2.1 Important General Information
The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect.The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect.
A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.
With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
Methadone has a narrow therapeutic index, especially when combined with other drugs.Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain
Methadone should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Consider the following important factors that differentiate methadone from other opioid analgesics:
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours.The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours.
Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [seeWarnings and Precautions (5.1)] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with methadone [seeWarnings and Precautions (5.2)] .
: Initiate treatment with methadone with 2.5 mg orally every 8 to 12 hours. Use of Methadone as the First Opioid Analgesic
: Discontinue all other around-the-clock opioid drugs when methadone therapy is initiated. Conversion from Other Oral Opioids to MethadoneDeaths have occurred in opioid-tolerant patients during conversion to methadone.
While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.
Consider the following when using the information in Table 1:
This is a table of equianalgesic doses. notThis is a table of equianalgesic doses. not
The conversion factors in this table are only for the conversion another oral opioid analgesic methadone. fromtoThe conversion factors in this table are only for the conversion another oral opioid analgesic methadone. fromto
The table be used to convert methadone another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. cannotfromtoThe table be used to convert methadone another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. cannotfromto
Table 1: Conversion Factors to Methadone
Total Daily Baseline Total Daily Baseline Oral
Morphine Equivalent Dose
Estimated Daily Estimated Daily Methadone Requirement Oral
as Percent of Total Daily Morphine Equivalent Dose
< 100 mg< 100 mg
20% to 30%20% to 30%
100 to 300 mg100 to 300 mg
10% to 20%10% to 20%
300 to 600 mg300 to 600 mg
8% to 12%8% to 12%
600 mg to 1000 mg600 mg to 1000 mg
5% to 10%5% to 10%
> 1000 mg> 1000 mg
< 5 %< 5 %
: To calculate the estimated methadone dose using Table 1
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone strength(s) available.
: Example conversion from a single opioid to methadone
: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) Step 1
50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine
: Calculate the approximate equivalent dose of Methadone Hydrochloride Oral Solution USP based on the total daily dose of Morphine using Table 1. Step 2: Calculate the approximate equivalent dose of Methadone Hydrochloride Oral Solution USP based on the total daily dose of Morphine using Table 1. Step 2
100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadone Hydrochloride Oral Solution USP daily100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadone Hydrochloride Oral Solution USP daily
: Calculate the approximate starting dose of Methadone Hydrochloride Oral Solution USP to be given every 12 hours. Round down, if necessary, to the appropriate methadone tablets strengths available. Step 3: Calculate the approximate starting dose of Methadone Hydrochloride Oral Solution USP to be given every 12 hours. Round down, if necessary, to the appropriate methadone tablets strengths available. Step 3
15 mg daily / 2 = 7.5 mg Methadone Hydrochloride Oral Solution USP every 12 hours15 mg daily / 2 = 7.5 mg Methadone Hydrochloride Oral Solution USP every 12 hours
Then 7.5 mg is rounded down to 5 mg Methadone Hydrochloride Oral Solution USP every 12 hoursThen 7.5 mg is rounded down to 5 mg Methadone Hydrochloride Oral Solution USP every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Methadone Hydrochloride Oral Solution USP.
: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone). Conversion from Parenteral Methadone to Methadone Hydrochloride Oral Solution USP
2.3 Titration and Maintenance of Therapy for Pain
Individually titrate methadone to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.
Because steady-state plasma concentrations are approximated within 24 to 36 hours, methadone dosage adjustments may be done every 1 to 2 days.
Patients who experience breakthrough pain may require a dose increase of methadone, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone dose.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.4 Discontinuation of Methadone for Pain
When a patient no longer requires therapy with methadone for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone.
2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction
For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.
Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.
To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear.
The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.
Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.
For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. Short-Term Detoxification:
2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification
Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.
2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction
There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction
Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms . Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients. [see ] Drug Abuse and Dependence (9.3)
2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment
Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.
2.10 Dosage Adjustment During Pregnancy
Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see ]. Use in Specific Populations (8.1)