Neurobiology of Pain Adjuvant analgesia

Transcription

1 Neurobiology of Pain Adjuvant analgesia Jason Brooks Consultant Anaesthesia and Pain Management BCH March 2017

2 The Brief A broad overview of the abnormal and normal anatomy and physiology of pain pathways in pain Adjuvant Analgesia agents

3 Things to know Definition Pain Neuroplasticity Peripheral sensitisation Central sensitisarion Pain Matrix

4 WHAT IS PAIN? 4

5 What is 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

6 What is 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

7 What is 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

8 What is 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

9 Pain Processing

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11 Pain Transmission

12 Outline of Sensory Processing Perception Transmission & Modulation Reception & Transduction

13 Pain Transmission Periphery Nociception

14 What is a Nociceptor? A number of receptors/channels that sense damage VR1 vanilloid receptor family - capsaicin/atp ASICs - respond to low ph/mechanical? P2X receptors - respond to ATP Chemical sensors - prostaglandins, 5HT, Bk etc - peripheral sensitization & inflammation

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18 Pain Transmission Spinal Level Dorsal Horn Integrates peripheral, local and descending input Changes in excitability at this level will control output to the brain

19 State 1 - Normal State Transient Pain Transient, non-tissue damaging stimulus Mediated by mainly by AMPA receptor activation Good correlation between pain sensation and functional specialization of primary afferents

20 State 1 Normal Transmission NK 1 Substance P AMPA Primary Afferent C-Fibre Glutamate NMDA Mg ++ Afferent Input Postsynaptic Output

21 Glutamate Receptors

22 Neurotransmitters mediating/modulating pain

23 State 3 - Sensitised State dorsal horn excitability is increased. Sensitisation initiated following tissue injury, inflammation and nerve injury. Low threshold input generates pain

24 Dorsal Horn Neurone Sensitisation Central Sensitisation Reversible changes in Dorsal horn last for hours. Long lasting alterations in expression of transmitters / receptors and ion channels.

25 Central Sensitisation in the excitability of DH neurones triggered by peripheral injury or nociceptive input Fundamental to the generation of clinical pain

26 The pain-signalling system is not a hard-wired structure, but is dynamic and plastic. This plasticity underlies persistent and chronic pain. Coderre T.J. et al Pain (1993);52:

27 Manifestations of Neuroplasticity Response Allodynia A painful response to a normally innocuous stimulus. Pain Threshold Stimulus intensity

28 Manifestations of Neuroplasticity Response Hyperalgesia An increased response to a normally painful stimulus. Stimulus intensity

29 Primary and Secondary Hyperalgesia Redrawn from Fields 1987 & Lewis 1942 Dry ice injury, Primary hyperalgesia Mainly C fibres Heat Blunt Pressure Impact Stimuli Secondary hyperalgesia Brushing (Aβ) Pin-prick (Aδ)

30 Mast cell CGRP Sub P Peripheral Sensitisation ATP, 5HT K +, H + Kinins Blood vessel CGRP Sub P Primary afferents sensitised by Compounds in the inflammatory medium

31 Mechanisms of peripheral sensitisation: effectors Ligand-gated channels ASIC P2X 3 VR 1 Voltage-gated channels Na + Ca ++ K + G-protein receptors EP B 2 β 2 P2Y p 1. Receptor sensitization 2. Channel sensitization 3. Gene expression p trka Tyrosine kinase receptors

32 Heat/H + /Capsaicin ATP H + ASIC Mechanisms of peripheral. sensitisation: effectors P2X 3 VR 1 Voltage-gated channels Na + Ca ++ K + Mechanical? p PGE 2 Bradykinin Adrenaline ATP EP B 2 β 2 P2Y p NGF trka Tyrosine kinase receptors

33 Central Sensitisation Basic Mechanisms NK 1 Substance P mglur Phosphorylation of Increased Transmitter Release Afferent Input Glutamate BDNF Ca ++ AMPA P NMDA Mg ++ trkb certain amino acid Ca 2+ residues NMDA Convergent signalling a) Relieves Activation cascades Mg 2+ block at Enhance PKC NMDA channel resting gating potential PKA, Src b) Changes the channels open time Postsynaptic Activity

34 INJURY Tracey, 2008 SYMPTOMS Tissue Damage Hyperalgesia Spontaneous Pain Allodynia PERIPHERAL ACTIVITY CENTRAL SENSITIZATION Nerve Damage Decreased threshold to peripheral stimuli Expansion of Receptive field Increased Spontaneous activity

35 Modification State 4 Structural reorganization Long-lasting alteration in the expression of transmitters/ ion channels or the structure, connectivity and survival of neurones Dorsal horn becomes modified Structural changes to dorsal horn neurones following Peripheral nerve injury

36 Inhibition of Pain PAIN = An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Exogenous Endogenous systems

37 State 2 -Suppressed Transmission Dorsal Horn under inhibitory control from inhibitory interneurones and descending inhibition Main inhibitory receptor = GABA Others- Glycine, opiate, cannabinoid, α 2, 5HT. Activated by peripheral sensory stimulation or cortical/subcortical inputs Result in reduced release of primary afferent firing and hyperpolarisation of the neurone

38 State 2 -Suppressed Transmission NK 1 Substance P AMPA Reduced Transmitter release MOR Glutamate Hyperpolarise post- synaptic membrane and directly block depolarisation of the neuron Afferent Input Postsynaptic activity GABA

39 Pain Perception

40 Pain perception: Located in Thalamus & Cortex Psychophysical features Components: Location; Intensity; Character; Duration 1 & 2 somatosensory cortex Affective features Components: Unpleasantness & Rejection Limbic cortex (Cingulate & Insula) Ascending pathway: Dorsal horn; Parabrachial nucleus; Amygdala

41 Pain Matrix Anterior cingulate cortex (ACC) Insular cortex (IC) Thalamus Sensorimotor cortex (SSI, SSII) Cerebellum Moseley GL. Man Ther. 2003;8(3):

42 Brain Centers Not just 1 center or one input (like from the tissues) Neurotag many parts of the brain activating in a unique pattern Sensory, motor, memory, emotion, autonomic nervous system, etc. Danger signal, on its own, is NOT enough to produce pain!

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44 Analgesia Adjuncts Is there a role? Why consider adjuncts? Which ones should we consider Ketamine Magnesium Gabapentinoids Clonidine IV Lidocaine

45 Ketamine as an Adjunct Analgesic Why use ketamine? Subpopulations? Any evidence? Practical applications

46 Perioperative ketamine for acute postoperative pain. The Cochrane Database of Systematic Reviews. 2006; 3; N = 37 trials (2240 participants) Methods: Search from Randomized, controlled trials being treated with perioperative ketamine or placebo Results & Conclusion: Subanesthetic doses of ketamine reduce rescue analgesia requirements, pain intensity, PCA morphine consumption, PONV. Adverse effects were mild or absent.

47 46 studies Heterogenous in dose/administration and surgery Reduced opioid consumption and time to first analgesia More effective if surgery produced higher pain scores Placebo groups also higher pain scores Dr Brooks

48 Dr Brooks

49 Ketamine Practical Applications Dose Consider Over 0.3mg/kg more psychosensory effects Studies use mg/kg Bolus dissipates minutes Suggest Bolus pre-incision Repeat boluses or infusion mg/kg/hr

50 Ketamine - Which Cases Painful procedures Surgery with high risk for developing chronic postsurgical pain Opioid tolerant patients Patients with opioid-induced hyperalgesia Desire to minimize perioperative opioids Dr Brooks

51 Gabapentinoids Why use? Any evidence? Problems? Practical aspects. Dr Brooks

52 22 studies Reduction morhine first 24hrs Reduced pain scores Not dose dependent Dr Brooks

53 Effect of preoperative gabapentin on postoperative opioid consumption. Tiippana E M et al. Anesth Analg 2007;104:

54 55 studies Various doses mg / single and repeated Reduced pain scores rest and movement upto 24hrs. Reduced morphine consumption Increase sedation, dizziness All doses effective 75/ /300

55 From: Perioperative Gabapentinoids:Choice of Agent, Dose, Timing, and Effects on Chronic Postsurgical Pain Anesthesiology. 2013;119(5): doi: /aln.0b013e3182a9a896

56 Gabapentin vs Lyrica Practical aspects Evidence for both/ no specific evidence superiority Dose Suggeston higher doses more efficacious Lyrica 300mg Gabapentin single dose mg Timing At least 2hrs pre op Duration Some evidence to support continued dosing 1-14 days

57 My Biased View Lyrica 150mg pre-op night before and 2hrs before Assess if any side-effects Continue 7-14 days (consider 75mg BD) Dr Brooks

58 Magnesium Why use Magnesium? Subpopulations? Any evidence? Practical applications

59 Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia Jan;68(1): trials Bolus / infusion Reduction in cumulative morphine 24hrs

60 Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis Anaesthesia Volume 68, Issue 1, pages 79-90, 1 NOV 2012 DOI: /j x

61 Anaesthesiology trials (1200pts) Majority bolus 30-50mg/kg and infusion Significant reduction in post-op opitae use (large effect) Small reduction in early pain scores No effect on late pain (>24hrs) Dr Brooks

62 Magnesium Practical Applications Dose - Bolus 50mg/kg Consider infusion? My Biased view Tend to use approx. 50mg/kg as a single bolus in majority cases. Dr Brooks

63 IV Lidocaine Infusion Why use Lidocaine Infusions? Subpopulations? Any evidence? Practical applications Dr Brooks

64 43 trials (2800 pts) Various surgical specialties Various dose regimens Reduction pain early/intermediate time points low quality evidence 1-3mg/kg bolus and 1.5 5mg/kg/hr Effect greatest lap Lower GI Surgery Positive effects postop ileus/ time to first flatus/ PONV/ morphine use

65 45 trials Similar outcomes to previous study low quality evidence for a reduction pain scores early intermediate time. Greatest for lap bowel surgery Little evidence for other outcomes morphine reduction and recovery bowel post op recovery

66 Practical Aspects Lidocaine Some evidence to support use as adjunct agent. Strongest in Lower GI lap surgery. My Biased view: Bolus 1.5mg/kg over 20 min Infusion 1mg/min if < 70 kg, 1.5mg/min if kg, 2 mg/min if > 100 kg Continue in recovery/pacu need protected pump.

67 Alpha 2 Agonists

68 30 studies Heterogeneous surgery / doses Minor significant reduction pain scores and opioid use in first 24 hrs Side effects hypotension & bradycardia Biased opinion Use in major surgery/ opioid tolerant patients 1-2ug/kg bolus Dr Brooks

69 Summary Thoughts For major surgery; opioid tolerant patients etc Consider adjuncts depending on other techniques. Consider Lyrica 150mg pre-op Magnesium 50mg/kg bolus Ketamine mg/kg bolus Consider lidocaine infusion Consider clondine

70 Presentation available (professional links) Papers available on my shared anaesthesia google drive Folder Adjucts. me on

71 Pre-emptive / preventive analgesia

72 Preemptive analgesia: concept, timing, goals. Concept: To protect the peripheral and central nervous system from afferent nociceptive inputs and to prevent pathologic modulations that are associated with pain transmission Timing: Analgesia is started before tissue injury Analgesia is maintained throughout and after surgery Goals: Prevention of acute postoperative pain Prevention of pain-related pathologic modulation of the central nervous system Prevention of persistent postoperative pain and development of chronic pain

73 Preemptive = evidence preoperative intervention pain / or analgesic consumption vs identical post incisional Preventive analgesia = pain / or analgesic consumption relative to another Rx as long as the effect observed at a point in time exceeds expected duration of action

74 Evidence Pre-emptive Analgesia Systematic Reviews

75 Included studies 15 RCTs 1987D1994 Tested analgesic intervention NSAIDs (oral, iv): 4 LA (epidural, caudal, infiltration): 7 Opioids (epidural, iv): 4 NSAIDs + LA + opioids: 1 Conclusion No preemptive effect: paracetamol, NSAIDs, LA Weak positive evidence: opioids 24 RCT s 1984 D200 0 LA (peripheral, intrathecal, epidural, intraperitoneal) +/ opioids: 15 Opioids (epidural, intraperitoneal, iv, im): 5 NSAIDs (oral, i m): 4 No specific recommendation; privileges individual and multimodal approach 80 RCTs 1983 D200 0 NSAIDs (oral, iv, im): 20 Opioids (iv): 8 NMDA receptor antagonists (iv, im): 8 LA (infiltration, peripheral, intraperitoneal): 20 Epidural (opioids, LA): 18 Caudal (opioids, LA): 6 No effect: NSAIDs, iv opioids, ketamine; epidural, intrathecal, caudal block; infiltrational LA Insufficient data: dextromethorphan, intraperitoneal and peripheral LA Some reduction in analgesic demand: epidural opioids +/ LA Some evidence for improved pain scores at 3 and 6 months: epidural LA Timing of analgesia has no influence on postoperative pain 40 RCTs 1989 D200 3 Magnesium (iv): 4 Ketamine (iv): 24 No effect: magnesium Some evidence for reduction in pain, analgesic consumption or both: dextrometorphan, ketamine

76 Dextrometorphan (iv): RCTs 1989 D200 3 Epidural LA and opioids: 19 LA (infiltration): 15 NMDA antagonists (iv): 7 NSAIDs (iv): 17 Opioids (iv): 8 Some evidence for decreased pain intensity: epidural Slightly decreased analgesic consumption and longer time to first analgesic: LA wound infiltration, NSAIDs 6 RCTs 1996 D200 3 LA (epidural): 1 LA + opioids (epidural): 5 Significant reduction of acute pain Non significant reduction of chronic pain

77 Pre-Op Intra-Op Post-Op Incision End Surgery

78 Ong et al Meta-analysis 2005 Ong C K et al. Anesth Analg 2005;100:

79 Evidence J Katz 2003 Search Criteria Randomised Double Blind Assessments of Pain and Analgesic use Reliable pain measure Analgesic consumption Criteria preventive as described

80 Agent Number Of Studies Evidence Preemptive Positive Preemptive Negative Preventive Positive Preventive Negative LA Opioids NSAIDS NMDA LAÕs and Opioids Multimodal studies included

81 Timing LA Many routes Most frequent design Preop LA (preventive) Preop admin vs per op or post op LA 30% studies preemptive positive 65% Preventive positive

82 NMDA Receptor Antagonist Most successful in number of studies showing significant preventive or preemptive effects

83 NSAIDS Not appear to have significant pre-emptive or preventive analgesic effects

84 Issues Inadequacy experimental models Insufficiency preemptive techniques Post-op pain may depend more on peripheral inflammation Analysing isolated effects preemptive analgesia difficult Outcome measures Small differences between groups hard to measure Many confounding factors No standardised measure

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