Brand names: Methadose, Diskets
Drug class: Opioid Agonists

Medically reviewed by Drugs.com on Sep 10, 2025. Written by ASHP.

Introduction

Synthetic diphenylheptane-derivative opiate agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist.

Uses for Methadone

Pain

Used for management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options (e.g., nonopioid analgesics, immediate-release opioid analgesics) are inadequate. Not indicated as an as-needed analgesic.

Pain management should be individualized, patient-centered, and multimodal. Opioids can be essential, but they are associated with considerable potential harm including opioid use disorder and overdose. Therefore, safer and more effective treatments should be considered prior to initiating opioid therapy.

Multiple nonpharmacologic treatments (e.g., exercise, psychological therapies) and nonopioid drugs (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, NSAIAs) have been shown to be at least as effective as opioids for common pain conditions.

If opioids are used, clinicians should carefully evaluate risk of opioid-related harms and incorporate appropriate risk mitigation strategies into treatment plan, including offering naloxone.

CDC guidelines provide recommendations for the management of acute (duration <1 month), subacute (duration 1–3 months), and chronic pain (duration >3 months) in adults in the outpatient setting. Other clinical practice guidelines provide recommendations for the management of specific types of pain; common elements include risk mitigation strategies, careful dosage titration, and consideration of risks and benefits.

Opioid Use Disorder

Used for opioid withdrawal management (e.g., detoxification) and maintenance treatment in individuals with opioid use disorder. Suppresses withdrawal symptoms in patients who are dependent on short-acting opioids such as heroin, morphine, and codeine.

Should be used as a component of a comprehensive treatment plan that includes counseling and other behavioral therapies, and administered in accordance with federal regulations.

Can only be dispensed in oral form by opioid treatment programs (OTP) certified by SAMHSA, but may be provided in acute care settings under limited circumstances.

Medications used in the treatment of opioid use disorder (e.g., methadone, buprenorphine, naltrexone) have been associated with reduced risk of overdose and deaths. Evidence-based treatment with these drugs should be offered to all patients who meet criteria for opioid use disorder.

When determining whether to use methadone, buprenorphine, or naltrexone, clinicians should consider patient preferences, past treatment history, current clinical condition, and treatment setting. The American Society of Addiction Medicine (ASAM) recommends the use of methadone in patients who may benefit from daily dosing and supervision in an OTP, or for patients who do not respond to buprenorphine for the treatment of opioid use disorder.

Neonatal Opioid Withdrawal

Used to manage manifestations of neonatal opioid withdrawal^{† [off-label]}.

Opioids recommended as first-line pharmacologic therapy when environmental and supportive measures (e.g., minimization of external stimuli, maximization of mother-infant contact [e.g., parental “rooming in”], breast-feeding when not contraindicated, swaddling, and gentle handling) are inadequate. May add other adjunctive therapy (e.g., clonidine, phenobarbital) if response to opioids is inadequate.

Use standardized protocols for identification, evaluation, and treatment.

Methadone Dosage and Administration

General

Pretreatment Screening

• Prior to initiation, carefully evaluate risks and benefits of opioid therapy, and assess for opioid-related harms (e.g., addiction, abuse, misuse). Incorporate risk mitigation strategies into the treatment plan, including offering naloxone. Consider a treatment discontinuation plan for use if benefits no longer outweigh risks.

• Review the patient’s history of controlled substance prescriptions using state PDMP data to determine whether the patient is receiving opioid dosages or combinations that put the patient at high risk for overdose.

• Screen patients for sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia.

Patient Monitoring

• When opioids are used for chronic pain, evaluate the benefits and risks within 1–4 weeks following initiation of therapy or an increase in dosage, and re-evaluate on an ongoing basis.

• Monitor patients closely for signs of sedation and respiratory depression, particularly when initiating therapy and following dosage increases.

• Monitor and manage common adverse effects of opioid therapy (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).

Dispensing and Administration Precautions

Handling and Disposal

• Advise patients to store opioids in a secure and preferably locked location and discuss options for safe disposal of unused opioids.

• Distribution of methadone 40-mg dispersible tablets is restricted to authorized opioid detoxification and maintenance treatment programs and to hospitals. Distribution is restricted because of reports of serious adverse effects.

• Based on the Institute for Safe Medication Practices (ISMP), methadone is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

• When used for the management of pain, methadone should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting and potent opioids and how to mitigate the associated risks.

Administration Precautions for Oral Solution

• Ensure accuracy when prescribing, dispensing, and administering methadone oral solution to avoid dosing errors due to confusion between mg and mL, and with other methadone oral solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both total dose in mg and total dose in volume.

• Instruct patients and caregivers on how to accurately measure and administer the correct dose of methadone oral solution.

• Strongly advise patients and caregivers to always use a graduated oral syringe when administering the oral solution to ensure the dose is measured and administered accurately.

REMS

• FDA approved a REMS for methadone under a shared REMS system (Opioid Analgesic REMS).

• The goals are to reduce the occurrence of addiction, unintentional overdosage, and death resulting from inappropriate prescribing, misuse, and abuse of opioid analgesics.

• The REMS program consists of educational programs for health professionals, a patient counseling guide, and a product-specific medication guide for patients.

Administration

Administer orally as tablets, solution, concentrated solution, or dispersible tablets or by IV, IM, or sub-Q injection.

Also has been administered rectally^{† [off-label]} and by epidural injection^{† [off-label]}.

Oral Administration

Tablets, dispersible tablets, oral solution, and oral concentrate solution are for oral administration only and must not be injected.

Conventional Tablets

Do not crush, chew, dissolve, snort, or inject the tablets which can result in uncontrolled delivery of methadone and potentially overdose and death.

Dispersible Tablets

Disperse dose in 120 mL of water, orange juice, or other acidic fruit beverage immediately prior to oral administration. Do not chew or swallow before dispersing in liquid. If any residue remains in cup after initial administration, add a small amount of liquid and administer the resulting mixture.

The 40-mg dispersible tablets are used for detoxification and maintenance treatment of opioid dependence.

Each 40-mg dispersible tablet can be divided in half or in quarters.

Because dispersible tablets can be administered only in 10-mg increments, this dosage form may be inappropriate in many patients for initial dosing during detoxification and maintenance treatment or for gradual dosage reduction following detoxification or a period of maintenance treatment.

Oral Concentrate

Dilute the dose with water or other suitable liquid to ≥30 mL prior to administration.

Parenteral Administration

Administer by IV, IM, or sub-Q injection. Absorption following IM or sub-Q injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.

Epidural Administration

Standardize 4 Safety

Standardized concentrations for epidural methadone^{† [off-label]} have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].

Dosage

Available as methadone hydrochloride; dosage expressed in terms of the salt.

Careful dosage selection and titration are essential to avoid overdosage.

Pediatric Patients

Neonatal Opioid Withdrawal† [off-label]

Oral

Use standardized protocols that base initiation, adjustment, and tapering of dosage on standardized patient assessments performed at regular intervals (e.g., Finnegan scoring system [original or modified versions] performed every 3–4 hours).

Treatment generally initiated at a dose of 0.05–0.1 mg/kg (as oral solution) based on Finnegan score. However, protocols vary in initial dosing frequency, incremental changes and thresholds for dosage adjustment, and tapering strategies. In general, increase dosage if Finnegan score remains elevated (e.g., 2 consecutive scores ≥8, 1 score ≥12), and taper dosage once patient is stable (e.g., average score <8 or no score >8 for 24 hours). Further studies needed to define optimal dosing strategies.

Some protocols based on pharmacokinetic modeling utilize a stepwise approach to dosage escalation and tapering. Such protocols use an initial dose of 0.1 mg/kg; dosing intervals are shorter during initial steps of the protocol, but then are lengthened to and maintained at 12 hours while the dose is tapered, if tolerated, by a modest amount every 24 hours until dosage is reduced to 0.01 mg/kg once daily; then discontinued. Such protocols increase early exposure to the medication; limited experience suggests shorter treatment duration and hospital stay with this approach.

Other clinicians recommend initial dosage of 0.05–0.1 mg/kg every 12 hours; dosage increases, when indicated, in increments of 0.02–0.05 mg/kg per dose or 10%; maximum dosage of 1 mg/kg daily; and/or tapering schedules of 10–20% per week.

Monitor neonate for 48–72 hours after methadone is discontinued.

Consult specialized protocols for further information on dosage and monitoring of Finnegan scores.

Adults

Pain

When selecting an initial dosage, consider the type, severity, and expected duration of the patient’s pain; the age, general condition, and medical status of the patient; concurrent medication therapy; and the acceptable balance between pain relief and adverse effects.

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

Appropriate dosage selection and titration are essential to prevent overdosage.

IV

Opioid-nontolerant patients: usual initial dose is 2.5–10 mg every 8–12 hours. Titrate dosage to provide adequate analgesia; increase slowly to avoid accumulation and potential toxicity. More frequent administration may be required during initiation of therapy to maintain adequate analgesia, but caution is necessary to avoid overdosage.

Patients being switched from oral methadone: Initiate parenteral methadone at a parenteral-to-oral dosage ratio of 1:2 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).

When patients are transferred from chronic therapy with another oral or parenteral opioid to parenteral methadone, select dosage carefully because cross-tolerance between methadone and other opioid agonists is incomplete, dosage conversion ratios are imprecise, and considerable interindividual variability exists. See Tables 2 and 3 for dosage conversion methods based on comparisons with morphine sulfate. These estimates provide a safe starting point; however, dosage must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).

Administer total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements. For patients being transferred from therapy with opioid agonists other than morphine, consult a comparative opioid agonist dosage table to determine the equivalent morphine sulfate dosage.

Derived from Table 2 assuming a 3:1 oral-to-parenteral morphine sulfate ratio.

Oral

Opioid-nontolerant patients: Initially, 2.5 mg every 8–12 hours. Carefully individualize dosage according to patient response. Dosage may be titrated to provide adequate analgesia, but should be increased slowly (no more frequently than every 3 to 5 days) to avoid accumulation of the drug and potential toxicity.

Patients switching from parenteral to oral methadone: initiate oral methadone at an oral-to-parenteral dosage ratio of 2:1 (e.g., 10 mg of oral methadone hydrochloride in patients previously receiving 5 mg of parenteral methadone hydrochloride).

When patients are transferred from chronic therapy with other oral or parenteral opioids, select dosage carefully because cross-tolerance between methadone and other opioid agonists is incomplete, dosage conversion ratios are imprecise, and considerable interindividual variability exists. See Table 4 for dosage conversion based on comparison with morphine sulfate. Individualize dosage (e.g., based on prior opioid use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).

Administer total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.

For patients being transferred from therapy with opioid agonists other than morphine, consult a comparative opiate agonist dosage table to determine equivalent morphine dosage.

May adjust dosage in intervals of 3–5 days with close monitoring to achieve adequate analgesia. Some patients may require substantially longer periods between dose increases (up to 12 days).

Patients who experience breakthrough pain may require dosage adjustment or rescue therapy with a small dose of an immediate-release analgesic.

If discontinuance of therapy is required, gradually taper dosage. For patients who are physically opioid-dependent, initiate the taper by a small increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

Detoxification and Maintenance of Opiate Dependence

Detoxification

Oral

Initiate therapy under supervision when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal.

A single dose of 20–30 mg will usually suppress withdrawal symptoms. Initial dose should not exceed 30 mg; use lower initial dose in patients whose tolerance is expected to be low.

Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear. If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose. If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg. Total daily dose for the first day generally should not exceed 40 mg unless this total dose does not suppress withdrawal symptoms.

During the first week, adjust dosage based on control of withdrawal symptoms at times of expected peak activity of methadone (2–4 hours after a dose). Use caution to avoid overdosage; methadone levels accumulate over the first several days of dosing. With continued dosing, symptoms are suppressed for a longer time.

For short-term detoxification, when the patient has been stabilized (i.e., substantial symptoms of withdrawal are absent) for 2 or 3 days, gradually decrease dosage daily or at 2-day intervals. Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level. In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.

Parenteral

Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria. Patients being switched from oral methadone usually initiate parenteral methadone at a parenteral-to-oral dosage ratio of 1:2 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).

Maintenance

Oral

Titrate dosage to a level at which opioid symptoms are prevented for 24 hours, drug craving is reduced, euphoric effects of self-administered opioids are blocked or attenuated, and tolerance to the sedative effect of methadone is evident.

Trough and peak plasma levels of methadone may be used in addition to clinical evaluation to assess safety and adequacy of a dose, particularly in patients who may be rapid metabolizers and may need a split dose. It has been suggested that trough plasma methadone concentrations >100–200 ng/mL may be necessary for optimal methadone maintenance, particularly during the first 6 months of treatment.

Stabilization of maintenance dosage usually occurs at 80–120 mg daily.

A single dose of methadone daily usually is adequate and there generally is no apparent advantage to divided doses. However, rapid metabolizers of methadone may not maintain adequate plasma methadone concentrations with usual dosing regimens.

Review maintenance dosage requirements regularly and reduce as indicated.

In patients desiring medically supervised withdrawal from methadone maintenance treatment, dosage generally should be reduced at intervals of 10–14 days by an amount that is <10% of the established tolerance or maintenance dosage.

Special Populations

Hepatic Impairment

Pharmacokinetics not extensively evaluated in patients with hepatic insufficiency. Initiate therapy with lower doses and titrate slowly while carefully monitoring for signs of CNS and respiratory depression.

Renal Impairment

Pharmacokinetics not extensively evaluated in patients with renal insufficiency. Initiate therapy with lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of CNS and respiratory depression.

Geriatric Patients

Geriatric patients ≥65 years of age may have increased sensitivity to methadone. In general, use caution when selecting dosage, usually starting at the low end of dosing range.

Cautions for Methadone

Contraindications

• Significant respiratory depression.

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

• Known or suspected GI obstruction, including paralytic ileus.

• Hypersensitivity to methadone (e.g., anaphylaxis).

Warnings/Precautions

Warnings

Addiction, Abuse and Misuse

Risk of addiction, abuse, and misuse (see Boxed Warning). Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing methadone and continue to assess during therapy.

Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioid agonists, but use necessitates intensive counseling about the risks and proper use of the drug along with frequent reevaluation for signs of addiction, abuse, and misuse.

Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion.

Life-threatening Respiratory Depression

Risk of serious life-threatening, or fatal respiratory depression, even when used as recommended (see Boxed Warning). Can occur at any time, but risk is greatest during initiation of therapy or following a dosage increase.

To reduce risk of respiratory depression, proper dosing and titration are essential.

Methadone should be prescribed only by clinicians knowledgeable about methadone's pharmacokinetic and pharmacodynamic properties and use of potent opioid analgesics for chronic pain management.

Overestimating the dosage when converting patients from another opioid agonist can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea and hypoxemia. In patients who present with central sleep apnea, consider decreasing the opioid dosage using best practices for opioid taper. Opioid use increases the risk of central sleep apnea in a dose-dependent fashion.

Routinely discuss availability of the opioid antagonist naloxone with all patients receiving new or reauthorized prescriptions for opioid analgesics, including methadone.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use with benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioid agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death (see Boxed Warning).

Reserve concomitant prescribing of these drugs for patients in whom alternative treatment options are inadequate.

If a benzodiazepine or other CNS depressant is used concomitantly with methadone in patients treated for pain, prescribe lowest effective dosages and minimum duration of concomitant use. In patients already receiving methadone, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

In patients treated for opioid use disorder, develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission or during methadone treatment. Medication-assisted treatment of opioid use disorder should not be categorically denied to patients taking these drugs. For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.

Life-threatening QT Prolongation

QT interval prolongation and serious cardiac arrhythmias, including torsades de pointes, reported (see Boxed Warning).

Generally occurred in patients receiving large, multiple-daily doses (>200 mg daily) for chronic pain management, but also occurred in patients receiving lower dosages for maintenance treatment of opioid dependence. In most patients receiving lower doses, concomitant medications and/or clinical conditions such as hypokalemia were contributing factors.

Closely monitor patients who may be at risk for QT prolongation (e.g., those with cardiac hypertrophy, hypokalemia, or hypomagnesemia; those receiving relatively high dosages or receiving concomitant drugs that can cause electrolyte disturbances or prolong QT interval) for changes in cardiac rhythm during initiation of therapy and dosage adjustments.

Use in patients with known prolongation of the QT interval not systematically evaluated.

If prolongation of the QT interval occurs, evaluate patient’s drug regimen to identify drugs that may prolong the QT interval, cause electrolyte abnormalities, or inhibit metabolism of methadone.

Use only if potential benefits outweigh possible risk of QT interval prolongation.

Neonatal Opioid Withdrawal Syndrome

Use of methadone for an extended period during pregnancy can result in withdrawal in the neonate (see Boxed Warning).

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

For management of pain: prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options.

For management of opioid addiction: untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Methadone is recommended as a treatment of opioid use disorder during pregnancy. Clinicians should discuss the known risk of neonatal opioid withdrawal syndrome with the patient.

Risks of Concomitant Use or Discontinuation of Cytochrome P450 Inhibitors and Inducers

Concomitant use with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors may increase plasma concentrations of methadone, prolong opioid adverse reactions, and cause potentially fatal respiratory depression (see Boxed Warning). Discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of methadone when used concomitantly with CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers, and evaluate patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with methadone may decrease methadone plasma concentrations, reducing efficacy and possibly leading to opioid withdrawal symptoms in patients physically dependent on methadone. When methadone is used concomitantly with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or when CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors are discontinued, assess patients for signs or symptoms of opioid withdrawal and consider increasing methadone dosage as needed.

Risk of Accidental Overdose and Death due to Medication Errors

Accidental ingestion of even one dose of methadone, especially by children, can result in fatal overdosage (see Boxed Warning).

Dosing errors can result in accidental overdose and death (see Boxed Warning). Avoid dosing errors that may result from confusion between mg and mL and confusion with methadone solutions of different concentrations, when prescribing, dispensing, and administering methadone oral solution. Ensure that the dose is communicated clearly and dispensed accurately.

Instruct patients and caregivers on how to measure and administer the correct dose of methadone oral solution and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices.

Other Warnings and Precautions

Opioid-Induced Hyperalgesia and Allodynia

Opioid-induced hyperalgesia (OIH) may occur when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).

If OIH is suspected, carefully consider decreasing dose of the current opioid analgesic or switching to a different opioid.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Serotonin syndrome reported during concurrent use of opioid agonists, including methadone, and serotonergic drugs.

Serotonin syndrome may occur at usual dosages. Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

Use in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with chronic pulmonary disease such as those with significant COPD or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages.

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Regularly monitor patients, particularly when initiating and titrating methadone and when it is given concomitantly with other drugs that depress respiration; consider patient access to naloxone. Alternatively, consider use of nonopioid analgesics in these patients.

Adrenal Insufficiency

Adrenal insufficiency reported with opioid use, usually with longer duration of use.

If adrenal insufficiency is suspected, confirm diagnosis. If diagnosed, treat with physiologic replacement doses of corticosteroids. Wean patient from the opioid to allow adrenal function to recover and continue corticosteroid treatment until recovery.

Severe Hypotension

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.

Increased risk of severe hypotension in patients whose ability to maintain BP is compromised by depleted blood volume or concomitant use of certain drugs (e.g., phenothiazines, general anesthetics).

Monitor patients for hypotension after initiation of therapy or dosage titration.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

May reduce respiratory drive; the resultant carbon dioxide retention can further increase intracranial pressure.

May obscure the clinical course in patients with head injuries; avoid use in patients with impaired consciousness or coma.

Risks of Use in Patients with GI Conditions

Contraindicated in patients with GI obstruction, including paralytic ileus. May cause increased serum amylase and spasm of the sphincter of Oddi.

Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

May increase frequency of seizures in patients with seizure disorders and may increase risk of seizures occurring in other clinical settings associated with seizures.

Regularly evaluate patients with a history of seizure disorders for worsened seizure control during methadone therapy.

Withdrawal

Do not abruptly discontinue in a patient physically dependent on opioids; gradually taper the dosage.

Avoid use of mixed opioid agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial opioid agonist (e.g., buprenorphine) analgesics in patients receiving a full opioid agonist analgesic, such as methadone. May reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Risks of Driving and Operating Machinery

May impair mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Advise patients not to drive or operate dangerous machinery unless they are tolerant to the effects of methadone and know how they will react to the medication.

Hypoglycemia

Methadone-associated hypoglycemia reported, sometimes requiring hospitalization.

If hypoglycemia suspected, monitor blood glucose levels and manage patient as clinically appropriate.

Laboratory Test Interactions

False positive urine drug screens for methadone reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.

Specific Populations

Pregnancy

Most available data do not indicate an increased risk of major malformations with use of methadone during pregnancy; however, some findings have been inconsistent. Based on animal data, advise pregnant women of potential risk to a fetus.

Untreated opioid addiction during pregnancy is associated with adverse obstetrical outcomes, including preeclampsia, fetal growth restriction, preterm birth, spontaneous abortion, and fetal death.

Pregnant women in methadone maintenance programs have reported improved prenatal care leading to reduced obstetric and fetal complications and neonatal morbidity and mortality compared to women using illicit drugs. Limited information available regarding dose and duration of methadone use during pregnancy, and most maternal exposure in these studies appears to occur after first trimester.

Methadone clearance may be increased, trough plasma concentrations of the drug may be lower, and half-life may be decreased during second and third trimesters of pregnancy; dosage adjustment may be necessary.

Methadone has been detected in umbilical cord plasma and amniotic fluid.

Prolonged maternal use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome; may be life-threatening and requires management according to protocols developed by neonatology experts.

Lactation

Use with caution in nursing women; distributed into human milk and present in low levels.

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.

In individuals receiving methadone for opioid use disorder and considering breastfeeding, CDC recommends that breastfeeding be supported if there has been no return to drug use for ≥90 days and there are no other contraindications; considered if there has been no return to drug use within 30–90 days; and discouraged if there is active substance use or a return to drug use within the last 30 days.

Monitor infants for excess sedation and respiratory depression.

Females and Males of Reproductive Potential

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. Not known whether these effects are reversible.

In animal studies, methadone administration adversely affected fertility and reproductive endpoints.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Geriatric patients ≥65 years of age may have increased sensitivity to methadone. In general, use caution when selecting dosage in geriatric patients.

Respiratory depression is main risk for geriatric patients treated with opioids and has occurred after administration of large initial doses to opioid-nontolerant patients or when opioids were co-administered with other respiratory depressant drugs.

Titrate dosage of methadone slowly in geriatric patients and frequently monitor for CNS and respiratory depression.

Methadone is substantially excreted by the kidney; risk of adverse reactions may be greater in patients with impaired renal function, and elderly patients are more likely to have decreased renal function.

Hepatic Impairment

Not studied extensively in patients with hepatic impairment; risk of accumulation with multiple doses because drug is metabolized in liver.

Initiate treatment with lower doses and titrate slowly while regularly evaluating for signs of respiratory and CNS depression.

Renal Impairment

Not studied extensively in patients with renal impairment.

Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.

Initiate treatment with lower doses and with longer dosing intervals and titrate slowly; regularly evaluate for signs of respiratory and CNS depression.

Pharmacogenomic Considerations

Genetic variations in CYP2D6, OPRM1(gene coding the mu opioid receptor mu1), and COMT (enzyme responsible for methylconjugation of catecholamines) can influence clinical effect or adverse effects of some opioid analgesic

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines for selected opioid analgesics based on these genotypes.

Although methadone is metabolized by CYP2D6 to some extent, CYP2D6 genotype does not appear to affect adverse effects, dosing requirements, or analgesic effects of the drug.

CPIC states that there is insufficient evidence and confidence to provide a recommendation to guide clinical practice at this time for methadone based on CYP2D6 genotype. In addition, there is insufficient evidence to support any therapeutic recommendations for dosing opioids, such as methadone, based on either OPRM1 or COMT.

Common Adverse Effects

Common adverse effects: lightheadedness, dizziness, sedation, nausea, vomiting, sweating.

Drug Interactions

Metabolized principally by CYP isoenzymes 3A4, 2B6, 2C19, 2C9 and 2D6.

Appears to be a P-gp substrate, but pharmacokinetics not substantially altered by P-gp inhibition.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers: Possible increased metabolism and decreased plasma concentrations of methadone. If concomitant use is necessary, consider increasing the methadone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone dosage reduction and monitor for signs of respiratory depression and sedation.

CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors: Possible decreased metabolism and increased plasma concentrations of methadone. If concomitant use is necessary, consider dosage reduction of methadone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone dosage until stable drug effects are achieved.

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (prolongation of the QT interval; potential for severe and/or life-threatening cardiac arrhythmias). Monitor patients closely for cardiac conduction changes.

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John’s wort, tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue methadone.

Specific Drugs

Methadone Pharmacokinetics

Absorption

Bioavailability

Well-absorbed following oral administration. Considerable interindividual variability in oral bioavailability (range: 36–100%). Peak concentrations occur 1–7.5 hours after oral administration.

Onset

Plasma concentrations and full analgesic effects generally are not achieved until completion of 3–5 days of therapy.

Peak respiratory depressant effects occur later than analgesic effects, particularly during the early dosing period.

Duration

With repeated dosing, the potency of methadone increases due to systemic accumulation.

Respiratory depressant effects persist longer than analgesic effects, particularly during the early dosing period.

Food

Effect of food on bioavailability not established.

Distribution

Extent

Highly lipophilic and widely distributed in body tissues. With repeated administration, methadone is stored in the liver and other tissues and is slowly released, prolonging the duration of effect despite low plasma concentrations.

Methadone crosses the placenta and is distributed into human milk.

Plasma Protein Binding

85–90% (mainly to α₁-acid glycoprotein).

Elimination

Metabolism

Extensively metabolized, principally by CYP isoenzymes 3A4, 2B6, 2C19, 2C9, and 2D6.

Undergoes N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP), and other metabolites with little or no pharmacologic activity.

Appears to be a P-gp substrate, but pharmacokinetics not substantially altered by P-gp polymorphism or inhibition.

Elimination Route

Excreted to varying degrees in urine and feces as metabolites and unchanged drug.

Half-life

Considerable interindividual variability in terminal elimination half-life; generally reported as 8–59 hours.

Special Populations

Elimination half-life is decreased during 2nd and 3rd trimesters of pregnancy.

Stability

Storage

Oral

Tablets

20-25°C (excursions permitted between 15–30°C).

Tablets, Dispersible

25°C (excursions permitted between 15–30°C).

Oral Solution

20–25°C (excursions permitted between 15–30°C).

Oral Concentrate

20–25°C.

Parenteral

Injection

20–25°C (15–30°C). Protect from light.

Actions

• A potent analgesic; shares the actions of the opioid agonists and is selective for the mu-opioid receptor.

• Principal therapeutic action of methadone is analgesia; also used therapeutically for detoxification and maintenance in opioid addiction.

• Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord; thought to play a role in analgesic effects of the drug.

• Agonist activity at the mu receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).

• May also act as antagonist at N-methyl-D-aspartate (NMDA) receptors.

Advice to Patients

• Inform patients that the use of methadone, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share methadone preparations with others and to take steps to protect the drug from theft or misuse.

• Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting methadone or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical assistance immediately in the event of a known or suspected overdose.

• Instruct patients to seek immediate medical attention if symptoms suggestive of an arrhythmia (e.g., palpitations, dizziness, lightheadedness, syncope) occur.

• Inform patients and caregivers that potentially fatal additive effects may occur if methadone preparations are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.

• Advise patients and caregivers not to increase methadone dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.

• Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

• Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

• Inform patients that methadone may cause hypotension and syncope. Instruct patients on how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

• Inform patients that anaphylaxis has been reported with methadone. Advise patients how to recognize such a reaction and when to seek medical attention.

• Inform patients that methadone may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

• Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

• Inform patients that methadone may cause hypoglycemia. Instruct patients how to recognize the symptoms of low blood glucose and to contact their healthcare provider if these symptoms occur.

• Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible.

• Advise patients to inform their clinician if they are or plan to become pregnant. Inform patients of reproductive potential that use of methadone for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

• Advise patients to inform their clinician if they are breastfeeding. Advise patients to carefully observe breastfeeding infants for increased sleepiness (more than usual), breathing difficulties, or limpness; instruct nursing mothers to seek immediate medical care if they notice these symptoms.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Patient Advice Related to Outpatient Use of Methadone

• Advise patients to store methadone prescriptions securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home because of the risks associated with accidental ingestion, misuse, and abuse. Inform patients leaving methadone unsecured can pose a deadly risk to others in the home.

• Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused methadone preparations should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit [Web] for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

• Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose and how to use naloxone in the event of an suspected overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help in all cases of known or suspected opioid overdose, even if naloxone is administered.

• Instruct patients not to discontinue methadone without first discussing a tapering plan with the prescriber.

• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.

Patient Advice Related to Dispersible Tablets

• Dispersible tablets are for oral administration only and must be initially dispersed in liquid before use.

• After dispersion in liquid, the prepared suspension must not be injected.

Patient Advice Related to Oral Solution

• Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication. Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure methadone oral solution.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Methadone hydrochloride is subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug and, in addition, is subject to FDA regulations (21 CFR 291.505) for medications that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.

Distribution of methadone hydrochloride 40-mg dispersible tablets is restricted to authorized opioid detoxification and maintenance treatment programs and to hospitals.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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