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Clinical Medicine and Diagnostics: 2011; 1(1): 1-7

DOI: 10.5923/j.cmd.20110101.01

Central Sensitization: Clinical Implications for Chronic
Head and Neck Pain
Arthur S. Roberts
Department of Oral Medicine, Indiana University School of Dentistry, Indianapolis, 46202

Abstract Chronic clinical pain associated with CS, is a potentially progressive, devastating, multimodal disease with a
significant worldwide economic and social burden. Effective intervention is dependent upon recognizing the fundamental
differences in acute and chronic pain, the effects on and by the neuromatrix upon the biopsychosocial health of the individual patient, and integrating that knowledge into a comprehensive multidisciplinary therapeutic plan.

Keywords Chronic Pain, Sensitization, Neuromatrix, Biopsychosocial, Polypharmacy

1. Introduction
Chronic pain is a multidimensional experience encompassing biological, psychological and social elements. Each
of these elements is entangled bi-directionally with the
neuromatrix as a whole. Figure 1.
There is a growing consensus that chronic pain is a disease
entity. This disease has been termed maldynia by the
American Medical Association. This new designation has
come about in recognition that acute and chronic pain are
fundamentally different experiences, demanding a fresh
approach to diagnosis, therapy, and prognosis. It has been
repeatedly demonstrated that many chronic pain disorders
have a major component of central sensitization. Assessment
and therapy for these several disorders is dependent on an
understanding of central sensitization.

eased descending inhibition, dysautonomia, and altered
serotonin production/utilzation. The resulting depression,
anxiety, sleep fragmentation, allodynia, and hyperalgesia
characterize a number of chronic pain disorders.[2-13]
At least two etiological pathways are posited for central
sensitization. The first is chronification of nociceptive pain;
and involves neuroplastic changes, and peripheral sensitization as precursors to central sensitization and the resulting
clinical pain. A more psychologically centered pathway is
offered as an alternative to this transformed nociception.
This alternate pathway begins with elevated levels of
chronic stress, and encompasses elements of anxiety, sleep
fragmentation, decreased pain thresholds, and dysautonomia. It is common to find both axes actively involved in the
etiology of a central sensitization syndrome. Central sensitization syndromes can be thought of as the archetypical
exemplars of a chronic biopsychosocial pain disorder.[1,3,5,14-18].

2. What is Central Sensitization (CS)
Central sensitization is thought to occur when “Sensory-afferent signals overwhelm the body's ability to filter
them”.[1,2] When this occurs a number of pathophysiologic
changes occur including neuro-immune dysfunction, neuro-endodrine dysfunction, NMDA (N-methyl-D-aspartate)
dysregulation, sympatho-afferent coupling; and altered serotonin and norepinephrine production and utilization.
These events are thought to occur predominantly in the
mid-brain and associated structures and are influenced by
elements of the neuromatrix delineated by Melzack, Woolf,
and others.[1,3-5]
These pathophysiologic changes are associated with decr-

2.1. What Are Central Sensitization Syndromes (CSS)

* Corresponding author: (Arthur Roberts)
Published online at
Copyright © 2011 Scientific & Academic Publishing. All Rights Reserved

“A similar and overlapping group of syndromes without
demonstrable pathology and bound by a common patho-physilogical mechanism of central sensitization.”[2]
The balance of expert opinion holds that the following are

Figure 1.

Adapted from Wallace and Clauw [2] MGN – Migraine. and is the result of approaching each of the varied presentations of CSS as a separate and distinct disease.12.13.Chronic Fatigue syndrome.14.21. CFS . [1-3] More specifically we can assess the patient to establish the presence of characteristic sequelae of the pathophsiologic changes associated with central sensitization. The pathways are few. fibromyalgia.8. is to address the effects of CS after it has occurred.8. In addition. is an indicator of the presence of CS. MPS – Myofascial pain syndrome. The first. there is a growing consensus that multiple chemical sensitivity. and autonomic nervous system alterations. [2. This produces altered accommodation of minimally painful events. periodic limb movement disorder and restless leg syndrome are strong candidates for inclusion as central sensitization syndromes. RLS .11. IBS .1. fatigue. Roberts: Central Sensitization: Clinical Implications for Chronic Head and Neck Pain part of that group: Migraine headache. In addition.[6. and contribute to immune abnormalities. BMS – Burning mouth syndrome. A part of this issue may derive from failing to differentiate chronic from acute pain. However.5. AO . and myofascial pain syndrome.4.Restless leg syndrome. we can establish a list of indicators for central sensitization. Each complaint not intuitively associated with CS. a major contributing etiologic factor in CS can be assessed using a number of non-invasive methodologies: • HPA axis – salivary cortisol • Autonomic nervous system – salivary alpha-amylase and heart rate variability • Neural and immune profiles – cutaneous sweat patch 3.5. 19] Figure 2.17.7.Atypical odontalgia. and anxiety via increased norepinephrine levels. post traumatic stress disorder. especially those deriving from transformed nociceptive pain. This contributes to dysfunctional sleep. and greater impact of peripheral sensitization.12. Therapy Polypharmacy is one of the problems attendant to CSS therapy. low vagal tone. The second is to interrupt the CS and let the body’s homeostatic mechanisms clear residual pathologic products. Allodynia.13] Use of anti-inflammatory drugs .2. hyperalgesia. Therapy and Prognosis By definition CSS are without demonstrable pathology. in concert they are highly suggestive of CS.14. [5.Post traumatic stress disorder.15-17. and iatrogenic contribution to decreased patient quality of life.23-25. hyperalgesia. irritable bowel syndrome. and contributes to depression.20. tension-type headache. Pharmacological Approaches Central sensitization is entangled with neuroplasticity and peripheral sensitization in many chronic pain syndromes. TMD – Tempoomandibulal dysfunction. and have fairly specific therapeutic protocols associated with them.1.13-15. Taken alone. and is reflected in lowered pain thresholds. This inevitably leads to polypharmacy. and poor sleep. PLMD . While the acute symptoms of CSS disorders need to be addressed. Optimal outcomes often depend on doing both. produce increased sympathetic tone. depression. primary dysmenorrhea. [7.32] There are two distinctly different approaches to CSS therapy.[8. 20] • Sympatho-afferent coupling of sensitized trigeminal complex leads to lowered parasympathetic drive and increased sympathetic drive.Primary dysmenorrhea.Periodic limb movement disorder. as is exacerbated widespread pain highly correlated with elevated stress levels.Irritable bowel syndrome. and historically more common. Diagnosis. DPSN – Depression. [2. allodynia. when seen in association with other disorders thought to have a significant CS component. Within these two broad categories we have both pharmacological and non-pharmacological therapeutic options. chronic fatigue syndrome.[1. MCS . 18.20. PD .23. These are posited to be: • Vagal dysregulation reduces endorphin release and alters serotonin production and utilization. none of these are pathognomonic. 40-44] 3.1.19. 3. stress related pain exacerbation. but not hyperalgesia. tempormandibular disorder.6. the probability of a CSS diagnosis is further increased.[1. 17.2 Arthur S. with the possible exception of allodynia and stress related pain.14.26-32] • Hypoactivity of the hypothalamic-pituitary-adrenal axis.13.33-38] Utilizing the resultant depression. allodynia. by either patient or provider. anxiety.Multiple chemical sensitivity.[1-3. FMS – Fibromyalgia. This leads us to clinical assessment as the most productive diagnostic approach. TTH Tension-type headache. This contributes to the fatigue and malaise often associated with CSS. IBS PD MCS DPSN MPS MGN TTH CSS PTSD BMS AO PLMD TMD FMS RLS CFS Figure 2. may result in treatment by a number of different prescribing specialists.21-25] • Decreased medullary descending inhibition of nociception. The concurrent presentation of multiple disorders with a significant CS component is an indicator of the presence of central sensitization syndrome. burning mouth syndrome. it is essential to treat the pathways in chronic pain disease.39] Stress. secondary to the side effects of the multiple medications. This increases the effective peripheral nociceptive input. PTSD . atypical odontalgia.

NMDA blockers (ketamine. and also improvement of cognitive function.46. norepinephrine and substance P. altering sensory-discriminative function. The resulting stimulation of.[56.44. a large number of opportunities are available for non-pharmacological therapies (NPT). Clinically it is common for these patients to cease responding to this class of drugs. originated pain. reduces the noxious input to the sensitized medulla.9. vagus and occipital afferents produce a number of changes in the neuromatrix.[42] N-methyl-D-Aspartate Receptor Blockers Activation of NMDA-receptors (and protein kinase C) will induce hyperalgesia. memantine and dextromethorphan) have been applied to interrupt this process. may respond to its second-generation analogue. disposable. use of opioid therapy for clinical pain remains a case-by-case judgment in carefully selected and well-monitored patients. In practice some of these interventions may well do both. all of which impact upon the neuromatix and ameliorate the pain experience. some investigators argue that the analgesic effects are independent of descending inhibitory control and are influenced by other elements of the neuromatrix. The overall effect of these drugs is to enhance sleep and coping. but do not directly treat the central sensitization. It would follow that in those cases of stress induced central sensitization. and thence serotonergic and noradrenergic neurons to increase descending inhibition. rather than peripherally.[13. leading to restoration of descending inhibition. Evidence is limited for these substitutions. 1(1): 1-7 may reduce levels of peripheral stimulus. like the pharmacological interventions. integrated circuit controlled. is of interest because of its multi-modal action.8. From one perspective. without a nociceptive component. primarily.2.Clinical Medicine and Diagnostics: 2011. but also have significant impact upon immune function (as does central sensitization). Though working through somewhat different pathways some clinicians have recommended the use of carbamazepine. an opioid-like drug.[1. Non-pharmacological Approaches Each influence upon the neuromatrix offers an opportunity to target therapeutic interventions.13.47] Serotonin. and its second-generation analogue oxcarbazepine.57] However.[44. in these resistant cases. as well as to diminish the central sensitization itself. Though its binding at mu receptor cites is low.54] 3. Unfortunately. or responding to the effects of CS. [42] Opioids and Tramadol The use of opioids for chronic pain is open to some controversy. and reduce the release of glutamate.42.[13] Many of the drugs that we use to address central sensitization will have a beneficial effect on the ability of the patient to cope with the pain.45] Drugs used to address the effects of central sensitization: • Acetaminophen • Serotonin (SSRI) and norepinephrine (SNRI) reuptake inhibitors and tricyclic antidepressants (TCA) • Opioids and Tramadol Drugs that may treat the central sensitization itself: • N-methyl-D-aspartate (NMDA) receptor blockers • Calcium channel alpha(2) ligands Acetaminophen Acetaminiphen acts on the periaquaductal gray. Gabapentin and pregabalin interrupt this action. affecting both spinal activity and descending inhibition via monoamine pathways in the brain.43. and apoptosis in the dorsal horn.1. It is interesting to note its greater efficacy in centrally. supraspinal facilitatory loops.52] Tramadol. and postsynaptic noxious transmission.47. and catastrophizing.[42. For clinical purposes these NPT. Repetitive Transcranial Magnetic Stimulation (rTMS) This relatively safe and non-invasive technique involves stimulation of the motor cortex and prefrontal cortex. can be divided into two broad operative groups: Reducing CS itself.and Norepinephrine-Reuptake Inhibitors Serotonin re-uptake inhibitors (SSRI) and the serotonin precursor tryptophan enhance descending inhibition and are of use in stress-induced hyperalgesia. however they 3 have a fairly narrow therapeutic window. While some of these targets are best addressed pharmacologically. In theory it reverses intra-cortical motor dysfunction. though to varying degree. power source the patient can discreetly wear these devices for extended periods. This.13. and contribute to interleukin-1 mediated inflammatory pain hypersensitivity. there is some evidence that nociceptive inflammatory pain that is resistant to gabapentin. Serotonin and norepinephrine inhibitors (SNRI) and tricyclic anti-depressants (TCA) have a dual action. and potentiate endogenous opioids.[43. it is also a reuptake inhibitor of both serotonin and norepinephrine. pregabalin. in turn. the trigeminal. calcium channel ligands may be less efficacious. Interestingly. Utilizing a small.2.[5.41.43. opioids have the capacity to target critical mechanisms of central sensitization. It has seen limited application due to the short duration of its effects and significant equipment costs.32.[53-55] Calcium Channel Alpha(2)Delta Ligands Voltage-sensitive Calcium channels at the junction of primary afferent and second order sensory neurons will sustain an enhanced release of neurotransmitters in chronic pain. Among the observed results of PENS . and may be analgesic in some circumstances.48] In addition. reduce anxiety. TCAs are also thought to have a beneficial neuro-hormonal impact. leading to reduction of both pre-.49-51] Taken with the significant positive reinforcement of these drugs on the reward centers of the brain.[58] Percutaneous Electroneural Stimulation (PENS) Direct access to peripheral branches of multiple cranial and cervical nerves is available via percutaneous placement of electrodes on the human auricle. they not only target pain mechanisms.

and thereby increase the endogenous stress levels. analgesia and inflammation control in the acute phase.35.74] Once the CS reaches this stage. mere removal of the initiating stimulus will not insure favorable outcomes.25-28. will improve the prognosis.). Additionally there are neuro-immune changes from upregulated pronociceptive immune mediators in primary afferent nociceptors. those representing various combinations of the two. but evidence regarding their safety and efficacy is limited. or prevention. The resultant analgesia and mood improvement appears to follow a ‘learning curve’[59]. [12.4 Arthur S. This is best accomplished with adequate anesthesia.62. Effective in- . As such.[13.17. In the case of transformed nociceptive pain. and additional elements of CS.13.[2. PENS is one of our few cost-effective. manual therapy. early psychosocial intervention. once initiated central sensitization will engender additional presentations (Figure 1. Prognosis CS is a potentially disabling and devastating disease whose prognosis is dependent upon the ability to identify and address the initiating and perpetuating pathways. However.61. hyper-excitable chronic pain patient and is related to sympatho-afferent coupling in the hypothalamic-pituitary-adrenal axis of the neuromatrix. The possibilities here fit into three classes: Those derived from transformed nociceptive pain. significant improvement in centrally mediated pain.14. as opposed to responding to the deleterious effects of CS. two of the major participants of CS. Its effect is thought to derive from distraction in the hyper-vigilant patient. leading to anxiety. This often leads to clinical observation of the irritable. their maladaptive behavioral responses and autonomic balance. and perhaps more importantly.[1] Neuroplasticity and peripheral sensitivity enable the central sensitivity. some complementary and alternative approaches are being investigated and show promise.8-10. is an intervention to address functional rehabilitation. However. rather than control or eradication of the CS. 55] The other broad category of non-pharmaceutical CS intervention encompasses manual therapy. Manual Therapy Manual therapy improves function and additionally produces an improvement in descending inhibition. and thorough patient education.53.40.[4. maladaptive behavior may engender biological issues that will contribute to maintenance and exacerbation of CS.20-23.[1. with patient improvement being graphically additive and cumulative based upon total wearing time of the device. multimodal disease with a significant worldwide economic and social burden. non-invasive. and most commonly. These elevated stress levels will eventually result in increased sympatho-afferent coupling. Reduction of stress levels can significantly improve the patient’s pain threshold. and autonomic dysfunction. three elements are necessary for development of chronic clinical pain: neuroplasticity. Removal.[2.42-44.74] In the case of stress induced CS.3. including the development of additional CS presentations (syndromes). 69-73] 3. It is not in widespread use and its clinical application is currently limited. and endorphin production.74] Unfortunately.[13. 4. Roberts: Central Sensitization: Clinical Implications for Chronic Head and Neck Pain therapy are improved autonomic regulation. and lowered pain thresholds. which increase the frequency and intensity of pain. Most of the observed improvement is putatively ascribed to changes in the function of the trigeminal complex and anterior cingulate portions of the neuromatrix. peripheral sensitization. poor sleep. the analgesia is of short duration and provides limited assistance in desensitizing the neuromatrix. devastating. and transcutaneous electric nerve stimulation. is a potentially progressive. As such. virtual reality. from a clinical perspective. low co-morbidity options for the treatment of central sensitization itself. sensory . will have a continuing stimulus for the development and/or maintenance of CS and are likely to experience an extended disease course. virtual reality has gained some support. and the focus devolves to dealing with the effects of the CS.60-64] Virtual Reality Though there is limited evidence.2.66-68] Transcutaneous Electrical Nerve Stimulation TENS is commonly employed in chronic pain states. improving stress tolerance. serotonin/norepinephrine production and utilization. no biological axis may exist in the early stages.65] Improving Stress Tolerance and Neuro feedback Training Stress is a major etiologic and exacerbating factor for CS.12-15. any therapy that reduces the overall burden on the neuromatrix will reduce the self-sustaining feedback that contributes to the progressive nature of CS. and central sensitization. It has some significant effect with focal. difficulty coping. of either or both of these. which results in widespread analgesia. however the results in widespread pain are equivocal.2. These can be thought of as addressing the functional deficits created by the CS.discriminatory functions. and would thus have potential benefit in patients with movement associated nociceptive etiology. 6.5.[2. Though primarily addressing the aftermath of CS. Conclusions Chronic clinical pain associated with CS. certain inflammatory diseases for instance.36. The chronic pain associated with PTSD and depression in the apparently healthy individual may well be examples of just this sequence. A corollary to this: Patients with persistent biological sources of nociception. Its effectiveness is related to activation of polysegmental inhibitory feedback. an increased risk of developing additional presentations of CS. Both endogenous (chronic pain) and exogenous (psychosocial changes) sources of stress can be involved. In addition. those derived from stress. segmental chronic pain.

Fibromyalgia and Other Central Pain Syndromes. Amrutkar DV.. 2009. 118: p. 30(25): p. Vagus nerve Educ. Effects of auricular electrostimulation on vagal activity in novel facilitory role in the development of persistent pain. 8624-8636 Clin Sci. J Neurophysiol. Burns C. ed. 1-12 Wulf-Johansson H. Treatment of central sensitization in patients with 'unexplained' chronic pain: what options do we have? Expert Opin Pharmacother. regulation and management. 2001. Clauw DJ. Cephalgia. 2010. Maldynia: Pathophysiology and management of neuropathic and guide to diagnosis and management. Ickmans K. 136-142. Oct 24 Epub ahead of print [22] Zhang Y. Lippincott Williams & Wilkins: [18] Graven-Nielsen T. 2009. large conductor calcium-activated potassium channels and morhine-resistant. Matharu MS. N. Scotland.Clinical Medicine and Diagnostics: 2011. 2010. Therapeutic neuromodulation in primary headaches. Editor 2001. Chronic vagus stimulation improves autonomic control and attenuates Graven-Nielsen T. Headache. 2519-2527 rat trigemino-neuronal pathway. 26(4): p. in Myofascial pain and fibromyalgia syndromes: a clinical [19] Dickinson BD.experimental data and new [20] Dorr AE. Pain Med. Arendt-Nielsen L. Silberstein S. Popovic ZB. Inanici F. Boas DA. 2-10 Yunus MB. Zhuo M.. Jansen-Oleson I. 2008. ed. Localization of [26] Miraucourt LS. Wei D. Clinical characteristics and biopathophysiological mechanisms of fibromyalgia syndrome. Huang Z. Debonnel G. 2007. 87: p. 47(7): p. Nat Med. Gebhart GF. OsterwijckJV. Bibevesky S. Moskowitz MA. J healthy men: evidence from a three armed randomized trial. Central Sensitization. and integrating that knowledge into a trigeminal ganglion: implications for migraine pathology. Matic M. Anderson B. 1(1): 1-7 5 p. Schoenen J. 413-417 Exp Ther. 651-661. Langford the neuromatrix upon the biopsychosocial health of the inLE. Glycine inhibitory dysfunction induces a selectively dynamic. 537-546. Voisin DL. 2(6): p. Freeman SE. 2006. 2001. Neurosci. 7(2): p. Pain and the Control of 8(2): p. 2006. Mense S. Bai G. 2225-2236 Exp Rev Neurotherapeutics. Head CA. Hay-Schmodt A. 2001. Dallel R. Nedeljkovic M. College of Medicine and Veterinary Medicine. Biphasic modulation of spinal visceral nociceptive transmission from the [25] George MS. Olesen J. Yuan L. Epub ahead of print This paper was prepared in partial fulfilment of require. Vagus nerve stimulation for the rostroventral medial medulla in the rat. Nijs J. 2007. 167(4): . Its prognosis is guarded. 7(1): p.2009. De Kooning M. maladaptive pain-A report of the AMA council on science Churchill Livingstone: Edinburgh and public health. J Pharmcol concepts. Central sensitization in tension-type headache: possible pathophysiological mechanisms. 1091-1102 tervention is dependent upon recognizing the fundamental differences in acute and chronic pain. 17(1): p. J Neurosci. and back Acta neurol belg. 11: p. Pathophysiology of low back pain and the transition to the chronic state . Curr Neurol Neurosci [23] Multon S. The peripheral apparatus of Philidelphia pain: evidence from animal and human studies. 2008. 318(2): p. Central sensitization: a biopsychosocial explanation for chronic widespresd pain in patients with ments for the MSc degree in pain management at University fibromyalgia and chronic fatigue syndrome. Trigeminal autonomic cephalgias: diagnosis and treatment. Molecular depletion of descending serotonin unmasks its [24] La Marca R. Pain: Pain transmission. May A. 2010.[14] Meeus M. Gitlow S. Moisset X. Vause CV. and neurokinin 1 receptor-independent their effect on calcitonin gene-related peptide release in the mechanical allodynia. 890-896 Melzack R. Durham PL. Frick C. Pain and the neuromatrix in the brain. A. [15] Bendtsen L. Nat Rev Rheumatol. Zou S. Nervenarzt. Neuron--glia signaling in dividual patient. Pain control by vagus nerve stimulation: from animal to man. 2000. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. 2002. Kose S. Headache. 29(8): p. Reuter U. . Ren K. Roussel N. et al. 20(5): p. The Biomedical & Life Sciences Collection. : London migraine: clinical implications. 465-473 Edinburgh. Woolf CJ. Clinic Rheum. 2007. Ehlert U. Central sensitization theory of Stewart Talks Ltd. 2011. Dunn AK. Schmerz. 2010. Poulsen AN. 62-67 Wei F. S182-191 Wallace DJ. Borckardt JJ. Cohen AS. 46 Suppl 4: p. 1008-1023 comprehensive multidisciplinary therapeutic plan. Osbahr AJ. 486-508 REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [16] Bolay H. Foust MJ. pain. Sengupta JN. Jurgens TP. of Edinburgh. ed. Patil VV. et al. Meeus M. Guo W. the effects on and by [12] Thalakoti S. 117-125 2005(105): p. Baldry P. Dubner R. treatment of depression and other neuropsychiatric disorders. Circ Heart Fail. Damodaram S. ACKNOWLEDGEMENTS [13] Nijs J. Assessment of systemic inflammation and heart failure progression in a mechanisms in localized and widespread musculoskeletal canine high-rate pacing model. 1635-1653 Mense S. 2010 692-699 Goadsby PJ. Neuroscience. J Dent [21] Schlaepfer TE. 2005. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Henry [17] Dodick D. Klaerke DA. Short EB. Maercker A. 65(12): p. 1378-1382 stimulation for depression: efficacy and safety in a European study. Rep. 15(6): p. Clin J pain. 2002. Zobel A.Z. B. 38(5): p. 2010. Psychol Med.

12(1): p. Harden N. 2000. 2010. 19(Suppl): p.. et al. Research [57] Lefaucheur JP. J Pain Symptom [36] Watkins LR. Woolf CJ. CGRP receptor antagonism and acetaminophen. A diathesis-stress model of chronic pain and disability following traumatic injury. Milligan [52] Crofford LJ.G. Nature. [56] Leo RJ. 2001. 8-19 Neurophysiol. Holland PR. et al.M.S. 15(2): p. Silva JA. 7: p. Management of chronic Trends in Neurosci. 355-374 . et al. Central sensitization and LTP: do pain and memory share similar mechanisms? [41] Fitzcharles MA. Pathophysiology of migraine: models to Neurotransmission underlies hyperalgesia induced by explain the generation of migraine headache. Burstein R. Pain. H. Adverse effects of chronic opioid therapy for ED. 2010. Implications of immune-to-brain [34] Ji RR.6 Arthur S. 26(12): p. COX-2 as a multifunctional neuronal modulator. Goadsby PJ. Nat Med. Ciampi de Andrade D. 2002. 7(12): p. et al. Potential analgesic mechanisms of [29] Edvinsson L. 2008. Pain. CGRP [48] Quintero L. Pain. Clin Drug Investig. Descending control of pain. Lasalanda MP. Drugs Aging. S. 147: p. et al. The pain of being sick: implications of immune to brain communication for understanding pain. Avila C.. 2002. Maier SF. Prog Neurobiol. Chan C. Proc Natl Acad Sci pain. 5-9 [38] Watkins LR. 453-459 [39] Turk DC. Wiesler-Frank J. inflammatory pain hypersensitivity. The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain. 149-153 [43] Millan MJ. 2000. 2004(252): p. Latif T. Shir Y. 1-21 facilitation and spinal dynorphin. 51: p. Diffuse analgesic effects of unilateral repetitive transcranial Clinical Trial Comparing Group-Based Multidisciplinary magnetic stimulation (rTMS) in healthy volunteers. 2010. [54] Chiechio S. 16-20 trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D recerptor agonists. et al.. 128-136. Ho TW.. 2009. Nater UM. Pharmacol Pharmacol. Lai J. 2001. 224-232. Therapist-Assisted Back Muscle Strengthening Exercises. 696-705 arthritis pain in the elderly. Glial proinflammatory cytokines mediate exaggerated pain states: implications for [55] Vanderah TW. Caraci F. Debes C. 96: p. Pedler A. Current pharmacotherapy of chronic pain. [45] Yamada K. 4274-7279 panic disorder and effectiveness of psychopharmacotherapy [28] Goadsby PJ. Neurotherapeutics. 2009. 2010. Montero M. Rheumatol. Thamsborg G Oefeldt A Lundsgaard C Stender S. Lussier D. Baron R. Pregabalin in the 2009. High prevalence of comorbidity of migraine in outpatients with 2004. Heim CM. 2009. Interleukin-1 beta Inhibition trigeminovascular dural nociceptive afferents by mediated induction of COX-2 in the CNS contributes to Ca(2+)-activated K(+) (MaxiK/BK(Ca) channel opening. 2010. Gordh T. Ossipov MH. Exp Rev Neurotherapeutics.E. Repetitive transcranial magnetic stimulation (rTMS) in experimentally induced and chronic neuropathic Ann Rev Psychol. 2007. Curr Opin hyperalgesia afterr subchronic swimm stress. Pain Physician. 2000. 1999. Capone JG. Best Pract Res Clin associated disorders: a pilot randomised controlled trial. 338-346 [51] Watkins LR. M. 21(2): p. Descending clinical pain. NMDA-receptors antagonists in neuropathic pain: Experimental methods to clinical trials. 269-280 migraine. syndromes. 7710-7713 [35] Watkins LR. Brain Behav Immun. Cervical lateral glide increases nociceptive flexion reflex threshold but not [42] Goldenberg DL. 66: p. 29-57 pain: a review. 2010 [59] Ji R-R.. 1 4 USA. Boas R. Sapirstein A. 2010. Moore KA. 499-511 Man Ther. Sci STKE. 6: p. 131 -146 [53] Sang CN. 471-490 [60] Sterling M. 9(1): p. repeated forced swimming stress Behav Brain Res. 92: p. 2007. Trends Pharmacol Sci. 51(8): p. [58] Nahmias F. Zammataro M. 21: p. Moore KA. 21-25 opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Treatment of Chronic Low Back Pain: A Randomized. Kohno T. Biopsychosocial Rehabilitation and Intensive Individual 2009. 117-124 [40] Dufour N. Moriwaki K. 23(101): p. 30(11): p. Roberts: Central Sensitization: Clinical Implications for Chronic Head and Neck Pain [27] Levy D. Geppetti P. 2001. M. Ishigooka J. J Pain. Marques AH. [61] Stanton-Hicks M.M. 29: p. Neurostimulation in primary headache for both disorders: a retrospective study Psyychiatry Res. Pharmacological treatment of fibromyalgia pressure or thermal pain thresholds in chronic whiplash and other chronic musculoskeletal pain. H. Maier SF. Neuroendocrine and immune contributors to fatigue. Jakubowski M. [49] Samad TA. Spine. 2007. Rice KC. 581-591 treatment of chronic pain: An overview. 9-14 Biochem Behav. J communication between peripheral and central Pain Sympt Manag. 414-415 PM R. 19(Suppl): p. 36: p. Cell signaling and the genesis of neuropathic communication for sickness and pain. Disruption of [44] Portenoy RK. Oiso H. 2003(521): p. 2001. Proc Natl Acad Sci USA. Clin And Management (7): p. 151(1): p. EM. Nat Rev Rheumatol. 2006. Maier SF. Glia as the "bad guys": implications for chronic musculoskeletal pain. Reduced [30] Ebersberger A. 164-175 [47] Suarez-Roca H. 159-169 [31] Benemei S. 449-458 [32] Ackerman S. May 21 (Epub ahead of print) 1785-1789 [46] Smith HS. Anaesthetist. 7(2): p. Sternberg [50] Bazan NG. Pain. 2007. Ledeboer A. 27(6): p. 67: p. Maier SF. Nicoletti P. 189: 2002. 2000. Adv Exp Med Biol. 661-667 p. 2(5): p. the "toll" Manage. et al. improving clinical pain control and the clinical utility of 191-197 opioids. Long-lasting delayed receptors in the control of pain and inflammation. 8: p. 410: p. 2009. 471-475 [33] Silverman M. Leal L. 203-213 [37] Watkins LR.

CE. Guo W. Gatchel RJ. Sluka KA. Progress in Pain Research and [70] Weiner DK. cytokine induction and NMDA .. 339(1) [72] Ghoname EA. Seattle WA: IASP pain. Percutaneous electrical nerve stimulation: an alternative Scientific evidence for the effectiveness of virtual reality for to TENS in the management of sciatica. Basic Science of Pain. 2010.. 83: p. C. Cochrane Library. Pain. Ernst E. Management is 78(1): p. Hamza MA. Raj P. 1998. 244-255 Turk DC. Goldsmith CH. Bouter LM. Glaeske G.A. Lippincott Williams & Contribution of primary afferent input to trigeminal Wilkins: Philadelphia astroglial hyperactivity. 2004. 2009.. Joint Bone Spine. Korner-Bitensky N. pharmacological and non-pharmacological perspectives. 4 ed. Psychosocial Aspects of Pain: A Handbook for Health Care Providers. 14(2): p.. C. Non-invasive physical treatments for chronic/recurrent headache (review). 2011. Flor H. J Bone Joint Surg Am. Fibromyalgia syndrome: Prevalence. Stud 193-199 Health Technol Inform. 88(suppl_2): p.. 144-152 Regional Pain Syndromes: Guidelines for Therapy [69] Wright A. p. 17: p. Dubner R Ren K. 80-84 more than pills. Nonpharmacological treatments for (Consensus Report).W. 1999. 58-62 [74] Fishman SM. 1(1): 1-7 [62] [63] [64] [65] [66] [67] [68] 7 Hendler N. White PF. Bonica's Wang H. Management of Pain. ed. !!! INVALID CITATION !!! Assendelft WJJ.H. 40-43 [73] Branfort G. 144: p. Clin J Pain. Haas M.. 2009(1) 2006. Open Pain J. pain reduction in adults with acute or chronic pain. Ma X. 155-166 musculoskeletal pain. 3: p.. Clin J Pain. Noe Shahrbanian S. 20: p. Complementary and alternative approaches to the treatment of persistent musculoskeletal Management. Turk DC. in Psychosocial factors in pain: critical [71] Sauer K. Wei F. 2009. Neuropathic pain. J. an analysis of Publications: New York. H. Guilford interventions in outpatient healthcare. Complex receptor phosporylation. Nilsson N. Editor 1999. Yang K. Ahmed HE. M. Evvans RL. DeLeo. Thacker M. BMJ. Clin J Pain. Flor H. 2001. Wilder R. 2004. 27. Vol. Simmonds MJ. Ballantyne JC. 2009. Rathwell JP. 43-46 Flor. 18-34 statutory health insurance data. Chronic pain: a biobehavaioral perrspective.Clinical Medicine and Diagnostics: 2011.G. Kemper C. Koltzenburg M.