have been increasing reports of methadone-associated mortality in
the United States over the course of the past five years. It is
understood that the majority of these deaths are the result of physicians
prescribing such medication to treat chronic pain in their private
medical practices and/or the illicit trafficking of methadone hydrochloride
products outside of the OTP setting. There have also been reports
of methadone-associated mortality of patients in the OTPs during
the induction period. This has been referenced in the SAMHSA/CSAT
TIP 43, Medication Assisted Treatment for Opioid Addiction
in Opioid Treatment Programs, as well as CSATs July
20, 2007 Guidelines for the Accreditation of Opioid Treatment
Programs, and Dr. Clarks September 4, 2007 Dear
Colleague letter to the field.
methadone overdose deaths have occurred in the first few days of
treatment, it is important to adjust methadone dosage carefully
until stabilization and tolerance are established. (TIP 43)
43 also provides a reference with regard to induction assessment,
underscoring the fact that
induction is the riskiest
stage of medication-assisted treatment and proper medical assessment
during induction requires an understanding of the pharmacology of
treatment medication. Although members of the clinical team may
collect dose response data, only the physician is authorized to
write a medical order for methadone ( Clark letter 9/4/07).
Patients should be assessed at least daily during induction for
signs of overmedication or undermedication, and dose adjustments
should be made accordingly. CSAT provides additional guidance
in their 2007 OTP Accreditation Guidelines The program physician
must diagnose addiction or dependence, documenting that diagnosis,
and admit patients to maintenance or detoxification as medically
necessary. AATOD concurs with these judicious recommendations.
again, TIP 43 provides the most comprehensive reference in providing
guidance to OTPs during the induction phase.
patients actively abusing opioids, a typical first dose of methadone
is 20-30mg and it is limited by regulations to no more than 30mg.
If withdrawal symptoms persist after 2-4 hours, the initial dose
could be supplemented with another 5-10mg. The total first day dose
of methadone allowed by federal regulations is 40mg unless a program
physician documents in the patient record that 40mg is insufficient
to suppress opioid withdrawal symptoms.
is understood that patients will vary in their individual response
to optimal dosing during the induction period. Only the presence
of withdrawal confirms the diagnosis of dependence. The severity
of withdrawal does not indicate the level of tolerance. All clinicians
in the OTP setting, from the medical director to dispensing personnel,
should be vigilant in observing the patient and documenting his
/her response to daily dosing during the first month of care or
until the patient stabilizes following the induction period. Once
again, TIP 43 makes reference to this point.
differences in patient response to methadone can be explained by
variations in individual rates of absorption, digestion, and excretion
of the drug, which in turn are caused by such factors as body weight
and size, other substance use, diet, co-occurring disorders and
medical diseases, and genetic factors. Because variation in response
to methadone is considerable, the consensus panel believes that
the notion of a uniform dosage range or an upper dosage limit for
all patients is unsupported scientifically.
American Association for the Treatment of Opioid Dependence recommends
that all OTPs treat each individual patient with care, responding
to the unique needs of such patients during the induction phase,
taking such differences into account, as noted above. Standardized
dosage induction protocols do not take the individual patient response
into proper account. Accordingly, dose levels must be done on an
individual basis; there is no substitution for individualized care.
issue is stressed in the Dosage Determination section
of TIP 43 in Chapter 5, Clinical Pharmacology.
is critical to successful patient management in MAT to determine
a medication dosage that will minimize withdrawal symptoms and craving
and decrease or eliminate opioid abuse. Dosage requirements for
methadone, LAAM (sic), and buprenorphine must be determined on an
individual basis. There is no single recommended dosage or even
a fixed range of dosages for all patients. For many patients, the
therapeutic dosage range of methadone may be in the neighborhood
of 80 to 120 mg per day, but it can be much higher, and occasionally
it is much lower.
TIP goes on to make the following statement with regard to dosage
determination and stability.
evidence supports the use of daily methadone doses in the range
of 80mg or more for most patients, but considerable variability
exists in patient responses. Some do well on dosages below 80-120mg
per day, and others require significantly higher dosages. OTPs should
exercise additional caution with higher dosages, guarding against
diversion of take-home methadone to individuals who are opioid-intolerant
because higher dosages can be lethal for such individuals.
following recommendations are contained within TIP 43 and suggest
a series of important steps as the patient experiences dosage induction
within the OTP.
first dose of any opioid treatment medication should be lower if
the patients opioid tolerance is believed to be low, the history
of opioid use is uncertain or no signs of opioid withdrawal are
evident. Some former patients, who have been released from incarceration
or are pregnant and are being readmitted because they have a history
of addiction, might have lost their tolerance. Loss of tolerance
should be considered for any patient who has abstained from opioids
for more than five days. In general, the safety principle start
low and go slow applies to early medication dosages in an
outpatient OTP. The amount of opioid abuse estimated by patients
usually gives only a rough idea of their tolerance. It should not
be used as a dosing guide for induction, nor should initial dosages
be determined by previous treatment episodes or patient estimates
on dollars spent per day on opioids.
adjustments in the first week of treatment should be based on how
patients feel at their peak period for their medication (e.g. 2-4
hours after a dose of methadone is administered), not on how long
the effect of a medication lasts. As stores of medication accumulate
in body tissues, the effects begin to last longer.
is also useful to excerpt the section of TIP 43, which references
the steady state of medication during the dosage induction period
within the OTP.
dosing should be followed by dosage increases over subsequent days
until withdrawal symptoms are suppressed at the peak of action for
[D]uring induction, even without dosage increases,
each successive dose adds to what is present already in tissues
until steady state is reached. Steady state refers to the condition
in which the level of medication in a patients blood remains
fairly steady because that drugs rate of intake equals the
rate of its breakdown and excretion.
state is based on multiples of the elimination half-life. Approximately
four to five half-life times are needed to establish a steady state
for most drugs. For example, because methadone has a half-life of
24 to 36 hours, its steady statethe time at which a relatively
constant blood level should remain present in the bodyis achieved
in 5 to 7.5 days after dosage change for most patients. However,
individuals may differ significantly in how long it takes to achieve
During induction, patients should be instructed
to judge their doses by how they feel during the peak period (the
point of maximum concentration of medication in the blood [for methadone,
2 to 4 hours after taking a dose]), rather than during the trough
period (the low point of medication concentration in blood just
before the next dose [for methadone, approximately 24 hours after
ingestion]). Patients who wake up sick during the first few days
of opioid pharmacotherapy might become convinced that they need
a dose increase, when in fact they need more time for tissue stores
to reach steady state. In contrast, patients who wake up sick after
the first week of treatmentwhen tissue stores have reached
steady-state levelsmight indeed need higher doses. During
the induction phase, caution should be exercised regarding overly
rapid increases in dosage because of the long half-life of methadone.
(CSAT Accreditation Guidelines 2007)
TIP 43 provides useful guidance as the patient stabilizes on methadone
and as the dosage induction period comes to an end.
methadone is administered daily in steady oral doses, its level
in blood should maintain a 24-hour asymptomatic state, without episodes
of overmedication or withdrawal. Methadones body clearance
rate varies considerably between individuals. The serum methadone
level (SML) and elimination half-life are influenced by several
factors, including pregnancy and patient absorption, metabolism
and protein binding, changes in urinary pH, common use of other
medications, diet, physical condition, age, and use of vitamins
and herbal products.
this advisory focuses on dosage-specific considerations for the
patient during the induction period, it is understood that the patient
should provide a complete medical history and receive a physical
examination prior to administration of the first dose to assure
patient safety during the induction period. Physicians should
be particularly aware of the potential QT-prolonging effects of
methadone especially with high doses. (CSAT Accreditation Guidelines
2007) Illustratively, cardiac-related issues, both personal
and familial, should be carefully evaluated and the appropriate
clinical determinations should be made, guiding the patient through
the dosage induction period.
summary, dosage induction represents the riskiest time for the patient
in treatment. Staff, who are involved in assessing and medicating
a patient during the induction period should be vigilant and in
frequent contact with each other as a clinical team, safeguarding
the patients treatment.
recommendations in this advisory are also consistent with the course
content in the AATOD Course for Clinicians, which has
been offered to treatment providers since 1994.