Opioid Analgesics

Question 1

What is the most important opioid receptor? What are these receptors? What happens with receptor activation?

Answer 1

Mu. GPCRs. Adenylyl Cyclase inhibited, Voltage-gated Ca2+ channels suppressed, K+ current activated, PKC & PLC activated.

Question 2

Give 10 effects of opioids. Give mxn.

Answer 2

Analgesia (inhibit substance P release & ascending pain pathways from dorsal horn neurons, activate pain control circuits descending from midbrain), Mood alteration & stimulation of reward centers (stimulate dopamine & limbic system), Miosis (via mu, no tolerance), Convulsions (lower seizure threshold), Decreased respiration (direct stim of brainstem respiratory centers), Cough suppresion/Antitussive (?), N/Emesis (direct stim of medullary trigger zone), Constipation (inhibit peristalsis via opiod receptros in mesenteric complex, no tolerance), Urinary retention, Vasodilatation & Urticaria (mast cell degranulation w/ histamine release)

Question 3

How can opioids be admnistered? Where are they metabolized? What is the significance?

Answer 3

Oral, transmucosal, sublingual, rectal, transdermal, SC, IM, IV, epidural, intrathecal. Significant first pass metabolism in the liver. Glucuronidation in the liver is the primary metabolic pathway with excretionin the kidney. MONITOR if liver/kidney disease.

Question 4

When is max serum concentration reached with IV? SC? IM? Oral? What is the average half-life? So when is steady state achieved? What is the bolus effect and how can it be addressed?

Answer 4

5-10 minutes with IV. 30 minutes for SC, IM. 1 hour for oral. Half-life is 3-4 hrs. Steady-state in 24 hrs. “Bolus effect” usually occurs with IV, IM and is the result of swings in plasma levels – sedation because of high levels, breakthrough pain with lower levels. Address with continuous IV infusion or ER formulations.

Question 5

Name mu-receptor opioid agonists.

Answer 5

Morphine, Codeine, Meperidine, Oxycodone, Methadone, Tramadol, Fentanyl

Question 6

Morphine is?

Answer 6

Mu-rec opioid agonist

Question 7

Codeine is?

Answer 7

Mu-rec opioid agonist

Question 8

Tramadol is?

Answer 8

Mu-rec opioid agonist

Question 9

Fentanyl is?

Answer 9

Mu-rec opioid agonist

Question 10

Methadone is?

Answer 10

Mu-rec opioid agonist

Question 11

Oxycodone is?

Answer 11

Mu-rec opioid agonist

Question 12

Meperidine is?

Answer 12

Mu-rec opioid agonist

Question 13

Prototype opioid? Its metabolites?

Answer 13

Morphine. Morphine-6-glucuronide (active, high potency), Mophine-3-glucuronide (low affinity)

Question 14

What is codeine’s affinity? How is codeine made to be analgesic? What is codeine especially useful for?

Answer 14

Low receptor affinity. It is demethylated (10%) to form the active analgesic morphine via CYP2D6 (10% of Caucasians do not have – experience side efects but no analgesia). Especially useful as an antitussive.

Question 15

What is tramadol? How is it’s affinity? How is some of it’s analgesia mediated? Why was it developed? What is one advantage over morphine? What is it best used for?

Answer 15

Synthetic codeine analog. Weak mu agonist, but its demethylated metabolite is more potent. Some analgesia mediated via inhibition of NE and 5HT uptake. Developed to be less addicting, but still addictive. Less constipating than morphine. Best for moderate but not severe pain.

Question 16

Is fentanyl strong or weak? How is it usually given? What is it’s half-life? What does this mean? What is it best used for?

Answer 16

Strong opioid. IV, transdermal patch. Very long half-life –> Dose changes should NOT be made more often than once a week in order to avoid OD. Best used once total dose of opioid needed for pain control is ID’d…not ideal to start with this.

Question 17

What is methadone best for? What is it’s half-life? What does this mean?

Answer 17

Best for chronic pain & maintenance tx of heroin or opioid addicts. Extended duration of action (90% bound in plasma proteins, with gradual accumulation in tissues) –> Dose changes should NOT be made more often than once a week in order to avoid OD.

Question 18

Oxycodone is very ____, widely ____, and administered as a _____ ______ analgesic. It is commonly ______.

Answer 18

effective, used, potent oral, abused (as Oxycontin, the long acting form)

Question 19

What’s the deal with meperidine?

Answer 19

It is no longer recommended because of toxicity. Its metabolite normeperidine accumulates in tissues and causes mental status changes and seizures.

Question 20

Opioid antagonists? These will cause?

Answer 20

Naloxone, Naltrexone. Will cause abrupt withdrawal symptoms.

Question 21

Naloxone is?

Answer 21

Opioid antagonist

Question 22

Naltrexone is?

Answer 22

Opioid antagonist

Question 23

Naloxone is used for? What is it’s half-life? What is the significance?

Answer 23

Useful for acute opioid toxicity. Short half-life – use as IV bolus then continuous IV in OD settings (if given orally, almost completely metabolized by the liver).

Question 24

What is Naltrexone approved for?

Answer 24

Alcoholism

Question 25

Congeners of Meperidine for diarrhea treatment? How do these work?

Answer 25

Diphenoxylate, Loperamide. Mxn: Slow peristalsis via opioid receptors in intestine & decrease GI secretion.

Question 26

Abrupt withdrawal symptoms can occur how? What are they? How can this be avoided?

Answer 26

Can occur with abrupt cessation of chronic opioid use. Yawning, sweating, piloerection, vomiting, pain. To avoid, reduce by half every 2-3 days. Abrupt withdrawal symptoms will also probably occur with antagonist. use.

Question 27

What opioids are available in immediate-release prep? How are these orally dosed? How should one adjust for mild/moderate, severe/uncontrolled pain?

Answer 27

Codeine, morphine, hydromorphone, oxycodone, hydrocodone. Q 4 hrs. Adjust DAILY ^ 25-50% for mild/moderate pain. ^50-100% for severe/uncontroled pain (can adjust quicker for even more severe pain).

Question 28

How are extended-release preps orally dosed? When should dose be adjusted?

Answer 28

Dose every 8-24 hours (usually every 12). Adjust dose every 2-4 days (when steady state is reached), but wait 4-7 days for METHADONE & FENTANYL because of longer half-lives and risk of OD.

Question 29

When can breakthrough dosing be given? How is this calculated?

Answer 29

Can give only after Cmax is reached (1 hr for po/pr, 30 min for SC/IM, 10-15 min for IV). Use immediate release preps (DO NOT USE EXTENDED RELEASE PREPS).

Question 30

What is a possible mechanism of tolerance?

Answer 30

Phosphorylation &/or receptor internalization.

Question 31

When changing opioids, what should one use? How should cross-tolerance be adjusted for?

Answer 31

Use equianalgesic table. Adjust for cross-tolerance: Start with 50-75% equianalgesic dose (more if pain, less if adverse effects), start much lower (10%) for methadone and fentanyl.

Question 32

How can we manage sedation as a side-effect?

Answer 32

Psychostimulants (methylphenidate)

Question 33

How can we manage delirium as a side effect?

Answer 33

Preventive measure: vigilance about dosing, check for underlying dehydration, kidney/liver disease, minimize drug regimen.

Question 34

How can we manage respiratory depression as a side effect?

Answer 34

Naloxone IV (will precipitate w/drawal symptoms)

Question 35

How can we manage N/V as a side effect?

Answer 35

Dopamine-blocking antiemetics (prochlorperazine), Haloperidol, Metoclopramide

Question 36

How can we manage constipation as a side effect?

Answer 36

We attempt to PREVENT this (only side effect that we attempt to prevent). Give stool softender (docusate) w/ stimulant laxative (senna, bisacodyl, glycerin) at initiation. Oxmotoc laxatives (MOM, lactulose, sorbitol). Prokinetic agents (metoclopramide, cisapride). AVOID fiber supplements.

Question 37

How can we manage urticaria, pruritis as a side effect?

Answer 37

Ensure this is not an allergic reaction (is there hypotension? wheezing?). Treat with a non-sedating antihistamine (loratadine, fexofenadine).

Question 38

Are opioid allergies common?

Answer 38

NO!

Question 39

What are common side effects versus uncommon?

Answer 39

Common: Constipation, dry mouth, N/V, sedation, sweats. Uncommon: Bad dreams/halucinations, dysphoria/delirium, myoclonus, seizures, pruritis/urticaria, respiratory depression, urinary retention.