Pain Management/NSAID Refresher 2024 PDF

Pain Management/NSAID Refresher Adapted from lecture by Dr. Asaf Keller  Pain (≠ nociception) Nociception: Neural encoding of impending or actual tissue damage Pain: The subjective experience of actual or impending harm...

Pain Management/NSAID Refresher Adapted from lecture by Dr. Asaf Keller  Pain (≠ nociception) Nociception: Neural encoding of impending or actual tissue damage Pain: The subjective experience of actual or impending harm iceptive & neuropathic pain conditions Do not memorize details Nociception principles  Nociceptive pain 100 Under “normal” conditions, a stimulus is Pain intensity Normal or perceived as painful only nociceptive after it exceeds a certain pain threshold 0 Innocuous Noxious That threshold varies in Stimulus intensity and between individuals. Not everyone perceives a painful stimulus with the same intensity  Nociceptive pain Activity (firing rate) in pain receptors varies with stimulus intensity Action potentials/sec Wide dynamic range (WDR) dependent on receptor type Nociceptive-specific (NS) Nociceptive specific receptors show no Low-threshold response to low intensity and yield painful Stimulus intensity perception when they respond Nociceptive peripheral detection Nociception is conveyed mainly by free nerve endings The fibers carrying this information are small diameter Sensitization  Physiological or acute pain Acute tissue injury shifts 100 Hyperalgesia the local response Pain intensity Normal or threshold Injury nociceptive pain Allodynia Previously innocuous stimuli at the site of 0 tissue injury are now Innocuous Noxious perceived as painful Stimulus intensity Allodynia from acute injury decreases as the Hyperalgesia: Increased pain from a stimulus that normally tissue heals provokes pain. Allodynia: Pain due to a stimulus that does not normally  Chronic pain Chronic pain sets in when Chronic pain the allodynia persists 100 Hyperalgesia past injury healing or occurs in the absence of Pain intensity Normal or injury nociceptive pain Allodynia Chronic pain may lead to depression, anxiety, stress, weakened immune 0 Innocuous Noxious responses, loss of Stimulus intensity appetite, insomnia, and other mental health issues Chronic pain is not a  Peripheral sensitization Increased sensitivity in the afferent nerve endings or axons Hyperalgesia or allodynia Produces primary hyperalgesia Considered a self-preservation response mechanism Don’t memorize these  Central sensitization Increased responsiveness of CNS neurons to either normal afferent input Hyperalgesia or allodynia Expanded receptive fields (secondary hyperalgesia) May cause lasting changes (plasticity) Can lead to chronic pain Referred pain Referred pain Referred pain is pain perceived at a location other To brain than the site of the painful stimulus/ origin The mechanisms of referred pain are still in dispute. Referred pain Visceral (organ) pain is almost never perceived at the affected organ (i.e., commonly organ pain is referred pain) Remember this chart from Foundations…? Do not memorize patterns for this lectur Pain pathways  Spinothalamic tract The spinothalamic tract carries nociceptive/temperature inputs to the primary somatosensory cortex (see previous class) This relays and encodes ‘sensory Spinothala discriminative’ pain qualities mic tract “Where is the pain”” “How intense is the pain?” Spinal second order neurons cross at level of origin and ascend to the thalamus, where third order neurons  Spino-parabrachial pathway The spino-parabrachial pathway starts the same as the spinothalamic (spinal cord second order neurons crossing at level of origin) Spino- parabrachial Terminates in the parabrachial pathway nucleus in the brainstem Spinothala mic The parabrachial nucleus projects to tract limbic structures (e.g., amygdala, hypothalamus, neocortex) This relays and encodes ‘affective cognitive’ pain qualities - Aversion, avoidance, emotion  Descending pain modulation pathways A collection of projections from multiple cortical and subcortical sites to brainstem and spinal cord These descending signals modulate pain sensation at multiple levels These involve endogenous opioid, cannabinoid, and other neurotransmitter signaling systems Pain management  NSAIDS - Non-steroidal anti-inflammatory drugs (NSAIDs) are highly effective for treating primary sensitization - The COX-1/COX-2 NSAID aspirin/ibuprofen are in common use (and aspirin other effects managing some in heart conditions) - The high COX-2 selective NSAIDs (e.g., celecoxib) have lowest gastric and platelet side-effects Don’t memorize these NSAID Overview Mechanism of Action Classification Adverse Effects Non-specific COX Inhibitors COX-2 Inhibitors 22  NSAIDs ·Drug properties · Mechanism · COX inhibition ·Pharmacology & indications · Mild to moderate pain · Musculoskeletal pain/inflammation · Headache/toothache · Post-operative ( need for opioid mgmt) 23 Cyclooxegenase (COX) An enzyme Synthesizes prostaglandins from arachidonic acid Mediates pain and inflammation Protects gastric mucosa Maintains renal perfusion, platelet aggregation COX 1 Maintains gastric mucosa integrity, renal parenchyma, platelets COX 2 At sites of injury, mediates pain and inflammation NSAIDS block the action of COX Reduces production of prostaglandin mediators Specifically prostaglandin E2 24 NSAID Therapeutic Profile Analgesia Peripheral inhibition of prostaglandin production Decrease activation of peripheral nociceptors in response to pain Anti-inflammatory Inhibition of COX Anti-pyretic Inhibition of Interleukin production of prostaglandins in hypothalamus Resetting thermoregulatory center, vasodilation, increased heat loss Synergistic effect with opioids Can decrease opioid use by 20-50% Less nausea and vomiting Absence of ventilatory depression 25 NSAID Adverse Effects Inhibit platelet aggregation COX-1 needed for synthesis of thromboxane A2 from prostaglandin Blocking COX-1 inhibits platelet aggregation Gastric ulceration Prostaglandins protect GI mucosa by maintaining mucosal blood flow, secreting mucus and bicarbonate Renal dysfunction Inhibiting prostaglandin synthesis leads to renal medullary ischemia Prostaglandins autoregulate renal blood flow Hepatocellular injury Increased levels of transaminases Allergic reaction Asthma NSAIDS can trigger bronchospasm in asthmatics Arachidonic acid makes bronchoconstrictors since shunted from making prostaglandin Tinnitus Myocardial Infarction Reflects COX-2 suppression of prostaglandin I2 which is vasoprotective 26 NSAID Classes Non-specific COX inhibitors Ibuprofen, naproxen, aspirin, acetaminophen, ketorolac COX-1 inhibition is responsible for many of the adverse side effects COX-2 selective inhibitors Celecoxib Better side effect profile 27  Non-selective COX Inhibitors Salicylates (Aspirin) COOH Analgesic O-CO-CH 3 Acetylsalicylic Acid For low intensity pain Small effective dose range Doses too high give toxic effects Antipyretic Anti-inflammatory IRREVERSIBLY acetylates (inactivates ) COX enzyme Prevents prostaglandin synthesis Rapidly absorbed from small intestine Metabolized in liver to salicylic acid Side effects GI upset, dyspepsia, bleeding, tinnitus, allergic reaction 28 Non-selective COX Inhibitors  Ibuprofen, naproxen  Propionic acid derivative  Analgesic, antipyretic, anti-inflammatory  Due to inhibition of prostaglandin synthesis  < GI irritation, dyspepsia, etc. than aspirin  Renal toxicity in pts with preexisting disease  Naproxen  Long elimination half life allows for BID dosing 29  Non-selective COX  Inhibitors Acetaminophen  Analgesic – antipyretic  Strong central inhibition of prostaglandin synthesis  Does not interact with platelets  No GI irritation  Converted by conjugation in liver to inactive metabolites  High doses of acetaminophen  Metabolized to N-acetyl-p-benzoquinone (HEPATOTOXIC)  Hepatic glutathione stores depleted  Glutathione can’t scavenge the metabolite and toxicity ensues  Treatment with N-acetylcysteine  Antioxidant  Replacement for glutathione  Acts as scavenger 30 Ketorolac Potent analgesic effects Moderate anti-inflammatory effects Potentiates actions of opioids Ketorolac 30 mg IM equals 10 mg Morphine Absence of ventilatory and cardiac depression Max plasma concentration 45-60 min Elimination half time 5 hours Hepatic metabolism Side effects Inhibits platelet aggregation Bronchospasm in ASA sensitive pts GI irritation Renal toxicity In setting of prerenal state 31 Selective COX-2 Inhibitors  Celecoxib  Analgesic, anti-inflammatory  Especially arthritis  Post-operative pain  Well absorbed from GI tract  Low first pass hepatic extraction  Crosses BBB  Highly lipophilic  Metabolized by CYP450  Lacks inhibition of platelet aggregation  Decreased GI side effects 32  Opioids Opioids act (primarily) in the CNS through opioid receptors Highly effective pain medications that suppress synaptic transmission and neuronal activity However, tolerance develops rapidly and can lead to addiction In some individuals, opioid induced hyperalgesia can occur rnessing the descending pain modulation pathw Pain Reprocessing Pain preprocessing therapy Therapy (PRT) is an emerging psychophysical therapy to address chronic pain In some individuals, these behavioral therapies can produce potent, and lasting reduction in pain perception and brain activity patterns Additional research is ongoing  High Yield Summary Nociception is the neural process of encoding noxious stimuli Pain is a personal perception influenced by biological, psychological, and social determinants - neuropathic pain is pain in response to a specific disease/injury Physiological or acute pain indicates a caution to avoid a harmful stimulus at an injury site while chronic pain is long lasting pain in the absence of harmful or presence of an innocuous stimulus Peripheral sensitization causes enhanced painful responses (hyperalgesia or allodynia) possibly as an adaptive self-preservation mechanism Central sensitization can cause secondary hyperalgesia and can transition to chronic pain Referred pain is pain from one region (usually an organ) that is perceived elsewhere on the body Pain pathways include the spinothalamic tract (sensory discrimination qualities of pain) and the spino-parabrachial pathway (emotive cognition qualities of pain) The spino-parabrachial pathway involves spinal cord second order neurons crossing at the level of origin, and ascending to terminate the parabrachial nucleus of the brainstem, third order parabrachial neurons target limbic regions (e.g., amygdala/hypothalamus) The spino-thalamic pathway involves spinal cord second order neurons crossing at the level of origin, and ascending to the thalamus, from third order neurons target cortical sensory areas Multiple descending pathways can modulate the ascending pain pathway (at brainstem and/or spinal) Pain management options include NSAIDs, opioids, and possibly behavioral preprocessing therapy