Pharmacological Treatment of Pain.pdf

Pharmacological Treatment of Pain Dr. Sumit Sontakke M.D. Asst. Professor of Medical Foundations Ross University School of Medicine Tel: +1(246)627-7846 [email protected] Learning Objectives List the drug classes for treating pain: Anti-inflammatories, opioids, local anesthetics, antidepressants,...

Pharmacological Treatment of Pain Dr. Sumit Sontakke M.D. Asst. Professor of Medical Foundations Ross University School of Medicine Tel: +1(246)627-7846 [email protected] Learning Objectives List the drug classes for treating pain: Anti-inflammatories, opioids, local anesthetics, antidepressants, anticonvulsants and general anesthetics List the following drugs and assign them to the appropriate class: Aspirin, ibuprofen, acetaminophen, morphine, codeine, lidocaine, capsaicin, amitriptyline, duloxetine, carbamazepine, gabapentin and ketamine Explain the terms nociceptive and neuropathic pain Identify drugs used for treatment of nociceptive pain and describe the molecular mechanisms of action of the drugs discussed in class Identify drugs used for treatment of neuropathic pain and describe the molecular mechanisms of action of the drugs discussed in class Drug List Definition of Pain According to 2020 revised definition of pain from the International Association of Pain (IASP): “Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” Nociceptive pain Pain can be broadly classified as: Neuropathic pain Types of Pain Nociceptive pain: Nociceptive pain is caused by stimuli that threaten or result from bodily tissue damage Nociceptive pain is expected after surgical and other acute traumatic injury Nociceptive pain is associated with a range of musculoskeletal and visceral conditions that involve inflammatory, ischemic, infectious, or mechanical injury Neuropathic pain: Neuropathic pain results from a maladaptive response to damage or disease of the somatosensory nervous system, and consists of a central and/or peripheral disorder of pain modulation Neuropathic pain can occur in the absence of active noxious stimulus, or as an exaggerated response to minor or moderate nociceptive stimulus Peripheral Chemical Mediators of Pain Tissue trauma releases local inflammatory mediators: Prostaglandins Substance P Histamine Bradykinin Local inflammatory mediators produce: Augmented sensitivity to stimuli in the area surrounding an injury (hyperalgesia) or Misperception of pain due to nonnoxious stimuli (allodynia) Bear MF, Connors BW, and Parasido MA. Neuroscience - Exploring the Brain, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2001. Copyright © 2001 Pain Pathways & Mechanisms https://www.uptodate.com/contents/approach-to-the-management-of-acute-pain-inadults?search=pain%20management%20adult&source=search_result&selectedTitle=1~150 &usage_type=default&display_rank=1 Differences Pain Types Nociceptive Neuropathic Definition Pain caused by physiological activation of pain receptors Pain caused by lesion or dysfunction of the somatosensory system, especially the nociceptive pathway Mechanism Natural physiological transduction Ectopic impulse generation, among others Localization Local + referred pain Confined to innervation territory of the lesioned nervous structure Quality of symptoms Ordinary painful sensation (good verbal descriptors) New strange sensations (poor verbal descriptors) Treatment Good response (conventional analgesics) Poor moderate response (antidepressants, antiepileptics) Chronic Pain Disorders Nociceptive Pain Mixed Pain Neuropathic Pain Mechanical low back pain Low back pain Neuropathic low back pain Rheumatoid arthritis Migraine Peripheral neuropathies Osteoarthritis Fibromyalgia Post herpetic neuralgia Chronic inflammatory conditions Phantom limb pain Trigeminal neuralgia Post-operative pain Multiple sclerosis Central post-stroke pain Sports/exercise pain Myofascial pain syndrome Spinal cord injury Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Aspirin (acetylsalicylic acid) & Ibuprofen Mechanism of action: Inhibition of cyclooxygenases 1 and 2 (COX-1 and COX-2) to decrease prostaglandins Aspirin: non-selective irreversible inhibition Ibuprofen: non-selective competitive inhibition Pharmacological effects: Aspirin: Analgesic, anti-inflammatory, antipyretic, antiplatelet aggregation Dose-dependent: antiplatelet → antipyretic/analgesic → anti-inflammatory Ibuprofen: Analgesic, anti-inflammatory, antipyretic Therapeutic use: Nociceptive pain (mild to moderate), inflammatory disease, fever Aspirin – as above plus anti-platelet effects for reduction of risk of MI and TIA MI – myocardial ischemia; TIA – transient ischemic attack Cyclooxygenases COX-1 A constitutive enzyme Expressed in most cells of the body Produce mucosal protective PGs, vascular homeostasis, platelet aggregation, and kidney function COX-2 Produced in many cells (inducible enzyme) Specially when bacterial polysaccharides (endotoxin), pro-inflammatory cytokines such as TNF alpha or IL-1b, or growth factors (mitogens) induce COX-2 expression COX-3 Alternative splice variant of COX-1 Acetaminophen potently inhibits COX-3, and this finding likely explains the reason that acetaminophen has little anti-inflammatory action Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Mechanism of action: The primary effect of NSAIDs is to inhibit COX (COX1 and /or COX2) Thereby impairing the conversion of arachidonic acid to prostaglandins Due to reduced prostaglandins, there is decrease in pain and inflammation Non-selective NSAIDs cause more side effects than selective NSAIDs Slim K, et al. Colonic anastomoses and non-steroidal anti-inflammatory drugs. Journal of Visceral Surgery (2016), http://dx.doi.org/10.1016/j.jviscsurg.2016.06.011 NSAIDs: Side Effects https://tmedweb.tulane.edu/pharmwiki/doku.php/nsaid_side_effects Atypical Analgesic Acetaminophen Mechanism of action: Inhibits COX-1 in CNS and decreases prostaglandins in brain Central actions to decrease pain and fever Pharmacological effects: Analgesic, antipyretic (not anti-inflammatory!) Therapeutic uses: Nociceptive pain Mild to moderate Moderate to severe when combined with opioids Fever https://www.tylenol.com/products/tylenol-family-oral-suspension-liquid-medicine Opioids Codeine & Morphine Mechanism of action: Opioid receptor agonists (at the mu-receptor subtype) Mimic the effect of endogenous opioids (endorphin, enkephalin) Metabolism: Codeine is metabolized to morphine Pharmacological effects: Analgesia Constipation, euphoria, miosis Therapeutic use: Codeine Mild to moderate nociceptive pain Morphine Moderate to severe nociceptive pain https://www.sciencenews.org/article/opioid-epidemic-spurs-search-new-safer-painkillers Opioids Cellular mechanisms by which opioid agonists mediate analgesia at the level of the spinal cord https://tmedweb.tulane.edu/pharmwiki/doku.php/opioid_receptor_pharmacology Local Anesthetics Lidocaine Mechanism of action: Blocks voltage-gated Na+ channels responsible for neuronal signal propagation Administration: Cream or injection Pharmacological effect: Local anesthetic at site of application Therapeutic uses: Local anesthesia, nerve block, epidural Nociceptive and neuropathic pain (Also, ventricular tachycardia) https://aneskey.com/local-anesthetics-14/ Local Anesthetics Capsaicin Mechanism of action: Agonist at TRPV1 receptors Pharmacological effects: Activates sensory neurons continuously leading to a desensitization of the sensory axons and depletion of substance P Administration: Cream or liquid (topically) Therapeutic use: Nociceptive and neuropathic pain Muscle/joint pain Diabetic peripheral neuropathy, postherpetic neuralgia https://pharmrev.aspetjournals.org/content/64/4/939/tab-figures-data Antidepressants Amitriptyline & Duloxetine Drugs with actions at norepinephrine transport sites (not just serotonin) are useful analgesics Mechanisms of action: Amitriptyline: first generation Drug class: TCA Blocks uptake of serotonin and norepinephrine Has a number of “off target” actions Duloxetine: second generation Drug class: SNRI Blocks uptake of serotonin and norepinephrine Therapeutic uses: Neuropathic pain - fast onset of action Major depressive disorder - slow onset of action https://wchh.onlinelibrary.wiley.com/doi/full/10.1002/pdi.1996 SNRI: serotonin norepinephrine reuptake inhibitor; TCI: tricyclic antidepressant Anticonvulsants Carbamazepine Mechanisms of action: Blockade of inactive neuronal voltage-gated Na+ channels preventing the generation of action potential (AP) and depolarization of cell Agonist at the GABA receptors allowing the entry of Cl- into the cell and preventing the generation of AP Increasing neuronal synaptic concentration of inhibitory neurotransmitter - Serotonin https://onlinelibrary.wiley.com/doi/10.1002/pdi.1485 Anticonvulsants Gabapentin Mechanisms of action: Structural analogue of GABA but NO effect on GABA receptors Inhibit presynaptic N, L, P/Q-type voltagegated Ca2+ channels Inhibit calcium influx, thereby inhibiting excitatory neurotransmitter release (e.g., glutamate, substance P) NMDA antagonism Enhanced inhibitory input of GABAmediated pathway https://www.stepwards.com/?page_id=5882 Anticonvulsants Therapeutic uses: Carbamazepine Neuropathic pain Trigeminal or glossopharyngeal neuralgia Epilepsy and bipolar disorder Gabapentin Neuropathic pain Postherpetic neuralgia Epilepsy https://my.clevelandclinic.org/health/diseases/12093-postherpetic-neuralgia NMDA Receptor Antagonists Ketamine Mechanism of action: Non-competitive inhibitor of NMDA receptors Therapeutic use: Neuropathic pain Used at sub-anesthetic doses General anesthetic Also, a drug of abuse https://wou.edu/chemistry/chemistry-degree/student-activities-2/chemistry-corner/ketamine/ Mechanism-based Analgesic Targets