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Brain and Behavior > Lecture 19: Opioids > Flashcards

Lecture 19: Opioids Flashcards

1
Q

Which two compounds are naturally found in opium?

A

Morphine and codeine

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2
Q

3 opioid receptors and their endogenous opioid. These receptors are all which type? Analgesics act where?

A

Mu (endorphin), delta (enkephalin), kappa (dynorphin); GPCRs; mu

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3
Q

Where is each receptor localized? Give more detail on the subtypes of mu receptors (function)

A

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

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4
Q

Which opioid receptor is associated with dysphoria?

A

Kappa

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5
Q

How do endogenous opioid peptides interact with receptors? When are they released?

A

Full agonists; during stress/excitement/pain

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6
Q

Where are opioid receptors prominently expressed? Main function here?

A

Terminals of excitatory and inhibitory neurons; hyperpolarize terminal/interfere with Ca2+ entry –> reduce transmitter release

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7
Q

Postsynaptic opioid receptors are excitatory or inhibitory?

A

Inhibitory

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8
Q

Describe mu-receptor agonist activity in the periphery

A

Bind to presynaptic MORs, inhibit release

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9
Q

Describe mu-receptor agonist activity in the CNS

A

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)

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10
Q

Do opioids ever effect receptors other than MORs? Give 4 examples.

A

Yes! Morphine = kappa agaonist, buprenorphine = kappa/delta antagonist, methadone = NMDA antagonist, tramadol = block 5HT uptake

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11
Q

Describe absorption, distribution, metabolism and excretion of opioids

A

Absorption: well absorbed via subcutaneous, intramuscular, oral; Distribution: highly perfused; Metabolism: first-pass by liver, polar metabolites excreted by kidneys

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12
Q

CNS effects of mu agonists

A

Analgesia, drowsiness, euphoria respiratory depression, cough suppression, lowered seizure threshold, miosis

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13
Q

Cardio effects of mu agonists. Hormone?

A

Vasodilation; increased histamine

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14
Q

GI effects of mu agonists

A

Decreased motility/secretions

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15
Q

Renal effects of mu agonists. Hormone?

A

Decreased urination; increased ADH

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16
Q

Skin effects of mu agonists. Hormone?

A

Flushing, itching; increased histamine

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17
Q

Immune effects of mu agonists

A

Altered lymphocyte proliferation, Ab production, chemotaxis

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18
Q

What are 3 OTHER uses for morphine

A

Anti-dyspneic (first line therapy for symptom relief), anti-tussive, anti-diarrheal

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19
Q

Morphine’s mechanism

A

Full MOR agonist

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20
Q

Morphine is good for treating these types of acute pain…Compare nociceptive to neuropathic.

A

Trauma, peri-operative, acute coronary; nociceptive > neuropathic

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21
Q

Morphine: bioavailability, metabolism, excretion

A

0.25 oral; hepatic, 10% is active (morphine-6-glucuronide, more potent than morphine), 90% is a neurotoxin (morphine-3-glucuronide); 90% urine

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22
Q

Morphine: adverse effects w/ tolerance (5).

A

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)

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23
Q

Morphine: precautions (4)

A

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)

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24
Q

Codeine’s mechanism and morphine relation

A

Weak MOR agonist; pro-drug for morphine

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25
Q

Main clinical uses of codeine

A

Analgesia and cough suppressant

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26
Q

T/F: The adverse effects of codeine are better than morphine

A

False! N/V and pruritus are both worse than morphine

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27
Q

Describe codeine’s metabolism and importance

A

Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of morphine while poor metabolizers may have no effect

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28
Q

Describe oxycodone’s metabolism and importance

A

Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of oxymorphone while poor metabolizers may have no effect

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29
Q

These two common drugs are related to oxycodone. What are their relationships?

A

Oxycontin: ER formula; Percocet: combo with acetaminophen

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30
Q

What is Vicodin?

A

Hydrocodone + acetaminophen

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31
Q

Hydrocodone is derived from what? Clinical uses (2)

A

Codeine; analgesia and anti-tussive (more potent than codeine)

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32
Q

What is special about hydromorphone? (3)

A
  1. Safer in patients with liver disease; 2. Safer in patients with kidney disease (no active metabolites); 3. More potent than morphine (7-8x)
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33
Q

How does heroin work?

A

Morphine prodrug that is hydrolyzed in blood, liver, RBCs and easily crosses BBB due to lipophilicity

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34
Q

What is special about fentanyl? (2)

A

Does not cause histamine release and has no active metabolites

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35
Q

What is the clinical use, mechanism, and side effects of loperamide?

A

Diarrhea; slows intestinal contractions to allow moisture reabsorption; GI pain, dry mouth, anorexia, hyperglycemia, rare: necrotizing enterocolitis

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36
Q

What is the mechanism of action of Tramadol? Adverse effects?

A

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)

37
Q

What agonist has low efficacy?

A

Codeine

38
Q

What agonists have moderate-to-high efficacy? (3)

A

Oxycodone, tramadol, buprenorphine

39
Q

What agonists have high efficacy? (5)

A

Morpine, heroin, hydromorphone, fentanyl, methadone

40
Q

Three theories of opioid tolerance

A
  1. Up-regulation of cAMP signaling pathway; 2. Reduced receptor recycling; 3. Receptor uncoupling from G proteins
41
Q

What do you develop tolerance to first (days)? Weeks? Maybe never?

A

Sedation, respiratory depression, vasodilation; dyspnea relief, N/V, pruritus; analgesia, constipation, miosis

42
Q

How do opioids cause miosis and why is this significant?

A

Disinhibit parasympathetic input to eye; no tolerance so reliable sign of opioid intoxication

43
Q

What are the “pain steps”

A

Step One: NSAIDS; Step Two: Weak opioids (moderate pain); Step Three: strong opioids (severe pain)

44
Q

What drugs produce toxic metabolites that can accumulate if pts have renal disease? What are better substitutes?

A

Morphine, oxycodone, codeine; fentanyl, methadone, hydromorphone

45
Q

What are the two steps of rotating opioids?

A
  1. Calcuate equianalgesic dose; 2. Adjust dose for incomplete cross-tolerance
46
Q

Why might incomplete cross-tolerance occur? What do you do when rotating opioids to take this into account?

A

Subtle differences in molecular structure/receptor interactions; reduce equianalgesic dose by 50%

47
Q

How are Schedule 1 drugs unique? (2)

A

No currently accepted medical use and a high potential for abuse

48
Q

Dependence

A

Development of withdrawal syndrome following dose reduction or administration of antagonist

49
Q

Tolerance

A

Change in dose-response relationship induced by exposure to drug and need for higher dose

50
Q

Craving

A

Desire for more of a substance/activity to experience the euphoric effect or avoid withdrawal aspects

51
Q

Opioid Use Disorder

A

Problematic pattern of opioid use leading to clinically significant impairment or distress

52
Q

Addiction

A

Compulsive use despite harm, craving, impaired control of drug use

53
Q

Pseudo-addiction

A

Behaviors that are reminiscent of addiction, but are driven by pain and disappear with more adequate analgesia

54
Q

What percent of adolescents use psychotherapeutics

A

About 7%, with opioids being the most common

55
Q

How prevalent is OUD? Deaths?

A

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

56
Q

Where are people getting these prescriptions?

A

Often just their one doctor or friend/relative’s one doctor; prescription rates are increasing

57
Q

How long do we have data on long-term safety/efficacy for use of opioids?

A

2 months

58
Q

What are some problems w/ opioids (4)

A
  1. Cause euphoria; 2. Limited safety/efficacy data for LT use; 3. Intensify response w/ snorting; 4. Tolerance
59
Q

Neurobiological reason of addiction. Opioids? (2)

A

Drugs of abuse increase DA neurotransmission through mesolimbic pathway; opiods specifically disinhibit GABA neurons –> more transission AND mimic endorphins with influence NA

60
Q

Substance Use Disorder

A

Recurrent use that causes clinically and functionally significant impairment; 2 symptoms over 12-month period; disease severity based on number of symptoms

61
Q

Signs of OUD or diverting prescribed opioids (9)

A

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

62
Q

Likelihood that a patient with develop OUD w/ chronic opioid prescription

A

Depends on substance abuse history, about 0-7%

63
Q

Factors associated w/ developing OUD

A

Personal/family history, male, poor social support, trauma history, comorbid psych disorder, history of conviction related to drugs/DWI

64
Q

What can healthcare providers do to prevent OUD?

A

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

65
Q

T/F: Urine drug screening is helpful all the time

A

False! Mixed efficacy (not all opiates identified, false positives), but probably helpful in identifying misuse in pain clinic

66
Q

Pyschosocial treatments (3)

A

Counseling, residential programs, peer support groups

67
Q

T/F: Recovery is greater when psychosocial + medication combined

A

True!

68
Q

Three clinical settings for care

A

Inpatient (detox), residential, outpatient care (methadone clinics)

69
Q

Methadone mechanism

A

Mu opioid receptor agonist and NMDA glutamate antagonist

70
Q

Methadone clinical use

A

Analgesia (chronic especially if other opioids don’t work), opioid abuse detox

71
Q

Methadone pharmacokinetics

A

Very greatly from person to person! Wide range in bioavailability (36 - 100%) and half-life (though long-acting), excreted renally and fecally

72
Q

Methadone side effects (3 categories)

A

Same as mu opioid + NMDA SEs = depression, hallucinations + other = prolonged QTc/arrythmias

73
Q

Why does methadone work?

A

Prevent withdrawal, slow release and less euphoria

74
Q

Methadone maintenance of OUD

A

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

75
Q

Buprenorphine mechanism

A

Partial mu receptor agonist, antagonist at delta/kappa receptors, blocks VG-Na+ channels

76
Q

Buprenorphine clinical use

A

Pain and opioid withdrawal/dependence

77
Q

Special features of Buprenorphine

A

High affinity but low intrinsic activity for mu receptors (displace other opiates), slow rate of dissociation, ceiling effect for opiate effects and respiratory depression

78
Q

How do you give Buprenorphine

A

Low oral bioavailability: sub-lingual

79
Q

Does Buprenorphine require a clinic?

A

Nope! But clinician must take special course

80
Q

Buprenorphine SEs

A

Similar to other opioids, safer in terms of overdose (less respiratory depression)

81
Q

Naloxone mechanism

A

Opioid antagonist

82
Q

Naloxone clinical use

A

Opioid overdose

83
Q

Naloxone comes in what special form…

A

Auto-injector

84
Q

Naloxone pharmacokinetics

A

Works quickly w/ short half-life

85
Q

What is the combination of naloxone and Buprenorphine. Why?

A

Suboxone; pts who try to crush medication will get the effects of the Naloxone causing withdrawal

86
Q

What is Naltrexone? Indication? Wait for what?

A

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

87
Q

Naltrexone common and rare but serious SEs

A

Headache, nausea, anxiety; DVTs, depression

88
Q

Symptoms of opioid withdrawal

A

Anorexia, rhinorrhea, goosebumps, yawning, tearing, N/V, abdominal pain, muscle craps, sweating

89
Q

T/F: Mortality is low in opioid withdrawal

A

True! As compared to alcohol

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