Pain Physiology Presented At St Thomases Hospital 2.3.07
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Transcript of Pain Physiology Presented At St Thomases Hospital 2.3.07
Pain Physiology
Dr. Christopher A. JennerConsultant in Pain Medicine and Anaesthesia, SMH
2nd March 2007
What can u say?
Its very complicated !!!
Agenda
• FRCA requirements
• Basic definitions
• Overview of pain pathways
• Tissue Injury
Agenda
• Nociceptors
• Pain transmission
• Spinal cord
Agenda
• Second order neurones
• Ascending spinal pathways
• Pain modulation
• Descending inhibitory pathways
Agenda
• Gate control
• Neurotransmitters
• Neuropathic pain
FRCA requirements
FRCA requirements
• Syllabus- Physiology and Biochemistry
• ‘Pain: afferent nociceptive pathways, dorsal horn, peripheral and central mechanisms, visceral pain, neuropathic pain…influence of therapy on nociceptive mechanisms…’
FRCA requirements
• Syllabus- Regional Anaesthesia
• ‘Indications, technique and management of complications of spinal and epidural (including caudal approach) analgesia…
FRCA requirements
• Multiple Choice Questions
FRCA requirements
• Primary FRCA Viva question
• Give a detailed description of the pain pathways that become activated if you prick your finger with a pin. What happens in the thalamus and cerebral cortex? Describe the neurotransmitters involved.
FRCA requirements
• Primary FRCA Viva question
• Describe the principles of management of neuropathic pain
Techniques for answering MCQ’s
A. Knowledge
1. Learning from MCQ’s
• Learning rather than just T/ F
• E.g: when measuring jugular venous saturations
• Good opportunity to learn
2. Method
• Decide on style eg: 10 MCQ’s at a time
• Mark them
• Break
• Go thru questions with suitable textbooks
• Sounds very labor intensive BUT can cover entire syllabus including minutiae
• Learn subjects relatively painlessly
• Small bite-sized topics!
3. References
• A-Z Anaesthesia/ Sasada n Smith/ Parbrook/ others
• Library!
4. Answers
• Answers in MCQ’s- both loose and books not necessarily correct
• Many answers maybe subject to interpretation
5. Beware!
• In exam hall- even if u see a question u recognise- it may be worded differently or otherwise altered
B. Techniques
Techniques
• Numerous!
• Research papers (including info on probability and guessing, etc)
• Simple method:
Techniques
• Read the question fully!
• Answers to the stem question can be roughly divided into 4 categories
• Each category has its own hit rate for answering it correctly
• However- u will have to find out your own hit-rate for answering these
Category Hit rate for answering correctly
Certain 80-100%
Fairly certain 60-80%
Probably 50-60%
No clue 50%!
• Remember- to get 55-60% and pass (mark varies with cohort) u must answer sufficient questions
• Overall need to answer at least 80%
• Answer 50-60%- start saving up!
• BEWARE
• Negative marking can seriously damage your health
• More MCQ u practice, more knowledge u will acquire, more questions u can answer, more ‘lucky’ u get
• Will become better at attempting difficult questions and getting them right
• Combination of knowledge, confidence and improving technique
• Other strategies- immediately identify 3 answers u are happy with
• DON’T PANIC
• If u see a very difficult/ complex question- everyone else facing the same
• Some new MCQ’s are tried out- if crap at differentiating candidates, are removed
Definitions
Definitions
• Pain• An unpleasant sensory or emotional experience
associated with actual or potential tissue damage. It is a subjective phenomenon.
• Nociception • The process by which the painful stimulus is conveyed
by the nervous system to the brain.
• Chronic Pain• Pain which persists even when the noxious stimulus is
removed. >3/12
• Acute pain
Overview to Pain Pathways
Cue the CD-ROM !
Nociceptors
Nociceptors
• Receptors respond to different noxious stimuli
• Mechanical
• Thermal – temps above 45-50 oC
• Chemical – exogenous eg capsaicin
- endogenous eg bradykinin, H+, substance P, histamine,
K+.
Receptors
• Unimodal or polymodal
Unimodal
Unimodal- Mechanical
Mechanoreceptors
High Threshold Mechanoreceptors
• Activated by intense mechanical stimulation
• Innervated by A fibres
• Sharp, prickling, localised pain
Unimodal- Thermal
Thermal- Noxious heat/ cold
Noxious cold CMR1
TRPM8
Noxious heat VR1
TRPV1
Unimodal- Chemical
Chemical
Receptor Ligand
PTX3 ATP
B2 Bradykinin
EP2 PGE2
ASIC H+
TTX-R (predominate) Na+
Chemical-other ligands
• GABA A/B
• Somatostatin
• Adrenaline
• Glutamate
• Capsaicin
Chemical-other ligands
• Angiotensin II
• ATP
• CCK
• Adenosine
Polymodal nociceptors
Polymodal nociceptors
– Activated by mechanical stimulation/ high temps/ irritant chemicals
– Innervated by unmyelinated C fibres
– Slow, burning, poorly localised pain
Tissue Injury
Tissue injury causes the release of various inflammatory and pain mediators resulting in peripheral
sensitisation
Pain Response Mediators
Pain Response Mediators
Released from Mediator
Damaged endothelial cells and platelets
ATP, ACh, serotonin, PG E2
Damaged vessels Bradykinin
Inflammatory Response Mediators
Inflammatory Response Mediators
Released from Mediator
Mast cells Histamine
Sub P, CGRP trigger mast cell degranulation
Blood cells Cytokines, Complement factors C3a, C5a, serotonin, PAF, NCF, LK, fibrinopeptides
Actions of Inflammatory Mediators
Inflammatory Mediators
• Peripheral vasodilatation
• Increased vascular permeability
• Plasma extravasation
• Leucocyte migration
• Clotting response
Outcome on pain pathways?
Outcome on pain pathways?
• Sensitisation primary afferent sensory fibres
• By mediators of the pain response- greater, more frequent transmission of APs to the nociceptive
Outcome?
• Synapse level, sensitised primary afferent sensory fibres decrease thresholds for activation of nociceptors
• These become hyperexcitable and transmit frequent APs.
Pain Transmission
Pain Transmission
• Cutaneous sensation- Low and high threshold primary afferents
• Low threshold
• Ab light touch, vibration, pressure
• Aa proprioception
Pain Transmission
• High threshold
• Stimulation of nociceptive afferents leads to propagation of impulses to the spine (via Ad and C fibres)
Properties of Ad and C fibres(rote learning!)
C Ad Ab
Myelination No Yes Yes
Diameter 0.4-1.2 mcm 2-5 mcm
Conduction velocity
0.5-2 m/s 12-30 m/s
Normal sensation
Slow pain
Diffuse, dull
Fast pain
Sharp, localised, reflex withdrawal
Pathological sensation
Hyperalgesia Allodynia
C Ad Ab
Threshold high high low
Main Transmitters
peptides EAA EAA
Main receptors activated
NK1,2
(neurokinin)
NMDA
AMPA
mGlu
AMPA
Lamina 1,2,5 1,2,5 3,4
Target sc neurones
NS
(nociceptor specific)
WDR LT
WDR
Note about Ad and C fibres
• NB: not all are nociceptor specific
• Some to low threshold eg: touching/ brushing
• Many thermoreceptors
Synapses
Activity of Synapses
Synapses
• Action potentials- voltage-gated Ca channels to open in terminals
Synapses
• Opening channels enables influx of Ca, causing neurotransmitter molecules to fuse with the pre-synaptic membrane and release their contents into the synaptic cleft
Synapses
• Neurotransmitters eg: glutamate, substance P diffuse across synaptic cleft
• Neurotransmitters bind to receptors on ion channels in post synaptic membrane
Synapses
• Activation via:
• G protein coupled effector enzymes
• direct on ion channels
• enabling efflux of K and influx Ca
• Na into post synaptic cell
• Influx Na enables continuation of AP
Spinal Cord
Spinal Cord
• Grey and White matter
• White matter- ascending/ descending fibres
• Grey matter- cells and central terminals of primary afferents from periphery
Dorsal Horn
Dorsal Horn
• Dorsal horn divided into 6 layers (laminae)
• Primary afferents terminate in the dorsal horn.
Dorsal Horn
• Majority at same segmental level
• Proportion travel up or down a few segments (tracts of Lissauer)
Dorsal Horn
• Cell bodies lie in DRG (dorsal root ganglia).
• Synapse with projection or interneurones
Dorsal Horn
• Dorsal horn is divided up into various laminae – Rexed’s laminae
– A synapse in I and V
– C synapse in substantia gelatinosa (II and III)
Anatomy of the spinal cord
Anatomy of the spinal cord
Rexed’s laminae
Rexed’s laminae
I,II Most nociceptors terminate in superficial layers via Ad and C
III, IV Tactile afferents synapse
V Some A project into deeper layers.
V Nociceptive and tactile afferents converge (directly or via inter-neurones)
V,VI Inter-neurones mainly regulate flow of nocicpetive info
Summary of the Spinal Cord
• SC not just a relay station
• Modulation of pain via spinal and supraspinal mechanisms
• Regulatory circuits involve primary afferents, spinal interneurones and descending fibres
Anyone been to …
…healthy eating…
…leads to…
Second Order Neurones
Second- order neurones• Primary afferents synapse with various
classes of second-order neurone
Second- order neurones
– Nociceptive specific – exclusively respond to noxious stimuli, small receptor fields, mainly found in superficial laminae
– Wide Dynamic Ranging (WDR) neurones – non-specific, large receptor fields, located in deeper laminae.
– Low-threshold neurones – for innocuous stimuli, predominatly in III and IV
Second- order neurones
• Inter-neurones can be inhibitory or excitatory
NMDA Receptors
NMDA Receptors
Ascending Spinal Pathways
Tract Information
STT Spinothalamic tract
Temp, Pain, Touch, Visceral
Mediates and separates discriminative (fast) and affective (slow) aspects into different regions of the tract
Anterior STT- simple touch
Lateral STT- pain and temperature
VPL, VPM, PO nuclei- conscious perception of pain
SRT Spinoreticular tract
To reticular formation- arousal-emotional pain. Slow pain
SMT
SPT
Others
• Paleospinothalamic tract
• Spinomesencephalic tract
• Neotrigeminothalamic tract
Details of the tracts
Direct (fast) Indirect (slow)
Tract Lateral STT Lateral STT
SRT
Origin I, IV, V I, IV, V (+VII,VIII)
Somatotopic organisation
Yes No
Direct (fast) Indirect (slow)
Body representation Contralateral Bilateral
Synapse in RF No Yes
Sub-cortical targets None Hypothalamus
Limbic system
Autonomic centres
Direct (fast) Indirect (slow)
Thalamic nucleus VPL Intra-laminar nuclei
Other midline nuclei
Cortical location Parietal lobe Cingulate gyrus
Role Discriminative pain (quality, intensity, location)
Affective-arousal component of pain
Other functions Temperature
Touch
Ascending Spinal Pathways
• Most secondary afferents decussate to ascend in the lateral spinothalamic tract. (Some pass up posterolateral part of cord)
Ascending Spinal Pathways
• Fibres pass through the medulla, mid-brain and pons giving off projection neurones.
Ascending Spinal Pathways
• Terminate in the ventral posterior and medial nuclei of the thalamus.
• Other pathways– Spinorecticular pathway – terminates in RF
then thalamus
– Spinomesencepthalic pathway – terminates in mid-brain and PAG
Ascending Spinal Pathways
• From the thalamus, there is a specific sensory relay to areas of the contralateral cortex
– To somatic sensory area I (SSI) in the post-central gyrus
– To somatic sensory area II (SSII) in the wall of the Sylvian fissue
– Cingulate gyrus – mediates the affective component of pain
Pain Modulation
Pain Modulation
• At numerous levels
• Dorsal horn, complex interaction between afferent input fibres, local intrinsic spinal neurones and descending central afferents.
Pain Modulation
• Afferent impulses arriving at the dorsal horn, themselves initiate inhibitory mechanisms.
Pain Modulation
• As fibre ascends collateral projections to higher centres (eg PAG and locus ceruleus of mid-brain).
• Descending fibres from PAG project to the nucleus raphe magnus (medulla) and RF to activate descending inhibitory neurones.
Pain Modulation
• Endogenous opioids- enorphins, enkephalins, dynorphins
• Action- bind opioid receptors, inhibit presynaptic release glutamate, increased K conductance across post synaptic membrane
Pain and Cannabinoids
Pain and Cannabinoids
• Endogenous cannabinoid system widespread n responsible for number modulatory functions, including analgesia
Pain and Cannabinoids
• Akin to endogenous opioid system, analgesic action mediated via:
• CB1- neuronal receptor
• CB2- immune cell-expressed receptor
Pain and Cannabinoids
• Animal data shown cannabinoids effective in many models of inflammatory and neuropathic pain
Pain and Cannabinoids
• Less evidence in human studies
• An effective cannabinoid analgesic should be therapeutic but without the ‘high’ of unwanted central side effects
Descending Inhibitory Pathways
Descending Inhibitory Pathways
• Travel in dorsolateral funiculus to terminate on interneurones in the dorsal horn.
• Fibres from PAG thought to be main source of inhibitory control.
Descending Inhibitory Pathways
• Descending inhibition also from LC (locus ceruleus) and NRM (nucleus raphe magnus).
• Inhibitory activity from PAG also stimulated by endorphins released from the pituitary- act directly at that site.
• 70% of endorphin/ enkephalin receptors in presynaptic membrane of nociceptors
Gate Control Theory
‘Gate’ control
• One aspect of modulation
• Synaptic transmission between 1o and 2o nociceptive afferents can be ‘gated’ by interneurones.
‘Gate’ control
• Neurones in SG exert pre-synaptic inhibition on 1o afferents and post-synaptic inhibition on 2o neurones
the pain response to a nociceptive stimulus.
• Inhibitory interneurones may be activated by afferents- subserve different sensory modalities eg: pressue (Aß fibres)
Gate theory
Gate theory
• Phenomenon underlies use of counter-irritation, dorsal column stimulation, TENS and mechanical stimulation (‘rubbing it better’)
• Descending central efferents from the PAG and locus
ceruleus can also activate these inhibitory interneurones.
Neurotransmitters
Neurotransmitters
• Numerous
• No single ‘pain neuro-transmitter’
Neurotransmitters
• Major excitatory transmitters at dorsal horn involved in nociceptive transmission:
– Glutamate
– Aspartate
Neurotransmitters
• Multiple receptors present at dorsal horn
– NMDA, non-NMDA, glutamate, AMPA, neurokinin, adenosine, 5-HT, GABA, -adrenergic and opioid receptors.
Neurotransmitters
• Primary afferents release various peptides, incl Substance P, neurokinin A and calcitonin gene-related peptide (CGRP).
Neurotransmitters
• Different neurotransmitters in various descending inhibitory pathways:
– Encephalins and endorphins in the PAG
– Metencephalin and 5-HT in the NRM pathway
– Noradrenaline in the locus ceruleus pathway
The Brain
The Brain
• Substantia Gelatinosa
• Periaqueductal Grey
• Reticular Formation
• Parabrachial Nucleus
The Brain
• Hypothalamus
• Cingulate Cortex
• Cortex
Neuropathic Pain
Neuropathic Pain
• Definitions?
• Causes?
More definitions
Term Definition
Allodynia Pain due to a stimulus which does not normally provoke pain
Analgesia Absence of pain in response to stimulation which would normally be painful
Central Pain Pain initiated or caused by a primary lesion or dysfunction in the CNS
Dysaesthesia An unpleasant abnormal sensation, whether spontaneous or provoked
Hyperalgesia An increased response to a stimulus which is normally painful
Hyperaesthesia Increased sensitivity to stimulation, excluding the special senses
Hyperpathia A painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold
Hypoalgesia Diminished pain in response to a normally painful stimulus
Neuralgia Pain in the distribution of a nerve or nerves
Neuritis Inflammation of a nerve or nerves
Neuropathic Pain
Pain initiated or caused by a primary lesion or dysfunction in the nervous system
Neuropathy A disturbance of function or pathological change in a nerve: in one nerve, momoneuropathy; in several nerves, momoneuritis multiplex; if diffuse and bilateral, polyneuropathy
Pain threshold The least experience of pain which a subject can recognise
Pain tolerance level
The greatest level of pain which a subject is prepared to tolerate
Paraesthesia An abnormal sensation, whether spontaneous or eveoked
Causes of Neuropathic Pain?
INVITE
DAMP C
Pathophysiology of Neuropathic Pain
Mechanisms
• Ectopic activity
• Changes in membrane thresholds
• Wind up
• Ephamptic cross talk
• Neuromas
• Ab sprouting
Mechanisms
• CNS plasticity- following nerve injury, anatomical and neurochemical changes can occur in CNS
• Increased spontaneous activity in dh
Mechanisms
• Decreased threshold
• Increased responsivity to afferent input
• Cell death in sc
Mechanisms
• Ab sprouting- from laminae III to I,II
Mechanisms
• Barrage of afferent inputs:
•
• ↑ mRNA for specific neurotransmitters
• differential expression of mRNA and receptors
Mechanisms
• ↓ opioid binding sites
• ↑ immediate early gene products eg: c-fos, alterations in relative levels of neuropeptides/ neuromodulators
Wind-up
Wind-up
• Repetitive noxious stimulation of C fibres- prolonged discharge of dh cells
• Wind-up- progressive increase in no. of APs elicited per stimulus in dh
Wind-up
• Repetitive episodes of wind-up can lead to LTP (long-term potentiation)
• Long lasting increase in efficacy of synaptic transmission
Wind-up
• Wind-up n LTP both part of sensitisation process in many chronic pain states
• Expansion of receptive fields with tissue injury
Wind-up
• Therefore peripheral stimulation will activate more dh cells due to overlap of receptive fields
Allodynia and Hyperalgesia
Allodynia and Hyperalgesia
• Ectopic activity- spontaneous
• Ab sprouting fron III to I,II
• Sympathetic efferents sprouting into dh
• ↓ intrinsic modulatory systems
• ↑ excitatory activity
NMDA Receptor
NMDA Receptor
• C fibres to dh interneurones which release EAA (glutamate, glycine) via NMDA receptor which excites WDR neurones
NMDA Receptor
• NMDA receptor activation triggers a cascade of events leading to sensitisation of dh WDR
• ↑ Ca, ↑ PK, ↑ phosphorylating enzyme
NMDA Antagonists
• AP5 (2-amino-5-phosphonopentanoate)
• Ketamine
• MK-801 (dizocilipine)
• Phencyclidine
• Dextromethorphan
• Memantine
RCT evidence of effect of drugs on evoked pain
Drug Effect on
Tramadol Mechanical allodynia
TCA Mechanical allodynia
Gabapentin Cold allodynia
Opioids Skin hypersensitivity
IV lidocaine Mechanical allodynia
Topical lidocaine Mechanical and thermal hyperalgesia
Clinical Confusion
Clinical confusion
• Current classification little use!
• Same symptom- several mechanisms
• Same mechanism- different symptoms
• Same lesion- different symptoms
…please visit…
www.frca.co.uk