Flashcards in Opioid Analgesics and Pain Management Deck (48):
What are the phenenthrene alkaloids?
• All derived from the opium poppy
• These are the narcotics kind of opioids
• Codeine (methylated morphine)
What are the benzylisoquinolines?
• Compounds lacking analgesic properties
It can treat angina, heart problems, and blood vessel problems by relaxing muscles and blood vessels. It can also relax muscles in the digestive system and other parts of the body.
○ Noscapine - cough suppressant
What are the four families of naturally occuring animal opioid peptides?
What are enkephalins?
• Act as modulatory neurotransmitters at synapses
• They are pentapeptides with different endings
○ Opioid moiety = Tyr-Gly-Gly-Phe
○ Methionine enkephalin
○ Leucine enkephalin
• Rapidly broken down by peptidases (act short distance, just assume active at synapse)
• Found in neurons throughout the brain and spinal cord
• Derived from pro-enkephalin
What are endorphins?
• Larger + different distribution than enkephalins
• Act as both NT and neurohormones (runners high)
• All peptides derived from POMC
○ POMC = proopiomelanocortin
• Found in hypothalamic neurons, and pituitary
What are the specific molecules derived from POMC?
• POMC = proopiomelanocortin
• These are endorphins
• Beta-lipotropin, ACTH, gamma-MSH
○ Beta-endorphin is important and most active end result
What are dynorphins?
• Physiological role less clear
• Kappa-receptor selective
○ fewer drugs for kappa-selective than mu-receptor selective
• Derived from prodynorphin
What are endomorphins?
• New family of opioid peptides
• Variation of opioid ligand motif
• Mu-receptor selective
○ Most important exogenous opiates are mu-receptor selective!
What should you generally keep in mind about the endogenous opiates?
• Peptide systems appear to be distinct
• Peptides demonstrate some selectivity for different receptors
○ Not enough to explain variance in function so there must be cell biology regulation in expression
• Effects can me antagonized by naloxone
• Peptides can mediate all responsponses seen with exogenous opiate drugs including analgesia, tolerance and dependence
What are the properties of the opioid receptors?
• Three major classes
○ Mu, delta, kappa
• All are coupled to Gi/Go GPCRs
• They all have a unique distribution profile through the CNS and PNS
○ Mu-receptor - analgesia (central), respiratory depression
○ Delta-receptor - analgesia
○ Kappa-receptor - spinal analgesia
What are the properties of the mu-receptor?
• Pharm response
○ Analgesia (central)
○ Respiratory depression
• Endogenous agonist (peptide)
• Exogenous agonist
What are the properties of the kappa-receptor?
• Pharm response
○ Spinal analgesia
• Endogenous agonist (peptide)
• Exogenous agonist
What are the properties of the delta-receptor?
• Pharm response
○ NO respiratory depression
• Endogenous agonist (peptide)
• Exogenous agonist
○ No drugs against delta-receptor as of yet
In what physiological systems are opiod receptors found that produce analgesia?
• Periaqueductal gray
○ Descending pain
• Medulla nuclei
○ Causes respiratory depression side effect
• Spinal cord dorsal horn
○ Ascending pain)
Where do opioid receptors live in the gut?
• Myenteric plexus
○ Causes the constipation side effect
What are the "reinforcement" regions in the CNS where opioid receptors live?
• Ventral tegmentum
• Nucleus accumbens
○ These all play a role in addiction and abuse
Where are the opioid receptors in the CNS that affect the limbic and motor CNS regions?
○ End result of these is the affective response to pain
When an opiate receptor is bound, what is the result? (receptor mechanism)
• Decrease neuronal excitability
• Direct inhibition of calcium channels, activation of potassium channels and inhibition of NT release (Gi/o GPCRs)
• Inhibition of cAMP synthesis
How does the opioid analgesic inhibit transmission in pain pathways?
• Inhibition of NT release from primary afferent terminals in dorsal horn of the spinal cord
○ Substance P, glutamate, others?
• Inhibition of spinothalamic "ascending" output neurons
• Activation of "descending" inhibitory output systems in the medulla, PAG, locus coeruleus
○ Mediated by 5-HT (serotonin) and NE
Besides physically modulating the relay of pain information, how else can opiates reduce pain?
• Reduce the subjective response to pain
○ Change perception of pain?
• Induce tranquility and euphoria
• Patients report feeling pain but the response to pain is blunted
• Possible involvement of limbic system, locus coeruleus, ventral tegmentum
What are the 5 aspects of opioid analgesia you should keep in mind?
• Opiod drugs are more efficacious than other analgesic drugs but are more dangerous for their respiratory depression
• Selectively eliminate pain without altering other sensations and without LOC
• Relieve dull, constant pain better than sharp, intermittent pain
• Reduce nociceptive pain, but not neurogenic pain
• Opioid drugs are not antipyretics but can be combined with antipyretics such as acetomenophen, aspirin, or ibuprofen
○ Vicodin, percocet, percodan
What are the typical clinical uses for opioids?
• Relief of moderate to severe pain (70% of patients respond well)
○ Pain with malignancy (chronic use)
○ Painful diagnostic procedures (in combo with local anesthetics and tranquilizers)
○ Post-op pain
○ Obstetrical anesthesia
§ Watch for newborn respiratory depression
○ Patient-controlled analgesia (PCA)
○ Cough - the non-analgesic kinds of opioids?
What are the behavioral effects of opioid drugs?
○ Relative to rapidity of onset (route of admin, lipid solubility)
○ Correlated with abuse potential
○ Primarily involves mu-receptor, activation of brain reward pathways
○ Psychotomimetic effect (hallucinations)
○ Often involves actions at kappa-receptor
○ Seen at higher doses usually
○ Salvinorin A is a kappa-receptor agonist that induces profound dysphoria
• Sedation, lethargy, confusion
○ Common side effects
○ CNS depression overall
• Behavioral excitation
○ This one is a sign of acute toxicity
○ More frequent with high concentrations of opioids
○ More frequent with certain drugs such as meperidine and codeine
○ Can be due to build-up of toxic metabolites
In terms of CO2 levels, what is the worry you have with opioids?
• In general, the primary cause of opioid-induced death is respiratory depression
• Increase in blood CO2 levels leads to cerebral vasodilation
• Vasodilation can make ICP and head injury worse
• CONTRAINDICATED in the use of suspected head injury
• Use with caution in any case of compromised respiratory function
○ Asthma, emphysema, obesity, etc
Opioid actions on brainstem nuclei can produce what?
• Useful and dangerous side effects
• Respiratory depression
• Nausea and vomiting
• Cough suppression
• Pupillary constriction (miosis)
How do opioids affect cough?
• They provide symptomatic relief from cough
• Mediated by inhibitory effects in cough center of medulla
• Prototypical cough suppressant = codeine
○ Lower doses than analgesia and resp. depression
○ But be aware of overdose
○ Can use non-analgesic forms
One sign of opiate abuse is "pinpoint pupils". Why?
• Pupillary constriction (miosis) is an action of opioid receptors in the brainstem nuclei
• Excitation of edinger-westphal nucleus
• No tolerance can build to this response so it can be indicative of abuse
Opioids can affect the GI system in what ways?
• GENERAL - constipation - work on myenteric plexus
○ Decreased intestinal secretion
○ Decreased gastric motility
○ Increased gastric emptying time
○ Increased tonus of sphincters
○ Little tolerance to GI effects
What can you use to block opioid-induced GI problems?
• Naloxone or it's various formes
• Naloxegol is a special form that inhibits BBB penetration
○ PEGylated naloxone
• Alvimopam has poor absorption
What are the GI only opioid drugs?
• Low abuse potential b/c of low water solubility
• Loperimide (imodium-AD)
One side effect of opioid use is biliary pain. What do you do about this?
• Opioids cause crazy constriction of sphincter of Oddi
• 10x increased in biliary pressure
• In the context of treating biliary pain (gall stones)
○ Administer with smooth muscle relaxant (atropine) or opioid makes pain worse
Does opioid treatment affect urination?
• Yes, increases tonus and contraction, but not synchronization
• Urine retention after surgery sometimes requires catheterization
• Rapid tolerance develops, so it's less a problem in chronic pain treatment
Can an anaphylaxis response happen with opioid admin?
• Yes, but it's rare. Only IV admin
• Symptoms can respond to antihistamines as the main problem is stimulation of histamine release
○ Local vasodilation
• Can make asthma worse
Are you worried about cardiovascular effects of opioid analgesics?
• Not really, as they have minimal effects on CV system at therapeutic doses
• Most effects are indirect (through histamine release)
○ Decrease cardiac work load
○ Inhibition of baroreceptor reflex and possible orthostatic hypotension
○ Use with caution in hypovolemia because of drop in BP
What are the all important situations in which opioid use is contraindicated?
• Respiratory dysfunction of any cause
○ One exception is pulmonary edema b/c of heart failure
○ Sleep apnea
○ Severe obesity (obesity hypoventilation syndrome and propensity for sleep apnea)
• Pathological situations
○ Head injury or increased ICP (increased cerebral vasodilation can cause problems)
○ Histamine release
○ Hypothyroidism (myxedema)
○ Impaired hepatic function (elderly, infants, alcoholics)
§ Increased bioavailability
§ Accumulation of toxic metabolites
What are the therapeutic uses of opioid analgesics in pulmonary edema?
• Useful when pulmonary edema is in the context of heart failure
• Alleviation of dyspnea
○ Works well, but don't know how or why
• Only exception for the contraindication of respiratory dysfunction use
What are the therapeutic uses of opioid analgesics in cardiovascular therapy?
• Myocardial infarction (MI)
○ Fentanyl and morphine
• Alleviate apprehension
• Decreases cardiac load
What are the opioid drug interactions (CNS depressants)?
○ Addictive or synergistic CNS depression
○ Can increase metabolism of some opioids
What are the opioid drug interactions (MAO inhibitors and tricyclic antidepressants)?
• Increase respiratory depression through unknown mechanisms
• Can induce CNS excitation, delirium and seizures
• Combo therapy using antidepressant 5HT and NE reuptake inhibition and opiate agonist activities may be useful in chronic pain treatment
○ Potentiating the inhibitory descending pain pathway
What are the opioid drug interactions (antipsychotics)?
• Penothiazines (subset of antipsychotics)
• Used to increase opioid analgesia but also increases respiratory depression
• Can increase hypotensive effects
• Can reduce analgesic actions of opioids sometimes
What are the three types of drug interactions with opioid use you need to know?
• CNS depressants
• MAO inhibitors and tricyclic antidepressants
What should you know about opioid absorption?
• Some are readily absorbed from GI, but most are not
○ Methadone and codeine well absorbed
• Most are more effective parenterally b/c of 1st pass metabolism
○ Morphine in particular
• All act more rapidly IV
• Rapidity of onset associated with lipid solubility and abuse potential
○ Heroin is the fastest
• Epidural or intrathecal admin is great for spinal level of analgesia with minimal respiratory depression
What's up with opioid distribution and fate?
• 1/3 of morphine is bound to proteins with therapeutic doses
• Small quantities of morphine get through BBB
○ Heroin or codeine are way better at CNS penetration
How are opioids metabolized?
○ Major pathway is conjugation with glucuronide in liver
○ Morphine-6-glucouronide is major metabolite of morphine
○ 100x more potent and may actually be the main analgesis
• After glucuronidation morphine is renally eliminated
What are the opioid phenanthrene mu-receptor agonists?
○ Used for post-op pain or acute trauma
○ Oral sustained release for chronic pain
○ Not a medicinal use drug
○ Highly lipophilic, fast onset
○ 2-3x more potent than morphine
○ Most commonly used
○ CYP2D6 metabolized
○ Often combined with acetaminophen or aspirin
○ Less potent than morphine
○ High oral bioavailability
○ 8x more potent than morpine
○ 10x more potent than morphine
○ Just as potent as morphine
○ Also blocks monoamine uptake and potentiates descending pain control pathway
What are the phenylpiperidine mu-receptor agonists?
○ For severe pain
○ Faster onset and offset than morphine
○ CNS excitation through toxic metabolites, thus not a chronic pain option
○ Frequent abuse by physicians
○ Decreased GI problems
○ Oral admin anti-diarrheal
○ Low solubility, low abuse
• Fentanyl (and relatives)
○ 100x more potent than morphine
○ Peri-operative and post-op pain management
○ IV admin
○ Short duration of action (1hr)
§ Morphine lasts 4-6 hours
○ Used as adjuncts to surgical anesthesia
○ Mechanical ventilation at high doses due to severe respiratory depression
*available in trandermal patches for slower release
Methadone is used for what?
• Opioid maintenance therapy for addiction
• Suppress withdrawal symptoms
• Orally not much euphoria
• Great analgesia though (full mu-receptor agonist)