3. Pharmacology
          3.5. Opioids
 3.5.1. Neuraxial Opioids

Neuraxial Opioids





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


  • 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



  • 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


  • 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



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

Urinary retention


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


  • 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


  • ... 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


  • 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

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