Neuraxial Opioids in Obstetrics

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Neuraxial Opioids in Obstetrics

• Dmitry Portnoy, MD
• Anesthesiology Department

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Objectives

• Description of known mechanisms of spinal
  opioids.
• Interaction with opioid receptors
• Distribution and redistribution of spinal opioids
• Properties that govern pharmacokinetics of spinal
  opioids
• Clinical application of spinal opioids.
• Specific drugs appropriate for spinal
  administration
• Sites and method of administration
• Recognition and treatment of side effects and
  complications.

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Historical Perspective

• 2000 b.c. opium used for pain relief in ancient
  China, Egypt, Rome and Greece.
• 1899 August Bier injected cocaine to produce
  spinal anesthesia.
• 1973 Pert and Snyder discovered specific opioid
  receptors of the spinal cord.
• 1979 Wang et al. reported the first clinical use
  of IT opioids.
• 1979 Behar et al. - epidural morphine in
  treatment of pain.

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The Physiology of Pain in Labor

• Pain during first stage of labor - visceral
• Dilation of the cervix and distention of the
  lower uterine segment
• Dull, aching and poorly localized
• Slow conducting, visceral C fibers, enter spinal
  cord at T10 to L1
• Can be blocked by spinal opioids alone
• Pain during second stage of labor somatic
• Distention of the pelvic floor, vagina and
  perineum
• Sharp, severe and well localized
• Rapidly conducting A-delta fibers, enter spinal
  cord at S2 to S4
• Difficult to block with spinal opioids alone

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The Physiology of Pain in Labor
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Mechanism of Action

• Universal molecular mechanism of opioids
• Binding to G-protein-coupled opioid receptor
• Inhibition of adenylate cyclase and voltage-gated
  Ca channels
• Decrease neuronal excitability, interruption of
  pain transmission
• Spinal effect the substantia gelatinosa of the
  dorsal horn
• Highly selective nociceptive pathways
• Presynaptic receptor action inhibition of
  substance P release
• Postsynaptic receptor action modulation of pain
  transmission
• Supraspinal effect inhibition of primary
  afferent transmission in the brainstem, thalamus
  and gray matter

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Mechanism of Action
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Mechanism of Action - Bioavailability

• Effect depends on affinity and ability to reach
  receptors
• Spinal and epidural opioids - same principle
  mechanism
• Penetration of neural tissue is the rate limiting
  step
• Factors affecting transmembrane movements of the
  opioids
• Molecular weight
• pK (the lower pK, the greater fraction of
  uncharged form at pH of 7.4)
• Protein binding
• Lipid solubility

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Mechanism of Action Reaching Receptors

• Epidurally administered drugs must travel
  through
• dura matter
• arachnoid matter
• CSF
• pia matter
• white matter
• gray matter dorsal horn
• Competing pathways
• Uptake into epidural epidural fat
• Uptake into systemic circulation

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Mechanism of Action Meningeal Permeability

• Proposed mechanisms of movements spinal drugs
• Diffusion through spinal meninges
• Preferential diffusion through spinal nerve root
  cuff
• Uptake and distribution via radicular blood flow
• Arachnoid matter is the principle meningeal
  barrier
• 6-10 layers of tightly adherent cells
• Repeated aqueouslipid interfaces
• Contains enzymes that metabolize substances
• Is intermediate hydrophobicity ideal for spinal
  delivery?

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Lipid Solubility and Meningeal Permeability
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The Fate of Intrathecal Drugs

• Diffusion into the epidural space systemic
  circulation
• Diffusion into the spinal
• cord systemic circulation
• Rostral spread
• Bulk movement vs. diffusion
• Lipid solubility controversy
• Patient position
• Baricity

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The Fate of Intrathecal Drugs
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Clinical Application of Neuraxial Opioids

• A medicine would be discovered which should
  suspend sensibility altogether and leave
  irritability or powers of motion unimpaired.
  Benjamine Rush, 1818
• Any opioid administered anywhere in the body
  will eventually produce analgesia
• Expectations from neuraxial opioids
  administration
• Selective enhanced analgesia
• Reduction in systemic effects and complications
  of opioids
• Dose-sparing effect (compared to parenteral
  administration)

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Clinical Application Epidural Opioids Alone

• No sympathectomy or motor block (except for
  meperidine)
• Unreliable in advanced labor
• Hydrophilic drugs Morphine
• Inconsistent analgesia (50), delayed onset
• Relatively large dose, increased frequency of
  side effects
• Increased level in umbilical cord (risk of
  neonatal depression?)
• Lipophilic drugs Fentanyl, Sufentanil,
  Alfentanil, Meperidine
• Better analgesia, rapid onset, but short duration
• Loss of dose-sparing effect, systemic
  absorption

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Clinical Application Epidural LA and Narcotics

• Provide both somatic and visceral analgesia.
• Hasten the onset, effective during 1st and 2nd
  stage of labor.
• Decrease concentration and total dose of local
  anesthetic
• Decrease risk of systemic toxicity
• Decrease risk of high/total spinal
• Decrease of LA in the fetus
• Decrease intensity of motor block
• 2-chloroprocaine mediated inhibition
• pH dependent (increases fraction of ionized form
  of the drugs)
• Not pH dependent (impairs mu-receptors activity)

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Clinical Application Intrathecal Opioids

• Advantages of intrathecal administration
• Simple and quick procedure, rapid onset of
  analgesia
• No motor or sympathetic blockade
• May be performed by other than anesthesiologist
  physician
• Limitations of spinal opioids
• Lack of flexibility for duration and intensity
  of labor
• Unreliable for advanced labor and instrumental
  delivery
• Methods to overcome spinal opioids limitations
• Catheter based techniques (intrathecal or
  combined spinal/epidural)
• Combination of intrathecal drugs

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Combine Spinal-Epidural Anesthesia

• by combining the two methods many of the
  disadvantages of both methods are eliminated and
  their advantages are enhanced to almost
  incredible degree.
• Soresi AL. Episubdural anesthesia. AA
  193716306-31

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Combine Spinal-Epidural Anesthesia

• Advantages of CSE analgesia and anesthesia
• Rapid onset of intense analgesia
• Flexibility of epidural blockade as labor
  progress
• Takes less time and efforts to induce analgesia
• Possibly more reliable placement of epidural
  catheter
• Proposed clinical use of CSE technique
• Early labor ( lt4 cm )
• Advanced labor ( gt7-8 cm )
• Second stage

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Combine Spinal-Epidural AnesthesiaPotential
Problems

• Spinal puncture
• Penetration by epidural catheter
• Leakage of CSF out
• Leakage of epidural solution in
• Inability to test epidural catheter
• Deposition of metallic
• microparticles
• Spinal to catheter insertion time, when using
  hyperbaric spinal solutions

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Maternal Complications and Side effects

• Classic side effects
• Respiratory depression
• Urinary retention
• Pruritus
• Nausea and vomiting

• Rare side effects
• Mental status changes
• Hyperalgesia
• Herpes simplex labialis
• Ocular dysfunction
• GI dysfunction
• Thermoregulation dysfunction
• Cardiac dysrhythmia
• Neurotoxicity

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Maternal Complications and Side
Effectsrespiratory depression

• Early respiratory depression
• Lipophilic epidural drugs
• Develops within 2 hours
• Likely results from systemic absorption
• Rostral spread of lipophilic agents also possible
• Delayed respiratory depression morphine
• Occurs 6-12 hr, up to 24 hr following
  administration
• Results from cephalad migration to ventral
  medulla
• Continues infusion of lipophilic drugs may also
  be implicated

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Maternal Complications and Side
Effectsrespiratory depression

• Factors increasing risk of respiratory depression
• High and repeated doses of opioids
• Sedatives, co-existing disease
• lack of opioid tolerance
• Patient position, increased abdominal and
  intrathoracic pressure
• Monitoring and management
• Frequent assessment of somnolence and respiratory
  rate
• Availability of naloxone at the bedside
• Standing order and protocol for treatment of
  respiratory depression
• Availability of a physician who can direct
  resuscitation

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Maternal complications and side effectspruritus

• Occurrence - very common, but severe only in 1
• May be caused by all opioids and dose unrelated
• Pathogenesis centrally mediated, due to
  cephalad spread
• Histamine release is probably not involved
• Concept of an itch center in lower medulla
• Altered CNS perception of pain
• Treatment and prophylaxis
• Diphenhydramine 25mg (most likely secondary to
  sedation)
• Nalbuphine 5mg, Naloxone 20 40 mcg, naltrexone
  25mg PO
• Propofol 10 mg (mechanism unknown)
• Limiting cephalad spread - use of hyperbaric
  spinal solution

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Addition of Low Concentration Dextrose to
Intrathecal Sufentanil for Labor Analgesia A Way
of Minimizing Pruritus without Affecting Quality
of Analgesia?
overall
gtT6
T6 to L1
ltL1
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Maternal Complications and Side Effects

• Nausea and vomiting
• Difficult to determine opioid mediated incidence
  during labor
• Probably due to rostral migration to
  chemoreceptor trigger zone
• More with morphine, dose nondependent
• Urinary retention
• Higher incidence with spinal morphine, not
  related to the dose
• Inhibition of sacral parasympathetic system
  outflow
• Detrussor muscle relaxation results in increased
  bladder capacity
• Treatment catheterization, opioid antagonists

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Maternal Complications and Side Effects

• Mental status changes, CNS excitation
• Sedation cephalad spread, dose related
• Excitation non-opioid receptors interaction
  (basal ganglia)
• Herpes simplex labialis virus (HSV-1)
  reactivation
• Trigeminal ganglion trigger (cephalad migration)
• Skin trigger mechanism secondary to pruritus and
  scratching
• Gastrointestinal dysfunction
• Secondary to spinal opioid receptors interaction
• Delay gastric empting, prolong intestinal transit
  time, dysphagia

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Maternal Complications and Side Effects

• Neurotoxicity
• Not all opioid agents tested for direct effect on
  neural tissue
• Intrathecal butorphanol may cause neural tissue
  damage
• Hypotension
• BP falls by 20 in 14 50 parturients
  following spinal opioid
• Unlikely secondary to direct sympathectomy effect
• Abrupt relief of pain, decrease the level of
  adrenaline
• Opioidergic BP control system?
• Require the same BP monitoring as a routine
  epidural analgesia

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Complications and Side EffectsLabor Progress
and Neonatal Morbidity

• Effect of neuraxial opioids on labor
• Cause-and-effect relationship is unclear
• One study showed prolongation of labor with
  spinal morphine
• Fetal effects
• Remote possibility of respiratory depression or
  FHR changes
• Mostly mediated by systemic absorption
• Small doses of neuraxial opioids appeared to be
  safe
• Epidural opioids tend to accumulate with time

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Neuraxial Opioids - Conclusion

• Effective and safe analgesia with minimal motor
  block
• For early labor may be used alone
• For advanced labor - combination with local
  anesthetics
• Superior postoperative pain control cesarean
  delivery patients
• Advantageous for high risk patients
• No sympathectomy, better hemodynamic control
• Decrease of local anesthetic toxicity
• Consider limitations and side effects of
  neuraxial opioids
• Narrow therapeutic ratio for some drugs
• Limited duration consider catheter based
  techniques
• Appropriate monitoring is mandatory

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Case 1

• 34 y/o male, anesthesiology resident
• Scheduled for left inguinal hernia repair
• Medical history unremarkable
• Allergies PCN, Sulfa
• Patient requests spinal anesthesia.
• Intraoperative course
• SAH with 12.5 mg of 0.75 Bupivacaine 0.2 mg
  Epinephrine 200 mcg of Duramorph. Sensory
  level at T8
• Sedation with 4 mg of Versed, 100 mcg of Fentanyl
  and incremental Propofol of total 160 mg
• Fluids 1300 cc of LR, surgical time 45 min