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90 Cards in this Set
- Front
- Back
Physiology of pain
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nociceptor neurons activated by pressure, heat, cold, stretch, or chemical stimuli
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Local mediators
monoamines peptides arachidonic acid metabolites |
(MA)- Histamine, serotonin, NE
(Peptides)-Substance P, CGRP, kinins(bradykinin) interleukins (ARA)- Cyclooxygenase products: prostaglandins, thromboxanes Lipoxygenase products: leukotrienes |
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Afferent Pain pathway
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Primary Adelta and C fibers--Spinothalamic tract (STT)--Spinoreticular and spinomesencephalic tracts
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STT vs. Spinoreticular/mesencephalic tracts
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Discriminative vs affective pain
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Desending Pain Control
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Signal from PAG via Raphe Magnus (ventral medulla) to Dorsal horn, reduces activation of pain primary afferents
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Endogenous opoid peptides are derived from three gene products, what are they
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Beta endorphin, methionine-enkephalin/leucine-enkephalin (by pro-enkephalin gene), dynorphins (pro-dynorphin gene)
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B-endorphin is found...
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Hypothalamus, brain stem, and pituitary
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B-endorphin cosynthesized with...
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ACTH or alpha-MSH in pro-opiomelanocortin (POMC)
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What happens to enkephalins in the PNS
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Rapidly degraded by peptidases
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Where is dynorphin found
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Brain, pituitary, neurons of supraoptic and paraventricular
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What happens to dynorphin
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Rapidly degraded by peptidases
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TENS
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Transcutaneous electrical stimulation. Patient controlled electrical stimulation of sensory neurons
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What TENS MA?
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Enhances descending pain control pathway both opiod and non-opiod (NE, 5HT)
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What's the TENS effect?
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Pain controlled at and below level of stimulation and last beyond stimulation
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Acupuncture
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Electrical or mechanical stimulation of needles placed at specific sites
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What is the effect of acupuncture?
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Pain relief beyond stimulation and analgesia is antagonized by opiate drug antagonists.
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PAG electrical stimulation
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Experimental stimulation of electrodes in the PAG to activate descending pain control pathways
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Is PAG electrical stimulation antagonized?
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Yes, by opoid antagonist release, release of enkephalins and Beta endorphin into CSF occurs.
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What are the agents that act at sensory nerve endings?
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Aspirin, salicylates(derivative of aspirin), NSAIDs, acetaminophen, bradykinin antagonists, and opiates
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What is the MA of aspirin, salicylates, NSAIDs, and acetaminophen
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Inhibition of cycloooxygenase
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What is the MA of opiates?
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hyperpolarization?
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What agents act at nerve trunks? How?
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local anesthestics, prevention of nerve conduction
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What agents work at the spinal cord, how?
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local anesthetics-nerve block
Opiates- hyperpol., (-)NT release Sub P antagonists- decrease substance P |
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What agents act at the thalamus? How
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Opiates- inhibit NT release
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What agents act at the PAG, ventral medulla?
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Opiates- activate descending pain control pathways
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What agents act at central cites?
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Acetaminophen
Aspirin? |
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What agents act at the cortex?
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Opiates- cause loss of consciousness
General anesthetics |
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Ziconotide (Prialt)
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Approved for neuropathic pain that responds to nothing else. Blocks N-type Ca channels.
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Where does opium come from?
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Opium poppy- papaver somniferum
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What are the opiates?
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Morphine
Codiene (weak analgesic) |
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What are the synthetic opiate drugs?
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methadone
meperidine fentanyl propoxyphene hydromorphone oxycodone |
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How are opiates absorbed?
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Readily by subcu,i.m, and from G.I.*
*significan first-pass effect Fentanyl can be transdermal |
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Are opiates protein bound?
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Partly, they are distributed to all tissues, mainly in kidney,liver,lungs, and spleen. Small amount to brain
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Where is the major site of metabolism for morphine
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Mainly in liver: major route by glucoronic acid conjugation
minor route by N-demethylation to normorphine(less active) |
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Metabolism of Codeine
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Mainly in liver, converted to morphine.
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Which enzyme determines codeine metabolism?
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CYP2D6
*not anaglesic in patients deficient in 2D6 |
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Excretion of opiods
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Most polar metabolites (conjugates) in urine, free morphine also in feces via bile
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What are the critical features of opiate activity?
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Aromatic ring with 3 position substituent
Hydroxyl @ 3 position is most potent Tertiary nitrogen Size of nitrogen substituent-larger groups confer antagonism |
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What are the 3 kinds of opiate receptors?
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mu (m), delta (&), and kappa (k)
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Function of m receptors
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Mediate analgesia, anesthesia, sedation, miosis, euphoria, constipation, respiratory depression
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Do m receptors have low or high affinity for morphine-like drugs?
(enkephalins and B-endorphin) |
High
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What happens when m receptors are chronically activated
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Dependence
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What do k receptors do
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Mediate analgesia, miosis, sedation, dysphoria.
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What do k receptors have a high affinity for?
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dynorphin
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What do delta receptors mediate? What do they have an affinity for?
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May influence behavior and central regulation of CV system
High affinity for Met/Leu-enkephalin, and B endorphin |
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Opioid Antagonists
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Naloxone
Naltrexone |
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What Naloxone and Naltrexone good antagonists?
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Large N-position substituents
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How does Naltrexone differ from Naloxone?
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Longer duration, used to treat addiction
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Opioid Partial Agonists
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Pentazocine
Nalbuphine Buprenorphine |
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Why give partial antagonists with morphine?
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Antagonize morphine lessening it's affects. Lower abuse potential
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Cellular effects of opioid receptor activation
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Increased K+ conductance
Reduced Ca conductance Inhibition of adenylyl cyclase |
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What is the consequence of increased K+ conductance?
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Membrane hyperpolarization, reduced excitability, reduced NT release
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What is the consequence of reduced Ca conductance
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Reduced signal for NT release
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What are the short term consequences of inhibition of adneylyl cyclase?
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Possible inhibition of NT release, lower cAMP, reduced activity of cAMP activated enzymes
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What are the long term consequences of inhibition of adneylyl cyclase?
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Altered expression of cAMP-regulated genes
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Opioid affect on neurons
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Inhibition of NT release, decreased Ach, NE, GABA, Sub P
Modification of gene expression |
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How much morphine to relieave moderate pain? Severe?
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10mg
15-20mg |
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What are the side effects of large doses of morphine
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drowsiness, nausea, vomiting, respiratory depression
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Is pain relief from morphine selective?
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Yes, touch, temp, sight, and sound senses are not affected
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Analgesia can be rapidly and completely reversed by what drug?
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Naloxone
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How long does 10-15mg of morphine last?
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2-5 hours
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Can you give 10mg morphine with aspirin or NSAIDs?
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Yes
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What is the most common cause of death in opiate overdose?
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Respiratory depression
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How can you rapidly reverse respiratory depression
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Naloxone i.v.
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How long does Naloxone last?
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about 2 hours, may need more than one dose
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Characteristics of respiratory depression caused by analgesia
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Depression of all phases
Irregular breathing Reduced sensitivity to PCO2 Direct depression of pontine and medullary centers to electrical stimulation Tolerance? (I assume for the antidote) |
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High dose opiates
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Can produce generalized neural depression and anesthesia
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Is morphine a good anesthetic
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No
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Use of Fentanyl
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Used as a primary anesthetic
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Features of opiate anesthetics
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Higer dose
Severe resp. depression, artificial respiration required little muscle relaxation- use other muscle relaxant |
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Advantages of opiate anesthetics
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No peripheral vasodilation (good in cardiac surgery)
Rapidly reversible |
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Disadvantages of opiate anesthetics
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Little muscle relaxation
Consciousness may not be fully lost |
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What are the stimulatory effects of opiods?
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Miosis, nausea, emesis, rush
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What is the major effect of opioids on the G.I. system
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Constipation
reduced motility, increased H2O retention, increased sphincter tone (esp. pyloric) |
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When is morphine contraindicated?
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In biliary colic, increases constriction of bile duct
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Antidiarrheal agents
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Diphenoxylate
loperimde (Imodium) |
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What is diphenoxylate with atropine?
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Lomotil
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Which hormones increase in respose to morphine and decrease in response to Naloxone?
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Prolactin, GH
(acidophil secretions) |
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Which hormones decrease in response to morphine and increase in response to Naloxone?
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TSH, ACTH, LH
(basophil secretions) |
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Antitussives
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Codeine
Dextromethorphan |
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Morphine Duration
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3-4 hours
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Codeine: more or less potent than morphine, duration
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less
3-4 hours |
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Heroin (diacetylmorphine)
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enters CNS more rapidly than morphine
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Hydromorphone (Dilaudid): more or less potent than Morphine, duration
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more
3-5 hours |
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Methadone: more or less, duration, use
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Equipotent to morphine
4-6 hours Treatment of heroin addiction |
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Meperidine (Demerol): more or less, duration
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less
2-3 hours |
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Oxycodone (Percodan): more or less, duration, use
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less
3-4 hours analgesic for mild pain |
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Fentanyl: potency, duration, delivery
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very potent
1 hour I.V. or transdermal patch |
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Loperamide characteristics
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highly potent demerol analog, does not enter brain or cause analgesia, resp depression. No abuse ability
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Naloxone (Narcan)
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Antagonizes actions of all opiates
1-2 hours |