Opioids

Question 1

What are opioids

Answer 1

• Opioids are natural, semi-synthetic, or synthetic compounds that
produce morphine-like effects.
• All opioids act by binding to specific opioid receptors in the CNS
to produce effects that mimic the action of endogenous peptide
neurotransmitters (e.g., endorphins, enkephalins, and dynorphins).
• Opioid drugs can be subdivided on the basis of their major
therapeutic uses, analgesic efficacy, or their interaction with the
receptor (agonist, antagonist, mixed).
• Widespread availability of opioids has led to abuse of those agents
with euphoric properties.
• Antagonists that reverse the actions of opioids are also clinically
important for use in cases of overdose.

Question 2

What are the different opioid receptors

Answer 2

Three major ones
µ, κ, & δ

They are all g protein coupled receptors ( inhibits adenyl cyclase)

The analgesic properties are primarily mediated by the μ receptors that
modulate responses to thermal, mechanical, and chemical nociception.

The κ receptors also contribute to analgesia by modulating the response to
chemical and thermal nociception.

Activation of receptors ↓ presynaptic Ca2+ influx or ↑ postsynaptic K+
efflux, thus impeding transmitter release or neuronal firing.

Presynaptic actions result in the inhibition of release of multiple
neurotransmitters, including ACh, NE, 5-HT, glutamate, and substance P.

Question 3

How do opioids work

Answer 3

Opioids relieve pain both by raising
the pain threshold at the spinal cord
level and, more importantly, by
altering the brain’s perception of
pain.

Question 4

What are the strong opioids

Answer 4

Morphine

Meperidine

Fentanyl

Hydromorphone and hydrocodone

Oxymorphone and oxycodone

Question 5

What is the morphine MOA

Answer 5

Morphine and other opioids interact with opioid receptors on the
membranes of certain cells in the CNS and other anatomic structures, such
as GI tract and the urinary bladder.

• Morphine also acts at κ receptors in the spinal cord. It decreases the release
of substance P, which modulates pain perception in the spinal cord.

• Morphine also appears to inhibit the release of many excitatory transmitters
from nerve terminals carrying nociceptive (painful) stimuli.

Question 6

What are the morphine actions (11 actions)

Answer 6

1) Analgesia (relief of pain without the loss of consciousness).

2) Euphoria: Morphine produces a powerful sense of contentment
(satisfaction and happiness) and well-being.

3) Respiratory depression: by reduction of the sensitivity of
respiratory center neurons to carbon dioxide. The most common
cause of death in acute opioid overdose.

4) Depression of cough reflex: Both morphine and codeine have
antitussive properties. Codeine has greater antitussive action.
• The receptors involved in the antitussive action appear to be different
from those involved in analgesia in general, cough suppression
does not correlate closely with analgesic properties of opioid drugs.

5) Miosis (the pinpoint pupil): all morphine abusers demonstrate
pinpoint pupils. This is important diagnostically, because many
other causes of coma and respiratory depression produce dilation
of the pupil.

6) Emesis: Morphine directly stimulates the chemoreceptor trigger
zone that causes vomiting.

7) GI tract: morphine produces constipation, with little tolerance
developing.

8) Histamine release from mast cells  urticaria, sweating,
bronchoconstriction, and vasodilation. should be used with caution
in patients with asthma.

9) Cardiovascular: no major effects on BP or HR at lower dosages.
• Large doses: hypotension & bradycardia may occur.
• Increased PCO2 may cause cerebrovascular dilation, resulting in
increased blood flow and increased intracranial pressure.
 Morphine is usually C/I in individuals with head trauma or severe brain
injury.

10) Hormonal actions: increases GH release and enhances prolactin
secretion. It increases ADH  urinary retention.

11) Smooth muscles:
Morphine increases bladder sphincter tone
in BPH, it may cause acute urinary retention.
Morphine reduces uterine contractions prolongation of labor.

Question 7

What are the therapeutic uses for morphine

Answer 7

Analgesia, treatment of diarrhea, relief of cough , treatment of acute pulmonary edema and anesthesia

Question 8

How can we administer morphine

Answer 8

Significant first-pass metabolism of morphine occurs in the
liver
 give IM, SC, or IV injections or in an extended-release form to
provide more consistent plasma levels.
• In cases of chronic pain associated with neoplastic disease a
pump can be used to allow the patient to control the pain
through self-administration.
• Epidural (intraspinal or intrathecal) injection has a long
duration because its low lipophilicity prevents redistribution
from the epidural space.
• Abusers inhale powders or smoke from burning crude opium,
which provide a rapid onset of drug action.

Question 9

How does morphine distribute through the body

Answer 9

• Morphine rapidly enters all body tissues, including the fetus of pregnant
woman.
• Infants born to addicted mothers show physical dependence on opioids and
exhibit withdrawal Symptoms
 should not be used for analgesia during labor.
• Only a small percentage crosses the BBB, because morphine is the least
lipophilic of the common opioids. In contrast, more lipid-soluble opioids,
e.g., fentanyl and methadone, readily penetrate into the CNS.

Question 10

What is the fate of morphine

Answer 10

• Morphine is conjugated in the liver to glucuronic acid to 2 main
metabolites. Morphine-6-glucuronide is a very potent analgesic, whereas
morphine-3-glucuronide does not have analgesic activity.
• Neonates should not receive morphine because of their low conjugating
capacity.
• The elderly are more sensitive to the analgesic effects of morphine
 should be treated with lower doses.

Question 11

What are the side effects of morphine

Answer 11

• Severe respiratory depression:
carefully monitor respiration if the patient has emphysema or cor
pulmonale.
• Vomiting
• Dysphoria
• Patients with renal or hepatic failure may experience extended
and increased effects.
• Because of its stimulating effect on the spinal cord, morphine
should not be used in convulsive states, such as those occurring
in status epilepticus.
• (at usual doses morphine has anticonvulsant effects. It rarely
can cause epilepsy, esp. in neonates).
• It should be used with caution in patients with asthma, liver
disease, or renal dysfunction

Question 12

The tolerance physical dependence on morphine is?

Answer 12

• Repeated use produces tolerance to the respiratory depressant,
analgesic, euphoric, and sedative effects of morphine.
• However, tolerance usually does not develop to the pupil-
constricting and constipating effects of the drug.
• Physical and psychological dependence readily occur with morphine.
• Withdrawal produces a series of autonomic, motor, and
psychological responses that incapacitate the individual and cause
serious—almost unbearable—symptoms. However, death due to
withdrawal is very rare.
• Clonidine can be used for detoxification of morphine-dependent
individuals.
• Abstinence syndrome vs. precipitated withdrawal (results when an
opioid antagonist is administered to a physically dependent
individual).

Question 13

What are the drug interactions for morphine

Answer 13

• The depressant actions of
morphine are enhanced by
phenothiazines, MAOIs, and
TCAs.

Question 14

what is meperidine?

Answer 14

A synthetic opioid structurally unrelated to morphine.
It is very lipophilic and has anticholinergic effects.

Therapeutic uses:
1) Analgesia (for acute pain)
Meperidine is preferred over morphine for analgesia during labor because:
a) It has significantly less effects on uterine smooth muscle than morphine
(morphine decreases uterine contractions)
b) Shorter action than morphine.

• Meperidine has an active metabolite (normeperidine) that is renally excreted.
• Normeperidine has significant neurotoxic actions that can lead to delirium,
hyperreflexia, and possibly seizures.

• C/I: in elderly patients or those with renal insufficiency,
hepatic insufficiency,
preexisting respiratory compromise, or concomitant or recent administration of MAOIs.
•
Serotonin syndrome has also been reported in patients receiving both
meperidine and SSRIs.

Question 15

what is fentanyl?

Answer 15

• Has 100-fold the analgesic potency of morphine
• Highly lipophilic has a rapid onset and short duration of action
(15 to 30 minutes).
• It is usually administered IV, epidurally, or intrathecally.

Therapeutic uses:
1) Analgesia:
• The oral transmucosal preparation is used in the treatment of
cancer patients with breakthrough pain who are tolerant to
opioids.

2) Anesthesia. It is combined with local anesthetics to provide
epidural analgesia for labor and postoperative pain.
• Muscular rigidity, primarily of the abdomen and chest wall, is
often observed with fentanyl use in anesthesia

Fentanyl transdermal patch can
cause life-threatening
hypoventilation.

C/I: in opioid-naïve patients, and
patches should not be used in
managing acute and postoperative
pain.

It is metabolized to inactive
metabolites by the CYP3A4, and
drugs that inhibit this isoenzyme
can potentiate the effect of
fentanyl.

Question 16

what are hydromorphone and hydrocodone

Answer 16

• Hydromorphone and hydrocodone are orally active, semisynthetic
analogs of morphine and codeine, respectively.
• Oral hydromorphone is approximately 8 to 10 times more potent
than morphine.
• It is preferred over morphine in patients with renal dysfunction due
to less accumulation of active metabolites.
• Hydrocodone is the methyl ether of hydromorphone, but is a weaker
analgesic than hydromorphone.
• This agent is often combined with acetaminophen or ibuprofen to
treat moderate to severe pain. It is also used as an antitussive.

Question 17

what is codeine? (low/moderate agonist)

Answer 17

• It is the prototype of the weak opioid agonists.
• It should be used only for mild to moderate pain.
• The analgesic actions of codeine are due to its conversion to
morphine by the CYP2D6, whereas the drug’s antitussive effects
are due to codeine itself.
• Rarely produces dependence & produces less euphoria than
morphine.
 Has a lower potential for abuse than morphine
• In cough preparations, codeine has been replaced by drugs which
have a relatively low potential for abuse such as
dextromethorphan. Still, dextromethorphan has some abuse
potential.

Question 18

what is the difference between Mixed Agonist-Antagonists and
Partial Agonists

Answer 18

• Partial agonists bind to the opioid receptor, but have less
intrinsic activity than full agonists

• Drugs that stimulate one receptor but block another are termed
mixed agonist-antagonists. The effects of these drugs depend
on previous exposure to opioids.
• In In individuals who have not received opioids (naïve
patients), they show agonist activity and are used to relieve
pain.
• In opioid-dependent patients, they show primarily blocking
effects—that is, produce withdrawal symptoms.
• The abuse liability is less than that of the full agonists

Question 19

what is Buprenorphine

Answer 19

• A partial agonist, acting at the µ receptor.
• Acts like morphine in naïve patients, but it precipitates withdrawal in
morphine users.
• Causes little respiratory depression, even at high doses. This property is an
advantage when compared with methadone, which may cause fatal
respiratory suppression.
Therapeutic uses:

1) Opiate detoxification (treatment of opioid dependence), because it has
shorter and less severe withdrawal symptoms compared to methadone.
•
Also available in a combination product containing buprenorphine and
naloxone (to prevent the abuse of buprenorphine via IV administration).

2) Analgesic for moderate to severe pain.
• It is administered sublingually, parenterally, or transdermally and has a
long duration of action because of its tight binding to the μ receptor.

Question 20

what is tramadol

Answer 20

• A centrally acting analgesic that is a weak µ-agonist.
• The drug undergoes extensive metabolism via CYP2D6, leading to
an active metabolite with a much higher affinity for the μ receptor.
• It weakly inhibits reuptake of NE and 5-HT.
• Used to manage moderate to moderately severe pain, and as an
adjunct to opioids in chronic pain syndromes.
• No significant respiratory-depressant activity.
• Overdose or drug–drug interactions with medications, such as SSRIs,
MAOIs, andTCAs, can lead to toxicity manifested by CNS
excitation and seizures.
• Relatively contraindicated in patients with a history of seizure

Question 21

what are opioid antagonists (naloxone)

Answer 21

• Have no profound effects in normal individuals.
• In patients dependent on opioids, antagonists rapidly reverse
the effect of agonists, such as morphine & heroin, and
precipitate the symptoms of opiate withdrawal

Question 22

what is naloxone

Answer 22

• An IV injection is used to reverse the
coma and respiratory depression of
opioid overdose within 30 seconds.
• Because of its relatively short duration
of action, a patient who has been
treated and recovered may lapse back
into respiratory depression.
• It is a competitive antagonist at µ, κ,
and δ receptors, with a 10-fold higher
affinity for µ than for κ receptors.