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Pain Physiology Presented At St Thomases Hospital 2.3.07
 

Pain Physiology Presented At St Thomases Hospital 2.3.07

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Pain Physiology....

Pain Physiology.

Presented At St Thomases Hospital for trainee Anaesthetists as part of their FRCA (Fellow of the Royal College of Anaesthetists) examination preparations.

2nd March 2007

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    Pain Physiology Presented At St Thomases Hospital 2.3.07 Pain Physiology Presented At St Thomases Hospital 2.3.07 Presentation Transcript

    • Pain Physiology Dr. Christopher A. Jenner Consultant in Pain Medicine and Anaesthesia, SMH 2 nd 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 o C
        • • 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 1 o and 2 o nociceptive afferents can be ‘gated’ by interneurones.
    • ‘ Gate’ control
      • Neurones in SG exert pre-synaptic inhibition on 1 o afferents and post-synaptic inhibition on 2 o neurones
      •  the pain response to a nociceptive stimulus.
      • Inhibitory interneurones may be activated by afferents- subserve different sensory modalities eg: pressue (A ß 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