Pain and Opioids Flashcards
Acute Pain
- the direct result of tissue damage or potential damage and is a symptom
- well defined onset and clear pathology
- protect from tissue damage and allow time for healing
- frequently observable tissue damage
- usually adequately treated by pharmacological and treatment methods
- acute pain is useful and protective
Gaba
inhibitory NTM effect on pain
-cerebral cortex, BG, cerebellum and spinal cord- increases Cl- which hyperpolarizes the cell
Acetylcholine
inhibitory NTM effect on pain
-increased K+ conduction in the peripheral parasympathetic NS
Dopamine
-most likely inhibitory by acting on adenylate cyclase
Norepi effect on pain
-RAS & hypothalamic-inhibitory
Epi effect on pain
-RAS- inhibitory
Glycine
spinal cord- increases Cl- = hyperpolarizes cell
Endorphins
-are excitatory for the descending pathways that inhibit pain transmission
serotonin
-inhibitory in the brain
Histamine
hypothalamus and RAS-inhibitory
Glutamate effect on pain
Excitatory NTM
- hippocampus, outer layer of cerebral cortex, and SG
- learning and memory: recall
- central pain transduction
- excitotoxic neuronal injury
- inotropic glutamate receptors: NDMA
- ligand operated channel opens- influx of cation (Na+), membrane depolarization
Opioids
- most efficacious analgesic drug available
- have receptor agonist activity with morphine-like effects at mu receptors throughout the body but also at kappa and delta receptors
- activation of mu receptor produces analgesia effects and other unwanted SE
- inhibit NTM, block Ca2+ influx and increase K+ efflux
- analgesia: absence of pain without loss of consciousness
- have different bioavailability, efficacy, relatively potency, duration of action, metabolism and metabolite activity
- may NOT eliminate pain
Opioid MOA
- agonist activity at stereospecific opioid receptors at pre and post synaptic sites in the CNS (brain and spinal cord) and peripheral nerves
- activate opioid receptors on the primary afferent sensory neurons
- these neurons are also activated by enkephalins, endorphins, and dynorphins
- only levi-rotatory opioid molecules exhibit agonist activity
- opioids need to be ionized for strong binding to the receptors
Principal effect of opioid receptor activation?
- decreased neurtransmission: this action occurs largely by presynaptic inhibition of the release of neurotransmitters
- acetylcholine, dopamine, norepi, substance P
- post synaptic inhibition of evoked activity may also occur
Opioid receptor occupied by agonist
- increased K+ conductance hyper polarizes membrane
- or/ and calcium channel inactivation
- leads to decreased neurotransmitter release
- opioid receptor mediated inhibition in cAMP is likely a delayed response
- opioids do NOT alter the responsiveness of peripheral nerves to noxious stimuli nor do they impair impulse transmission
The BBB
opioids cross the BBB based on:
- molecular size (smaller is better)
- lipid solubility (lipid soluble is better)
- non-ionized is better (more lipid soluble)
- protein binding: greater protein binding means less drug available to cross
Protein binding: which drugs have the highest and lowest?
Highest: alfentanil
lowest: morphine
Match receptors with endogenous opioids:
mu, delta, kappa to endomorphins, endorphins, enkephalins, dynorphins
Mu: endomorphins and endorphins
Delta: endorphins and enkephalins
kappa: dynorphins
Mu receptors: location (4) and actions (8)
Location: Brain mu1 in brain spinal cord: SG peripheral sensory neurons intestinal tract
Actions: sedation analgesia physical dependence (mu2) respiratory depression (mu2) miosis euphoria reduced GI motility vasodilation
Kappa: location (4) and actions (8)
Location: brain spinal cord peripheral sensory neurons high intensity painful stimulation may be resistant to K receptor effects
Actions: analgesia anticonvulsant effects dissociative and delirium diuresis dysphoria miosis sedation reduces shivering
Delta receptor location (1) and actions (4)
Location:
Brain
NOT spinal cord*****
Actions: analgesia antidepressant effects convulsant effects physical dependence
Generalized opioid side effects
sedation: precursor to respiratory depression
respiratory depression-usually prevented by intense pain
nausea & vomiting: treat with antiemetics
— decrease GI motility and constipation
— decrease secretions
— prescribe a laxative with the opioid
CV:
orthostatic hypotension
bradycardia
peripheral vasodilation– d/t histamine release
SIDE NOTE: histamine release on morphine and fentanyl
morphine is naturally occurring from poppy seed plant
A LOT more histamine release= more vasodilation than with fentanyl
Generalized opioid side effects
-euphoria- meperidine antitussive (cough syrup w/ codeine) pupillary constriction-- miosis pruritis (itching)-- histamine and non histmine biliary spasm-- gallbladder surgeries myoclonus/seizures-- high doses chest wall rigidity-- high/misc. dose
Morphine
-classic Mu receptor agonist
-influences motivational-effective aspect of pain
-produces analgesia in the:
— brain mu1
— spinal level mu2
Only 23% ionized– able to cross BBB
lipid solubility 1.4 so slow onset of action
t1/2 2-3 hours
duration of actions: 4-6 hrs
opioid: mu agonist, kappa agonist, delta agonist
Morphine analgesia
central: mu1
- -periaqeductal gray, locus cerelus, medullary nuceli
- -sends descending inhibitory signals
spinal level– mu2
–presynpatic inhibition of primary afferents
–decrease substance P
-post synaptic hyper polarization of interneurons
substancia gelatinosa (Rexed II and V)
-decreases afferent transmission of nociception
–central and spinal synergy
Women have slower onset and slower resolution of analgesia at the same plasma level of morphine
–not observed with Alfentanil or M-G-Glucoronide
–women may require 10-30% more morphine than males
Morphine respiratory depression
causes respiratory depression
- -a shift to the right of the CO2 response curve to resting paCO2 and to apnea
- -classically see slowly respiratory rate and normal TV
- -with analgesia comes resp depression– protective?
ventilatory response to hypoxia/emia is also decreased
-the onset of respiratory depression with morphine parallels the onset of analgesia (usually the shift in the CO2 curve and hypoxia response protects the patient from too much morphine)
Morphine: N&V, muscle rigidity, itching
- induces N&V by direct stimulation of the chemoreceptor trigger zone- studies show no difference in N&V with equal doses of different opioids
- large doses or rapid administration may cause skeletal muscle rigidity (eliminated with GABA agonists and paralytic agents)
- result in dose dependent pupillary constriction
- pruritis (itching) is a mu receptor effect at the medullary dorsal horn, NOT histamine release *** treat with naloxone
Morphine: what happens when drug is given to patient over time?
Tolerance develops with continued exposure
- -requires larger doses to produce same level of pain relief
- hyperalgesia may develop with prolonged use
- pt shows S&S of withdrawal when morphine is dc’d
- decreased cough reflex 2/2 direct effect of medullary cough center
- decreases GI motility, gastric emptying, increases constipation
- increase biliary pressure by increasing phasic wave frequency of sphincter of do (cholangiograms)
- triggers release of histamine– allergic reaction
- reduces centrally mediated SNS activity— peripheral vasodilation
Morphine metabolism and elimination
metabolized 70% in liver via glucuronidation
- liver disease has minimal effect on morphine metabolism
- –reduced liver blood flow reduces morphine clearance
- –very young (<2 months) and elderly (>60) have reduced liver flow
excretion of metabolites by kidney
M-3-glucuronide 75-85% inactive metabolite– no analgesia– maybe hyperalgesia
M-6-glucuronide 5-10% active metabolite–10X potent than parent morphine
renal disease affects the elimination of morphine
- M6G is secreted by organic ion transporters in the kidney which is impaired in renal disease. M3G also accumulates
- a patient receiving high doses of morphine who develops renal insufficiency may develop prolonged sedation or coma due to M6G accumulation
Hydromorphone (Dilaudid)
-IV 5X potent than morphine Onsets 5 minute peaks 10-20 minutes 1-2 mg dilaudid= 10-20 mg IV morphine 2-4 mg every 4-6 hours onset 20-40 minutes peak 1.5 hours
Codeine
-low affinity for opioid receptors
-analgesic effects are due to 10% conversion to morphine with causes analgesia
-less 1st pass metabolism than morphine when taking orally-so slightly more effective
–tyelnol #3 (30 mg codeine + 300 mg tyelnol)
–tyelnol #4 (60 mg codeine + 300 mg tyelnol)
hydrocodone (vicodin–hydro + acetaminophen)
-oxycodone (percodan)
—-percocet (oxycodone + acetaminophen)
—-oxycontin
Oxycodone
less 1st pass metabolism than morphine
- percocet 5 mg oxycodone + 325 mg acetaminophen
- adults 5-15 mg (1-3 tabs) every 6 hours
- peds 0.05-0.15 mg/kg every 4-6 hours (beware tylenol limits)
Oxycontin
-sustained release tablets
10-20mg q12 hours
80-160 mg for opioid tolerant pts (cancer)
sustained release when taken whole
bolus “high” when rushed or chewed– abuse problem
Nalaxone
competitive antagonist at mu, kappa, delta
IV, IN, SQ admin is effective
peak effect 1-2 minutes IV
metabolized liver (glucuronidation)
excreted urine
half life 65 min (adults), 3 hours (neonates)
standard ampule: 0.4 mg or 400 mcgs
adults dose: 0.5-1.5 mcg/kg (40-100 mcg)
will reverse excessive opioid induced respiratory depression
-give 400 mcg or whole amp in a code blue respiratory depression or narcotic OD (beware of withdrawal, ht., tachycardia, pulmonary edema, PONV)
Naltrexone
long acting oral opioid antagonist used to treat opioid and alcohol dependent addiction
Meperidine
1/10th the potency of morphine but more lipid soluble=faster onset
-less bradycardia and less respiratory depression than equianalgesic doses of morphine
-some local anesthetic activity–sensory and motor block (SABs)
-has dysphoric and psychomimetic effects- K receptor
-less biliary pressure effect
>histamine release than morphine
liver metabolism
active metabolite normeperidine T1/2 14-21 hrs
very useful for post operative shivering- K receptor affect
Serotonin Syndrome
Meperidine inhibits the repute of serotonin
-when given to a patient taking MAO inhibitors or selective serotonin reuptake inhibitors (SSRIs), Meperidine may cause Serotonin Syndrome
Manifests as:
- Delirium
- Fever
- Convulsions
SS does not occur with Meperidine derivatives (Fent)
Fentanyl
-almost complete mu receptor agonist
50-100X more potent than morphine
100 mcg fent= 10 mg morphine
effects and se similar at equal dose
Onset 3-5 minutes IV
- more rapid brain equilibration than morphine
- lipid solubility 816
- rapid onset of analgesia= rapid resp depression
- fentanyl induction will reduce your MAC requires of inhaled anesthetic
- NO direct reduction in myocardial contractility (BP will drop if pain is relieved)
Opioid effects on inhaled anesthetic MAC
- Increased opioid allows reduced ISO
- MAC reduction may be >75%
- MAC reduction occurs at moderate plasma levels of opioid
- Isoflurane can NOT be eliminated
Fentanyl
- no histamine release-no vascular tone hypotension
- synergy with benzodiazepines=respiratory depression
- 100% hepatic extraction- inactive metabolites
- clearance directly correlated to liver blood flow
- decrease with P450 inhibitors
CSHT depends on length of administration
1 minute= t/12 5 minutes
1 hour=t1/2 20 minutes
8 hour infusion=t1/2 250 minutes
infusions:
LD: 8-12 mcg/kg
MD: 1-1.5-2 mcg/kg/hr
transdermal patches used for cancer and chronic pain
Alfentanil
-almost completely mu receptor agonist
10X as potent as morphine
1/10th-1/4th as potent as fentanyl
1000mcg alfentanil=100 mcg fent=10 mg morphine
extremely rapid onset: 1-2 minutes
90% unbound is unionized at pH 7.4
rapidly crosses the BBB
metabolized in the liver 30-50%
inactive metabolites
clearance is directly proportional to liver blood flow
reduced with P450 inhibitors
lower in elderly and CHF
-CSHT: changes less over time, lower lipid solubility (less redistribution) and higher liver clearance
Alfentanil loading dose
35-70 mcg/kg
2,500- 5,000 mcg in 70 kg pt
Alfentanil comes in 500 mcg/cc
-maintenance infusion 0.25-0.50 mcg/kg/min
-rapid onset of action= rapid onset of respiratory depression (Beware)
Remifentanil
-almost completely mu receptor agonist
equipotent to fentanyl
very rapid onset 1 minute
metabolism is by non-specific plasma esterases (NOT pseudocholinesterase)
-clearance is constant and not affected by liver flow, renal failure or length of infusion
-no residual analgesia— need long acting opioid before turned off
infusions– only way to use remifentanyl
LD: 1-2 mcg/kg
infusions: 0.05-0.25 mcg/kg/min
CSHT: 3 minutes
duration: 6-9 minutes after infusion turned off
DOA Policy:
mix 4 mcg/cc (1mg/250 ml) for non intubated cases
mix 10 mcg/cc (1 mg/100 ml) for intubated/GA cases
Spinal Opioids
Preservative Free
- spinal mu receptors are present in DH
- morphine and fentanyl administered spinally is analgesia
- morphine or fentanyl can be administered intrathecally (directly into CSF) for chronic pain and intrathecally or epidurally (just outside spinal column) for acute pain
When administered spinally or epidurally:
1. Morphine controls pain well and produces less sedation and respiratory depression for same amoutn of analgesia
—but resp depression, N/V, sedation, itching can occur
intrathecal injection: pain relief in 2 minutes
epidural: 20 minutes for onset of relief
Opioid Synergism
-when admin alone= potent resp depressant
Bezos alone= minimal respiratory depression
propofol= mild resp depression when adminstered as constant infusion of 25-150 mcg/kg/min
Opioid+benzo OR Opioid + propfol= significant synergy and can cause significantly greater respiratory depression, obtundation, and resp arrest at much lower doses than those given when agents administered alone
Active Metabolites: Morphine Hydrocodone Meperidine Oxycodone Codeine Tramodol
Morphine: M6 glucuronide Hydrocodone: hydromorphone Meperidine: normeperidine Oxycodone: oxymorphone codeine: morphine tramodol: o-des-methyl tramodol
