Acute/chronic pain - dr alloteh

Acute/chronic pain

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1. ACUTE/CHRONIC PAIN ROSE ALLOTEH MBChB ASSOCIATE PROFESSOR DEPARTMENT OF ANESTHESIA AND PERI-OPERATIVE MEDICINE RUTGERS-ROBERT WOOD JOHNSON MEDICAL SCHOOL MAY 6, 2020
2. SYLLABUS (ABA) Painful Disease States a. Pathophysiology 1) Acute Pain 2) Cancer-Related Pain 3) Chronic Pain States
3. SYLLABUS • 3) Chronic Pain States a) Acute and Chronic Neck and Low Back Pain b) Neuropathic Pain States (1) Complex Regional Pain Syndrome, Types I and II (2) Postherpetic Neuralgia (3) Phantom Limb, Post-Stroke (4) Peripheral Neuropathies (e.g., Diabetic Neuropathy) c) Somatic Pain Conditions: Myofascial Pain, Facet Arthropathy etc.
4. SYLLABUS Treatment 1) Acute Postoperative and Posttraumatic Pain a) Postoperative Epidural Analgesia b) Neuraxial Opioids c) Peripheral Nerve Blockade and Catheters d) Patient-Controlled Analgesia e) Other Modalities, Multimodal Analgesia (Nonsteroidal Analgesics, Electrical Stimulation, Acupuncture, Ketamine, etc.)
5. SYLLABUS • 2) Cancer-Related Pain • a) Systemic Medications, Tolerance and Addiction • b) Continuous Spinal and Epidural Analgesia • c) Neurolytic and Non-Neurolytic Blocks to Treat Cancer Pain • d) World Health Organization Analgesic Ladder
6. SYLLABUS 2) Chronic Pain (Non-Cancer-Related) a) Systemic Medications: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Opioid Analgesics, Anti-Epileptics, Antidepressants b) Spinal and Epidural Analgesia c) Peripheral Nerve Blocks d) Sympathetic Nerve Blocks e) Other Techniques: TENS, Spinal Cord Stimulation, Neuroablation (Surgical and Chemical Neurolysis) 2
7. OBJECTIVES • Neurophysiology of Acute and Chronic Pain • Pain Pathways • Medical therapy • Interventional techniques • Non-Medical therapy
8. ACUTE PAIN - DEFINITIONS • An unpleasant sensory and emotional experience • Associated with actual or potential tissue damage or • Described in terms of such damage
9. PAIN - DEFINITIONS • The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” (1979) • This classification further states that pain is always subjective • At the same time, pain is unpleasant • Pain has an emotional component
10. PAIN - DEFINITIONS • Aside from malignant disease, many people report pain in the absence of tissue damage or any likely pathophysiologic cause • Usually, no way exists to distinguish their experience from a condition resulting from tissue damage • If patients regard their experience as pain or if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. • This definition avoids tying pain to a stimulus.
11. IASP PAIN DEFINITION CRITICISMS • It does not apply to living organisms that are incapable of self-report. This includes newborn and older infants, small children, mentally retarded, comatose, demented, or verbally handicapped individuals, and all primate and non-primate animals. (Anand and Craig Anand KJ, Craig KD. New perspectives on the definition of pain. PAIN 1996;67:3–11 1996) • Requires patients to describe their pain, by default establishing the primacy of self-report as a ‘gold standard.’ This definition lacks applicability to non-verbal populations and ignores the cognitive and social dimensions of pain.” Anand KJS. Defining pain in newborns: need for a uniform taxonomy? Acta Pædiatrica 2017;106:1438–44. • Does not including the “cognitive and social” components of pain: (Williams AC, Craig KD. Updating the definition of pain. PAIN 2016;157:2420–23) • Acknowledging only sensory and emotional features excludes major and clinically important characteristics, in particular, cognitive, and social components. These components are often considered to be characteristic of chronic pain and can be overlooked in understanding acute pain, despite much evidence to the contrary.” (Williams and Craig PAIN 2016: 2421)
12. PAIN DEFINITIONS – ACUTE PAIN • It is normal • It is predicable • It is a neurophysiologic response to noxious stimuli • Stimuli may be mechanical, thermal, or chemical stimuli; • It is generally time-limited; • It resolves with the cessation of the noxious stimuli • The etiology, often, is known or understood. • It is typically associated with invasive procedures, trauma, or medical diseases. • The pain sensation is usually limited to the area of trauma or damage or the area that immediately surrounds it. • The painful sensations associated with such an injury are expected to resolve over time when adequate wound healing has occurred
13. PAIN • Physiologic Pain • Acute, nociceptive pain • An essential early warning sign • Usually elicits reflex withdrawal • Promotes survival by protecting the organism from further injury • Pathologic • In contrast, pathologic (e.g., neuropathic) pain is an expression of the maladaptive operation of the nervous system • It is pain as a disease
14. PAIN - DEFINITIONS • Nociception is neurophysiologic activity in peripheral sensory neurons (nociceptors) and higher nociceptive pathways • Is defined by the IASP as the “neural process of encoding noxious stimuli.” • Nociception is not synonymous with pain. • Pain is always a psychological state, even though it often has a proximate physical cause
15. NEUROBIOLOGY • Physiologists distinguish between Pain and nociception • Nociception refers to signals arriving in the CNS from activation of specialized receptors called Nociceptors • Nociceptors provide information about tissue damage • Pain is the unpleasant emotional experience that accompanies nociception • (‘Laugh till you cry’ – Tickling activates hypothalamic areas involved in the pain response. Both pain and touch receptors are activated during tickling)
16. NEUROBIOLOGY • Perception is a process that allows us to interpret sensory information • One can make a distinction between the sensory information we receive and how we perceive that information • Pain is a Perception, a process that allows us to process a certain type of sensory information • E.g. Music, food may be perceived as great by one person and extremely bad by the next • Sometimes link between sensory information and perception is suppressed eg during NFL game
17. NEUROBIOLOGY • Types of Pain • Nociceptive • Somatic Pain – emanating from joints and muscles • Visceral Pain – emanating from internal organs • Neuropathic • Peripheral – Damage to a primary nociceptor • Central – Damage to the CNS
18. ACUTE PAIN CAUSED BY Injury Disease process Abnormal function of muscle or viscera Limited Duration (1 to 6 months)
19. SKIN SOMATOSENSORY RECEPTRS • Pressure receptors in skin. Meissner, Pacinian, Merkel and Ruffini. Innervated by A delta and A beta fibers -> dorsal columns • Free nerve endings function as cutaneous nociceptors and are essentially used by vertebrates to detect pain.
20. NOCICEPTION Nociception is the sensory nervous system's response to certain harmful or potentially harmful stimuli In nociception, intense chemical, mechanical, or thermal stimulation of sensory nerve cells called nociceptors produces a signal that travels along a chain of nerve fibers via the spinal cord to the brain Nociception triggers a variety of physiological and behavioral responses and usually results in a subjective experience of pain in sentient beings
21. NOCICEPTORS • Thermal • Mechanical • Chemical • Silent/Sleeping • Polymodal
22. ACUTE PAIN – PHYSIOLOGIC PROCESSES • TRANSDUCTION • TRANSMISSION • MODULATION • PERCEPTION
23. ACUTE PAIN • Self Limited • Resolve with treatment in a few days or weeks • Usually up to three (3) months –> (1-6) • Somatic • Visceral
24. ACUTE PAIN • SOMATIC • VISCERAL
25. ACUTE PAIN – VISCERAL PAIN Dull, diffuse, usually midline + Associated with abnormal sympathetic or parasympathetic activity Nausea, vomiting, changes in blood pressure and heart rate May be referred
26. ACUTE PAIN ANATOMY - AFFERENT SENSORY PATHWAYS From Periphery to Perception
27. EFFERENT PATHWAYS IN NOCICEPTIVE REGULATION From Perception to Action
28. NOCICEPTIVE MODULATION • Inhibitory interneurons minimize transmission • Gate control theory
29. NOCICEPTIVE MODULATION • Gate Control Theory of Pain
30. GATE CONTROL THEORY OF PAIN • That’s why you squeeze your thumb when you hit it with a hammer • #besafe
31. CHEMICAL MEDIATORS OF TRANSDUCTION AND TRANSMISSION • EXCITATORY AMINO ACIDS • ASPARTATE • GLUTAMATE • EXCITATORY NEUROPEPTIDES • SUBSTANCE P • NEUROKININ A • INHIBITORY AMINO ACIDS • GABA • GLYCINE
32. Neurobiology of Nociception • Surgery produces tissue injury • Injury produces release of histamine • Inflammatory mediators such as Peptides (e.g., bradykinin), Lipids (e.g., prostaglandins), Neurotransmitters (e.g., serotonin), and Neurotrophins (e.g., nerve growth factor). • Release of inflammatory mediators activates peripheral nociceptors
33. ACUTE PAIN – PHYSIOLOGIC PROCESSES • TRANSDUCTION • TRANSMISSION • MODULATION • PERCEPTION
34. Neurobiology of Nociception • Peripheral nociceptors initiate transduction and transmission of nociceptive information to the central nervous system (CNS) • Initiate the process of neurogenic inflammation • Initiate release of neurotransmitters (Substance P and calcitonin gene–related peptide) in the periphery which induces vasodilatation and plasma extravasation. • Noxious stimuli are transduced by peripheral nociceptors and transmitted by A-delta and C nerve fibers from peripheral visceral and somatic sites to the dorsal horn of the spinal cord • In the SC, integration of peripheral nociceptive and descending modulatory input (i.e., serotonin, norepinephrine, γ-aminobutyric acid, enkephalin) occurs.
35. ACUTE PAIN ANATOMY - AFFERENT SENSORY PATHWAYS
36. ELEMENTS OF PAIN PROCESSING
37. Neurobiology of Nociception • Sensitization of peripheral nociceptors may occur and is marked by a • decreased threshold for activation • increased rate of discharge with activation • and increased rate of basal (spontaneous) discharge. • Intense noxious input from the periphery may also result in • Central sensitization → persistent postinjury changes in the CNS that result in pain hypersensitivity • Hyperexcitability→ exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage
38. Neurobiology of Nociception • Noxious input may lead to functional changes in the dorsal horn of the spinal cord and other consequences that may later cause postoperative pain to be perceived as more painful than it would otherwise have been. • Certain receptors (e.g., N -methyl- d -aspartate [NMDA])are especially important for the development of chronic pain after an acute injury • Other neurotransmitters or second messenger effectors (e.g., substance P, protein kinase C) may also play important roles in spinal cord sensitization and chronic pain
39. Neurobiology of Nociception • Further transmission of nociceptive information is determined by complex modulating influences in the spinal cord. • Some impulses pass to the ventral and ventrolateral horns to initiate segmental (spinal) reflex responses, which may be associated with increased skeletal muscle tone, inhibition of phrenic nerve function, or even decreased gastrointestinal motility. • Others are transmitted to higher centers through the spinothalamic and spinoreticular tracts, where they induce suprasegmental and cortical responses to ultimately produce the perception of and affective component of pain. • Continuous release of inflammatory mediators in the periphery sensitizes functional nociceptors and activates dormant ones
40. Neurobiology of Nociception • An understanding of the neurobiology of nociception is important for appreciating the transition from acute to chronic pain. • Acute pain may quickly transition into chronic pain. • Noxious stimuli can produce expression of new genes (which are the basis for neuronal sensitization) in the dorsal horn of the spinal cord within 1 hour, and these changes are sufficient to alter behavior within the same time frame • The intensity of acute postoperative pain is a significant predictor of chronic postoperative pain • Control of perioperative pain (e.g., preventive analgesia) and the manner in which it is implemented (e.g., multimodality perioperative management) may be important in facilitating short- and long-term patient convalescence after surgery.
41. Neurobiology of Nociception • Chronic postsurgical pain (CPSP) is a largely unrecognized problem that may occur in 10% to 65% of postoperative patients (depending on the type of surgery), with 2% to 10% of these patients experiencing severe CPSP • Poorly controlled acute postoperative pain is an important predictive factor in the development of CPSP • The transition from acute to chronic pain occurs very quickly, and long-term behavioral and neurobiologic changes occur much sooner than was previously thought • CPSP is relatively common after procedures such as limb amputation (30% to 83%), thoracotomy (22% to 67%), sternotomy (27%), breast surgery (11% to 57%), and gallbladder surgery (up to 56%) .
42. Neurobiology of Nociception • Although the severity of acute postoperative pain may be an important predictor in the development of CPSP • Factors predicting severity of post op pain include the severity of the patient’s preoperative pain • Patients with more intense levels of preoperative pain may also develop a degree of CNS sensitization predisposing them to the increased likelihood of higher postoperative pain and the subsequent development of chronic pain • Thus, it is important that acute pain service clinicians understand chronic pain conditions and involve themselves in the patient’s preoperative care. The increased involvement of the acute pain medicine team in preoperative anesthesia clinics or services can positively attenuate the incidence and severity of postoperative pain.
43. Neurobiology of Nociception • Control of acute postoperative pain may improve long-term recovery or patient- reported outcomes • Patients whose pain is controlled in the early postoperative period (especially with the use of continuous epidural or peripheral catheter techniques) may be able to actively participate in postoperative rehabilitation, which may improve short- and long-term recovery after surgery. • Optimizing treatment of acute postoperative pain can improve health-related quality of life (HRQL) • Postoperative chronic pain that develops as a result of poor postoperative pain control may interfere with patients’ activities of daily living.
45. ELEMENTS OF PAIN PROCESSING
46. MULTIMODAL TECHNIQUES • Multimodal Pain management whenever possible • Unless contraindicated, round the clock NSAIDS, COXIBs or Acetaminophen • Consider regional blockade with local anesthetics
47. PERI-OP TECHNIQUES FOR PAIN MANAGEMENT • 1. Epidural or Intrathecal opioids • 2. PCA • 3. Regional techniques
48. SOMATIC • OPIOIDS • NSAIDS • ACETAMINOPHEN • REGIONAL
49. KNOWN BENEFITS OF POSTOPERATIVE EPIDURAL ANALGESIA • Superior analgesia • Improved pulmonary function • Better graft survival after lower limb vascular procedures • Increased bowel mobility, associated with shorter hospital stay • Fewer cardiac ischemic events • Shorter recuperation after joint surgery, associated with early aggressive mobilization
50. NSAIDS/STEROIDS
51. CHRONIC PAIN
52. CHRONIC PAIN DEFINITIONS • Chronic pain is defined by the American Society of Anesthesiologists as “extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual.” • The IASP subcommittee on taxonomy defined it in 1986 as “pain without apparent biological value that has persisted beyond the normal tissue healing time usually taken to be three months.” • The presence or extent of chronic pain often does not correlate with the documented tissue disorder.
53. CHRONIC PAIN • Persists after usual course of acute disease or injury • Persists after a reasonable time for healing to occur • Psychological and environmental factors play a role • Diminished or absent stress response • Prominent mood disturbances
54. CHRONIC PAIN • The normal physiology of neuronal function, receptors, and ion channels, is altered by persistent pain. • Because of the large number of sources and manifestation of chronic pain, classification must include cancer-related, neuropathic, inflammatory, arthritis, and musculoskeletal pain • Interdisciplinary management of chronic pain must include specialists in psychology, physical therapy, occupational therapy, neurology, and anesthesiology. • Drugs used for chronic pain are multiple and include opioids, nonsteroidal anti- inflammatory drugs and antipyretic analgesics, serotonin receptor ligands, antiepileptic's, antidepressants, topical analgesics (e.g., nonsteroidal anti-inflammatory drugs, capsaicin, local anesthetics, opioids), and adjuvants such as local anesthetics, α 2 -agonists, baclofen, botulinum toxin, antiemetics, novel drugs such as cannabinoids, and ion channel blockers. • Interventional management of chronic pain includes the use of diagnostic blocks, therapeutic blocks, continuous catheter techniques (peripheral, epidural, intrathecal), and stimulation techniques such as acupuncture, transcutaneous electrical nerve stimulation, and spinal cord stimulation.
55. CHRONIC PAIN - MECHANISMS • Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. • The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N -methyl- d -aspartate (NMDA), neurokinin (NK 1 ), and tyrosine kinase receptors, respectively. • Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). • In spinal neurons, such a progressive increase of output in response to persistent nociceptor excitation has been termed wind-up. • Sensitization can then be sustained by changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons • Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca 2+ and Na + channels, cytokines, and chemokines expressed by neurons and/or glial cells. • In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous systems.
56. CHRONIC PAIN - MECHANISMS • Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. • The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N -methyl- d -aspartate (NMDA), neurokinin (NK 1 ), and tyrosine kinase receptors, respectively. • Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity- dependent plasticity
57. CHRONIC PAIN – MECHANISMS (Excitatory) • In spinal neurons, such a progressive increase of output in response to persistent nociceptor excitation has been termed wind-up. • Sensitization can then be sustained by changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons • Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca 2+ and Na + channels, cytokines, and chemokines expressed by neurons and/or glial cells. • In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous systems.
58. CHRONIC PAIN – MECHANISMS (Inhibitory) • In the spinal cord, inhibition is mediated by the release of opioids, γ-aminobutyric acid (GABA), or glycine from interneurons. • These activate presynaptic opioid or GABA receptors, or both, on central nociceptor terminals to reduce excitatory transmitter release. • In addition, the opening of postsynaptic potassium (K + ) or chloride (Cl − ) channels by opioids or GABA, respectively, evokes hyperpolarizing inhibitory potentials in dorsal horn neurons. • During ongoing nociceptive stimulation, spinal interneurons up-regulate gene expression and the production of opioid peptides. • Powerful descending inhibitory pathways from the brainstem also become active by operating mostly through noradrenergic, serotonergic, and opioid systems. • A key region is the periaqueductal gray, which projects to the rostral ventromedial medulla, which then projects along the dorsolateral funiculus to the dorsal horn. • The integration of signals from excitatory and inhibitory neurotransmitters with cognitive, emotional, and environmental factors eventually results in the central perception of pain. • When the intricate balance of biologic, psychological, and social factors becomes disturbed, chronic pain can develop.
59. NOCICEPTIVE MODULATION
60. Drugs Targets Mechanisms Functional Consequences Side Effects Opioids G-protein coupled μ, δ, κ receptors ↓ cAMP ↓ Ca 2+ currents ↑ K + currents ↓ Excitability of peripheral and central neurons ↓ Release of excitatory neurotransmitters μ, δ: Sedation, nausea, euphoria/reward, respiratory depression, constipation κ: Dysphoria/aversion, diuresis, sedation NSAIDs Cyclooxygenases (COX-1, COX-2) ↓ Prostaglandins ↓ Thromboxanes ↓ Sensitization of sensory neurons ↑ Inhibition of spinal neurons Nonselective: gastrointestinal ulcers, perforation, bleeding, renal impairment COX-2: thrombosis, myocardial infarction, stroke Serotonin agonists G-protein coupled 5-HT receptors 5-HT 3 : ion channels ↓ cAMP (5-HT 1 ) ↑ cAMP (5-HT 4-7 ) ↑ PLC (5-HT 2 ) ↓ Release of excitatory neuropeptides ↓ Neurogenic inflammation ↑ Vasoconstriction Myocardial infarction, stroke, peripheral vascular occlusion Antiepileptics Na + , Ca 2+ channels GABA receptors ↓ Na + currents ↓ Ca 2+ currents ↑ GABA receptor activity ↓ Excitability of peripheral and central neurons ↓ Release of excitatory neurotransmitters Sedation, dizziness, cognitive impairment, ataxia, hepatotoxicity, thrombocytopenia Table TABLE 64-1 ANALGESIC DRUGS, TARGETS, MECHANISMS, AND SIDE EFFECTS
61. Interdisciplinary Management of Chronic Pain • Psychology • Physical Therapy • Occupational Therapy • Anesthesiology
62. SOMATIC • OPIOIDS • NSAIDS • ACETAMINOPHEN • REGIONAL
63. NEUROPATHIC • NMDA • α2 AGONISTS • α2 δ SUBUNIT (Ca channel ligand)
64. Nonsteroidal Antinflammatory Agents • Consist of a diverse group of analgesic compounds with different pharmacokinetic properties • The primary mechanism by which NSAIDs exert their analgesic effect is through inhibition of cyclooxygenase (COX) and synthesis of prostaglandins, which are important mediators of peripheral sensitization and hyperalgesia • In addition to being peripherally acting analgesics NSAIDs can also exert their analgesic effects through inhibition of spinal COX • At least two COX isoforms: COX-1 →constitutive, COX-2 → inducible • COX-1 → Platelet aggregation, hemostasis, and gastric mucosal protection • COX-2 → Pain, inflammation, and fever
65. Ketamine • Ketamine is traditionally an anesthetic • Small-dose (analgesic) ketamine can facilitate postoperative analgesia because of its NMDA-antagonistic properties • NMDA antagonist properties important in attenuating central sensitization and opioid tolerance • Can be administered orally, intravenously, subcutaneously, or intramuscularly • Perioperative analgesic doses of ketamine reduce rescue analgesic requirements or pain intensity • Perioperative ketamine reduced 24-hour PCA morphine consumption and postoperative nausea or vomiting with minimal adverse effects • Intravenous ketamine was an effective adjunct for postoperative analgesia particularly in patients undergoing painful procedures. • Caution with impact of ketamine’s amnestic effects on the neurologic and cognitive level of patients with use of perioperative ketamine infusions • These effects infrequently occur when the medication is given in analgesic doses • Ketamine has also been given epidurally and intrathecally, but racemic mixtures of ketamine are neurotoxic, and therefore the use of neuraxial racemic ketamine is strongly discouraged.
66. Single-Dose Neuraxial Opioids • Administration of a single dose of opioid may be efficacious as a sole or adjuvant analgesic drug when administered intrathecally or epidurally. • One of the most important factors in determining the clinical pharmacology for a particular opioid is its degree of lipophilicity (versus hydrophilicity) • Once they have reacted the cerebrospinal fluid (CSF) through direct intrathecal injection or gradual migration from the epidural space, hydrophilic opioids (i.e., morphine and hydromorphone) tend to remain within the CSF and produce a delayed but longer duration of analgesia, along with a generally more frequent incidence of side effects because of the cephalic or supraspinal spread of these compounds. • Neuraxial administration of lipophilic opioids, such as fentanyl and sufentanil, provides a rapid onset of analgesia, and their rapid clearance from CSF may limit cephalic spread and the development of certain side effects such as delayed respiratory depression. • The site of analgesic action for hydrophilic opioids is overwhelmingly spinal, but the primary site of action (spinal versus systemic) for single-dose neuraxial lipophilic opioids is not as certain.
67. ACUTE PAIN - 1 • 1. Which of the following statements regarding chronic pain is/are TRUE? • A. It is defined as pain without apparent biologic value that has persisted beyond the normal tissue healing time. • B. Antiarrhythmics and anticonvulsants may be used for treatment. • C. Associated psychiatric diagnoses may include hypochondriasis. • D. it is often associated with depression, anxiety and psychosis.
68. ACUTE PAIN - 2 • 2. Which of the following statements concerning non-opioid analgesics is FALSE? • A. Dexmedetomidine is a highly selective 2 -agonist that does not depress respiration. • B. Gabapentin is effective for neuropathic pain syndrome and postoperative pain. • C. Paracetamol has both analgesic and antipyretic properties but is devoid of anti- inflammatory effects. • D. Acetaminophen is associated with impaired platelet function and gastrointestinal (GI) ulceration.
69. ACUTE PAIN - 3 Which of the following statements is NOT associated with increased risk of nephrotoxicity in the perioperative period? • A. Hypovolemia • B. Chronic renal insufficiency • C. Congestive heart failure • D. Concomitant morphine use
70. ACUTE PAIN - 4 • 4. Which of the following statements concerning the analgesia provided by intrathecal clonidine is FALSE? • A. It produces respiratory depression comparable to that produced by morphine. • B. It binds to pre- and postsynaptic receptors in the dorsal horn. • C. It interacts synergistically with opioids and local anesthetics. • D. It prolongs sensory and motor blockade. • E. It may cause hypotension and bradyardia
71. ACUTE PAIN - 5 • 6. Cyclo-oxygenase (COX) exists as two separate isomers, COX-1 and COX-2. Which of the following statements regarding these isomers is/are TRUE? • A. COX-1 is the constitutive enzyme form. • B. COX-2 is the inducible form. • C. COX-1 mediates hemostasis. • D. COX-2 mediates pain and fever.
72. 6 - ACUTE PAIN • Which of the following are opioid sparing and may be used in the perioperative period to attenuate excessive sedation induced by opioids? • A. N-methyl-D-asparate (NMDA) receptor antagonists • B. Gabapentin • C. nonsteroidal anti-inflammatory drugs (NSAIDs) • D. acetaminophen
73. IV PCA
75. Central perception of pain
76. Acute/Chronic Pain - Physical treatments • Heat or cold • Massage • Physical therapy or exercise, along with stretching and strengthening • TENS unit • Ultrasound • Acupuncture
77. Acute Pain - Behavioral treatments • Relaxation using imagery (mental pictures) • Distraction • Breathing exercises • Music therapy • Hypnosis • Biofeedback
78. Acute Pain - Pharmacotherapy • Direct blockade of pain receptor activity eg lidocaine • Antiinflammatory agents eg aspirin, nonsteroidal antiinflammatory drugs →diminish the local hormonal response to injury → decreasing pain receptor activation. • Target the activity of neurotransmitters by inhibiting or augmenting their activity eg ketamine, clonidine, acetaminophen, gabapentin, pregabalin • Targeting the activity of neurotransmitters eg substance P, calcitonin gene- related peptide, aspartate, glutamate, and gamma-aminobutyric acid (GABA).
79. PHARMACODYNAMICS • OPIOIDS ARE LIGANDS • BIND TO ENDOGENOUS OPIOID RECEPTORS WHICH ARE G PROTEINS • µk δ NOP (Nociception) • INITIATE CASCADE INVOLVING • INHIBITION OF ADENYLATE CYCLASE • DECREASED c-AMP • ACTIVATION OF K and Ca CHANNELS
80. MEPERIDINE • Is used only for the short-term management of acute pain • It is contraindicated for patients receiving monoamine oxidase inhibitors • Meperidine lowers seizure threshold and may have a dysphoric effect, and therefore is not recommended for repeated dosing when compared with other available drugs • Meperidine has a slower rate of metabolism in the elderly and in patients with hepatic and renal impairment • Accumulation of meperidine and its active metabolite normeperidine, which can cause seizures • Meperidine is not used for PCA because of the risk of accumulation of normeperidine with prolonged administration.
81. PHARMACODYNAMICS • Tapentadol – • Active at MOR at spinal and supraspinal levels and • Norepinephrine Reuptake Inhibitor at spinal level • No Serotonergic effect • Lower incidence of nausea and vomiting
82. PHARMACODYAMICS MIXED AGONIST/ANTAGONISTS • SUBOXONE (BUPRNORPHINE + NALOXONE) • USED TO TREAT NARCOTIC, SPECIFICALLY OPIATE ADDDICTION
83. OPIOIDS – MECHANISM OF ACTION CENTRAL BRAIN PERIAQUEDUCTAL GREY MODULATION OF DESCENDING INHIBIORY PATHWAYS SPINAL CORD -> SUBSTANTIA GELATINOSA PERIPHERAL INHIBIT THE PRESYNAPTIC RELEASE AND POSTSYNAPTIC RESPONSE TO EXCITATORY NEUROTRANSMITTERS FROM NOCICEPTIVE NEURONS OPIATE RECEPTORS ON OR NEAR TERMINALS OF UNMYELINATED (SOMMATIC AND SYMPATHETIC) PERIPHERAL NERVES PERIPHERAL TISSUE
84. PHARMACODYNAMICS • OPIOIDS ARE LIGANDS • BIND TO ENDOGENOUS OPIOID RECEPTORS WHICH ARE G PROTEINS • µk δ (Nociception) • INITIATE CASCADE INVOLVING • INHIBITION OF ADENYLATE CYCLASE • DECREASED c-AMP • ACTIVATION OF K and Ca CHANNELS
85. PHARMACODYNAMICS • At the spinal cellular level • Presynaptically to decrease release of substance P • Hyperpolarizes post synaptic neurons • Postsynaptically to decrease afferent transmission of nocicpetive impulses
86. SIDE EFFECTS OF OPIOIDS • All opioids share common side effects • These include somnolence, depression of brainstem control of respiratory drive, urinary retention, and nausea and vomiting due to direct stimulation of the chemoreceptor trigger zone • Histamine release often follows morphine administration and may produce flushing, tachycardia, hypotension, pruritus, and bronchospasm • Gastrointestinal transit slows with prolonged administration, resulting in constipation and ileus in many patients; this effect reflectS binding to local opioid receptors in the gut • Methylnaltrexone, an opioid antagonist that does not cross the blood–brain barrier, may diminish the peripherally mediated side effects of opioids while maintaining central analgesic effects.
88. OPIOID INDUCED EMESIS
89. NOCICEPTIVE FIBERS
90. CHRONIC PAIN PATHWAYS AND MANAGEMENT
92. NOCICEPTIVE MODULATION
93. PAIN MODULATING DEVICE • 1.8 Litre Classic Comfort Rubberless Part Ribbed Hot Water Bottle Without Cover Perfect For Aches, Cramps & Pain Relief - Mint Blue • $24.86
94. NEUROPATHIC PAIN
95. NEUROPATHIC PAIN • Mechanical or thermal allodynia • Hyperalgesia • Spontaneous shooting pains • Spontaneous burning • Sensory deficits
96. NEUROPATHY-EVALUATION AND DIAGNOSIS • TIME COURSE • DISTRIBUTION – Of Neuropathy Symptoms and Signs • MODALITIES AFFECTED – Motor, Sensory (small or large fiber), Autonomic • PRIMARY LOCUS OF PATHOLOGY – Axon or Myelin
97. NEUROPATHY-EVALUATION AND DIAGNOSIS - TIME COURSE • Most common neuropathies progress over months or years • Metabolic or genetic • Insidious progression • Few have rapid progression eg Guillan Barre • Some have unpredictable relapses and remissions • Some toxic neuropathies present after neurotoxin exposure and progress after removal of source
98. NEUROPATHY-EVALUATION AND DIAGNOSIS - DISTRIBUTION • Distribution of symptoms and signs • Identified by history • Confirmed by examination and EP studies • Types : • Symmetric, length dependent • Asymmetric nonlength dependent • Multifocal
99. NEUROPATHY – DISTRIBUTUION 1 • The symmetric, length dependent pattern • Begins with symptoms in both feet • Progresses rostrally in a symmetric fashion. • The pattern and rate of change are uniform. • Symptoms usually do not appear in the hands until lower limb symptoms have progressed to the proximal calves or thighs. • Symptoms appear last in the trunk and face. • The term length dependent refers to the fact that nerve dysfunction in these patients begins in the longest axons and progresses rostrally. • The implication vis-a ` -vis pathophysiology is that all nerves are exposed in equal measure to a systemic stressor, and that the effect of this stressor on nerve function is closely correlated to the distance of the nerve terminal from the cell body. • Many metabolic, toxic, and genetic disorders of nerve present in a symmetric, length-dependent pattern.
100. NEUROPATHY – DISTRIBUTUION 2 • Asymmetric, nonlength-dependent neuropathies : • Are widespread but can affect proximal and distal nerve segments concomitantly • Do not present in a symmetric fashion. • CIDP (Chronic inflammatory demyelinating polyradiculoneuropathy) typically demonstrates this distribution.
101. NEUROPATHY – DISTRIBUTUION 3 • Multifocal neuropathies • Affect individual named nerves or nerve trunks, often with a stepwise progression • Necrotizing vasculitis, granulomatous disorders, hereditary neuropathy with liability to pressure palsies (HNPP), and lymphomatous infiltration are examples of conditions that can present in this fashion • When a sufficient number of nerves are affected, multifocal neuropathies become confluent and are thereby transformed into the asymmetric, pattern.
102. NEUROPATHY – MODALITIES AFFECTED • Refers to motor axons, large fiber (myelinated) sensory axons, small fiber (A ∂ and C) sensory axons, and autonomic (cardiorespiratory, vasomotor, and visceromotor) axons. • Involvement of these fiber classes identified by the history and confirmed by the neurological examination and electrophysiological studies • Numerous clinical tools have been developed in recent decades to assist in the confirmation of small fiber sensory and autonomic involvement. • Virtually all neuropathies demonstrate prominent involvement of sensory axons
103. NEUROPATHY – MODALITIES AFFECTED • Most symmetric, length dependent neuropathies with metabolic or toxic etiologies are clinically sensory-predominant or pure sensory neuropathies until they are relatively advanced • The relative involvement of large and small sensory axons varies among, and in some cases within, etiologies. • Patients with clinical findings isolated to smallfiber modalities are often referred to as having small-fiber neuropathy (SFN), although there is evidence that this progresses over time to involve both smalland large-fiber types. • SFN can be seen in diabetes or HIV infection but is also often idiopathic. • Large-fiber sensory symptoms predominate in those neuropathies in which the primary pathology is a disorder of myelin, such as Charcot-Marie-Tooth
104. NEUROPATHY - PRIMARY LOCUS OF PATHOLOGY • The primary locus of pathology (axon or myelin) is most reliably determined by nerve conduction studies and by nerve biopsy • The neurological examination can be used to draw inferences about this. • For example, muscle stretch reflexes are lost early in CIDP • Because demyelination alone does not result in denervation, denervation atrophy does not develop unless or until there is secondary axonal injury from longstanding demyelination
105. DIAGNOSIS OF NEUROPATHIC PAIN • HISTORY • EXAM • DIAGNOSTIC STUDIES (NCS or EMG)
106. PAINFUL NEUROPATHIES – DISTAL SYMMETRICAL POLYNEUROPATHIES • METABOLIC • INFECTIOUS • TOXIC • NUTRITIONAL • HERIDITARY
107. OTHER WIDESPREAD BUT NON LENGTH DEPENDENT NEUROPATHIES • Neuropathy with Paraproteinemia • Autoimmune Demyelinating Neuropathies (GBS) • CIDP - Chronic Inflammatory Demyelinating Polyradiculoneuropathy. Lupus HIV
108. PAINFUL NEUROPATHIES - Painful Mononeuropathy Multiplex and Focal Neuropathic Syndromes Painful Mononeuropathy Multiplex and Focal Neuropathic Syndromes Vasculitic Neuropathy Diabetic Amyotrophy Neuralgic Amyotrophy Diabetic Mononeuropathy
109. SENSORY NEUROPATHIES • Post herpetic Neuralgia • Sjogrens Syndrome • Paraneoplastic Sensory Neuropathy
110. NEUROPATHIC PAIN – PRINCIPLES OF PHARMACOTHERAPY • Treat underlying disease process • Treat as early as possible • Goal of 30% improvement in pain severity or • A reduction in pain severity by at least 2 points on a 0 to 10 Likert scale is clinically meaningful.
111. NEUROPATHIC PAIN - PHARMACOTHERAPY • Tricyclic Antidepressants • α 2 ƌ Ligands • Serotonin and Norepinephrine Reuptake Inhibitors • Opioids • Tramadol • Others • Topical Agents
112. OPIOIDS • Opioids strongly inhibit central nociceptive neurons mainly through interaction with mu -opioid receptors, producing neuronal membrane hyperpolarization. • Controlled-release oxycodone has been shown to reduce pain from diabetic neuropathy in two small randomized controlled trials, with an NNT for moderate pain relief of 2.6 in one. • Administration of opioids requires specific treatment programs for patients with a history of chemical dependence and caution in patients with pulmonary disease • Opioid-induced dependence, tolerance, and hyperalgesia are risks of opioid use • Prophylactic treatment of common side-effects such as nausea or constipation can improve patient compliance. Fishman, Scott M.. Bonica's Management of Pain, Wolters Kluwer, 2009.
113. SNRIs • Serotonin and norepinephrine reuptake inhibition is believed to alleviate neuropathic pain by • Facilitate descending inhibition of afferent pain signaling • Descending inhibition is mediated by neurons of the rostroventral medulla. • Likely both neurotransmitters are important in this pathway, which may explain the observation that selective serotonin reuptake inhibitors (SSRIs) alone are of little benefit in alleviating pain from neuropathy. • Duloxetine, an SNRI with relative balance between serotonergic and noradrenergic effects, has demonstrated efficacy in relieving pain from diabetic neuropathy • Venlafaxine, an SNRI with balanced pharmacology at high doses, has also been shown to be beneficial high doses
114. SNRIs • SNRIs can cause nausea, hyperhidrosis, and sexual side effects in some patients • While they do not have substantial anticholinergic properties, they can cause some symptoms of dry mouth and dizziness • Effects are probably less frequent or severe than with tricyclic medications. • Combining SNRIs with other serotonergic agents, including other antidepressants, triptans, and tramadol, should be done with caution because of the risk of serotonin syndrome. • SNRIs are also known to inhibit the metabolism of other antidepressants, thus substantially increasing blood levels of such drugs when they are used in combination. • For these reasons, it is usually best to avoid the use of SNRIs with other antidepressants, and to consider using one SNRI or tricyclic agent alone to treat both pain and depression if treatment of both conditions
115. TRAMADOL • Tramadol is both an inhibitor of serotonin and norepinephrine reuptake and amu -opioid agonist. • Tramadol has been shown to effectively alleviate pain in diabetic neuropathy as well as a mixed group of neuropathy patients among whom many had diabetic neuropathy. • Tramadol has a short duration of action and therefore is given every four to six hours or is used on an as needed basis as an adjuvant medication. • It is now also available in an extended release formulation. Fishman, Scott M.. Bonica's Management of Pain, Wolters Kluwer, 2009.
116. OTHER • Several other agents approved for the treatment of epilepsy have demonstrated limited evidence of efficacy in the management of pain from neuropathy. • These include oxcarbazepine, which has demonstrated benefit in one randomized controlled study in diabetic neuropathy pain • Lamotrigine, and Topiramate, both agents which have demonstrated conflicting results in randomized controlled trials for pain from diabetic neuropathy. • Despite limited evidence of efficacy, these have all been used on occasion as second or third-line agents for patients who have not responded to or tolerated other treatments • Carbamazepine, which is approved for pain from trigeminal neuralgia, has been found to be effective in two double-blind placebo-controlled studies for control of pain in diabetic neuropathy. • Prior to the availability of many of the aforementioned agents for neuropathic pain management, phenytoin was shown to be effective. Fishman, Scott M.. Bonica's Management of Pain, Wolters Kluwer, 2009.
117. OTHER - CTD • Bupropion, a unique agent which inhibits norepinephrine and dopamine uptake, has shown benefit in one study involving pain from a variety of neuropathy etiologies. • Acetyl-L-carnitine (ACL) is believed to have several potentially neuroprotective properties that have led to extensive study of this agent as a treatment for diabetic, HIV, and chemotherapyinduced neuropathy. It also has analgesic properties. ACL has been administered at doses between 1 and 3 g per day. • Alphalipoic acid, a potent antioxidant, has also been studied as a potential treatment of both diabetic neuropathy and diabetic neuropathy pain. Fishman, Scott M.. Bonica's Management of Pain, Wolters Kluwer, 2009.
118. TOPICAL • Capsaicin stimulates the release of substance P from small caliber primary afferent neurons • Is believed to alleviate neuropathic pain with regular use by exhausting stores of substance P • Capsaicin also causes prompt epidermal denervation so reliably that capsaicin denervation has become an important human model of neuropathy. • While capsaicin can alleviate neuropathic pain with sustained use, it also causes considerable burning discomfort which limits its use • A high-potency capsaicin patch is presently undergoing clinical trials • Topical lidocaine, a local anesthetic which acts via sodium channel blockade, has been approved for the treatment of postherpetic neuralgia. • It is used on occasion to treat cutaneous pain from other neuropathic conditions as well. • Systemically administered lidocaine, mexiletine, and tocainide have also been demonstrated to have analgesic effects for control of diabetic neuropathic pain and in postherpetic neuralgia. • Systemically administered local anesthetics block ectopic discharges due to experimental peripheral nerve injury and in axotomized dorsal root ganglion cells of the peripheral nerves probably by blocking sodium channels • In addition, there is evidence that lidocaine and similar local anesthetics have actions on G protein coupled receptors that can result in long-lasting modulation of pain via effects both on sensitization and on the immune response
119. CRPS • Complex regional pain syndrome (CRPS) is the current diagnostic label for the syndrome previously known by various names, including • Reflex sympathetic dystrophy (RSD) • Causalgia • Sudeck’s atrophy • Shoulder– hand syndrome • Neuroalgodystrophy • Reflex neurovascular dystrophy • It is an inflammatory and neuropathic pain disorder principally characterized by involvement of the autonomic nervous system • It is often a chronic disease that involves a full measure of biopsychosocial features, and it can become significantly disabling in some cases.
120. CRPS- PATHOPHYSIOLOGY • INFLAMMATION • AFFERENT DYSFUNCTION • CENTRAL DYSFUNCTION • SYMPATHETIC DYSFUNCTION • TROPHIC DYSTROPHIC AND NUTRITIONAL ABNORMALITIES • MOTOR AND MOVEMENT DISORDER • IMMOBILIZATION AN DISUSE
121. CRPS - EPIDEMIOLOGY • Fractures and sprains appear to be the most common events triggering CRPS. • CRPS appears to be more common in the upper extremities • Is more common in females • Is most likely to occur in the 50– 70 year age range.
122. IASP DIAGNOSTIC CRITERIA FOR COMPLEX REGIONAL PAIN SYNDROME • IASP DIAGNOSTIC CRITERIA FOR COMPLEX REGIONAL PAIN SYNDROME • 1) The presence of an initiating noxious event or a cause of immobilization. 2) Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event. • 3) Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain. • 4) This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. • Type I: Without obvious nerve damage (aka RSD) • Type II: With obvious nerve damage (aka Causalgia)
123. “BUDAPEST’’ DIAGNOSTIC CRITERIA FOR CRPS • ‘‘General Definition of the Syndrome CRPS describes an array of painful conditions that are characterized by • A continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. • The pain is regional (not in a specific nerve territory or dermatome), but may spread, and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. • The syndrome shows variable progression over time. • To make a clinical* diagnosis, the following criteria must be met: 1) Continuing pain, which is disproportionate to any inciting event. 2) Must report at least one symptom in three of the four following categories: • — Sensory : Reports of hyperesthesia and/or allodynia. • — Vasomotor : Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry. • — Sudomotor/Edema : Reports of edema and/or sweating changes and/or sweating asymmetry. • — Motor/Trophic : Reports of decreased range of motion and/ or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin).
124. CRPS – DIAGNOSTIC CRITERIA 3) Must display at least one sign at time of evaluation in two or more of the following categories: — Sensory : Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement). — Vasomotor : Evidence of temperature asymmetry and/or skin color changes and/or asymmetry. — Sudomotor/Edema : Evidence of edema and/or sweating changes and/or sweating asymmetry — Motor/Trophic : Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin). • 4) There is no other diagnosis that better explains the signs and symptoms. *For research purposes, diagnostic decision rule should be at least one symptom in all four symptom categories and at least one sign observed at evaluation in two or more sign categories (modified from Harden 143 ). Sequential Stages of Complex Regional Pain
125. CRPS - THERAPY • Condition/Presentation - Mild to moderate pain • Excruciating, intractable pain Inflammation/swelling and edema • Significant osteopenia, immobility, and trophic changes Profound vasomotor disturbance • Suggested Response- Simple analgesics and/or blocks • Opioids and/or blocks • Steroids, systemic or targeted (acutely) or NSAIDs (chronically) • Immunemodulators • Sedative analgesic • Antidepressant/anxiolytics (and/or psychotherapy) Anticonvulsants and/or other sodium channel blockers and/or N -methylD- aspartate-receptor antagonists • Calcitonin or bisphosphonates Calcium channel blockers, sympatholytics and/or blocks
126. CRPS – TREATMENT • PHARMACOTHERAPY • PSYCHOTHERAPY • INTERVENTIONAL THERAPIES • OTHER
127. CHRONIC PAIN - MECHANISMS • Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. • The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N -methyl- d -aspartate (NMDA), neurokinin (NK 1 ), and tyrosine kinase receptors, respectively. • Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). • In spinal neurons, such a progressive increase of output in response to persistent nociceptor excitation has been termed wind-up. • Sensitization can then be sustained by changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons • Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca 2+ and Na + channels, cytokines, and chemokines expressed by neurons and/or glial cells. • In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous systems. 1 5
128. PAIN PATHWAYS
129. CHRONIC PAIN INTERVENTION • Nerve Blocks • Myofascial pain and Trigger point injections • Low Back Pain Therapies • ESIs • Intradiscal Electrothermal Annuloplasty (Destroys nociceptive fibers in the disc annulus) • Facet Blocks • Spinal Cord Stimulation • IT Drug delivery
130. INDICATIONS FOR SCS • Failed Back Surgery • CRPS • Peripheral Ischemic Disease • Peripheral Neuropathy
131. ABLATIVE BRAIN PROCEDURES FOR CHRONIC PAIN • MEDULLARY AND PONTINE SPINOTHALAMIC TRACTOTOMY • MEDULLARY TRIGEMINAL TRACTOTOMY • TRIGEMINAL DORSAL ROOT ENTRY ZONE LESIONS • THALAMOTOMY • HYPOTHALAMOTOMY • PRE- AND POSTCENTRAL GYRECTOMY • FRONTAL LOBE OPERATIONS • CINGULOTOMY • (STEREOTAXIS)
132. ABLATIVE/SURGICAL SC PROCEDURES FOR CHRONIC PAIN • PERIPHERAL NEURECTOMY • DORSAL RHIZOTOMY • GANGLIONECTOMY • SYMPATHECTOMY • ANTEROLATERAL CORDOTOMY • MYELOTOMY • DORSAL ROOT ENTRY ZONE LESIONS
133. SUMMARY • Neurophysiology of Acute and Chronic Pain • Pain Pathways • Medical therapy • Interventional techniques • Non medical therapy
134. REFERENCES • Bonica’s Management of pain: Ballantyne, Jane, 1948- editor.; Fishman, Scott, 1959- editor.; Rathmell, James P., editor.; 2019 • Millers Anesthesia 9th Edition, Copyright 2020, Gropper, Michael A., MD, PhD • Clinical Anesthesia Lippincott Williams & Wilkins, Copyright 2009, Edited By Paul G. Barash MDBook • Guyton and Hall Textbook of Medical Physiology; Hall, John E. (John Edward), 1946- author. 2016