Michel P. Rathbone
Neurologist
McMaster University
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Definition
Anatomy of pain
Types of pain - neuropathic and nocioceptive
Chronic pain – epidemiology
Sensitization – peripheral and central
Imaging
Pain and mental status - cognition
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Pain -“An unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage”
International Association for the Study of Pain
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There is a new realization that chronic
pain is a disease of the brain
 Neuropathic
 Nociceptive
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in clinical practice, there
is usually the combination of
these types of pain in a patient
with chronic pain
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Pain initiated as a direct consequence of a lesion or
disease affecting the somatosensory system
No physiological advantage (warning)
Causes suffering and distress
Characteristics include burning, paresthesias,
painful cold, electric shocks, itchiness, and can be
associated with numbness
Allodynia (painful response to non painful stimuli)
and/or hyperalgesia (increased response to painful
stimuli)
Neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the nervous system
Peripheral neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the
peripheral nervous system
Central neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the
central nervous system
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Spinal cord injury – central neuropathic pain
Cervical or lumbar radiculopathies
Brachial plexus injuries
Peripheral nerve injuries (median, ulnar,
radial, peroneal nerves)
Phantom Limb pain (after amputation)
Complex Regional Pain Syndrome (CRPS)
Brain infarction (especially in the thalamus
and brainstem)/traumatic brain injury
Fibromyalgia (?)
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An appropriate physiological response transmitted
to a conscious level
Nociceptors activated in any body tissue
Organism warned of tissue damage
Coordinated reflexes and behavioral responses
Low back pain is the most common complaint and
can arise from degenerative changes in the spine
aggravated by changes in gait and posture.
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Low back pain
Headaches
Spasticity e.g. in brain and spinal cord injured
patients
Whiplash injuries
Fractured/sprained/strained joint (ankle,
shoulder, wrist)
Arthritis
Fibromyalgia (?)
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It is estimated that about 15% to 29% of
Canadians suffer from chronic pain
(Boulanger, 2007).
About one million patients in Canada have
neuropathic pain (Moulin, 2002)
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Definition: Increased responsiveness of nociceptive
neurons to their normal input, and/or recruitment of
a response to normally subthreshold inputs.
Peripheral sensitization: Increased responsiveness
and reduced threshold of nociceptive neurons in the
periphery to the stimulation of their receptive fields.
Central sensitization: Increased responsiveness of
nociceptive neurons in the central nervous system to
their normal or subthreshold afferent input
IASP, 2012
Pain Pathophysiology
Peripheral Sensitization Leads
to Central Sensitization
1. Local trauma
Thalamus
2. Release of kinins from injury site
3. Area of Primary Hyperalgesia
HI
S
BK
IL
Pain Pathophysiology
Peripheral Sensitization Leads
to Central Sensitization
4. Antidromic release of peptides from axon
collaterals => FLARE, WHEAL
Thalamus
PERIPHERAL SENSITIZATION
5. Zone of secondary hyperalgesia
mediated by SP, Glu, CGRP
CGRP
SP
Gl
u
SP
Gl
u
CGRP
Pain Pathophysiology
Peripheral Sensitization Leads
to Central Sensitization
6. Increased nociceptive input from the periphery
Thalamus
7. Wind up of dorsal horn neurons
CENTRAL SENSITIZATION
CGRP
SP
Gl
u
SP
Gl
u
CGRP
Lee et al, 2011
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Headache/migraine
Fibromyalgia
Chronic low back pain
Whiplash Associated Disorders
Osteoarthritis
Rheumatoid Arthritis
Studies looking at mechanical stimuli for chronic
whiplash and central sensitization:
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Deep tissue stimulation: pressure algometry
Skin and nerve tissue stimulation: light touch, pinwheel,
vibration, Brachial Plexus Provocation test
Thermal stimulation: heat, cold
Electrical stimuli: EMG, transcutaneal electrical stimulation
Local anesthetic use does not impact central sensitization, but
facet blocks help, suggesting nociceptive input arise from the
zygapophyseal joint.
The coexistence of sensory hypersensitivity and hypoaesthesia in
chronic WAD indicates that both central facilitatory and inhibitory
processes are affected in these patients
(VanOsterwijck, 2013)
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14 whiplash patients and 14 healthy controls were given painful stimuli (single
electrical stimulus intramuscular, repeated electrical stimulation both
intramuscular and transcutaneous, and heat) and thresholds were measured at the
neck and lower limb.
All patients in the whiplash group had significantly lower pain threshold for all
painful stimuli except for heat.
The authors found a hypersensitivity to peripheral stimulation in whiplash
patients. Hypersensitivity was seen after cutaneous and muscular stimulation both
at the neck and lower limb.
Because hypersensitivity was observed in healthy tissues, it resulted from
alterations in the central processing of sensory stimuli (central hypersensitivity).
Use of local anesthetic did not influence pain thresholds or hypersensitivity at the
neck and the lower limb sites in response to single and repeated intramuscular
and transcutaneous electrical stimulation, and it did not influence neck pain
intensity. These results suggest generalized hypersensitivity was not dependent
on nociceptive input arising from the painful and tender muscles.
Central hypersensitivity was not dependent on a nociceptive input arising from the
painful and tender muscles.
Neuro-immunological involvement
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A cascade of events are proposed following an injury within the central nervous system
at the cellular level.
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Cells (glia, neurons) become activated and produce and release cytokines leading to
further activation and release of pain mediators.
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Glial or neuronal pro-inflammatory cytokines can sensitize peripheral nociceptive fields
and dorsal root ganglia.
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Cytokines and growth factors have been associated in the involvement of generating
pathological pain states throughout the nervous system – especially proinflammatory
cytokines like IL-1, IL-6, and TNF, which are upregulated both at the local site of injury
and in the spinal cord in persistent pain.
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Immune activation with cytokine production may indirectly induce pain mediators such
as glutamate, nitric oxide, and prostaglandins in the CNS, leading to further spinal
sensitization.
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Neuroinflammation occurs in which immune cells migrate from the periphery to the CNS
in association with pain; leading to further changes in the CNS and potentially to central
sensitization. These infiltrating immune cells contribute to neuronal activation and
algesic mediator release, further perpetuating the maintained excitability and
sensitization in the CNS which leads to behavioral sensitivity and pain.
Winkelstein et al, 2004)
Proposed relationship between mechanical injury (e.g. musculoskeketal
disorder) and nociceptive physiological responses. Winkelstein et al, 2014)
Sava et al., 2009, Mol Pain
The central areas in the brain associated with central sensitization include the thalamus,
amygdala, insula cortex, supplementary motor cortex, posterior parietal cortex, prefrontal
cortex, anterior cingulate cortex, periaquedutal gray, basal ganglia, cerebellar cortex, and
the primary and secondary sensory cortex. (May, 2011)
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Lee et al (2007)
Brainstem activity contributed to the
maintenance of the CS state
Activity in the somatosensory cortex reflected
the perceptual consequence of CS, that is an
increase in the intensity of pain experienced
Results of mixed-effects analysis of the average group response for controls and patients in response to
cold and punctuate stimuli. Figure one is all areas affected by pain. Red – primary somatosensory cortex;
Light blue – secondary somatosensory cortex; Dark blue – anterior cingulate cortex; Green - insula
a. Patients vs. Controls
b. High PainDETECT vs. Low PainDETECT
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Chronic pain has been associated with poorer
performance in various cognitive functions.
Tamburin et al (2014) found patients with
chronic low back pain had poorer decision
making performance and cognitive flexibility
skills compared to healthy controls.
Compared to controls, chronic pain patients took
longer to complete tests of sustained attention
and mental flexibility (Oosterman et al, 2012).
Reduction in psychomotor speed (Sjogren, 2004)
Neurocognitive Test Performances In Chronic Pain Patients.
William Parkinson PhD, Yasir Rehman MD, Michel Rathbone MD,
Mohit Bhandari MD, Shucui Jiang PhD, Dinesh Kumbhare MD,
Jonathan Adachi.
Background & Purpose: Chronic pain is likely to be associated with
weaknesses, relative to control groups, in at least some cognitive functions
including processing speed, attention, and possibly working memory, but
differences between studies obscure the size of effects. This study provided a
quantitative analysis of the magnitude of the association between chronic pain
and neurocognitive test performances.
Methods: Meta-analysis was performed using the Cochrane, PRISMA
guidelines.
Conclusions:
1. Chronic pain was associated with Effect Sizes of 1/3 to close to a full SD poorer
performance.
2. Correlates of chronic pain were non-specific, with relative weaknesses in tests
requiring speed, working memory, learning, executive functions, and a range of
attention abilities.
3. More research is needed to test non-verbal abilities, executive functions, and to
control for estimated pre-morbid IQ.
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Definition
Types of pain - neuropathic and nocioceptive
Chronic pain – epidemiology
Sensitization – peripheral and central
Imaging
Pain and mental status – cognition
Research studies vs. Individuals
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Most treatments for CS should target the brain (mainly
pharmacological)
Pain neuroscience education and cognitive behavioral
therapy targeting cognitive and emotional sensitization.
Dry needling
Transcranial magnetic stimulation
Melatonin
Cervical radiofrequency neurotomy for cervical facet joint
pain (whiplash patients)
Targeting metabolic factors – low carbohydrate or
ketogenic diet to diminish hyperexcitability of the CNS.
Manual therapy (Sterling et al, 2010)
Exercise therapy – activates endogenous analgesia, and
has been shown to reduce fMRI changes (Micalos et al,
2014)
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As most chronic pain conditions involve
central sensitization, treatment strategies
need to be able to desensitize the CNS.
Most conditions require a multimodal
analgesic approach to include
pharmacotherapy, cognitive-information
processing therapies, and rehabilitation.
Medication
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TCAs
SSRIs
SNRIs
Alpha adrenergic agents
Opioids
Tramadol
Descending
Inhibitory
Pathways
(NE/5HT, opioid
receptors)
Central Sensitization
Peripheral
Sensitization
Na+
CBZ
OXC
TCA
TPM
LTG
Lidocaine
Spinal
Cord
Ca++: GBP
LVT
OXC
LTG
PREGAB
NMDA: Ketamine
Dextromethorphan
Methadone
Memantine
TCA: Tricyclic antidepressant, SSRI: Selective serotonin reuptake inhibitor, SNRI: Serotonin and norepinephrine reuptake inhibitor,
CBZ: Carbamazepine, OXC: Oxcarbazepine, TPM: Topiramate, LTG: Lamotrigine; GBP: Gabapentin; LVT: Levetiracetam; PREGAB: Pregabalin;.
Adapted from Beydoun A., Backonja M.M; Mechanistic stratification of antineuralgic agents. Journal of Pain and Symptom Management, 2003:25:5S (p.S27)
with permission from the U.S. Cancer Pain Relief Committee