Your activity: 161 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

Methadone: Drug information

Methadone: Drug information
(For additional information see "Methadone: Patient drug information" and see "Methadone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Addiction, abuse, and misuse:

Methadone is an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit. Methadone exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing methadone, and monitor all patients regularly for the development of these behaviors and conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. The peak respiratory depressant effect of methadone occurs later and persists longer than the peak analgesic effect, especially during the initial dosing period. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase.

Life-threatening QT prolongation:

QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone.

Accidental ingestion (oral formulations):

Accidental ingestion of even one dose of methadone, especially by children, can result in a fatal overdose of methadone.

Neonatal opioid withdrawal syndrome:

Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or addiction. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur.

Conditions for distribution and use of methadone products for the 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, including limitations on unsupervised administration.

Cytochrome P450 interaction:

The concomitant use of methadone with all cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used CYP450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing.

Risk of medication errors (1 mg/mL and 2 mg/mL oral solution)

Ensure accuracy when prescribing, dispensing, and administering methadone oral solution. Dosing errors due to confusion between mg and mL, and other methadone oral solutions of different concentrations can result in accidental overdose and death.

Brand Names: US
  • Dolophine [DSC];
  • Methadone HCl Intensol;
  • Methadose;
  • Methadose Sugar-Free
Brand Names: Canada
  • JAMP Methadone;
  • Metadol;
  • Metadol-D;
  • Methadose;
  • ODAN-Methadone;
  • ODAN-Methadone Dye Free
Pharmacologic Category
  • Analgesic, Opioid
Dosing: Adult

Note: Individualize dosing regimen based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals. Methadone has high interpatient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated dosing, resulting in increased methadone potency. Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements. Deaths have occurred during conversion from chronic high-dose treatment with other opioids and in patients with a history of opioid use disorder. Special attention is required during treatment initiation, during conversion from one opioid to another, and during dose titration. Steady-state plasma concentrations and full analgesic effects are not attained until at least 3 to 5 days on a dose and methadone has a narrow therapeutic index, especially when combined with other drugs.

Opioid use disorder, maintenance treatment

Opioid use disorder, maintenance treatment: Note: Diskets can be administered only in 10 mg increments; may not be appropriate product for initial dosing or dose reductions. In patients with pain, temporarily increasing the dose or dosing frequency (eg, divide total daily dose over 3 to 4 times per day) may maximize the analgesic properties for pain management (ASAM 2020). IV route is for use only in patients unable to take oral medication (such as during hospitalization). For IV dosing, convert patient's oral methadone dose to an equivalent parenteral dose using the conversions provided in "Pain, chronic."

Initial:

Patients with no or low tolerance at initiation (eg, absence of opioids ≥5 days, do not take opioids daily, use of weaker opioids [eg, codeine]): Oral: 2.5 to 10 mg (as a single dose) (ASAM 2020; SAMHSA 2021).

Patients engaging in problem drinking, those with lower levels of opioid tolerance or individuals with medical conditions that may cause hypoxia, hypercapnia or cardiac arrhythmias (eg, asthma, chronic obstructive pulmonary disease, cor pulmonale, electrolyte abnormalities, family history of cardiac arrhythmias, dizziness or fainting or sudden death, kyphoscoliosis, obesity, QTc prolongation, sleep apnea): Oral: 10 to 20 mg (as a single dose) (SAMHSA 2021).

Patients with no signs of sedation or intoxication but with symptoms of withdrawal: Oral: 20 to 30 mg (as a single dose); maximum initial dose: 30 mg.

Note: Regardless of initial dose, observe patients for over-sedation and withdrawal symptoms for 2 to 4 hours after initial dose (ASAM 2020; SAMHSA 2021); an additional 5 to 10 mg orally may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear after 2 to 4 hours; total daily dose on the first day should not exceed 40 mg.

Maintenance: Oral: Titrate cautiously to a dosage which prevents opioid withdrawal symptoms for 24 hours, prevents craving, attenuates euphoric effect of self-administered opioids, and tolerance to sedative effects of methadone. Some experts recommend increasing by no more than 10 mg every 5 days. Slower titrations such as 5 mg every week should be considered in patients with no or low tolerance at initiation (eg, absence of opioids ≥5 days, do not take opioids daily, use of weaker opioids [eg, codeine]) (ASAM 2020; SAMHSA 2021). If a patient experiences sedation 2 to 4 hours after their last dose and craving or withdrawal prior to the next dose, consider dividing the daily dose into twice daily dosing. If patient experiences relief from withdrawal 4 to 12 hours after their last dose, maintain this dose for a few days so methadone can reach steady state (SAMHSA 2021). Levels will accumulate over the first few days; deaths have occurred in early treatment due to cumulative effects. Usual range: 60 to 120 mg/day (ASAM 2020).

Missed dose: In patients who miss >4 doses, consider restarting at the initial dose or decrease the next dose substantially and gradually re-titrate (SAMHSA 2021).

Switching therapies:

Methadone to buprenorphine: Taper the methadone dose gradually to 30 to 40 mg and remain on that dose for ≥7 days. Discontinue methadone at least 24 hours before the first dose of buprenorphine; the patient should be in mild withdrawal before starting buprenorphine, which is typically 24 to 48 hours after the last dose of methadone. Initiating buprenorphine at lower doses (eg, 2 mg) decreases risk of precipitated methadone withdrawal (ASAM 2020; SAMHSA 2021).

Methadone to naltrexone: Taper the methadone dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone (ASAM 2020).

Naltrexone to methadone: Begin methadone ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (ASAM 2020).

Discontinuation of therapy: When discontinuing methadone for long-term treatment of opioid use disorder, reduce dose gradually by 5% to 10% every 1 to 2 weeks. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both. In some cases, patients who experience cravings at low doses (20 to 40 mg) may choose to switch to buprenorphine to complete discontinuation or to naltrexone for maintenance treatment (SAMHSA 2021).

Opioid withdrawal, short-term medically supervised

Opioid withdrawal, short-term medically supervised:

Note: Maintenance treatment with methadone is associated with better outcomes than short-term medically supervised withdrawal. Reserve medically supervised withdrawal for patients who do not wish to undergo maintenance treatment or who will be transitioning to maintenance treatment with naltrexone (SAMHSA 2021).

Initial: Oral: Titrate to ~40 mg/day in divided doses to achieve stabilization.

Maintenance: Oral: May continue 40 mg/day dose for 2 to 3 days.

Discontinuation of therapy: After 2 to 3 days at a stable dose, gradually decrease the dose on a daily basis or at 2-day intervals. Keep dose at a level sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a total daily dose decrease of 20%; ambulatory patients may require a slower reduction.

Pain, chronic

Pain, chronic:

Note: When used for managing moderate to severe pain, opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (CDC [Dowell 2016]).

Opioid-naive patients:

Initial:

Oral: 2.5 to 5 mg every 8 to 12 hours.

IM, IV, SUBQ: Note: For use only in patients unable to take oral medication (such as during hospitalization). 2.5 to 10 mg every 8 to 12 hours.

Titration and maintenance: May increase dose by 2.5 mg per dose no more often than every 5 to 7 days (gradual titration) or by 2.5 to 5 mg per dose every 3 days (faster titration in monitored setting). Once a stable dose is reached, the dosing interval may be extended to every 8 to 12 hours or longer (VA/DoD 2017). Because of high interpatient variability, substantially longer periods between dose increases may be necessary in some patients (up to 12 days). If unacceptable adverse reactions are observed, reduce dose and/or dosing interval (ie, every 8 to 12 hours). Breakthrough pain may require a dose increase or rescue medication with an IR analgesic. Some guidelines note that dose increases should not be >10 mg per day every 5 to 7 days (Chou 2014).

Opioid-tolerant patients:

Conversion from oral morphine to oral methadone: 1) There is not a linear relationship when converting to methadone from oral morphine. The higher the daily morphine-equivalent dose the more potent methadone is, and 2) conversion to methadone is more of a process than a calculation. In general, the starting methadone dose should not exceed 30 to 40 mg/day, even in patients on high doses of other opioids. Patient response to methadone needs to be monitored closely throughout the process of the conversion. There are several proposed ratios for converting from oral morphine to oral methadone (Ayonrinde 2000; Mercadente 2001; Ripamonti 1998). The estimated total daily methadone dose should then be divided to reflect the intended dosing schedule (eg, divide by 3 and administer every 8 hours). Patients who have not taken an opioid for 1 to 2 weeks should be considered opioid naive (Chou 2014).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Discontinue all other around-the-clock opioids when methadone therapy is initiated; fatalities have occurred in opioid-tolerant patients during conversion to methadone. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily methadone requirement and provide breakthrough pain relief with rescue medication (eg, IR opioid) than to overestimate requirements. Patient response to methadone needs to be monitored closely throughout the process of the conversion. For patients on a single opioid, sum the current total daily dose of oral opioid, convert it to a morphine-equivalent dose according to conversion factor for that specific opioid, then multiply the morphine equivalent dose by the corresponding percentage to calculate the approximate oral methadone daily dose. Divide total daily methadone dose by intended dosing schedule (ie, divide by 3 for administration every 8 hours). Round down, if necessary, to the nearest strength available. 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, and divide the total daily methadone dose by the intended dosing schedule (ie, divide by 3 for administration every 8 hours). For patients on a regimen of fixed-ratio opioid/nonopioid analgesic medications, only the opioid component of these medications should be used in the conversion. Note: Conversion factors listed below are only for the conversion from another opioid analgesic to methadone and cannot be used to convert from methadone to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This does not provide equianalgesic doses.

Critically ill patients in the ICU (analgesia and sedation) (alternative agent) (off-label use):

Note: May be used to slow development of tolerance when escalation with other opioids is required or to help wean prolonged continuous opioid infusions. Unpredictable pharmacokinetics/pharmacodynamics in opioid-naive patients. Monitor adverse effects (eg, QTc) and drug-drug interactions (Al-Qadheeb 2012; Elefritz 2016; SCCM [Barr 2013]; Wanzuita 2012).

Oral: 10 to 40 mg every 6 to 12 hours (SCCM [Barr 2013]).

IV: 2.5 to 10 mg every 8 to 12 hours (SCCM [Barr 2013]).

Note: When used to wean prolonged continuous opioid infusions, titrate no more than every 3 to 5 days and wean continuous opioid infusion to off as tolerated; once continuous opioid infusion is weaned off, methadone can be tapered down by 10% to 25% every 2 to 3 days; discontinue methadone once daily doses of 10 to 15 mg are reached (Elefritz 2016).

Conversion from oral opioids to oral methadone:

Oral Morphine to Oral Methadone Conversion Factors

Total daily baseline oral morphine dose

Estimated daily oral methadone requirement as percent of total daily morphine dose

<100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 to 1,000 mg

5% to 10%

>1,000 mg

<5%

Conversion from oral morphine to parenteral methadone:

Switching a patient from another chronically administered opioid to methadone requires caution because of the uncertainty of dose conversion ratios and incomplete cross-tolerance. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

Conversion ratios in many commonly used equianalgesic dosing tables do not apply for repeated methadone dosing. Although the onset and duration of analgesic action and the analgesic potency of methadone and morphine are similar with single-dose administration, methadone's potency increases over time with repeated dosing. Furthermore, the conversion ratio between methadone and other opiates varies dramatically, depending on baseline opiate (morphine equivalent) use.

Oral Morphine to IV Methadone Conversion for Chronic Administration

Total daily baseline oral morphine dose

Estimated daily IV methadone as percent of total daily oral morphine dosea

a The total daily methadone dose derived from the previous table may then be divided to reflect the intended dosing schedule (ie, for administration every 8 hours, divide total daily methadone dose by 3).

<100 mg

10% to 15%

100 to 300 mg

5% to 10%

300 to 600 mg

4% to 6%

600 to 1,000 mg

3% to 5%

>1,000 mg

<3%

Conversion from parenteral morphine to parenteral methadone:

Parenteral Morphine to IV Methadone Conversion for Chronic Administrationa

Total daily baseline parenteral morphine dose

Estimated daily parenteral methadone requirement as percent of total daily morphine doseb

a Derived from previous table assuming a 3:1 oral:parenteral morphine ratio.

b The total daily methadone dose derived from the previous table may then be divided to reflect the intended dosing schedule (ie, for administration every 8 hours, divide total daily methadone dose by 3).

10 to 30 mg

40% to 66%

30 to 50 mg

27% to 66%

50 to 100 mg

22% to 50%

100 to 200 mg

15% to 34%

200 to 500 mg

10% to 20%

Note: Equianalgesic methadone dosing varies among patients and within a single patient, depending on baseline morphine (or other opioid) dose. The conversion tables have been included in order to illustrate this concept and to provide a safe starting point for opioid conversion. Methadone dosing should not be based solely on these tables. Methadone conversion and dose-titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use.

Conversion from IV methadone to oral methadone:

Initial dose: IV to Oral ratio: Although the 1:2 (IV methadone to oral methadone) ratio is recommended by the manufacturer, consider using the more conservative ratio of 1:1.3 (IV methadone to oral methadone), especially in patients at risk of somnolence and/or respiratory depression (Liu 2021; manufacturer’s labeling). Example of 1:1.3 ratio (IV to oral): 8 mg of IV methadone equals ~10 mg of oral methadone.

Conversion from oral methadone to IV methadone:

Initial dose: Oral to IV ratio: No direct conversion or equivalency exists. Alternatives to conversion to IV methadone include conversion to a different oral or IV opioid (at an equivalent dose) or consider converting oral methadone to IV methadone using a conservative conversion ratio of 2:1 (oral methadone:IV methadone); monitor closely for adequate pain relief and adverse effects (McPherson 2019). Example: 10 mg of oral methadone equals 5 mg of IV methadone.

Discontinuation of therapy: When discontinuing or tapering chronic opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of chronic therapy) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Individualize based on discussions with patient to minimize withdrawal while considering patient-specific goals and concerns as well as the opioid’s pharmacokinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects (CDC [Dowell 2016]). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Methadone concentrations are not substantially altered in patients with kidney impairment (Kreek 1980); however, patients with advanced chronic kidney disease are more likely to have multiple comorbidities, a prolonged QT interval, and take sodium bicarbonate supplements (alkalinization of the urine can prolong methadone excretion [Nilsson 1982]) and other concomitant therapies increasing the risk of drug-drug interactions; close monitoring by a pain or addiction specialist is warranted in these patients (expert opinion).

Note: Parenteral administration is for use only in patients unable to take oral medication (such as during hospitalization).

Altered kidney function: Oral, parenteral:

CrCl ≥30 mL/minute: No dosage adjustment necessary (Aronoff 2007; Kreek 1980; expert opinion).

CrCl >10 to <30 mL/minute: Initial: No dosage adjustment necessary; use with caution and consider more gradual dose titration (Aronoff 2007; Kreek 1980; expert opinion).

CrCl ≤10 mL/minute: Initial: Administer 50% to 75% of the usual indication-specific dose; use with caution; titrate gradually (Aronoff 2007; expert opinion).

Hemodialysis, intermittent (thrice weekly): Not significantly removed by hemodialysis (~2% to 15% removal) (Furlan 1999; Opdal 2015; Perlman 2013):

Oral, parenteral: Initial: Administer 50% to 75% of the usual indication-specific dose; titrate gradually. Supplemental post-hemodialysis dosing is not necessary (Furlan 1999).

Peritoneal dialysis: Not significantly removed (Kreek 1980):

Oral, parenteral: Initial: Administer 50% to 75% of the usual indication-specific dose; titrate gradually (expert opinion).

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Close monitoring of response and adverse reactions (eg, CNS and respiratory depression) due to drug accumulation is important.

Oral, parenteral: Use of alternative agents may be preferred, particularly in methadone-naive patients, since use of methadone in patients on CRRT has not been evaluated; however, if use of methadone is deemed necessary, a dose reduction (eg, administer 50% to 75% of the usual indication-specific dose) should be considered in patients initiating and established on methadone therapy, based on patient's clinical condition and comorbidities. Titrate based on tolerance and response (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions (eg, CNS and respiratory depression) due to drug accumulation is important.

Oral, parenteral: Use of alternative agents may be preferred, particularly in methadone-naive patients, since use of methadone in patients on PIRRT has not been evaluated; however, if use of methadone is deemed necessary, a dose reduction (eg, administer 50% to 75% of the usual indication-specific dose) should be considered in patients initiating and established on methadone therapy, based on patient's clinical condition and comorbidities Titrate based on tolerance and response (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, undergoes hepatic metabolism and systemic exposure may be increased after repeated dosing. Initiate at lower doses and titrate slowly; monitor closely for respiratory and CNS depression.

Dosing: Pediatric

(For additional information see "Methadone: Pediatric drug information")

Pain, severe

Pain, severe: Limited data available: Note: Doses should be titrated to effect, the potency of methadone varies according to patient’s current exposure to opioids (APS 2016); use lower doses in opioid naïve patients. Methadone has high interpatient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated dosing, resulting in increased methadone potency. Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements. Methadone may accumulate due to its long half life; if sedation occurs, withhold doses until sedation resolves and consider reduction in dose and/or increasing the dosing interval (eg, every 8 to 12 hours).

Infants ≤6 months, nonventilated (Berde 2002):

IV, SubQ: 0.025 mg/kg/dose every 4 to 8 hours

Oral: 0.025 to 0.05 mg/kg/dose every 4 to 8 hours

Infants >6 months, Children, and Adolescents, nonventilated (Berde 2002):

IV, SubQ:

Patient weight <50 kg: 0.1 mg/kg/dose every 4 to 8 hours

Patient weight ≥50 kg: 5 to 8 mg every 4 to 8 hours

Oral:

Patient weight <50 kg: 0.1 to 0.2 mg/kg/dose every 4 to 8 hours

Patient weight ≥50 kg: 5 to 10 mg every 4 to 8 hours

Iatrogenic opioid dependency

Iatrogenic opioid dependency: Limited data available, optimal regimen not defined. Methadone dose and taper schedule must be individualized and will depend upon patient's previous opioid dose, length of time on opioids, and severity of opioid withdrawal.

Prevention: Children and Adolescents: Several reports have been published, varying in conversion equivalence factors, when to convert to oral, and how long the taper should be, none of which have been proven to be superior to another; follow institutional protocols as appropriate. Patients receiving opioids for >14 days are more likely to experience opioid withdrawal and usually require opioid doses to be weaned, which may require transition to methadone. Once methadone dose is stabilized, a weaning schedule of ~10% to 20% reduction of the original dose every 24 to 48 hours has been recommended (AAP [Galinkin 2014]).

Treatment: Infants and Children: Oral: Initial: 0.05 to 0.1 mg/kg/dose every 6 hours; increase by 0.05 mg/kg/dose until withdrawal symptoms are controlled; after 24 to 48 hours, the dosing interval can be lengthened to every 12 to 24 hours; to taper dose, wean as tolerated until a dose of 0.05 mg/kg/day, then discontinue (Anand 1994)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; initiate at lower doses and titrate slowly; monitor closely for respiratory and CNS depression.

Infants, Children, and Adolescents: Specific pediatric data is lacking; the following dosage adjustments have been recommended: Oral, IV:

GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR 30 to 50 mL/minute/1.73 m2: Based on pharmacokinetic data and experience with adult patients in renal failure, most suggest no adjustment necessary (Dean 2004; Golightly 2013); however, in patients receiving doses every 4 hours, an increased dosing interval (eg, every 6 to 8 hours) should be considered (Aronoff 2007)

GFR 10 to 29 mL/minute/1.73 m2: Based on pharmacokinetic data and experience with adult patients in renal failure, most suggest no adjustment necessary (Dean 2004; Golightly 2013); however, in patients receiving doses every 4 or 6 hours, an increased dosing interval (eg, every 8 to 12 hours) should be considered (Aronoff 2007)

GFR <10 mL/minute/1.73 m2: Reduce dosing interval; administration every 12 to 24 hours has been suggested (Aronoff 2007)

Intermittent hemodialysis: Does not increase the elimination of methadone; reduce dosing interval; administration every 12 to 24 hours has been suggested (Aronoff 2007)

Peritoneal dialysis (PD): Does not increase the elimination of methadone; reduce dosing interval; administration every 12 to 24 hours has been suggested (Aronoff 2007)

Continuous renal replacement therapy (CRRT): Administer every 8 to 12 hours, titrate to effect; after 4 to 5 doses extend the interval to every 8 to 24 hours (Aronoff 2007)

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; however, methadone undergoes hepatic metabolism and systemic exposure may be increased after repeated dosing. Initiate at lower doses and titrate slowly; monitor closely for respiratory and CNS depression.

Dosing: Older Adult

Refer to adult dosing. Use with caution; initiate at the low end of dosage range and titrate slowly. For treatment of opioid use disorder, a lower initial oral dose of 10 to 20 mg has been recommended for patients >60 years of age (SAMHSA 2021).

Dosing: Adjustment for Toxicity: Adult

Excessive opioid-related adverse events: Reduce next dose. Assess and reduce both the maintenance dose and dosing interval if necessary. Some guidelines recommend holding the dose if there is evidence of sedation (Chou 2014).

QTc prolongation (Chou 2014):

QTc >450 to 499 msec: Discuss potential risks and benefits. Evaluate and correct potential causes of QTc interval prolongation prior to initiating therapy. Consider alternative therapies or reduced methadone dose if QTc interval becomes ≥450 to 499 msec during treatment.

QTc ≥500 msec: Alternative therapies for opioid use disorder or chronic pain are recommended. If QTc ≥500 msec occurs during therapy, switch to an alternative therapy or immediately decrease the dose of methadone; correct any reversible causes of QTc interval prolongation and repeat ECG.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Concentrate, Oral, as hydrochloride:

Methadone HCl Intensol: 10 mg/mL (30 mL) [unflavored flavor]

Methadose: 10 mg/mL (1000 mL) [contains fd&c red #40 (allura red ac dye), methylparaben, propylene glycol, propylparaben; cherry flavor]

Methadose Sugar-Free: 10 mg/mL (1000 mL) [dye free, sugar free; unflavored flavor]

Generic: 10 mg/mL (30 mL, 1000 mL)

Solution, Injection, as hydrochloride:

Generic: 10 mg/mL (20 mL)

Solution, Oral, as hydrochloride:

Generic: 5 mg/5 mL (5 mL, 500 mL); 10 mg/5 mL (500 mL)

Tablet, Oral, as hydrochloride:

Dolophine: 5 mg [DSC], 10 mg [DSC]

Generic: 5 mg, 10 mg

Tablet Soluble, Oral, as hydrochloride:

Methadose: 40 mg [scored; contains fd&c yellow #5 (tartrazine)aluminum lake, fd&c yellow #6 (sunset yellow), fd&c yellow #6(sunset yellow)alumin lake]

Generic: 40 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Concentrate, Oral, as hydrochloride:

Metadol: 10 mg/mL (100 mL) [contains propylene glycol, sodium benzoate]

Metadol-D: 10 mg/mL (100 mL) [contains propylene glycol, sodium benzoate]

Methadose: 10 mg/mL (1000 mL)

Generic: 10 mg/mL (1000 mL)

Solution, Oral, as hydrochloride:

Metadol: 5 mg/5 mL (250 mL) [contains methylparaben, polyethylene glycol (macrogol), sodium benzoate]

Metadol-D: 1 mg/mL (100 mL, 250 mL) [contains methylparaben, polyethylene glycol (macrogol), sodium benzoate]

Tablet, Oral:

Metadol: 1 mg [contains fd&c blue #1 (brill blue) aluminum lake]

Metadol: 25 mg

Tablet, Oral, as hydrochloride:

Metadol: 5 mg [contains fd&c yellow #6(sunset yellow)alumin lake]

Metadol: 10 mg [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Controlled Substance

C-II

Prescribing and Access Restrictions

When used for treatment of opioid addiction: May only be dispensed in accordance to guidelines established by the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Center for Substance Abuse Treatment (CSAT). Regulations regarding methadone use may vary by state and/or country. Obtain advice from appropriate regulatory agencies and/or consult with pain management/palliative care specialists.

Note: Regulatory Exceptions to the General Requirement to Provide Opioid Agonist Treatment (per manufacturer's labeling):

1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction, to facilitate the treatment of the primary admitting diagnosis.

2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Dolophine tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/006134s050lbl.pdf#page=36

Administration: Adult

Oral: Tablets for oral suspension: For oral administration only; do not inject (contains insoluble excipients). Disperse tablet in ~120 mL of water, orange juice, or other acidic fruit beverage prior to administration; if insoluble excipients remain and do not entirely dissolve, add a small amount of liquid to cup and administer remaining mixture. Do not chew or swallow tablet before dispersing in liquid.

Injection: Administer IM, SUBQ, or IV; rate of IV administration not defined. Absorption of SUBQ and IM appears to be unpredictable. Local tissue reactions may occur.

Administration: Pediatric

Oral:

Oral solution (1 mg/mL): Administer using an accurate measuring device (calibrated oral syringe).

Dispersible tablet: Oral dose for detoxification and maintenance may be administered with juice or water; dispersible tablet should not be chewed or swallowed; completely dissolve before administration; if residue remains in cup after administration rinse with small amount of liquid and administer remaining mixture.

Parenteral: May be administered IM, IV, or SUBQ; rate of IV administration is not defined. The absorption of IM and SUBQ appears to be unpredictable. Local tissue reactions may occur.

Use: Labeled Indications

Opioid use disorder, maintenance treatment: Maintenance treatment of opioid use disorder, in conjunction with appropriate social and medical services.

Limitations of use: Injection: Not approved for outpatient treatment of opioid use disorder; only use in patients unable to take oral medication (eg, hospitalized patients).

Opioid withdrawal, short-term medically supervised: Short-term, medically supervised opioid withdrawal, in conjunction with appropriate social and medical services.

Limitations of use: Injection: Not approved for outpatient treatment of opioid use disorder; only use in patients unable to take oral medication (eg, hospitalized patients).

Pain, chronic:

Injection: Management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate.

Oral: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Dolophine is not indicated for use as an as-needed analgesic.

Medication Safety Issues
Sound-alike/look-alike issues:

Methadone may be confused with dexmethylphenidate, ketorolac, memantine, Mephyton, methylphenidate, Metadate CD, Metadate ER, metOLazone, morphine

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Bigeminy, bradycardia, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG abnormality (including inversion T wave on ECG and prolonged QT interval on ECG), edema, extrasystoles, flushing, hypotension, palpitations, phlebitis, shock, syncope, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia

Dermatologic: Diaphoresis, hemorrhagic urticaria (rare), pruritus, skin rash, urticaria

Endocrine & metabolic: Amenorrhea, antidiuretic effect, decreased libido, decreased plasma testosterone, hypoglycemia (dosage >40 mg/day [Flory 2016]), hypokalemia, hypomagnesemia, weight gain

Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, constipation, glossitis, nausea, vomiting, xerostomia

Genitourinary: Asthenospermia, decreased ejaculate volume, defective spermatogenesis (morphologic abnormalities), hypogonadism, male genital disease (reduced seminal vesicle secretions), prostatic disease (reduced prostate secretions), urinary hesitancy, urinary retention

Hematologic & oncologic: Thrombocytopenia (reversible, reported in patients with chronic hepatitis)

Local: Erythema at injection site (IV), pain at injection site (IV), swelling at injection site (IV)

Nervous system: Agitation, confusion, disorientation, dizziness, drug abuse, drug dependence, dysphoria, euphoria, hallucination, headache, insomnia, myasthenia, sedated state, seizure

Neuromuscular & skeletal: Amyotrophy, asthenia, bone fracture, osteoporosis

Ophthalmic: Nystagmus disorder, strabismus, visual disturbance

Respiratory: Pulmonary edema, respiratory depression

Postmarketing: Endocrine & metabolic: Increased serum prolactin (transient increase with chronic use) (Molitch 2008)

Contraindications

Hypersensitivity (eg, anaphylaxis) to methadone or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma (in the absence of resuscitative equipment or in an unmonitored setting); GI obstruction, including paralytic ileus (known or suspected).

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Contraindications may vary per product labeling; refer also to product labels: Diarrhea associated with pseudomembranous colitis or caused by poisoning until toxic material has been eliminated from the GI tract; concurrent use or use within 14 days of an MAOI; hypercarbia; obstructive airway; mild, intermittent, or short duration pain that can be managed with other pain medications; management of acute pain; patients naive to opioids; diseases/conditions affecting bowel transit (known or suspected); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); status asthmaticus; cor pulmonale; acute alcohol intoxication; delirium tremens; convulsive disorders; severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; breastfeeding, pregnancy and during labor/delivery

Warnings/Precautions

Concerns related to adverse effects:

• Accidental opioid overdose: Patients who had been treated with methadone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Patients should be aware that they may be more sensitive to lower doses of opioids after treatment with methadone is discontinued, after a missed dose, or near the end of the dosing interval.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Constipation: May cause constipation, which may be problematic in patients with unstable angina and patients post-myocardial infarction (MI). Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• QT prolongation: QT interval prolongation and serious arrhythmias (torsades de pointes) have occurred during treatment. QT interval prolongation and torsades de pointes may be more commonly associated with, but not limited to, higher dose treatment >200 mg/day. QT prolongation has been reported in patients with no prior cardiac history who have received high doses of methadone. Only initiate therapy in patients for whom anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias. Other agents should be used in patients with a baseline QTc interval ≥500 msec (Chou 2014). If methadone is continued in a patient who develops a QT interval ≥500 msec, consider decreasing the dose, discontinuing other medications that prolong the QT interval, or eliminating other risk factors (ASAM 2020).

• Respiratory depression: Respiratory depression, including fatal cases, has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Avoid use in patients with obstruction.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, because these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, suicidal tendencies, anxiety disorders, posttraumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2016]). Methadone is ineffective for the relief of anxiety.

• Obesity: Use with caution in patients who are morbidly obese.

• Opioid use disorder: When used for detoxification and maintenance of opioid addiction, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration. Regulatory exceptions to the general requirements for certification to provide opioid agonist treatment include inpatient treatment of other conditions and emergency period (not >3 days) while definitive substance use disorder treatment is being sought.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Older adult: Use with caution in elderly patients; may be more sensitive to adverse effects. Decrease initial dose and monitor closely when initiating and titrating. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Tartrazine: Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions in certain individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: Methadone exposes patients and other users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Use with caution in patients with a history of substance use disorder; potential for opioid use disorder exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use.

• Appropriate use: For chronic pain (pain >3-month duration or beyond time of normal tissue healing), outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment, opioids should not be used as first-line therapy in outpatient settings in adults due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (CDC [Dowell 2016]). In patients taking methadone who have acute pain refractory to other treatments and require additional opioid-based analgesia, adding short-acting full agonist opioids may be considered; however, the dose required is anticipated to be higher than the typical dose in opioid-naive patients (ASAM 2020).

• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder with methadone; patients may continue treatment indefinitely as long as treatment is beneficial. Increased duration of therapy is associated with better treatment outcomes. Advise patients who are not yet stable of the potential to relapse to illicit drug use following discontinuation of methadone medication-based opioid use disorder treatment (SAMHSA 2021).

• Incomplete cross-tolerance: Use caution in converting patients from other opioids to methadone. Follow appropriate conversion schedules. Patients tolerant to other mu opioid agonists may not be tolerant to methadone and at risk for severe respiratory depression when converted to methadone.

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: In patients undergoing elective surgery (excluding caesarean section), consider discontinuation of methadone the day before or day of surgery. In patients unable to abruptly discontinue methadone prior to surgery, full opioid agonists may be added to the methadone to maintain proper analgesia. If opioid therapy is required as part of analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in in the conduct of the surgical or diagnostic procedure. The decision whether to discontinue methadone prior to elective surgery should be made in consultation with the surgeon and anesthesiologist. If discontinued, methadone can be resumed postoperatively when there is no longer a need for full opioid agonist therapy; in general, presurgery daily doses may be resume if held for <2 to 3 days (ASAM 2020).

• Switching formulations: Use caution with close monitoring if switching from one methadone formulation to another in patients with opioid use disorder; decreased efficacy, including withdrawal symptoms, has been reported; dose adjustments may be necessary (Health Canada 2020).

Metabolism/Transport Effects

Substrate of CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abacavir: Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the CNS depressant effect of Methadone. Risk X: Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amiodarone: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Aromatase Inhibitors: May increase the serum concentration of Methadone. Risk C: Monitor therapy

Atazanavir: Methadone may decrease the serum concentration of Atazanavir. Atazanavir may decrease the serum concentration of Methadone. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Benzodiazepines: May enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabidiol: May enhance the CNS depressant effect of Methadone. Cannabidiol may increase the serum concentration of Methadone. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Carbetocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ceritinib: May enhance the QTc-prolonging effect of Methadone. Ceritinib may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with ceritinib. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Risk D: Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Risk X: Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Risk X: Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

ClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Cobicistat: May increase the serum concentration of Methadone. Risk C: Monitor therapy

CYP2B6 Inducers (Moderate): May decrease the serum concentration of Methadone. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Methadone. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Methadone. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Methadone. Management: If coadministration with moderate CYP3A4 inhibitors is necessary, consider methadone dose reductions until stable effects are achieved. Monitor patients closely for respiratory depression and sedation. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Methadone. Management: If coadministration with strong CYP3A4 inhibitors is necessary, consider methadone dose reductions until stable effects are achieved. Monitor patients closely for respiratory depression and sedation. Risk D: Consider therapy modification

Dabrafenib: May enhance the QTc-prolonging effect of Methadone. Dabrafenib may decrease the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and reduced methadone efficacy. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

DAPTOmycin: Methadone may decrease the serum concentration of DAPTOmycin. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Darunavir: May decrease the serum concentration of Methadone. More specifically, the combination of Darunavir and Ritonavir may decrease Methadone serum concentrations. Risk C: Monitor therapy

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Didanosine: Methadone may decrease the serum concentration of Didanosine. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: Avoid combination

Doxepin-Containing Products: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Droperidol: May enhance the CNS depressant effect of Methadone. Droperidol may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives. If combined, dose reductions are recommended. Monitor for additive toxicities such as QTc interval prolongation, ventricular arrhythmias, and CNS depression. Patients with additional risk factors are at even higher risk. Risk D: Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Etelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Fexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Risk X: Avoid combination

FluvoxaMINE: Methadone may enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Methadone. Management: Monitor for increased methadone effects/toxicities if combined with fluvoxamine. Also monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if these agents are combined. Risk C: Monitor therapy

Fosamprenavir: May decrease the serum concentration of Methadone. Risk C: Monitor therapy

Fostemsavir: May enhance the QTc-prolonging effect of Methadone. Fostemsavir may increase the serum concentration of Methadone. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Gemifloxacin: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk Risk D: Consider therapy modification

Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Haloperidol: May enhance the CNS depressant effect of Methadone. Haloperidol may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation or those taking IV haloperidol may be at even higher risk. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Imipramine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Interferons (Alfa): May increase the serum concentration of Methadone. Risk C: Monitor therapy

Isavuconazonium Sulfate: May decrease the serum concentration of Methadone. Risk C: Monitor therapy

Itraconazole: May enhance the QTc-prolonging effect of Methadone. Itraconazole may increase the serum concentration of Methadone. Risk X: Avoid combination

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Methadone. Risk X: Avoid combination

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Lopinavir: May enhance the QTc-prolonging effect of Methadone. Lopinavir may decrease the serum concentration of Methadone. More specifically, the combination of Lopinavir and Ritonavir may decrease Methadone serum concentrations. Risk C: Monitor therapy

Lubiprostone: Methadone may diminish the therapeutic effect of Lubiprostone. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Meglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Mequitazine: Methadone may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to methadone or mequitazine when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: Methadone may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk X: Avoid combination

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification

Nelfinavir: May decrease the serum concentration of Methadone. Risk C: Monitor therapy

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Risk X: Avoid combination

Nirmatrelvir and Ritonavir: May decrease the serum concentration of Methadone. Risk C: Monitor therapy

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Oxytocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Pacritinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pacritinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

PAZOPanib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of PAZOPanib. Risk X: Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

PHENobarbital: May enhance the CNS depressant effect of Methadone. PHENobarbital may decrease the serum concentration of Methadone. Management: Avoid concomitant use of methadone and phenobarbital when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk X: Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Risk X: Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of Methadone. Primidone may decrease the serum concentration of Methadone. Management: Avoid concomitant use of methadone and primidone when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Risk X: Avoid combination

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Propafenone: May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Propofol: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the CNS depressant effect of Methadone. Methadone may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, sedation, and respiratory depression. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Miscellaneous Agents (Highest Risk): Methadone may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Methadone may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for increased methadone toxicities (eg, respiratory depression, QTc interval prolongation). Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Methadone. QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reductions may be necessary. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Risk D: Consider therapy modification

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Risk X: Avoid combination

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Risk C: Monitor therapy

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Risk X: Avoid combination

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ritonavir: May decrease the serum concentration of Methadone. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Saquinavir: May enhance the QTc-prolonging effect of Methadone. Saquinavir may decrease the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and opioid withdrawal symptoms. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Serotonergic Agents (High Risk): Methadone may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Risk X: Avoid combination

Stavudine: Methadone may decrease the serum concentration of Stavudine. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

SUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Tipranavir: May decrease the serum concentration of Methadone. More specifically, the combination of Tipranavir and Ritonavir may decrease Methadone serum concentrations. Risk C: Monitor therapy

Toremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Voriconazole: May enhance the QTc-prolonging effect of Methadone. Voriconazole may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Risk D: Consider therapy modification

Zidovudine: Methadone may increase the serum concentration of Zidovudine. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Grapefruit/grapefruit juice may increase levels of methadone. Management: Monitor for increased effects/toxicity with concomitant use.

Reproductive Considerations

Pregnancy testing is recommended prior to initiating therapy for opioid use disorders. Long-term opioid use and misuse may cause infertility, including erectile dysfunction, decreased sperm motility, menstrual disorders, and amenorrhea in patients of reproductive potential (SAMHSA 2021). Initiation of methadone maintenance treatment may improve fertility resulting in unplanned pregnancy. Contraception counseling is recommended (Dow 2012; SAMHSA 2021).

Pregnancy Considerations

Methadone crosses the placenta and can be detected in cord blood, amniotic fluid, and newborn urine.

An increased risk of major malformation has not been observed in the majority of available studies. Information related to specific malformation or other adverse events such as decreased fetal growth, premature birth, and sudden infant death syndrome is inconsistent. Children exposed to methadone in utero may have mild persistent deficits in performance on psychometric and behavioral tests; visual abnormalities may also occur. Pregnant patients in methadone treatment programs are reported to have improved prenatal care and fetal outcomes compared to pregnant patients using illicit drugs. Untreated opioid addiction is also associated with adverse pregnancy outcomes including low birth weight, preterm birth, and fetal death.

Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or dependence. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur. Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), GI (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). The risk of neonatal opioid withdrawal is greater following illicit opioid use than when methadone is used as part of a treatment program (ASAM 2020). The onset and duration of neonatal withdrawal symptoms are dependent upon the specific opioid used, maternal dosing, and rate of elimination by the newborn. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during pregnancy and/or labor should be monitored.

Opioid agonist pharmacotherapy is recommended for pregnant patients with an opioid use disorder (ACOG 2017; ASAM 2020; SAMHSA 2021). Treatment should begin as early in pregnancy as possible (ASAM 2020). Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of methadone may be altered as pregnancy progresses (clearance may be increased and half-life may be decreased). Dose adjustments or splitting of a once-daily dose may be required in some patients (ASAM 2020; SAMHSA 2021).

Maintenance doses of methadone will not provide adequate pain relief during labor. Patients receiving methadone for the treatment of opioid use disorder should be maintained on their daily dose of methadone in addition to receiving the same pain management options during labor and delivery as opioid-naive patients. Opioid agonist-antagonists should be avoided for the treatment of labor pain in patients maintained on methadone due to the risk of precipitating acute withdrawal. Use of a multimodal approach to pain relief which can maximize nonopioid interventions is recommended. Monitor for maternal oversedation and somnolence (ACOG 2017; Krans 2019; SAMHSA 2021).

Breastfeeding Considerations

Methadone is present in breast milk.

Data related to the presence of methadone in breast milk is available from 2 studies presented in the product labeling:

- Methadone 10 to 80 mg/day was administered orally to 10 breastfeeding women. Breast milk concentrations ranged from 50 to 570 mcg/L and were lower than steady state maternal serum concentrations in most cases. Methadone peak concentrations in breast milk occurred ~4 to 5 hours after the maternal dose.

- Methadone 20 to 80 mg/day was administered orally to 12 breastfeeding women. Breast milk concentrations ranged from 39 to 232 mcg/L. Using this information, relative infant dose to a breastfed infant was calculated to be 2% to 3% of the maternal dose.

Methadone has been detected in the plasma of some breastfed infants whose mothers are taking methadone. Sedation and respiratory depression have been reported in breastfeeding infants. Some infants may be more sensitive to these adverse events; deaths were reported in 2 infants exposed to methadone via breast milk (possibly due to genetic factors; however, other risk factors may have contributed) (Madadi 2016). According to the manufacturer, breastfeeding infants should be monitored for increased drowsiness and breathing difficulties, and mothers should be instructed as to when to contact their health care provider for emergency care. In addition, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

When methadone is used to treat opioid use disorder in breastfeeding patients, guidelines allow breastfeeding as long as the infant is tolerant to the dose and other contraindications, such as HIV infection or other illicit drug use, do not exist (AAP 2012; ABM [Reece-Stremtan 2017]; ACOG 2017; SAMHSA 2021). Breastfeeding can be encouraged for patients on stable maintenance doses, regardless of maternal methadone dose (ABM [Reece-Stremtan 2017]). If additional illicit substances are being abused, patients treated with methadone should express and discard breast milk until sobriety is established (Dow 2012).

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs of misuse, abuse, and dependence; liver function (baseline and during treatment); hepatitis and HIV testing, particularly for patients with opioid use disorder (prior to initiation) (SAMHSA 2021); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013). Consider monitoring blood glucose for doses at or exceeding 40 mg/day (Flory 2016). Consider methadone serum concentrations in patients with opioid dependence on a stable methadone dose that develop symptoms of increased sedation (drowsiness 2 to 4 hours following a dose) but also develop cravings or withdrawal symptoms before the next scheduled dose (SAMHSA 2021).

Obtain baseline ECG (evaluate QTc interval) prior to therapy in patients with risk factors for QTc interval prolongation, a prior ECG with a QTc >450 msec, or a history suggesting prior ventricular arrhythmia. Consider a baseline ECG when using high doses of methadone (ie, >120 mg) or if there is a personal or family history of cardiac risk factors, abnormal liver enzymes, electrolyte abnormalities, or concomitant medications that prolong the QT interval (ASAM 2020). If an ECG was obtained within the previous 3 months and it showed a QTc interval <450 msec, it can be used as a baseline for patients without new risk factors. Repeat ECG 2 to 4 weeks after initiating therapy and after significant dose increases; follow-up ECG should also be done if new risk factors present or signs/symptoms of arrhythmia occur. Repeat ECG when the methadone dose reaches 30 to 40 mg per day (when started at lower doses) and again at 100 mg per day (Chou 2014). Obtain ECG annually during treatment if >120 mg/day (ASAM 2020).

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Additional monitoring: Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2016]).

Reference Range

Opioid use disorder: Levels may be considered in patients on a stable dose with symptoms of increased sedation 2 to 4 hours after administration or signs of withdrawal before the next dose is due.

Timing of serum samples: Draw peak and trough levels (3 hours and 24 hours after dose, respectively).

Therapeutic levels: Due to highly variable patient responses, there is no defined therapeutic window, but levels usually correlate with dose. Minimum trough concentrations of 300 to 400 ng/mL may reduce risk of heroin use; however, dose should be based on individual patient response. A peak:trough ratio >2:1 may be a sign of rapid metabolism (SAMHSA 2021).

Mechanism of Action

Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression. Methadone has also been shown to have N-methyl-D-aspartate (NMDA) receptor antagonism.

Pharmacokinetics

Onset of action: Oral: Analgesic: 0.5 to 1 hour; Parenteral: 10 to 20 minutes.

Peak effect: Parenteral: 1 to 2 hours; Oral: Continuous dosing: 3 to 5 days.

Duration:

Analgesia: Oral: 4 to 8 hours (single-dose studies); duration of analgesia may increase to 8 to 12 hours with repeated dosing due to the slow release from the liver and other tissues (Alford 2006; Fishman 2002; Mercadante 1996; Toombs 2005).

Craving: 24 to 36 hours (ASAM 2020).

Distribution: Lipophilic

Vd:

Neonates PNA: <72 hours: 2.53 L/kg (Wiles 2015).

Children and Adolescents: 7.1 ± 2.5 L/kg (Berde 1987).

Adults: 1 to 8 L/kg.

Protein binding: 85% to 90%, primarily to alpha-1 acid glycoprotein.

Metabolism: Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6 to inactive metabolites.

Bioavailability: Oral: 36% to 100%.

Half-life elimination: Terminal:

Children and Adolescents: 19.2 ± 13.6 hours (range: 3.8 to 62 hours) (Berde 1987).

Adults: 8 to 59 hours; may be prolonged with alkaline pH. Auto-induction of metabolism may shorten the half-life during first month of treatment in some patients (Eap 2002).

Time to peak, plasma: 1 to 7.5 hours.

Excretion: Urine (<10% as unchanged drug); increased with urine pH <6; Note: Methadone may persist in the liver and other tissues; slow release from tissues may prolong the pharmacologic effect despite low serum concentrations.

Pharmacokinetics: Additional Considerations

Hepatic function impairment: Methadone is metabolized by hepatic pathways; therefore, there is a risk of drug accumulation after multiple dosing in patients with hepatic impairment.

Pricing: US

Concentrate (Methadone HCl Intensol Oral)

10 mg/mL (per mL): $0.85

Concentrate (Methadone HCl Oral)

10 mg/mL (per mL): $0.10 - $0.13

Concentrate (Methadose Oral)

10 mg/mL (per mL): $0.10

Concentrate (Methadose Sugar-Free Oral)

10 mg/mL (per mL): $0.10

Solution (Methadone HCl Injection)

10 mg/mL (per mL): $21.00 - $23.34

Solution (Methadone HCl Oral)

5 mg/5 mL (per mL): $0.08 - $0.32

10 mg/5 mL (per mL): $0.14 - $0.63

Tablet,Dispersible (Methadone HCl Oral)

40 mg (per each): $0.30 - $0.33

Tablet,Dispersible (Methadose Oral)

40 mg (per each): $0.33

Tablets (Methadone HCl Oral)

5 mg (per each): $0.07 - $0.46

10 mg (per each): $0.15 - $0.70

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Adolan (IL);
  • Amidona (CN);
  • Amidone (CR, DO, GT, HN, NI, PA, SV);
  • Aseptone (MY);
  • Bennaston (MY);
  • Biodone (AU, NZ);
  • Depridol (HU);
  • Dolmed (FI);
  • Eptadone (ES, GB, IT, NL);
  • Gobbidona (AR);
  • Heptadon (AT);
  • Ketalgin (CH);
  • Mephenon (BE, LU);
  • Metacalmans (AR);
  • Metadol (PE);
  • Metadon (DK, EE, FI, HU, IS, LT, NO, SE);
  • Metapad (CL);
  • Metasedin (ES);
  • Methaddict (DE);
  • Methadone chlorhydrate (FR);
  • Methadone Hydrochloride (PL);
  • Methadose (CO);
  • Methapain (JP);
  • Methasan (AT);
  • Misyo (CZ, HU, IT, PL, RO);
  • MISYO (SK);
  • Mytadon Cristalia (UY);
  • Mytedom (BR);
  • Phymet DTF (IE);
  • Physeptone (AE, AU, GB, ZA);
  • Pinadone DTF (IE);
  • Rubidexol (CR, DO, GT, HN, MX, NI, PA, SV);
  • Sublana (PL)


For country code abbreviations (show table)
  1. ACOG Committee on Obstetric Practice. Committee opinion no. 711: opioid use and opioid use disorder in pregnancy. Obstet Gynecol. 2017;130(2):e81-e94. doi: 10.1097/AOG.0000000000002235. [PubMed 28742676]
  2. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]
  3. Al-Qadheeb NS, Roberts RJ, Griffin R, Garpestad E, Ruthazer R, Devlin JW. Impact of enteral methadone on the ability to wean off continuously infused opioids in critically ill, mechanically ventilated adults: a case-control study. Ann Pharmacother. 2012;46(9):1160-1166. doi: 10.1345/aph.1R132. [PubMed 22872749]
  4. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144(2):127-134. doi:10.7326/0003-4819-144-2-200601170-00010 [PubMed 16418412]
  5. American Academy of Pediatrics (AAP); Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129(3):e827-e841. doi:10.1542/peds.2011-3552 [PubMed 22371471]
  6. American Pain Society (APS). Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 7th ed. Glenview, IL: American Pain Society; 2016.
  7. American Society of Addiction Medicine (ASAM). The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14(2S)(suppl 1):1‐91. doi:10.1097/ADM.0000000000000633 [PubMed 32511106]
  8. Anand KJ, Arnold JH. Opioid tolerance and dependence in infants and children. Crit Care Med. 1994;22(2):334-342. [PubMed 8306694]
  9. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007.
  10. Ayonrinde OT, Bridge DT. The rediscovery of methadone for cancer pain management. Med J Aust. 2000;173(10):536-540. [PubMed 11194738]
  11. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi: 10.1097/CCM.0b013e3182783b72. [PubMed 23269131]
  12. Berde CB, Sethna NF, Holsman RS, Reidy P, Gondek EJ. Pharmacokinetics of methadone in children and adolescents in the perioperative period. Anesthesiology. 1987;67(3A):A519. http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931395. Accessed May 3, 2017.
  13. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med. 2002;347(14):1094-1103. [PubMed 12362012]
  14. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828-842. doi:10.1016/j.mayocp.2015.04.003 [PubMed 26046416]
  15. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3)(suppl 1):S12-S18. doi: 10.1016/j.amjmed.2012.12.001. [PubMed 23414717]
  16. Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol. 2015;35(4):278-283. doi:10.1038/jp.2014.194 [PubMed 25357093]
  17. Centers for Disease Control and Prevention (CDC). Common elements in guidelines for prescribing opioids for chronic pain. https://www.cdc.gov/drugoverdose/pdf/common_elements_in_guidelines_for_prescribing_opioids-a.pdf. Published 2015. Accessed June 30, 2021.
  18. Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]
  19. Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321-337. doi: 10.1016/j.jpain.2014.01.494. [PubMed 24685458]
  20. Davis JM, Shenberger J, Terrin N, et al. Comparison of safety and efficacy of methadone vs morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial. JAMA Pediatr. 2018;172(8):741-748. doi:10.1001/jamapediatrics.2018.1307 [PubMed 29913015]
  21. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497-504. [PubMed 15504625]
  22. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299. [PubMed 30113379]
  23. Diskets (methadone) [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals; October 2019.
  24. Dolophine (methadone) [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals; June 2021.
  25. Dominguez KD, Lomako DM, Katz RW, Kelly HW. Opioid withdrawal in critically ill neonates. Ann Pharmacother. 2003;37(4):473-477. doi:10.1345/aph.1C324 [PubMed 12659598]
  26. Dow K, Ordean A, Murphy-Oikonen J, et al. Neonatal abstinence syndrome clinical practice guidelines for Ontario. J Popul Ther Clin Pharmacol. 2012;19(3):e488-e506. [PubMed 23241498]
  27. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. doi: 10.15585/mmwr.rr6501e1. [PubMed 26987082]
  28. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-1193. doi:10.2165/00003088-200241140-00003 [PubMed 12405865]
  29. Elefritz JL, Murphy CV, Papadimos TJ, Lyaker MR. Methadone analgesia in the critically ill. J Crit Care. 2016;34:84-88. doi: 10.1016/j.jcrc.2016.03.023. [PubMed 27288616]
  30. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications with related concerns. Pain Med. 2002;3(4):339-348. doi:10.1046/j.1526-4637.2002.02047.x [PubMed 15099239]
  31. Flory JH, Wiesenthal AC, Thaler HT, et al. Methadone Use and the Risk of Hypoglycemia for Inpatients With Cancer Pain. J Pain Symptom Manage. 2016;51(1):79-87.e1. [PubMed 26342726]
  32. Franck LS, Scoppettuolo LA, Wypij D, Curley MAQ. Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain. 2012;153(1):142-148. doi: 10.1016/j.pain.2011.10.003 [PubMed 22093817]
  33. Furlan V, Hafi A, Dessalles MC, Bouchez J, Charpentier B, Taburet AM. Methadone is poorly removed by haemodialysis. Nephrol Dial Transplant. 1999;14(1):254-255. doi:10.1093/ndt/14.1.254 [PubMed 10052536]
  34. Galinkin J, Koh JL; Committee on Drugs; Section On Anesthesiology and Pain Medicine; American Academy of Pediatrics. Recognition and management of iatrogenically induced opioid dependence and withdrawal in children. Pediatrics. 2014;133(1):152-155. [PubMed 24379233]
  35. Golightly LK, Teitelbaum I, Kiser TH, et al, eds. Renal Pharmacotherapy. New York: Springer; 2013.
  36. Hall ES, Isemann BT, Wexelblatt SL, et al. A cohort comparison of buprenorphine versus methadone treatment for neonatal abstinence syndrome. J Pediatr. 2016;170:39-44.e1. doi:10.1016/j.jpeds.2015.11.039 [PubMed 26703873]
  37. Hall ES, Meinzen-Derr J, Wexelblatt SL. Cohort analysis of a pharmacokinetic-modeled methadone weaning optimization for neonatal abstinence syndrome. J Pediatr. 2015;167(6):1221-5.e1. doi:10.1016/j.jpeds.2015.09.038 [PubMed 26477866]
  38. Health Canada. Methadone treatment of opioid dependence and potential risk of lack of effect when switching between different products. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/73547a-eng.php. Published July 17, 2020.
  39. Hudak ML, Tan RC, Committee On Drugs, et al. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560. [PubMed 22291123]
  40. "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. [PubMed 9024461]
  41. Isaac L, van den Hoogen NJ, Habib S, Trang T. Maternal and iatrogenic neonatal opioid withdrawal syndrome: Differences and similarities in recognition, management, and consequences. J Neurosci Res. 2022;100(1):373-395. doi:10.1002/jnr.24811 [PubMed 33675100]
  42. Krans EE, Campopiano M, Cleveland LM, et al. National partnership for maternal safety: Consensus bundle on obstetric care for women with opioid use disorder. Obstet Gynecol. 2019;134(2):365-375. [PubMed 31306323]
  43. Kreek MJ, Schecter AJ, Gutjahr CL, Hecht M. Methadone use in patients with chronic renal disease. Drug Alcohol Depend. 1980;5(3):197-205. doi:10.1016/0376-8716(80)90180-5 [PubMed 6986247]
  44. Lai A, Philpot P, Boucher J, Meyer A. An outpatient methadone weaning program by a neonatal intensive care unit for neonatal abstinence syndrome. Popul Health Manag. 2017;20(5):397-401. doi:10.1089/pop.2016.0192 [PubMed 28430046]
  45. Lainwala S, Brown ER, Weinschenk NP, Blackwell MT, Hagadorn JI. A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations. Adv Neonatal Care. 2005;5(5):265-272. doi:10.1016/j.adnc.2005.06.003 [PubMed 16202968]
  46. Lauriault G, LeBelle MJ, Lodge BA, et al. Stability of methadone in four vehicles for oral administration. Am J Hosp Pharm. 1991;48(6):1252-1256. [PubMed 1858805]
  47. Liu J, Smith KE, Riker RR, et al. Methadone bioavailability and dose conversion implications with intravenous and enteral administration: a scoping review. Am J Health Syst Pharm. 2021;78(15):1395-1401. doi:10.1093/ajhp/zxab166 [PubMed 33872344]
  48. Madadi P, Kelly LE, Ross CJ, Kepron C, Edwards JN, Koren G. Forensic investigation of methadone concentrations in deceased breastfed infants. J Forensic Sci. 2016;61(2):576-580. doi: 10.1111/1556-4029.12972. [PubMed 26513313]
  49. McPherson ML, Walker KA, Davis MP, et al. Safe and appropriate use of methadone in hospice and palliative care: expert consensus white paper. J Pain Symptom Manage. 2019;57(3):635-645.e4. doi:10.1016/j.jpainsymman.2018.12.001 [PubMed 30578934]
  50. Mercadante S, Sapio M, Serretta R, Caligara M. Patient-controlled analgesia with oral methadone in cancer pain: preliminary report. Ann Oncol. 1996;7(6):613-617. doi:10.1093/oxfordjournals.annonc.a010679 [PubMed 8879376]
  51. Metadol (methadone) [product monograph]. St-Laurent, Quebec, Canada: Paladin Labs Inc; February 2021.
  52. Metadol-D (methadone) [product monograph]. St-Laurent, Quebec, Canada: Paladin Labs Inc; February 2021.
  53. Methadone Hydrochloride Intensol [prescribing information]. Eatontown, NJ: Hikma Pharmaceuticals USA Inc; April 2021.
  54. Methadone Hydrochloride oral concentrate [prescribing information]. Largo, FL: VistaPharm Inc; January 2022.
  55. Methadone Hydrochloride oral solution [prescribing information]. Eatontown, NJ: Hikma Pharmaceuticals USA Inc; July 2020.
  56. Methadone Hydrochloride oral solution [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals Corp; May 2021.
  57. Methadone Hydrochloride tablets [prescribing information]. Webster Groves, MO: SpecGx LLC; February 2022.
  58. Methadone injection [prescribing information]. Morgantown, WV: Mylan Institutional LLC; May 2022.
  59. Methadose oral concentrate and Methadose sugar-free oral concentrate (methadone hydrochloride) [prescribing information]. Webster Groves, MO: Mallinckrodt Inc; August 2022.
  60. Methadose (methadone) tablet for oral suspension [prescribing information]. Webster Groves, MO: SpecGx LLC; September 2021.
  61. Methadose (methadone) [product monograph]. Pointe-Claire, Quebec, Canada: Mallinckrodt Canada ULC; February 2019.
  62. Molitch ME. Drugs and prolactin. Pituitary. 2008;11(2):209-218. [PubMed 18404390]
  63. Nilsson MI, Widerlöv E, Meresaar U, Anggård E. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol. 1982;22(4):337-342. doi:10.1007/BF00548403 [PubMed 6286317]
  64. Opdal MS, Arnesen M, Müller LD, et al. Effects of hemodialysis on methadone pharmacokinetics and QTc. Clin Ther. 2015;37(7):1594-1599. doi:10.1016/j.clinthera.2015.04.009 [PubMed 25963997]
  65. Perlman R, Giladi H, Brecht K, et al. Intradialytic clearance of opioids: methadone versus hydromorphone. Pain. 2013;154(12):2794-2800. doi:10.1016/j.pain.2013.08.015 [PubMed 23973378]
  66. Reece-Stremtan S, Campos M, Kokajko L; Academy of Breastfeeding Medicine. ABM Clinical Protocol #15: Analgesia and Anesthesia for the Breastfeeding Mother, Revised 2017. Breastfeed Med. 2017;12(9):500-506. doi:10.1089/bfm.2017.29054.srt [PubMed 29624435]
  67. Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral methadone in treating cancer pain: what Is the equianalgesic dose ratio? J Clin Oncol. 1998;16(10):3216-3221. [PubMed 9779694]
  68. Sevarino KA. Medically supervised opioid withdrawal during treatment for addiction. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 30, 2021. [PubMed 9779694]
  69. Substance Abuse and Mental Health Services Administration (SAMHSA). Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63. Publication No. PEP21-02-01-002. Substance Abuse and Mental Health Services Administration; 2021. https://store.samhsa.gov/product/TIP-63-Medications-for-Opioid-Use-Disorder-Full-Document/PEP21-02-01-002. Accessed February 7, 2022.
  70. Toombs JD, Kral LA. Methadone treatment for pain states. Am Fam Physician. 2005;71(7):1353-1358. [PubMed 15832538]
  71. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for opioid therapy for chronic pain. https://www.healthquality.va.gov/guidelines/Pain/cot/VADoDOTCPG022717.pdf. Published February 2017. Accessed June 15, 2020.
  72. van Donge T, Samiee-Zafarghandy S, Pfister M, et al. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019;85(6):1348-1356. doi:10.1111/bcp.13906 [PubMed 30805946]
  73. Wachman EM, Minear S, Hirashima M, et al. Standard fixed-schedule methadone taper versus symptom-triggered methadone approach for treatment of neonatal opioid withdrawal syndrome. Hosp Pediatr. 2019;9(8):576-584. doi:10.1542/hpeds.2018-0165 [PubMed 31270130]
  74. Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012;16(2):R49. doi: 10.1186/cc11250. [PubMed 22420584]
  75. Wiles JR, Isemann B, Mizuno T, et al. Pharmacokinetics of oral methadone in the treatment of neonatal abstinence syndrome: a pilot study. J Pediatr. 2015;167(6):1214-1220.e3. doi: 10.1016/j.jpeds.2015.08.032. [PubMed 26364984]
  76. Wiles JR, Isemann B, Ward LP, Vinks AA, Akinbi H. Current management of neonatal abstinence syndrome secondary to intrauterine opioid exposure. J Pediatr. 2014;165(3):440-446. doi:10.1016/j.jpeds.2014.05.010 [PubMed 24948346]
Topic 9623 Version 500.0