L47 - L48: Opioids

Question 1

Spinal cord (dorsal horn)

Answer 1

Reflex withdrawal

Question 2

Spino-thalamic

Answer 2

Conscious perception

Question 3

Spino-hypothalamic

Answer 3

Endocrine response

Visceral response

Question 4

Spino-reticular

Answer 4

General arousal

Visceral response

Question 5

Spino-mesencephalic

Answer 5

Major pain processing center

Question 6

Primary sensory cortex

Answer 6

Conscious perception

Emotional response

Question 7

What is mood alteration (euphoria, tranquility) attributed to?

Answer 7

Mu receptor activation in ventral tegmental area (one of the ‘pleasure’ or ‘reward’ centers of hypothalamus

Question 8

Why does nausea and vomiting occur?

Answer 8

Opioids activate brainstem chemoreceptor trigger zone (CTZ) stimulating nausea and vomiting

Symptoms may be worse during ambulation - may have vestibular contribution

Question 9

What are the hormonal effects of opioids?

Answer 9

Opiates modify release of many hormones from hypo-thalamic-pituitary-adrenal axis

Reproductive hormones (LH, FHS testosterone) and beta-endorphins - female addicts have irregular cycles and males have reduced sex drive

Oxytocin and ADH - can cause hypotension

Body temperature - decrease body temp by action on hypothalamic heat regulating centers; high dose to chronic users may cause temperature elevation

Question 10

What are the motor system effects of opioids?

Answer 10

Opioids block neurotransmitter release in the basal ganglia, e.g. stratium

Mixed effects - relaxation and rigidity; eyelid droop, speech slurred, “heaviness in limbs”, walking is slow

High doses - catatonia, muscular rigidity

Question 11

Effects of opioids on GI tract

Answer 11

High density of opioid receptors in GI tract

Constipation, increased muscle tone, inhibition of smooth muscle contraction and propulsive activity

Question 12

Effects of opioids on biliary tract

Answer 12

Opioids constrict biliary smooth muscle and may result in colic causing pain

Question 13

Effects of opioids on ureter and urinary bladder

Answer 13

Opioids increase urethral and bladder tone

Produce sense of urinary urgency

Increased sphincter tone causes urinary retention, particularly in postoperative patients

Question 14

Effect of opioids on pupillary constriction

Answer 14

Opioids produce miosis (pinpoint pupils)

Act on parasympathetic pathways from oculomotor complex (cranial nerve III); blocked by atropine

Tolerance doesn’t develop to this

Question 15

What can precipitate opiate withdrawal syndrome?

Answer 15

Antagonists can precipitate opiate withdrawal within a few minutes of administration

Question 16

What is addiction of opioids due to?

Answer 16

Action on reward center in hypothalamus

Psychological dependence on state of euphoria, indifference

Wish to avoid withdrawal symptoms

Question 17

Why does heroin have to be injected?

Answer 17

First pass effect

Question 18

How are opioids metabolized and excreted?

Answer 18

Most converted to polar metabolites in the liver by addition of something like glucuronide to it

These metabolites can have significant pharmacological effects themselves

M6G and M3G excreted by kidneys

Question 19

Heroin

Answer 19

Diacetylmorphine

Most lipophilic of all opioids - acetyl groups at 3 and 6 hydroxy positions

Cross blood-brain barrier rapidly since very lipophilic

In brain, quickly hydrolyzed to morphine; builds up high concentration in brain

3 -4 times analgesic potency

Withdrawal symptoms more intense than morphine

Overdose frequent

Question 20

Codeine

Answer 20

Orally effective

Antitussive - drug of choice for cough

Analgesic: used for relief of dull, continuous pain in ambulatory person

Has respiratory depressant and sedative effects

1/10 potency of morphine

Side effects are like morphine, but toned down

Tolerance can develop

Takes a while for physical dependence to occur

Question 21

Oxycodone

Answer 21

Chemical modification of codeine

Good oral efficacy

Primary use: oral analgesics and antitussive

Similar to morphine in important pharmacology

Question 22

Percodan

Answer 22

Oxycodone + aspirin

Question 23

Percocet

Answer 23

Oxycodone + acetaminophen

Question 24

OxyContin

Answer 24

Longer lasting dosage

Pill had high drug content and was crushed and injected

Now reformulated w/ abuse-resistant polymer making pill more difficult to crush

Question 25

Methadone

Answer 25

Similar to morphine: analgesia, sedation, respiratory depression, miosis, constipation, antitussive effects

Good oral absorption

Duration: single dose - 6 hours; repeated doses - 16 to 20 hours (long acting)

Used as replacement for heroin in “methadone treatment” of addition - potent; orally effective; high persistent effect when given repeatedly (unlike morphine) even though single dose has same duration of action; can be used as single daily dosage to suppress withdrawal symptoms

Useful for treatment of chronic pain

Question 26

Fentanyl

Answer 26

Sublimaze of china white

Potent analgesic with relatively short durations of actions: 80 - 100x more potent than morphine; more lipid soluble than morphine, which accounts for more rapid onset and shorter duration of action; onset = 5 min; duration = 0.5 to 1 hour

Intravenous supplements to general anesthesia and induction of anesthesia

Major advantage - cardiovascular stability

Highly absued (china white is street name) bc of immediate rush; there is a lot of mixing a little bit of fentanyl w/ heroin

Question 27

Duragesic

Answer 27

Fentanyl patch

Delivers fentanyl for ~3 days: used only for severe pain, not treated by less potent drugs

Question 28

Diphenoxylate

Answer 28

Lomotil

Therapeutic use: antidiarrheal
Not an analgesic, not an anti-tussive

CNS depression action, some euphoric effects

Lomotil is combination w/ atropine; diphenoxylate is potentially addictive, but atropine makes abuse unlikely (if you try to up the dose, atropine kicks in and makes you sick so you’ll stop)

Question 29

Tramadol

Answer 29

Synthetic codeine analog

Weak mu receptor agonist

Also acts as norepinephrine and serotonin uptake inhibitor

Used for moderate to moderately severe pain

Side effects may include seizures

Question 30

Nalbuphine

Answer 30

Strong kappa receptor agonist, mu receptor antagonist

Used for moderate to severe pain

May have ‘ceiling’ to respiratory depression

But may be additive with some mu receptor agonists at lower doses

Question 31

Buprenorphine

Answer 31

Partial mu receptor agonist and antagonist

Less euphoria and respitaroy depression than heroine or methadone

At moderate doses reach ‘ceiling’ effect

Injected: Rapid onset 2 - 3 min, 15 min IM

Analgesic duration 3 - 6 hours (pretty long-lasting)

Very slow release from receptor (which is why, at high doses, is an antagonist)

Use in ‘methadone’ opiate replacement therapy

Question 32

Naloxone

Answer 32

Perfect antagonist - no action or cross-antagonism

Requires IV admin

Almost immediate onset: 1 - 2 min for response

Relatively short duration of action (b/w 1 -4 hours); have to re-inject

Once stabilized, use naltrexone

Question 33

Naltrexone

Answer 33

Effective orally

Remarkably long duration of action

Single oral dose blocks opioid agonists for 48 - 72 hours

Can’t use for acute toxicity if need rapid onset

Very useful for treating morphine overdose - patient does not need to be monitored for relapse of respiratory depression

Reduces alcohol and opioid cravings - probably by acting on pleasure centers in hypothalamus

Question 34

What is the benefit of packing naloxone with an orally absorbed agonist?

Answer 34

Co-packaging to prevent abuse

Taken orally, agonist works as pain medication

Injected, nalaxone prevents agonist action

(E.g. oxycodone and naloxone)

Taken orally, naloxone has no effect

Crushed and injected, naloxone blocks receptors