Centrally and Peripherally Acting Non-Opioid Analgesics

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Questions and Answers

What is a benefit of using centrally acting non-opioid analgesics?

Increased risk of respiratory depression

Increased risk of abuse

Reduced risk of physical dependence (correct)

Increased risk of neurotoxic effects

What is a result of chronic opioid use?

Increased release of analgesic mediators

Release of proinflammatory cytokines and chemokines (correct)

Decreased release of inflammatory mediators

Release of anti-inflammatory cytokines

What is a mechanism of action of αlpha2 Adrenergic Agonists?

Inhibit pain in ventral horns

Stimulate norepinephrine release

Inhibit α2 adrenergic receptors on sympathetic pre-ganglionic neurons

Activate α2 adrenergic receptors on sympathetic pre-ganglionic neurons to inhibit NE released (correct)

What is an effect of neuraxial clonidine? (select 2)

Inhibits nociceptive impulses at post-junctional α2 receptors in the dorsal horn Signup and view all the answers

What is a characteristic of clonidine?

A selective partial α2 receptor agonist Signup and view all the answers

What is the mechanism of action of ketamine in the dorsal horn?

Non-competitive antagonism of NMDA receptors Signup and view all the answers

What is the primary mechanism of action of midazolam in the spinal cord?

Stimulation of GABA receptors by increasing the affinity for GABA to the GABA-A Signup and view all the answers

What is the primary effect of ziconotide (snail poison) on the spinal cord?

Blockade of voltage-gated calcium channels to inhibit NE Signup and view all the answers

What is the primary mechanism of action of baclofen in the spinal cord?

Agonism of GABA-B receptors Signup and view all the answers

What is the primary effect of dexmedetomidine on the spinal cord?

Stimulation of alpha-2 receptors Signup and view all the answers

What is the primary effect of tramadol?

Inhibition of serotonin and norepinephrine uptake Signup and view all the answers

What is the primary effect of ketorolac on the spinal cord?

Inhibition of cyclo-oxygenase 1 and 2 Signup and view all the answers

Which of the following neuraxial analgesics is contraindicated in obstetric patients?

Clonidine Signup and view all the answers

What are common side effects of neuraxial a2 agonists?

Hypotension and Bradycardia Signup and view all the answers

What is the mechanism of action for baclofen?

GABA-B agonist Signup and view all the answers

What is the effect of COX1 inhibition on platelet function?

Decreased thromboxane A2 production - increased risk of bleeding Signup and view all the answers

What is the site of action for peripherally acting analgesics?

Damaged tissues Signup and view all the answers

What is the function of COX1 in the GI tract?

Mucosal protection Signup and view all the answers

What is the consequence of hypoalbuminemia on NSAID pharmacokinetics?

Decreased bound fraction of NSAID - leading to more free drug to exert effects Signup and view all the answers

What is the primary site of NSAID metabolism?

Liver Signup and view all the answers

What is the effect of COX2 selective inhibitors on platelet aggregation?

No effect on platelet aggregation Signup and view all the answers

What is the effect of high doses of NSAIDs on the risk of ulcers, perforation, and bleeding?

It increases the risk Signup and view all the answers

What is the effect of NSAIDs on the excretion of sodium?

NSAIDs decrease the excretion of sodium Signup and view all the answers

What is the effect of COX1 inhibition on the production of prostaglandins?

COX1 inhibition decreases the production of prostaglandins Signup and view all the answers

What is the mechanism by which NSAIDs increase the risk of anaphylaxis?

By inhibiting the production of prostaglandins Signup and view all the answers

Which of the following patients is at a higher risk of developing bronchoconstriction when taking NSAIDs?

A patient with a history of asthma Signup and view all the answers

What is the mechanism by which aspirin prevents the production of prostaglandins?

By inhibiting the action of COX enzymes Signup and view all the answers

What is the effect of NSAIDs on the platelet aggregation?

It decreases platelet aggregation Signup and view all the answers

What is the leading cause of acute liver failure in the US?

Acetaminophen overdose Signup and view all the answers

Which COX enzyme is associated with renal function, gastric mucosal protection, and platelet function?

COX-1 Signup and view all the answers

Which enzyme is associated with pain, inflammation, and fever mediation?

COX2 Signup and view all the answers

What is COX in relation to arachidonic acid?

Cyclooxygenase, an enzyme that converts arachidonic acid to pro-inflammatory prostaglandins Signup and view all the answers

What is the mechanism of action of NSAIDs on prostaglandin biosynthesis?

By blocking the biosynthesis of prostaglandins from arachidonic acid by binding to the COX enzyme active site Signup and view all the answers

Moderate to severe liver and renal disease impair NSAID metabolism and elimination

True Signup and view all the answers

What is a benefit of selective COX-2 inhibitors?

Less GI side effects Signup and view all the answers

What is the mechanism by which NSAIDs are associated with increased risk of cardiovascular events? (select 2)

Prostacyclin usually prevents platelet aggregation and vasoconstriction Signup and view all the answers

What is the least risky NSAID to administer to a patient with cardiovascular disease?

Naproxen Signup and view all the answers

How do NSAIDs affect GFR?

Reversible reduction of GFR Signup and view all the answers

COX-2 inhibitors inhibit the vasodilatory properties of _____

prostaglandins Signup and view all the answers

What are some complications of NSAID use?

All of the above Signup and view all the answers

What effect does acetaminophen have on neurotransmission at the spinal cord level?

Antagonizes neurotransmission by NMDA, substance P, and nitric oxide pathways Signup and view all the answers

What is true about the effect of aspirin on platelet aggregation?

Aspirin inactivation is irreversible for the life of the platelet and inhibits platelet aggregation. Signup and view all the answers

Aspirin overdose results in ____

Metabolic acidosis Signup and view all the answers

What is the mechanism of action of corticosteroids?

decreased production of a variety of inflammatory mediators amplifying and maintaining pain Signup and view all the answers

Which of the following steroids has the greatest anti-inflammatory potency? (select 2)

Dexamethasone (25) Signup and view all the answers

Less potent corticosteroids (e.g. methylprenisolone, prednisone) tend to have shorter durations of action

True Signup and view all the answers

What are many of the untoward effects of steroids associated with?

Mineralocorticoid properties Signup and view all the answers

What is the primary corticosteroid against which the pharmacologic properties of various synthetic corticosteroids are judged?

Hydrocortisone Signup and view all the answers

What is the effect of mineralocorticoids on the body?

Water and electrolyte balance Signup and view all the answers

What is the primary function of glucocorticoids, such as cortisol (hydrocortisone)?

Regulating metabolism and immune response Signup and view all the answers

What is the primary function of mineralocorticoids, such as aldosterone, in the body?

Regulating electrolyte and fluid balance Signup and view all the answers

What do steroids do in relation to anesthesia?

Enhance analgesia, prolong regional anesthesia block duration, and reduce postoperative nausea and vomiting Signup and view all the answers

What is the mechanism of action of IV lidocaine, oral mexiletine, and tocainide?

They block voltage-gated sodium channels within the spinal cord or dorsal root ganglia Signup and view all the answers

What is the mechanism of action of capsaicin?

Activation of TRPV1 receptors to cause continued release of substance P and C fiber stimulation (like a depolarizing NMB) Signup and view all the answers

Ketamine can be used as a local anesthetic due to its ____ channel blocking ability

Sodium Signup and view all the answers

What is the mechanism by which opioids injected locally produce potent analgesic effects?

By acting on peripheral opioid receptors Signup and view all the answers

Where do peripheral analgesics primarily act to block transmission of pain impulses to higher cortical structures?

Sensory level Signup and view all the answers

Study Notes

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.

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Description

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.