Block 3 Lecture 4 -- Pain Pathways and Non-opioid Analgesics, and Lecture 5 Opioids Flashcards
When is amantadine preferred?
new patients with mild symptoms
What are the chemical mediators of pain?
1) bradykinin
2) 5-HT
3) neuropeptides
4) ATP, K+
5) chemokines
6) PGE2
7) Na, Ca, Glu ion channels
8) ASICs
9) TRPV1
What neuropeptides mediate pain?
CGRP: calcitonin-gene-related peptide– especially in migraine
What is TRPV1?
transient receptor potential vanilloid-1 channel– Ca-permeable ionotrope activated by protons
Where are protons as a source of pain produced?
1) tumor
2) heat
3) inflammation
4) capsaicin
5) gaseous anesthetics
What are the 3 important factors to treating pain?
1) site of drug action
2) timing
3) nature of pain
What drugs target the site of pain initiation?
1) methylene blue
2) ASA, NSAIDs
What drugs target the transmission pathway of pain?
local anesthetics
What is methylene blue?
neurotoxicant; injection destroys nerve endings
What drugs target the spinal cord?
1) topical counterirritants
2) transcutaneous electrical nerve stimulation
What is capsaicin’s MoA? Any counseling points?
TRPV1 agonist
2-4 weeks for max efficacy
How do topical counterirritants work?
reduce referred pain in same dermatome
What things act on the spinothalamic tract fibers to reduce pain?
1) EtOH (kill fiber)
2) anterolateral cordotomy
What things act on the spinal cord and brain to reduce pain?
opioids
What are the benefits of pre-emptive acute pain treatment?
decreases risk of progression from acute to chronic pain
What things are known pruritogens?
1) histamines
other chemicals, drugs
What mediates itch?
MrgrprA3 (mas-related GPCR)
- not a sub-modality of pain
- ALST
Differentiate COX-1 vs. COX-2 structure.
COX-2 has 523 Val (allows larger side chain)
COX-1 has Ile 523
What are prostanoids?
all the products of COX pathway
What are eicosanoids?
20C metabolites of arachidonic acid
What are the effects of PGE2?
1) pain
2) inflammation
3) inhibit acid secretion
4) increase GI mucous, bicarb
5) maintain renal blood flow; increase Na/H2O excretion
What are the effects of TXA2?
1) vasoconstriction
2) platelet aggregation
What are the effects of PGI2?
1) vasodilation, esp. mucosal
2) increase GI mucous, bicarb
3) inhibit GI acid secretion
4) maintain renal blood flow; increase Na/H2O excretion
5) platelet disaggregation
What are the major COX-1 products?
PGE2 + TXA2
What are the major COX-2 products?
PGE2 + PGI2
What are the beneficial effects of inhibiting COX?
1) Analgesia
2) antipyresis
3) platelet disaggregation
4) anti-inflammatory
5) reduced cancer risk
6) reduced dysmenorrhea symptoms
What are the bad effects of inhibiting COX?
1) GI
2) uncoupled oxidative phosphorylation
3) decreased renal blood flow
4) erythema
What forms of cancer does COX inhibition reduce risk of?
1) colorectal
2) gastric
3) lung
4) breast
5) ovarian
6) prostate
7) skin
How does COX inhibition decrease cancer risk?
1) decreased inflammation
- - decreased cell turnover
2) +apoptosis
3) decreases angiogenesis
4) decreases cell proliferation
What are adjuncts to reduce GI side effects?
1) H2RAs
2) PPIs
3) PGE analog misoprostol
4) anti-H. pylori
5) antacids
6) acid-barriers
What are acid-barriers for GI adjunct?
sucralfate
– no evidence of efficacy
What are risk factors for GI ADRs?
1) h. pylori
2) h/o GI bleed
3) oral anticoag
4) long-term NSAID tx
5) hi NSAID dose
6) smoking
7) EtOH
8) CVD
How do NSAIDs compare to ASA in decreasing renal blood flow?
NSAIDs more effective
How does ASA differ from other salicylates and NSAIDs?
ASA irreversibly inhibits COX-1
What are topical forms of salicylates?
methyl salicylate
triethanolamine salicylate
bismuth subsalicylate
What are the secondary MOAs of salicylates?
1) increases endocannabinoids
2) inhibits spinal nociceptive processing by 5-HT, NE, ACh
3) decreases NO production
What’s the usual ASA dose for kids and adults?
kids = 10 mg/kg adults = 10-15 mg/kg
What defines ASA intolerance? What’s the prevalence compared to hypersensitivity?
intolerance = proven hypersensitivity or severe indigestion after low-dose ASA
6-20% vs. 0.6-2.5% hypersensitivity
Are salicylates cross-reactive in allergy to NSAIDs?
Yes – altered eicosanoid metabolism
What are the ADRs of salicylates?
1) fecal occult blood loss
- - 1.2 g/day = 4.5 mL
- - 3.6 g/day = 11.2 mL
- - menses = 1-2mL
2) acute GI hemorrhage
- - dose, not duration-related
What are ASA interactions?
1) GI irritants (EtOH)
2) PPB
- - sulfonylureas, valproate, oral anticoag
3) drugs competing for URAT1
Where is URAT1 located?
proximal tubule
What is the pregnancy category of ASA?
C – no evidence
What are the recommendations of ASA during pregnancy?
- avoid 2 weeks prior to delivery
- - lo-dose daily ASA in 1st trimester lowers preeclampsia risk in hi-risk women
What is the current pre-eclampsia cure?
premature delivery
What are the effects of ASA on pregnancy?
1) not effective in preventing further pregnancy losses
2) increases duration of labor
3) increases complicated deliveries and still-births
4) increases bleeding in newborn and during elivery
How is ASA poisoning treated?
1) lavage, charcoal
- - if EC, whole body irrigation
2) hydrate
3) alkalinize urine with bicarb to 7.8-8
What nomogram for ASA poisoning?
Done
– no indication of severity until 6h
What are the symptoms of ASA poisoning?
1) 20 mg/dL = tinnitus
2) 35 = respiratory alkalosis
3) 50-80 = n/v, fever, lethargy/excitability
4) severe = medullary depression, metabolic acidosis
Why does metabolic acidosis occur in ASA OD?
1) medullary depression
2) accumulation of metabolic acids and decreased renal fx
3) fat catabolism = ketoacids
4) inability to buffer
What is the toxic level for child/adult?
160mg/dL
What are the uses of ASA?
1) mi/stroke/vascular prophylaxis in those with CVD
2) daily ASA to decrease cancer mortality 16%
- - efficacy increases after 5 years
- - GI, colorectal, esophageal best
What are contraindications to NSAID use?
1) ASA-associated asthma
2) hypersensitivity to asthma
3) 3rd trimester
What are the ADRs of NSAIDs?
1) non-selective CV risk (VT)
2) GI (stomach more than duodenal)
3) nephrotoxicity
4) renal cell cancer
5) hepatotoxicity
Why can NSAIDs be hepatotoxic?
metabolites form covalent adducts with proteins
– form immunogen
What are the forms of nephrotoxicity from NSAID use?
1) acute renal failure
- - reversible, dose- and duration-dependent
2) renal papillary necrosis
- - hypoxia
3) nephrotic syndrome with acute interstitial nephritis
- - hypersensitivity, days to develop
- - reversible
What are signs of nephrotoxicity?
hyperNa, hyperK, hyperCl; edema
When should you use NSAIDs with caution due to potential nephrotoxicity?
1) low GFR
2) low Na
3) heart failrue
4) liver disease
5) diabetes
6) ACE inhibitors
What are the tNSAIDs selective for COX-2?
meloxicam
diclofenac
etodolac
What does APAP stand for?
acetyl-para-amino phenol
What are the ADRs of celecoxib?
1) increased MI risk
2) sulfa allergy
3) HA, GI
- - but fewer GI ulcers than tNSAIDs
How is celecoxib metabolized?
2C9
– inhibits 2D6
What are the CV ADRs of NSAIDs?
1) increased CV risk in cardiac patients
- - least=naproxen; most=diclofenac
2) bleeding risk doubled for anti-coag patients
How to limit CV risk in cardiac NSAID patients?
most COX-1 selective
min dose
min duration
What is the MoA of APAP?
1) selective COX-2 inhibitor mainly in brain
2) stimulates descending serotonergic pathways
- - inhibits afferent pain fibers
3) CB1r agonist
Describe A for APAP.
1) good oral F
2) interpatient variability for rectal
3) IV available
Describe metabolism of APAP?
80% metabolized in liver
- most via UGT (60%) or SULT (30%)
- 10% via CYP2E1 to yield imine
- imine detox by GST
can inhibit 3A4
half-life = 2h
What are ADRs of APAP?
1) INR increase
- - if warfarin metabolized by 3A4 and 2C9
2) increased asthma risk in kids exposed to APAP in utero
What’s the APAP toxicity level?
7.5-10g in adults
150 mg/kg in kids
What is used to evaluate APAP toxicity?
Rumack-Matthew Nomogram
How is APAP toxicity treated?
N-acetylcysteine
– effective if given in 8-10h
Describe toxicity symptoms of APAP.
6-14 h
– non-specific flu-like sxs
3-5 days
– acute liver and/or renal failure
Why can’t you use alcohol with APAP?
EtOH induces 2E1 (imine metabolism)
- toxicity with less than 2-4g/day
- concurrent EtOH use increases renal risk 2x
How do opioids generally compare to non-opioids?
1) greater efficacy
2) good for visceral pain
3) central action
4) structurally homogeneous
How do the opioids vary?
source and structure
– C3, 6, 17
What is the structure of endorphins?
31aa w/ met-enkephalin
What is the structure of dynorphins?
13-17aa w/ leu-enkephalin
What is structure of enkephalins?
5aa: Tyr-Gly-Gly-Tyr +leu or met
What are the effects of mu1 agonism?
1) supraspinal analgesia
2) sedation
3) euphoria
4) physical dependence
What are the effects of mu2 agonism?
1) spinal analgesia
2) sedation
3) respiratory depression
4) GI immobility
What are the effects of delta1/2 agonism?
1) analgesia
2) anti-depressant
3) dependence
4) respiratory depression
5) fewer GI effects
What are the effects of kappa1/2/3 agonism
1) GI immobility
2) sedation
3) diuresis
4) DYSPHORIA
How do kappa receptors vary?
1 is spinal
2, 3 are supraspinal
Describe A of morphine.
Fpo,rectal = 25%
– first pass
Finj = 50%
Describe PPB of morphine
35%
Describe M for morphine
t1/2 = 2 hr
UGT2B7
– 90% yields M3G
– 10% yields M6G
What is morphine-6-glucuronide?
active morphine metabolite
- 100x more affinity
- can be formed and trapped in brain
What morphine isomers are active for antitussive? What do these isomers lack?
D-isomers of HC, DM, codeine
– lack analgesia, respiratory depression, tolerance, drowsiness
Opioid tolerance does not occur to…
1) miosis
2) GI
3) smooth muscle tone
4) kappa agonists/mu antagonists
What are the effects of morphine opioids?
1) euphoria
2) satiation
3) sedatoin
4) analgesia
5) respiratory depression
6) antitussive
7) hypothermia
8) miosis
9) n/v
10) decreased cardiac work
11) increased sm tone
12) histamine release
What are symptoms of opioid-induced, non-allergic histamine release?
1) pruritis
2) flushing
3) hypotension
- - no hives, bronchoconstriction, edema
How do opioids cause respiratory depression?
1) decreased neurogenic drive
2) decreased CO2 response
How do opioids act as analgesics?
1) increase pain threshold
2) change pain perception (limbic connection)
What are morphine’s effects on CV system?
1) decreased left ventricular diastolic pressure
2) decreased cardiac work
3) decreased venous return
no HR/CO effect
not with mixed agents
What is fibromyalgia?
chronic disorder mainly affecting females characterized by chronic, non-malignant pain, fatigue, and sleep problems
How is fibromyalgia treated?
muscle relaxants
anticonvulsants
antidepressants
Opioid efficacy lacking
How is low-back pain treated?
1) acute: NSAIDs/APAP, muscle relaxants, PT
2) chronic: strengthening
not opioids
– increases time from work and medical expenses
How does codeine compare to morphine?
more complete absorption
lower abuse potential
What is the WHO model for pain treatment?
Step 1: mild-moderate
Step 2: mild-moderate or Step 1 failure
Step 3: moderate-severe or step 2 failure
What is Step 1 in the who model?
non-opioid +/- adjuvant
What is Step 2 in the who model?
short-acting prn
+/- non-opioid ATC
+/- adjuvant
What is step 3 in the who model?
SR opioid ATC
+/- short-acting
+/- adjuvant
What is the MoA of caffeine?
1) A2 antagonist
- - cerebrovasoconstriction
2) increases rate and extent of drug absorption
3) increases analgesic activity
MoA of buprenorphine
partial mu agonist
kappa antagonist
MoA of butorphanol
kappa agonist
mu antagonist
MoA of pentazocine
kappa agonist
mu antagonist
MoA of tramadol
weak mu agonist
NET, SERT inhibition
How is hydrocodone metabolized?
1) 2D6 O-demethylation (hydromorphone, 2D6 variability)
2) 3A4 N-demethylation (norhydrocodone, weak active)
How is methadone used?
1) analgesic
2) opioid detox
3) maintenance of detox
How is fentanyl metabolized?
3A4, 2.5-12h half-life
How is meperidine used?
moderate acute pain for 24-48h max
– active metabolite accumulates in brain
Diphenoxylate MoA
synthetic meperidine-like opioid with poor CNS penetration
Loperamide MoA
synthetic meperidine-like opioid with poor CNS penetration
What are the synthetic opioids?
meperidine
fentanyl
What are the semi-synthetic opioids?
hydros and oxys
heroin
What are the natural opioids?
morphine, codeine
What are ADRs of tramadol?
1) seizure
2) anaphylactoid
3) hypoglycemia
How is tramadol metabolized?
2D6 to active metabolite
– higher affinity
3A4
What is suboxone?
buprenorphine + naloxone SL film
MoA of pentazocine
kappa agonist, mu antagonist
MoA of butorphanol
kappa agonist, mu antagonist
ADRs of pentazocine?
use-limiting psychotomimesis
What opioids require REMS?
1) ER & LA for moderate-severe chronic pain
2) transmucosal IR fentanyl
3) buprenorphine transmucosal for opioid dependence
What are the reasons for interpatient variability to opioids?
1) OPRM1 (mu receptor1 gene) SNP
2) kids have poorly developed BBB and more H2O
- - hydrophilics eliminated slower
3) geriatrics less sensitive, reduced cardiac and hepatic fx
What are contraindications to opioid use?
1) hypersensitivity
2) acute bronchial asthma
3) head injury
In what opioids is renal insufficiency an issue?
morphine, meperidine
What are common co-analgesics?
1) antidepressants
2) SERT/NET inhibitors
3) anticonvulsants
3) hydroxyzine, phenothiazines
4) corticosteroids
5) clonidine
MoA naloxone
full mu antagonist
kappa antagonist
delta antagonist
MoA naltrexone
full mu, kappa antagonist
partial delta antagonist
