Central Sensitization: Clinical Implications for Chronic Head and Neck Pain Arthur S. Roberts DDS, MD, MSc Indiana Craniofacial Center, PC Indiana University.

Central Sensitization: Clinical Implications for Chronic Head and Neck

Pain

Arthur S. Roberts DDS, MD, MScIndiana Craniofacial Center, PC

Indiana University School of DentistryOral Medicine

University of Edinburgh College of Medicine and Veterinary Medicine

Pain Management

WHY IS THIS IMPORTANT?

One in twenty-five can magnify the pain severity and duration of the rest

These are Central Sensitization Syndromes

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!!!

Case # 761Referred for TGN

• 52 Y/O Well nourished, well developed, fit female dentist – self-described as “fitness nut”

• CC: Continuous (6 Years), left mid-face (CN V d2) 4/10 pain with episodic exacerbations to 10/10

• Missing 11,12,13• PDH: restorative, endo, apico, extraction, failed implants 11,12,13• Co-morbid CDH (4 years), MFP (1 Year), IBS (10 years), TMD (24

years), Depression (since adolescence)• PSH: T&A, total hysterectomy (age 36)• Initial Presenting Meds: HRT, hydrocodone, imitrex (sumatriptan),

ibuprofen, acetaminophen, fluoxetine• DDX: Transformed TGN or Atypical Odontalgia • DX: Atypical Odontalgia, Chronic Fibrosing Osteomyelitis, Central

Sensitization Syndrome

Chronic pain is not acute pain

• Pathologic not protective• Multidimensional (Biopsychosocial)• Entangled with neuromatrix• Entangled via neuromatrix• Alters– Endocrine function– Immune function– Psychologic status– ????

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.” Melzack 2001

Neuromatrix

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

The Process Is The Filter

Central Sensitization

• Potentially progressive • Devastating • Multimodal disease • Significant worldwide economic and social

burden

Common CS symptoms

•Depression•Anxiety•Sleep fragmentation •Allodynia•Hyperalgesia•Fatigue [1,3-5]

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

Two etiological pathways

Chronification of nociceptive pain

Chronic stress

Central Sensitization Syndromes (CSS)

Adapted from Wallace and Clauw [2] Tension-type HAMigraineLimb Movement DisorderFibromyalgiaRestless Leg SyndromeChronic Fatigue SyndromeTMDAtypical OdontalgiaBurning Mouth SyndromePost Traumatic Stress DisorderDepressionPrimary DysmenorrheaIrritable Bowel SyndromeMultiple Chemical SensitivitiesMyofascial Pain Syndrome

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]

Diagnosis

• Without demonstrable pathology • Clinical assessment – Allodynia– Hyperalgesia +/- – Widespread pain highly correlated with elevated

stress levels– Comorbid presentation of multiple disorders with a

significant CS component is an indicator of the presence of central sensitization syndrome

[1-3]

Vagal dysregulation

• Reduces endorphin release • Alters serotonin production and utilization– Altered accommodation of minimally painful

events– Contributes to depression [7, 18, 20]

Sympatho-afferent coupling

• Sensitized trigeminal complex• Lowered parasympathetic drive• Increased sympathetic drive– Increased norepinephrine levels – Dysfunctional sleep– Anxiety [6,21-25]

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]

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]

Indicators for central sensitization.

• depression• anxiety• hyperalgesia• allodynia• stress related pain exacerbation• fatigue • poor sleep

Stress assessment

•HPA axis – salivary cortisol•Autonomic nervous system – salivary alpha-amylase and heart rate variability•Neural and immune profiles – cutaneous sweat patch

Therapy

• 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]

THE PATIENT FUNNEL

Central Sensitization

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]

. 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– Calcium channel alpha(2) ligands

Acetaminophen

• Acetaminophen acts on the periaquaductal gray, and thence serotonergic and noradrenergic neurons to increase descending inhibition

[13,32,43,44,46,47]

Serotonin- and Norepinephrine-Reuptake Inhibitors

• Serotonin re-uptake inhibitors (SSRI) and the serotonin precursor tryptophan – Enhance descending inhibition– Stress-induced hyperalgesia

• Serotonin/norepinephrine inhibitors (SNRI) and tricyclic anti-depressants (TCA)

• Dual action – Spinal activity and – Descending inhibition via monoamine pathways in the brain

• Enhance sleep and coping • Reduce anxiety, and catastrophizing

– Impact neuromatix– Ameliorate the pain experience [5,13,42,43,48]

TCAs

•Beneficial neuro-hormonal impact•Potentiate endogenous opioids [42]

Opioids and Tramadol

• The use of opioids for chronic pain is open to some controversy.– Target critical mechanisms of central sensitization– Negative impact upon immune function (as does central sensitization)– Contribute to interleukin-1 mediated inflammatory pain

hypersensitivity [43,49-51]– Significant reinforcement on the reward centers of the brain – Use of opioid therapy for clinical pain remains a case-by-case

judgment in carefully selected and well-monitored patients [44,52]• Tramadol, an opioid-like drug

– Multi-modal action• Binding at mu receptor cites is low• Reuptake inhibitor of both serotonin and norepinephrine [42]

N-methyl-D-Aspartate Receptor Blockers

• Activation of NMDA-receptors (and protein kinase C) induces:– Hyperalgesia– Supraspinal facilitatory loops– Apoptosis in the dorsal horn.

• NMDA blockers – ketamine, memantine and dextromethorphan– Analgesic in some circumstances– Narrow therapeutic window

[53-55]

Calcium Channel Alpha(2)Delta Ligands

• Voltage-sensitive Calcium channels at the junction of primary afferent and second order sensory neurons

• Enhanced release of neurotransmitters in chronic pain – Gabapentin and pregabalin interrupt this action– Reduces pre- and post-synaptic noxious transmission– Reduces the noxious input to the sensitized medulla.

• Less effective in stress induced central sensitization• Common for patients to cease responding to this class

of drugs – Alt: Carbamazapine/oxcarbazapine (off-label Limited

evidence)[42,47,54]

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

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]

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]

The other broad categories of non-pharmaceutical CS intervention

• Manual therapy• Virtual reality• Improving stress tolerance (CBT)• Transcutaneous electric nerve stimulation (TENS)– Address the functional deficits created by the CS

• Complementary and alternative approaches – Evidence regarding safety and efficacy is limited

• Primarily address aftermath of CS – Reduces the overall burden on the neuromatrix – Reduce the self-sustaining feedback that contributes to

the progressive nature of CS

Manual Therapy

• Improves function • Improves descending inhibition

• Widespread analgesia. • Short duration• Limited assistance in desensitizing the neuromatrix• Addresses functional rehabilitation

[4,13,60-64]

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]

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]

Transcutaneous Electrical Nerve Stimulation

• Activates polysegmental inhibitory feedback and additional elements of CS

• Significant effect ith focal, segmental chronic pain

• Results in widespread pain are equivocal[13,40, 69-73]

Prognosis

• Dependent upon: – Ability to identify and address the initiating and

perpetuating pathways. • Transformed nociceptive pain• Stress

– Combinations of the two

Transformed nociceptive pain• Three elements are necessary for development of chronic clinical pain:

– neuroplasticity – peripheral sensitization – central sensitization [1]

• Neuroplasticity and peripheral sensitivity enable the central sensitivity. • Removal, or prevention, of either or both of these, will improve the

prognosis– Acute phase

• adequate anesthesia • Analgesia • inflammation control

– Chronic phase • early psychosocial intervention• thorough patient education

[2,61,62,74]

Once initiated central sensitization will 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

[2,74]

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

CSrather than control or eradication of the CS [2,3,74]

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

Conclusions

• Potentially progressive • Devastating• Multimodal disease • Worldwide economic and social burden

Effective intervention

• Fundamental differences in acute and chronic pain

• Effects on and by the neuromatrix • biopsychosocial health of the individual

patient• Integrating a comprehensive multidisciplinary

therapeutic plan

Prognosis

Guarded