Centrally and Peripherally Acting Non-Opioid Analgesics

Centrally Acting Non-opioid Analgesics

• Widespread dependence, misuse, and abuse of opioids have driven the exploration of alternative analgesia modalities
• Opioids have limited efficacy for managing non-cancer chronic pain
• Non-narcotic medications relieve pain by mechanisms unrelated to opioid receptors, and do not cause respiratory depression, physical dependence, or abuse

Neuroaxial Use of Centrally Acting Non-Opioid Analgesics

• Higher CSF concentrations are achieved by bypassing the blood-brain barrier
• Agents act through different mechanisms than opioids
• May allow elimination or reduction in opioid use
• Caution: Neurotoxic effects of some compounds are unknown

α2 Adrenergic Agonists

• Clonidine and Dexmedetomidine are examples
• Mechanism of Action:
  • Activate α2 adrenergic receptors on sympathetic pre-ganglionic neurons, reducing norepinephrine release
  • Stimulation of α2 adrenergic receptors decreases norepinephrine in the brain, causing decreased wakefulness, decreased blood pressure in smooth vessels, and inhibition of pain in the dorsal horn
  • Result: leading to analgesia, hypotension, bradycardia, and sedation

Neuraxial Clonidine

• Clonidine is a selective partial α2 receptor agonist
• Inhibits nociceptive impulses at post-junctional α2 receptors in the dorsal horn
• Prolongs local anesthetic analgesia and reduces postoperative opioid requirements
• Prolongs sensory and motor block of local anesthetics
• Acts synergistically with neuraxial opioids
• Black box warning in obstetric patients
• Anti-hyperalgesic properties

Dexmedetomidine

• Selective α2 receptor agonist
• Higher receptor affinity and selectivity for α2 receptors than clonidine
• Fewer hemodynamic systemic effects
• Intrathecal dose: 3 ug
• No neurotoxicity reported for intrathecal or epidural administration
• Major side effects: bradycardia and hypotension

Epidural Dexmedetomidine

• Prolongs neuraxial sensory and motor blockade
• Decreases intraoperative anesthetic requirements
• Improves postoperative analgesia
• Decreases heart rate and blood pressure in cesarean sections
• Black box warning for hypotension and bradycardia in cesarean sections

Neuraxial Neostigmine

• Neostigmine inhibits acetylcholinesterase, preventing the metabolism of acetylcholine
• Analgesic effects due to stimulation of muscarinic cholinergic receptors
• Prolongs analgesia with minimal side effects with intrathecal (10-100 ug) or epidural (100-200 ug) use
• High incidence of nausea (50-100%)
• Does not affect motor blockade

Ketamine

• Non-competitive antagonism of NMDA (glutamate) receptors in the dorsal horn
• Mechanism of Action:
  • Counts the release of glutamate, aspartate, and neurokinin
  • These neurotransmitters are linked to central sensitization, windup, and other elements of neuroplasticity
  • Ketamine counters these effects

Neuraxial Ketamine

• Intrathecal use is limited due to the risk of neurotoxicity
• Epidural dose: 10-30 mg produces excellent postoperative analgesia
• Synergist with opioids
• Use of preservative-free solutions is mandatory
• Side effects: headache, sedation, transient burning pain with injection, and hints at possibility of neurotoxicity

Neuraxial Midazolam

• Intrathecal midazolam increases the affinity of GABA for the GABAA receptor
• The transmembrane conductance of chloride results in hyperpolarization of the neuron, reducing action potential propagation
• High density of GABAA receptors in the dorsal horn of the spinal cord
• Intrathecal (1-2 mg) or epidural midazolam has an analgesic effect and may be beneficial for treating perioperative and chronic pain
• Epidural midazolam reduces postoperative nausea and vomiting

Tramadol

• Binds to mu receptors
• Inhibits serotonin and norepinephrine uptake

Droperidol

• Reduces postoperative nausea and vomiting
• Do not use this neuraxially

Conopeptides: Snail Poisons

• Ziconotide
  • Selectively blocks dorsal horn voltage-gated calcium channels
  • Inhibits norepinephrine release, decreasing mean and diastolic pressures
  • Approved for treatment of neuropathic pain
  • Has a narrow therapeutic window and provokes neuropsychiatric side effects
  • Side effects: dizziness, confusion, ataxia, abnormal gait, memory impairment, and suicidal ideation

Baclofen

• GABA-B receptor agonist, suppressing neuronal transmission in the cerebral cortex, basal ganglia, thalamus, cerebellum, and spinal cord
• Actions at laminae II & III:
  • Increase potassium conductance, resulting in hyperpolarization
  • Inhibit calcium conductance
  • Resulting in hyperpolarization and inhibition of glutamate and substance P release
• Intrathecal baclofen is effective in treating pain with multiple sclerosis, complex regional pain syndrome type I, and low back pain

Ketorolac

• Cyclo-oxygenase inhibitor
• COX1 and COX2 facilitate production of prostaglandins leading to hyperalgesia and allodynia after injury
• Intrathecal ketorolac appears to have little analgesia benefit

Magnesium Sulfate

• Acts on NMDA receptors by regulating calcium influx into cells
• Magnesium is the natural antagonist to calcium
• Has some analgesic effect when administered intrathecally or in the epidural space
• Animal studies have reported neurotoxicity, and human safety is not proven

COX Enzymes and NSAIDs

• COX1 is inhibited by aspirin and NSAIDs, while COX2 specific inhibitors have no effect on COX1.
• COX1 maintains normal renal function, provides mucosal protection of the GI tract, and produces thromboxane A2 following platelet activation.
• COX2 mediates pain, inflammation, and fever, and may also modulate nociception centrally.

NSAIDs Side Effects

• NSAIDs are associated with ulcers, perforation, and bleeding, particularly at high doses, in older adults, and with certain comorbidities.
• COX2 specific inhibitors carry less risk of GI side effects.
• NSAIDs are also associated with increased risk of adverse cardiovascular events due to an imbalance between COX2 mediated thromboxane production and antiaggregatory prostaglandin I2 production in endothelial cells.
• Risks may be substantially lower with naproxen.

Other NSAIDs Risks

• NSAIDs may decrease excretion of sodium, increase risk of interstitial nephritis, alter filtration rate and tubular transport, and induce reversible impairment of GFR.
• Risk factors for renal impairment include diabetes, hypertension, atherosclerosis, hypovolemia, salt depletion, and hypoalbuminemia.
• In the liver, aspirin/NSAID use is associated with a decreased risk of hepatocellular carcinoma and death due to chronic liver disease.

Peripheral Analgesics

• Peripheral analgesics have their site of action within damaged tissues, acting at the sensory level to block transmission of pain impulses to higher cortical structures.
• Activators of primary sensory neurons include prostanoids, bradykinin, adenosine triphosphate, histamine, serotonin, and others.
• Nociceptors have their cell bodies in the DRG and synapse with second-order neurons in the dorsal horn.

Anti-Inflammatory Drugs

• NSAIDs block the biosynthesis of prostaglandins from arachidonic acid by binding to the COX enzyme active site.
• COX1 and COX2 are both inhibited, with COX2 inhibition modulating nociception centrally.

Kinetics and Pharmacology of NSAIDs

• NSAIDs are rapidly absorbed from the GI tract, 90% bound to albumin, and metabolized in the liver and eliminated in urine and bile.
• Hypoalbuminemia increases the fraction of unbound drug and risk of adverse events.
• Impaired renal function prolongs NSAID half-life, and moderate to severe liver disease impairs NSAID metabolism, increasing the potential for toxicity.

Platelet Function and Pulmonary Effects

• Platelet COX1 catalyzes thromboxane A2 production.
• NSAIDs inhibit prostaglandin synthesis, increasing the risk of anaphylaxis, particularly in patients with allergic rhinitis, nasal polyposis, and/or history of asthma.

Hypersensitivity and Allergic Reactions

• NSAIDs can cause bronchoconstriction, rhinitis, urticaria, idiosyncratic adverse events, skin rash, photosensitivity, aseptic meningitis, tinnitus, and hearing loss.
• Drug-drug interactions can occur, including additive inhibition of platelet aggregation, decreased lithium clearance, decreased digoxin clearance, and displacement of phenytoin and valproic acid from their binding sites.

Acetaminophen

• Acetaminophen has antipyretic and analgesic effects, but little anti-inflammatory effects.
• Central analgesic effect is mediated through activation of descending serotonergic pathways.
• At the spinal cord level, acetaminophen antagonizes neurotransmission by NMDA, substance P, and nitric oxide pathways.
• IV formulation (Ofirmev) is currently available, but acetaminophen is the leading cause of acute liver failure in the U.S.

Aspirin

• Aspirin blocks the action of COX enzymes and prevents the production of prostaglandins.
• Aspirin inactivation is irreversible and inhibits platelet aggregation.

Explore alternative analgesia modalities to opioids for managing non-cancer chronic pain. Non-narcotic medications relieve pain without opioid receptors, reducing respiratory depression, physical dependence, and abuse.