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