Narcotic analgesics

Question 1

Endogenous opioid peptides are

Answer 1

endorophins; its precursor has commonality with ACTH, MSH, b-LPH (ACTH could account for stress analgesia);
they will
1. inhibit responses to painful stimuli
2. Modulate GI, endocrine, autonomic function
3. Rewarding (addicting) propertiesr

Question 2

Where can you find opioid receptors? What do agonists to opioid receptors do?

Answer 2

1. Brain, spinal cord, and peripheral nerves
2. Inhibit release of substance P and inhibit ascending transmission from dorsal horn; also activate pain control circuits descending from midbrain

Question 3

Opioid receptors are ____, and they activate and inhibit which channels respectively?

Answer 3

GPCR; they activate receptor-operated K currents and suppress voltage-gated Ca currents!!!

Question 4

Major opioid receptor subtype?

Answer 4

Mu, or MOR: most important for analgesia and the most prescribed opioids are selective for mu!!

Question 5

What does tolerance entail?

Answer 5

Decreased effectiveness with repeated administration (could involve phosphorylation or receptor internalization in short term, other mech’s in long term)

Question 6

Routes of administration of narcotic analgesics:

Answer 6

1. Rapid GI absorption (sublingual, oral, rectal)
2. also SC, IM, IV, epidural and intrathecal
3. Orally: FIRST PASS METABOLISM BY LIVER;
   conjugation with glucuronic acid in liver and excreted by kidney, so NEED both liver and kidney to be normal functioning

Question 7

Which route of admin is quickest for opioids? What is the half-life at steady state and duration of effect of most immediate release formulations except methadone?

Answer 7

IV = 6 min; SC, IM = 30 min; PO = 1 hr;
half-life at SS for po, pr, SC, IM, IV = 3-4 hr;
SS after 4-5 .5 lives, or about ONE DAY; duration of effect is 3-5 hrs po/pr

Question 8

Bolus effect is; solution?

Answer 8

swings in plasma concentration where one is drowsy .5-1 hr after ingestion and you have pain before the next dose given; move to EXTENDED release prep and continuous SC, IV infusion

Question 9

For routine oral dosing of immediate-release preps,

Answer 9

dose every 4 hours and adjust the dose daily, especially for severe uncontrolled pain (codeine, hydrocodone, morphine, hydromorphone, oxycodone)

Question 10

For extended-release preps and dosing

Answer 10

1. we see IMPROVED COMPLIANCE, adherence
2. Dose every 8, 12, or 24 hours; adjust dose every 2-4 days as the SS is reached; for METHADONE, dose every 4-7 days!! (long half life and risk of OD)

Question 11

For breakthrough dosing use

Answer 11

immediate-release opioids (10% of 24 hr dose) which you offer after Cmax has been reached; do NOT use extended release opioids

Question 12

Mixed agonists-antagonists include ____ and are

Answer 12

pentazocine, butorphanol, nalbuphine, dezocine;
NOT RECOMMENDED (compete with agonists and can lead to withdrawal); there is NO analgesic ceiling effect but there is a ceiling based on SE's

Question 13

______ can develop to most SE’s over time except

Answer 13

constipation and also the pinpoint pupils!!

Question 14

Physical dependence is a; how to avoid?

Answer 14

process of neuroadaptation; reduce dose by 50% every 2-3 days, and ANTAGONISTS will cause abrupt withdrawal symptoms

Question 15

In the case of pain poorly responsive to opoids

Answer 15

dose escalation could lead to adverse effects;
INSTEAD, try alternative route or rotate opioids;
you might even want to try a coanalgesic (antidepressant) or a nonpharmacologic approach

Question 16

With equianalgesic dosing, what could be necessary? List some alternative routes of admin:

Answer 16

1. Need to convert to alternative routes of delivery and convert between opioids while MAINTAINING ANALGESIA, which requires conversion of doses from po/pr to SC/IV/IM and vice versa;
   enteral feeding tubes, transmucosal, rectal, transdermal, parenteral (SC, IM, IV, bolus vs. continuous), and then epidural vs. intrathecal

Question 17

With changing opioids, what do you have to account for?

Answer 17

INCOMPLETE cross-tolerance (so start with 50-75% equianalgesic dose); if methadone and fentanyl, start with much lower, like 10%!!!

Question 18

If a patient presents with delirium, what would this show? How could you minimize risk?

Answer 18

Confusion, bad dreams/hallucinations, restless and agitated, myoclonic jerks, depressed LOC, respiratory depression;
follow dosing guidelines and CHECK LIVER AND KIDNEY;

Question 19

Sedation can start with

Answer 19

onset of opioids, but tolerance usually develops within several days; if persistent change opioid or route or even give PSYCHOSTIMS

Question 20

LOC precedes

Answer 20

respiratory depression, but tolerance is rapid;

manage: maybe reduce opioid dose, but if unstable vital signs, O2 sat, CO2 retention, use NALOXONE!!

Question 21

If urticaria or pruritis emerges:

Answer 21

due to mast cell destabilization by morphine, hydromorphone;

treat with long-acting, nonsedating anti-H1’s: loratidine and fexofenadine!!

Question 22

Constipation is common to all opioids and should be treated with

Answer 22

stimulant laxative (e.g. senna) and combined with a stool softener (now senna PLUS docusate sodium);
osmotic laxatives like milk of magnesia could work, but start the first two once you START THE OPIOID!!

Question 23

What should we know about CNCP and opioids?

Answer 23

Widespread prescriptions for CNCP has resulted in increasing substance abuse;
could cause unintentional and intentional overdose, increased numbers of ER visits related to drug OD, and overtreatment of chronic pain

Question 24

Morphine

Answer 24

Class: Opioid
Mech: Mu-opioid receptor agonist
Thera: Severe analgesia, mood alteration, antitussive, sedation
Important SE’s: Miosis, constipation, respiratory depression
Other SE’s: Dry mouth, nausea/vomiting, sedation, sweating; dreams, dysphoria, delerium, myoclonus, seizures, pruritis, urticaria, urinary incontinence
Misc: 2 major active metabolites: M6 (more potent/active), M3 (little affinity); intraspinal administration possible

Question 25

Codeine

Answer 25

Class: Opioid
Mech: Mu-opioid receptor agonist (low receptor affinity); demethylated to form morphine (10% of oral ingestion, via CYP2D6)
Thera: Moderate analgesia, antitussive (found in many cough medicines)
SE’s same as morphine
Misc: 10% of Caucasians unable to convert codeine to morphine (can still experience side effects, though)

Question 26

Tramadol (Ultram)

Answer 26

Class: Opioid
Mech: Mu opioid receptor agonist (weak); some NE/5HT uptake inhibition (leading to analgesia); synthetic codeine analog
Thera: Moderate (not severe) analgesia
SE’s same as mor
Misc: 1 metabolite: demethylated, more potent analgesic

Question 27

Fentanyl (Duragesic)

Answer 27

Class: Opioid
Mech: Mu-opioid receptor agonist (strong); highly lipid-soluble
Thera: Severe analgesia after identification of dose level via other opiod (e.g., morphine)
SE’s: same as mor
Misc: IV, transdermal; do not change dose more than 1/week (long half-life); intraspinal administration possible; might not be effective with THIN patient

Question 28

Methadone (Methadose)

Answer 28

Class: Opioid
Mech: Mu-opioid receptor agonist
Thera: Chronic, severe pain; treatment of heroin and opiod addicts
SE’s: same as mor
Misc: 90% bound to plasma protein, accumulates in tissues (thus, extended duration of action); do not change dose more than 1/week (long half-life)

Question 29

Oxycodone

Answer 29

Class: Opioid
Mech: Mu-opioid receptor agonist
Thera: Moderate to severe analgesia
SE's same as mor
Misc: Oxycontin is extended release (seen widespread abuse and OD's)

Question 30

Meperidine (Demerol)

Answer 30

Class: Opioid
Mech: Mu-opioid receptor agonist
Thera: Don’t use this (metabolite toxicity)
IMportant SE’s: Miosis, constipation, respiratory depression; mental status changes and seizures (normeperidine)
Misc: 1 metabolite: normeperidine

Question 31

Naloxone (Narcan)

Answer 31

Class: Opioid antagonist
Mech: Competitive mu-, delta-, and kappa-opioid receptor antagonist
Thera: Acute opioid toxicity (depressed RR best predicts reponse)
Important SE’s: Can precipitate withdrawal (flu-like symptoms of nausea, vomiting, diarrhea; piloerection, yawning, irritability)
Misc: Continuous parenteral infusion, as lasts only 15-30 minutes (oral almost completely metabolized by liver); patient has normal mental status

Question 32

Naltrexone (Revia)

Answer 32

Class: Opioid antagonist
Mech: Mu-opioid receptor antagonist
Thera: Alcoholism
Important SE’s: May produce a prolonged withdrawal state (nausea, vomiting, piloerection, yawning)