdam:Elsevier, 2000; 129: 259–76.

18. Casey KL. Concepts of pain mechanisms: the contribution offunctional imaging of the human brain. In: Sandkuhler J, BrommB, Gebhart GF (eds). Nervous system plasticity and chronic pain.Prog. Brain Res. Amsterdam: Elsevier, 2000; 129: 277–88.

K Baker

72

19. Loeser J, Melzack R. Pain: an overview. Lancet 1999; 353: 1607–9.

20. Willis W, Westlund K. Neuroanatomy of the pain system and ofthe pathways that modulate pain. J. Clin. Neurophysiol. 1997; 14:2–31.

21. Sorkin L, Wallace M. Acute pain mechanisms. Surg. Clin. N. Am.1999; 79: 213–29.

22. Bolay H, Moskowitz M. Mechanisms of pain modulation inchronic syndromes. Neurology 2002; 59 (Suppl. 2): S2–7.

23. Calignano A, La Rana G, Loubet-Lescoulie P, Piomelli D. A rolefor the endogenous cannabinoid system in the peripheral controlof pain initiation. In: Sandkuhler J, Bromm B, Gebhart GF (eds).Nervous system plasticity and chronic pain. Prog. Brain Res.Amsterdam: Elsevier, 2000; 129: 417–82.

24. Peters M, Schmidt A, Van den Hout M, Koopmans R, Sluijter M.Chronic back pain, acute postoperative pain and the activationof diffuse noxious inhibitory controls (DNIC). Pain 1992; 50:177–87.

25. Urban M, Gebhart G. Central mechanisms in pain. Med. Clin. NAm. 1999; 83: 585–96.

26. Cummins TR, Dib-Hajj SD, Black JA, Waxman SG. Sodium chan-nels and the molecular pathophysiology of pain. In: SandkuhlerJ, Bromm B, Gebhart GF (eds). Nervous system plasticity andchronic pain. Prog. Brain Res. Amsterdam: Elsevier, 2000; 129:3–20.

27. Bromm B, Scharein E, Vahle-Hinz C. Cortex areas involved inthe processing of normal and altered pain. In: Sandkuhler J,Bromm B, Gebhart GF (eds). Nervous system plasticity and

chronic pain. Prog. Brain Res. Amsterdam: Elsevier, 2000; 129:289–302.

28. Kaplan H, Fields H. Hyperalgesia during acute opioid abstinence:evidence for a nociceptive facilitating function of the rostralventromedulla. J. Neurosci. 1991; 11: 1433–9.

29. Li X, Angst M, Clark J. Opioid induced hyperalgesia and inci-sional pain. [Abstract]. Anesth. Analg. 2001; 93: 204–9.

30. Kim D, Fields H, Barbaro N. Morphine analgesia and acutephysical dependence-rapid onset of two opposing, dose relatedprocesses. [Abstract]. Brain Res. 1990; 516: 37–40.

31. Prager J. Chronic pain management. [audiocassette] Audio-Digest Emergency Medicine. Proceedings of the 16th AnnualNational Conference on Advances in Emergency Medicine andPrimary Care; 2003, April 11–13; Coronado, California. AudioDigest Foundation., 2003 June 21: 20 (issue 12).

32. Kerr BJ, Wynick D, Thompson SWN, McMahon SB. The biolog-ical role of galanin in normal and neuropathic states. In:Sandkuhler J, Bromm B, Gebhart GF (eds). Nervous system plas-ticity and chronic pain. Prog. Brain Res. Amsterdam: Elsevier,2000; 129: 219–30.

33. Cervero F, Laird J. Viceral pain. Lancet 1999; 353: 2145–8.

34. Nielson W, Weir R. Biopsychosocial approaches to the treatmentof chronic pain. Clin. J. Pain 2001; 17 (Suppl.): S114–27.

35. Ducharme J. Acute pain and pain control: state of the art. Ann.Emerg. Med. 2000; 35: 592–603.

36. MacLeod DB, Swanson R. A new approach to chronic pain inthe ED. Am. J. Emerg. Med. 1996; 14: 323–6.