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 â self-described as âfitness nutâ
⢠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⢠Altersâ Endocrine functionâ Immune functionâ Psychologic statusâ ????
Chronic pain implies an altered neuromatrix
⢠âThe 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.â Melzack 2001
Neuromatrix
Central Sensitization
⢠âSensory-afferent signals overwhelm the body's ability to filter themâ [1,2] â neuro-immune dysfunction,â neuro-endodrine dysfunction â NMDA (N-methyl-D-aspartate) dysregulationâ sympatho-afferent couplingâ 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
â˘Depressionâ˘Anxietyâ˘Sleep fragmentation â˘Allodyniaâ˘Hyperalgesiaâ˘Fatigue [1,3-5]
Two etiological pathways
⢠Chronification of nociceptive pain â Neuroplastic changes â Peripheral sensitization â Central sensitization
⢠Chronic stress â Elevated levels of chronic stressâ Anxiety â Sleep fragmentation â Decreased pain thresholdsâ 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
â 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 â Allodyniaâ Hyperalgesia +/- â Widespread pain highly correlated with elevated
stress levelsâ 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 utilizationâ Altered accommodation of minimally painful
eventsâ Contributes to depression [7, 18, 20]
Sympatho-afferent coupling
⢠Sensitized trigeminal complex⢠Lowered parasympathetic drive⢠Increased sympathetic driveâ Increased norepinephrine levels â Dysfunctional sleepâ Anxiety [6,21-25]
Decreased medullary descending inhibition
⢠Increases effect of peripheral nociceptive inputâ Lowered pain thresholds â Hyperalgesia,â Allodyniaâ 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
â˘HPA axis â salivary cortisolâ˘Autonomic nervous system â salivary alpha-amylase and heart rate variabilityâ˘Neural and immune profiles â cutaneous sweat patch
Therapy
⢠Polypharmacy ⢠different prescribing specialists ⢠iatrogenic contribution â 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. â Pharmacological â Non-pharmacological
[1,4,6,8,13,14, 40-44]
. Pharmacological Approaches
⢠Treating the effectsâ Acetaminophenâ Serotonin (SSRI) and norepinephrine (SNRI) reuptake
inhibitors and tricyclic antidepressants (TCA)â Opioids and Tramadol
⢠Drugs that may treat the central sensitization itself:â N-methyl-D-aspartate (NMDA) receptor blockersâ 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 â Enhance descending inhibitionâ Stress-induced hyperalgesia
⢠Serotonin/norepinephrine inhibitors (SNRI) and tricyclic anti-depressants (TCA)
⢠Dual action â Spinal activity and â Descending inhibition via monoamine pathways in the brain
⢠Enhance sleep and coping ⢠Reduce anxiety, and catastrophizing
â Impact neuromatixâ Ameliorate the pain experience [5,13,42,43,48]
TCAs
â˘Beneficial neuro-hormonal impactâ˘Potentiate endogenous opioids [42]
Opioids and Tramadol
⢠The use of opioids for chronic pain is open to some controversy.â Target critical mechanisms of central sensitizationâ Negative impact upon immune function (as does central sensitization)â Contribute to interleukin-1 mediated inflammatory pain
hypersensitivity [43,49-51]â Significant reinforcement on the reward centers of the brain â 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
â 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:â Hyperalgesiaâ Supraspinal facilitatory loopsâ Apoptosis in the dorsal horn.
⢠NMDA blockers â ketamine, memantine and dextromethorphanâ Analgesic in some circumstancesâ 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 â Gabapentin and pregabalin interrupt this actionâ Reduces pre- and post-synaptic noxious transmissionâ 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 â 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: â Reducing CS itselfâ 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
â Short duration of effectsâ Significant equipment costs â Greater efficacy in centrally, rather than peripherally, originated painâ Reverses intra-cortical motor dysfunctionâ Alters sensory-discriminative functionâ Restores of descending inhibitionâ Improves cognitive function [56,57] â 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 â Discreet â 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 âlearning curveâ[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)â Address the functional deficits created by the CS
⢠Complementary and alternative approaches â Evidence regarding safety and efficacy is limited
⢠Primarily address aftermath of CS â Reduces the overall burden on the neuromatrix â 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 â Etiologic and exacerbating factor for CS â Endogenous (chronic pain)â Exogenous (psychosocial changes)â Irritable, hyper-excitable chronic pain patientâ Related to sympatho-afferent coupling in the hypothalamic-pituitary-
adrenal axis of the neuromatrix. â 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: â Ability to identify and address the initiating and
perpetuating pathways. ⢠Transformed nociceptive pain⢠Stress
â Combinations of the two
Transformed nociceptive pain⢠Three elements are necessary for development of chronic clinical pain:
â neuroplasticity â peripheral sensitization â central sensitization [1]
⢠Neuroplasticity and peripheral sensitivity enable the central sensitivity. ⢠Removal, or prevention, of either or both of these, will improve the
prognosisâ Acute phase
⢠adequate anesthesia ⢠Analgesia ⢠inflammation control
â 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 â anxietyâ poor sleepâ difficulty copingâ lowered pain thresholdsâ increased risk of developing additional presentations of CS
[2,74]
Removal of the initiating stimulus will not insure favorable outcomes
â˘Continuing stimulus for the development and/or maintenance of CS â Extended disease courseâ Additional CS presentations (syndromes)â 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 â Maladaptive behavior⢠Engender biological issues⢠Contribute to maintenance and exacerbation of CS
â PTSD â Depression
â 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