Pharmacology: Multimodal Pain PDF

Pharmacology: Multimodal Pain (Lecture 1 for Pharmacology; Lecture 1 Overall) [2.5 hour lecture] Multimodal therapy The optimal strategy includes opioids BUT with a focused approach to minimize the need for opioids through other modalities (this is the multimodal approach) Starts w...

Pharmacology: Multimodal Pain (Lecture 1 for Pharmacology; Lecture 1 Overall) [2.5 hour lecture] Multimodal therapy The optimal strategy includes opioids BUT with a focused approach to minimize the need for opioids through other modalities (this is the multimodal approach) Starts with assessing the patient (background is persistent, breakthrough rises above background, and intermittent/transitory comes and goes) Mechanism: various receptors, centrally versus peripherally, ascending and descending, acute, chronic What is the exception for targeting the perception of pain? Regional anesthesia Medications that inhibit the ascending pain pathway ○ Acetaminophen, NSAIDs, lidocaine, capsaicin, menthol, opioids, cannabinoids, ketamine Medications that facilitate the descending pain modulation ○ Antiepileptics (gabapentinoids, Na+ channel agents), antidepressants (TCAs, SNRIs), cannabinoids, ketamine Which two agents work on the ascending and descending pathways? Cannabinoids + ketamine Overarching goal: inhibit the ascending, promote the descending Preventive preoperative analgesia ○ Foundational to multimodal regimen but can be controversial ○ Attempt to block pain transmission before the injury (incision) AND after the injury throughout recovery; GOAL = prevent pain before it happens and is sustained ○ 3 principles = (1) good depth (2) good analgesic coverage (3) good timeframe coverage ○ Want to reduce central sensitization, hyperalgesia and allodynia Pain (review overview) Types of pain ○ Acute pain Poorly treated acute pain = catabolic effect = poor wound healing Normal, predicted response to chemical, thermal mechanical stimulus Time frame: generally resolves within 1 month ○ Chronic pain Pain without apparent biologic value that has persisted beyond normal tissue healing time Time frame: generally considered to be greater than 3 months ○ Nociceptive pain Activation of a-delta (myelinated) and c fibers (unmyelinated) through noxious stimuli Stimuli can be mechanical, chemical or thermal See opioids, NSAIDs, acetaminophen, regional ○ Neuropathic pain Abnormal pain processing due to lesions and damage to CNS, PNS, or both See gabapentinoids, NMDA antagonists, alpha-2 agonists, nerve stimulation ○ Inflammatory See injury, release of PLA2, forms arachidonic acid, 2 pathway cascade Cyclooxygenase (COX) → see prostaglandin, prostacyclin, thromboxane release Lipoxygenase → see leukotrienes See NSAIDs, tylenol, toradol, ibuprofen, celebrex ○ Idiopathic  Seen with chronic pain states No identifiable cause and difficult to treat Somatosensory pain pathway Involves transduction → transmission → modulation → perception → interpretation → behavior Transduction: noxious stimuli transduced into an AP Transmission: signal transmitted from periphery to CNS (via dorsal horn of SC) Perception: signal recognized by brain (cortex to limbic system for emotion and reticular formation for arousal) Modulation: to promote or suppress nociceptive transmission, the bringing down of the signal ○ SO pain can be further amplified (bad) or inhibited what we want Serotonin, NE and endorphins/enkaphelins (endogenous opioids), GABA are the main ones in modulation ○ Order of modulation: cortical neuron —> PAG —> NRM —> 2nd order sensory neurons ○ Cortical neurons project down from the cerebral cortex down the spinal cord, See the locus coeruleus and decreased release NE throughout brain Project down to the midbrain/pons and stimulate the PAG PAG releases enkaphelins (reduces pain response) Project down to the medulla, and stimulate the raphe nuclei (NRM) Nucleus raphae nucleus releases serotonin at dorsal horn ○ Then travel down to the second order sensory neuron and release more inhibitory chemical modulators (which in all reduce pain) ○ Transmission of painful stimulus is inhibited ○ Supraspinal: mu1 = kappa > delta ○ Spinal cord: mu1 = kappa = delta (all in equal quantity) Hyperalgesia allodynia Hyperalgesia: heightened response to a painful stimulus; “exaggerated response to pain” Allodynia: normally non painful stimulus is perceived as painful Plays an IMPORTANT role in the conversion of acute pain to chronic pain Acute pain to chronic pain = repeated stimulation of C-fibers and mechanoreceptors ○ See windup (hyperalgesia and allodynia) + central sensitization + secondary hyperalgesia Peripheral sensitization: process where inflammation triggers afferents that become hyperresponsive to pain ○ Tissue injury → "Inflammatory Soup": Substance P, CGRP, histamine, 5-HT, NE, prostaglandins, H+ ions. Some molecules released by the nociceptor Central sensitization: persistent post-injury changes in the CNS that result in pain hypersensitivity ○ Seen with chronic pain states, repeated firing of Type C fibers in the dorsal horn, see inflammation, hyperalgesia + allodynia Opioids Known as the ** gold standard ** Work on GPCRs (7 transmembrane layers): mu, delta, kappa, OPRL1 ○ Work all throughout the peripheral and central nervous system ○ Convert extracellular signals to intracellular responses by 2nd messenger systems (cAMP, inositol 1,4,5 triphosphate) ○ OPRM1 gene encodes the mu receptor Primary receptor for endorphins and enkephalins Mu receptors are located peripherally and centrally  Peripherally: on afferent sensory nerve fibers (GIT, heart, lungs, mouth, kidneys, joints) Centrally: in the dorsal horn, specifically the substantia gelatinosa and PAG Opioids can bind presynaptically and postsynaptically to mu receptors Presynaptic: reduce Ca2+ (calcium) influx → decreased release of substance P and glutamate Postsynaptic: increase K+ (potassium) efflux → see hyperpolarization → inhibition of excitatory NTs ○ Common side effects: sedation, pruritus, respiratory depression, vomiting, nausea, constipation, dizziness, urinary retention, dry mouth, can see opioid-induced constipation and pneuomonia brought on by hypoventilation/atelectasis, can also see ileus ○ What patient populations COME with careful monitoring with administration due to side effects? COME = children, OSA, morbidly obese, elderly ○ There is a difference between CSA and OSA CSA: brain doesn’t send proper signals to the muscles that control breathing OSA: upper airway gets blocked, oftentimes by the tongue falling back BOTH have hypercapnia and hypoxia MUST combat both by 3 methods: continuous pulse ox + multi-modal pharmacotherapy + regional anesthesia ○ Opioid-induced hyperalgesia Paradoxical and fast increase in sensitivity to pain even with opioid use Mainly seen with phenanthrenes, such as morphine Combatted with NMDA antagonists, such as ketamine ○ Phenanthrene (prototypic) derivatives [full mu-receptor agonists]: morphine, hydromorphone, oxymorphone Morphine (MSO4): gold standard prototype Mu agonist Short onset (5 min), peak effect (20 min). long acting (4-5 hours) For acute AND chronic pain VERY hydrophilic (does not cross BBB) Can see delayed respiratory depression when given intrathecally ot epidurally due to slow rostral CSF spread Has an active metabolite (MG6) = N/V, respiratory depression, coma, sedation, prolonged effect in renal patients and (MG3) which we see delirium, agitation, hyperalgesia See histamine release The MOST common side effect is pruritus due to histamine release Hydromorphone: semi-synthetic Mu agonist 5x more potent than morphine (common concentration = 2 mg/ml) Short onset (15-30 min), peak effect (30 min), long acting (4-5 hours) Start slow (1mg) and do NOT stack the doses Side effects: N/V, sedation, cognitive impairment Has an inactive metabolite (H3G) via liver conjugation Pruritus and histamine release is less than morphine Use is safe in renal patients ○ Phenylpiperidine derivatives [synthetic opioids]: alfentanil, fentanyl, sufentanil, remifentanil Fentanyl: Mu agonist 100x more potent than morphine (common concentration = 50 mcg/mL)  Rapid onset (2 min) Highly lipophilic (crosses the BBB) (rapid onset, brisk peak, shooter DOA) Many forms: oral lollipop, nasal, SQ, IV, IM, patch, neuraxial Metabolism via the liver and excreted via the kidneys Has inactive metabolites (good for renal), no histamine release ○ Active metabolites = bad for renal ○ Inactive or no metabolites = ok and good for renal Sufentanil Mu agonist Derivative of fentanyl (common concentration 50 mcg/mL) Infusion = 0.25-0.5 mcg/kg/hr Mix with 8 mL of NS for 10 mcg/mL syringe 5 mcg bolus of sufentanil = 50 mcg of fentanyl (remember its 10x more potent) 1000x potency of morphine and 10x fentanyl Rapid onset (2 min), DOA (2-3 hrs) Metabolism via the liver and excreted via the kidneys “Sufenta smooth” = known for beautiful wakeups Less chest wall rigidity, HD instability, respiratory depression than fentanyl and alfentanil ○ Tramadol Centrally acting, mu agonist AND NE and serotonin reuptake inhibitor (oral) How is nucynta different? It only inhibits reuptake of NE (still good for postop pain relief) Extreme caution with MAOIs and SSIs due to risk of serotonin syndrome ○ Methadone Mu agonist AND NMDA antagonist (not an opioid) Antagonist of glutamate Good for neuropathic pain Onset (30 min-1hr for PO, 10 min for IV), half life is super long (8-59 hours) Long DOA, long coverage can be beneficial Effective for 24 hours No active metabolites so good for renal See pause-dependent dysrhythmia Rare side effect with bradycardia + QT prolongation + Torsades Avoid QTc interval 450+ msec ○ Buprenorphine Lipophilic, opioid partial mu agonist Also a kappa antagonist AND ORL1 agonist Safer alternative to opioids, less abuse potential Great for opioid dependence and opioid use disorder and opioid withdrawal Good for neuropathic pain, secondary hyperalgesia, mild cancer pain ○ MAT = medications for opioid addiction Buprenorphine + naltrexone + methadone ○ Perineural analgesia (small catheter, for brachial and lumbar plexus, up to 40 hours of analgesia) Buprenorphine + LA + clonidine + decadron NSAIDs (non-steroidal anti-inflammatory)  The MOST common analgesic adjunct See decreased dose of opioids and thus side effects (PONV, sedation, respiratory depression) Have 3 main effects = analgesia + anti-inflammatory + antipyretic Main use: mild to moderate postoperative pain and inflammation The inflammatory pathway ○ Cell injury → PLA2 forms arachodnic acid ○ Produces 2 pathways = Leukotrienes + Cyclooxygenase (COX-1 and COX-2) Leukotrienes remember we see bronchoconstriction (caution in asthmatics/COPDers) COX 1: widespread throughout the body, good for homeostasis, PLT aggregation, gastric mucosal integrity, renal function When blocked: see GI ulcers, PLT dysfunction, nephrotoxicity COX-2: inducible enzyme, in the presence of inflammation, see prostaglandin release Prostaglandins amplify substance P, bradykinin, serotonin and glutamate ○ Contribute to hyperalgesia ○ Inhibit the release of descending inhibitory neurotransmitters NSAIDs works by inhibiting prostaglandins ○ Celecoxib (Celebrex) The ONLY selective COX-2 inhibitor Used preoperatively 400 mg oral load, 200 mg Q12 DO NOT give with CAD or CVD or allergy to sulfonamides Careful with asthmatics (unopposed leukotrienes) Do NOT give with Samter’s triad Samter’s triad = asthma + aspirin allergy + nasal polyps Affects bone healing (does not promote osteoblast and clast functioning), but has orthopedic use (weird) Does NOT inhibit PLT aggregation, it is without risk of bleeding BLACK BOX WARNING for CAD (so careful with HTN, stroke, heart disease; because NSAIDs cause an increased risk in CV thrombotic events including MI and stroke) ○ Toradol Non-selective NSAID Used postoperatively Usual dose is IV 15-30 mg (at the end of the case) More potent than morphine (15x IM) Reduces opioid consumption by 25-40% MUST decrease the dose for renal patients and elderly 65+ to 15 mg (this is really only seen if given for more than 5 days) See a ceiling dose with this medication at 10 mg 10 mg = 15 mg = 30 mg - similar rates of relief Contraindications = coagulopathies, renal failure, PUD, GIB, asthma, hypersensitivity to NSAIDs, surgery with high-risk bleeding Controversy with bone healing Affects the renal system (associated with serious kidney damage) = linear relationship with NSAID use and post-op AKI Risk factors: elderly, dehydrated, diabetic, pre-existing kidney/liver impairment, concurrent medications that affect the kidneys The factors for AKI: diuretic use, ARB/ACEI, NSAIDs linear dose/injury relationship  There is a higher incidence with a specific patient population, which is the THA (total hip arthroplasty) population Recommendations: hydration, blood management, late day NPO monitored carefully, watch large blood loss, closely monitor kidney function, diabetes was associated with increased risk of AKI ○ Acetaminophen Centrally-acting Analgesic, antipyretic, anti-inflammatory (minimal) See reduced prostaglandin synthesis IV IS effective in treating moderate and severe with adjuncts Saw no big difference between oral and IV acetaminophen However, IV is more rapid (5 min), faster time to peak (15 min) versus rectal and oral (onset being up to an hour) PO: 500-1000 mg Q4-6 hours, max = 3000 mg IV: 1g/100 mL, given over 15 min Best effect is when combined with another NSAID Celecbrex is more potent than acetaminophen??? (2 g acetaminophen = 200 mg Celebrex) Contraindicated in liver failure ○ ALL others (vioxx, bextra) have been recalled Preoperative: give celebrex (watch heart) Postoperative: give toradol (watch kidney) Postoperative: give acetaminophen (watch liver) NMDA antagonists The NMDA receptor ○ Has 4 subunits ○ Agonist binding sites: glutamate + glycine (required for opening) In other words, has glycine and glutamate binding sites (at the top) ○ Magnesium within the receptor channel (required for closing; it’s a blocker) (in the center) ○ Sodium (Na+) and calcium (Ca2+) move into the cell ○ Potassium (K+) moves out of the cell ○ Present in high density in the brain: hippocampus + cerebral cortex ○ When NMDA is excited/stimulated: see persistent postoperative pain, hypersensitivity, wind-up, allodynia, OIH, chronic pain → the entire goal is to BLOCK THIS ○ When NMDA is inhibited: see pain relief Ketamine: NMDA antagonist/inhibitor (non-competitive) Works on several receptors: mu opioid receptors, monoaminergic receptors, cholinergic receptors, GABA receptors (to block sodium channels) = COMPLEX See analgesia, anesthesia, antidepressant, anti-inflammatory, central sensitization, chronic pain relief Higher dose = psychotomimetic adverse effects, dissociative state = 20+ min Side effects: pain attacks, aggression, hallucinations, crying, increased ICP, dissociative state in PACU, nystagmus (eye surgery?) Vital sign side effects: increased HR, BP, ICP, cardiac arrest, bronchodilation Increased salivation (may need an antisalogue like scopolamine) Ketamine (methods, DOA, considerations, dosing)  Method: IV (30-40 seconds), IM (3-4 min), epidural, spinal, intranasal, SL, rectally DOA: dose dependent (5-10 min IV; 10-25 min) Metabolism: liver Excretion: kidneys What to give pre-incision? 0.25 – 0.5 mg/kg (for example, 70 kg patient = 20 mg) Low dose ketamine is amazing, reduces opioid consumption, minimal side effect ○ What is considered low-dose? 1 mg/kg or 1.2 mg/kg/hr or less Used in a 1:1 ratio with propofol (1 mg ketamine for every 1 mL propofol) ○ Propofol = 200 mg/20 cc; therefore, give 20 mg ketamine ○ MUST watch your concentrations with ketamine and propofol Dextromethorphan (non-competitive) D-isomer of codeine synthetic analog MOA: inhibits secondary hyperalgesia and reduces temporal summation of pain Used as a cough suppressant (antitussive) Side effects: TACHYCARDIA and HYPOTENSION VERY bad side effect of serotonin syndrome when used with MAOIs Magnesium NO direct analgesic effect ○ How? Blunts autonomic, somatic, endocrine reflexes to noxious stimuli Acts like an NMDA antagonist Inhibits calcium influx, blocks NMDA receptors Plays a role in central sensitization and hypersensitivity ○ Also good for neuropathic pain, malignancy-related, postherpetic neuralgia, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, migraines IV magnesium reduces pain score in first 24 hours Opioid-sparing and may be useful in opioid-tolerant patient population (or where there are concerns related to opioid use) Side effects are minimal Bolus: 30-50 mg/kg (40 mg.kg “magnesium has 4 syllables”) Infusion: 10 mg/kg/hr Alpha-2 agonists Work in the locus coeruleus ○ See decreased NE, decreased noradrenergic neuron activity ○ See increased downstream activity of GABA ○ Increased ACh levels via the release of NE from the descending noradrenergic pathway Alpha-7 (Ach receptor) in the VL-PAG provides a prolonged analgesic effect when stimulated ○ Intrinsic blockade of a-delta and C fibers Alpha-2 receptors are located through the CNS (presynaptic, superficial laminae of the SC, many brainstem nuclei) seen in analgesia Provide analgesia, sedation, anxiolysis, antishivering  Are substance-P inhibitors, see decreased NE release at the presynaptic peripheral site (75% reduced NE) Precedex = 8x more selective for a-2 receptor than clonidine , highly selective a-2 agonist ○ 1620:1 = a2:a1; cardioprotective, neuroprotective and renal-protective against injury ○ MUST watch for hypotension so go slow (this is predictable) ○ See a decrease in pediatric emergence delirium with this agent ○ **NO effect on GI motility, prevents PONV, and shivering ○ 4 mcg/mL ○ Bolus dose 0.5-1 mcg/kg then maintenance of 0.2-1 mcg/kg/hr ○ Does NOT decrease respirations ○ Advantages: analgesic, sedative, anxiolytic and sympatholytic properties, good for sleep as well Clonidine = centrally acting, partial a-2 agonist, most potent in neuraxial space ○ 220:1 = a2:a1 ○ Prolongs peripheral and neuraxial blocks ○ SE: sedation, hypotension, bradycardia if dose is 150 mcg+ ○ Dose = 5 mcg/kg Gabapentinoids Bind to Alpha-2 delta subunit of voltage-gated calcium channels Decreased influx of Ca2+, reduce the release of excitatory glutamate, reduce neuropathic pain Works on glutamate, inhibits glutamate Main options: pregabalin (lyrica) and gabapentin (neurontin) Used for neuropathic pain (1st line treatment) and chronic pain Used as an antiepileptic (partial-onset) Also see decrease in PONV, delirium, pruritus, urinary retention Glucocorticoids Have 3+ properties = anti-inflammatory + antiemetic + analgesia + immunosuppressant Inhibit leukotriene and prostaglandin production by inhibiting CP A2 Do NOT give IV push because side effect is perineal itching (50-70% incidence) Main option ○ Decadron (dexamethasone) Inhibit leukotriene and prostaglandin production by inhibiting CP A2 Great for inflammation (edema), and pain caused by inflammation Airway edema (4-12 mg) Allergic rx (4-8 mg); Great as an antiemetic (PONV) PONV (4-8mg) Is an immunosuppressant MUST use caution in cancer patients because is an immunosuppressant Risks include hyperglycemia, immunocompromised and poor wound healing Beta antagonists There are limitations specifically here (need larger clinical trials) Selective Beta-1 antagonists (beta blocker) Main 2 options: Esmolol, metoprolol ○ Esmolol Brisk onset, 9 minute DOA Side effect: bradycardia; therefore, contraindication: AV block + bradycardia  Give a small dose and see how patient’s HR adjusts Possible possible benefits: reduce postoperative pain, opioid consumptions, PONV HOWEVER, again, need large clinical trials ○ Metoprolol Brisk onset, 5 minutes, 5-8 hour DOA Dose: 1-5 mg for tachycardia (titrate); start with 1 mg then redose in 5 minutes Predictable and drug of choice for rate control Side effect: bradycardia; therefore, contraindication: AV block + bradycardia + SSS + severe LV dysfunction Remember, beta blockers can mask hypoglycemia (by causing hyperglycemia) Antidepressants Per the graph, adults over 60 years have the highest usage of antidepressants Antidepressants can be used for pain, even when a patient isn’t suffering from depression ○ For arthritis, diabetic neuropathy, postherpetic neuralgia, nerve pain, tension HA, migraine, facial pain, fibromyalgia, low back pain, pelvic pain, pain due to MS The MOST common antidepressant used for pain are TCAs (tricyclic antidepressants) ○ Options: amitriptyline, nortriptyline, protriptyline, doxepin, imipramine, clomipramine, desipramine Other antidepressants: SNRIs and SSRIs ○ SNRIs: (for chronic pain) venlafaxine (effexor), duloxetine (cymbalta, drizalma), savella, pristiq ○ SSRIs: (lack of evidence for nerve pain) paroxetine and fluoxetine How to remember? The main 2 types are PF (paroxetine and fluoxetine) Local anesthetics (regional anesthetics) Inhibit action potentials along a nerve fiber by blocking sodium channels ○ Also see inhibitory actions on voltage-gated calcium channels, GPCRs, potassium channels, NMDA receptors and glycinergic system Block sodium channels in BOTH afferent and efferent neuronal membranes to inhibit pain transmission Often the sole anesthetic (used in diagnosis, management and treatment) Several forms: infiltration in operative area, peripheral nerve blocks, epidural, SAB (spinal), caudal, intraarticular, intrapleural, trigger injections, upper and lower extremity, abdominal and thoracic blocks, liposomal form (EXPAREL) Also see topical anesthesia with lidocaine via laryngeal tracheal anesthesia (LTA) ○ Depth is at the level of the vocal cords ○ Uses 4mL of 4% lidocaine instilled as a spray ○ Works very well for preventing coughing and blunting the SNS stimulation from intubation Can be used via IV infusion for pain, when regional anesthesia is not possible ○ When given via IV = analgesic, antihyperalgesic, anti-inflammatory Studies show it works best with colon or big abdominal surgeries MUST consider LAST (local anesthetic systemic toxicity) with IV lidocaine administration ○ LAST = CV and CNS toxicity symptoms ○ Avoid in arrhythmia, heart failure, CAD, heart block Desired dosings and levels ○ Bolus dose = 2 mg/kg, infusion = 2 mg/kg/hr ○ Desired serum concentration = 1-5 mcg/mL ○ MAX = 4 mg/kg ○ MAX with EPI = 7 mg/kg Peripheral and neuraxial blocks (regional anesthesia) May provide more superior pain control than systemic opioids with less side effects Always have a plan B, because ○ (1) block may not have enough time to set-up ○ (2) black may fail (skill, anatomy) ○ (3) surgery may extend beyond the duration of the block Brachial plexus blocks: SIIA: supraclavicular, infraclavicular, interscalene, axillary Lower extremity blocks: LAACSS: lateral femoral cutaneous, adductor canal, ankle, sciatic (popliteal; lateral) Continuous nerve blockade Neuraxial and other regional techniques are useful for sustained post-procedural analgesia Patient-controlled anesthesia (PCAs) When compared to intermittent IV opioid injections, PCAs are advantageous: ○ Provide better analgesia with more safety, less total drug use, fewer sleep disturbances, more rapid return to physical activity, more patient acceptance due to autonomy, dose tapering with recovery Topical analgesics Great locally with minimal systemic absorption for acute and chronic pain Options: counterirritants, topical NSAIDs, capsaicin, lidocaine, clonidine, opioids ○ Counterirritants: produce irritation of sensory nerve endings ○ Topical NSAIDs: inhibit cyclo-oxygenase and prostaglandins ○ Capsaicin: activates TRPV1 channels and deplete substance P release ○ Lidocaine: inhibit voltage-gated sodium channels in sensory neurons (locals) ○ Clonidine: alpha-2 adrenergic agonist ○ Opioids: activate opioid receptors in peripheral nerve terminals Used for osteoarthritis: capsaicin, topical NSAIDs Used for post-herpetic neuralgia and peripheral neuropathy: capsaicin, lidocaine, clonidine Pillars, pearls, and final thoughts Opioid avoidance in acute pain conditions is ill-advised; it is NOT patient-centered nor evidence-based Gabapentinoids have a complex risk/benefit ratio and require nuanced decision-making Throughout acute pain episodes, methadone and buprenorphine should be continued Throughout acute pain episodes, naltrexone should be discontinued Combination of analgesics = lower doses of any one drug = less incidence of unpleasant side effects