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Dear List Colleagues,
During past decade and for every country, the idea collected by
prescription labels including tramadol have stated that concomitant
administration with carbamazepine causes a significant increase in
tramadol metabolism, presumably through metabolic induction by
carbamazepine, and therefore a decrease in analgesic effectiveness
and a
shorter duration of action would be expected.
However, thinking about tramadol metabolism I wonder if the plausible
scenario would be just the opposite: A rapid bioavailability and an
increase in concentrations of M1 (the active metabolite of tramadol,
some times more active for opioid receptor) and therefore an
increase in
analgesia would be anticipated.
Unfortunately, I have not been able to find a particular study or
report
that demonstrates the former knowledge, firstly the pharmacokinetic
interaction and secondly the decrease of analgesic effect from
carmabazepine / tramadol coadministration.
My question to the List would be:
Have anyone data about this non confirmed PK and PD interaction? Any
literature reference, personal experience or opinion would be
welcome.
Candido Hernandez-Lopez, MD, PhD
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Dr. Lopez:
I was not able to find any case reports of tramadol toxicity when given
concomitantly with carbamazepine.
The explanation found in Metabolic Drug Interactions is that induction
by
carbamazepine would increase the fraction of the tramadol dose
eliminated by
N-demethylation verus the 0-demethylation by CYP2D6.
Carol Collins MD
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Dear Candido,
Tramadol is metabolised to more than one metabolite. CYP3A4, which can
be
induced by carbamazepine, converts tramadol to the non analgesic active
metabolite N-demethyl tramadol M2. The active metabolite O-demethyl
tramadol
M1 is formed via CYP2D6, which should be not affected by carbamazepine.
M1 is further metabolized to N,O-di-demethyl tramadol (M5) via CYP3A4,
which
leads even to lower M1 concentrations after induction of CYP3A4.
Therefore
the prescription labels for tramadol are ok.
Joachim
Joachim Ossig, PhD
Grunenthal GmbH
Department of Pharmacokinetics (FO-PK)
52099 Aachen, Germany
Office: Zieglerstr. 6, 52078 Aachen, Germany
Tel.: +49-(0)241-569-2409
Fax.: +49-(0)241-569-2501
Mailto:Joachim.Ossig.-at-.grunenthal.de
http://www.grunenthal.com
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The US product labeling for tramadol cautions against the
coadministration
of tramadol and carbamazepine. For those clinicians in the US, the very
fact
this warning appears in the prescribing information has important
implications in terms of malpractice liability.
The concern with concomitant administration is induction of CYP3A4 and
an
increase in the production of N-desmethyltramadol. I have not been able
to
find out much information on the toxicological profile of this
metabolite
other than it is not an opiod agonist. However, it has been suggested
that
the neurotoxicity of tramadol (including seizures) is more related to
its
MAOI activity. My question for the group is what is the MAOI activity
and
toxicity profile of N-desmethyltramadol?
Carol Collins
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