Central Sensitization: Clinical Implications for Chronic Head and Neck Pain

1. Central Sensitization: Clinical Implications for Chronic Head and Neck Pain Arthur S. Roberts DDS, MD, MSc Indiana Craniofacial Center, PC Indiana University School of Dentistry Oral Medicine University of Edinburgh College of Medicine and Veterinary Medicine Pain Management

2. DISCLOSURES • Innovative Health Solutions • American Academy of Pain Management

3. WHY IS THIS IMPORTANT?

4. Prototype • 35-55 y/o female • Extensive PMH • Multiple prior providers • Polypharmacy • Often hypervigilant • Either non-communicative or circumstantial • May be none of the above!!!

5. Chronic Pain Is Not Acute Pain • Pathologic not protective • Multidimensional (Biopsychosocial) • Entangled via neuromatrix • Pan-Systemic

6. Chronic pain implies an altered neuromatrix • “The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.”Melzack2001 * Emphasis added

7. Neuromatrix Is A Process

8. Central Sensitization • “Sensory-afferent signals overwhelm the body's ability to filter them”[1,2] • neuro-immune dysfunction, • neuro-endodrine dysfunction • NMDA (N-methyl-D-aspartate) dysregulation • Sympatho-afferent coupling • Altered serotonin and norepinephrine production and utilization Melzach, Woolf 2001

9. Common CS symptoms • Depression • Anxiety • Sleep fragmentation • Allodynia • Hyperalgesia • Fatigue [1,3-5]

10. Two Etiological Pathways • Chronification of nociceptive pain • Neuroplastic changes • Peripheral sensitization • Central sensitization • Chronic stress • Elevated levels of chronic stress • Anxiety • Sleep fragmentation • Decreased pain thresholds • Dysautonomia

11. Etiology of CSS • Genetic predisposition • Environmental • Trauma • Physical • Psychological • Infectious • Lyme disease • Chronic EBV • Parasites • Toxins • Heavy metal • Biotoxins • Medications • Sleep disturbances • Sleep apnea • Circadian rhythm disorders • Metabolic • Thyroid disease • Autoimmune • Celiac disease

12. Dysregulation of the hypothalamic pituitary adrenal axis Damage to hippocampal neurons and reduced neurogenesis • Disruption of the normal circadian cycle • Reduced basal cortisol levels Kaplan 2013

13. Depression and chronic pain share common neurophysiology and neurobiology. They are mutually reinforcingneuropathologicprocesses. • Bimodality • Pain • Depression Kaplan 2013

14. Common genetic vulnerabilities • Common neurobiology • Neuroanatomy • Neuroendocrinology • Neuroimmunology • Neurotransmitters

15. From CS to CSS Microglial Activation

16. Microglia Activation Neurodegenerative Diseases Ischemia Hypoxia Infections Medication Trauma Toxins Kaplan 2013

17. Central Sensitization Syndrome CSS = Chronic Pain + Neuropsychiatric Condition • Neuroinflammatory • Neurodysregulatory • Neurodegenerative Kaplan 2013

18. 50% to 65% 1,2,3,4,5,7,9,11

19. When depression and chronic pain occur together, treatment success is dramatically lower and cost is dramatically higher than when these conditions occur separately.

20. Central Sensitization Syndromes (CSS) Adapted from Wallace and Clauw [2] Tension-type HA Migraine Limb Movement Disorder Fibromyalgia Restless Leg Syndrome Chronic Fatigue Syndrome TMD Atypical Odontalgia Burning Mouth Syndrome Post Traumatic Stress Disorder Depression Primary Dysmenorrhea Irritable Bowel Syndrome Multiple Chemical Sensitivities Myofascial Pain Syndrome

21. Characteristic sequelae central sensitization • Vagal dysregulation [7, 18, 20] • Sympatho-afferent coupling of sensitized trigeminal complex [6,21-25] • Decreased medullary descending inhibition [8,11,12,15-17,23,26-32] • Hypoactivity of the hypothalamic-pituitary-adrenal axis • Autonomic nervous system alterations • Increased sympathetic tone • Low vagal tone [5,12,14,20,21,23-25,33-38]

22. Vagal dysregulation • Reduces endorphin release • Alters serotonin production and utilization • Altered accommodation of minimally painful events • Contributes to depression [7, 18, 20]

23. Sympatho-afferent coupling • Sensitized trigeminal complex • Lowered parasympathetic drive • Increased sympathetic drive • Altered norepinephrine levels • Dysfunctional sleep • Anxiety [6,21-25]

24. Decreased medullary descending inhibition • Increases effect of peripheral nociceptive input • Lowered pain thresholds • Hyperalgesia, • Allodynia • Greater impact of peripheral sensitization [8,11,12,15-17,23,26-32]

25. Hypoactivity of the hypothalamic-pituitary-adrenal axis • autonomic nervous system alterations • increased sympathetic tone • low vagal tone • Immune abnormalities • Fatigue • Malaise [5,12,14,20,21,23-25,33-38]

26. Indicators for central sensitization. • depression • anxiety • hyperalgesia • allodynia • stress related pain exacerbation • fatigue • poor sleep

27. Therapeutic Problems • Polypharmacy • different prescribing specialists • iatrogenic contribution • failing to differentiate chronic from acute pain • Symptomatic - Acute symptoms of CSS disorders need to be addressed • Syndromic - Essential to treat the pathways in chronic pain disease [2,5,7,8,13-15,17,19,20,32]

28. Two approaches to CSS therapy • Symptomatic approach: Address the effects of CS after it has occurred • Syndromic approach: Interrupt the CS • Optimal outcomes often depend on doing both. • Pharmacological • Non-pharmacological [1,4,6,8,13,14, 40-44]

29. . Pharmacological Approaches • Treating the effects • 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 • Namenda, Ketamine, Memantine • Calcium channel alpha(2) ligands • Gabapentin, Lyrica

30. Non-pharmacological Approaches (NPT) • Each element of neuromatrix is potential therapeutic target • Two broad operative groups: • Reducing CS itself • Responding to the effects of CS

31. Repetitive Transcranial Magnetic Stimulation (rTMS) • Safe and non-invasive • Stimulation of the motor cortex and prefrontal cortex • Limited application • Short duration of effects • Significant equipment costs • Greater efficacy in centrally, rather than peripherally, originated pain • Reverses intra-cortical motor dysfunction • Alters sensory-discriminative function • Restores of descending inhibition • Improves cognitive function [56,57] • Some investigators argue that the analgesic effects are independent of descending inhibitory control and are influenced by other elements of the neuromatrix [58]

32. Manual Therapy • Improves function • Improves descending inhibition • Widespread analgesia. • Short duration • Limited assistance in desensitizing the neuromatrix • Addresses functional rehabilitation [4,13,60-64]

33. Virtual Reality • Limited evidence • Distraction in the hyper-vigilant patient • Potential benefit in patients with movement associated nociceptive etiology • Not in widespread use [13,65]

34. Improving Stress Tolerance and Neuro feedback Training • Stress • Etiologic and exacerbating factor for CS • Endogenous (chronic pain) • Exogenous (psychosocial changes) • Irritable, hyper-excitable chronic pain patient • Related to sympatho-afferent coupling in the hypothalamic-pituitary-adrenal axis of the neuromatrix. • neuro-immune changes from upregulated pronociceptive immune mediators in primary afferent nociceptors • Reduction of stress levels improves: • Pain threshold • Maladaptive behavior • Autonomic balance [12,14,17,35,36,66-68]

35. Transcutaneous Electrical Nerve Stimulation • Activates poly-segmental inhibitory feedback • Significant effect with focal, segmental chronic pain • Results in widespread pain are equivocal [13,40, 69-73]

36. Percutaneous Electroneural Stimulation (PENS) • Percutaneous stimulation of peripheral branches of multiple cranial and cervical nerves • Trigeminal, Vagus, Occipital • Discreet • Stimulates afferents • improved autonomic regulation • Improves centrally mediated pain • Improves sensory - discriminatory functions • serotonin/norepinephrine production and utilization • endorphin production • analgesia and mood improvement appears to follow a ‘learning curve’[59] • cost-effective, non-invasive, low co-morbidity option [1,2,5, 6,8-10,12-15,20-23,25-28,42-44,53, 55]

37. Once initiated central sensitization can engender additional presentations • Increased frequency and intensity of pain • Increased endogenous stress levels • Increased sympatho-afferent coupling • Autonomic dysfunction • anxiety • poor sleep • difficulty coping • lowered pain thresholds • increased risk of developing additional presentations of CS • Persistent microglial inflammation [2,74]

38. Removal Of The Initiating Stimulus Will Not Insure Favorable Outcomes • Continuing stimulus for the development and/or maintenance of CS • Extended disease course • Additional CS presentations (syndromes) • Devolves to dealing with the effects of the CS rather than control or eradication of the CS [2,3,74]

39. Stress Induced CS • No biological axis may exist in the early stages • Maladaptive behavior • Engender biological issues • Contribute to maintenance and exacerbation of CS • PTSD • Depression • HPA induced changes • Microglial activation

40. Conclusions • Potentially progressive • Devastating • Multimodal disease • Worldwide economic and social burden

41. Effective intervention • Fundamental differences in acute and chronic pain • Effects on and by the neuromatrix • biopsychosocial health of the individual patient • Integrate a comprehensive multidisciplinary therapeutic plan

42. CSS Prognosis Guarded

43. The comorbidity of neuropsychiatric disease (depression, GAD, PTSD) and chronic pain are common.

44. When depression and chronic pain occur together, treatment success is dramatically lower and cost is dramatically higher than when these conditions occur separately.

45. THANK YOU