Version October 2024
Because the use of 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 and reassess all patients regularly for the development of these behaviors and conditions.
Dispersible tablets and oral concentrate contain methadone, an opioid agonist and schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit.
Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.
Serious, life-threatening, or fatal respiratory depression may occur with use of methadone, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential.
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. Proper dosing and titration are essential, and methadone should only be prescribed by health care professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period.
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 of even one dose of methadone, especially by children, can result in a fatal overdose of methadone.
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
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.
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.
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Concomitant use with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Reserve concomitant prescribing of benzodiazepines or other CNS depressants in patients in methadone treatment to those for whom alternatives to benzodiazepines or other CNS depressants are inadequate. 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.
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.
Dosage guidance:
Safety: Due to high interpatient variability in methadone’s relative analgesic potency and increased potency following repeated methadone dosing, 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. Consider prescribing naloxone for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, patients with sleep-disordered breathing, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), and/or concomitant benzodiazepine use (Ref). Methadone has a narrow therapeutic index, especially when combined with other drugs.
Dosing: Individualize dosing regimen based on patient-specific factors (eg, comorbidities, severity of pain, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals. Steady-state plasma concentrations and full analgesic effects are not attained until at least 3 to 5 days on a dose.
Chronic pain:
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 (Ref).
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 (Ref). 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 (Ref).
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 (Ref). 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 (Ref).
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 (Ref).
Oral: 10 to 40 mg every 6 to 12 hours (Ref).
IV: 2.5 to 10 mg every 8 to 12 hours (Ref).
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 (Ref).
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 (Ref). 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) (Ref).
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) (Ref).
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 (Ref); 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]) (Ref). 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 (Ref). 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 (Ref).
Missed dose: In patients who miss >4 doses, consider restarting at the initial dose or decrease the next dose substantially and gradually re-titrate (Ref).
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 (Ref).
Methadone to naltrexone: Taper the methadone dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone (Ref).
Naltrexone to methadone: Begin methadone ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (Ref).
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 (Ref).
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 (Ref).
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.
Conversion from oral opioids to oral methadone:
|
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.
|
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:
|
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 (Ref). 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 (Ref). Example: 10 mg of oral methadone equals 5 mg of IV methadone.
Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. 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 autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Ref); 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 (Ref) and other concomitant therapies increasing the risk of drug-drug interactions; close monitoring by a pain or substance use disorder specialist is warranted in these patients (Ref).
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 (Ref).
CrCl >10 to <30 mL/minute: Initial: No dosage adjustment necessary; use with caution and consider more gradual dose titration (Ref).
CrCl ≤10 mL/minute: Initial: Administer 50% to 75% of the usual indication-specific dose; use with caution; titrate gradually (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly removed by hemodialysis (~2% to 15% removal) (Ref):
Oral, parenteral: Initial: Administer 50% to 75% of the usual indication-specific dose; titrate gradually. Supplemental post-hemodialysis dosing is not necessary (Ref).
Peritoneal dialysis: Not significantly removed (Ref):
Oral, parenteral: Initial: Administer 50% to 75% of the usual indication-specific dose; titrate gradually (Ref).
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 (Ref).
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 (Ref).
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.
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 (Ref).
QTc prolongation (Ref):
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.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).
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 (Ref).
(For additional information see "Methadone: Pediatric drug information")
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 (Ref).
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 (Ref).
Pain; chronic, severe or palliative care: Limited data available:
Note: Methadone is not generally used for management of acute pain. Doses should be titrated to effect; use lower doses in opioid-naive patients. Management of breakthrough pain should be addressed with another opioid (short-acting). 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; monitor closely.
Infants >6 months, Children, and Adolescents:
IV (preferred), SUBQ: Initial: 0.05 to 0.1 mg/kg/dose every 6 to 24 hours; maximum initial dose: 5 mg/dose; adjust dose and/or interval based on clinical response no more frequently than every 72 hours (Ref). Note: When used in the palliative care setting, some patients may require higher initial doses based on current opioid dosing for pain (Ref).
Oral: Initial: 0.05 to 0.2 mg/kg/dose every 6 to 24 hours; maximum initial dose: 5 mg/dose; adjust dose and/or interval based on clinical response no more frequently than every 72 hours (Ref). Note: When used in the palliative care setting, some patients may require higher initial doses based on current opioid dosing for pain (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Ref); however, in patients receiving doses every 4 hours, an increased dosing interval (eg, every 6 to 8 hours) should be considered (Ref)
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 (Ref); however, in patients receiving doses every 4 or 6 hours, an increased dosing interval (eg, every 8 to 12 hours) should be considered (Ref)
GFR <10 mL/minute/1.73 m2: Reduce dosing interval; administration every 12 to 24 hours has been suggested (Ref)
Intermittent hemodialysis: Does not increase the elimination of methadone; reduce dosing interval; administration every 12 to 24 hours has been suggested (Ref)
Peritoneal dialysis (PD): Does not increase the elimination of methadone; reduce dosing interval; administration every 12 to 24 hours has been suggested (Ref)
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 (Ref)
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.
Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction, which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Symptoms of OIC may include decreased frequency of bowel movements, straining to pass bowel movements, a sense of incomplete evacuation, and/or hard stools (Ref). Tolerance does not develop to OIC (Ref). Symptoms are reversible after discontinuation of the opioid (Ref). Reported incidence of OIC with methadone ranges from 17% to over 50% (Ref). OIC is the most common reason for discontinuation reported by patients and may often result in a longer hospital stay and increased overall healthcare costs (Ref). Opioid dose or route of administration does not appear to alter risk (Ref).
Mechanism: Time-related; mu-opioid receptor stimulation in the GI tract results in delayed gastric emptying, decreased peristalsis, decreased water and chloride secretion into the intestinal lumen, and slowed bowel motility (Ref).
Onset: Varied; constipation has been reported within the first several weeks of methadone maintenance therapy initiation and after longer periods of treatment (Ref). However, OIC is defined based on a 7-day period of change (Ref).
Risk factors:
• Concurrent use of other medications that cause constipation
• Females (Ref)
Methadone is associated with serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD). Effects include hypoventilation, hypoxia, hypercapnia, and respiratory acidosis, as well as reduced ventilatory responses to hypoxia and hypercapnia (Ref). Peak respiratory depression from methadone occurs later and lasts longer than the peak analgesic effect (Ref). Respiratory depression may be reversible upon drug discontinuation (with opioid antagonist therapy in appropriate patients).
Mechanism: Dose-related; stimulation of mu-opioid receptors in the brainstem leads to suppression of the respiratory control network and depression of normal hypoxic and hypercapnic ventilatory responses (Ref).
Onset: Rapid; OIRD develops within 12 to 14 hours after oral administration (Ref).
Risk factors:
• Improper dosing and/or titration during initiation, following a dose increase, or conversion to methadone
• Opioid naïve (Ref)
• Opioid misuse (Ref)
• Acute overdose
• Concurrent administration of benzodiazepines, alcohol, or other CNS depressants (Ref)
• Postoperative patients with comorbid cardiac or respiratory disease (Ref)
• Age >60 years (Ref)
• Males (Ref)
• Sleep disorder (eg, obstructive sleep apnea) (Ref)
• Chronic pulmonary disease (eg, COPD, cor pulmonale, hypoxia, hypercapnia)
• Cachexia
• Debilitation
Abruptly stopping or reducing opioid use in patients with physical dependence on opioids can result in opioid-induced withdrawal (OIW) (Ref). Physical symptoms may include nausea, vomiting, diarrhea, abdominal cramps, tachycardia, chills, muscle aches, bone pain, agitation, anxiety, and insomnia. Cases of withdrawal psychosis have also been reported (Ref). Symptoms of withdrawal from methadone may be milder than symptoms from withdrawal of short-acting opioids but may last longer (Ref).
Mechanism: Withdrawal; opioids bind to mu-opioid receptors on neurons in the locus coeruleus (LC) of the brainstem, causing decreased norepinephrine (NE) release. Upon abrupt discontinuation, the absence of opioid stimulation causes LC hyperactivity, excessive NE release, and subsequent autonomic hyperactivity (Ref).
Onset: Rapid; symptoms peak at 72 to 96 hours after the last methadone dose and may persist for 2 weeks or longer (Ref).
Risk factors:
• Opioid use disorder (Ref)
• Prolonged exposure to opioids (Ref)
• Abrupt discontinuation or rapid tapering
• Initiation of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients currently or recently taking methadone can cause precipitated opioid withdrawal (Ref). Precipitated withdrawal is similar to OIW, but with a faster onset, and is associated with a decrease in opioid use disorder treatment retention (Ref).
Methadone is associated with life-threatening prolonged QT interval on ECG, torsades de pointes, and sudden cardiac death (Ref). QT prolongation to >500 msec is estimated to occur in 2% to 10% of patients treated with methadone and is reversible upon discontinuation (Ref).
Mechanism: Dose-related; however, QT prolongation has also been reported at lower doses (Ref). Inhibition of the human ether-à-go-go–related gene (hERG) channel and rapid component of the delayed rectifier potassium current (I Kr) leads to prolonged cardiac repolarization, prolonged action potential, and increased QT interval (Ref), thereby increasing the risk of torsades de pointes and sudden cardiac death. Additional prolongation of the cardiac action potential through inhibition of the inward rectifier potassium current (I K1) has also been proposed (Ref).
Onset: Varied; initial detection of QT prolongation has been reported within 1 month of methadone initiation to beyond 12 months of therapy (Ref).
Risk factors:
• Higher daily methadone doses (eg, >120 mg/day) (Ref)
• IV > oral administration if IV formulation contains the preservative chlorobutanol (Ref)
• QTc >450 msec (Ref)
• Impaired hepatic drug metabolism (eg, hepatic dysfunction or drug-drug interactions) (Ref)
• CYP450 2B6 slow metabolizer (Ref)
• Hypokalemia (Ref)
• Hypomagnesemia (Ref)
• Concurrent use of medications that prolong the QT interval (Ref)
• Concurrent use of diuretics (Ref)
• History of cardiac conduction abnormalities
• Structural heart disease (Ref)
• Bradycardia (Ref)
• Females (Ref)
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Bigeminy, bradycardia, cardiac arrhythmia, cardiomyopathy, edema, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, shock, syncope, tachycardia, ventricular fibrillation
Dermatologic: Diaphoresis, hemorrhagic urticaria, pruritus, skin rash, urticaria
Endocrine & metabolic: Amenorrhea, antidiuretic effect, decreased libido, decreased plasma testosterone, hypokalemia, hypomagnesemia, weight gain
Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, 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
Local: Erythema at injection site (IV), pain at injection site (IV), swelling at injection site (IV)
Nervous system: Agitation, asthenia, confusion, disorientation, dizziness, drug abuse, drug dependence, dysphoria, euphoria, hallucination, headache, insomnia, neonatal withdrawal, sedated state, seizure
Neuromuscular & skeletal: Amyotrophy, bone fracture, osteoporosis
Ophthalmic: Nystagmus disorder, strabismus, visual disturbance
Respiratory: Pulmonary edema, respiratory depression
Postmarketing:
Cardiovascular: ECG abnormality (including inversion T wave on ECG and prolonged QT interval on ECG) (Krantz 2003), torsades de pointes (Traficante 2017), ventricular tachycardia (Tam 2020)
Endocrine & metabolic: Hyperprolactinemia (transient increase with chronic use) (Molitch 2008), hypoglycemia (Flory 2016; Malboosbaf 2023)
Gastrointestinal: Constipation (Kandhi 2022)
Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), neurotoxicity (including choreiform movements and encephalopathy) (Gasimova 2022)
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).
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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.
• 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.
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, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Obesity: Use with caution in patients who are morbidly obese.
• Opioid use disorder: When used for detoxification and maintenance of opioid use disorder, 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.
• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate seizures.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Special populations:
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment), resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
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:
• Abuse/misuse/diversion: Use with caution in patients with a history of substance use disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Appropriate use: Outpatient setting: Opioids should not be used as first-line therapy for acute (<1 month duration), subacute (1 to 3 month duration), or chronic pain (>3 month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications, antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, 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. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]). 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 opioid-induced respiratory depression/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).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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:
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
Yes
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): $25.65
Solution (Methadone HCl Oral)
5 mg/5 mL (per mL): $0.08 - $0.32
10 mg/5 mL (per mL): $0.14 - $0.18
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.
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
Generic: 1 mg, 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]
Generic: 5 mg, 10 mg
C-II
When used for treatment of opioid use disorder: 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 use disorder, 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 substance use disorder is being sought in an appropriately licensed facility.
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.
Oral:
Oral solution (1 mg/mL): Administer using an accurate measuring device (calibrated oral syringe).
Tablets for oral suspension: Disperse tablet in ~120 mL (4 oz) of water, orange juice, or other acidic fruit juice; 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.
Parenteral: May be administered IV or SUBQ; rate of IV administration is not defined. The absorption of SUBQ appears to be unpredictable; local tissue reactions may occur.
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
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, oral: Management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.
Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve methadone for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) have not been tolerated, or are not expected to be tolerated; have not provided adequate analgesia, or are not expected to provide adequate analgesia. Not indicated for use as an as-needed analgesic.
Methadone may be confused with dexmethylphenidate, ketorolac, memantine, Mephyton, methylphenidate, Metadate CD, Metadate ER, metOLazone, morphine
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration; pediatric liquid medications requiring measurement) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
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)
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 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
Agents with Clinically Relevant Anticholinergic Effects: 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
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
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Aromatase Inhibitors: May increase the serum concentration of Methadone. Risk C: Monitor therapy
Atazanavir: May decrease the serum concentration of Methadone. Methadone may decrease the serum concentration of Atazanavir. 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
CYP2C19 Inducers (Moderate): May decrease the serum concentration of Methadone. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Methadone. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Methadone. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase 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 Methadone. Encorafenib may decrease the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and decreased methadone effects/withdrawal. Patients with additional risk factors for QTc prolongation may be at even higher risk. 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). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
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
Grapefruit Juice: May increase the serum concentration of Methadone. Management: Consider advising patients to avoid grapefruit consumption during treatment with oral methadone. If coadministration is necessary, monitor patients closely for increased methadone effects, including respiratory depression and sedation. 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
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
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
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
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
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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
Loxapine: CNS Depressants may enhance the CNS depressant effect of Loxapine. Risk D: Consider therapy modification
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
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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
Nabilone: May enhance the CNS depressant effect of CNS Depressants. 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
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
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
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Quizartinib: 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
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
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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
Terbutaline: 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
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
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Grapefruit/grapefruit juice may increase levels of methadone. Management: Monitor for increased effects/toxicity with concomitant use.
Pregnancy testing is recommended prior to initiating therapy for opioid use disorders (ASAM 2020; SAMHSA 2021).
Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).
Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]). Contraception should also be discussed with patients undergoing treatment for opioid use disorders (ASAM 2020).
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. Data related to specific malformations or other adverse events such as decreased fetal growth, premature birth, and sudden infant death syndrome are 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 issue disorder is also associated with adverse pregnancy outcomes including low birth weight, preterm birth, and fetal death.
Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]). The risk of NAS/NOWS is not greater when methadone is used as part of a treatment program compared to the risk following illicit opioid use (ASAM 2020).
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; CDC [Dowell 2022]) and may continue when pregnancy occurs during treatment (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 for the treatment of opioid use disorder 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).
Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 5 to 7 days following exposure to methadone (AAP [Patrick 2020]; CDC [Dowell 2022]).
Opioids are not preferred for the treatment of chronic noncancer pain during pregnancy; consider strategies to minimize or avoid opioid use. Advise pregnant patients requiring long-term opioid use of the risk of NAS/NOWS and provide appropriate treatment for the neonate after delivery. NAS/NOWS is an expected and treatable condition following chronic opioid use during pregnancy and should not be the only reason to avoid treating pain with an opioid in pregnant patients (ACOG 2017; CDC [Dowell 2022]). Do not abruptly discontinue opioids during pregnancy; taper prior to discontinuation when appropriate, considering the risks to the pregnant patient and fetus if maternal withdrawal occurs (CDC [Dowell 2022]).
Methadone is present in breast milk.
Data related to the presence of methadone in breast milk are 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).
Due to pregnancy-induced physiologic changes, the dose of methadone used during pregnancy may need reduced postpartum (ASAM 2020).
When methadone is used to treat opioid use disorder in lactating patients, breastfeeding may help mitigate potential newborn withdrawal. 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 [Patrick 2020]; ABM [Reece-Stremtan 2015]; ACOG 2017; SAMHSA 2021). Breastfeeding can be encouraged for patients on stable maintenance doses, regardless of maternal methadone dose (ABM [Reece-Stremtan 2015]). Breastfeeding is not recommended if relapse with illicit drug use or legal substance misuse has occurred within 30 days prior to delivery, and breastfeeding should be suspended if a relapse occurs (ABM [Reece-Stremtan 2015]; ACOG 2017). Both mother and infant should be monitored (AAP [Patrick 2020]).
When opioids for chronic pain are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; both mother and infant should be monitored (AAP [Meek 2022]; AAP [Patrick 2020]).
Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 2019). In addition, the manufacturer, recommends monitoring breastfeeding infants for breathing difficulties; mothers should be instructed as to when to contact their health care provider for emergency care. Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.
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]).
Subacute or 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. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, reevaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). 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 2022]).
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 (SI: 1 to 1.3 micromole/L) 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).
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.
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.
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.
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