RACS ANNUAL SCIENTIFIC CONGRESS and ANZCA ANNUAL SCIENTIFIC MEETING

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1 RACS ANNUAL SCIENTIFIC CONGRESS and ANZCA ANNUAL SCIENTIFIC MEETING Sands Expo and Convention Center, Marina Bay Sands, Singapore 2014 Refresher Day 4 May 2014 Pain After Surgery New Directions in Neuromodulation PHYSIOLOGY OF NEUROMODULATION Robert D. Foreman, Ph.D. GEORGE LYNN CROSS RESEARCH PROFESSOR DEPARTMENT OF PHYSIOLOGY Adjunct Professor of Anesthesiology University of Oklahoma Health Sciences Center Oklahoma City, OK USA

2 DISCLOSURES Boston Scientific Respicardia W. L Gore & Associates

3 UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER Department of Physiology

4 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

5 GATE CONTROL THEORY: THE STIMULUS FOR DEVELOPING NEUROSTIMULATION FOR PAIN RELIEF

6 GATE CONTROL THEORY Noxious Pinch Skin Touch Noxious Pinch Skin Pain Stimulate Touch Fibers

7 SPINAL CORD STIMULATION (SCS): Proposed Mechanisms Antidromic Activation of the Large Primary Afferent Fibers Activation of the Classical Gate Control Mechanism of Melzack & Wall SCS In: Linderoth & Meyerson, 1995 Bear, 2001

8 HISTORY Gate-Control Theory 1965 Melzack, R, & Wall, PD (1965). Pain mechanisms: A new theory. Science, 150, First Clinical Report 1967 Shealy, CN, Mortimer, JT, Reswick, JB (1967).Electrical inhibition of pain by stimulation of the dorsal columns: Preliminary clinical report. Anesthesia and Analgesia, 46,

9 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

10 USE OF ANIMAL MODELS

11 USE OF ANIMAL MODELS Pros: Use of analyses that cannot be applied to humans (LD 50; histology; lesional studies; various surgeries and pharmacol treatments, etc) Large numbers of subjects can be used Life time studies take short time Simple, or simplified systems may be studied Genetically manipulated animals available Small animals more economical/less public interest

12 USE OF ANIMAL MODELS Cons: No verbal communication--only behavioural, anatomical,histological and chemical studies Animal systems different from human Animal systems differ between species Ethical problems; especially primate studies Can the results be transferred to the human situation??

13 ACTUAL AND POTENTIAL ANIMAL Neuropathic pain Peripheral ischemia Cardiac ischemia Diabetes Visceral Dysfunction Inflammatory Pain Cancer Pain Skeletal Pain Arthritic (Joint) Pain Other Models? MODELS

14 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

15 THE CONSTANT DEBATE Relevance of Animal Models Clear differences exist between most animal models and clinical conditions they resemble Paucity of direct collaboration among scientists, clinicians, and engineers Collaboration is needed to develop models, design experiments and discuss results Collaboration would facilitate translation of studies between bench and bedside

16 Basic level Clinical Problem Basic-applied level 1 Models Basic-applied level 2 Receptors Basic-applied level 3 Substances; drugs Clinical Trial

17 FRIEND, COLLEAGUE, TRANSLATOR Dr. Bengt Linderoth, MD, PhD Karolinska Hospital Stockholm, Sweden NEUROSURGEON Visiting Professor University of Oklahoma HSC

18 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

19 ANIMAL MODELS OF PERIPHERAL NEUROPATHY

20 ANIMAL MODELS OF NEUROPATHIC PAIN Spinal Nerve Ligation (SNL)

21 INCREASED SENSITIVITY TO INNOCUOUS TACTILE STIMULI IN AN ANIMAL MODEL OF MONONEUROPATHY Partial Sciatic Nerve Ligation Miniature SCS system Test of SCS response Spinal Cord Stimulation (SCS) Parameters: 66%, 200 us, 50 Hz Cui &Linderoth.

22 ANIMAL MODEL OF MONONEUROPATHY EFFECT OF SCS ON WIDE DYNAMIC RANGE SPINAL NEURONS Yakhnitsa et al., 1999

23 MICRODIALYSIS PROBE PENETRATION INTO THE DORSAL HORN Cui and Linderoth, 1999 Cui et al., Pain 73: 87-95, 1997

24 ANIMAL MODEL OF NEUROPATHY EFFECT OF SCS ON GABA AND GLUTAMATE RELEASE Cui & Linderoth If the Gamma-Amminobutyric Acid (GABA)-B receptor is blocked, the reduction of GLU is abolished Cui et al., Pain 73: 87-95, 1997

25 THEORETICAL GATE CONTROL MECHANISM SPINAL CORD SCS Dorsal Column Myelinated A afferents (touch) EAA Interneuron EAA? GABA WDR Spinothalamic Tract Cell Unmyelinated C afferents Nociception EAA Excitation Inhibition

26 UPDATE OF SCS MECHANISMS FOR NEUROPATHIC PAIN MODULATION Ach Acetylcholine Aden Adenosine DLF Dorsolateral Funiculus NE Norepinephrine 5-HT Serotonin X future transmitters or modulators Section Summary Adapted from Linderoth & Meyerson, Anesthesiology 2010

27 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

28 PERIPHERAL VASCULAR DISEASE Pre-implant 3 months SCS 1 year SCS

29 PERIPHERAL VASCULAR DISEASE Peripheral Arterial Occl. Disease (PAOD) caused by atherosclerosis and expressed as reproducible ischemic muscle pain (intermittent claudication) and inadequate blood flow Diabetic Angiopathy calcification of the media of larger vessels and major effects in the microcirculation Buerger s Disease rare combination of inflammation and clots in blood vessels that impairs blood flow Vasopastic Disorders several pathologies involving intermittent localized vessel spasm that affects blood supply walls of the blood vessels look normal Raynaud s Disease causes fingers, toes, tip of the nose and ears to feel numb and cool in response to cold temperatures and stress. Arteries supplying these areas narrow Frostbite extreme cold damages skin and severely constricts blood vessels

30 CLINICAL HISTORY Peripheral Vascular Disease Cook et al., 1976 Introduced the treatment Meglio, 1981 Tallis et al., 1983 Augustinsson, 1985 Broseta et al., 1985 Jivegard et al., 1987 Galley et al., 1988 Jacobs et al., 1988

31 CLINICAL RESULTS Limb Salvage: improvement Jacobs et al. Journal Vascular Surgery 1990 Rickman et al. Journal Vascular Nurs 1994 Horsch et al. Ann Vascular Surgery 1994 Jivegard et al. Eur J Vasc Endovasc Surg 1995 Gersbach et al. Eur J Vasc Endovasc Surg 1997 Ubbink et al. J Vasc Surg 1999 Amann et al. Eur J Endovasc Surg 2002

32 SCS OUTCOMES: Vasospasm > 70% Arterial Insuff % Cameron, T. (2004). Safety and efficacy of spinal cord stimulation for the treatment of chronic pain: A 20-year literature review. Journal of Neurosurgery, 100,

33 SCS AND PERIPHERAL VASODILATION Mechanisms Inhibition of Sympathetic Efferent Activity (Linderoth) AND/OR Antidromic Activation of Sensory Afferent Fibers releasing CGRP (Foreman)

34 Ventilator Computer And A/D Converter Stimulator SCS Left Side ~66% MT L1-L2 segments Linderoth et al., 1991 Laser Doppler Flowmeter 6 6 % Stim on Cutaneous Vasodilation in the ipsilateral footpad Stim off

35 LINDEROTH TEAM SCS Before and After Sympathectomy: Inhibition of Sympathetic Efferent Fibers Purpose: Transection of the sympathetic efferent fibers eliminates peripheral vasodilation. This result suggests that SCS occurs as a result of sympathetic inhibition. SCS Hexamothonium (nach receptor antagonist which acts in autonomic ganglia) also markedly attenuates vasodilation. This is further evidence that the sympathetic nervous system is involved in peripheral vasodilation. Linderoth, et al., 1991

36 FOREMAN TEAM Spinal Cord Stimulation at 30%, 60%, and 90% MT Antidromic Activation of Dorsal Root Afferents: Release of CGRP CGRP-(8-37) Calcitonin Gene-Related Peptide Antagonist Tanaka, Barron, Chandler, Linderoth & Foreman, 2001

37 Dorsal Root Activation! Sympathetic Inhibition! Croom JE, Foreman RD, Chandler MJ, Barron KW. Cutaneous vasodilation during dorsal column stimulation is mediated by dorsal roots and CGRP. Am J Physiol Feb;272(2 Pt 2):H Linderoth B, Gunasekera L, Meyerson BA. Effects of sympathectomy on skin and muscle microcirculation during dorsal column stimulation: animal studies. Neurosurgery Dec;29(6): To Agree or Disagree, that is the Question A Toast to the Team that solved the Root Problem Tanaka S, Barron KW, Chandler MJ, Linderoth B, Foreman RD. Local cooling alters neural mechanisms producing changes in peripheral blood flow by spinal cord stimulation. Auton Neurosci Mar 28;104(2):

38 THE ROOT OF THE PROBLEM Stockholm Cold; Oklahoma City Warm Role of Sensory Afferents and Sympathetic Efferents Cooled Paw (20-25ºC) Normal (31 o C) SCS 60% of MT Antidromic Activation 90% of MT Sympathetic Inhibition inhibited by CGRP-(8 37) and dorsal rhizotomy inhibited by both hexamethonium and CGRP-(8 37) Tanaka S, Barron KW, Chandler MJ, Linderoth B, Foreman RD, 2003 SCS

39 CONCLUSION SCS Dorsal Root Aδ & C Afferents 5 CGRP + STT Endothelial cells Nitric Oxide Sympathetic Efferent Fibers Relaxation of Vascular smooth muscle cells

40 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

41 CHRONIC VISCERAL PAIN Chronic visceral abdominal pain is common in disorders such as Chronic pancreatitis Irritable bowel syndrome (IBS) Conventional approaches for treating chronic visceral pain have limited efficacy and poor side effect profiles

42 IRRITABLE BOWEL SYNDROME(IBS) Chronic disorder of unknown origin Abdominal pain Abnormal bowel habits Comorbid somatic pain Associated with anxiety Exacerbated by emotional stress Subset of patients develop symptoms following an enteric infection, early life stress. U.S. prevalence: up to 20% Up to 40% of military veterans Cost: $1.2 billion/year Grundmann & Yoon (2010); Choung & Locke (2011) Yunus (2011); Tuteja et al (2009); White et al (2010) Trivedi et al (2011); NIDDK Report (2008)

43 VISCERAL HYPERSENSITIVITY IN IBS Colorectal balloon distention in humans Allodynia Hyperalgesia (Mertz, 2003a from Ritchie, 1973)

44 ANIMAL MODEL In a freely moving rat colorectal distention (CRD) produces a visceromotor response (VMR) that is dependent on the distention pressure. VMR: behavioral response induced by colorectal distention, # of contractions/10 min Balloon Distention (mmhg) (Ness and Gebhart, 1988)

45 SPINAL CORD STIMULATION ATTENUATES COLONIC HYPERSENSITIVITY Beverley Greenwood Van-Meerveld, Robert D. Foreman and Bengt Linderoth Oklahoma Foundation for Digestive Research V.A. Medical Center, Oklahoma City, OK Department of Physiology, OUHSC, Oklahoma City, OK Dept. of Neurosurgery, Karolinska Institutet and Karolinska University Hospital, Stockholm Sweden. Basic Animal Model Data Published in 2003 and 2005.

46 The OUHSC Physiology Team

47 EXPERIMENTAL SETUP Grass Chart Recorder Preamplifier A. Chronic Implantation of Stimulating Electrode B. Strain Gauges implanted in Abdominal Muscle- 3-7 days later C. Colorectal distention 90% MT, 200 µs, 50 Hz Stimulator A T12/L1 B C Measures Visceromotor Reflexes (Muscle Contractions)

48 METHODS Implantation of Strain Gauges Recovery CRD SCS CRD 30 min 10 min 30 min 10 min VMR to CRD Strain-gauge force transducer Colorectal balloon catheter

49 EFFECT OF SCS ON NOCICEPTIVE PRESSURES OF COLORECTAL BALLOON DISTENTION # of contractions/10 min ** Balloon Distention (60 mmhg)

50 EFFECT OF SCS ON DURATION # of contractions/10 min ** ** * * Balloon Distention (60 mmhg) Following SCS (90% MT/30 min)

51 EXPERIMENTAL SETUP Oscilloscope Discriminator Pen writer Stimulator A B Microelectrode C2 L2 C A, SCS on C1-C2 or L1-L2segments; B, cell recording at L6-S2 segments; C, colorectal distention

52 A 20 Rate 10 (imp/s) 0 CRD S1 SPINAL NEURON RESPONSES TO SCS (mmhg) SCS on C1-C2 20 s B Rate (imp/s) CRD (mmhg) SCS on L2-L3 SCS: 90% MT, 50 Hz, 0.2 ms, 3-5 min

53 NEURAL HIERARCHY ORIGINATING FROM C1-C2 SEGMENTS C1-C2 Spinal Cord Stimulation 90%MT, 200 us, 50 Hz L6-S2 Spinal cord Excitation Inhibition

54 NEURAL HIERARCHY ORIGININATING FROM L5-S2 SEGMENTS Spinal Cord Stimulation 90%MT, 200 us, 50 Hz L5-S2 Spinal cord Excitation Inhibition

55 ANIMAL MODEL OF IRRITABLE BOWEL SYNDROME (IBS) 1. Briefly anesthetize with isoflurane 2. Give sedated animal an enema of trinitrobenzenesulfonic acid (TNBS) 3. This treatment produces: a. Active inflammation from 3-5 days b. Post-inflammatory visceral hypersensitivity for 21-60days 4. Animals were studied 30 days post enema. Greenwood-Van Meerveld B, Johnson AC, Foreman RD, Linderoth B. Auton Neurosci. 2005

56 SCS INHIBITS POST-INFLAMMATORY COLONIC HYPERSENSITIVITY 30 Days post enema ** Balloon Distention (30 mmhg for 10 min) TNBS = Trintrobenzenesulfonic acid

57 SCS IN IBS MODEL Take Home Message SCS (90% MT/30 min): Normalizes the response to nociceptive distention in the colon. Does not alter colonic compliance. Normalizes the hypersensitive response to non-nociceptive distention in the sensitized colon.

58 CASE STUDY: ES KRAMES and DG MOUSAD: Spinal Cord Stimulation Reverses Pain and Diarrheal Episodes of Irritable Bowel Syndrome: a Case Report Neuromodulation 2004;7(2):82-88 Intractable IBS in a 43 yr old female Abdominal Pain and Severe Diarrhea Based on our Study (Greenwood et al 2003), SCS was used for treatment of this hopeless case 2 week trial Diarrhea free 75% Pain Reduction 6 months Diarrhea Free Pain Reduction not as effective After 1 yr accidental IPG turn-off happened and the symptoms relapsed. After resuming SCS symptoms again were controlled

59 PHYSIOLOGY OF NEUROMODULATION Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

60 COMPARISON OF BURST AND TONIC (40 Hz) SPINAL CORD STIMULAITON ON SPINAL NEURONAL PROCESSING IN AN ANIMAL MODEL. Tang, Martinez, Goodman-Keiser, Farber, Qin, and Foreman. Neuromodulation: 17: , Burst stimulation: 40 Hz burst mode with five pulses at 500 Hz per burst and a pulse width of 1ms with 1ms interspike interval Figure from De Ridder et al., Neurosurgery 2010;66:

61 EXPERIMENTAL SETUP Visceromotor Reflexes Computer CED 1401 Data Acquisition System Spike 2 software package Oscilloscope WPI Stimulator B A L2 C A, SCS (90% MT, 0.2 ms, 40 Hz or Burst) on L2-L3segments; B, EMG recordings from abdominal muscle; C, Noxious (60 mm Hg) Colorectal Distention (CRD)

62 MOTOR THRESHOLD OF ANIMALS in Microamperes (μa) SCS VMR group Lumbosacral group Gracile group Burst 182.5± ± ±8.6 Tonic 328.0±48.5 * 366.8±38.8 * 353.6±18.5 * *compared to burst SCS, p<0.05

63 EMG RECORDINGS FROM ONE ANIMAL IEMG Integrated EMG REMG Raw EMG

64 SUPPRESSIVE EFFECT OF TONIC AND BURST SCS OF VMR RESPONSES TO CRD A VMR response suppressed by SCS B Recovery time of VMR response Ipsilateral Contralateral 0 30 Reduction of AUC (%) Burst Tonic Recovery time (min) Burst Tonic 90 * Burst 0 Ipsilateral Contralateral Tonic

65 EXPERIMENTAL SETUP Gracile Nucleus Paresthesia? Computer CED 1401 Data Acquisition System Spike 2 software package Oscilloscope Discriminator Microelectrode A WPI Stimulator L2 B A, Dorsal Column Nuclei (DCN); Cell recording from the Gracile Nucleus of the DCN; B) SCS (60%MT, 0.2 ms 40 Hz or Burst) L2-L3 Segments

66 GRACILE NEURON TRACING SHOWING SPONTANEOUS ACTIVITY A Without SCS Extracellular Action potential B With Tonic SCS C With Burst SCS 5 ms 13 ms 25 ms

67 SUMMARY OF SPONTANEOUS ACTIVITY DURING TONIC AND BURST SCS Spontaneous activity (imp/sec) * Tonic SCS A: WDR neuron B: LT neuron Burst SCS Before SCS During SCS Spontaneous activity (imp/sec) 60 * n=10 n= Tonic SCS Burst SCS Before SCS During SCS

68 CONCLUSIONS Burst SCS is more efficacious than tonic SCS in attenuating visceral nociception Reduced or abolished paresthesia in patients may be due in part to burst SCS not increasing spontaneous activity of neurons in the gracile nucleus

69 PHYSIOLOGY OF NEUROMODULATION SUMMARY Neuromodulation and the Gate Control Theory Use of Animal Models Translational Research Examples of Models Using SCS Peripheral Neuropathy and SCS Peripheral Vascular Disease and SCS Irritable Bowel Syndrome and SCS Selecting Parameters Burst-Tonic

70 Stockholm Oklahoma City Thank You