Tony Dickenson, Neuroscience, Physiology and Pharmacology University College London PAIN - WHAT DOES IT DO TO US, AND WHAT CAN WE DO ABOUT IT?

Transcription

1 Tony Dickenson, Neuroscience, Physiology and Pharmacology University College London PAIN - WHAT DOES IT DO TO US, AND WHAT CAN WE DO ABOUT IT?

2 Cortex - where and how much pain Limbic areas - unpleasantness Brain stem descending controls Central reward and co-morbidities Peripheral events Tissue and nerve damage Peripheral channel and sensors Peripheral sensitization Spinal events Wind-up Impact of the brain Central sensitization

3 Key types of pain Post-surgical pains Nociceptive pain Pain caused by an inflammatory or non-inflammatory response to a noxious stimulus Tissue damage Chemical activation Nociplastic Osteoarthritis Both types of pain can co-exist Low back pain, cancer pain etc Neuropathic pain Pain initiated or caused by a primary lesion or disease in the peripheral or central nervous system Nerve damage Ion channel changes

4 The patients with pain after joint replacement? Thakur M, Dickenson AH, Baron R, Nature Reviews Rheumatology 2014;10:

5 Inflammation and Neuropathy in Cancer Induced Bone Pain Tissue Damage Tumor pro-pain chemicals Immune cells Nerve Damage Hyperinnervation Denervation Invasion Stretch

6 Translating from spinal neurones to humans

7 Inflammation ongoing activation of pain sensors capsaicin heat NSAIDS COX 1/2 H+ ATP Na +, K +, PGs Ca 2+ channels NGF 5HT C-fibre cytokines sensitize, activate

8 NGF - nerve growth factor Direct peripheral, direct gene effects and indirect Xian CJ and Zhou X-F et al. (2009) Treating skeletal pain: limitations of conventional anti-inflammatory drugs, and anti-neurotrophic factor as a possible alternative Nat Clin Pract Rheumatol doi: /ncprheum0982

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10 Tanezumab - humanized Monoclonal Antibody 10pM >100 hr stable binding Prevents TrkA action Excess of NGF in states of inflammation But.premature joint replacement

11 Neuropathy - nerves tend not to heal DRG A -beta fibres Non-noxious A -delta fibres Some noxious C- fibres Noxious Disordered conduction Accumulations of channels Ectopic and ephatic activity De-novo channels Calcium Potassium Sodium

12 A-beta fibres - tactile sensations C and A-delta fibres - nociceptors - heat, mechanical and chemicals Allodynia - Ectopic activity - ongoing pain central sensitization Disconnection - numbness Still connected - evoked pains All types of fibres can be damaged

13 gabapentin pregabalin lidocaine carbamazepine Calcium channels Potassium channels Sodium channels Release of transmitter Brakes Accelerator - action potentials Problem of driving with faulty brakes and transmission opioids

14 lidocaine Calcium channels Potassium channels Sodium channels Release of transmitter Brakes Accelerator - action potentials

15 Inherited mutations gain of function can be loss of inactivation, gain of activation but can alter lidocaine actions

16 Channelopathic pain syndromes Inherited erythromyalgia Nav 1.7 Lower threshold, enhanced responses Attacks of burning pain and redness in extremities Paroxysmal extreme pain disorder Nav 1.7 Impaired inactivation Enhanced response Episodic lower body visceral, ocular, jaw pain Channelopathy associated insensitivity to pain Nav 1.7 Loss of function Inability to sense pain Familial episodic pain syndrome TRPA1 Enhanced response Episodic upper body pain, triggered by fasting, cold, fatigue

17 Transduction, propagation and.transmission. error. Na v 1.8 and Na v 1.7 Peripheral restriction may be an Na v 1.8 Na v 1.7 C-fibre Ad-fibre Ab-fibre

18 Channels are key to neuropathic pain Major spinal increases in excitability a2 a 2 d ligands s s Damaged Zone Electrical activity a1 d b i Release of transmitters Carbamazepine Lidocaine

19 Upregulated alpha-2 delta subunits in the spinal cord on the side of nerve injury Pregabalin at effective doses prevents function of the subunit Bauer CS et al. J Neurosci 2009;29:

20 Nociceptive pain Chemical activation Neuropathic pain Electrical events NSAIDs The Search for the Holy Grail? Lido GBP

21 Pain and molecular gastronomy - the fine line.

22 A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome Irritant sensor Upper body pain Prodermal pain 1.5 hrs..sleep Triggered by cold hunger fatigue exertion emotions Normal acute pain Kremeyer B et al. Neuron 2010;66(5):671-80

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24 Tissue damage Primary hyperalgesia Hyperalgesia Spontaneous pain Allodynia FMS OIH PERIPHERAL ACTIVITY CENTRAL SENSITIZATION Nerve damage Decreased threshold to peripheral stimuli Expansion of receptive field Increased spontaneous activity Secondary hyperalgesia

25 Neuronal response NMDA receptors and wind-up 40 NMDA-R mediated amplification & prolongation of response 30 Decay dependent on peripheral input 20 Stimulus no ketamine 10 0 secs - hours -weeks Increased excitability (intensity and frequency of stimulus) Stimulus number D Mello RD, Dickenson AH. Br J Anaesthesia 2008;101:8-16

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27 Spinal mechanisms - central hypersensitivity Subsequent inputs Tactile, cold Altered pain states Early C-fibre inputs Wind-up - temporal summation Long-term potentiation Peripheral and descending pathways converge

28 Ketamine NMDA - Receptor For glutamate Powerful analgesic but cognitive and other side-effects

29 Loss of spinal GABA and chloride controls after nerve injury

30 Human hyperekplexia Glycine R mutation Cl - Descending inhibitions Brain Peripheral nerve Ad C Aa/b Spinal cord + + Ad I II III IV V + Glycine inhibitions + Withdrawal reflex

31 What is the Pharmacology of Descending Controls? NA and 5-HT are Key Transmitters Anterior cingulate cortex.. Limbic System Amygdala Hypothalamus Off-Cell PAIN Parabrachial Periaqueductal grey PAG Locus coeruleus Neutral Cell 5-HT7R Sub reticularis dorsalis DNIC/CPM Noradrenaline Alpha-2 adrenoceptor Inhibitory controls Rostroventral medial medulla RVM 5-HT 2 and 3R Excitatory controls Adapted from: Bannister K, Bee LA, Dickenson AH. Neurotherapeutics On-Cell

32 Neuropathy - ongoing and evoked asymmetrical neuronal changes..with time Pain related changes Anxiety Goncalves & Dickenson, Eur J Neurosci 2012

33 Pain changes our brain functions Difficulty sleeping 60 Lack of energy 55 Drowsiness Concentration difficulties Depression Anxiety 27 Poor appetite % patients with moderate to very severe discomfort due to symptoms (n=126) Meyer-Rosberg K et al. Eur J Pain 2001;5:379 89

34 Psychology is part of neurobiology Beliefs, distraction, anxiety

35 Noradrenaline and 5-HT AND THE CONTROL OF PAIN PAIN Limbic System Amygdala Hypothalamus Same circuits imaged in humans Periaqueductal grey PAG Mood, fear, anxiety, rage panic, sleep-wake. Neutral Cell Off-Cell Locus coeruleus Rostroventral medial medulla RVM On-Cell Noradrenaline Alpha-2 adrenoceptor Inhibitory controls 5HT excitatory controls

36 Brain noradrenaline pathways - ascend and descend

37 Descending inhibitions Descending excitations CHANGED IN PERSISTENT PAINS Noradrenaline 5-HT Protects Promotes Alpha2 AR 5HT2/3R NA

38 Response Frequency (%) Punctate mechanical hypersensitivity 100 vf 8g Post-operative Day Maintained hypersensitivity after peripheral neuropathy and abnormal cold Ablation of RVM descending facilitations Control values Could there be time-related events in neuropathic pain? Bee LA, Dickenson AH. Pain 2008;140:209-23

39 Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine.caterina Mainero MD, PhD 1, Jasmine Boshyan BS 1, Nouchine Hadjikhani MD, PhD 1,2,*

40 % change of BOLD signal (vmax) within PAG mask Translation to patients.. PAG activation Psychophysical and Functional Imaging Evidence Supporting Presence of Central Sensitisation in a Cohort of Osteoarthritis Patients Patients > Controls High PainDETECT > Low PainDETECT Pain DETECT score Gwilym SE et al. Arthritis Rheum 2009; 61(9):

41 5HT promotes pain NA protects Noradrenaline

42 Diffuse Noxious Inhibitory Controls (DNIC) Conditioned Pain Modulation Descending inhibitions - via brain Altered by gender, age. Relate to chronic post-op pain Reduced in fibromyalgia, osteoarthritis, after peripheral neuropathy and in opioid hyperalgesia Peripheral and central pain states have a common loss of inhibition - compounded by depression and sleep issues Failure of descending inhibitions in patients

43 Reduced CPM in many pain conditions Peripheral neuropathy Fibromyalgia, Irritable Bowel Syndrome, Migraine, Tension-type headache, Temporomandibular joint (TMJ) disorders, Osteoarthritis and muscle pain, Interstitial cystitis, Patients at risk of developing chronic post-surgical pain Cancer pain patients with greater opioid-induced hyperalgesia. Yarnitsky D, Curr Opin Anaesth 2010; 23:

44 Probing the pharmacology of DNIC 100% DNIC normal DNIC With NA a2r block DNIC normal DNIC nerve injury DNIC nerve injury + 5HT3 block 0 DNIC uses descending NA systems - lost after nerve injury Overcome by facilitations

45 LOSS OF CPM IN PATIENTS - RELATES TO ACTIONS OF DULOXETINE AND TAPENTADOL - both have NA actions Pain Jun;153(6): Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Yarnitsky D1, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Br J Anaesth Jul;113(1): doi: /bja/aeu056. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Niesters M1, Proto PL2, Aarts L2, Sarton EY2, Drewes AM3, Dahan A

46 A struggle between the outer and inner worlds.when and which? What targets for chronic pain prevention? Ø Altered peripheral transduction, altered nerve function Ø Consequent shift in spinal cord to hypersensitive state gain of excitation.. Ø Enhanced drive into brain areas responsible for sensory and affective aspects of pain Ø Shifts towards lower effective stimuli for pain Ø Comorbidities - anxiety, sleep problems etc Ø Impaired descending inhibitions, enhanced facilitations

47 Mechanism Symptom/sign Mechanism Ongoing/ evoked Mechanism

48 Three subgroups of patients aetiology is unimportant Subgrouping patients with peripheral neuropathic pain based on sensory signs It is likely that brexpiprazole affects individual patients in a different way, as the effects of antipsychotics in general depend a lot on the specific symptoms, which show especially high variability in schizophrenia. The same drug can be beneficial for one patient, while not improving symptoms in another patient. Reproduced with permission from Baron, R. et al., Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles, Pain, 158, 2, , Fulltext/2017/02000/Peripheral_neuropathic_pain a_mechanism_ related.10.aspx Colloca, L. et al. (2017) Neuropathic pain Nat. Rev. Dis. Primers doi: /nrdp

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50 A struggle between the outer and inner worlds Pain intensity Abnormal touch, cold etc Internal processes Anxiety Sensory inputs Life

51 When we can t fixed the source - we can modulate the pain Cortex - where and how much pain Limbic areas - unpleasantness Brain stem descending controls Restore normal modulation Peripheral events Tissue and nerve damage Spinal events Risk factors Failure of descending inhibition Presence of central sensitisation

52 The peripheral and central changes induced by nerve injury or peripheral neuropathy Adapted with permission from Tesfaye, S., Boulton, A. J. & Dickenson, A. H. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 36, (2013), American Diabetes Association, Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association Colloca, L. et al. (2017) Neuropathic pain Nat. Rev. Dis. Primers doi: /nrdp

53 Thank you!