Neuraxial Opioids

[SH4:p90-p93]

 

 

 

Opioid receptors (mostly MOR) are present in substantia gelatinosa of the spinal cord

 

Effects of neuraxial opioid

• Analgesia
  * Effects are dose-dependent
  * Specific for visceral, not somatic pain
• Unlike IV opioid or neuraxial LA, neuraxial opioids:
  * Does NOT cause sympathetic system denervation
  * Does NOT cause skeletal muscle weakness
  * Does NOT cause loss of proprioception

Epidural opioids

Fate of epidural opioids

• Diffusion across dural into CSF, then to mu receptors on the spinal cord
• Systemic absorption
  * Similar to IV administration
• Can enter epidural fat

Effects of lipid-solubility in epidural opioids

High lipid-solubility

Highly lipophilic opioid (e.g. fentanyl, sufentanil)

• Most of the effects are due to systemic absorption

Low lipid-solubility

Poorly lipid-soluble opioid (e.g. morphine)

• Slower onset of analgesia
• Longer duration of action

Pharmacokinetics of neuraxial opioids

Epidural opioids

Penetration of opioid through dura into CSF depends on

• Molecular weight
• Lipid solubility

Lipid solubility

• Fentanyl = 800 times as lipid soluble as morphine
  * Or 955 times [SH4:table3-5]
• Sufentanil = 1600 times as lipid soluble as morphine
  * Or 1727 times [SH4:table3-5]

CSF concentration after epidural administration

After epidural administration, CSF concentration of

• Fentanyl - peak in 20 min
• Sufentanil - peak in 6 min
• Morphine - peak in 1-4 hours (only 3% of morphine enters CSF)

Blood concentration after epidural administration

After epidural administration, blood concentration of

• Fentanyl - peak in 5-10 min
• Sufentanil - sooner than fentanyl
• Morphine - 10-15 min

NB:

• Blood concentration of opioids after epidural administration is similar to after equivalent IM dose
• Adding epinephrine to epidural opioids
  * Decreases systemic absorption
  * No influence on diffusion into CSF
• Adding epinephrine to intrathecal morphine
  --> Enhance analgesia

 

Cephalad movement of opioids in CSF

 

... depends on lipid solubility

• High lipid-solubility drugs (fentanyl and sufentanil)
  --> Faster uptake into spinal cord
• Low lipid-solubility drugs (e.g. morphine)
  --> More drugs remain in CSF
  --> More to be transferred to more cephalad location

Bulk flow of CSF

... is the mechanism of cephalad movement of opioids in CSF

• From lumbar, CSF moves to:
  * Cisterna magna in 1-2 hours
  * 4th and lateral ventricles in 3-6 hours
• Accelerated by coughing or straining
• Unaffected by body position

Side effects of neuraxial opioids

4 main side-effects of neuraxial opioids

1. Pruritus
2. Nausea and vomiting
3. Respiratory depression
4. Urinary retention

 

Other side effects include:

• Sedation/CNS excitation
• Viral reactivation
  * Cold sores
• Neonatal morbidity
• Sexual dysfunction
  * In young male volunteers, sustained erection and inability to ejaculate
• Ocular dysfunction
  * Miosis, nystagmus, vertigo
  * Especially with neuraxial morphine
• GIT dysfunction
  * Delayed gastric emptying
• Thermoregulatory dysfunction
  * Inhibition of shivering
  --> Decrease in core temperature
• Water retention
  * Oligouria due to release of ADH stimulated by cephalad migration of opioids
• Spinal cord damage from toxic preservatives

Pruritus

Incidence

• Most common side effect with neuraxial opioids
  * Most cases are mild
  * 1% has severe pruritus
• Incidence may or may not be dose-dependent
• More likely with obstetric patients
  * Possible interaction between oestrogen and opioid receptors

Presentation

• More likely localised to face, neck, and upper thorax.
  * Can also be generalised
• Occurs within a few hours
  * May precede onset of analgesia

Mechanism of action

• Histamine-release is NOT the mechanism of pruritus
• Pruritus is likely due to cephalad migration of opioids in CSF and subsequent interaction with opioid receptors in trigeminal nucleus

Treatment of pruritus

• Naloxone is effective in relieving opioid-induced pruritus
• Antihistamine may also be effective due to its sedative effects

Respiratory depression

• Most reliable clinical signs of ventilation depression is depressed level of consciousness
  * ? Due to hypercarbia

Incidence of respiratory depression

• After neuraxial opioids, incidence of ventilatory depression requiring intervention
  = 1%
  * Same as after IV or IM

Early depression of ventilation

• Within 2 hours
• Most cases involve fentanyl or sufentanil
  * Unlikely to occur with intrathecal morphine
• Most likely due to systemic absorption of the lipid-soluble opioids

Delayed depression of ventilation

• Occurs after 2 hours
• All cases involve morphine
• Due to cephalad migration of morphine in CSF
  --> Action on opioid receptors in the ventral medulla
• Delayed respiratory depression due to neuraxial morphine
  * Characteristically occurs 6-12 hours after intrathecal or epidural administration
  * Not reported to occur more than 24 hours after administration

Risk factors for respiratory depression

• Coughing
  --> Increased intrathoracic pressure
  --> Increased CSF cephalad migration
  --> Increased risk
• Concomitant IV opioid or sedative
• High opioid dose
• Low lipid solubility
• Lack of opioid tolerance
• Advanced age

 

NB:

• Obstetric patients are at LESS risks
  --> Possible increased stimulation to ventilatory drive due to progesterone

Urinary retention

Incidence

• Incidence varies widely and most common in young males
• More common after neuraxial, than with IV/IM
• Incidence is NOT dose-dependent

Presentation

• Epidural morphine causes marked detrusor muscle relaxation within 15 minutes
  --> Persists up to 16 hours
  * Reversed by naloxone

Mechanism of action

• Urinary retention is NOT related to systemic absorption
• Opioid acting on opioid receptors in the sacral spinal cord
  --> Promotes inhibition of sacral parasympathetic nervous system outflow
  --> Detrusor muscle relaxation + Increased bladder capacity
  --> Urinary retention

 

Other side effects of neuraxial opioids

Sedation

• ... is dose-related
• Most common after neuraxial sufentanil
• Must also consider respiratory depression as a cause for sedation

 

CNS excitation

Tonic skeletal muscle rigidity

• Resembles seizures
• Occurs after large IV doses of opioid
• Rare after neuraxial opioids

NB:

• True seizures has been induced in animals but not in humans
  * Most likely due to cephalad migration of opioids in CSF
  --> Interaction with non-opioid receptors in brainstem or basal ganglia

Viral reactivation

Epidural morphine in obstetric patients
--> Reactivation of herpes simplex labialis (2-5 days after administration)

• Occurs in the same sensory innervations
  * Usually in the facial area innervated by trigeminal nerve
• Mechanism:
  * Cephalad migration of morphine in CSF
  --> Interacts with trigeminal nucleus