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Flashcards in Analgesics Deck (62):

Hyperalgesia vs. allodynia vs. spontaneous pain

Hyperalgesia: pain out of proportion to noxious stimuli
Allodynia: pain evoked by a non-noxious stimuli
Spontaneous pain: pain with no apparent stimuli


Where do A delta fibers synapse vs. C fibers?

A delta: lamina I, II, III, V
C: lamina I and II (substantia gelatinosa is lamina II/III, it is richly populated with opioid receptors)


The dorsal horn neurons (from lamina I and V) send fibers via the pathway of neospinothalamic tract vs. paleospinothalamic tract.. what is the difference?

Neospinothalamic: fast pain pathway, to the thalamus then to the somatosensory cortex
Paleospinothalamic tract: slow pain pathway, to the brain stem (and thalamus) then to the thalamus, hypothalamus and elsewhere


When modulating pain signals, descending inhibitory pathways originate in the _____ and project to the ______ which sends neurons down the spinal cord to synapse in the ________

Descending inhibitory pathways originate in the **midbrain/brain stem and project to the **nucleus raphe magnus which sends neurons down the spinal cord to synapse in the **substantia gelatinosa


What are the three major sites of action of opioids?

Brain (supraspinal): opioids work pre and post synaptically to activate descending inhibitory pathways
Spinal cord (spinal): directly on the dorsal horn of the spinal cord
Periphery: nociceptive neurons


Why are opioids used in anesthesia?

Lessen SNS response to noxious stimuli
Adjunct to inhaled agents
Sole anesthetic
Peri-op and post-op control of pain


Opioid characteristics: do they have a ceiling effect?

There is no max dose (no ceiling effect)


Which of these are naturally occurring vs. semisynthetic?
Morphine, heroin, codeine, dihydromorphone

Naturally occurring: morphine and codeine
Semisynthetic: heroin and dihydromorphone


Opioid mechanism of action? G-protein response?

Synthetic opioids mimic the action of endogenous opioids by binding to opioid receptors
G-protein response: presynaptic- inhibits release of excitatory neurotransmitters (Ach, dopamine, norepi, substance P)
postsynaptic- decreases neurotransmission by increased K conductance (hyperpolarization), Ca channel inactivation, modulates phospoinositide, inhibits adenylate cyclase (decreased cAMP)


Mu-1 receptor effects

SUPRASPINAL, spinal, and peripheral analgesia, euphoria, miosis, bradycardia, urinary retention, and hypothermia
*All endogenous and synthetic opioid agonists act on these receptors


Mu-2 receptor effects

Hypoventilation, physical dependence, SPINAL analgesia (some supraspinal), constipation
**All endogenous and exogenous agonists act on these receptors


Kappa receptor effects

SUPRASPINAL, SPINAL and peripheral analgesia, dysphoria, sedation, miosis, diuresis
**Dynorphins act on these receptors
Opioid agonist-antagonists often have principle actions at the kappa receptors


Delta receptor effects

PERIPHERAL, supraspinal, and spinal analgesia
Hypoventilation, constipation, urinary retention
**Enkephalins work on these receptors


Why do people respond differently to the same opioid?

Receptor binding can be affected by SNP or other mutations that don't allow the binding, ex: chromosome 6q24-q25, nucleotide 118 and 17 affect nucleotide binding
Also metabolism can be affected by genetics, ex: CYP2D6 has common mutations


Opioid CV side effects, which drug is the big exception?

MINIMAL when used alone, additive with other anesthetics
Dose dependent bradycardia due to vagal stimulation and direct SA/AV node depression
Vasodilation/decreased SVR (esp in hypovolemic state), impaired SNS response, decreased CO and BP with venous pooling
Morphine and Meperidine (demerol) cause dose dependent histamine release which will cause bronchospasm, drop in SVR/BP
Meperidine is the big exception, for causing tachycardia and more myocardial depression than the other opioids


CNS effects of opioids

Analgesia, euphoria
Miosis (pupil constriction)
Nausea (chemoreceptor trigger zone)
If hypoventilation prevented, decrease in ICP/CBF
Does NOT produce amnesia (problem with recall)


GI/Liver/Renal side effects of opioids

Increased tone and peristaltic activity of ureter and increased detrusor muscle tone = increased URGENCY but less ability to void
Decrease catecholamine release/ stress response
Spasm of sphincter of Oddi with increased biliary pressure
Spasms of GI smooth muscle can cause constipation and prolonged gastric emptying
N/V- chemoreceptor triggers nausea but medullary vomiting center is depressed (so more nausea than vomiting)


Pruritis is a side effect of opioids, where do people commonly itch?

"Fentanyl nose itch"
Histamine release can cause this


Opioid skeletal muscle side effects

RIGIDITY in chest, abdomen, jaw, extremities, glottic ("wooden chest syndrome", hard to ventilate) especially in large doses -> high airway pressures decrease venous return


Opioids ventilatory effects

Dose dependent respiratory depression (small doses increase TV, decrease RR; large doses decrease RR and TV).. this is why people die of OD
Decreased chest wall compliance
Constriction of pharyngeal and laryngeal muscles
Cough suppression
Decreased response to hypercarbia/hypoxia
Morphine and Meperide cause histamine related bronchoconstriction


What do opioids do to the ventilatory response curve?

Shift down and to the right


How does codeine work?

It is a pro-drug meaning the body metabolizes 10% of the drug (using CYP2D6) to its active form, morphine. If the patient lacks the enzyme for this then the body won't convert it and the drug will not have an analgesic effect (some caucasians and asians lack 2D6)
Codeine is better for cough at a lower dose than pain relief, even without conversion to morphine


Uses and routes for morphine vs. codeine

Morphine: sharp, acute pain; route PO/IM/IV (PO delayed onset, e1/2t 3-4 hrs, converted to active metabolite- bad for renal pt)
Codeine: mild pain; route PO (e1/2t 3 hrs, combined with acetaminophen, guaifenesin, or promethazine)


Hydrocodone, also known as ______, is used for what?

Used for chronic pain (also antitussive)
Always combined with acetaminophen, aspirin, ibuprofen, antihistamine


Oxycodone, also known as ______, is used for what?

Oxycontin, percocet, percodan
PO for moderate to severe pain, chronic pain, or post-op pain
Used in combination with acetaminophen and aspirin
No active metabolites (safer with renal patients)


Methadone: route, e1/2t, uses?

PO, IV, subQ
Long, variable, unpredictable E1/2t 8-100 hrs (so risk of respiratory depression)
Used for chronic pain (bid/tid dose) and for opioid addiction treatment (maintenance, qd dose)
No active metabolites- safer in patients with renal dysfunction


What is the reversal for opioid agonists?

Naloxone (narcan)
Competitively binds to opioid receptors


What are signs of tolerance to opioids? When can this occur?

Tolerance is common after 2-3 weeks of opioid use
Pt notices a reduction in adverse effects, shorter duration of analgesia followed by a decrease in effectiveness of each dose
This includes tolerance to respiratory and CNS depression, but NOT constipation (they need laxatives/stool softeners)


When does physical dependance occur with opioids?

Physical dependence causes symptoms upon sudden d/c. It takes about 25 days to develop fully but some degree of dependence occurs after only 48 hours of continued IV use
Note: addiction involves psychological dependence and biologic/social factors


How is PO dosage determined for opioids?

No min/max unless it contains acetaminophen or aspirin, the dose is decided by what relieves pain with tolerable side effects
For chronic pain, sustained release formula should be used
Immediate release doses are for breakthrough pain


What are the neuraxial effects of opioids?

Analgesia across dura to mu receptors in substantia gelatinosa then into the vasculature for a systemic effect (NOT true with morphine bc it is not as lipid soluble)
Penetration into CSF/vasculature and movement in CSF depends on lipid solubility


Dose for epidural is 5-10x _____(lower/higher) than spinal dose

Opioids placed in epidural space may undergo uptake into fat, systemic absorption or diffusion into CSF
Spinal is given directly to CSF, requires lower dose


A ______(more/less) lipid soluble opioid will remain in CSF for transfer to cephalic location

Ex. Morphine
A highly lipid soluble drug, fentanyl, will be limited in migration by uptake into the spinal cord


Is there a ceiling effect to non-opioid analgesics? Does tolerance develop?

Ceiling effect of aspirin and acetaminophen between 650-1300 mg (other NSAIDS may be higher)
Exceeding the ceiling dose of these drugs will result in increased adverse effects with no added efficacy
Tolerance does NOT develop


Acetaminophen: uses, MOA

Uses: antipyretic, anti-prostaglandin effect, pain reliever, weak anti-inflammatory, good for peptic ulcer disease, peds, and pt who need well functioning platelets
MOA: NOT a true NSAID, pain reduced via blockade of NMDA receptor activation in CNS, blocks substance P in the spinal cord


Acetaminophen dose: po and IV

PO: 325-650 mg q4-6h
IV: 1 gram over 15 min, q4-6h
Don't exceed 4g in 24 hours! If someone is an alcoholic its a good idea to cut this in half.


Acetaminophen OD causes what? What is the antidote?

Hepatic injury
Liver can only metabolize a limited amount of the toxic metabolite using intrinsic glutathione, when it is outnumbered, hepatic injury occurs
Acetylcystein can substitute for glutathione and prevent hepatic injury within 8 hours of OD


What carries a higher risk of renal toxicity? Acetaminophen or NSAIDS?

NSAIDS are a higher risk of renal toxicity
**Acetaminophen does carry some risk due to accumulation of metabolites which can cause renal cell necrosis


Arachadonic acid released from phospholipids by the enzyme phospholipase A2. It is immediately metabolized by what?

Cyclooxygenase, leading to the formation of prostaglandins, prostacyclin, and thromboxanes
Lipoxygenase, leads to the formation of leukotrienes and lipoxins
Epoxygenase (not clinically relevant)


COX-1 vs. COX-2, what happens when we only block COX-2?

Both COX 1 and 2 lead to prostaglandin production
COX-1 is an enzyme widespread through the body, it also does platelet aggregation, GI protection, and renal function
COX-2 is an enzyme only active at the site of inflammation
When we block ONLY COX-2, risk of platelet aggregation -> stroke/MI
Prostaglandins also prevent renal failure, so when blocked, that's an issue. Also when blocking both 1 and 2, we block GI protection, leads to GI bleeds.


Salicylates (Aspirin): what are uses and how does it work?

Uses: mild to moderate pain (headache, muscle pain, arthritis), antipyretic, MI/stroke prevention, protection during MI (anti-platelet)
Unlike other NSAIDS, it is a IRREVERSIBLE inhibitor of COX (for a lifetime of platelet, 8-10 days), large doses can decrease prothromin
When held before surgery, held for 8-10 days bc lifetime of a platelet


Is ESRD induced by chronic aspirin use or are other NSAIDs more likely to do this?

Other NSAIDs cause ESRD, NOT aspirin


Salicylate side effects?

Prolonged bleeding
Increased LFTs
Asthma ppt
Cross-sensitivity with other NSAIDS
GI bleed, PUD
CNS stimulation


Salicylate dosing? What is the E1/2t?

Analgesic/antipyretic: 325-650 mg
Anti-inflammatory: 1000 mg (3-5 g/day).. rarely used bc GI effects
E1/2t 15-20 min for aspirin and 2-3 hr for active metabolite salicylic acid


Salicylate overdose symptoms?

Metabolic acidosis, tinnitis


Why is Aspirin not used during viral syndromes in children?

Risk of Reye's syndrome


Are acetylated or non-acetylated salicylates more favorable by not interfering with platelet aggregation, less GI bleed, and better tolerated by asthmatics?



NSAID uses and MOA

Uses: analgesic (musculoskeletal pain, headaches, more effective than aspirin/acetaminophen) but ceiling effect with post-op pain, anti-inflammatory, antipyretic
MOA: COX inhibition, blocks conversion of arachidonic acid to prostaglandins


NSAID is a weak ____ (acid/base), well absorbed, ______ (high/low) protein binding, ______ (small/large) Vd, and what is the half-life?

Weak acid
highly protein bound
Small Vd
Variable half-life, 6-12 hours


Side effects of NSAIDs, what are peri-op side effects?

Asthma and anaphylactic reaction in aspirin-sensitive patients
Reversible inhibition of platelet aggregation
No physical dependence
Rare hepatic injury and aseptic meningitis
GI effects, renal effects
Peri-op inhibition of COX results in renal injury, gastric ulcers, excessive bleeding, and impaired bone healing


What pregnancy category are NSAIDs?

Category B until 3rd trimester, category D because usage of NSAIDs can cause the fetus ductus arteriosis could close


What GI effects do NSAIDs have? Who is at most risk for these effects?

Dyspepsia, GI bleed, PUD,
Increased acid production, decreased mucus production
At high risk with high doses, prolonged use, previous GI bleed/ulcer, excessive ETOH intake, elderly, and CORTICOSTEROID use (corticosteroids block higher up on the arachidonic acid chain)


What causes the renal effects of NSAIDs? What are the effects? Who is at highest risk?

Due to decreased synthesis of renal vasodilator prostaglandin
Decreased renal blood flow
Fluid/sodium retention
Renal failure, hypertension
Interstitial nephritis
Risk factors: elderly, CHF, hypertension, DM, renal insufficiency, ascites, volume depletion, diuretic therapy


Which specific NSAIDs are at higher risk of renal effects? Which are at lower risk of renal effects?

Higher: ketorolac, indomethacin
Lower: sulindac, nabumetone, celecoxib


NSAID drug interactions?

Displaces other highly protein-bound agents (increases levels of warfarin, phenytoin, sulfonylureas, digoxin)
Reduces effect of diuretics, beta-blockers, ACEIs
Increases lithium levels
Increased risk of GI bleed with anticoagulants
Probencid increases levels of NSAIDs


How does Ketorolac compare to other NSAIDs? What is the onset, e1/2t, and doa?

Ketorolac (toradol), is the only IV NSAID
Comparable to mild opioid pain relief
Adverse effects of NSAIDs are more extreme
IV onset in 10 min, E1/2t of 5 hours, DOA 6-8 hours
Shouldn't be used for more than 5 days
99% protein bound, conjugated in the liver


Ketorolac dose?

30 mg IV once or q6h
Daily max 120 mg
Decrease dose by 1/2 for elderly


Celecoxib (celebrex): What is it and why would you give it? Why would you avoid it

Selective NSAID, selectively inhibits Cox-2
You would give this to someone with NO cardiac or GI issues but arthritis issues (otherwise, use an NSAID)
Same risk of renal effects
Avoid in patients with a sulfonamide allergy (and cardiac/GI issues)


Celecoxib dose?

200 mg/day PO or less (similar effect as naproxen 500 mg bid)
Take with food


What is the black box warning for selective and non-selective NSAIDs?

CV: increased risk for serious thrombotic events, contraindicated for CABG surgery
GI: bleeding, ulcers, perforation


Antidepressants and anticonvulsants are good for what type of pain?

Neuropathic pain syndromes
TCAs (amitriptyline, nortriptyline)
Venlafaxine (effexor), Duloxetine (cymbalta)
Anticonvulsants: gabapentin (neurontin), pregabalin (lyrica), carbamazepine (tegretol), phenytoin (dilantin, sodium valproate (depakote), clonazepam (klonopin), topiramate (topamax), lamitrogen (lamictal)


Adjunctive analgesics such as hydroxyzine, corticosteroids, and local anesthetics are good for what type of pains?

Hydroxyzine for post op pain, reduces N/V, additive effect to opioids in cancer
Corticosteroids for nerve or inflammatory disease
Topical analgesics such as 5% lidocaine (lidoderm) for post herpetic neuralgia
Topical EMLA for cutaneous anesthesia
Capsaicin cream (zostrix) for neuropathic/OA pain
Clonidine transdermal patch for pain/hyperalgesia