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Hi all,
Fentanyl is a synthetic opioid analogue used eg in breakthrough pain in
cancer
patients.
Methadone is sometimes used to relieve severe pain
Both drugs have metabolism by CYP3A4 as a major route of clearance, in
man.
There is therefore the potential for an interaction between these two
drugs,
possibly leading to exaggerated fentanyl effects, especially drowsiness.
My open questions are:
Does anybody know of such an interaction and is it referenced in the
literature?
Does anybody know of any evidence of an interaction between these two
drugs ?
Many thanks in advance
Dave Vowles
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Dave:
Fentanyl is a CYP3A4 ( and a probable Pgp) substrate. There are no
pharmacokinetic studies with methadone but there is a study with the
CYP3A4
probe substrate midazolam where fentanyl at an IV dose of 200 ug
increased
the AUC of midazolam by 54% (Hase et al. Br J Anaesth 1997 ).
Methadone is a CYP3A4 substrate but it is also metabolized by CYP2B6 and
CYP2C19. There are no in vivo clinical studies published with CYP3A4
substrates but there is an in vitro study with the CYP3A4 substrate
nifedipine using human liver microsomes where methadone inhibited
nifedipine metabolism with a Ki of 100 uM (Iribane et al. Toxicology
1997),
There is one published drug interaction report; however, there are not
enough details to determine whether it was pharmacokinetic versus
pharmacodynamic (del Rosario et al. J Pain Symptom Mange 2001).
Carol Collins MD
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Dear Dave:
There is a excelent review about methadone (Methadone for relief of
cancer
pain:a review of pharmacokinetics,pharmacodynamics, drug interactions
and protocols of administration. Support Care Cancer
2001;9:73 - 83).
By now, I think that there is no evidence of an interaction between
fentanil and methadone. However, I think that if it might ocurr, it
probably would be a pharmacodinamic interaction, which could seen as
increasing of narcotic effects, sach as sedation, respiratory
depression.
Sincerily
Pedro Amariles M
Proffesor Clinical Pharmacy
Universidad de Antioquia
Medellin-COlombia
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There's another paper that explores this subject:
Drug interactions with patient-controlled analgesia.
Lotsch J, Skarke C, Tegeder I, Geisslinger G.
Clin Pharmacokinet. 2002;41(1):31-57.
Regards,
Alessandra
Alessandra Milesi-Halle, M.D.
Department of Pharmacology and Toxicology
University of Arkansas for Medical Sciences
4301 West Markham, slot 611
Little Rock, Arkansas 72205
Phone: (501)686-6551
Fax: (501)686-5521
MilesihalleAlessandr.-at-.uams.edu
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