Opioid Analgesics (finished)

Question 1

Describe the ways in which drugs can relieve pain

Answer 1

Eliminate cause of pain:
Anti-inflammatory (NSAIDs)
Chemotherapy (including antimicrobials)
Antiulcer

Prevent transmission:
Local anesthetics

Affect the way pain is perceived:
General anesthetics
Opioids

Affect patient’s reaction to pain:
Anxiolytics
Opioids

Question 2

Compare and contrast the terms opioid, opiate and narcotic

Answer 2

Opiate: drug derived from opium poppy
Opium, morphine, codeine

Opioid: more generic term; all substances, endogenous and exogenous, that bind opioid receptors
Endorphins (endogenous)
Morphine, also an opiate
Fentanyl, synthetic so not an opiate

Narcotic: originally meant sleep inducing (Greek “narcos”
Now a legal term encompassing illicit drug use
Includes opioids, cannabinoids, stimulants, etc.

Question 3

Discuss the advantages and disadvantages (limitations) of opioids and NSAIDs in terms of type and level of pain, adverse effects and drug dependence

Answer 3

be able to do this

Question 4

Describe and distinguish among the subtypes of opioid receptors

Answer 4

Mu (μ)
Analgesia
Respiratory depression
Decreased gastrointestinal motility
Physical Dependence

Kappa (κ)
Analgesia
Sedation
Decreased gastrointestinal motility

Delta (δ)
Modulates μ activity

ORL1 – Orphanin opioid receptor-like 1
Structurally similar to μ but insensitive to opioid ligands

Question 5

Give examples of opioids with active and toxic metabolites and the significance of this information in the treatment of pain

Answer 5

Pharmacologically Active
Morphine-6-glucoronide (morphine metabolite)
Excreted in urine, so can impact morphine’s effect and duration if renal function is compromised

Toxic metabolites
Normeperidine, a metabolite of meperidine
Excitotoxic: tremor, twitching, convulsions
Meperidine should only be used acutely

Question 6

List the clinical uses of opioids and how they relate to their sites of action centrally

Answer 6

Cortex:
Pain perception, reaction to pain, euphoria, sedation

Medulla:
Respiratory depression
Antitussive effects
Nausea, vomiting
Thermoregulation

Spinal Cord:
Depresses pain reflexes
Stimulates non-pain reflexes

Eye, occulomotor nerve:
Miosis (pinpoint pupils) – little tolerance so good indicator of opioid use

Vagus nerve:
Bradycardia
Increased GI tone

Question 7

Mu (μ)

Answer 7

Analgesia
Respiratory depression
Decreased gastrointestinal motility
Physical Dependence

Question 8

Kappa (κ)

Answer 8

Analgesia
Sedation
Decreased gastrointestinal motility

Question 9

Delta (δ)

Answer 9

Modulates μ activity

Question 10

ORL1 – Orphanin opioid receptor-like 1

Answer 10

Structurally similar to μ but insensitive to opioid ligands

Question 11

Opioid Receptor Signal Transduction

Answer 11

Presynaptic inhibition of afferent neurons:
Receptor activation blocks voltage-gated Ca2+ channels
Reduced release of glutamate and substance P

Postsynaptic inhibition:
Receptor activation opens K+ channels
Inhibit excitation of postsynaptic neuron

Enhanced inhibition of ascending pathway:
Pain inhibitory neuron indirectly activated

Opioid receptor activation blocks release of GABA from inhibitory interneuron

Greater inhibition of nociceptive processing in dorsal horn of spinal cord

Question 12

Agonist

Answer 12

Receptor binding produces effect

Examples:
Morphine
Methadone
Oxycodone
Heroin

Question 13

Antagonist

Answer 13

Receptor binding produces no effect
Reverses effect of morphine-like opioids

Examples:
Naloxone
Naltrexone

Question 14

Partial Agonist

Answer 14

Less efficacy than full agonist
Lower abuse potential

Example:
Buprenorphine
Often used with naloxone, an antagonist (Suboxone)

Question 15

Mixed Agonist-Antagonist

Answer 15

Agonist at one receptor
Antagonist at another

Example:
Pentazocine
Agonist at Kappa
Antagonist at Mu

Clinical relevance:
can initiate withdrawal symptoms

Question 16

Routes of Administration:

Oral

Answer 16

Convenient, but high first pass metabolism can be limiting
Slower onset, delayed peak effect, longer duration (relative to parenteral routes)
Better for chronic treatment

First pass metabolism: drugs absorbed from GI tract go to liver, are rapidly and efficiently metabolized
Oral morphine clinically effective, just requires 3-6x higher dose (relative to parenteral)
By contrast, methadone less impacted by first pass metabolism (1.5-2x higher dose)
Altered liver function – Clinical relevance?

Question 17

Routes of Administration:

Intravenous

Answer 17

Precise and accurate dosing
Rapid onset, but increased risk of adverse effects
Bolus versus continuous
Can be patient controlled (PCA)

Question 18

Routes of Administration:

Intramuscular/Subcutaneous

Answer 18

Rapid onset

Duration between oral and IV

Question 19

Routes of Administration:

Spinal

Answer 19

Longer duration at lower doses than systemic
Can avoid some brain-mediated adverse effects
Respiratory depression

Question 20

Routes of Administration:

Rectal suppository

Answer 20

Administration may be easily discontinued

Question 21

Routes of Administration:

Buccal/Sublingual

Answer 21

Faster onset than oral, avoids first pass metabolism
Convenient (no injection)
Example: Fentanyl “lollipop”

Question 22

Routes of Administration:

Transdermal

Answer 22

Convenient, avoids first pass metabolism
Better for chronic treatment
Examples: Fentanyl, Buprenorphine

Question 23

Sites of action and effects outside CNS

Answer 23

GI Tract:
Constipation, decreased gastric emptying, cramping, spasm
Slow tolerance, so always an issue with opioid therapy

Bronchiolar constriction (high doses)

Uterus – prolongs labor

Ureters – difficulty urinating

Causes histamine release
Flushing and itching of the skin

Question 24

Therapeutic uses

Answer 24

Analgesia
Especially severe pain
Cancer, chronic illness

Obstetric labor
Crosses placental barrier (neonatal respiratory depression)
Slows progress of labor

Anesthesia
Pre- and post-surgery
Sedative, anxiolytic, analgesic
Cardiovascular surgery
Minimizes CV depression

Cough
Codeine, dextromethorphan (non-opioid)

Diarrhea
GI effect (constipation)
All opioids effective
Loperamide (Imodium)
Doesn’t cross BBB
Diphenoxylate + Atropine (Lotomil)
Atropine – anticholinergic to discourage abuse

Question 25

Acute overdose

Answer 25

Naloxone
Short duration of action
Single dose – could relapse after 1-2 hrs
Injection to avoid first pass

Question 26

Addiction

Answer 26

Naltrexone
Orally effective
Single dose, alternate days blocks heroin effects
Prevent relapse in opioid addiction and alcohol addiction

Question 27

Opioid tolerance

Answer 27

Reduction in effect over time with repeated delivery
Increase in dose required for equivalent response

Rate of tolerance varies with endpoint

Question 28

Opioid dependence

Answer 28

Removal of drug, or administration of antagonist (e.g., naloxone) leads to withdrawal syndrome

Physical Dependence

Psychological Dependence

Addiction: Compulsive use, drug seeking behavior
Driven by euphoria, indifference to stimuli, sedation, “rush”
Methadone treatment: orally effective, long t1/2, low cost
Buprenorphine + naloxone (Suboxone)
Partial agonist + antagonist, can precipitate withdrawal
Lower abuse potential

Question 29

Opioid withdrawal

Answer 29

Unpleasant but not life threatening

Rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility

Onset, intensity and duration determined by drug used and degree of physical dependence

Reintroduction of opioid eliminates withdrawal symptoms