Narcotic Opioid Analgesics

Question 1

What does the class of phenanthrenes include?

Answer 1

• morphine (strong opioid agonist)
• codeine (weak opioid agonist)
• thebaine (precursor for synthesis of naloxone, buprenorphine and other opioid drugs)

Question 2

What are endogenous opioid peptides?

Answer 2

Three major families:

• beta endorphin
• enkephalins
• dynorphins

Question 3

Where are the sites if opioid receptors regulating pain?

Answer 3

• peripheral nociceptive terminals (peripheral analgesia)
• the spine (spinal analgesia)
• the brain (supraspinal analgesia)

Question 4

What are the three major types of opioid receptors?

Answer 4

Mu, delta and kappa.
They are G protein coupled receptors.

Mu receptor is the major receptor underlying not just analgesia, but also the adverse effects and psychoactive effects.

For dysphoria (feeling of unease) -> kappa receptor underlies it

Question 5

What are some important dosingfeatures of opioids?

Answer 5

• elderly patients usually requure a lower dose than younger patients
• neuropathic pain usually requires higher opioid doses than nociceptive pain
• lower doses usually required for continuous maintenance of pain relief rather than administration in response to reccurence of pain

Question 6

How do we dose opioids to effect?

Answer 6

• start at low dose and carefully titrate until 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 opioid naive pt may indicate unresponsiveness to opioid therapy
• for some pts with chronic pain, opioids do not exert an appreciable analgesic effect until a threshold dose is achieved

Question 7

What are the clinical uses of opioid agonists?

Answer 7

Analgesia: codeine, morphine, pethidine

Anesthetic adjuvant: fentanyl

Cough suppressant: codeine

Anti diarrhoea: diphenoxylate

Question 8

What is morphine?

Answer 8

• morphine is a strong opioid agonist
• strong mu agonist
• high liability for abuse

Question 9

What is methadone and fentanyl?

Answer 9

They are strong opioid agonist (strong mu agonist)
High liability for abuse

Methadone is long acting
Fentanyl is short acting (used as anaesthetic adjuvant)

Question 10

What is pethidine?

What is the duration of action of pethidine?

What are the 3 adverse effects of pethidine?

Answer 10

Strong opioid agonist (strong mu agonist)
Shorter duration of action than morphine (especially in neonates, hence used in labour as epidural)
N-demethylated in liver to norpethidine -> hallucinogenic and convulsant effects at high dose
- restlessness rather than sedation
- antimuscarinic -> dry mouth, blurring of vision but no miosis and less spasm of smooth muscle

Question 11

What are the moderate opioid agonists?

Answer 11

Codeine:

• weak mu and delta agonist
• moderate liability for abuse
• ~10% converted to morphine by the liver
• ~10% of population show reduced analgesic effect due to lack of demethylating enzyme

Tramadol:
Weak mu agonist
Weak inhibitor of serotonin and NA reuptake

Question 12

How does opioids lead to respiratory depression?

Answer 12

Actions in the nucleus tractus solitarius and nucleus ambiguus of the brain -> reduce responses to CO2 -> 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

DO NOT USE OPIOIDS IN INFANTS!

Question 13

What are 8 common adverse effects of opioids?

Answer 13

• nausea and vomiting due to actions on chemoreceptor trigger zone (usually reduces with repeated use)
• constipation due to reduced gastro motility (esp with chronic use)
• drowsiness -> caution against operating machinery or driving
• miosis (pinpoint pupils) due to actions in oculomotor nucleus (diagnositic feature of opioid overdose. But if hypoxia occurs, mydriasis can occur.)
• urinary retention due to increased bladder sphincter tone (esp in pts with prostatic hypertrophy)
• postural hypotension and bradycardia due to actions on cardioregulatory nuclei in medulla
• immunosuppressant effect with long term use, most likely through CNS effects on the immune system
• morphine can also trigger histamine release from mast cells -> urticaria, bronchoconstriction and hypotension due to vasodilation -> USE MORPHINE WITH CAUTION IN ASTHMATICS

Question 14

What is the difference between tolerance, physical dependence and addiction?

Answer 14

Tolerance: less effective after prolonged use, need to increase dose

Addiction: psychological craving for the drug, compulsive use, loss of control over use

Physical dependence: physiological dependence such that stopping the drug leads to physical withdrawal symptoms

Addiction and tolerance can lead to overdose

Question 15

How do we treat opioid overdose?

Answer 15

Use opioid antagonists.

Naloxone: 
Strong mu antagonism 
Naloxone is short acting (usually IV) 
Naltrexone is long acting (oral) 
Nalmefene is long acting (IV) - new, replace naloxone naltrexone combination 

Use with extreme caution in patients with opioid dependency as they can precipitate potentially fatal withdrawal symptoms