Opioid Pharmacology

Question 1

Opiate

Answer 1

a naturally-occurring plant-derived alkaloid

compound

Question 2

Opioid

Answer 2

any compound that works at an opioid receptor - includes naturally-occurring and synthetic agents

Question 3

3 Families of Opioid Receptors

Answer 3

mu, delta and kappa

Mu is most heavily distributed in CNS regions related to pain, reward

Question 4

Presynaptic - decrease release of

neurotransmitters

Answer 4

1. Inhibition of AC, cAMP and PKA - prevents vesicle docking

2. Inhibition of voltage-gated Ca2+ channels - prevents vesicles from releasing contents into synapse

Question 5

Postsynaptic - decrease action potentials

Answer 5

3. Stimulating K+ efflux keeps
   neurons more polarized, less likely
   to fire an action potential

Question 6

Tolerance development MOA

Answer 6

Acute desensitization (caused by G subunit phosphorylation after activation) occurs within minutes to hours

occurs over a period of days to weeks, and is thought to involve:

• up regulation of cAMP system
• beta-arrestin mediated receptor endocytosis and down regulation

Question 7

Opioids are used for…

Answer 7

nociceptive (sensory) and emotional (affective) pain, NOT neuropathic pain

Question 8

OPIOID ANALGESIA MOA

Answer 8

1. Pain signal transduction - inhibiting activity of nociceptor neurons, which sense noxious stimuli and send pain signals to spinal nerves
2. Transmission - reducing activity of spinal neurons that transmit pain signals up to brain
3. Perception - acting in brain processing centers to limit cognitive awareness of & emotional response to pain
4. Modulation - up or down regulation of pain signals throughout the spinal cord and the brain

Question 9

Fentanyl, and Su, Al, and Remi fentanil

Answer 9

CLINICAL USES - ANALGESIA

More potent opioids are reserved for treatment of higher levels of pain

Opioids are often used for premedication before anesthesia
and surgery

DOA: shorter-acting opioids are generally preferred for use during anesthesia

Question 10

Codeine

Answer 10

CLINICAL USES - COUGH

Antitussive - medication that suppresses coughing

Opioids directly inhibit the cough center in the medulla

Suppression of cough occurs at much lower doses than used for analgesia

Codeine is sometimes used as antitussive, although less common currently, since other safer options exist

Question 11

loperamide (Imodium ®; PO)

Answer 11

CLINICAL USES - DIARRHEA

Diarrhea from any cause can be treated with opioids

Opioids reduce GI motility and inhibit GI secretions by acting at neurons in the gut

Opioids receptors are widely distributed in the GI tract; they decrease activity of enteric nervous system neurons

Loperamide is a strong substrate Mice with no P-gp at the BBB for the blood-brain barrier efflux transporter, P-glycoprotein (so it acts in the body but does not enter brain)

Question 12

Naltrexone

Answer 12

CLINICAL USES - SUBSTANCE USE DISORDERS

Alcohol use disorders - preventing relapse - naltrexone (long acting) indicated in treating and preventing relapse of alcohol use disorders and may similarly prevent relapse of opiate dependence

Opioid detoxification - full detoxification involves transition to opioid antagonist (naltrexone)

Question 13

Methadone, Buprenorphine, Clonidine

Answer 13

CLINICAL USES - SUBSTANCE USE DISORDERS

*Opioid withdrawal treatment - treating opioid withdrawal symptoms (craving, anxiety, GI distress, diaphoresis, tachycardia)

Buprenorphine advantages include relatively long duration of action and greater safety in overdose than full agonists like methadone

As a partial agonist, buprenorphine activates OP receptors, but to a
lesser extent than a full agonist → occupation of receptors prevents
full agonists from reaching maximum efficacy

Question 14

Naloxone (Narcan ®; IV/IM/IN)

Answer 14

OPIOID OVERDOSE REVERS

Naloxone is an opioid receptor pure antagonist (no agonist effects)

Competitive antagonist - no effects alone; only in the presence of opioids

Short duration of action (t ½ = 30-80 min), often necessary to give additional
doses until agonist is cleared

Question 15

Respiratory depression

Answer 15

Adverse Effects of Opioids

Respiratory depression - opioids act directly on OPRs in brainstem respiratory
centers to depress respiratory function (reduce rate, depth of breathing)
-major cause of fatality in opioid clinical use and overdose (respiratory collapse and hypoxic brain death)

Pruiritis / urticaria - some opioids can stimulate mast cell-mediated histamine release, causing itching and hives

Question 16

Constipation

Answer 16

Adverse Effects of Opioids

Constipation - all opioids slow GI motility (see section on anti-diarrheal uses); common

Potential cause of mortality, particularly in elderly or cancer patients

Requires treatment, since tolerance does not develop for opioid constipating effects

Question 17

Naloxegol (Movantik ® PO)

Answer 17

REVERSAL OF PERIPHERAL OPIOID EFFECTS

Naloxegol is a pegylated derivative of naloxone, for treatment of opioid-induced constipation

Pegylation limits ability of the drug to cross the blood-brain barrier → only peripheral
effects

Question 18

Nausea

Answer 18

Adverse Effects of Opioids

Nausea - with or without vomiting, nausea can affect overall outcome, medication compliance, enteral absorption, quality of life

Can be treated with anti-emetics, although tolerance to nausea usually develops within days to weeks

Question 19

Sedation (effects on sleep)

Answer 19

Adverse Effects of Opioids

Sedation (effects on sleep) - drowsiness and sleep, with disrupted sleep
patterns → potential for interaction with CNS depressants

Question 20

Addiction

Answer 20

Adverse Effects of Opioids

Addiction - pathologic pursuit of reward and relief through substance use

Dysfunction in reward, motivation memory circuitry

Rewarding effects of opioids are mediated by opioid receptor on dopamine reward pathways and other mechanisms

Question 21

Drug Interactions with Opioids

Answer 21

• Sedative-hypnotics*: increased CNS depression, especially respiratory depression
• Antipsychotics agent*: increased sedation, variable effects on respiratory depression. Accentuation of cardiovascular effects (anti-muscarinic and alpha-blockng actions)
• Monoamine oxidase inhibitors*: contradiction to all opioid analgesics due to high incidence of hyperpyrexic come, also HTN

Question 22

GENETIC POLYMORPHISMS

Answer 22

Opioids are generally converted to polar metabolites and excreted in urine

Some opioids are transformed by P450 enzymes to active metabolites of greater potency (e.g., codeine is metabolized to morphine)

Polymorphisms in CYP 2D6 can result in responses to opioids that are greater or less than expected

Question 23

OPIOID OVERDOSE DEATHS

Answer 23

Most recently, overdose death increase is associated with fentanyl and synthetic opioids

Question 24

OPIOID PRESCRIBING

Answer 24

Overprescription can contribute to diversion and misuse

Balance caution in prescribing opioids with risk of leaving pain untreated or under-treated