Opioid and Non-Opioids

Question 1

What is the endogenous ligands for the Mu Opioid Receptor?

A. Endorphin
B. Enkephalins
C. Dynorphins
D. Dykephalins

Answer 1

A - Endorphins.
Endorpins are the endogenous ligands for the Mu Opioid Receptor

Enkephalins are the endogenous ligands for the Delta Opioid Receptor

Dynorphins are the endogenous ligands for the Kappa Opioid Receptor

Question 2

Match the Mu Receptor Subtype to their subsequent effects.

1. Mu-1
2. Mu-2
3. Mu-3

A. Immune Suppression
B. Analgesia (supraspinal and spinal) & Euphoria
C. Respiratory Depression & Physical Dependence

Answer 2

Answer: 1-B, 2-C, 3- A

The Mu-1 Subtype’s effects include analgesia (supraspinal and spinal), bradycardia, euphoria, low abuse potential, Miosis, hypothermia and urinary retention.

The Mu-2 receptor subtype’s effects include bradycardia, respiratory depression, constipation, physical dependence and analgesia (spinal only).

The Mu-3 receptor subtype’s effects include immune suppression.

Question 3

Where are the opioid receptors found in the brain? (Choose 3)

A. Periaqueductal Grey
B. Interneurons
C. Locus Coeruleus
D. Dorsal Horn
E. Rostral Ventral Medulla
F. Immune Cells

Answer 3

A, C, E

In the brain, opioid receptors are found in the periaqueductal gray, locus coeruleus and rostral ventral medulla.

In the spinal cord, opioid receptors are found int he primary afferent neurons in the dorsal horn and interneurons

In the periphery, opioid receptors are found in sensory neurons and immune cells

Question 4

Put the following in the correct order:
1. Modulation
2. Transduction
3. Perception
4. Transmission

Answer 4

2, 4, 1, 3

Signal Transduction occurs when the injured tissue releases a variety of chemicals that activate peripheral nerves and/or cause immune cells to release pro inflammatory compounds. The peripheral nerves transduce this into a action potential

Signal transmission occurs when the pain signal is relayed through the three-neuron afferent pain pathway along the spinothalamic tract

Signal modulation occurs when the signal is modified (inhibited or augmented) as it advances towards the cerebral cortex

Signal Perception describes processing of afferent pain signals in th cerebral cortex and limbic system. It tells us how we “feel” about pain.

Question 5

What drugs target signal transduction?

Answer 5

NSAIDs, Local Anesthetics, Steroids, Antihistamines and Opioids

Question 6

What is the most important site of signal modulation?

Answer 6

Answer: The Substantia Gelatinosa

The descending inhibitory pain pathway begins in the periaqueductal gray and the rostroventral medulla. It projects to the substantia gelatinous.

Question 7

How does gender play a role in PK/PD differences in morphine?

Answer 7

In women, Morphine is associated with:
1. Greater analgesic potency
2. Slower onset of action
3. Longer duration of action
4. Lower postoperative opioid consumption

Question 8

What cardiovascular effects are seen with opioids?

Answer 8

HR: Bradycardia

BP: Minimal effect of BP in healthy patients
Decreased BP with morphine and meperidine
Dose dependent vasodilation
Baroreceptor reflex is not affected by

Myocardial function: Myocardial contractility not affected
** NOTE: Can be affected when combined with N2O

Question 9

How do opioids cause respiratory depression?

Answer 9

They shift the CO2 response curve to the right and reduce ventilatory response to CO2. Therefore, this decreases RR and increases the tidal volume.

PaCO2 will increase ICP if ventilation is not maintained

Question 10

What nucleus stimulation causes pupillary constriction during opioid administration?

Answer 10

Edinger Westphal Nucleus Stimulation

this causes increased PNS stimulation of ciliary ganglion and oculomotor nerve (CN3)

this causes pupillary constriction

NOTE: Tolerance does not develop to miosis

Question 11

What is tolerance and physical dependence due to?

Answer 11

Tolerance and physical dependence on opioids is likely due to a receptor desensitization and increased synthesis of cAMP. These phenomena are not due to enzyme induction.

Question 11

In comparison to 10mg morphine, What is the equianalgesic doses of the following?
Meperidine:
Hydromorphone:
Alfentanil:
Remifentanil:
Fentanyl:
Sufentanil:

Answer 11

Meperidine: 100mg
Hydromorphone: 1.4mg
Alfentanil: 1000 mcg
Remifentanil: 100 mcg
Fentanyl: 100 mcg
Sufentanil: 10 mcg

Question 12

In comparison to 10mg IV Morphine, what is the relative potency of the following?
Meperidine:
Hydromorphone:
Alfentanil:
Remifentanil:
Fentanyl:
Sufentanil:

Answer 12

Meperidine: 0.1
Hydromorphone: 7
Alfentanil: 10
Remifentanil: 100
Fentanyl: 100
Sufentanil: 1000

Question 13

What are the inactive and active metabolites of morphine?

Answer 13

Inactive: Morphine 3-glucuronide (M3G)
Active: morphine-6-glucuronide (M6G)

Question 14

Why is morphine a poor choice for people on dialysis?

Answer 14

Answer: Patients on dialysis are unable to excrete M6G, so they are prone to accumulation of this metabolite. A larger concentration gradient between blood and the brain helps M6G enter the CNS (Law of mass action).

This is why renal failure patients are more likely to experience respiratory depression and toxicity after morphine.

Question 15

What patient populations should meperidine be avoided in? worrisome in?

Answer 15

Meperidine should be avoided in patients on dialysis and the elderly population

Meperidine also reduces the seizure threshold and increases CNS excitability so care should be taken when administering to patients with a seizure history

Question 16

How is Remifentanil dosed and metabolized?

Answer 16

Hydrolyzed in the plasma by erythrocyte and tissue esterases. It behaves like a drug that has a low volume of distribution.

Remifentanil is ALWAYS dosed at lean body weight.

Question 17

What opioid receptors does Meperidine stimulate?

Answer 17

Answer: Mu and Kappa Opioid Receptors

Meperidine is a synthetic phenylpiperidine opioid and stimulates the mu and kappa opioid receptors

Stimulation of the kappa receptor reduces postoperative shivering.

NOTE: shivering increases oxygen consumption, so meperidine reduces oxygen consumption in the shivering patient.

Question 18

What happens when meperidine is co-administered with MAOIs?

Answer 18

Answer: Serotonin Syndrome

Meperidine is a weak serotonin reuptake inhibitor

Since MAO dominates serotonin in the synaptic cleft, co-administration of meperidine with a MAO inhibitor can cause SEROTONIN SYNDROME.

S/sx include:
- Hyperthermia
- AMS changes
- Hyperreflexia
- Seizures
- Death

MAOI include: Phenelzine, isocarboxazid, tranylcypromine

Question 19

What medication is meperidine structurally similar to?

Answer 19

Answer: Atropine

It exhibits anticholinergic effects such as:
- Tachycardia
- Mydriasis
- Dry mouth

Question 20

What are some instances that methadone would be useful as a racemic mixture?

Answer 20

Answer:
1. Chronic treatment of opioid abuse (prevention of withdrawal)
2. Chronic pain syndromes
3. Cancer pain.

Question 21

How does methadone decrease pain?

Answer 21

1. Mu receptor agonist
2. NDMA receptor antagonist (dextrorotary isomer)
3. Inhibits reuptake of monoamines in the synaptic cleft

Question 22

What is the rare consequence of methadone we need to aware of?

Answer 22

Answer: QT Prolongation

It inhibits the delayed rectifier potassium ion channel (IKr)

This can lead to torsades de pointes

It is prudent to evaluate the patient’s preoperative EKG for a prolonged QT interval if you plan to administer methadone

Question 23

What is Oliceridine, what does it work on and how should you dose it?

Answer 23

Answer: Oliceridine is an IV opioid analgesic that primarily selects the Mu-opioid receptor. It is indicated for adults with acute pain when other opioid analgesics and alternative treatments fail to provide adequate pain relief.

Dosing:
- Bolus Dosing:
o Loading dose IV: 1-2 mg IV
o Supplemental doses 1-3mg Q1-3H PRN
- PCA dosing:
o Loading dose: 1.5mg
o Demand dose: 0.35 – 0.5mg
o Lockout: 6 minutes

NOTE: Cumulative dose should not exceed 27mg

Question 24

What are the contraindications to Oliceridine?

Answer 24

Answer: Significant respiratory depression, acute or severe asthma in an unmonitored setting and without resuscitative equipment and GI Obstruction (including paralytic ileus)

Can also cause
- Mild QT interval prolongation
- Risk of hypotension
- Lower seizure threshold
- Serotonin syndrome in patients on serotonergic drugs

Question 25

Describe skeletal muscle rigidity with opioid administration, what medications it is more common with and how to deal with it?

Answer 25

Answer: Historically called “Chest wall Rigidity” or “Stiff Chest syndrome”. Rapid IV administration of opioids can cause skeletal muscle rigidity.

This condition is more common with potent (lipophilic) compounds such as: sufentanil, fentanyl, remifentanil, and alfentanil

Opioid-induced muscle rigidity is believed to be a result of the Mu-receptor stimulation in the CNS
- Ultimately a result from influencing the dopamine and GABA motor receptor pathways

Best treatment is paralysis and intubation

NOTE: Narcan can also reverse rigidity but giving this prior to surgery seems counterproductive, given that there is a better alternative.

Question 26

What are some common characteristics of opioid partial agonists?

Answer 26

Produce analgesia with a reduced risk of respiratory depression

Having a ceiling effect beyond which additional analgesia is not possible

Reduce the efficacy of previously administered opioids

Can cause acute opioid withdrawal in the opioid-dependent patient

Can cause dysphoric reactions

Carry a low risk of dependence

Are used in patients who cannot tolerate a full opioid agonist

Question 27

What are some examples of partial opioid agonists?

Answer 27

“-ocine”
- Pentazocine
- Nalorphine
- Bremazocine
- Dezocine
- Meptazinol

Question 28

What is Naloxone, and what are some indications for it?

Answer 28

Answer: NALOXONE is the prototype opioid antagonist. It competitively antagonizes the Mu, Kappa and Delta opioid receptors. However, it has the greatest affinity at the Mu-Receptor

Some common indications for naloxone include:
- Acute reversal of opioid-induced respiratory depression
- Reversal of respiratory depression in the neonate whose mother received an opioid
- Treatment of opioid overdose

Question 29

What must you be careful of with the administration of Naloxone?

Answer 29

Answer: analgesic reversal activates the SNS. This can cause neurogenic pulmonary edema, tachycardia, cardiac dysrhythmias, and sudden death. Slow titration minimizes these effects.

It can also cause nausea and vomiting. Slow titration over 2-3 minutes causes less N/V.

Can cross placenta and precipitate acute opioid withdrawal in the neonate.

Question 30

What is Methylnaltrexone and what are some key facts about it?

Answer 30

Answer: It has a quaternary amino group that prohibits the passage across the BBB. It does not cause respiratory depression. It is useful for mitigating the peripheral effects of opioids, such as opioid-induced bowel dysfunction.

Question 31

What is Nalmefene and how is it dosed?

Answer 31

Nalmefene is similar to naloxone except its duration of action is much longer (10H).

It is dosed as 0.1-0.5 mcg/kg.

Question 32

How does naltrexone differ from Naloxone?

Answer 32

Unlike Naloxone, Naltrexone does not undergo significant first-pass metabolism.

It can be given orally and has a DOA of up to 24H

An extended-release may be used for alcohol withdrawal treatment

It can also be used to maintain recovering opioid abusers.