Opioid

Question 1

Phenanthrenes

Answer 1

 Morphine (~10 % of opium)
 Strong opioid agonist

 Codeine (~0.5 % of opium)
 Weak opioid agonist

 Thebaine (~0.2 % of opium)
 Precursor for synthesis of naloxone, buprenorphine, and other opioid drugs

Question 2

Endogenous opioid peptides

Answer 2

Three major families derived from precursors:
 β-endorphin (30 amino acids) from preproopiomelanocortin (POMC)
 Enkephalins (pentapeptides) from preproenkaphalin
 Dynorphins (~18-20 amino acids) from preprodynorphin

Previously known collectively as endorphins, now generally know as opioid peptides

Question 3

endogenous opioid function

Answer 3

 Inhibit of the propagation of pain signals
 Alter the emotional perception of pain
 Elevate the pain threshold?

Sites of opioid receptors regulating pain include:
 Peripheral nociceptive terminals (peripheral analgesia)
 The spine (spinal analgesia)
 The brain (supraspinal analgesia)

Three major opioid receptors types: 
 µ (Mu) 
 δ (Delta) 
 κ (Kappa)
G-protein coupled receptors

Question 4

effect of opioid

Answer 4

Spinal Analgesia
Peripheral Analgesia

Pupil constriction
Supraspinal Analgesia
Cough suppression

Reduced gut motility
Constipation

Dysphoria
Respiratory depression
Euphoria 
Severe sedation 
Sedation

Question 5

 Elderly patients usually require a lower dose to achieve effective pain relief than younger patients.
 Neuropathic pain usually requires higher opioid doses than nociceptive pain.
 Lower doses are usually required for continuous maintenance of pain relief than administration in response to recurrence of pain.

Answer 5

 Elderly patients usually require a lower dose to achieve effective pain relief than younger patients.
 Neuropathic pain usually requires higher opioid doses than nociceptive pain.
 Lower doses are usually required for continuous maintenance of pain relief than administration in response to recurrence of pain.

Question 6

 Opioid analgesics should be started at a low dose and carefully titrated until an adequate level of analgesia is obtained, or until persistent and unacceptable side effects warrant a re-evaluation of therapy.
 Failure of at least partial analgesia with incremental dosing in the opioid-naive patient may indicate that the pain syndrome is unresponsive to opioid therapy
 For some patients with chronic pain, opioids do not exert an appreciable analgesic effect until a threshold dose has been achieved

Answer 6

 Opioid analgesics should be started at a low dose and carefully titrated until an adequate level of analgesia is obtained, or until persistent and unacceptable side effects warrant a re-evaluation of therapy.
 Failure of at least partial analgesia with incremental dosing in the opioid-naive patient may indicate that the pain syndrome is unresponsive to opioid therapy
 For some patients with chronic pain, opioids do not exert an appreciable analgesic effect until a threshold dose has been achieved

Question 7

Analgesia

Answer 7

 Analgesia: Codeine, morphine, pethidine

Question 8

Anaesthetic adjuvant

Answer 8

Anaesthetic adjuvant: Fentanyl

Question 9

Cough suppressant / antitussive

Answer 9

 Cough suppressant / antitussive: Codeine

Question 10

Anti-diarrhoeal:

Answer 10

 Anti-diarrhoeal: Diphenoxylate

Question 11

Strong Opioid Agonists

and receptor binding efficacy addiction

Answer 11

Morphine:
 Strong m agonist (weaker d and kagonist).
 High maximum analgesic efficacy.
 High liability for addiction/abuse.

Methadone and Fentanyl:
 Strong m agonists (no significant d and kaffinity).
 High maximum analgesic efficacy.
 High liability for addiction/abuse

Methadone is long-acting (plasma half-life > 24 hrs).
Fentanyl is short-acting (anaesthetic adjuvant).

Pethidine (Meperidine):
 Strong m agonist (probably weaker d and kagonist).
 Shorter duration of action than morphine (especially in neonate therefore used in labour).
 N-demethylated in the liver to norpethidine (hallucinogenic and convulsant effects at high dose)
 Restlessness rather than sedation

 Antimuscarinic (i.e. parasympatholytic) therefore dry mouth, blurring of vision but no miosis and less spasm of smooth muscle.

Question 12

Moderate opioid agonists

Answer 12

Codeine / Dihydrocodeine:
 Weak m and d agonist (probably not a k agonist).
 Low maximum analgesic efficacy.
 Moderate liability for addiction/abuse.
 ~10 % converted to morphine / dihydromorphine.
 ~10 % of population show reduced analgesic effect due to lack of demethylating enzyme.

Tramadol:
 Weak m agonist.
 Weak inhibitor of 5-HT and noradrenaline re-uptake

Ondansetron blocks analgesic effect: Also a 5-HT3 agonist?

Question 13

Respiratory depression

Answer 13

Actions in the nucleus tractus solitarius and nucleus ambiguus:
 reduce responses to CO2 (and H+).
 suppress voluntary breathing.

Should not occur at normal therapeutic doses but can be lethal in:
 overdose
 respiratory disease
 hepatic dysfunction
 combination with other CNS depressants
 young children

Question 14

Common ADR

Answer 14

Nausea / vomiting
most probably due to actions on the chemoreceptor trigger zone in the area postrema of the medulla (usually reduces with repeated or chronic use).

Constipation
due to reduced gastrointestinal motility (esp. with chronic use).

Miosis (pinpoint pupils)
due to actions in the oculomotor nucleus.
Pinpoint pupil is a diagnostic feature of opioid overdose
But note that mydriasis can also follow if hypoxia occurs.

Urinary retention
due to increased bladder sphincter tone (esp. in patients with prostatic hypertrophy.)

Postural hypotension and bradycardia
due to actions in cardioregulatory nuclei in the medulla.

Drowsiness

Morphine can also trigger histamine release from mast cells
urticaria and itching
bronchoconstriction
hypotension due to vasodilatation

Morphine should be used with caution in asthmatics.

Immunosuppressant effect with long-term use, most likely through CNS effects on the immune system.

Question 15

Opioid withdrawal symptoms

Answer 15

anxiety, 
irritability, 
chills, 
hot flushes, 
joint pain, 
lacrimation (tears), 
rhinorrhea (runny nose),
nausea, 
vomiting, 
abdominal cramps, 
diarrohea.

Question 16

Opioid Antagonists

Answer 16

Naloxone / Naltrexone / Nalmefene:
 Strong m antagonism; also d and k antagonism.
 Naloxone is short-acting (usually intravenous)
 Naltrexone is long-acting (oral administration)
 Nalmefene is long-acting (intravenous)
 Used to counteract opioid overdose.

Use with extreme caution in patients with opiate dependency as they can precipitate potentially fatal withdrawal syndrome.