Question 17

College Answer

These are both level 1 drugs commonly used as an infusion in daily practice. This question specifically asked the candidates to frame their answers around an intravenous infusion of fentanyl in comparison to morphine. A tabular listing of general properties of the two drugs highlighting the differences between the drugs would not score well. The question asks for a considered response that should focus on context sensitive half-life, compartments and metabolism, instead many focused on the speed of onset and potency, which are minor considerations when drugs are given for long periods by infusion. Candidates often demonstrated a superficial knowledge of key pharmacokinetic concepts with limited application of these principles in the context of an intravenous infusion. Better answers also related the above to various relevant pharmacodynamic influences such as age, liver and renal impairment.

Discussion

The importance of this question is escalated considerably by the knowledge that Rinaldo Bellomo published an article on this exact topic in his journal, approximately a year before it appeared in the exam. This question filtered out the people who read Critical Care and Resuscitation.

• Pharmaceutical  and administrative considerations
  • The cost of morphine is approximately half the cost of fentanyl, and the longer duration of effect could make it even more cost-effective.
  • The prolonged action of its effect, however, may increase the duration of ventilation of ICU stay, increasing the overall healthcare cost.
  • Fentanyl is 100 times more potent than morphine, which means theoretically it should be more cost-effective to use it for analgesia
• Compartment distribution and context-sensitive half time  
  • Fentanyl is widely and rapidly distributed, accumulating in tissues with sustained infusion
  • Because of tissue compartment distribution, context-sensitive half time for fentanyl is markedly prolonged following a long course of use as analgo-sedation (eg. after a 4-hour infusion, context-sensitive half time is 200 minutes)
  • Morphine is distributed less widely, and its context-sensitive half-time is independent of the duration of infusion
  • However, the accumulation of morphine metabolites in critically ill patients may still produce a prolonged effect sustained long after the infusion has ceased.
• Protein-binding
  • Fentanyl is 80-90% protein bound; with hypoalbuminaemia of critical illness, the free fraction will be increased, potentiating the clinical effects
  • ​​​​​​​Morphine is only 30-35 % protein-bound and therefore less affected by hypoproteinaemia​​​​​​​
• The effect of lipid solubility on offset of effect:
  • ​​​​​​​Morphine has relatively poor lipid solubility as compared to fentanyl.
  • The clearance of morphine from the CNS is therefore delayed, producing a prolonged  duration of effect 
  • Fentanyl has excellent lipid solubility, and is cleared rapidly from the CNS
  • The rapid clearance of fentanyl is more likely to lead to opioid withdrawal following a long-term sustained infusion as part of ICU sedation (opioid withdrawal is an under-recognised contributor to ICU delirium)
• Differences in metabolism
  • ​​​​​​​Morphine is metabolised into morphine6-glucuronide, an active metabolite which accumulates in renal failure.
  • Fentanyl does not have active metabolites
• Pharmacodynamic differences
  • M​​​​​orphine may act as a direct vasodilator through its histaminergic effects, which may be beneficial (eg. in CCF) or a disadvantage (eg. septic shock), whereas fentanyl does not have direct cardiovascular effects.

Casamento, Andrew, and Rinaldo Bellomo. "Fentanyl versus morphine for analgo-sedation in mechanically ventilated adult ICU patients." Critical Care and Resuscitation 21.2 (2019): 76-83.