Natural Opioids vs Synthetic Opioids

as Adjuvant in Regional Anesthesia:

Which one is better?
 OPIOID
 The three main types of opiate receptors:
 mu (m)
 The most important target for opioids is the m-receptor (endorphin), and
intrathecal opioids appear to selectively modulate C- and A-fibres
with minimal impact on dorsal root axons.
 delta (d)
 The enkephalins are the primary endogenous ligands of the d
receptor and are involved with spinal analgesia.
 kappa (k)
 Dynorphin is the prototypic ligand for the k receptor. Activation of
the k receptor results in segmental spinal analgesia and sedation.
 Most of the mixed agonist- antagonist opioids (e.g., butorphanol) bind
to the k receptor.

LENNART CHRISTIANSSON. (2009). Update on adjuvants in regional anaesthesia. Periodicum Biologorum, Vol. 111, No 2, 161–170, 2009
 OPIOID
 Any drug given intrathecally rapidly redistributes within
the CSF; opioid is detectable in the cisterna magna after
lumbar intrathecal administration within 30 min, even
with lipophilic drugs like sufentanil.

LENNART CHRISTIANSSON. (2009). Update on adjuvants in regional anaesthesia. Periodicum Biologorum, Vol. 111, No 2, 161–170, 2009
 OPIOIDS
 1970  first time to be given to human in the
neuraxial spaces
 Most frequently used for adjuvants.
 Addition to a LA solution:
 extending the duration of pain relief
 decreasing the dosage of LA required for pain treatment
 Mechanism: G-protein-coupled-receptor system

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
U BAKSHI, S CHATTERJEE, S SENGUPTA, D GUPTA. (2009). Adjuvant Drugs In Central Neuraxial Analgesia- A Review.The Internet Journal of
Anesthesiology. Vol. 26, No. 1.
 OPIOIDS
 Opioid hyperpolarize the afferent sensory neurons 
pain relief
 Opioid receptor: located in CNS and on peripheral cells
 Evidence demonstrating the benefits of administering opioids
into peripheral tissues is inconclusive

CORRIE T. M. ANDERSON. Adjuvants in Regional and Neuraxial Anesthesia: An Update. Washington: Department of Anesthesiology and Pain
Medicine, University of Washington School of Medicine, Seattle Children's Hospital.
LENNART CHRISTIANSSON. (2009). Update on adjuvants in regional anaesthesia. Periodicum Biologorum, Vol. 111, No 2, 161–170, 2009
 OPIOIDS
 Factors that play an important role on the eventual effect
produced:
 Dose
 Lipophilicity
 Site of injection
 Condition of the milieu into which the injection is made

CORRIE T. M. ANDERSON. Adjuvants in Regional and Neuraxial Anesthesia: An Update. Washington: Department of Anesthesiology and Pain
Medicine, University of Washington School of Medicine, Seattle Children's Hospital.
 MORPHINE
 A hydrophilic phenanthrene derivative
 100 times less potent then fentanyl.
 Slow onset (15 minutes intrathecal, 30 minutes epidural)
 longer duration of action (approximately 12-24 hours).
 terminal elimination half life is approximately 170 minutes
 Only the preservative free form is recommended for regional
anesthesiology.
 Improve post surgical pain in both children and adults
 Morphine: hydrophilic properties
 Not easily absorbed to the surrounding tissue
 Cephalad spread  increase analgesia area, risk for respiratory
depression

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 MORPHINE
 Respiratory depression:
 Can occur within the first 6 hours (or many hours later) after
neuraxial administration
 Side effect: nausea, vomiting, itching, and urine retention
(side effect of inadequate pain relief)
 Prolonged intrathecal infusion of morphine  granuloma
formation

CORRIE T. M. ANDERSON. Adjuvants in Regional and Neuraxial Anesthesia: An Update. Washington: Department of Anesthesiology and Pain
Medicine, University of Washington School of Medicine, Seattle Children's Hospital.
 FENTANYL
 Widely used opiates in conduction anesthesia
 Fentanyl:
 Short acting opiate (5 minutes intrathecal, 10 minutes epidural)  often
administered as a continuous infusion (intrathecal/epidural)
 More potent (70 to 100 time stronger) than morphine
 Short duration (2-4 hours intrathecal and epidural): Fentanyl
rapidly taken up into blood vessels and redistributed into well-
perfused tissues (not due to rapid metabolism)

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
KIRKSEY MA, HASKINS SC, CHENG J, LIU SS. (2015) Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A
Systematic Qualitative Review. PLoS ONE 10(9): e0137312. doi:10.1371/journal.pone.0137312
 FENTANYL
 800 times more lipid soluble than morphine
 Long terminal elimination half life (190 minutes)
 Fentanyl will accumulate in fatty tissues that act as a
depot.
 Increased risk of respiratory compromise if other
depressant agents (lorazepam) are administered
concomitantly.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
CORRIE T. M. ANDERSON. Adjuvants in Regional and Neuraxial Anesthesia: An Update. Washington: Department of Anesthesiology and Pain
Medicine, University of Washington School of Medicine, Seattle Children's Hospital.
 SUFENTANIL
 extremely potent lipophilic phenylpiperidine derivative.
 It has a faster onset (2-3 minutes intrathecal, 4-6 minutes
epidural)
 shorter duration of action then fentanyl (1-3 hours
intrathecal and epidural).
 analgesic potency: 5-7 times greater than fentanyl
 1600 times more lipid soluble than morphine.
 terminal elimination half life is shorter than fentanyl (150
minutes)  accumulation is less likely
 Like fentanyl, the intrathecal administration of sufentanil
for postoperative analgesia is limited by its short duration
of action.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
LENNART CHRISTIANSSON. (2009). Update on adjuvants in regional anaesthesia. Periodicum Biologorum, Vol. 111, No 2, 161–170, 2009
 PETHIDINE
 lipophilic phenylpiperidine derivate 10 times less potent
and 30 times more lipid soluble then morphine.
 It has a faster onset (5 minutes intrathecal, 10 minutes
epidural)
 shorter duration (4-8 hours intrathecal and epidural) of
action than morphine.
 Pethidine has an active metabolite (norpethidine), which
in high concentrations may cause seizures and
hallucinations.
 Pethidine differs from other opioids in that it possesses
local anaesthetic properties (motor and sensory fibre
block).

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 PETHIDINE
 incidence of adverse effects is high and its use by this
route is not recommended.
 Epidural pethidine is effective as a single agent for
postoperative analgesia after caesarean delivery and may
be administered as a patient controlled epidural analgesia
technique. In this setting the incidence of adverse effects
is relatively low.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 TRAMADOL
 A μ-agonist opioid that inhibits reuptake of norepinephrine
and serotonin
 Involved in descending inhibitory pain pathways associated
with pain relief
 When used in PNBs, tramadol has been demonstrated to
increase the duration of analgesia
 FDA does not approve tramadol for perineural administration
 Findings on the use of tramadol in PNBs are equivocal

JASON A. PATACSIL, MAURA S. MCAULIFFE, LEAH S. FEYH, LORIE L. SIGMON. (2016). Local Anesthetic Adjuvants Providing the Longest
Duration of Analgesia for Single-Injection Peripheral Nerve Blocks in Orthopedic Surgery: A Literature Review. AANA Journal,Vol. 84, No. 2.
CHAD M. BRUMMETT, BRIAN A. WILLIAMS. (2011). Additives to Local Anesthetics for Peripheral Nerve Blockade. Int Anesthesiol Clin.; 49(4):
104–116. doi:10.1097/AIA.0b013e31820e4a49.
 Natural Opioid vs. Synthetic Opioid
 When used alone, the utility of most lipophilic neuraxial
opioids is limited by a short duration of effect and dose
related side effects. The most frequently used neuraxial
opioids include morphine, diamorphine, fentanyl, sufentanil
and pethidine.
 The study confirmed that after epidural administration,
morphine has much greater bioavailability in the spinal
cord than alfentanil, fentanyl, and sufentanil

LENNART CHRISTIANSSON. (2009). Update on adjuvants in regional anaesthesia. Periodicum Biologorum, Vol. 111, No 2, 161–170, 2009
 Natural Opioid vs. Synthetic Opioid
 Lipophilic opioids such as fentanyl and sufentanil diffuse
rapidly across the dura into the CSF compared to
hydrophilic opioids such as morphine. Lipophilic opioids
produce rapid onset of analgesia which is of short overall
duration. After epidural delivery, CSF opioid levels peak at
6 minutes for sufentanil, 20 minutes for fentanyl and 1-4
hours for morphine.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 Natural Opioid vs. Synthetic
Opioid
 Lipophilic opioids such as sufentanil and fentanyl are
absorbed the most rapidly, and are therefore more likely
to cause early respiratory depression. After epidural
delivery, plasma levels peak at less than 5 minutes for
sufentanil, 5-10 minutes for fentanyl and 10-15 minutes
for morphine.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 Epidural Labour Analgesia
 Epidural opioids improve quality of analgesia and reduce
the number of failed epidurals due to patchy blocks.
 Different opioids can be used, however those with low
lipid solubility such as morphine are associated with
delayed respiratory depression and should be used with
caution.
 Fentanyl is the most frequently used opioid for labour
analgesia.
 Intrathecal opioids are also effective for labour analgesia,
however no single intrathecal drug can reliably provide
analgesia for the duration of labour.

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women
 Epidural Labour Analgesia
 Neuraxial morphine has been shown to be as effective as
fentanyl at improving the quality of analgesia for labour
pain, caesarean delivery, and more effective than a single
dose of fentanyl at providing postoperative pain relief
 Side effects: Morphine > Fentanyl

NICOLE KHANGURE. (2011). Adjuvant Agents in Neuraxial Blockade. Western Australia: King Edward Memorial Hospital for Women