Download The Psychopathology of Pain

Introduction to Chronic Pain
Definitions and Pathophysiology
Rachael Rzasa Lynn, MD
4 November 2015
Definition of Chronic Pain
• Pain that persists past the normal time of healing
– Variable: less than 1 month to more than 6 months
• Typically use 3 months as the point of transition from
acute to chronic pain
– Six months is more often used in research
IASP Classification of Chronic Pain, Second Edition (Revised),
http://www.iasp-pain.org/files/Content/ContentFolders/Publications2/ClassificationofChronicPain/Introduction.pdf
Pathogenesis of Chronic Pain
Marcus DA. Am Fam Physician. 2000; 61:1331-8)
Nociceptive and Acute Pain
• Reflects actual or imminent tissue injury
• Can result in hypersensitivity as part of the
normal healing process in order to promote
guarding/protection of the injured tissue
eg, sunburn
• This pain can become more persistent and
chronic via both peripheral and central
mechanisms
Nociceptors
•
Neurons that detect intense stimuli
– Mechanical
– Thermal
– Chemical
 Transduced into electrical signals
•
•
2 major classes
–
Aδ-fibers
•
–
Medium-diameter, myelinated 
detect well-localized, first, fast pain
C-fibers
•
•
Most are polymodal
Small-diameter, unmyelinated 
poorly localized, second, “slow” pain
Pseudounipolar = Bidirectional
•
•
–
–
Ca++-dependent release of transmitters at the central terminal
Ca++-dependent release of neurogenic inflammatory molecules (CGRP, Substance P) that influence the peripheral tissue
milieu
Only peripheral terminal can respond to mechanical/temperature, but both terminals can respond to
endogenous chemical signals
Different fiber types project to distinct lamina within the spinal cord dorsal horn (DH)
•
•
•
lamina I & II receive primarily nociceptive input via Aδ and C-fibers of different sub-classes
lamina III & IV receive non-nociceptive, innocuous input via Aβ fibers
lamina V contains the Wide Dynamic Response (WDR) neurons that receive input from a variety of classes such that they
respond to a wide variety of stimulus intensities ranging from innocuous to noxious via Aβ, Aδ and C-fiber input
–
These also commonly receive visceral input, which likely contributes to referred pain (injury to visceral tissue is referred to
somatic location)
Basbaum et al. Cell 2009; 139: 267-284
Supraspinal pathways in nociception
•
•
•
•
Involves multiple levels of of brain structures:
brainstem (medulla, pons, midbrain)
diencephalon (thalamus, hypothalamus)
primary and secondary somatosensory
cortices
• fronto-limbic circuits (prefrontal cortex [PFC],
anterior cingulate cortex, insula, amygdala,
hippocampus)
Nociceptive Pathways
• Spinothalamic tract
important for
discriminitive aspects of
pain
– Where, how intense
• Spinoreticulothalamic tract
more relevant for poorly
localized pain
• Parabrachial region of the
pons communicates with
amygdala
= affective experience of pain
Basbaum et al. Cell 2009; 139: 267-284
Reduced descending inhibition
• Midbrain and medullary structures control nociception (↑ & ↓)
– Periaqueductal gray (PAG) receives inputs from higher brain centers 
descending, inhibitory, analgesic effect
• Via endogenous opioids
– Rostroventromedial medulla (RVM) can enhance or inhibit nociceptive
input
• Connects with PAG
• inputs from the thalamus, parabrachial region and locus coeruleus
(norepinephrine)
– LC and pontine nuclei exert descending inhibitor NE signals on dorsal horn
– Activating spinal α2 adrenergic receptors is analgesic
• Includes nucleus raphe magnus (serotonin), the nucleus reticularis
gigantocellularis-pars alpha and the nucleus paragiganto-cellularis lateralis
(serotonin)
• Dysregulation of this inhibitory input may promote chronic pain
Ossipov MH et al. Curr Opin Support Palliat Care. 2014;8:143-51
Supraspinal changes in pain
• Chronic pain states can be
associated with cortical
changes.
– Supraspinal regions
involved (either increased
excitation or↓d gray
matter) in chronic
pain/plasticity include:
• somatosensory cortex, PFC
(particularly dorsolateral
prefrontal cortex), insula,
thalamus and the cingulate
cortex
REV I EW S
b
c
Brain
S1
Dorsal root
ganglion
Unmyelinated
C- bres
Lightly myelinated
Aδ- bres
Heavily myelinated
Aδ- bres
ACC
PFC
IC
Thalamus
Cortex
CeA
Dorsal
PAG
Midbrain
LC
Pons
RVM
Medulla
Ventral
Second-order pain
projection neurons
Spinal cord
Spinal sites
a
Peripheral terminal
Noxious stimuli
Thermal
Mechanical
Chemical
In ammation
Tissue damage
Ion
channels
TRPA
TRPM
TRPV
Nav
KCNK
ASICs
Peripheral tissue
First-order
neuron
Normal,
physiological pain
TRP: Transient receptor potential channel (many
subtypes)
TRPA1=cold (<15°C) in injury (not normal,
acute cold), menthol
TRPM8=cold(<25°C), menthol
TRPV1=heat (>43°C), capsaicin
ASICs: Acid-sensing ion channels
KCNK: Potassium channel subtypes
Nav: Voltage-gated sodium channel isoforms
Also Voltage-gated Calcium channels (N- and T-type);
α2δ subunit ↑’d after injury
Mechanical transduction may occur via TRP, ASIC
KCNK channels
Figure 1 | Physiological pain processing. a | Nociceptive signals areand/or
transmitted
from the periphery by nociceptive
Nature Reviews | Immunology
Grace PM, et al. Nat Rev Immunol. 2014; 14: 217-231
sensory neurons (first-order primary afferent neurons) the peripheral terminals of which are clustered with ion
Basbaum et al. Cell 2009; 139: 267-284
Mechanistic Stratification of Medications Used
to Treat Neuropathic Pain
Fig. 4. Mechanistic stratification of antineuralgic agents. PNS = peripheral nervous system; CBZ = carbamazepine; OXC =
oxcarbazepine; PHT = phenytoin; TPM = topiramate; LTG = lamotrigine; TCA = tricyclic antidepressant; NE =
norepinephrine; SSRI = selective serotonin re-uptake inhibitor; SNRI = serotonin and norepinephrine re-uptake inhibitor; GBP
= gabapentin; LVT = levetiracetam; NMDA = N-methyl-D-aspartate; NSAID = nonsteroidal anti-inflammatory drug.
Beydouna & Backonja M. J Pain Symptom Manage. 2003;25:S18-30
Persistent Pain: Sensitization
•
•
The differences between acute and chronic pain reflect neuronal plasticity
Usually due to inflammatory changes in the neuron environment
– Tissue damage  accumulation of endogenous factors released by activated nociceptors or
non-neural cells (eg, mast cells, basophils, platelets, Mθ, PMNs, endothelial cells,
keratinocytes, fibroblasts)
•
•
•
•
•
•
•
neurotransmitters
peptides (substance P, CGRP, bradykinin)
eicosinoids and lipids such as prostaglandins, thromboxanes, leukotrienes, endocannabinoids
Neurotrophins (eg, NGF)
cytokines (such as IL-1β, IL-6 and TNF-α) and chemokines
Proteases
H+
– Nociceptors have receptors for these molecules (TRPA1, TRPV1, TrkA, ASICs, etc.)  increased
excitability  pro-inflammatory and pro-algesic!
•
•
Targeting these receptors should reduce pathological (inflammatory) pain without inhibiting normal
nociception
Sensitization is a unique feature of nociceptors
–
–
–
–
Increase in nociceptor excitability = increased response to stimulus
Reduced threshold for activation and sometimes development of spontaneous activity
Responsible for primary hyperalgesia (eg, sunburn)
Triggers increased excitability in central neurons within the pain pathway
= Central Sensitization
Basbaum et al. Cell 2009; 139: 267-284
Central Sensitization
• 3 major proposed pathways
– Glutamate/NMDA-mediated hypersensitivity
– Loss of inhibitory controls
– Glia-neuron interactions
• Microglia and astrocytes
Central Sensitization:
Glutamate/NMDA
• Glu = excitatory neurotransmitter (NT)
– Released from central terminal of nociceptors to
stimulate 2nd order dorsal horn neuron
• Primarily AMPA & kainate Glu receptors (ion channels)
– Summation of many inputs results in action potential
• NMDA normally quiet BUT
– In tissue injury, increased neurotransmitter release results in
depolarization that activates NMDA receptors  Ca++ influx 
strengthened connection btwn nociceptor and pain-transmitting
DH neuron  heightened response to noxious stimuli =
hyperalgesia
» Also, innocuous inputs around the site of injury become
painful = allodynia
• Now Aβ (normally light touch) activate pain
transmission circuits
Central Sensitization:
Loss of Inhibitory Control
• GABA and glycine (gly) = inhibitory NT
– Normally tonically active
• When experimentally blocked  hypersensitivity
behavior
• Decreased activity with peripheral injury thus
enhanced excitation of spinal 2nd order neurons 
increased activity in response to both painful
(hyperalgesia) and non-painful (allodynia) stimuli
Central Sensitization:
Glia-Neuron Interaction
• Microglia are MΘ resident within CNS
– Signal injury or infection within CNS
– Immune activity involved in sickness response (lethargy,
depression, anxiety) associated with illness and also chronic pain
– Following peripheral nerve injury (but NOT
inflammatory tissue injury) they accumulate in the
superficial DH where the injured nerve terminates
(and also surround and damage adjacent
motorneurons)
• Activated  release inflammatory signals (TNF-α, IL-1β, IL-6)
 sensitization of central neurons and maintenance of pain
Grace PM, et al. Nat Rev Immunol. 2014; 14: 217-231
Basbaum et al. Cell 2009; 139: 267-284
Central Sensitization:
Glia-Neuron Interaction
• Physical damage of peripheral afferent results in
release of signals detected by microglia
– ATP  microglial P2-purinergic receptors (P2Xn)
• May ultimately result in decreased GABA-ergic inhibition and thus
increased excitability
– Other neuronally released cytokines and chemokines (eg,
CX3CL1) that activate the microglia when their receptors
(CX3CR1) are bound
• May be part of a positive-feedback loop
» microglia produce the protein that frees CX3CL1 from neuronal cell
surface
– Glia are activated not just in spinal cord but also in the
brainstem, contributing to facilitation of pain processing at
supraspinal levels
Grace PM, et al. Nat Rev Immunol. 2014; 14: 217-231
Basbaum et al. Cell 2009; 139: 267-284
Central Sensitization:
Glia-Neuron Interaction
• Toll-Like Receptors (TLR2 and TLR4)
– Innate immune receptors that respond to diverse
pathogens and pathogen- or damage-associated molecular
patterns (PAMPs & DAMPs) as well as endogenous signals
such as IL-1b, TNFα, IL-6 and nitric oxide
– Activation of TLRs results in immune-like processes, such
as the release of pro-inflammatory (and neuroexcitatory)
cytokines and phagocytosis
• Exposure to DAMPs may increase glial expression of P2X receptors
  increased neuronal excitability
• Development of nociceptive hypersensitivity correlates temporally
with increased TLR4 expression after injury
– Sensory neurons themselves may express TLRs and adaptor proteins
Milligan and Watkins Nat Rev Immunol. 2009; 10: 23-36
Grace PM, et al. Nat Rev Immunol. 2014; 14: 217-231
Central Sensitization:
Glia-Neuron Interaction
• Glia may become “primed” following stress, aging,
illness or injury such that subsequent injury leads to
unregulated activation that maintains central
sensitization and leads to chronic pain
• Opioids like morphine (and its “inactive” metabolites)
activate TLR4 resulting in such priming and central
sensitization, which actually opposes analgesia!
– This non-opioid receptor activity is also implicated in opioid
reward, craving and withdrawal
– As well as opioid-induced hyperalgesia
Summary
• Complex changes in both pain sensation,
transmission and processing lead to chronic
pain
– Peripheral
– Central
• Spinal Cord
• Supraspinal structures