NEUR3101_Lec15_Pain_FvW_Part1-3_1perpage.pdf

Muscle pain Part 1: The physiology of muscle pain Dr. Frederic von Wegner WARNING...

Muscle pain Part 1: The physiology of muscle pain Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Pain: anatomical structures Purves, Neuroscience Guyton-Hall, Textbook of Medical Physiology Pain: anatomical structures Purves, Neuroscience Guyton-Hall, Textbook of Medical Physiology Pain: anatomical structures Purves, Neuroscience Guyton-Hall, Textbook of Medical Physiology  Nociceptive nerve ending: Nociceptive nerve ending Receptor diversity: The perceived sensation of pain (cortex) can be evoked by many different physical and chemical triggers heat chemicals pH (acidic) cell damage mechanical (capsaicin) Abbreviations:  PG E2: prostaglandin E2  5-HT: serotonin  PKA: protein kinase A activation (intracellular) Proportion of nociceptors  VR-1: vanilloid receptor responding to different stimuli  SP: substance P  CGRP: calcitonin-gene related peptide  Glu: Glutamate  cAMP: cyclic adenosine monophosphate  TTX: tetrodotoxin Mense, Curr Pain and Headache Rep, 2003  Pain terminology Allodynia Hyperalgesia Referred pain pain evoked by a normally non- increased pain intensity evoked by a Painful area distant from injury nociceptive stimulus (light touch) nociceptive (painful) stimulus (allo-: other) (hyper-: too much) Transition from acute to chronic pain: peripheral and central sensitization  modification of deep and superficial sensitivity (group III and IV muscle nociceptors)  dorsal horn neurons hypersensitive, prolonged neuronal discharges, responses to non-noxious stimuli  larger receptive field (mainly animal data, few human experiments)  Referred pain: an important feature of muscle pain Definition: pain perceived at a site adjacent to or distant from the site of origin (injury)  known for a long time as “referred tenderness”  important diagnostic tool for clinicians Pathophysiology: numerous theories, few hard facts Explanation: neurons in the spinal cord and brainstem receive converging input from muscles, joints+bones, skin and internal organs  neurons becomes confused about origin of the signal Duus’ Topical Diagnosis in Neurology Referred pain: internal organs Referred pain of internal organs is a diagnostic tool for physicians  The skin regions where pain is localized by the patient are called the Head zone of the corresponding internal organ (Sir Henry Head, 1861-1940)  In the muscle context: a local muscle/tendon injury can be perceived at a distance from the site of injury and lead to errors in identifying the injured muscle (solution: additional diagnostics, e.g. ultrasound, functional testing) Duus’ Topical Diagnosis in Neurology Referred muscle pain: an example  same dorsal horn neuron Referred pain occurs with a latency Arendt-Nielsen, Clin J Pain 24(4), 2008 Referred muscle pain: trigger points Observation: gastrocnemius injury leads to sensitive trigger point Mechanism: unmasking of previously silent synapses via near the sacroiliac joint Sensitization (substance P, CGRP) referred pain trigger point 3 GC nerve gastro- local pain cnemius trigger point 3 trigger point from sacroiliac joint Mense, Schmerz 2003 (in German) Differences between muscle and skin pain subjective differences - muscle: acute injury has no first/second pain sequence, (skin has 1./2.) first pain: sharp, second: dull, burning, drilling - muscle: cramp like, pressing, localization difficult skin: burning, sharp, clear localization - muscle: referred pain component strong skin: almost no referred pain - muscle: emotionally more difficult to bear/suppress Mense, Schmerz (Pain), 2003 Differences between muscle and skin pain subjective differences objective differences - muscle: acute injury has no first/second - muscle: no flexor reflex pain sequence, (skin has 1./2.) skin: marked flexor reflex first pain: sharp, second: dull, burning, drilling - muscle: unmyelinated afferent axons have little - muscle: cramp like, pressing, localization difficult effect on spinal cord neurons (skin: opposite) skin: burning, sharp, clear localization - cortex: muscle pain strongly activates anterior - muscle: referred pain component strong cingulate cortex skin: almost no referred pain - muscle: strong tonic inhibition by antinociceptive - muscle: emotionally more difficult to bear/suppress descending tracts (from mesencephalon) skin: weaker descending inhibition Mense, Schmerz (Pain), 2003 Muscle pain & disease Muscle pain can be a symptom of serious diseases: - myopathies, (genetic, drugs,...) - myositis (autoimmune, infectious,...) - rheumatological disease - exercise in these cases can lead to massive decay of muscle tissue  kidney failure and life-threatening conditions due to myoglobin and K+ release from injured fibres  Muscle pain Part 2: Experimental methods and findings Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Measuring pain – the visual analogue scale VAS - numerical scale: 0..10 is at least an ordinal scale (“more” or “less” pain) - this VAS: no qualitative character  Experimental procedures to induce muscle pain - ischemia (tourniquet and voluntary muscle contraction) - pain depends on force, number of repetitions, duration of ischemia - mechanisms: largely unclear - chemical factors likely: K+ ions, adenosine, lactate - disadvantage: not only muscle pain, also skin and periosteum Arendt-Nielsen, Clin J Pain 24(4), 2008  Experimental procedures to induce muscle pain - ischemia (tourniquet and voluntary muscle contraction) - pain depends on force, number of repetitions, duration of ischemia - mechanisms: largely unclear - chemical factors likely: K+ ions, adenosine, lactate - disadvantage: not only muscle pain, also skin and periosteum - exercise: - concentric contractions: short-lasting, probably due to ischemia - eccentric contractions: delayed onset muscle soreness (DOMS), peak 24-48 hours post exercise Arendt-Nielsen, Clin J Pain 24(4), 2008  Experimental procedures to induce muscle pain - ischemia (tourniquet and voluntary muscle contraction) - pain depends on force, number of repetitions, duration of ischemia - mechanisms: largely unclear - chemical factors likely: K+ ions, adenosine, lactate - disadvantage: not only muscle pain, also skin and periosteum - exercise: - concentric contractions: short-lasting, probably due to ischemia - eccentric contractions: delayed onset muscle soreness (DOMS), peak 24-48 hours post exercise - electrical: - intramuscular stimulation and recording (microneurography) - reliable method to measure referred pain and temporal summation - disadvantage: induces muscle twitches Arendt-Nielsen, Clin J Pain 24(4), 2008  Experimental procedures to induce muscle pain - ischemia (tourniquet and voluntary muscle contraction) - pain depends on force, number of repetitions, duration of ischemia - mechanisms: largely unclear - chemical factors likely: K+ ions, adenosine, lactate - disadvantage: not only muscle pain, also skin and periosteum - exercise: - concentric contractions: short-lasting, probably due to ischemia - eccentric contractions: delayed onset muscle soreness (DOMS), peak 24-48 hours post exercise - electrical: - intramuscular stimulation and recording (microneurography) - reliable method to measure referred pain and temporal summation - disadvantage: induces muscle twitches - mechanical: - external, pressure algometers, computer controlled  but: activates muscle and skin Arendt-Nielsen, Clin J Pain 24(4), 2008  Experimental procedures to induce muscle pain - ischemia (tourniquet and voluntary muscle contraction) - pain depends on force, number of repetitions, duration of ischemia - mechanisms: largely unclear - chemical factors likely: K+ ions, adenosine, lactate - disadvantage: not only muscle pain, also skin and periosteum - exercise: - concentric contractions: short-lasting, probably due to ischemia - eccentric contractions: delayed onset muscle soreness (DOMS), peak 24-48 hours post exercise - electrical: - intramuscular stimulation and recording (microneurography) - reliable method to measure referred pain and temporal summation - disadvantage: induces muscle twitches - mechanical: - external, pressure algometers, computer controlled  but: activates muscle and skin - chemical: e.g. saline injection, serotonin, capsaicine Arendt-Nielsen, Clin J Pain 24(4), 2008 Interaction of pain and motor control - common experience: impaired performance during muscle pain - resting muscle activity: no increased EMG activity when compared to sham (open discussion) Arendt-Nielsen, Clin J Pain 24(4), 2008 Interaction of pain and motor control - common experience: impaired performance during muscle pain - resting muscle activity: no increased EMG activity when compared to sham (open discussion) - static muscle activity: a) reduced MVC, normal fibre properties, normal max. force when muscle is electrically stimulated  central effect (reduced cerebral output, spinal inhibition) b) reduced endurance, possible central fatigue c) probably not due to microcirculation/metabolites in acute pain d) not only in the painful muscle, also synergists Arendt-Nielsen, Clin J Pain 24(4), 2008 Interaction of pain and motor control - common experience: impaired performance during muscle pain - resting muscle activity: no increased EMG activity when compared to sham (open discussion) - static muscle activity: a) reduced MVC, normal fibre properties, normal max. force when muscle is electrically stimulated  central effect (reduced cerebral output, spinal inhibition) b) reduced endurance, possible central fatigue c) probably not due to microcirculation/metabolites in acute pain d) not only in the painful muscle, also synergists - dynamic muscle activity: example lower back pain: limited movement of pain-affected muscles, agonist activity reduced, antagonist activity increased  limited movement, probably adaptive and protective, but impaired coordination Arendt-Nielsen, Clin J Pain 24(4), 2008 Interaction of pain and motor control - common experience: impaired performance during muscle pain - resting muscle activity: no increased EMG activity when compared to sham (open discussion) - static muscle activity: a) reduced MVC, normal fibre properties, normal max. force when muscle is electrically stimulated  central effect (reduced cerebral output, spinal inhibition) b) reduced endurance, possible central fatigue c) probably not due to microcirculation/metabolites in acute pain d) not only in the painful muscle, also synergists - dynamic muscle activity: example lower back pain: limited movement of pain-affected muscles, agonist activity reduced, antagonist activity increased  limited movement, probably adaptive and protective, but impaired coordination  risk: additional activation and load on muscles that are normally not used in a specific movement  abnormal movements  more pain, risk of injury  do not train under pain  early theories unproven (vicious cycle: pain – muscular hyperactivity) Arendt-Nielsen, Clin J Pain 24(4), 2008 Pain effects on primary cortices (S1, M1) - hypothesis: pain affects the function of primary somatosensory cortex (S1) and primary motor cortex (M1) - review of evidence: Burns et al., European Journal of Pain, 20, 2016 1. Functional MRI: inconsistent results for S1 activity (+/-) 2. Electrophysiology (evoked somatosensory potentials): reduced S1 excitability, interpretation: defensive reaction, but possibly impaired coordination 3. Inconsistent findings for the corresponding primary motor cortex M1 (+/-) 4. Motor evoked potentials (MEP): reduced excitability / output contralateral to pain, no consistent findings for ipsilateral cortex  Muscle pain Part 3: Delayed onset muscle soreness (DOMS) Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice DOMS – delayed onset muscle soreness  “overexertion-functional type muscle disorder”  more pronounced after eccentric contractions or unusual types of exercise  symptoms:  delayed onset 48-72 h post exercise  reduced force production (not only pain)  character: no pain at rest, but to pressure and activity (unlike experimentally induced pain)  painful limitation in movement  increased muscle tone  local swelling  classified as a mild condition, but very common => large impact, also on professional training DOMS – delayed onset muscle soreness  “overexertion-functional type muscle disorder”  more pronounced after eccentric contractions or unusual types of exercise  symptoms:  delayed onset 48-72 h post exercise  reduced force production (not only pain)  character: no pain at rest, but to pressure and activity (unlike experimentally induced pain)  painful limitation in movement  increased muscle tone  local swelling  classified as a mild condition, but very common => large impact, also on professional training  pathophysiology: details unknown, mechanical components (higher forces during eccentric contr.), Ca2+ changes stiffness of titin, etc...  proposed mechanism: ultrastructural damage (sarcomer damage + destruction), release of pain mediators  findings: protein degradation, autophagy, local and systemic inflammatory reaction  NSAID efficiency in limb muscles unproven, but big problem (renal damage, stomach ulcera) (non-steroidal antiinflammatory drugs, ibuprofen etc.) Reminder: concentric vs. eccentric (isotonic) contractions concentric: muscle shortens eccentric: muscle elongates Martini, Fundamentals of Anatomy & Physiology DOMS – concepts Inflammation 24-72 hours Heiss, Advances in DOMS, Thieme 2019 DOMS – structural findings, microscopy healthy skeletal muscle DOMS structural changes Hotfiel, Advances in DOMS, Thieme 2018 DOMS – structural findings, microscopy healthy skeletal muscle damaged Z-disk intact Z-disk Boening, Dt. Z. f. Sportmed., 2000 DOMS – structural findings, MRI Magnetic resonance tomography (leg, transversal) before (A-C) and after (D-F) eccentric exercise inflammatory reaction increases vascular permeability  edema, swelling edema medial gastrocnemius Hotfiel, Advances in DOMS, Thieme 2018 DOMS – structural findings, MRI M. triceps brachii edema 4 days after exhausting crossfit training: normal muscle muscle edema subcutaneous edema Hotfiel, Advances in DOMS, Thieme 2018 DOMS – structural findings, ultrasound Ultrasound of dorsal calf: normal condition muscle 48 hours after exhausting exercise: arrows: altered ultrasound signal (hyperechogenic) = max. pain areas Hotfiel, Advances in DOMS, Thieme 2018 DOMS – therapy and prevention strategies a) prevention: training methods b) treating the inflammatory response leading to DOMS c) treating DOMS symptoms when they appear DOMS – therapy and prevention strategies a) prevention: training methods b) treating the inflammatory response leading to DOMS c) treating DOMS symptoms when they appear 1. cold water immersion therapy (CWI) / whole body cryotherapy (WBC): analgesic, anti-inflammatory, slower metabolism, but then: slower repair? impaired perfusion? meta-analyses: CWI slightly better than passive recovery 2. compression: during/after exercise, less swelling? during ex: findings for DOMS inconsistent; post-ex.: less symptoms, faster recovery 3. active forms of regeneration: low-intensity exercise, stretching, foam rolling, flossing long tradition, little evidence when tested statistically, foam rolling: less pain 4. physical therapy: vibration, ultrasound, electromyostimulation, massage, acupuncture 5. medication + nutrition: omega 3, antioxidants, vitamin D, non-steroidal anti-inflammatory drugs Short introduction: Cochrane library https://www.cochranelibrary.com/  Cochrane reviews: methods  all databases must be named  all search criteria must be listed  each study is analyzed in detail (inclusion criteria, demographics, statistical analysis)  each study result is listed individually  author interpretations are clearly marked Costello et al., Cochrane Review, 2015 Cochrane reviews: bias? Costello et al., Cochrane Review, 2015 Cochrane reviews: summary statistics Costello et al., Cochrane Review, 2015 Example-1: whole body cryotherapy (WBC)  single or repeated exposure to extremely cold dry air (below -100°C), 2-4 Min./session goal: reduce muscle soreness after exercise  vs. control condition: rest, no treatment, placebo treatment  vs. active interventions: cold water immersion, infrared, active recovery  outcomes: muscle soreness, subjective recovery, adverse effects Costello et al., Cochrane Review, 2015 Example-1: whole body cryotherapy (WBC)  single or repeated exposure to extremely cold dry air (below -100°C), 2-4 Min./session goal: reduce muscle soreness after exercise  vs. control condition: rest, no treatment, placebo treatment  vs. active interventions: cold water immersion, infrared, active recovery  outcomes: muscle soreness, subjective recovery, adverse effects Results of 4 laboratory-based, randomized controlled trials:  trials very heterogeneous, methodological problems: e.g. 1 study 64 young adults (60 male), different temperatures, durations, frequencies of WBC, different exercise types  none reported active surveillance of predefined adverse events  all studies high risk of bias in their design Costello et al., Cochrane Review, 2015 Example-1: whole body cryotherapy (WBC)  single or repeated exposure to extremely cold dry air (below -100°C), 2-4 Min./session goal: reduce muscle soreness after exercise  vs. control condition: rest, no treatment, placebo treatment  vs. active interventions: cold water immersion, infrared, active recovery  outcomes: muscle soreness, subjective recovery, adverse effects Results of 4 laboratory-based, randomized controlled trials:  trials very heterogeneous, methodological problems: e.g. 1 study 64 young adults (60 male), different temperatures, durations, frequencies of WBC, different exercise types  none reported active surveillance of predefined adverse events  all studies high risk of bias in their design Conclusions:  insufficient evidence whether WBC reduces (self-reported) muscle soreness  no evidence in elite athletes  lack of evidence on adverse events Costello et al., Cochrane Review, 2015 Example-2: antioxidants  theory: inflammatory effects mediated by oxidative processes, reactive oxygen species (ROS)  50 randomised and quasi-randomised studies involving antioxidant supplementation  outcome: preventing DOMS, reducing severity and duration, adverse effects? Ranchordas et al., Cochrane Review, 2017 Example-2: antioxidants  theory: inflammatory effects mediated by oxidative processes, reactive oxygen species (ROS)  50 randomised and quasi-randomised studies involving antioxidant supplementation  outcome: preventing DOMS, reducing severity and duration, adverse effects? Results of 50 randomized, placebo-controlled trials, N=1089 (961 male):  studies heterogeneous: pre-/post-exercise, frequency, dose, duration, type of antioxidant supplement, all above recommended daily dose, different types of exercise  no study contained low- vs. high-dose  only 9 studies investigated adverse effects (2/9 had gastrointestinal side effects)  all studies high risk of bias: selective reporting, poorly described allocation concealment (assignment to treatment groups)  slight reduction of soreness at 6, 24, 48, 72 h, not at 96 h, effect negligible Ranchordas et al., Cochrane Review, 2017 Example-2: antioxidants  theory: inflammatory effects mediated by oxidative processes, reactive oxygen species (ROS)  50 randomised and quasi-randomised studies involving antioxidant supplementation  outcome: preventing DOMS, reducing severity and duration, adverse effects? Results of 50 randomized, placebo-controlled trials, N=1089 (961 male):  studies heterogeneous: pre-/post-exercise, frequency, dose, duration, type of antioxidant supplement, all above recommended daily dose, different types of exercise  no study contained low- vs. high-dose  only 9 studies investigated adverse effects (2/9 had gastrointestinal side effects)  all studies high risk of bias: selective reporting, poorly described allocation concealment (assignment to treatment groups)  slight reduction of soreness at 6, 24, 48, 72 h, not at 96 h, effect negligible Conclusions:  weak-moderate evidence that high-dose antiox. suppl. does not affect soreness, effect size!  no evidence on subjective recovery (return to normal activity without symptoms) – not tested  limited evidence on adverse events Ranchordas et al., Cochrane Review, 2017