Introduction
There 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 CSAT’s July 20, 2007 “Guidelines for the Accreditation of Opioid Treatment Programs”, and Dr. Clark’s September 4, 2007 “Dear Colleague” letter to the field.

“Because 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)

TIP 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.

Initial Dosing
Once again, TIP 43 provides the most comprehensive reference in providing guidance to OTPs during the induction phase.

“For 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.”

It 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.

“Most 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.”

The 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.

This issue is stressed in the “Dosage Determination” section of TIP 43 in Chapter 5, “Clinical Pharmacology.”

“It 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.”

The TIP goes on to make the following statement with regard to dosage determination and stability.

“Strong 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.”

The following recommendations are contained within TIP 43 and suggest a series of important steps as the patient experiences dosage induction within the OTP.

“The first dose of any opioid treatment medication should be lower if the patient’s 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.

Dosage 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.”

It 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.

“Initial dosing should be followed by dosage increases over subsequent days until withdrawal symptoms are suppressed at the peak of action for the medication…[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 patient’s blood remains fairly steady because that drug’s rate of intake equals the rate of its breakdown and excretion.

Steady 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 state—the time at which a relatively constant blood level should remain present in the body—is 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 steady state…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 treatment—when tissue stores have reached steady-state levels—might 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)

Finally, TIP 43 provides useful guidance as the patient stabilizes on methadone and as the dosage induction period comes to an end.

“When 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. Methadone’s 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.”

While 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.

In 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 patient’s treatment.

The 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.