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ORIGINAL RESEARCH
The Use of Serum Methadone/Metabolite Ratios to
Monitor Changing Perinatal Pharmacokinetics
John J. McCarthy, MD, Ernest J. Vasti, MD, Martin H. Leamon, MD,
Joseph Graas, PhD, Coburn Ward, PhD, and Catherine Fassbender, PhD
Objectives: Pregnancy profoundly alters drug metabolism, acceler-
ating clearance and confounding medication management, primarily
through induction of CYP450 enzymes. Methadone is a CYP450
substrate with altered pharmacokinetics during pregnancy. We report
on the use of serum methadone/metabolite ratios (MMRs) to monitor
changes in methadone metabolism through the perinatal period and
to objectively guide methadone dosing. Previous research found
average MMRs in nonpregnant populations of between 11.3 and
12.7.
Methods: Serum methadone and its major metabolite 2-ethylidene-
1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed
in 67 samples from 23 pregnant patients treated for opioid use
disorder, and their calculated ratio was used to document changes
in methadone clearance across trimesters and postpartum. Lower
ratios indicate increased clearance.
Results: The average MMR during pregnancy was 6.1. Ratios
declined significantly from trimester 1 to trimester 3 (P ¼ 0.007),
and then rose significantly from trimester 3 to postpartum
(P ¼ 0.001). The per cent of ratios that were 4 or less, indicating
ultrarapid metabolism, increased from 8% to 30% to 38% across
trimesters, and decreased to 5% postpartum. Forty-four per cent of
individual patients had at least 1 prepartum ratio of 4 or less.
Conclusions: This study documents significant metabolic changes
occurring perinatally, which indicate the need for both changes in
methadone dose and dose frequency to maintain maternal/fetal
stability, and also dose reductions as hypermetabolism reverses
postpartum. MMRs provide an objective tool to more efficiently
improve the safety and efficacy of methadone dosing perinatally.
Key Words: CYP450, metabolic ratio, methadone/metabolite,
pharmacokinetics, pregnancy
(J Addict Med 2018;xx: xxx–xxx)
From the Department of Psychiatry, University of California, Davis, CA
(JJMC, MHL, CF); Department of Family Medicine, University of
California, Davis, CA (EJV); San Diego Reference Laboratory, San
Diego, CA (JG); and University of the Pacific, Stockton, CA (CW).
Received for publication October 14, 2017; accepted February 8, 2018.
The authors report no conflicts of interest.
Send correspondence to John J. McCarthy, MD, PO Box 561, Tahoma, CA
96142. E-mail: drjackmac9@gmail.com.
Copyright ß 2018 American Society of Addiction Medicine
ISSN: 1932-0620/16/0000-0001
DOI: 10.1097/ADM.0000000000000398
J Addict Med  Volume 00, Number 00, Month/Month 2018
Copyright © 2018 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
T here has been a dramatic increase over the past decade in
the United States in the use of opioids during pregnancy
(whether related to opioid use disorder or pain management),
and a concurrent increase in newborns developing neonatal
abstinence syndrome (NAS) (Corr and Hollenbeak, 2017).
This makes improvements in management of dependence
during pregnancy an urgent priority. A recent Cochrane report
identified methadone and buprenorphine as effective medi-
cations for treatment of opioid use disorder, but only under
conditions of adequate dosing (Mattick et al., 2014). However,
at fixed doses of methadone, as the pregnancy progresses,
most pregnant women will experience recurrent withdrawal
symptoms. In addition to threatening a woman’s sobriety,
withdrawal may result in increases in maternal stress hormone
activity (catecholamines and corticosteroids) that have poten-
tial adverse consequences both for neonatal and long-term
health (McCarthy et al., 2017).
Pharmacogenetics, the study of individual variations in
drug response based on a subject’s genetic profile, has impor-
tant implications for safety and efficacy of medication usage
(Weinshilboum, 2003). Methadone is primarily metabolized
by cytochrome P450 (CYP) enzymes 2B6, 3A4, and by lesser
and variable contributions from 2D6, 2C19, 2C9, and 1A2,
with the parent molecule being demethylated into inactive 2-
ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)
(Eap et al., 2002; Kharasch et al., 2009). CYP genetic
polymorphism contributes to a 17-fold variation in methadone
serum concentration for a given dosage (Eap et al., 2002). This
metabolic system’s ancestral gene is more than 2 billion years
old, but its diversity accelerated 800 million years ago as a
result of animal/plant competitive evolution: plants producing
protective toxins and animals, who eat the plants, producing
enzymes to metabolize the toxins (Nebert et al., 1989). The
expansion of the P450 system also provided an evolutionary
advantage in protecting the animal offspring (and ultimately
the human fetus) from toxins and xenobiotics. However, this
also creates significant challenges to safe and efficacious
medication management perinatally for many medications,
including methadone.
Superimposed on this background of genetic variability
are metabolic changes during the perinatal period which
further alter medication pharmacokinetics through changes
in blood volume, absorption, protein binding, metabolism,
and elimination (Jeong, 2010). However, these changes are
less relevant than the most important change related to
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medication use, which is the pregnancy-related activation of
genes coding for the CYP enzymes (Weinshilboum, 2003).
Changing levels of pregnancy hormones induce gene expres-
sion and regulate P450 RNA, which drives the altered phar-
macokinetics (Isoherranen and Thummel, 2013). There is
evidence of induction of both CYP2D6 (Wadelius et al.,
1997) and CYP3A4 (Isoherranen and Thummel, 2013) by
progesterone in the luteal phase of the menstrual cycle, and, if
this phase ends in pregnancy, the CYP system has already
been primed for the profound changes in drug metabolism and
transport that occur during pregnancy. Pregnancy specifically
induces CYP3A4 (Tracy et al., 2005), 2D6 (Wadelius et al.,
1997), and 2B6 (Dickmann and Isoherranen, 2013). Changes
in pregnancy can shorten the effective half-life of methadone
from its more usual 24-hour range to 12 hours (Bogen et al.,
2013), and at times to as short as 4 to 6 hours (McCarthy et al.,
2015).
Defining optimal methadone dosing in pregnancy has
been difficult due to a lack of pharmacokinetic information to
guide dosing (Jeong, 2010). In a study of the newly appre-
ciated primary role of CYP2B6 in methadone metabolism,
Amunugama et al. (2012) conclude that: ‘‘Our understanding
of the metabolism of methadone is incomplete; our ability to
accurately predict pharmacokinetics in individuals leads to
adverse effects, to significant drug–drug interactions, and to a
number of fatalities.’’ Further, the unpredictability of meth-
adone’s effects at a specific dose results in a high incidence of
over and underdosing which can cause severe adverse events
such as withdrawal symptoms, respiratory depression, and
potential QTc prolongation that can result in sudden death (Lu
et al., 2010).
Serum methadone levels provide an objective measure
of metabolism, and, indirectly, of fetal exposure. Although a
relationship between methadone serum concentration and
therapeutic effect is not precisely defined (Shiu and Ensom,
2012), a concentration range of 200 to 600 ng/mL has long
served as a clinical guide to effective treatment (Dole, 1988),
and this range has been found to be a clinically safe and
effective range for pregnant patients (McCarthy et al., 2015).
Peak and trough serum concentration ratios (PTRs) (the
trough before the morning dose and the peak 4 hours later)
have traditionally been used to document hypermetabolism,
with a ratio greater than 2 indicating more rapid clearance
than the usual 24-hour norm (Westermeyer et al., 2016).
However, requiring 2 blood draws 4 hours apart on the same
day poses a prohibitive logistical barrier for many patients. A
single blood test measuring methadone, the EDDP metabolite,
and their calculated ratio (methadone/metabolite ratio
[MMR]) is more practical and provides a more dynamic
picture of metabolism than simple serum levels, with the
additional ability to categorize individuals based on their
phenotypic ratios stratified into poor metabolizers (PMs, ratio
greater than 16), intermediate metabolizers (IMs, ratio 12–
15), extensive metabolizers (EMs, ratio 5–11), and ultrarapid
metabolizers (URMs, ratio 4 or less) (Zanger and Schwab,
2013). The MMR gives information on the net effect of the
multiple enzymes involved in methadone metabolism. A
lower ratio indicates more rapid metabolism, and accordingly
less opioid activity at a given dose.
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J Addict Med  Volume 00, Number 00, Month/Month 2018
We added EDDP serum levels assays to our clinic’s
routine methadone serum protocol to assess the relevance and
utility of metabolic ratios in actual patient care. This paper
will report the use of sequential MMRs during pregnancy and
the postpartum period to monitor pharmacokinetic changes as
an additional aid to safe and effective individualized dosing.
METHODS
Starting in January 2015, serum methadone and EDDP
levels and ratio data were collected from pregnant patients
enrolled in a specialized pregnancy program within a metha-
done maintenance program. Routine care involved weekly
meetings with a pregnancy counselor, attendance at weekly
physician-guided pregnancy groups, and monthly individual
meetings with the clinic physician. Serum level and ratio data
were routinely collected as clinically determined every 4 to
6 weeks during the pregnancy and within a week after
delivery. Patients who manifested recurrent withdrawal symp-
toms requiring repeated dose increases had levels drawn more
often as part of individualized patient care. The data were
further collectively monitored as part of internal program
quality assurance. Serum level and ratio data were discussed
in both group and individual settings to assist mothers in
understanding their unique metabolism and the implications
for fetal exposure and individualized dosing.
Dose regimens were adjusted clinically based on patient
assessment and on symptoms reported on the Subjective Opiate
Withdrawal Scale (SOWS) augmented for pregnancy (McCar-
thy et al., 2015). Using 600 ng/mL as the upper limit for
methadone trough serum concentration, dose and dose fre-
quency were increased to minimize emergent maternal with-
drawal symptoms. Because single doses of methadone are
associated with physiologic abnormalities in the fetus (Whitt-
mann and Segal, 1991; Jansson et al., 2009), all pregnant
patients were transitioned to a twice daily regimen (2 equally
divided doses) within a few days of admission, pending regu-
latory approval for a daily take home dose. Our divided dosing
protocol is described elsewhere (McCarthy et al., 2015). Most
patients were on 3 to 4 times a day dosing at the time of delivery,
although the regimen varied between 2 and 6 times daily.
Postpartum serum levels were drawn upon return to the clinic
after delivery (usually 3–7 days postpartum), and repeated in 2
to 3 weeks. Most patients had dose reductions in the early
postpartum period, with patients delivering on higher doses
undergoing more rapid dose reductions.
All serum levels were drawn at the clinic just before the
morning dose and sent to San Diego Reference Laboratory.
Measurements for methadone and metabolite were done using
high pressure liquid chromatograph/triple quadrupole mass
spectrometer (HPLC/MSS/MS). The data for comparing dif-
ferent trimesters contain a mix of paired and unpaired data.
Our analysis used the permutation test of Einsporn and
Habtzghi (2013) with 5000 replications. When a patient
had several measurements in a period, this analysis used
the mean for that period. All significant results were con-
firmed with t tests using only paired or independent parts of
the data depending on the greatest degrees of freedom.
Calculations were made using R version 3.4.1. Reported
P values are 2-tailed.
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J Addict Med  Volume 00, Number 00, Month/Month 2018 Monitoring Changing Perinatal Pharmacokinetics

TABLE 1. Dose, Serum, Metabolite, and Ratio Means and Ranges

Dose (Range), mg/d Serum (Range), ng/mL Metabolite (Range), ng/mL M/M Ratio (Range)
Prepartum 154 (35–355) 288 (78–854) 50 (16.9–142.3) 5.9 (2.6–11.6)
Postpartum 205 (95–340) 434 (169–1020) 66 (21–231.8) 7.2 (3.7–19.8)

Means use within period patient averages.

The UC Davis IRB Administration reviewed this study
and determined it was not research involving human subjects
(FWA No: 00004557).
RESULTS
Between January, 2015 and January, 2016, 23 patients
provided 67 levels during pregnancy (13 from first trimester,
30 from second, 24 from third), and 11 of these patients
provided 22 postpartum levels. Sixteen patients (70%) con-
ceived on methadone and 7 (30%) started treatment who were
already pregnant.
Prepartum, the average methadone dose for the cohort
was 154 mg/d; the average serum level was 288 ng/mL; the
average metabolite level was 50 ng/mL; and the average ratio
was 5.9. Postpartum, the average dose was 205 mg/d; the
average serum level was 434 ng/mL; the average EDDP
metabolite level was 66 ng/mL; and the average ratio was
7.2 (see Table 1 for additional summary data). To illustrate
individual trends over time, data from 4 patients with the most
pre/postpartum tests results are shown in Table 2.
Prepartum, methadone serum level and dose were posi-
tively correlated (correlation ¼ 0.53, P < 0.0001), as were
serum level and metabolic ratio (correlation ¼ 0.41,
P ¼ 0.002). Dose and ratio were negatively correlated, but
not significantly (correlation ¼ 0.15, P ¼ 0.29). Ratios
changed significantly over time. Table 3 shows average
within-patient ratios decreasing from 7.2 in the first trimester,
to 5.9 in the second trimester, to 5.1 in the third trimester, and
then increasing to 7.2 postpartum. The ratios declined signifi-
cantly from trimester 1 to trimester 3 (P ¼ 0.007). Ratios then
rose rapidly and significantly from trimester 3 to the postpartum
period (P ¼ 0.001), reaching levels similar to those of trimester
1. There was a highly significant increase in average serum
levels from third trimester to postpartum (P ¼ 0.001). Four of
13 patients (31%) had serum levels that exceeded the therapeu-
tic range of 600 ng/mL, 1 going as high as 1020 ng/mL.

TABLE 2. Individual Trends in Methadone Dose, Metabolite, and Ratio (Example Data)
Trimester/ Methadone Methadone Serum EDDP Serum Methadone/
Patient ID Postpartum Daily Dose, mgy Level, ng/mL Level, ng/mL EDDP Ratio
15 T2 220 251 48 5.2
T3 280 365 88 4
T3 325 370 94 3.9
T3 355 361 84 3.8
PP1 340 672 89 7.6
PP2 300 591 61 9.7
PP3 300 756 56 13.5
PP4 140 494 25 19.8
16 T1 200 435 82 5.3
T2 260 340 89 3.8
T2 270 447 118 3.8
T2 280 469 72 6.5
T3 280 516 91 5.7
T3 310 854 143 6
PP1 260 1020 230 4.4
PP2 240 987 156 6.3
PP3 200 909 126 7.2
17 T2 125 195 44 3.4
T2 135 125 37 3.4
T3 190 129 33 3.9
PP1 200 206 35 5.9
PP2 190 192 27 7.1
23 T2 160 213 53 4
T3 210 294 30 8.6
T3 260 315 96 3.3
T3 280 321 80 4
T3 310 310 118 2.6
PP1 280 727 131 5.5
PP2 240 467 55 8.5
PP, postpartum; T, trimester.

Listed chronologically, time intervals between samples varied based on clinical need. All postpartum levels were within the first month postpartum.
yTotal daily dose, divided into 2 or more separate doses across the day.

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McCarthy et al.
TABLE 3. Methadone/Metabolite (EDDP)
Trimester
Mean Median
Trimester Ratio Ratio SD
1 7.2 7.2 1.9
2 5.9 5.2 2.7
3 5.1 4.9 1.3
PP 7.2 6.5 3.3
PP, postpartum.

Data using each patient’s average ratio per trimester.
The percent of ratios that were 4 or less, indicating
ultrarapid metabolism, increased from 8% (n ¼ 1/13) in the
first trimester, to 30% (n ¼ 9/30) in the second, to 38% (n ¼ 9/
24) in the third, and decreased to 5% (n ¼ 1/22) postpartum.
Forty-four per cent (n ¼ 10/23) of individual patients had at
least 1 prepartum ratio of 4 or less. The number of ultrarapid
metabolizers by trimester was n ¼ 1 (9%) in trimester 1, n ¼ 7
(44%) in trimester 2, n ¼ 5 (31%) in trimester 3, and n ¼ 1
(9%) postpartum.
DISCUSSION
This is the first report, to our knowledge, of the use of
methadone/metabolite serum ratios to monitor metabolic
changes in the perinatal period, providing information on
the net effect that the various P450 enzyme changes induced
by pregnancy have on methadone metabolism. Our use of
sequential ratios allowed measurement of a significant
decrease in ratios from first to third trimesters, and signifi-
cantly increased ratio from third trimester to postpartum. This
clinical data support the CYP enzyme induction study of
dextromethorphan metabolism by Tracy et al. (2005), who
found that CYP2D6 activity was increased throughout the
pregnancy (25% at 14–18 weeks, 35% at 24–28 weeks, and
48% at 36–40 weeks), and CYP3A was consistently and
significantly increased (35–38%) during all stages of preg-
nancy. Our data document accelerated metabolism through all
phases of pregnancy and do not support the concept that
accelerated metabolism and need for dose changes are only a
third trimester event. In some patients, the lowest ratios were
in the second trimester. In 1 patient, serum level and ratio
unexpectedly increased before delivery, indicating that the
accelerated metabolism of pregnancy, although generally
increasing during pregnancy, can fluctuate, illustrating the
importance of close serum level/ratio monitoring. Different
CYP450 enzymes appear to be induced at different points in
time and likely at different levels of expression all through
the pregnancy.
Our data indicate that 44% of the patients, at some point
in the pregnancy, show ratio evidence of ultrarapid metabo-
lism (URM), and that 44% and 31% of patients in second and
third trimesters, respectively, have evidence of URM. This is
much higher than known baseline rates of URM in nonpreg-
nant populations. Diong et al. (2014) found that 15% of a
nonpregnant population had a peak/trough ratio greater than 2,
indicating URM by that measure. URM has been associated
with poor response to treatment (Eap et al., 2001). The very
high rate of URM in pregnant patients raises special concerns,
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J Addict Med  Volume 00, Number 00, Month/Month 2018
Ratio by as failure to identify such patients and increase doses and
dosing frequencies will likely result in significant
maternal withdrawal.
N (Individual
Patients)
Methadone/metabolite ratios have been the subject of
toxicological studies in patient populations. A study of 32
11 nonpregnant methadone maintenance patients measured
16
16 ratios at both peak and trough, and found mean ratios virtually
11 identical: peak mean 11.3 and trough mean 12.7 (Diong et al.,
2014). Metabolic ratios, unlike serum levels, are constant
through a 24-hour period. Another toxicological study of
MMRs in 23 nonpregnant patients found a mean ratio of
11.9 (Alburges et al., 1996). Our ratio data found a mean
of 6.3 for all patients (pregnant and postpartum), and a mean
of 6.1 for all actively pregnant patients. Furthermore, in our
population, the average first trimester ratio was 7.2, indicating
that even in the first trimester, pregnant patients had ratios
well below the ratios found in nonpregnant samples.
A study of peak/trough methadone serum ratios (PTRs)
in an all-male population found a strong effect of dose on peak
serum level, but a weak effect on trough level (Westermeyer
et al., 2016). This illustrates the important point that, once
adequate peak level has been achieved, merely increasing the
dose in rapid metabolizing patients (ie, with a PTR of greater
than 2) would unnecessarily increase the peak, while having
minimal effect on the trough. This is especially important in
pregnancy. Merely increasing doses to treat emergent with-
drawal in pregnant patients exposes the fetus to higher peak
levels without effecting the trough, resulting in potential
adverse effects on fetal physiology which is sensitive to
peak/trough extremes. Achieving pharmacodynamic stability
at the fetal mu receptor in the context of dramatically altered
maternal methadone pharmacokinetics requires altering both
the dose and the dose regimen to compensate for the reduced
half-life of the medication. Westermeyer et al. (2016) con-
clude that greater use of serum levels can ‘‘help clinician/
patient dyads collaborate in detecting inadequate doses and
flawed dosing strategies, thereby preventing needless with-
drawal symptoms, craving, and recurrent addiction.’’
The use of PTRs and our use of MMRs are different
ways of monitoring the same metabolic process, but use of
MMRs has the significant advantage of requiring only a single
blood draw, which can even be done using a finger stick
without the need for sometimes difficult phlebotomies. PTRs
also lack the element of standardization achieved through the
4 established categories of metabolism (slow, intermediate,
extensive, and ultrarapid). Furthermore, there is the potential
to be explored of extrapolating from MMRs to an estimation
of half-life of methadone, a concept more familiar to physi-
cians, since ratios are a surrogate for half-life. MMRs, then,
are an advance over PTRs in terms of ease of use and
metabolic information, and their use should promote better
physician understanding and more effective of dosing of
mother and fetus.
Postpartum ratios increased rapidly by 41% over third
trimester values, making the postpartum period, arguably, the
most dramatic period of pharmacokinetic change in adult
human physiology. Monitoring postpartum serum levels and
ratios are important for patient safety, as escalating serum
levels can cause oversedation and impair mothering. Dose
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reductions should occur in most patients in the immediate
postpartum period, especially those requiring higher doses.
Further, it is important that the mothers not become dependent
on high, clinically unnecessary, serum levels. There is evi-
dence from a study of midazolam (a 3A4 substrate) metabo-
lism in pregnancy that the return to a prepartum metabolic
state may take longer than 10 weeks, making serial serum
level monitoring advisable (Hebert et al., 2008). Serum levels
and ratios after delivery provide a clear measure of individual
changes to guide safe dosing, especially when late third
trimester levels are used for comparison.
Dose increases in our study were significantly corre-
lated with serum level increases, indicating that increases
required to eliminate withdrawal symptoms are not just
returning the patient serum level to the previous baseline.
It suggests that there are other factors that affect drug dispo-
sition and efficacy in pregnancy. Permeability glycoprotein
(P-gp) is a cell membrane protein that actively transports
drugs out of the cell, reducing drug levels at the target site (Lin
and Yamazaki, 2003). Methadone is a P-gp substrate and its
activity is increased during pregnancy (Rollason et al., 2008).
P-gp would be expected to decrease the efficacy of methadone
serum concentrations by actively transporting methadone
away from the mu receptor. Further, CYP450 enzymes have
been found to have brain-specific expression that may differ
from hepatic forms, such that patient response may not be
predicted by serum levels (Levran et al., 2013). These factors
are consistent with the range of serum levels in our study
(range 58–854 ng/mL) that were associated with, at least
temporary, clinical stability.
Three studies have found evidence of increased metha-
done clearance during pregnancy: studies by Pond et al. (1985),
Jarvis et al. (1999), and Wolff et al. (2005). However, metha-
done concentration is influenced by pharmacokinetic factors
beyond CYP450 metabolism. Jarvis et al. (1999) found evi-
dence of decreased absorption of methadone in pregnancy,
which would decrease concentration but would not alter the
MMR. Pregnancy can increase renal clearance of drugs (Jeong,
2010). However, although clearance of both total and unbound
methadone is greater during pregnancy, renal clearance was
found to contribute only minimally to methadone clearance
(Pond et al., 1985), at least at normal urinary pH (Diong et al.,
2014). Furthermore, the percentage of methadone dose
excreted as methadone and its metabolites did not change
during pregnancy, that is, there was no change that would alter
their metabolic ratio (Pond et al., 1985). Blood volume expan-
sion in pregnancy reduces concentration of albumen and alpha
1 glycoprotein, leading to decreased binding and a potential
increase in unbound drug (Jeong, 2010). While protein binding
was found to be less early in pregnancy than postpartum (Pond
et al., 1985), any increase in unbound methadone would be
offset by the greater clearance of both bound and unbound drug.
Lehotay et al. (2005) found that the R-form (the active enan-
tiomer) MMR was the same regardless of dose, so different
doses would not affect the MMR. In summary, while serum
concentration could be affected by various physiologic
changes, the MMR is independent of these factors and is
therefore an adequate unitary measure of methadone metabo-
lism during pregnancy and post-partum.
ß 2018 American Society of Addiction Medicine
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Monitoring Changing Perinatal Pharmacokinetics
While this pilot study focused on pregnancy as an
inducer of methadone metabolism, the MMRs may have
important use in other clinical situations. Foremost would
be the potential use of MMRs to monitor drug–drug inter-
actions, such as occurs with co-administration of some anti-
depressants, anticonvulsants, and antifungals. The effect of
these interactions on methadone concentration is poorly
predicted by current studies. Further, there is not yet full
consensus on the involvement of the various CYP450
enzymes known to metabolize methadone (Levran et al.,
2013), and it has been suggested that guidelines warning of
CYP3A4-mediated drug interactions may be incorrect (Khar-
asch et al., 2009). The metabolic ratio, representing the net
effect of whatever CYP enzymes are involved in a particular
patient, could provide a quantitative alert to the clinician of
the effect of such medications on methadone metabolism, if a
baseline ratio is obtained before starting a new medication.
Further, metabolic changes can occur as a result of illness (eg,
renal or hepatic disease), and the MMR could be used to
document such changes. One could even make a case for
establishing a baseline ratio on all patients treated with
methadone. The MMR is a unique identifier for an individual
patient, based on his/her genetic polymorphisms for the
enzymes that are involved with the kinetic conversion of
methadone. Ratios not only identify URM who are at risk
for poor treatment response, but also poor metabolizers who
are at risk for unusually high serum levels at routine doses
with potential for sedation, overdose (Richards-Waugh et al.,
2014), and arrhythmias (Wadelius et al., 1997).
The goal of individualized medicine is for physicians to
have the information necessary to prescribe an appropriate
medicine to the right target of the disease at the right dose and
dose frequency for individual patients to achieve maximal
benefit with minimal side effects (Ma and Lu, 2011). Serum
levels and metabolic ratios improve the quality of information
physicians need to achieve these goals in the case of pregnant
patients on methadone. In the future, patients could be
genotyped for their response to methadone. At this time,
however, a simple, inexpensive blood test can give important
clinical information on the net effect of both genetics and
pregnancy on stability of maternal, and also fetal, methadone
exposure. The pregnant patient and her fetus deserve scien-
tifically based dosing and close physician monitoring as a
standard of care if we are to optimize outcomes of
these pregnancies.
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