Lecture 19: Opioids Flashcards
Which two compounds are naturally found in opium?
Morphine and codeine
3 opioid receptors and their endogenous opioid. These receptors are all which type? Analgesics act where?
Mu (endorphin), delta (enkephalin), kappa (dynorphin); GPCRs; mu
Where is each receptor localized? Give more detail on the subtypes of mu receptors (function)
Mu: brain, spinal cord, peripheral nerves, intestinal tract; mu1 = analgesia, mu2 = respiratory depression, miosis, euphoria, GI motility, mu3 = vasodilation; Delta: brain, peripheral nerves; Kappa: brain, spinal cord, peripheral nerves
Which opioid receptor is associated with dysphoria?
Kappa
How do endogenous opioid peptides interact with receptors? When are they released?
Full agonists; during stress/excitement/pain
Where are opioid receptors prominently expressed? Main function here?
Terminals of excitatory and inhibitory neurons; hyperpolarize terminal/interfere with Ca2+ entry –> reduce transmitter release
Postsynaptic opioid receptors are excitatory or inhibitory?
Inhibitory
Describe mu-receptor agonist activity in the periphery
Bind to presynaptic MORs, inhibit release
Describe mu-receptor agonist activity in the CNS
Mu agonists inhibit GABA interneurons in the PAG, which disinhibits the medulla –> 5HT and NE release in dorsal horn, inhibiting 2nd order sensory neurons (decrease pain signal)
Do opioids ever effect receptors other than MORs? Give 4 examples.
Yes! Morphine = kappa agaonist, buprenorphine = kappa/delta antagonist, methadone = NMDA antagonist, tramadol = block 5HT uptake
Describe absorption, distribution, metabolism and excretion of opioids
Absorption: well absorbed via subcutaneous, intramuscular, oral; Distribution: highly perfused; Metabolism: first-pass by liver, polar metabolites excreted by kidneys
CNS effects of mu agonists
Analgesia, drowsiness, euphoria respiratory depression, cough suppression, lowered seizure threshold, miosis
Cardio effects of mu agonists. Hormone?
Vasodilation; increased histamine
GI effects of mu agonists
Decreased motility/secretions
Renal effects of mu agonists. Hormone?
Decreased urination; increased ADH
Skin effects of mu agonists. Hormone?
Flushing, itching; increased histamine
Immune effects of mu agonists
Altered lymphocyte proliferation, Ab production, chemotaxis
What are 3 OTHER uses for morphine
Anti-dyspneic (first line therapy for symptom relief), anti-tussive, anti-diarrheal
Morphine’s mechanism
Full MOR agonist
Morphine is good for treating these types of acute pain…Compare nociceptive to neuropathic.
Trauma, peri-operative, acute coronary; nociceptive > neuropathic
Morphine: bioavailability, metabolism, excretion
0.25 oral; hepatic, 10% is active (morphine-6-glucuronide, more potent than morphine), 90% is a neurotoxin (morphine-3-glucuronide); 90% urine
Morphine: adverse effects w/ tolerance (5).
Sedation (tolerance); nausea (tolerance); constipation; respiratory depression (most common cause of morbidity but not significant at standard doses); other (delirium, seizure, dry mouth, urinary retention, pruritus)
Morphine: precautions (4)
Abdominal (worsen GI bc of reduced motility); hepatic (may metabolize poorly –> increased bioavailability); renal (neurotoxic metabolites may accumulate); respiratory disease/head injury (depressed response to pCO2 can worsen respiratory problems and increase ICP)
Codeine’s mechanism and morphine relation
Weak MOR agonist; pro-drug for morphine
Main clinical uses of codeine
Analgesia and cough suppressant
T/F: The adverse effects of codeine are better than morphine
False! N/V and pruritus are both worse than morphine
Describe codeine’s metabolism and importance
Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of morphine while poor metabolizers may have no effect
Describe oxycodone’s metabolism and importance
Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of oxymorphone while poor metabolizers may have no effect
These two common drugs are related to oxycodone. What are their relationships?
Oxycontin: ER formula; Percocet: combo with acetaminophen
What is Vicodin?
Hydrocodone + acetaminophen
Hydrocodone is derived from what? Clinical uses (2)
Codeine; analgesia and anti-tussive (more potent than codeine)
What is special about hydromorphone? (3)
- Safer in patients with liver disease; 2. Safer in patients with kidney disease (no active metabolites); 3. More potent than morphine (7-8x)
How does heroin work?
Morphine prodrug that is hydrolyzed in blood, liver, RBCs and easily crosses BBB due to lipophilicity
What is special about fentanyl? (2)
Does not cause histamine release and has no active metabolites
What is the clinical use, mechanism, and side effects of loperamide?
Diarrhea; slows intestinal contractions to allow moisture reabsorption; GI pain, dry mouth, anorexia, hyperglycemia, rare: necrotizing enterocolitis
What is the mechanism of action of Tramadol? Adverse effects?
Weak MOR agonist, 5HT releasing agent, NE reuptake inhibitor, NMDA antagonist, nicotinic antagonist, muscarinic antagonist; N/V, sweating, seizures but NOT sedative (respiratory depression, sedation, drowsiness, constipation)
What agonist has low efficacy?
Codeine
What agonists have moderate-to-high efficacy? (3)
Oxycodone, tramadol, buprenorphine
What agonists have high efficacy? (5)
Morpine, heroin, hydromorphone, fentanyl, methadone
Three theories of opioid tolerance
- Up-regulation of cAMP signaling pathway; 2. Reduced receptor recycling; 3. Receptor uncoupling from G proteins
What do you develop tolerance to first (days)? Weeks? Maybe never?
Sedation, respiratory depression, vasodilation; dyspnea relief, N/V, pruritus; analgesia, constipation, miosis
How do opioids cause miosis and why is this significant?
Disinhibit parasympathetic input to eye; no tolerance so reliable sign of opioid intoxication
What are the “pain steps”
Step One: NSAIDS; Step Two: Weak opioids (moderate pain); Step Three: strong opioids (severe pain)
What drugs produce toxic metabolites that can accumulate if pts have renal disease? What are better substitutes?
Morphine, oxycodone, codeine; fentanyl, methadone, hydromorphone
What are the two steps of rotating opioids?
- Calcuate equianalgesic dose; 2. Adjust dose for incomplete cross-tolerance
Why might incomplete cross-tolerance occur? What do you do when rotating opioids to take this into account?
Subtle differences in molecular structure/receptor interactions; reduce equianalgesic dose by 50%
How are Schedule 1 drugs unique? (2)
No currently accepted medical use and a high potential for abuse
Dependence
Development of withdrawal syndrome following dose reduction or administration of antagonist
Tolerance
Change in dose-response relationship induced by exposure to drug and need for higher dose
Craving
Desire for more of a substance/activity to experience the euphoric effect or avoid withdrawal aspects
Opioid Use Disorder
Problematic pattern of opioid use leading to clinically significant impairment or distress
Addiction
Compulsive use despite harm, craving, impaired control of drug use
Pseudo-addiction
Behaviors that are reminiscent of addiction, but are driven by pain and disappear with more adequate analgesia
What percent of adolescents use psychotherapeutics
About 7%, with opioids being the most common
How prevalent is OUD? Deaths?
5% of adults used opioids non-medically w/ 1.8 million OUD due to prescriptions and 500,000 due to heroin; 17,000 deaths annually due to OUD
Where are people getting these prescriptions?
Often just their one doctor or friend/relative’s one doctor; prescription rates are increasing
How long do we have data on long-term safety/efficacy for use of opioids?
2 months
What are some problems w/ opioids (4)
- Cause euphoria; 2. Limited safety/efficacy data for LT use; 3. Intensify response w/ snorting; 4. Tolerance
Neurobiological reason of addiction. Opioids? (2)
Drugs of abuse increase DA neurotransmission through mesolimbic pathway; opiods specifically disinhibit GABA neurons –> more transission AND mimic endorphins with influence NA
Substance Use Disorder
Recurrent use that causes clinically and functionally significant impairment; 2 symptoms over 12-month period; disease severity based on number of symptoms
Signs of OUD or diverting prescribed opioids (9)
Call for early refills/lose, demands specific opioid, neg urine drug screen (should be positive), doctor shopping, refuses communication with other providers, uses for indication other than pain, change in behavior, signs of opiate intoxication, pain out of proportion to exam
Likelihood that a patient with develop OUD w/ chronic opioid prescription
Depends on substance abuse history, about 0-7%
Factors associated w/ developing OUD
Personal/family history, male, poor social support, trauma history, comorbid psych disorder, history of conviction related to drugs/DWI
What can healthcare providers do to prevent OUD?
Prescribe responsibly: screen, give opioids when other treatments not effective, prescribe only necessary quantity, patient-provider agreements, talk with w/patients about safe use, storage, disposal; use drug monitoring programs; learn about pain
T/F: Urine drug screening is helpful all the time
False! Mixed efficacy (not all opiates identified, false positives), but probably helpful in identifying misuse in pain clinic
Pyschosocial treatments (3)
Counseling, residential programs, peer support groups
T/F: Recovery is greater when psychosocial + medication combined
True!
Three clinical settings for care
Inpatient (detox), residential, outpatient care (methadone clinics)
Methadone mechanism
Mu opioid receptor agonist and NMDA glutamate antagonist
Methadone clinical use
Analgesia (chronic especially if other opioids don’t work), opioid abuse detox
Methadone pharmacokinetics
Very greatly from person to person! Wide range in bioavailability (36 - 100%) and half-life (though long-acting), excreted renally and fecally
Methadone side effects (3 categories)
Same as mu opioid + NMDA SEs = depression, hallucinations + other = prolonged QTc/arrythmias
Why does methadone work?
Prevent withdrawal, slow release and less euphoria
Methadone maintenance of OUD
Must be enrolled in methadone maintenance program w/ strict rules (18+, dependent on opioids for >1 year); low doses w/ titration until withdrawal/craving disappears
Buprenorphine mechanism
Partial mu receptor agonist, antagonist at delta/kappa receptors, blocks VG-Na+ channels
Buprenorphine clinical use
Pain and opioid withdrawal/dependence
Special features of Buprenorphine
High affinity but low intrinsic activity for mu receptors (displace other opiates), slow rate of dissociation, ceiling effect for opiate effects and respiratory depression
How do you give Buprenorphine
Low oral bioavailability: sub-lingual
Does Buprenorphine require a clinic?
Nope! But clinician must take special course
Buprenorphine SEs
Similar to other opioids, safer in terms of overdose (less respiratory depression)
Naloxone mechanism
Opioid antagonist
Naloxone clinical use
Opioid overdose
Naloxone comes in what special form…
Auto-injector
Naloxone pharmacokinetics
Works quickly w/ short half-life
What is the combination of naloxone and Buprenorphine. Why?
Suboxone; pts who try to crush medication will get the effects of the Naloxone causing withdrawal
What is Naltrexone? Indication? Wait for what?
Long-lasting version of Naloxone; opioid/alcohol use disorders to maintain abstinence (blocks access of narcotics to opiate receptors sites); patient must have been through detox
Naltrexone common and rare but serious SEs
Headache, nausea, anxiety; DVTs, depression
Symptoms of opioid withdrawal
Anorexia, rhinorrhea, goosebumps, yawning, tearing, N/V, abdominal pain, muscle craps, sweating
T/F: Mortality is low in opioid withdrawal
True! As compared to alcohol
