A: Bottom Line:
Post-marketing surveillance of mifepristone use in numerous countries for the past 25 years has not raised concerns about this interaction. Although there are limited trials and published literature on this drug interaction, the precautionary principle states that women using both drugs simultaneously be adequately informed, accompanied during the abortion process and followed for the occurrence of adverse events and completion of the abortion. Even if arrhythmia were not a potential side effect based on pharmacodynamics, it may emerge as an adverse drug reaction as mifepristone penetrates the population more widely including opioid/opiate dependent women.
We include below an opinion from a Pharmacology professor at UBC. Additionally, three highly experienced leaders in mifepristone provision in the USA have offered their opinion that they have not seen evidence for any adverse effect interaction. The answer from a Drug Metabolism/Pharmacokinetic point of view is: probably not. The (slightly longer) explanation is as follows: Methadone primarily binds the "mu" opioid receptor similar to other opioids, which is why it is a replacement therapy for people with addictive and tolerant issues. Methadone does have some off-target effects at the N-methyl-D-aspartate (NMDA) receptor, which is a glutamate receptor, an excitatory receptor in the brain. In terms of metabolism and excretion, methadone is subjected to a great deal of CYP (cytochrome P450 enzymes) metabolism from CYP3A4, CYP2D6, and CYP2B6 as well. In addition, one of the problems with methadone is that it is readily transported by the P-gp (P-glycoprotein 1) transporter. This transporter protein is found in the human blood: brain barrier (few others are) and in the significant minority of people who express high P-gp, it makes methadone a "not very good" drug.
In contrast, mifepristone (RU486) is a massively strong binder of the progesterone receptor (IC50 = 0.025 nM for the Progesterone Receptor according to Katzung). What that means for abortion is that the placenta cannot stay cleaved to the uterine wall (which requires progesterone signaling), and will slough off - that is the mechanism of action of mifepristone. Mifepristone itself acts as a moderate inhibitor of CYP3A4 metabolism and can thereby alter concentrations of other drugs. Due to its prolonged half-life and irreversible binding, potential interactions of mifepristone should be checked particularly for medications that have a narrow therapeutic index. Examples include: immune-suppressants (eg, cyclosporine, sirolimus, tacrolimus); cardiovascular drugs (eg, calcium channel blockers, anti-arrhythmics, others); analgesic/anesthetic agents (eg, fentanyl, ketamine, methadone, others). The effect of a single dose of mifepristone on metabolism and effect of other drugs highly dependent upon CYP3A4 for their metabolism or activation may persist for up to two weeks. Interactions with these medications should be checked prior to administration of mifepristone.
There are no current reports in the literature about people on methadone having better or worse experiences with RU486 as an abortifacient, with the following two exceptions: (1) these patients are less likely to be compliant and so might report taking the drug without doing so and (2) there are conflicting reports re: methadone having effects on heart rhythm (this is odd) and that combined with mifepristone this might cause serious arrhythmia.
In short, it would seem that Mifegymiso could slow the metabolism of methadone for a period of time and thus, methadone levels could be slightly higher.