Opioids

[Ref: SH(H)2:p81]

Overview

Levorotatory isomers are more active

Mechanism of action

Acts on stereospecific opioid receptors
* Only levorotatory forms have agonist activity
--> Increased K+ conductance and/or Ca2+ channel inactivation
--> Decreased neurotransmitter release
--> Decreased neurotransmission

NB:

Opioids need to be in ionized state to bind strongly to (anionic) opioid receptor site

Opioid receptors

Classified into mu, delta, and kappa receptors
* All G-protein coupled

Mu receptors are responsible for supraspinal and spinal anaesthesia

Location of opioid receptors

• CNS (mainly the brain stem and the spinal cord)
• Peripheral tissues

Brain

• Periaqueductal gray matter of the brain stem
• Amygdala
• Corpus striatum
• Hypothalamus

Spinal cord

• Substantia gelatinosa

 

Neuraxial opioids

Administration of opioids by spinal or epidural (compared with IV administration)
* No sympathetic nervous system depression
* No skeletal muscle weakness
* No loss of proprioception
* More specific for visceral pain than somatic pain

Epidural

Analgesia is produced by
* Diffusion across the dura, and
* Systemic absorption of the opioid

Penetration of the dura is dependent on the lipid solubility
* Fentanyl CSF level peak in 20min
* Sufentanil CSF level peak in 6 min
* Morphine CSF level peak in 1-4 hours

NB:

• Plasma concentration of morphine, fentanyl, and sufentanil after epidural administration is similar to an IM injection of the same dose
• Adding epinephrine decreases systemic absorption but does not influence diffusion of morphine across dura

CSF bulk flow

CSF ascends from lumbar region in cephalad direction
--> Reaching cisterna magna in 1-2 hours
--> Reaching 4th and lateral ventricle by 3-6 hours

Cough and straining affects CSF movement

Body position does not affect CSF movement

Side-effects of neuraxial opioids

• Pruritis
• Nausea and vomiting
• Urinary retention
• Depression of ventilation
• Sedation
• CNS excitation
• Viral reactivation
• Neonatal morbidity
• Sexual dysfunction
• Ocular dysfunction
• GIT dysfunction
• Thermoregulatory dysfunction
• Water retention

Pruritis

Often localized to face, neck, and upper thorax

Precede the onset of analgesia

In the case of neuraxial opioids, pruritis is not due to histamine release
--> Caused by interaction with opioid receptors in the trigeminal nucleus

Can be relieved by opioid antagonist (e.g. naloxone)

Antihistamine can help due to sedation effect

Urinary retention

More common with neuraxial opioid administration

Interaction with opioid receptors in the sacral spinal cord
--> Inhibition of sacral parasympathetic nervous system outflow
--> Detrusor muscle relaxation
--> Increased maximum bladder capacity
--> Urinary retention

Depression of ventilation

Early depression

Early depression of ventilation occurs within 2 hours of neuraxial injection of opioid (fentanyl or sufentanil)
* Most likely from systemic absorption of opioid
* Cephalad migration of opioid in the CSF is also a possible cause

Clinically significant early depression of ventilation after intrathecal injection of morphine is unlikely

Delayed depression

Delayed depression of ventilation after neuraxial opioid
--> Cephalad migration of opioid in CSF
--> Interaction with opioid receptors in the ventral medulla

After neuraxial administration of morphine (intrathecal or epidural)
--> Delayed depression of ventilation occurs 6-12 hours afterwards

Signs of ventilation depression

Most reliable clinical sign of ventilation depression is
* Depressed level of consciousness
* Possibly caused by hypercapnia

Risk factors for ventilation depression

• High opioid dose
• Low lipid solubility of the opioid
• Concomitant administration of parenteral opioids or other sedatives
• Lack of opioid tolerance
• Advanced age
• Increased intrathoracic pressure
• ?Patient position

Other side-effects of neuraxial opiods

Sedation
* Most commonly associated with sufentanil

CNS excitation
* Tonic skeletal muscle rigidity
* Common after large IV dose, but rare with neuraxial opioids

Viral reactivation
* Possible link between epidural morphine in obstetric patients and reactivation of herpes simplex labialis virus

Neonatal morbidity
* Systemic absorption leads to opioid build-up in neonates

GIT dysfunction
* Cause delayed gastric emptying

Thermoregulatory dysfunction
* Inhibition of shivering
--> Decreased body temperature

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Separate subtype

mu1, mu2, kappa 1,2,3, deta1,2

Possible from post-translational modification

 

Spinal opioids

Act preferentially on receptors in the dorsal horn

Analgesic effect through modulation of afferent sensory input via A-delta and C fibres

Some effect by rostral spread and action on supraspinal opioid receptors

 

Adverse effects

Pruritis (80%) but most do not complain

N&V

Resp depression

 

Pethidine has sodium channel blocking properties (like LA)

When used in spinal, creates acceptable block alone but can also cause hypotension

 

Tolerance - exposure to a drug results in the dimunution of effect or the need for a higher dose to maintain an effect

--> A shift to the right of the dose-response curve

 

Have a comparative overview of the opioid agonists in pharmacokinetics

Pethidine - high pKa

Fentanil - faster redistribution but slower elimination halftime than morphine

Sufentanil - very lipid soluble, very fast redistribution, accumulates, slow elimination half-time

Alfentanil - low pKa, very fast effect-site equilibration time, redistribution not significant, small Vd (context-sensitive halftime hits ceiling earlier than sufentanil), CSHT more variable due to P450 enzyme activity variance (CYP3A4)

Remifentanil - low pKa (not as low as alfentanil), rapid clearance, tight-concentration-effect relationship,

 

 

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volume of epidural space is reduced in elderly

compensatory mechanism are limited in elderly