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Therapeutic Drug Monitoring in
Methadone Maintenance
Eric T. Moolchan a , Annie Umbricht MD a & David
Epstein PhD a
a National Institutes of Health, National Institute on
Drug Abuse, Intramural Research Program , USA
Published online: 12 Oct 2008.
To cite this article: Eric T. Moolchan , Annie Umbricht MD & David Epstein PhD
(2001) Therapeutic Drug Monitoring in Methadone Maintenance, Journal of Addictive
Diseases, 20:2, 55-73
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Therapeutic Drug Monitoring
in Methadone Maintenance:
Choosing a Matrix
Eric T. Moolchan, MD
Annie Umbricht, MD
David Epstein, PhD
ABSTRACT. Methadone maintenance is the premier pharmacological
treatment for opioid addiction, but it is rarely informed by evidence-
based practice guidelines for dosage monitoring and adjustment. Such
guidelines are crucial because the pharmacokinetics of methadone vary
greatly among patients, and this variation may account for differences
in treatment outcome. We review the pharmacokinetics of methadone
and factors that may alter it (including drug interactions, disease states,
and idiosyncratic differences among patients). Also reviewed are pros-
pects for therapeutic drug monitoring (TDM) of methadone in plasma,
urine, sweat, and saliva. Due to its ease of collection and its presumed
representation of the bioavailable free-fraction of methadone, saliva
may be a promising matrix. However, saliva methadone concentrations
are influenced by salivary pH, and future studies are needed to determine
how to control for that. Administrative, medical, and social implications
of methadone TDM are briefly discussed. [Article copies available for a
fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail
address: <getinfo@haworthpressinc.com> Website: <http://www.HaworthPress.
com>]
Eric T. Moolchan, Annie Umbricht, and David Epstein are affiliated with the
National Institutes of Health, National Institute on Drug Abuse, the Intramural Re-
search Program.
Address correspondence to: Eric T. Moolchan, MD, Department of Health and
Human Services, National Institutes of Health, National Institute on Drug Abuse-
IRP, Clinical Pharmacology and Therapeutics Research Branch, 5500 Nathan Shock
Drive (P.O. Box 5180), Baltimore, MD 21224 (E-mail: emoolcha@intra.nida.nih.gov).
The authors wish to acknowledge Dana J. Jackson for technical assistance and Dr.
Jeffrey A. Hoffman for his critical review of the manuscript.
55
Journal of Addictive Diseases, Vol. 20(2) 2001

JOURNAL OF ADDICTIVE DISEASES
56
KEYWORDS. Methadone maintenance, opioid addiction, pharmaco-
kinetics
THERAPEUTIC DRUG MONITORING (TDM) VERSUS
DOSE IN METHADONE MAINTENANCE
An effective dose of methadone will prevent opioid withdrawal and crav-
ing, and will extinguish continued heroin use by blocking its euphoric effects.
Multiple studies suggest a dose-response relationship with a threshold dose
of 60-80 mg per day for optimal therapeutic efficacy as measured by treat-
ment retention, increased abstinence, and decreased mortality.1-3 Above this
threshold, however, the dose-response curve is less clear.4,5 In some cases, it
may be smudged by the effects of concurrently administered psychosocial or
behavioral interventions.6-11 But in other cases, a seemingly adequate dose
may be inadequate due to pharmacokinetic differences among individual
patients.12,13 This possibility is rarely considered in practice. Dose deter-
mination is either policy-driven, or speculatively based on clinical factors
such as self-reported duration, quantity, and route of heroin use. These factors
correlate poorly with dependence severity, as other environmental variables
such as purity of available heroin influence the equation. Dose adjustments
later in treatment are largely based upon behavioral determinants: continued
opioid-positive urine screens, patient complaints of dose not ‘‘holding,’’ or
physical evidence of opioid withdrawal. Guidelines for methadone dose de-
termination through plasma levels were articulated by the Center for Sub-
stance Abuse Treatment.14 These guidelines reflected the state of the art
when they were published in 1993, but, as we discuss below, there have been
subsequent advances in the use of plasma and other matrices. Unfortunately,
even the 1993 guidelines seem rarely to be applied in clinical practice, leav-
ing dose determination to the vagaries of staff or patient biases and resulting
in treatment disparity.
Many medications (such as antimicrobials, digoxin, anticonvulsants, and
lithium) are prescribed with routine therapeutic drug monitoring (TDM), to
check patients’ compliance and to maintain concentrations within therapeutic
windows. This practice is necessary because, for these drugs, plasma levels
do not depend solely on dose, but also on drug interactions, genetic or ac-
quired differences in metabolism, and various medical conditions. Research
increasingly suggests that TDM is also indicated for methadone treatment, as
higher plasma levels predict better treatment outcome.15-17 Some argue that,
in compliant patients, plasma levels of methadone reliably correlate with
dose18 thus obviating the need for TDM in such patients. However, such a
relationship is not always demonstrated; in one study, trough methadone
plasma levels correlated more closely with rate of body clearance (r =

Moolchan, Umbricht, and Epstein
57
ꢀ0.697) than with daily dose (r = 0.502).19 In another study, over 18 months,
mean trough plasma levels correlated with mean daily dose (r = .947), yet at a
given dose, the amount of variation was unacceptably high; in other words,
the seemingly impressive correlation obscured a clinically-significant num-
ber of individual exceptions.20 Some of this variability may reflect differ-
ences in pharmacokinetic disposition of methadone.
PHARMACOKINETICS OF METHADONE
Normal Pharmacokinetics of Methadone
Considering that methadone has had wide clinical use for decades, defini-
tive information on its pharmacokinetics is surprisingly sparse in sources that
most clinicians might initially consult. For example, the Physician’s Desk
Reference contains no such information, and a standard textbook of phar-
macology21 contains only minimal information. The paucity of pharmacoki-
netic data may be partly attributable to stigma from segments of the health-care
community and lack of research interest from pharmaceutical corporations.
Yet there are other impediments to a clear characterization of methadone’s
pharmacokinetics, such as wide variation across clinical populations. For ex-
ample, the elimination rate of one methadone dose is slowest in methadone-
maintained patients, intermediate in heroin users at initiation of methadone
treatment, and most rapid in healthy non-opioid-using volunteers.22
The mean bioavailability of orally administered methadone (plasma AUC
after oral versus intravenous administration) was 89% (SD 20%) on the first
day of maintenance for 12 patients kept drug-free on a residential ward for 30
days; it decreased to 81% after a 24-day stabilization period.23,24 In patients
on long-term maintenance, the mean apparent volume of distribution was 6.7
L/kg;18 peak plasma level (a doubling of trough concentrations) was reached
in 2-4 hours.22 The critical minimum trough level for clinical effectiveness
has been suggested to be 150 ng/ml25 (see page 64 for further discussion).
Plasma proteins act as a storage site for methadone, in equilibrium with the
bioavailable free fraction. Typically, 86-89% is bound to plasma proteins
such as albumin, globulin, and B1-acylglycoprotein (B1-AGP);26-29 however,
protein binding varies from 83% to 97%.30 Some methadone is also stored in
the liver and released unchanged into the bloodstream;31 this may account for
small secondary peaks in plasma levels sometimes observed 3-7 hours after
oral dosing.32,33
Methadone’s main metabolite is EDDP (2-ethylene-1,5-dimethyl-3,3-di-
phenylpyrrolidine), which is believed to be inactive, though this has been
questioned (de Vos, 1995).13,19 N-demethylation of methadone to EDDP

JOURNAL OF ADDICTIVE DISEASES
58
occurs primarily in the liver via CYP3A434-37 with some possible minor
involvement of CYP2C9 and CYP2C19.34 Some authors have emphasized
the role of CYP1A238 and CYP2D639,40 but recent evidence does not support
this; in the case of CYP2D6, methadone appears to inhibit it without being a
substrate for it.34 In any case, the expression of CYP3A4 varies substantially
among individuals41 and there are sex differences in levels and anatomical
distributions of many of the CYP enzymes.42 Such differences may contrib-
ute to clinical heterogeneity in methadone metabolism.
Methadone’s half-life ranges from 10 to 18 hours in healthy volunteers to
9-47 hours for opioid-tolerant patients at initiation of methadone maintenance,
and 19-43 hours at steady-state maintenance.18 Some of these estimates may
be low due to inadequate sampling time: longer observations showed metha-
done’s half-life to be 41 hours in healthy volunteers, and possibly longer and
more variable in illicit-opiate users given a single dose of methadone.22
Methadone and EDDP are both eliminated by the kidney and the liver. The
proportion of methadone eliminated by the kidney increases with dose,
length of treatment, and urinary pH.43 Mean oral clearance (i.e., whole-body
clearance corrected for oral bioavailability) is slow: 115 ml/min in healthy
volunteers, 53 mL/min in opiate users at first dose.22 Elimination is slower in
women than in men--a difference that could lengthen methadone’s plasma
half-life in women by approximately 7 hours.19
Alterations in the Pharmacokinetics of Methadone
Drug interactions: Drug interactions with methadone may occur through
competition for metabolic pathways in the liver, competition at protein bind-
ing sites in plasma, and changes in urinary pH. Studies of drug interactions
are difficult because they typically require subjects to remain under observa-
tion during at least 5 half-lives of the drug with the slowest elimination,
calculated after expected changes. For example, if the half-life of methadone
is estimated at 24-36 hours at initial dosing, baseline steady state is reached at
5-7 days. To study an interaction with a medication suspected to double
methadone’s half-life would require a period of at least 10 days (while on
both medications) to reach a new steady state, then 2-3 days of serial blood
levels taken at the same dosing schedule, followed by a washout period of 5-7
days on methadone only--and this if the interaction is expected to stop imme-
diately upon discontinuation of the second medication, an unlikely scenario.
It is likely that the cost of such studies (typically conducted on closed wards)
in addition to other factors, such as stigma and prohibition, have curtailed the
systematic evaluation of methadone’s interactions. Consequently, only a few
of the many possible interactions have been characterized systematically, and
most have been documented by less than rigorous clinical reports. Some
potential interactions are reviewed here and summarized in Table 1.

Moolchan, Umbricht, and Epstein
59
TABLE 1. Factors Altering Methadone Pharmocokinetics
Factors
Direction of Influence
(Plasma Level)
Reference
Drug Interactions
Prescribed Medications
Ritonavir
Decrease
Decrease
Iribarne et al. 1998
Nelfinavir
Beauverie et al. 1998
Hsu et al. 1998
Geletko 2000
Zidovudine
Increase
Increase
Decrease
Decrease
Increase
Increase
Decrease
Decrease
Mckance-Katz et al. 1998
Novick et al. 1985
Cobb et al. 1998
Fluconazole
Rifampin
Phenytoin
Tong et al. 1981
Fluoxetine
Iribarne et al. 1998
Alderman & Frith 1999
Fluvoxamine
Tricyclic antidepressants
H
2
antagonists
Charuvastra 1997
Drugs of Abuse
Heroin
Decrease free fraction
Decrease
Calvo et al. 1996
Cocaine
Tennant & Shannon 1995
Nicotine
Increase
Kalow & Tang 1991
Kell 1995
Alcohol (Acute)
Increase (competition)
Decrease (induction)
Cushman et al. 1978
Kreek 1988
Alcohol (Chronic)
Disease States
Liver Cirrhosis
Unstable, complex interaction
Unchanged
Kreek et al. 1976
Novick et al. 1985
Renal Failure
Kreek et al. 1980
Wolfert & Sica 1988
Diseases with changes
in plasma protein
Alteration in free fraction
Wilkins et al. 1997
Abramson 1982
Craig & Stitzel 1990
Idiosyncratic Alterations
in Methadone Pharmacokinetics decrease
Increase or
Nilsson et al. 1983
Dyer et al. 1999

JOURNAL OF ADDICTIVE DISEASES
60
Prescribed Medications
Protease inhibitors: Ritonavir inhibits CYP3A6 while inducing other en-
zymes. In an in vitro study of human microsomes, ritonavir (though not
indinavir or saquinavir) inhibited methadone metabolism to a degree that
seemed likely to have clinical significance.44 In clinical studies, however, the
opposite was found: ritonavir (and nelfinavir) decreased methadone plasma
levels.45,46
Antinucleosides: A clinical report suggested that methadone increases
zidovudine levels in HIV-infected injection drug users,47 but no definitive
effect as been documented.
Antibiotics and antifungals: Fluconazole and rifampin both affect metha-
done concentration and elimination.12,48 Specifically, fluconazole increases
48
methadone concentration while rifampin accelerates methadone elimina-
tion through induction of CYP3A4.
Anticonvulsants: Phenytoin accelerates methadone elimination.49
Antidepressants: Fluvoxamine, and fluoxetine to a lesser extent, inhibit
methadone metabolism.44,50 Tricyclic antidepressant on the other hand accel-
erate methadone metabolism.
H2 antagonists: Cimetidine, a potent inhibitor of CYP450 enzymes, in-
creases plasma methadone levels.51,52
Interested readers can find a list of medications influencing CYP3A4, and
thus potentially methadone metabolism, at the URL <www.urmc.rochester.
edu/urmc/AAPCC/tables.html>
Drugs of Abuse
Illicit opiates: Chronic heroin users have elevated plasma B1-AGP, which
could reduce the free fraction of methadone.53
Cocaine: In a clinical setting, 72% of 67 cocaine users sampled 24 hours
after their daily 100 mg dose of methadone had inadequate serum concentra-
tions (< 100 ng/ml), suggesting an acceleration of methadone elimination by
cocaine.54
Nicotine: Substances inhaled in cigarette smoke could induce CYP1A2.55
However, as discussed above, the role of CYP1A2 in methadone metabolism
has been questioned. Moreover, Kell20 described a patient for whom heavy
smoking (3 packs/day) seemed to inhibit rather than induce methadone metab-
olism: after abrupt smoking cessation, his plasma methadone decreased nearly
21% (p < .05) for at least 8 weeks, and he reported ‘‘not feeling right . . .’’ It is
not clear to what extent his subjective complaints could be attributed to
nicotine withdrawal itself.
Alcohol, acute intake: At high doses, alcohol is metabolized partly by

Moolchan, Umbricht, and Epstein
61
CYP450 enzymes; this could slow the metabolism of methadone through
competition for those enzymes.56
Alcohol, chronic abuse: When chronic alcoholic methadone patients be-
come abstinent, methadone elimination may be abruptly accelerated due to a
sudden decrease in competition for chronically induced CYP450 enzymes,
and also due to increased renal clearance.26
Disease and Physiologic States
The disposition of methadone is expected to be altered by pathology in any
of the systems involved in its distribution, metabolism, storage, or elimina-
tion; only a few examples are reviewed here.
Liver cirrhosis: As mentioned above, the liver not only metabolizes meth-
adone, but also, acting as a storage site, participates in prolonging its duration
of action during steady state. In liver cirrhosis, the half-life of methadone is
increased (possibly doubled) due to impairment in metabolism, yet plasma
levels of methadone are generally low, due to impairment in the liver’s ability
to store and release methadone, and to produce albumin.12,37 The decrease in
plasma albumin results in alterations in protein binding, and the time-con-
centration curve flattens. Therefore, close monitoring and reduction in meth-
adone dosage are indicated.12
Renal failure: No changes in plasma levels of methadone were observed in
patients with end-stage renal failure on dialysis, and they remained within the
expected range (0.09-0.68 microgram/ml) for the doses received (40-50 mg/
day).58,59
States of decreased metabolism (hypothyroidism, congestive heart failure):
These are likely to change methadone’s volume of distribution, degree of
protein binding, and elimination rate. No studies to date have evaluated these
issues.
Diseases resulting in changes in plasma proteins: Several disease states
alter drug kinetics via changes in protein binding.60 Methadone’s protein
binding varies as a function of B1-AGP levels, albumin levels, and their
ratio.61 Increased levels of B1-AGP are found in cancer,62 physiological stress
(surgery, trauma), rheumatoid arthritis, and celiac disease.63 Fluctuations in
protein binding confound interpretation of total plasma levels, as only the
free fraction is bioavailable and can access the CNS; in hypoalbuminemia, a
seemingly small decrease in methadone plasma level may represent a larger
absolute change in the free fraction. As already noted, the percentage of
protein-bound methadone varied from 83.4% to 96.6% in an unselected
group of methadone-maintenance patients.30 Plasma protein levels also change
in end-stage AIDS (wasting, cardiomyopathy, proteinuria), hepatitis C (a pos-
sible cause of increased IgG observed among intravenous drug users), liver
insufficiency, protein malnutrition, congestive heart failure and nephrotic

JOURNAL OF ADDICTIVE DISEASES
62
syndromes. In such conditions, the ability to perform TDM of methadone
appears to be crucial for clinical evaluation and dose adjustment, especially
for the differential diagnosis of changes in mental status--yet overall plasma
levels, by not reflecting the free fraction, could be misleading.
Pregnancy: Data suggest that late pregnancy seems to increase the appar-
ent clearance of methadone because of a decrease in absorption.64-67
Idiosyncratic Alterations in Methadone Pharmacokinetics
In studies comparing methadone-maintenance patients who reduce or stop
their illicit-opiate use versus those who do not, unexplained pharmacokinetic
differences are sometimes found. Nilsson et al.68 found that methadone’s
plasma half-life was shorter in ‘‘therapeutic failures’’ (persistent heroin us-
ers) than in ‘‘responders’’ (24.5 á 2.6 vs. 34.0 á 7.0 hrs). Similar rates of
body clearance were reported for both groups (104 vs. 111 ml/min), but the
‘‘therapeutic failures’’ had a smaller volume of distribution (2.74 á 0.96 vs.
4.20 á 0.78 l/kg). Similarly, a more recent study33 compared plasma levels
of methadone in 9 ‘‘nonholders’’ (9 patients complaining of daily withdrawal
symptoms) and 9 ‘‘holders.’’ Overall area under the curve did not differ
between the 2 groups; in fact, trough levels were somewhat higher in non-
holders than in holders. However, the nonholders showed a more rapid rate of
decline in plasma methadone, and that rate of decline correlated with the
severity of withdrawal symptoms (r = 0.60, p < .001). Therefore, both studies
point to sharper daily fluctuations in methadone plasma levels in those unable
to stop heroin use and in those complaining of withdrawal symptoms. In each
study, the authors concluded that an appropriate response would be to shorten
the dosage interval, a clinical decision that is rendered impractical given the
restrictions imposed on methadone treatment throughout the last three de-
cades.
WHICH BODY FLUID TO MONITOR?
In the preceding section we demonstrated the potential usefulness of TDM
for determining the adequacy of an individual’s methadone dose. We now
discuss the properties of the different matrices available or in development
for this purpose (see Table 2 for summary).
Plasma
As discussed above, measures of plasma methadone appear to differentiate
treatment responders from nonresponders and predict pharmacological effi-
cacy.33,38,40 Weekly measures of trough methadone levels have been used to

Moolchan, Umbricht, and Epstein
63
TABLE 2. Methadone maintenance: perceived advantages and disadvantages
of potential methods for TDM
Matrix
Advantages
Disadvantages
Plasma
Abundance of published data
Access to specimen
can be difficult
Basis for TDM recommendations
Easy access to specimen
Aversive reactions
Urine
Inference of plasma
concentrations is
technologically complex
Clearance-dependent validity
Specimen not always
obtainable on demand
Patients may view collection
as invasive
Sweat
Saliva
Easy access to specimen
Easy access to specimen
Qualitative only
Concentrations subject to
physico-chemical variations
of milieu (wide variations)
May reflect plasma free-fraction
guide dose adjustments; dose increases for patients whose troughs were less
than 200 ng/ml reduced or eliminated the use of heroin, benzodiazepines,
alcohol, and stimulants, and increased patients’ reports of subjective well-be-
ing.69 Despite these results, the use of plasma for TDM has obvious draw-
backs. It is impractical to obtain blood specimens from longstanding injection
drug users with poor venous access. There are also psychological risks: the
sight of blood may remind patients of drug-related activities such as ‘‘boot-
ing’’70 and ‘‘jacking’’;71 the sight of syringes and needles may elicit condi-
tioned craving or may result in aversive reactions. These drawbacks become
even more salient in light of recommendations (cited on page 62) to measure
methadone’s rate of decline; if done in plasma, this would require serial
venipunctures or several hours of monitoring with an indwelling catheter.33
Consequently, even if relevant and helpful, it is unlikely that this strategy for
TDM using plasma could be adopted by non-research methadone-treatment
programs. Therefore, other avenues for TDM merit consideration.
Urine
Kell43,72 showed that 24-hour trough methadone plasma concentrations
can be estimated from urine samples. He described cases in which supple-

JOURNAL OF ADDICTIVE DISEASES
64
mentation with illicitly obtained methadone and other tampering procedures
could be detected with estimates of plasma levels from urine. Kell20 also
showed that urine-estimated plasma levels of methadone can be reliable
guides for dose adjustment. For a group of patients whose dose adjustments
were made on purely clinical grounds (such as patient complaints), around
10-15% of urine samples remained positive for illicit opiates. For a group of
patients whose dose adjustments were made on the basis of urine-estimated
plasma levels, only 2-3% of urine samples remained positive for illicit opi-
ates. Kell was thus able to calculate methadone’s EC90 (90% effective con-
centration: the plasma trough at which 90% of urines were negative for illicit
opiates) to be 80 ng/ml and the EC98 to be 600 ng/ml. (The mean and median
daily doses that produced opiate-negative urines for 90 days were 73 mg and
80 mg, respectively.) Although encouraging, this method is complex and may
not be ‘‘exportable’’ to a community setting: it requires fluorescent polariza-
tion immunoassay (FPIA) combined with software that accounts for sex,
volume of distribution, urine pH and specific gravity. Furthermore, the meth-
od is not valid for patients with atypical clearance of methadone (e.g., pa-
tients with renal or hepatic disease).24
Sweat
Sweat is a noninvasive alternative to plasma monitoring that could serve to
monitor compliance in treatment and probation programs.73-75 A qualitative
study showed concordance between sweat patches and urine tests for metha-
done and for illicit drugs, and showed that women preferred the sweat
patches over urine tests.76 A quantitative study of methadone concentration
in sweat patches found no correlation with ingested methadone dose, but
correlation with plasma levels was not reported,77 limiting interpretation of
the results. More studies are needed to determine the place of sweat patches
in methadone TDM.
Saliva
Saliva may be an attractive matrix for TDM, for both theoretical and
practical reasons. Its theoretical benefit is that, as a nearly protein-free ultra-
filtrate of plasma, it should be accessible only to the plasma free fraction of
methadone. (Although the free fraction could be determined from a plasma
sample,30 this is not routinely done, for reasons of cost; moreover, it would
carry all the disadvantages of blood drawing.) Thus, a drug’s saliva con-
centration could represent the true bioavailable portion of the drug that reach-
es the intended target tissue.78 This approach has been exploited for pheny-
toin, whose salivary concentration correlates better with cerebrospinal fluid
concentration than with serum concentration.79

Moolchan, Umbricht, and Epstein
65
However, there are 4 other physiochemical determinants of drug penetra-
tion into saliva: (1) molecular mass, (2) lipid solubility, (3) ionization in
plasma (pKa), and (4) saliva pH (which increases with flow rate).78 Metha-
done’s small molecular mass and high lipid solubility are such that, indeed, if
these were the only factors to consider, saliva methadone concentration
would be a pure reflection of its free plasma concentration.80 However,
methadone is a basic drug with a high pKa (8.3-10.1),81-83 so that small
decreases in salivary pH can lead to dramatic increases in its saliva:plasma
(S/P) ratio,80 as was recently demonstrated in a sample of 10 methadone-
maintenance patients.83 This may explain some of the wide variations of
methadone saliva:plasma ratio across studies: 10:1;84 4:1;85 1.3:1.0;86 or
even 0.5:1.0.81 Before saliva can be used for methadone TDM, the first
question to be answered is whether salivary methadone levels reliably predict
free plasma levels across the therapeutic dose ranges, at a given salivary pH.
If variation in saliva pH turns out to be problematic, it could be reduced
through the use of candy-stimulated saliva specimens, whose pH is usually
stable at approximately 7.0.87 The second question is whether (once cor-
rected for pH) saliva methadone level--the presumed free fraction--will better
predict methadone’s therapeutic effectiveness than plasma level.
If these questions are answered in the affirmative, the practical advantages
of saliva collection would make it the method of choice for TDM in metha-
done-maintained patients. Many of these patients have poor venous access
due to long histories of intravenous drug use, so a noninvasive and painless
saliva collection would be more humane and acceptable. Saliva collection
requires no specialized skills and (because saliva inhibits HIV replication)
poses little risk of HIV transmission to clinic staff. Furthermore, saliva
collection is unlikely to be hampered by patients’ inability to produce speci-
mens on demand.78 Finally, serial saliva monitoring might be performed
easily to evaluate methadone’s rate of elimination.
TDM AND SOME LONGSTANDING ISSUES
IN METHADONE MAINTENANCE
Patient-treatment matching: Due to constraints on the availability of re-
sources, an ongoing challenge is the judicious allocation of intensive psycho-
social interventions to the patients who need them most.8 Refinement and
standardization of methadone TDM could help determine which patients do
require methadone dosage adjustments from those who require intensifica-
tion of psychosocial or yet other therapeutic components.
Risk management: Individual differences in methadone metabolism and
tolerance can lead to marked departures from the therapeutic range.13,15,40,88
When this is suspected, objective confirmation would decrease the risk of

JOURNAL OF ADDICTIVE DISEASES
66
inadvertent overdose or withdrawal. Moreover, such documentation im-
proves patient care, increases physician confidence in dose prescribed, and
decreases physician liability.
Administrative issues: Surreptitious addition of methadone to urine sam-
ples by patients who divert and sell the majority of their take-home metha-
done has been suspected in several clinical settings.89 This problem, if not
addressed, could lead to loss of accreditation under the proposed regulations
for methadone maintenance outside of specialized settings.
Forensic applications: By more accurately reflecting bioavailable drug
levels at the time of sample collection, saliva may allow more specific assess-
ment of the impairing potential of a substance; indeed, it has already been
suggested that saliva be sampled for roadside drug tests.90
CURRENT CHALLENGES FOR TDM
IN METHADONE MAINTENANCE
We suggest that TDM will become increasingly important, given upcom-
ing changes in methadone treatment, and ongoing population changes among
those seeking treatment, and that further investigation of TDM using saliva is
necessary.
The rise of medical maintenance: Until now, in the U.S., methadone has
been available solely through specialized clinics, subject to FDA regulation.
It is now proposed that the Center for Substance Abuse Treatment oversee
methadone treatment programs. Given the shortage of treatment slot avail-
ability relative to demand, it is hoped that methadone will then be dispensed
in more varied clinical settings. The prospect of the medicalization of metha-
done and other opioid agonists for long-term treatment of opioid dependence
prompts us to reassess current MMTP practices. TDM could help this process
and have direct implications for the future acceptance of methadone treat-
ment by the broader medical community and other entities, such as the
insurance and health-care industries. The nonintrusive nature of saliva moni-
toring may be especially appropriate for office-based opioid-agonist mainte-
nance; many private practitioners are reluctant to collect observed urines
from their patients, perceiving it as a violation of the principles of the physi-
cian-patient relationship, which are based on trust and mutual respect.
Credentialing requirements: It is not yet known how treatment delivery
will change under CSAT,91 but it seems likely that credentialing organiza-
tions will seek to standardize treatment and improve quality of care on the
basis of objective measures of treatment effectiveness. TDM will help vali-
date quality of care as well as the need for ancillary behavioral or psychoso-
cial interventions at methadone doses demonstrated to be within the effective
therapeutic range.

Moolchan, Umbricht, and Epstein
67
The rise of polypharmacy: As the methadone-treated population ages,92
patients themselves are increasingly likely to be on polypharmacy regimens
for HIV/AIDS, HCV, tuberculosis, or other chronic health problems.93 As
discussed above, patients with chronic health problems require careful moni-
toring for both updated clinical evaluation and methadone dose and schedule
adjustment.
CAVEATS ON THE USE OF TDM
The focus of this review is on the ranges and causes of individual differ-
ences in the pharmacokinetics of methadone, and on methods, available or in
development, to monitor these differences. Clinical responses are also deter-
mined by psychological factors such as conditioned craving for opiates,32
and by pharmacodynamic factors such as potentiation of methadone through
concurrent use of benzodiazepines.93-95 Therefore, pharmacokinetic data must
be evaluated within their appropriate clinical context.
CONCLUSIONS
The practice of opioid-dependence treatment is changing. Factors affect-
ing these changes include intercurrent infectious-disease epidemics, aging of
the methadone-maintained population, multi-drug medical treatments, shift-
ing prevalences of cocaine abuse, the increased availability of cheap, high-
purity heroin leading to the prospect of a contingent of younger, highly
tolerant opioid addicts,96 and, finally, policy changes. Adopting practical and
accurate analytical TDM methods will be desirable for the appropriate man-
agement of patients maintained on methadone.
For the present, plasma remains the best-studied matrix for TDM in meth-
adone maintenance. However, the theoretical and practical benefits of saliva
merit further investigation. The use of saliva for TDM has been advocated in
the scientific literature over the past three decades, but its application to
methadone maintenance has been scant, and there have been no systematic
studies of the correlation among pH-corrected saliva methadone concentra-
tion, plasma free fraction of methadone, and treatment outcome. Such studies
are needed to determine whether saliva assays can provide a convenient,
cost-effective way to monitor the free fraction of methadone--the fraction of
methadone that matters.

JOURNAL OF ADDICTIVE DISEASES
68
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