pain Flashcards
chronic pain types
Inflammatory: arthritis, throbbing, pulsating
Neuropathic: diabetes, carpal tunnel; burning, tingling, shooting, electrical
Visceral: deep, squeezing
Fibromyalgia, Migraine, phantom (amputation), Psychogenic
peripheral receptors
Temperature Sensitive: TRP, TRPV (heat), TRPM (cold)
Acid sensitive: ASIC (acid sensing ion channel) – activated by H to conduct Na
Chemical irritant sensitive: histamine, bradykinin
vascular neuropathy
Hereditary or acquired by diabetes, chemical, infections, diet, trauma, carpal tunnel
Treatments: Na, Ca channel blockers; TRPV1 agonist
reflex upon painful stimuli
Pain originates at the skin travels afferent nerve to spinal cord, response travels back out efferent nerve
characterization of pain
temporal features:onset, duration, course, pattern
intensity: average, least, worst, current
location: focal, multifocal generalized, reffered, superficial, deep
quality: aching, throbbing, stabbing, burning, shooting
pain fibers
Aβ Fibers: non-noxious; very fast
Aδ Fibers: Pain, cold; myelinated = fast; take place in reflex arc of immediate response to pain
C-fibers: pain, temperature, touch, pressure, itch; unmyelinated = slow - Peptidergic: containes substance P (role in chronic pain and pain sensitiziation), Non-peptidergic
Blockade of Aδ Fibers and C-fibers are nociceptors
peripheral sensitization
Substance P Repeated stimuli (due to chronic pain and inflammation) reduces firing threshold = release prostaglandins and substance P => increased expression of pain receptors and expressing more pain fibers Compared to healthy people: allodynia = painful without stimulus; for example sunburns hurt without any touch Painful stimuli: hyperalgesia = increased sensitivity to pain and touching would be more painful than to any healthy person
pain circuitry - spinal
Central Sensitization: enhanced activation of glutamate system
- Substance P activates NK1 increasing phosphorylation of AMPA and NMDA = extra sensitive to glutmate = enhanced pain response
- BDNF activates TrkB to activate PKA and phosphorylation of NMDA receptors leading to increased expression and sensitivity of AMPA and NMDA = hypersensitivity to pain
pain circuitry - brain
Pain transmission travels in from dorsal horn up through ascending nerves through thalamus
Brain sends signals down descending nerves to come back out the dorsal horn
opiates
natural occurring narcotic opioids from the opium plant (morphine, codeine, thebaine, papaverine, noscapine)
opioids
all drugs acting on opiod receptors
- Heroin is an opioid
- Oxymorphone is an opioid
- Synthetic derivatives from morphine
structure acitivity relationships
3-position ester/ether = decreased potency (codeine)
6-position increases activity (hydroxyl or ketone)
14-position hydroxyl = increased potency (oxycodone)
N-allyl gives antagonist (naloxone or naltrexone)
metabolism of morphine/phenanthrenes
Morphine-3-(50-60%) and morphine-6-glucuronide (10%) are active
Excretion: glomerular filtration
opiod receptors
GPCR i/o: inhibition of cAMP production -Mu -Kappa -Delta -Nociceptin All FDA-approved drugs target mu receptors or kappa/delta receptors
Transduction for Opioid Receptor
Gi signal activates K+ leading to hyperpolarization that inhibits action potentials
Gi signal decreases cAMP production = decreased Ca = no release of neurotransmitter or pain signals
Mu opioid receptor
Beta-endorphins: POMC, anandamide, 5HT, DA
Therapeutic Targets: Hard to target in chronic pain due to tolerance, Can lead to sedation, and be an anti-tussive
Mu opioid receptor side effects
Mechanism of Action
Respiratory Depression: originates from mu receptors in brain stem
Constipation: mu receptors in GI tract = motility is stopped
Pruritus, Addiction, Urinary Retention
Nausea/Vomiting: receptors in chemoreceptor trigger zone in medulla
Miosis: oculomotor nerve (meperidine does not cause)
Opioids as anti-diarrheal? Could be safe and effective for opioids not crossing blood brain barrier, but not ideal for addictive properties
kappa opioid receptor
Dynorphins = natural ligand
Potential for use of treatment of addiction
Counterbalance mu opioid receptor effects
delta opioid receptor
Enkephalins = natural ligand
More dynamic expression upon chronic stimuli
opioid receptor trafficking
Opioid agonist binds to mu receptor
Decreased cAMP production
Phosphorylation of GPCR to desensitize
Increased affinity of GPCR to β-arrestin
Binding of β-arrestin = mu receptor internalized
Mu receptor internalized = temporarily reduces receptors on surface
Resensitization and recycling of receptors back to surface
Controls amount of receptors available to stimulate and prevents tolerance
opioid tolerance
Morphine (not endogenous peptide) binds to mu receptor
Decreased cAMP production
Activation doesn’t lead to desensitization and phosphorylation of receptor
Morphine continues to inhibit cAMP production -> body must find different way to adapt and increase cAMP production
Chronic morphine: cell has adapted to continuing to produce cAMP - cAMP superactivation = opioid induced hyperalgesia
opioid clinical therapeutic effects
Pain: traumatic pain; surgergy, anesthesia, post-op pain, cancer pain, chronic pain Cough: codeine; dextromethorphan SSRI, NMDA antagonist (at high doses) Constipating Effect (anti-diarrheal): Diphenoxylate with Atropine; Loperamide (low BBB penetration)
non-phenanthrene opiods clinical therapeutic effects
Tramadol, Tapentadol: mild opioid analgesic, SNRI properties, management of mild neuropathic pain
Meperidine: active metabolite can accumulate and cause CNS irritability and myoclonic seizures
Why use meperidine? Nonresponsive to other opioids or allergy
opioids with NMDA effects
Methadone: primarily used for opioid dependence; NMDA antagonist
Levorphanol: NMDA antagonist
mixed agonis-antagonist and partial agonist opioids clinical effects
Partial agonist: limit euphoric effects and abuse
Partial agonist = partial antagonist = can precipitate withdrawal because not getting full effect
Butorphanol, Pentazocine: partial kappa agonist/ mu antagonism
Side effects: less dysphoria, increase BP and HR
Nalbuphine: full kappa agonist/ mu antagonist
Antagonism produces withdrawal
Buprenorphine: partial mu agonist, weak kappa agonist, and delta antagonist
negative consequences of opioid use
Side effects: comfortable limited side effects -> constipation/somnolence -> itch, urinary retention -> respiratory depression/death
Itch: opioid release histamine from mast cells (side effect, not allergy)
Hyperalgesia - Tolerance: increase dose required to produce equivalent effect; Hyperalgesia: compensatory changes, altered excitability of target neurons; lower stimulus intensity = same amount of pain
Therapeutic Applications of NSAIDs
Analgesic: headache, chronic postsurgical pain, myalgias/arthralgias, inflammatory pain
Antipyretic: fever
Anti-inflammatory: bursitis, tendonitis, osteoarthritis, RA, gout/hyperuricemia
inflammation
Acute: vasodilation, increased permeability
Subacute: infiltration
Chronic: proliferation
Mediators: eicosanoids and arachidonic acid metabolites
NSAID are COX inhibitors in the arachidonic acid pathway
COX-1:
-Constitutively expressed in platelets, stomach, kidney
-PGE2 and PGI2 are protective in stomach by inhibiting acid secretion, promoting mucus, inhibition (caused by NSAIDs) can lead to stomach ulcers
-TXA2 synthesis induces platelet aggregation = blood thinning
COX-2: present constitutively in brain and spinal cord; induced in inflammation by cytokines and inflammatory mediators
aspirin
irreversibly inhibits COX1/2 by acetylation of COX
Main use for anti-coagulation
No tolerance to analgesic effects
other NSAIDs
reversible inhibitor of COX ½
Some inhibit leukotriene synthesis = great anti-inflammatory effect
Indomethacin and Diclofenac
Arylpropionic Acids
Ibuprofen, Naproxen
Better tolerated than aspirin
Half-life: naproxen 14 hours vs. ibuprofen 2 hours
acetic acid derivatives
Diclofenac: increased risk of peptic ulcer and renal dysfunction; used with Misoprostol (PGE1 analog) to protect stomach
Indomethacin: high incidence and severity of side effects long-term
Sulindac: still significant side effects
acetaminophen
High effective as an analgesic and antipyretic
Advantages: no GI toxicity, no effect on platelets, no Reye’s correlation,
salicylates AE
GI distress, can treat with misoprostol (Why does it work? Produces prostaglandins that salicylates inhibit)
-Overdose: metabolic acidosis and respiratory alkalosis
NSAIDs AE
GI intolerance/ ulceration; renal function (higher risk with long term use); transient inhibition of platelet aggregation; inhibition of uterine motility: therapeutic use for delaying preterm labor
acetaminophen AEs
Renal toxicity
Dose-dependent potentially fatal hepatic necrosis: increased risk with high alcohol consumption -> alcohol up-regulates CYP mediated metabolism to NAPQI = toxic metabolite
Appears in many combination products: Lortab, Percocet
selective COX2 inhibitors
Nonselective (COX 1 /2 ): aspirin, acetaminophen, non-salicylates NSAIDs => stomach ulcers, bleeds
Selective COX-2: reduce ulcers and GI bleeds
COX-2 inhibitor Vioxx: high chance of blood clots, strokes, and heart attacks
Black box label for Celecoxib
Na channel
expressed in peripheral neurons, role in neuropathic pain, role in congenital insensitivity to pain
topical anesthetics
Na channel blockers
Lidocaine
Bupivicaine
Benzocaine: OTC use, lower allergy risk
Na channel blockers
Lamotrigine: off label for neuropathy and migraine
Amitriptyline: post-herpetic neuralgia, polyneuropathy, fibromyalgia, visceral pain
Carbamazepine: trigeminal neuralgia