L06 Opioid Analgesics Flashcards
What does “somniferum” means in Latin?
Somnus: sleep
Ferre: bring
Which opiate was the first to be isolated?
Morphine
Which chemical class of opiates do morphine & codeine originated from?
Phenanthrenes
Which phenanthrene is a stronger opioid agonist?
Morphine
What were opioid peptides formerly known as?
Endorphins
What are the three major families derived from precursors of opioid peptides?
1) Beta-endorphin (30 aa) from preproopiomelanocortin
2) Enkephalines (pentapeptides) from preproenkaphaline
3) Dynorphins (~18-20 aa) from preprodynorphins
Briefly describe the pathophysiology of pain.
The brain has modulatory circuits to regulate pain perception.
- Attitude, mood & physical exercise can influence the perception of pain (subjective).
- Better to control pain before it becomes severe
- Primary efferent neuron helps to modulate pain perception received from primary afferent A-delta-/C-fibre via depolarisation of afferent spinothalamic tract pathway
How does opioid analgesics modulate the perception of pain?
Opioid analgesics play on endogenous mechanisms to:
- Inhibit the propagation of pain signals
- Alter the emotional perception of pain
- Potentially elevate the pain threshold (i.e. level of noxious stimuli required to illicit pain is increased)
Via binding to respective major opioid receptor types (i.e. mu, delta or kappa G-protein coupled receptors) for corresponding therapeutic effect.
Name the locations in which the sites of opioid receptors regulating pain perception reside.
Name the corresponding type of opioid analgesics that is appropriate in targeting these receptors at their locations.
1) Peripheral nociceptive terminals (peripheral analgesics)
2) Spine (spinal analgesics)
3) Brain (supraspinal analgesics)
List the three major types of opioid receptors.
What type of receptors are they?
Mu, delta and kappa G-protein coupled receptors
Which major type of opioid receptor is responsible for eliciting most of the functional effects except dysphoria?
Mu
Which major type of opioid receptor is responsible for causing dysphoria upon binding with an opioid analgesic?
Kappa
At which functional effect of opioid analgesia do we suspect as a sign of overdose?
Pupil constriction
List the functional effects of opioid analgesia, starting from the lowest dose-dependent effect to the highest.
[Lowest dose] Peripheral analgesia Spinal analgesia Cough suppression Supraspinal analgesia Sedation Reduced gut motility Euphoria Pupil constriction -> sign of overdose Constipation Dysphoria Severe sedation Respiratory depression [Highest dose]
What are some therapeutic rationales to bear in mind to help guide our dosing of opioid analgesia?
Individual differences exist between drugs!
1) Elderly pt usually requires lower dose to achieve effective pain relief than younger pt.
2) Neuropathic pain (i.e. spinal analgesia & above) requires higher opioid doses than nociceptive pain.
3) Lower doses are usually required for continuous maintenance of pain relief, instead of administering reactively in response to recurrence of pain; otherwise, higher dose is required upon pain recurrence.
4) Start low, go slow & carefully titrate until adequate level of analgesia is obtained.
5) Failure of at least partial analgesia w/ incremental dosing in opioid-naive pt may indicate pain syndrome is unresponsive to opioid therapy.
6) For some pt w/ chronic pain, opioids do not exert appreciable analgesia until a threshold dose has been achieved.
Differentiate between ‘tolerance’, ‘physical dependence’ & ‘addiction’.
Tolerance:
- Less effective after prolonged use
- Dose escalation required
- Increased risk of overdose
Physical dependence:
- Physiological dependence such that stopping leads to physical withdrawal symptoms
Addiction:
- Psychological craving leading to compulsive use
- Loss of control over use
- Increased risk of overdose
What are some withdrawal symptoms observed upon abrupt discontinuation of opioid analgesics?
- Anxiety, irritability,
- Chills, hot flushes, joint pain
- Lacrimation (tears), rhinorrhea (runny nose)
- N/V/D, abdominal cramps
Which opioid analgesic can be clinically used as an anaesthetic adjuvant?
Fentanyl
Which opioid analgesic can be clinically used as a cough suppressant?
Codeine
Which opioid analgesic can be clinically used for anti-diarrheal?
Diphenoxylate
Which opioid analgesic can be clinically used as an analgesic for labour?
Pethidine (meperidine)
Which opioid analgesics are considered strong opioid agonists?
Morphine, methadone, fentanyl & pethidine
Which opioid analgesics are considered moderate opioid agonists?
Codeine, tramadol & diphenoxylate
Which opioid analgesic is a strong mu agonist with weaker delta and kappa agonist?
Morphine
Which opioid analgesics are strong mu agonists with no significant delta and kappa agonist activities?
Methadone & fentanyl
Which opioid analgesics have high maximum analgesic efficacy but have a high liability for addiction / abuse?
Morphine, methadone & fentanyl
Which strong opioid agonist is short-acting?
Fentanyl
Which strong opioid agonist is long-acting?
Methadone (T1/2 > 24h)
Besides the common side effects of opioid analgesics, what additional side effects is pethidine known to cause?
- Hallucination & convulsant effects at high dose
- Restlessness instead of sedation
- Anticholinergic effect (i.e. dry mouth, blurred vision) BUT NO miosis (pupil constriction) & less smooth muscle spasms
Which opioid analgesic has both weak mu and delta agonist activity, but no kappa agonist activity?
Codeine / dihydrocodeine
Briefly explain why codeine has a lower analgesic efficacy, as compared to morphine?
Codeine is methylated morphine:
- however, ~10% is converted to morphine / dihydromorphine
- ~10% of population lack demethylating enzyme to convert into morphine -> reduced analgesic effect
- Thus, moderate liability for addiction / abuse instead.
Which antiemetic blocks the analgesic effect of tramadol?
Ondansetron
Which opioid analgesic is both a weak mu agonist and a weak inhibition of 5-HT3 & NA reuptake?
Tramadol
- Venlafaxine has a similar chemical structure to tramadol.
Under what conditions are opioid analgesics contraindicated?
CH(A)IR: Combination w/ other CNS depressants Hepatic dysfunction Asthma (specific to morphine) Infants & young children Respiratory diseases
What are some possible side effects when taking opioid analgesics?
1) Respiratory depression
- Occurs in nucleus tractus solitarus & nucleus ambigus
- Mu agonism reduce response to CO2 (and H+) & suppresses voluntary breathing
- Lethal on overdose
2) Nausea/Vomiting
- Activates chemoreceptor trigger zone in area postrema of medula w/ chronic/repeated use
3) Drowsiness (caution w/ machinery)
4) Constipation (reduced GI motility)
5) Miosis
- Due to mu agonism in oculomotor nucleus
- Mydriasis (dilation) can follow if hypoxia occurs (i.e. via respiratory depression)
6) Urinary retention
- Increased bladder sphincter tone (esp. in pt w/ prostatic hypertrophy)
7) Postural hypotension & bradycardia
- Due to mu agonism at cardioregulatory nuclei in medulla
8) Immunosuppressant effect
- Only w/ long-term use via CNS effects on immune system
Why should morphine be used with caution in patients w/ asthma?
Morphine can trigger histamine release from mast cells, resulting in:
- Urticaria & itching
- Bronchoconstriction
- Hypotension due to vasodilation
What medications can be used to reverse opioid toxicity?
Mu opioid antagonist:
- Naloxone: short-acting IV
- Naltrexone: long-acting PO
- Nalmefene is long-acting IV that can replace naloxone + naltrexone combination
Under what conditions should opioid antagonists be used with extreme caution?
Patient w/ opiate dependency as they can precipitate fatal withdrawal syndrome
