3. Pharmacology
          3.5. Opioids
              3.5.3. Opioid agonists Fentanyl






Blunt circulatory response to
* Direct laryngoscopy
* Sudden changes in sergical stimulation


  • Phenylpiperidine-derivative
  • Synthetic opioid agonist
  • Structurally related to mepridine



  • 75-125 times more potent than morphine

Mechanism of action

?? MOP receptor agonist



  • Large doses of fentanyl can produce changes in somatosensory evoked potentials
    --> Does not interfere with entropy/BIS monitoring
Intracranial pressure
  • Modest increase in ICP (6-9mmHg)
    * Despite normal PaCO2
    * Could be due to autoregulatory cerebrovasodilation due to decreased BP
    * Other mechanism could be possible


  • No histamine-release
    * Even in large doses, fentanyl does not cause histamine release like morphine does
  • Bradycardia
    * More prominent in fentanyl than in morphine
  • Carotid sinus baroreceptor control of heart rate can become depressed


  • Respiratory depression
  • Reflex coughing may be associated with preinduction administration of fentanyl, sufentanil, and alfentanil

Skeletal muscle rigidity

  • Opioid-induced skeletal muscle rigidity is possible
  • Myoclonus secondary to depression of inhibitory neurons can also be possible


Allergic reation is rare

Secondary peaks

Ion trapping
--> Fentanyl or morphine could become sequestrated in acidic gastric acid
--> Later on absorbed in intestine
--> Possible secondary peaks in plasma concentration of fentanyl and morphine


Alternative explanation
--> Restoration of VQ relationship in lung in postoperative period
--> Washout of fentanyl from the lung
--> Secondary peak in plasma concentration

Biliary spasm

  • Biliary spasm effect is the greatest with fentanyl
    * Fentanyl > Morphine > Meperidine > Pentazocine
    * See [Pharmacokinetics of opioids]



IV, S/C, Transdermal, Transmucosal



  • Vd = 335 L
    * Larger than morphine (224L)
    * Due to the greater lipid solubility
  • Vd = 3-5 L/kg (steady state)
    * [RDM6:p401]
  • Protein-binding = 84%
  • More than 80% of the injected fentanyl leaves plasma within 5 minutes

Inactive sites

  • Lung is a large inactive storage site
    --> About 75% of fentanyl dose undergoes first-pass pulmonary uptake
  • Fat
  • Muscles


  • Hepatic extraction ratio = 0.8-1.0
    * [RDM6:p401]
  • Fentanyl is extensively metabolised by N-demethylation
  • Hepatic P450 enzyme CYP3A is involved
    --> Fentanyl is susceptible to drug interaction


Metabolites include:

  • Norfentanyl
    * Structurally similar to normeperidine
    * Principle metabolite in human
    * Excreted by kidney
    * Still detectable in urine after 72 hours
  • Hydroxyproprionyl-fentanyl
  • Hydroxyproprionyl-norfentanyl


  • Fentanyl metabolites are thought to have minimal pharmacological activity


  • Clearance = 1530 L/min
  • Clearance = 10-20 mL/kg/min
    * [RDM6:p401]
  • < 10% of fentanyl is excreted unchanged in urine

Action profile

  • More rapid onset and shorter duration than morphine
  • Time lag between the peak plasma fentanyl concentration and the peak slowing on the EEG
  • Elimination half-time = 3.1-6.6 hours
    * Longer than morphine (1.7-3.3 hours)
    * Due to larger Vd and similar clearance
  • Effect-site (Blood/brain) equilibration time = 6.8 min
  • Short duration of action is due to
    * Rapid redistribution to inactive tissues (fat and muscles)
  • Duration of action = 30-60 min
    * [SS3:p154]

Context sensitive half-time

  • For fentanyl, context sensitive half-time increases as inactive sites become saturated
  • After 2 hours of infusion, context sensitive half-time for fentanyl is longer than that for sufentanil
  • Context sensitive half-time (after 4 hours) = 260 min

Physicochemical properties

  • Weak base
  • pKa = 8.4
    --> 8.5% of fentanyl is non-ionised at pH 7.4
  • Partition coefficient (lipid solubility) = 955
    * Morphine being 1

Overall, rapid tissue uptake due to higher lipid solubility, despite the lower non-ionised fraction.



Transdermal fentanyl

  • From 12.5 microgram/hr (2.1mg) to 100 microgram/hour (16.8mg)



  • Analgesia = 1-2 microgram/kg IV
  • Labour analgesia
    = max 25 micrograms intrathecal
    * Maximum benefit achieved at 25 micrograms
  • Reduction in sympathetic response = 1.5-3 micrograms/kg IV (5 minutes before induction)
  • Surgical anaesthesia = 50-150 microgram/kg IV


Transmucosal fentanyl

In 2-8 years old,

  • 15-20 microgram/kg, 45 min before induction
  • But may cause increased incidence of PONV (not influenced by prophylactic droperidol)
    * Conflicting studies regarding PONV


For postoperative pain

  • 1 mg of oral transmucosal fentanyl = 5 mg of IV morphine

Transdermal fentanyl

  • From 12.5 microgram/hr (2.1mg) to 100 microgram/hour (16.8mg)
  • Peak plasma fentanyl concentration in about 18 hours

Surgical anaesthesia

When large doses of fentanyl is used as the sole anaesthetic agent


  • Stable haemodynamic state, due to
    * Lack of direct myocardial depression
    * Absence of histamine release
    * Suppression of stress response to surgery


  • Failure to completely prevent sympathetic response to painful surgical stimulation
  • Possible patient awareness
  • Postoperative depression of ventilation

Drug interaction

  • Analgesic concentrations of fentanyl could
    * Potentiate effects of midazolam
    * Reduce dose requirement of propofol
  • Marked synergism between fentanyl and benzodiazepine regarding
    * Hypnosis
    * Respiratory depression

Special considerations


In elderly,

  • Elimination half-time is increased due to
    * Reduced clearance
    * Vd is unchanged

Reduced clearance could be due to

  • Reduced hepatic blood flow
  • Reduced microsomal enzyme activity
  • Decreased albumin production
    * Fentanyl is highly protein-bound

Hepatic disease

  • Hepatic cirrhosis does NOT prolong elimination half-time of fentanyl significantly

Transdermal patches

  • Topical heating could increase the rate of release from the patch

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