CA-1 · intraoperative teaching CA-1 Bootcamp day 10. Authored from cited abstracts; every claim carries a PMID.
THE QUESTIONWhere the evidence disagrees
This topic was selected because an evidence synthesis beats a textbook on it: the trials disagree, or the guidance has moved recently.
THE EVIDENCE
What each source contributes, and how strong it is
Study design first — a cohort and a randomised trial do not carry the same weight.
Design
Year
Journal
What it found
Other
1983
Clin Pharmacokinet
Fentanyl is 50 to 100 times as potent as morphine
Other
1983
Clin Pharmacokinet
The half-life on the reference card is not the number that predicts when your
Other
2012
Basic Clin Pharmacol Toxicol
These drugs differ at the effect site and not just at the syringe
Other
1986
Br Med J (Clin Res Ed)
Morphine's danger in renal impairment is not morphine but morphine-6-glucuroni
Other
2000
Clin Exp Pharmacol Physiol
Hydromorphone's principal metabolite, hydromorphone-3-glucuronide, carries no
Other
2011
Palliat Med
Equianalgesic tables are estimates rather than conversions
10 resolved citations behind this deck; every point above traces to one of them.
IN PRACTICE
What the cohorts and reviews add
6 findings, each on the slide that follows.
Clin Pharmacokinet 1983
Fentanyl is 50 to 100 times as potent as morphine
Fentanyl is 50 to 100 times as potent as morphine
Clin Pharmacokinet 1983
The half-life on the reference card is not the number that predicts when your
The half-life on the reference card is not the number that predicts when your patient will wake up: reported terminal half-lives for fentanyl range…
Basic Clin Pharmacol Toxicol 2012
These drugs differ at the effect site and not just at the syringe
These drugs differ at the effect site and not just at the syringe: pharmacokinetic-pharmacodynamic studies give fentanyl and its derivatives a…
Br Med J (Clin Res Ed) 1986
Morphine's danger in renal impairment is not morphine but morphine-6-glucuroni
Morphine's danger in renal impairment is not morphine but morphine-6-glucuronide, an active renally excreted metabolite: three patients with renal…
IN PRACTICE
Fentanyl is 50 to 100 times as potent as morphine
Other · Clin Pharmacokinet
Fentanyl is 50 to 100 times as potent as morphine, and the short duration you see after a single intravenous dose is redistribution-limited rather than clearance-limited, in the same way thiopentone is — which is why repeated or large doses stop being short-acting and can leave a patient with delayed recovery and prolonged respiratory depression.
The half-life on the reference card is not the number that predicts when your
Other · Clin Pharmacokinet
The half-life on the reference card is not the number that predicts when your patient will wake up: reported terminal half-lives for fentanyl range from about 1.5 to 6 hours in healthy volunteers and up to 15 hours in geriatric patients, and comparing half-lives between opioids is not a rational way to choose one — effect-site concentration and context-sensitive half-time are.
These drugs differ at the effect site and not just at the syringe
Other · Basic Clin Pharmacol Toxicol
These drugs differ at the effect site and not just at the syringe: pharmacokinetic-pharmacodynamic studies give fentanyl and its derivatives a blood-to-effect-site equilibration half-life of only 0.2 to 9 minutes, while morphine's analgesic time course is observed with a prolonged delay behind its plasma concentration — so a second dose of morphine given because the first one 'is not working yet' is a dose you will meet again later.
Ing Lorenzini et al., Basic Clin Pharmacol Toxicol 2012 · PMID 21995512
IN PRACTICE
Morphine's danger in renal impairment is not morphine but morphine-6-glucuroni
Other · Br Med J (Clin Res Ed)
Morphine's danger in renal impairment is not morphine but morphine-6-glucuronide, an active renally excreted metabolite: three patients with renal failure showed classical signs of morphine intoxication with prolonged respiratory depression while having no measurable morphine in plasma at all, and concentration-effect modelling in volunteers put morphine-6-glucuronide at four to eight times morphine's potency for miosis and for suppression of salivation.
Osborne et al., Br Med J (Clin Res Ed) 1986 · PMID 3087512
IN PRACTICE
Hydromorphone's principal metabolite, hydromorphone-3-glucuronide, carries no
Other · Clin Exp Pharmacol Physiol
Hydromorphone's principal metabolite, hydromorphone-3-glucuronide, carries no analgesic activity and is neuroexcitatory — allodynia, myoclonus and seizures on intracerebroventricular administration — and in anuric haemodialysis patients it accumulated more than twelvefold between treatments while hydromorphone itself barely accumulated at all, though dialysis removed the metabolite effectively.
Equianalgesic tables are estimates rather than conversions
Other · Palliat Med
Equianalgesic tables are estimates rather than conversions: the most consistently supported ratio is about 5 to 1 for oral morphine to oral hydromorphone, no large well-designed randomised trial underpins the tables in common use, and calculating a dose from one of them alone in a patient whose clinical status is changing is an oversimplification of pain management with real potential for harm.
Colour is the strength of the evidence behind each step, not the urgency.
1
1
Fentanyl is 50 to 100 times as potent as morphine, and the short duration you see after a single intravenous dose is redistribution-limited rather than clearance-limited, in the same way thiopentone is — which is why repeated or large doses stop being short-acting and can leave a patient with delayed recovery and prolonged respiratory depression.
2
2
The half-life on the reference card is not the number that predicts when your patient will wake up: reported terminal half-lives for fentanyl range from about 1.5 to 6 hours in healthy volunteers and up to 15 hours in geriatric patients, and comparing half-lives between opioids is not a rational way to choose one — effect-site concentration and context-sensitive half-time are.
3
3
These drugs differ at the effect site and not just at the syringe: pharmacokinetic-pharmacodynamic studies give fentanyl and its derivatives a blood-to-effect-site equilibration half-life of only 0.2 to 9 minutes, while morphine's analgesic time course is observed with a prolonged delay behind its plasma concentration — so a second dose of morphine given because the first one 'is not working yet' is a dose you will meet again later.
4
4
Morphine's danger in renal impairment is not morphine but morphine-6-glucuronide, an active renally excreted metabolite: three patients with renal failure showed classical signs of morphine intoxication with prolonged respiratory depression while having no measurable morphine in plasma at all, and concentration-effect modelling in volunteers put morphine-6-glucuronide at four to eight times morphine's potency for miosis and for suppression of salivation.
5
5
Hydromorphone's principal metabolite, hydromorphone-3-glucuronide, carries no analgesic activity and is neuroexcitatory — allodynia, myoclonus and seizures on intracerebroventricular administration — and in anuric haemodialysis patients it accumulated more than twelvefold between treatments while hydromorphone itself barely accumulated at all, though dialysis removed the metabolite effectively.
The oral-boards stem on the next slide puts these into one scenario.
KEY TAKEAWAYS
What to carry into the next case
Fentanyl is 50 to 100 times as potent as morphine
Clin Pharmacokinet 1983
The half-life on the reference card is not the number that predicts when your
Clin Pharmacokinet 1983
These drugs differ at the effect site and not just at the syringe
Basic Clin Pharmacol Toxicol 2012
Morphine's danger in renal impairment is not morphine but morphine-6-glucuroni
Br Med J (Clin Res Ed) 1986
Fentanyl is fast on and, after one dose, fast off because it redistributes rather than because it is cleared; morphine is slow on and, in a kidney that cannot excrete morphine-6-glucuronide, slow off in a way that can stop a patient breathing hours after the dose looked fine.
Questions I'll ask you in the room
You gave fentanyl 45 minutes ago and she is comfortable. Is that dose gone, or is it just somewhere else in her?
What does a creatinine of 2.4 change about this choice — and which molecule are you actually worried about?
You want to switch her to hydromorphone. What ratio are you using, and where did that number come from?
If she becomes obtunded at 3 a.m., which drug did it, and why then rather than now?
Oral boards stem
A 71-year-old woman with a creatinine of 2.4 mg/dL has just had a hip hemiarthroplasty under general anaesthesia. She is comfortable in recovery on the fentanyl you gave intraoperatively, but she will need something that lasts for the ward. The examiner asks which of morphine, hydromorphone and fentanyl you would choose, how you would convert from what she has already had, and what specifically you are worried about at three o'clock tomorrow morning.
The bottom lineFentanyl is fast on and, after one dose, fast off because it redistributes rather than because it is cleared; morphine is slow on and, in a kidney that cannot excrete morphine-6-glucuronide, slow off in a way that can stop a patient breathing hours after the dose looked fine.
Sources
[1] Mather, Clin Pharmacokinet 1983 · PMID 6226471 open
[2] Scholz et al., Clin Pharmacokinet 1996 · PMID 8896944 open
[3] Ing Lorenzini et al., Basic Clin Pharmacol Toxicol 2012 · PMID 21995512 open
[4] Osborne et al., Br Med J (Clin Res Ed) 1986 · PMID 3087512 open
[5] Westerling et al., Ther Drug Monit 1995 · PMID 7624926 open