an additional service to our readers, we have made the following
Research Update available in PDF format as well as HTML. You will
need Acrobat Reader 5.0 or higher to view files. To download, click
on the PDF icon below to download. If you do not have Acrobat Reader,
download it free from Adobe by clicking on the icon box on the
Dosing & Safety in the Treatment of Opioid Addiction (PDF
file size 312K)
treatment (MMT) has a long history of effectiveness and
safety as a therapy for opioid addiction. However, since
it is a highly potent drug, methadone's improper prescription
and/or its misuse can be harmful or even fatal.
The most adequate methadone dose provides an effective response
in the patient, with a margin for safety, for an appropriate
duration of time. However, there is wide variation in patient
response, due in part to the complexities of how methadone
works and individual patient differences. Methadone dosing
should be determined on an individual basis, without artificial
dose limits, while exercising caution to avoid adverse effects.
The key to initiating methadone dosing is to start low and
go slow. However, research evidence confirms that maintenance
doses ultimately greater than commonly considered in some
MMT programs may be necessary for many patients. Clinical
signs and patient-reported symptoms of either overmedication
or withdrawal, along with drug craving and/or continuing
illicit-opioid use, are vital indicators for achieving dose
Finally, patient education is an essential component of safety
in MMT. This should be combined with efforts to foster open,
trusting relationships between patients and clinic staff,
which will produce the most successful treatment outcomes.
Methadone, a synthetic-opioid medication, is among the oldest and
most thoroughly studied drugs in modern medicine. Since the advent
of methadone maintenance therapy (MMT) in the mid-1960s for treating
opioid addiction, it has helped millions of persons worldwide
in recovery to achieve more normal and productive lives.
When properly prescribed and used, methadone is an effective and
safe medication. Yet, many MMT professionals have been guided in
their methadone-prescribing practices more by philosophical, moral,
or psychological rationales than by sound pharmacological and clinical
principles (Loimer and Schmid 1992).
This paper examines evidence-based principles and expert
opinions regarding "best practice" approaches.
Such information can help shape clinical intuition allowing
practitioners to reliably prescribe more adequate and safe
doses of methadone for better patient care and achieving
favorable treatment outcomes.
Balancing Risks & Benefits
There are three immediate objectives of methadone maintenance (Maremmani
et al. 2002, 2003; Payte 2002):
1) suppress signs and symptoms of opioid withdrawal,
2) extinguish opioid-drug craving, and
3) block the reinforcing effects of illicit opioids ("blockade").
Each of these objectives is accomplished in phases, rather than at
once, relying on the administration of adequate methadone doses to
achieve and sustain optimum blood levels of the drug (Health Canada
2001). Although too much methadone can be harmful, insufficient methadone
is largely ineffective (Verster and Buning 2000).
Methadone has been demonstrated throughout many years of clinical
study as having a favorable safety profile. No serious adverse reactions
or other organ damage have been associated with continued MMT (Kreek
1973a) extending more than 20 years in some patients (Novick et al.
All-cause mortality in methadone-treated patients is typically many-fold
lower than in untreated opioid addicts (Gearing and Schweitzer 1974;
NIH 1997), and studies have consistently shown that the risk of communicable
infection is significantly reduced by participation in MMT, even
in patients falling short of total abstinence from illicit drugs
(Leshner 1999). Studies over the years have demonstrated that the
relative risk of death is at least 3 to 4 times less for patients
continuing in MMT compared with those who discontinue treatment (Bell
and Zador 2000; Humeniuk et al. 2000).
Still, methadone is a potent drug and there have been reported cases
of fatal poisoning associated with it. The primary toxic effect of
excessive methadone in the non-tolerant individual is respiratory
depression with pulmonary edema and/or aspiration pneumonia (Harding-Pink
1993b; Humeniuk et al. 2000; White and Irvine 1999). Relatively large
proportions of methadone-associated deaths, beginning with the earliest
reports, occurred during start-up of methadone maintenance, usually
linked to a failure to determine the presence and extent of existing
opioid tolerance in new patients and/or patients' continued substance
During later stages of MMT, other drugs in addition to methadone
have been detected in most but not all cases of drug-induced death.
Deaths among MMT patients often have been associated with physical
disorders related to pretreatment lifestyles (e.g., infectious diseases),
and deaths in those leaving MMT often were connected to drug-related
violence, accidents, or overdose, which had been diminished during
participation in treatment (Appel et al. 2000; Petry et al 1998).
How Methadone Works - Pharmacology
In the treatment of opioid addiction, methadone works primarily via µ-opioid
receptors in the brain, where it attaches and, in sufficient quantity,
blocks effects of other opioid agents, such as heroin. Oral methadone
is 80 to 95% bioavailable, compared with only 30% for oral morphine,
and readily enters the circulation after ingestion (Eap et al. 2002).
Methadone is broken down (metabolized) to form a number of metabolites
that are essentially inactive and nontoxic (Moody et al. 1997). The
elimination half-life of methadone averages 24 to 36 hours at steady
state, but may range from 4 to 91 hours, and its rate of clearance
from the body can vary by a factor of almost 100 (Inturrisi and Verebely
1972; Loimer and Schmid, 1992; Payte and Zweben 1998).
Methadone is stored extensively in the liver and secondarily in other
body tissues (Humeniuk et al. 2000). The amount in the blood stream the
serum methadone level or SML is kept relatively constant by
the slow release of methadone from tissues, which helps account for
its long half-life (Borg and Kreek, 2003).
Typically, 4 to 5 half-lives of a drug are required to attain steady-state
SMLs, wherein elimination of the drug is in balance with the amount
of drug remaining in the body (Benet et al. 1996). In the case of
methadone, steady-state usually requires 4 to 5 days; although, it
can take much longer in some individuals (Eap et al. 2002; Payte and
Khuri 1993). Once steady state concentration is reached, peak (high)
and trough (low) SMLs remain about the same from one dosing interval
to the next (Figure 1), unless something offsets the
balance; such as, physical illness or an interacting substance.
During the start-up methadone-induction period, prior to steady-state,
an essential consideration is that half of each day's dose remains
in the body and is added to the next day's, producing rising SMLs even
without any increase in dose (Payte 2002). Therefore, dose
increases until full steady-state is reached must be considered
cautiously. After each increase in methadone, it will take 4 to
5 days, or more, to achieve steady-state at the new total dose
(Payte et al. 2003).
The SML typically reaches a peak in 2 to 4 hours on average (range
1-5 hours) after dosing, but its elimination half-life and the patient's
physiologic response may be influenced by numerous factors (Table
1). Considerable flexibility in dosing is required to stabilize
patients in whom methadone's actions may be so variably affected (Borg
and Kreek 2003; Eap et al. 2002; Leavitt et al. 2000; Payte et al.
methadone used in MMT comes as solid tablets, dispersible
tablets, or premixed liquid. Research has demonstrated
that the three formulations are equally potent in effect
(Kreek 1973b, Gourevitch et al. 1999), although subjective
reactions of patients to each formulation can vary.
Methadone metabolism is largely a function of liver enzyme
activity involving cytochrome P450 isoforms (CYP450 enzymes).
Drugs that induce activity of these enzymes can accelerate
methadone metabolism, abbreviate the duration of its effect,
lower the SML, and precipitate abstinence (withdrawal)
syndrome. Conversely, CYP450 inhibitors may slow methadone
metabolism, raise the SML, and extend the duration of its effects (Kreek
et al. 1976; Leavitt et al. 2000; Payte and Zweben 1998). Several CYP450
isoforms CYP3A4, CYP2D6, and to a smaller extent CYP1A2 are
significantly involved in methadone metabolism (Eap et al. 2002; Foster
et al. 1999).
Genetic and environmental factors can act on those enzymes, leading
to a high degree of individual variation in methadone's apparent potency.
In patients taking exactly the same dose of methadone, corrected for
body weight, concentrations of active methadone can vary extensively
even in the absence of interacting substances (Eap et al. 2002).
When interactions with other substances occur, changes in SMLs could
result in problematic methadone under- or overmedication. Various sources
may be consulted regarding drugs/substances that are metabolized via
CYP450 enzymes and could alter methadone blood levels (DeMaria 2003;
Eap et al. 2002; Gourevitch 2001; Leavitt 1997) or have metabolic potential
for interacting with methadone (Flockhart 2003 at http://drug-
SMLs vs Signs/Symptoms
Some researchers have recommended using serum methadone levels (SMLs)
as a diagnostic tool for guiding dosing decisions (Loimer and Schmid
1992), and have noted a correlation between "poor performance" in
MMT and lower methadone plasma levels (Tennant et al. 1984). Measuring
SMLs in nanograms (1-billionth gram) per milliLiter, ng/mL might
be a helpful diagnostic aid in difficult cases; however, the methadone
dose does not always correlate with the SML.
Although a strong correlation between methadone dose and SML was originally
reported by Wolff et al. (1991), extensive differences across individual
patients must be considered (Leavitt et al. 2000; Okruhlica et al.
2002). Recent data have demonstrated virtually no correlation between
trough or peak SMLs at doses above 100 mg/d (Dorsey 2003, see Figure
2). Thus, it appears that methadone dose may have poor overall
predictive value for estimating trough or peak SML values.
2: Lack of correlation between methadone dose and
either trough or peak SML values in methadone-maintained patients
Payte and colleagues (2003) have emphasized that the
ratio between peak and trough SML measures can be most clinically
useful. The peak SML occurring at roughly 2 to 4 hours post-dosing
should be no more than twice the trough level. This would provide an
optimal peak-to-trough ratio of 2 or less.
Regardless of particular serum level readings or ratios
the patient may not be properly dosed (Leavitt et al. 2000;
Maxwell and Shinderman 1999). Clinical signs and patient-reported
symptoms can be the most effective indicators of dose adequacy
As the SML rises, objective signs of withdrawal disappear
and subjective symptoms are a guide for further dose increases.
At the optimal methadone dose, the SML stays in the therapeutic "comfort" range
for that individual patient throughout the dosing
period. If the methadone SML becomes too high, signs/symptoms
of overmedication appear.
It is important to note that subtle effects of overmedication
can include mild euphoria ("feeling good"), extra
energy, staying up late to work, etc., which patients
may perceive as falsely beneficial. The effects wear off and,
then, patients may seek unnecessary and possibly harmful
dose increases (Payte 2002).
Each patient poses a unique clinical challenge. Practitioners
are cautioned against making the mistake of "treating SML test results" or
dogmatically adhering to biased preconceptions of what is "enough" methadone,
and thereby ignoring signs/symptoms as a guide to achieving optimal
dosing (Leavitt et al. 2000).
The Importance of Tolerance
Methadone can be toxic to anyone who is not tolerant of
opioids and a single dose can cause life-threatening respiratory
depression (Harding-Pink 1993b). However, an opioid-tolerant
person can function normally at doses that can be fatal
to a non-tolerant person. Opioid tolerance is a complex
process of neuroadaptation and even experienced opioid users
can be at risk of toxic methadone effects (Strang 1999).
It is essential to estimate an individual's opioid-dependence,
and associated tolerance, prior to initiating methadone
treatment. Most methadone-associated deaths have been
in persons with little or no tolerance to opioids (Buster
and van Brussel 1996).
The traditional definition of tolerance is reduced response
to one or more effects of a drug after repeated administrations
(Kosten and George 2002; O'Brien 1996). Essentially, cells
with opioid receptors become less sensitive to opioid stimulation
and more drug is needed to achieve the same effects.
However, tolerance develops much more rapidly to some opioid
effects than others. For example, tolerance develops quickly
to the euphoric effects of opioids, while tolerance to gastrointestinal
effects (e.g., constipation), sedation, or respiratory depression
is slower to develop. This can be potentially fatal if users
ingest increasingly greater amounts for euphoria (Harden
2002; White and Irvine 1999). In the case of methadone, tolerance
development is incomplete (Kosten and George 2002), so respiratory
depressant effects of other agents e.g.,
alcohol, sedatives, opioids or acutely excessive methadone
may not be completely blocked even in persons at stabilized methadone-maintenance
Dosing Stages & Safety
The outpatient MMT process moves through different phases,
from start-up induction through
stabilization on a maintenance dose (Table 3).
Dose variations may be required throughout treatment in response
to changing physiologic conditions and environmental influences
affecting the patient.
Starting methadone induction requires caution.
Several risk factors have been noted: 1) initial dose
quantity, 2) concomitant use of other drugs, and 3)
general health of the patient (Humeniuk et al. 2000).
The risk of death during methadone induction has been
calculated as nearly 7-fold greater than patients' risks
of death prior to entering MMT (Caplehorn and Drummer
1999), and nearly 98 times greater for new patients than
for patients who have been safely receiving methadone
for more than two weeks (Karch and Stephens 2000). Deaths usually
occur during the first 3 to 10 days of treatment (Payte 2000; Zador
and Sunjic 2000; Wagner-Servais and Erkens 2003), at home during
sleep, many hours after peak SML has occurred (Caplehorn 1998). Abnormal
methadone metabolism or other factors in an individual can mean that
methadone doses that would usually have been safe and appropriate
can lead to potentially fatal overdose (Humeniuk et al. 2000).
A most critical aspect is the person's opioid tolerance at
the time of initiating treatment, based on the patient's
history of opioid type used, frequency, quantity, and route
of administration (Payte and Khuri 1993; Strang 1999; Tenore
2003). However, tolerance level can be difficult to gauge.
For example, urinalysis may indicate illicit opioid use,
but it does not indicate the dose, frequency, or time of
last use (van Beusekom and Iguchi 2001). Some persons claiming
to be regular opioid abusers may be either opioid naïve
or occasional users, and infrequent opioid use does not
engender tolerance with any certainty. Also, severity
of withdrawal signs/symptoms alone, in the absence of other
evidence, is not necessarily an indicator of tolerance or the
need for higher starting doses. If any persons are started at methadone
doses in excess of their established tolerance it can lead to
overdose (Baden 1970).
Furthermore, U.S. federal regulations require that a complete
physical examination, including all laboratory tests, must
be completed for each patient within 14 days following admission
to MMT (Federal Register 2001). However, considering the
potential for physical disorders and adjunctive medications
to interact with methadone, a physical examination, including
a comprehensive history taking and cardiac health assessment,
might be advised as part of the admission process. Researchers
have reported deaths during induction associated with pre-existing
physical illness, such as bronchopneumonia, hepatitis, or
epilepsy (Drummer et al. 1992; Zador and Sunjic 2000). Any
illness affecting respiratory health, drug metabolism or
elimination, neurologic status, or cardiac function would
be of special concern, suggesting closer monitoring of patients
during induction and ongoing MMT.
Induction Dose Recommendations
The objective of the methadone induction process is to approximate
the patient's opioid-tolerance level with methadone, thereby reducing
withdrawal and opioid craving. A further aim is to diminish or eliminate
other opioid use as rapidly as possible without sacrificing patient
safety (Payte 2000).
Since there is no scientific formula for calculating opioid
tolerance, the prudent methadone-dosing advice is to initially start
low and go slow (Health Canada 2001). However, with an
overly conservative approach to induction, the patient may self-medicate
withdrawal symptoms with illicit substances (Humeniuk et al,
2000). Conversely, an overly aggressive strategy may result in
methadone overdose or at least overmedication as peak SMLs rapidly
rise (Health Canada 2001; Payte 2000).
Authorities in various countries have published guidelines for
methadone induction dosing, and these are summarized in Table
In general, care is needed in starting a dose toward the upper
part of the indicated ranges; however, if a small dose is used
(e.g., 10 mg), further small doses (5-15 mg range) may be given
based on the severity of observed withdrawal signs once
peak SML has been reached (Payte et al. 2003).
maximum of 40 mg allowed the first day by some guidelines
might be considered excessive and require extra vigilance.
Deaths during the first week of MMT in patients started
at that dose have been reported by several sources
(Humeniuk et al. 2000; Wagner-Servais and Erkens 2003;
Zador and Sunjic 2000).
During methadone induction, patients may be in mild withdrawal
toward the end of the dosing interval, so doses
are NOT automatically
increased based on how patients feel at 12 or more hours after
dosing. Rather, patients are asked how they felt 3 to 8 hours after
the last dose, and if they were relatively comfortable no increase
is given (Payte 2000; Tenore 2003).
Some guidelines specify that, during the first week, doses
should be increased by no more than 5 to 10 mg on any day
and the total weekly increase beyond the starting day's
dose should not exceed 20 mg (Verster and Buning 2000) or
30 mg (Strang 1999); although, some modifications of these
limits might apply in special circumstances. At any dose,
use of alcohol, sedatives, and/or short-acting opioids (e.g.,
heroin, oxycodone, hydrocodone) during induction significantly
increases the risk of overdose death (Health Canada 2001; van Beusekom
and Iguchi 2001).
There is no induction dosing protocol that has proved absolutely
safe for all patients and, during the early days of induction, clinical
observation of patients after dosing until peak SMLs are reached
might be recommended. Methadone blood levels may rise up to 7-fold
during the induction period with no change in dose, SMLs continue
to rise for roughly 5 days after increasing a dose (Verebely et al.
1975), and toxic accumulation can occur even two weeks after treatment
initiation (Health Canada 2001). If patients experience overmedication
effects, their dose should be reduced or, at most, maintained an
additional 5 to 7 days while more opioid tolerance develops (Tenore
The induction phase lasts until a steady-state methadone
level is achieved (Payte et al. 2003). Payte (2000) has
suggested a helpful checklist of induction safety tips,
presented in Table 5.
Once at a steady-state level, methadone should be present
in sufficient concentration to maintain a therapeutic "comfort
the dosing interval (Payte et al. 2003). There is no clear relationship
between prior "heavy" abuse of an opioid and the methadone
dose ultimately required for stabilization (Health Canada 2001).
Initial research discovered that 80 to 120 milligrams
of methadone for daily maintenance, on average, was sufficient
for many patients (Dole et al. 1966). Due to individual
patient factors (Table 1,
above) some require significantly greater doses for treatment
success, sometimes exceeding 200 mg/d (Leavitt et al. 2000; Payte et al.
Criteria for continued dose increases for stabilization include
(Health Canada 2001):
Signs/symptoms of withdrawal (objective and subjective);
Persistent craving for opioids;
The amount or frequency of opioid use not decreasing.
Dose adjustments during stabilization are usually in the 5 to 10
mg/d range no more frequent than every 3 to 4 days (Health
Canada 2001), or 5 days (Tenore 2003) or a 20 mg/d total
increase per week (Verster and Buning 2000). Some flexibility
in this approach might be acceptable, provided there are no signs/symptoms
of overmedication. Adequate dose cannot be determined by solely
objective measures (including SMLs), and early withdrawal is
purely subjective, so a consideration of patient self-reports
is an important guide to continued dose increases (Payte and
Khuri 1993; Verster and Buning 2000).
High doses of methadone are often necessary and safe, provided
dose increases are modest and sufficient time elapses between
escalations. However, patients with debilitating illness
or who are sensitive to opioid effects may require longer
intervals between dose increases and ultimately lower doses
Ongoing Methadone Maintenance
Continued opioid use or relapse can be virtually elim-inated in most
patients via adequate methadone dosing
practices (Eap et al. 2000). How-ever, as Harding-Pink (1993a) once
observed, one person's methadone maintenance dose is another's
poison, and vice versa. Hence, the importance of individualized methadone
dosing regimens for maintenance must be stressed.
What Is An Optimal Dose?
Over the years there have been many clinical trials comparing
various doses of methadone for maintenance treatment. A
consistently reported finding is that patients receiving
higher methadone doses compared with those at lower doses
exhibit superior outcomes; in terms of such variables as
illicit-opioid abstinence, retention in treatment, and
psychosocial rehabilitation (Eap et al. 2002; Leavitt 2003;
Maremmani et al. 2003, Payte et al. 2003).
For example, in a review of 29 clinical studies examining
methadone dosing in MMT comparing average doses ranging from
0 mg/d (placebo) up to 250 mg/d (and 780 mg/d in one trial) Maremmani
et al. (2003) concluded that there is no evidence of lower doses
being adequate for the vast majority of patients. Just how large
a dose is "enough" depends
on individual patient needs.
Clearly, while some patients thrive on doses well below
100 mg/d, others require hundreds of milligrams of methadone
daily. For example, patients with high levels of emotional
distress or psychiatric disorders often need increased
methadone for stability (Maremmani and Shinderman 1999;
Maxwell and Shinderman 1999; Verster and Buning 2000).
Vincent Dole (a developer of MMT), once observed: "There is
no compelling reason for prescribing doses that are only marginally
adequate. As with antibiotics, the prudent policy is to give
enough medication to ensure success" (Dole 1988).
Also, Payte (2002) recently noted, "Arbitrary dose ceilings
have no foundation in science or clinical medicine. Programs
caps' can expect problems with accreditation." Furthermore,
such "caps" are
not endorsed by the U.S. federal regulations or addiction medicine
From a safety perspective, in a meta-analysis of methadone
dosing studies, Caplehorn et al. (1996) found that patients
having access to "high-dose
maintenance" were at reduced risk of fatal heroin
overdose during treatment compared with those at lower doses.
Unfortunately, there have been no published studies directly
examining effects of methadone maintenance dose amount on MMT
The Utility of SMLs
Serum methadone levels (SMLs) are often of minimal clinical
value, but they can be helpful in special cases to
confirm a need for methadone dose increases and in identifying
patients who may benefit from split daily dosing (Tenore
2003). On average, researchers have affirmed the benefit
of a 150 to 600 ng/mL trough SML
to suppress opioid craving and a trough level at or above 400
ng/mL to provide sufficient opioid blockade during methadone
maintenance (Dole 1988; Eap et al. 2002; Leavitt et al.
2000; Payte et al. 2003). Clinical studies have demonstrated
that methadone doses widely ranging from 50 mg/d to more
than 900 mg/d may be necessary to achieve those optimal
steady-state trough SMLs (Eap et al. 2000).
The goal is a trough level of 400 to 500 ng/mL and a peak of about
twice that amount (e.g., 800-1000 ng/mL). Lower or much higher levels
are acceptable if patients are illicit-opioid-free and exhibit neither
withdrawal nor overmedication. Based on clinical experience, Tenore
(2003) has divided trough SMLs into several ranges for interpretation
(Table 6). However, the clinical presentation of the
patient should always override serum level values (Gagjewski
and Apple 2003).
A definitively toxic serum level of methadone for all persons
is undetermined. SMLs reported in methadone-associated deaths commonly
overlap those SMLs considered as therapeutic during MMT (Gagajewski
and Apple 2003; Milroy and Forrest 2000; Sorg and Greenwald 2002).
In review articles, methadone concentrations observed as fatal have
ranged from 60 to 4,500 ng/mL (Mikolaenko et al. 2002; Wolff 2002).
Therefore, monitoring patients for clinical signs/symptoms of overmedication
is more critical than merely following trough or peak SML values.
At any dose, if a patient is clinically overmedicated several
hours after dosing but experiences withdrawal before it is
time for the next dose and/or the peak SML is more than twice the
trough level (P:T ratio > 2.0) splitting the daily methadone dose
should be considered (Figure 3). In such cases, further once-a-day
dose increases will not make the dose last longer and would only
elevate the peak level, not the trough level. This results in greater overmedication
during early hours but continued opioid withdrawal later (Payte and
Khuri 1993; Payte 2002, Tenore 2003).
3: Splitting the dose (red line) keeps SML within the
therapeutic range (gray zone), which corrects a high peak
and low trough level (black line).
Take-home methadone doses for unsupervised self-administration are
allowed under U.S. federal regulations (Federal Register 2001, Table
7). However, individual state requirements may be more
To qualify for more
than a single day's take-home dose per week (if the clinic is closed
for Sundays or a holiday), patients are expected to demonstrate capabilities
of handling and taking methadone unsupervised, including: abstinence
from unauthorized substances, regular clinic attendance, absence
of behavioral problems or criminality, stability of home environment
and social relationships, assurance that methadone can be safely
stored, and whether the rehabilitative benefits to the patient of
decreased clinic attendance outweigh potential concerns regarding
methadone diversion (Federal Register 2001).Current U.S. federal
regulations do not specify patient employment as a qualification
for take-home methadone, nor are there restrictions on the dose amount
in mg/d. Oral methadone may be distributed for take-home as liquid,
solid tablets, or dispersible tablets (Federal Register 2001).
Long ago, Roizin and colleagues (1972) called attention
to the "poison
cocktail" resulting from the intake of multiple psychotropic ("mind-acting")
drugs, including methadone. Interactions can be additive, in
which the net effect is the sum of the substances' individual harmful
effects, or supra-additive (synergistic or potentiating) when
total effects are greater than if just additive.
In cases of methadone-associated death, alcohol, benzodiazepines, and/or
other opioids are frequently implicated (Zador and Sunjic 2000). In
themselves, these other substances can be relatively moderate respiratory
depressants, but when combined with each other and/or methadone the
effects may be lethal (White and Irvine 1999). Numerous factors affect
toxic drug interactions and their lethality, including: health status
and pre-existing tolerance of the person, the number and type of drugs
taken, and drug dosages (Roizin et al. 1972).
Patient Education is Essential
Educating patients, and their "significant others" (with
permission), is essential for safety and treatment success. There are
many myths and much misinformation surrounding methadone. Patients
expecting MMT to quickly and easily solve their addiction problems
are likely to be disappointed and uncooperative.
Among other things, patients need a basic understanding of how methadone
works and what to realistically expect. They must appreciate that there
is a delay of 2 to 4 hours before methadone has peak effect and there
can be an accumulation of the drug after a dose increase.
Patients must be cautioned about the hazards of continued substance
abuse or deceit about such practices. They, and those close to them,
should be provided adequate information about signs/symptoms of methadone
overmedication, which is especially critical during the induction stage.
Efforts to foster open, trusting relationships between patients
and clinic staff will produce the most successful treatment
outcomes. Patients need to feel that dosage adjustments,
up or down, are for their comfort and safety; rather than
rewards or punishments. Dosing decisions should always be
made on clinical grounds, with patients involved in decisions
and informed of the reasons just as would be the case with other
prescribed medications or medical procedures.
Appel PW. Joseph H, Richman BL. Causes and rates of death among methadone
maintenance patients before and after the onset of the HIV/AIDS epidemic.
Mt Sinai J Med. 2000;67(5-6):444-451.
Baden MM. Methadone related deaths in New York City. Int J Addict. 1970;5(3):489-498.
Bell J, Zador D. A risk-benefit analysis of methadone maintenance treatment.
Drug Saf. 2000;22(3)179-190.
Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics. In: Hardman
JG, Limbird LE, eds. Goodman & Gilmans The Pharmacological
Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:3-27.
Borg L, Kreek MJ. The pharmacology of opioids. In: Graham AW, Schultz
TK, Mayo-Smith MF, Ries RK, Wilford BB. Principles of Addiction Medicine.
Chevy Chase, MD: American Society of Addiction Medicine; 2003:
Buster M, van Brussel G. Is methadone more likely to kill you than
heroin? Euro-Methwork. 1996 (Nov);9.
Caplehorn JRM. Deaths in the first two weeks of maintenance treatment
in NSW in 1994: identifying cases of iatrogenic methadone toxicity.
Drug Alcohol Rev. 1998;17:9-17.
Caplehorn JRM, Drummer OH. Mortality associated with New South Wales
methadone programs in 1994: lives lost and saved. Med J Aust. 1999;170(3):104-109.
Caplehorn JRM, Dalton MSYN, Haldar F, Petrenas A-M, Nisbet
JG. Methadone maintenance and addicts risk of fatal
heroin overdose. Subst Use Misuse. 1996;3(2):177-196.
DeMaria Jr PA. Methadone drug interactions. J Maint Addic. 2003;2(3):69-75.
Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Int Med. 1966;118:304-309.
Dole VP. Implications of methadone maintenance for theories of narcotic
addiction. JAMA. 1988;260:3025-3029.
Dorsey JS. Serum methadone levels and optimal dosing in methadone maintained
patients. Poster presented at: American Association for the Treatment
of Opioid Dependence Conference; April 13-16, 2003; Washington,
DC. Poster P9. Additional analyses by S. Leavitt, data on file.
Drummer OH, Opeskin K, Syrjanen M, Cordner SM. Methadone toxicity causing
death in ten subjects starting on a methadone maintenance program.
Am J Forensic Med Pathol. 1992;13(4):346350.
Eap CB, Bourquin M, Martin J-L, et al. Plasma concentrations of the
enantiomers of methadone and therapeutic response in methadone maintenance
treatment. Dru Alcohol Dep. 2000;6(11):47-54.
Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical
pharmacokinetics of methadone: implications for the treatment of opioid
dependence. Clin Pharmacokin. 2002;41(14):1153-1193.
Federal Register. Opioid drugs in maintenance and detoxification treatment
of opiate addiction; final rule. 2001 (Jan 17);66(11):4085. 42 CFR
Flockhart D. Cytochrome P450 drug interaction table: Indiana University
School of Medicine. Available at: http://drug-interactions.com. Updated
April 11, 2003.
Foster DJR, Somogyi AA, Bochner F. Methadone N-demethylation in human
liver microsomes: lack of stereoselectivity and involvement of CYP3A4.
Br J Clin Pharmacol 1999;47:403-412.
Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County
Minnesota: 1992-2002. J Forensic Sci. 2003;48(3):1-4.
Gearing FR, Schweitzer MD. An epidemiologic evaluation of longterm
methadone maintenance treatment for heroin addiction. Am J Epidemiology. 1974;100:101111.
Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of
methadone. A clinical and pharmacodynamic comparison. J Subst Abuse
Gourevitch MN. Interactions between HIV-related medications and methadone:
an overview. Mt Sinai J Med. 2001;68(3):227-228.
Harden RN. Chronic opioid therapy: another reappraisal. APS Bulletin. 2002;12(1).
Harding-Pink D. Methadone: one persons maintenance dose is anothers
poison. Lancet. 1993a;341:665.
Harding-Pink D. Opioid toxicity. Lancet. 1993b;341:665-666.
Health Canada. Methadone Maintenance Guidelines. Toronto, Ontario:
College of Physicians of Ontario; 2001. Available at: http://www.cpso.on.ca.
Humeniuk R, Ali R, White J, Hall W, Farrell M. Proceedings of Expert
Workshop on the Induction and Stabilisation of Patients Onto Methadone.
Monograph Series No. 39. Commonwealth Department of Health and Aged
Care: Adelaide, South Australia; 2000. Available at: http://www.health.gov.au.
Inturrisi CE, Verebely K. The levels of methadone in the plasma in
methadone maintenance. Clin Pharm Ther. 1972;13(5 part 1):633-637.
Karch SB. Stephens BG. Toxicology and the pathology of deaths related
to methadone: retrospective review. West J Med. 2000;172:11-14.
Kosten TR, George TP. The neurobiology of opioid dependence:
implications for treatment. Science & Practice Perspectives. 2002;1(1):13-20.
Kreek MJ, Gutjahr CL, Garfield JW, Bowen DV, Field FH. Drug interactions
with methadone. Ann NY Acad Sci. 1976;281:350-370.
Kreek MJ. Medical safety and side effects of methadone in tolerant
individuals. JAMA. 1973a;223:665-668.
Kreek MJ. Plasma and urine levels of methadone. NY State J Med. 1973b;73(23):
Leavitt SB. Methadone at work. Addiction Treatment Forum. 1997;4(2):1,6.
Available at: http://www.atforum.com.
(Drug interaction tables to be updated in fall 2003.)
Leavitt SB. Methadone induction; a safety first approach. Addiction
Treatment Forum. 1999;8(2):1,5. Available at: http://www.atforum.com.
Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When enough is
not enough: new perspectives on optimal methadone maintenance dose.
Mt Sinai J Med. 2000;67(5-6):404-411.
Leavitt SB. The methadone dose debate continues. Addiction Treatment
Forum. 2003;12(1):1,3. Available at: http://www.atforum.com.
Leshner AI. Drug abuse research helps curtail the spread of deadly
infectious diseases. NIDA Notes. 1999;14(2):3-4. NIH Pub# 99-3478.
Loimer N, Schmid R. The use of plasma levels to optimize methadone
maintenance treatment. Drug Alcohol Depend 1992;30(3):241-246.
Maxwell S, Shinderman M. Optimizing response to methadone maintenance
treatment: higher-dose methadone. J Psychoactive Drugs April-June 1999;31(2).
Maremmani I, Barra M, Bignamini E, et al. Clinical foundations
for the use of methadone. Italian consensus panel on methadone
treatment. Heroin Add & Rel Clin Probl. 2002;4(2):19-32.
Maremmani I, Pacini M, Lubrano S, Lovrecic M. When enough is
still not enough: effectiveness of high-dose methadone
in the treatment of heroin addiction. Heroin Add & Rel Clin Probl. 2003;5(1):17-32.
Maremmani I, Shinderman M. Alcohol, benzodiazepines and
other drugs use in heroin addicts treated with methadone:
polyabuse or undermedication? Heroin Add & Rel Clin
Mikolaenko I, Robinson A, Davis GG. A review of methadone deaths in
Jefferson County, Alabama. J For Med Path. 2002;23(3):299-304.
Milroy CM, Forrest ARW. Methadone deaths: a toxicological analysis.
J Clin Pathol. 2000;53:277-281.
Moody DE, Alburges ME, Parker RJ, Collins JM, Strong JM. The involvement
of cytochrome P450 3A4 in the N-demethylation of L-a-acetylmethadol
(LAAM), norLAAM, and methadone. Drug Metab Disp. 1997;25(12):1347-1353.
NIH (National Institutes of Health). Effective Medical Treatment of
Opiate Addiction. NIH Consensus Statement. Bethesda, MD: National Institutes
of Health; 1997(Nov 17-19);15(6):1-38. (See also: JAMA. 1998;280:1936-1943.)
Novick DM, Richman BL, Friedman JM, et al. The medical status of methadone
maintained patients in treatment for 11-18 years. Drug Alcohol Dep. 1993;33:235-245.
OBrien CP. Drug addiction and drug abuse. In: Hardman JG, Limbird
LE, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics.
9th ed. New York: McGraw-Hill; 1996:557-577.
Okruhlica L, Devinsk F, Valentova J, Klempova D. Does therapeutic
threshold of methadone concentration in plasma exist? Heroin
Add & Rel Clin
Payte JT. Clinical take-homes. J Maint Addict. 2000;1(4):113-114.
Payte JT, Khuri ET. Principles of methadone dose determination. In:
Parrino MW. State Methadone Treatment Guidelines. Treatment Improvement
Protocol (TIP) Series 1. Rockville, MD: U.S. Department of Health and
Human Services; Center for Substance Abuse Treatment;1993:47-58
DHHS Pub# (SMA) 93-1991. (This publication is being revised for possible
release in late 1994.)
Payte JT. Opioid agonist treatment of addiction. Slide presentation
at ASAM Review Course in Addiction Medicine, 2002. See: http://www.jtpayte.com.
Payte JT, Zweben JE, Martin J. Opioid maintenance treatment. In: Graham
AW, Schultz TK, Mayo-Smith MF, Ries RK, Wilford BB. Principles of Addiction
Medicine. Chevy Chase, MD: American Society of Addiction Medicine; 2003:
Payte JT, Zweben JE. Opioid maintenance therapies. In: Graham AW, Schultz
TK, eds. Principles of Addiction Medicine. 2nd ed. Chevy Chase, MD:
American Society of Addiction Medicine, Inc; 1998:557-570.
Petry NM, Bickel WK, Badger GJ. A 12-year study (1975 - 1986) of mortality
in methadone maintenance patients: Selected demographic characteristics
and drug-use patterns of AIDS and non-AIDS-related deaths. Subst Use
Misuse. 1998; 33(12):2521-2534.
Roizin L, Helpern M, Baden M. Methadone fatalities in heroin addicts.
Psychiatric Quart. 1972;46(3):393-410.
Sorg MH, Greenwald M. Maine Drug-Related Mortality Patterns:1997-2002.
State of Maine; December 27, 2002. (Report in cooperation with
the Maine Office of the Attorney General and Maine Office of Substance
Strang J (chair). Drug Misuse and Dependence - Guidelines on Clinical
Management. Department of Health, The Scottish Office Department of
Health, the Welsh Office and the Department of Health and Social Services,
Northern Ireland. UK: Norwich; 1999. Available at: http://www.doh.gov.uk/drugdep.htm.
Tennant FS Jr, Rawson RA, Cohen A, Tarver A, Calbough D. Methadone
plasma levels and persistent drug abuse in high dose methadone patients.
NIDA Res Monogr 1984;49:262-268.
Tenore PL. Guidance on optimal methadone dosing. Addiction Treatment
Forum. 2003;12(3):1,6-7. Available at: http://www.atforum.com.
van Beusekom I, Iguchi MY. A review of recent advances in knowledge
about methadone maintenance treatment. Cambridge, UK: Rand Europe; 2001.
Available at: http://www.rand.org/publications/MR/MR1396/index.html.
Verebely K, Volavka J, Mule S, Resnick R. Methadone in man: pharmacokinetic
and excretion studies in acute and chronic treatment. Clin Pharmacol
Verster A, Buning E. Methadone Guidelines. Amsterdam, The Netherlands:Euro-Methwork; 2000.
Available at: http://www.q4q.nl/methwork/
Wagner-Servais D, Erkens M. Methadone-related deaths associated with
faulty induction procedures. J Maint Addic. 2003;2(3):57-67.
White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999;94(7):961-972.
Wolff K, Sanderson M, Hay AWM, Ralstrick D. Methadone concentrations
in plasma and their relationship to drug dosage. Clin Chem. 1991;37(2):205-209.
Wolff K. Characterization of methadone overdose: clinical considerations
and the scientific evidence. Ther Drug Monit. 2002;24(4):457-470.
Zador D Sunjic S. Deaths in methadone maintenance treatment in New
South Wales, Australia 1990-1995. Addiction. 2000;95(1):77-84.