Brand names: Dolophine, Methadose
Drug class: Opiate Agonists
VA class: CN101
CAS number: 1095-90-5

Medically reviewed by Drugs.com on Apr 19, 2023. Written by ASHP.

Introduction

Opiate agonist; a synthetic diphenylheptane derivative.^{217 222 a}

Uses for Methadone

Pain

Used parenterally for the relief of moderate to severe pain that has not responded to nonopiate analgesics.²²²

Used orally for the relief of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.^{217 225 226} Oral preparations are not indicated for relief of acute (e.g., postoperative) pain, for relief of pain that is mild or is not expected to persist for an extended period of time, or for use on an as-needed (“prn”) basis.^{217 225 226}

For relief of chronic pain in both opiate-naive patients and in individuals being switched to methadone therapy from other opiate agonists because of inadequate pain relief or adverse effects from the previous drug (opiate rotation).^{228 232 254}

Clinical studies suggest that efficacy may be similar to that of morphine and other opiates in patients with chronic malignant pain.^{228 232} However, experts generally agree that methadone should be prescribed for chronic pain management only by clinicians knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetics,^{410 411 412 413 414 415} and should not be the first choice for an extended-release or long-acting opiate analgesic.^{411 415}

Benefits associated with use of methadone for management of chronic pain include the commercial availability of multiple dosage forms of the drug,²³² good oral bioavailability,^{228 229} rapid onset of action,^{228 229} reduced dosing frequency (because of the drug’s long half-life),^{228 232} low cost,^{228 229 232 235} and lack of active metabolites.^{228 229 232}

Disadvantages associated with use include increased potential for accumulation with repeated doses (which may result in toxicity),^{217 228 254} considerable interindividual variability in pharmacokinetic parameters,^{217 228 229} potential for drug interactions,^{217 228 232} challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists,^{217 228} and commercial availability and relative ease of use of extended-release preparations of other opiate agonists.²²⁸

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing^{410 411 412 413} ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.^{411 412 413 414 422 429}

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).^{411 412 413 422 429}

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life^{411 423 431 432 436} or is superior to other pharmacologic or nonpharmacologic treatments.⁴³² Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose).^{411 431 436} (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Detoxification and Maintenance of Opiate Dependence

Used in detoxification treatment and maintenance treatment as an oral substitute for heroin or other morphine-like drugs to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs.^{212 213 216 217 226 263}

Success of treatment is dependent on the selection of properly motivated patients and on availability of social, psychologic, vocational, and educational as well as medical supportive services.^a

Neonatal Opiate Withdrawal

Has been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates^{† [off-label]} exposed to opiates in utero.^{350 352 353 355 357 359}

Opiates 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.^{350 352 353 355 357 359} May add other adjunctive therapy (e.g., clonidine, phenobarbital) if response to opiates is inadequate or add phenobarbital if neonate was exposed to additional substances in utero.^{350 352 353 355 357 358 359 365 368}

While morphine has been used more extensively than other opiates in the management of neonatal opiate abstinence syndrome,^{352 357 359 360} some studies suggest methadone or buprenorphine may be associated with shorter treatment durations and hospital stays.^{360 361 362 363} Additional study needed to establish optimal dosage schedules and preferred opiate drugs and to evaluate longer-term (e.g., neurodevelopmental) outcomes.^{351 353 354 355 360}

Use of standardized protocols for identification, evaluation, and treatment recommended; use of protocols improves overall response, including shorter hospital stays and durations of pharmacologic treatment.^{350 352 353 358 359} Some evidence suggests that use of a standardized protocol may be more important than use of a specific opiate agonist (e.g., methadone versus morphine) in improving outcomes.^{352 359 363}

Methadone Dosage and Administration

General

• Individualize dosage carefully; repeated doses may result in substantial accumulation of the drug, prolonging its duration of action and possibly resulting in adverse effects.^{217 222 232} There is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.^{217 222 232}

• Carefully monitor patients during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.^{217 222}

• Consider the specific characteristics of methadone (i.e., half-life is longer than duration of analgesic effect, peak respiratory depressant effects occur later and persist longer than peak analgesic effects, full analgesic effect not attained for several days, potential for drug interactions) when making treatment decisions regarding use of the drug.^{217 222 270}

Conversion from Other Opiate Analgesic Therapy

• Consider the daily dosage, potency, and specific characteristics (e.g., elimination half-life) of the previously administered opiate; adverse effects of and response to the previous regimen; degree of opiate tolerance; and the relative potency estimate used to calculate an equianalgesic dosage of methadone.^{217 222 236 259}

• A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.^{217 222} Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.^{217 222 236}

• Select dosage carefully when transferring patients from chronic therapy with another oral or parenteral opiate to therapy with oral or parenteral methadone, since cross-tolerance between methadone and other opiate agonists is incomplete, dosage conversion ratios are imprecise, and substantial interindividual variability exists.^{217 222 235} (See Conversion from Other Opiate Therapy under Dosage.) Overestimation of dosage when transferring patients from other opiate therapy to methadone therapy can result in fatal overdosage with the first dose.²¹⁷

• Published equianalgesic dosage conversion ratios between methadone and other opiate agonists generally are based on single-dose studies in patients who are not opiate tolerant.^{217 222} These single-dose equivalency tables may overestimate dosage requirements during chronic therapy, since methadone may accumulate with repeated doses secondary to the long elimination half-life (see Elimination under Pharmacokinetics).^{217 222 227} Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.^{217 222}

Managing Opiate Therapy for Chronic Noncancer Pain

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.^{410 411 414 415 423}

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction;^{411 412 413 415 422 429} establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.^{411 415}

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.^{411 412 413}

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.^{411 412 413 414 415}

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage.^{411 415} Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.^{412 413} Experts generally agree that methadone should be prescribed for chronic pain management only by clinicians knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetics,^{410 411 412 413 414 415} and should not be the first choice for an extended-release or long-acting opiate analgesic.^{411 415}

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase^{411 413} and reevaluate on ongoing basis (e.g., at least every 3 months⁴¹¹ ) throughout therapy.^{411 412 413} Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.^{412 413 422 423} Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).^{412 413 415} If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.^{411 412 413 415}

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks.^{412 413} Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.^{412 413 415}

• Higher dosages require particular caution,^{410 412 415} including more frequent and intensive monitoring or referral to specialist.^{411 412 413} Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).^{411 415 423 424 425 426}

• CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify decision to prescribe such dosages.⁴¹¹ Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.^{423 431} Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended)^{411 420 421 423} or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).^{411 419 423}

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.^{410 411 412 413 414 415 422 423 429}

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion.^{412 413 415} Offer or arrange treatment for patients with OUD.^{412 413}

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage^{411 431 750} or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.⁷⁵⁰ (See Respiratory Depression under Cautions.)

Detoxification and Maintenance Treatment

• Administer or dispense only in an oral form (e.g., tablet, dispersible tablet, liquid) that is formulated and packaged in such a way as to reduce potential for parenteral abuse and accidental ingestion.^{214 261 262 263 264}

• Hospitalized patients unable to take oral medication may receive parenteral methadone on a temporary basis.²²² If at any time during detoxification or maintenance treatment the patient cannot tolerate oral medication because of nausea or vomiting associated with acute complicating illness, hospitalize the patient and continue methadone by the parenteral route.^{222 a}

• Short-term detoxification: Administer in decreasing doses under close observation over a period of ≤30 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.^{201 213 263}

• Long-term detoxification: Administer in decreasing doses over a period of >30 but ≤180 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.^{201 213 263}

• Maintenance treatment: Administer at a stable dosage for >21 days in the treatment of opiate dependence.^{212 213 216 263 267}

• Patients with ≥2 unsuccessful detoxification episodes within a 12-month period should be assessed for alternative forms of treatment.²⁶³ An opiate treatment program may not admit a patient for >2 detoxification treatments within 1 year.²⁶³

• Patients undergoing short-term detoxification are not eligible for unsupervised administration.^{263 264}

• Any patient in a comprehensive maintenance treatment program, including long-term detoxification treatment, may receive 1 dose to take at home for a day that the clinic is closed.^{263 264} Decisions to allow additional unsupervised administration by these patients should be based on the following factors: absence of recent abuse of drugs (including alcohol), regularity of clinic attendance, absence of serious behavioral problems at the clinic, absence of known recent criminal activity, stability of the patient’s home environment and social relationships, length of time in the program (see below), assurance that the drug can be safely stored in the patient’s home, and assessment of whether the rehabilitative benefit derived from decreased clinic attendance outweighs potential risks of diversion.²⁶³

• Patients meeting these criteria may be permitted to receive additional supplies of the drug to take at home each week, in the following amounts: 1-day supply during the 1st 90 days of treatment, 2-day supply during the 2nd 90 days, and 3-day supply during the 3rd 90 days (each in addition to the 1 dose allowed for clinic closure).^{263 264 265} All other doses must be administered while the patient is closely observed.²⁶³

• During the remainder of the 1st year of treatment, the patient may receive a maximum 6-day supply of the drug and must visit the clinic once weekly.^{263 265}

• After 1 year of continuous treatment, the patient may receive a maximum 2-week supply and must make twice monthly visits.^{263 265} After 2 years of continuous treatment, the patient may receive a maximum 1-month supply of the drug and must make monthly visits.^{263 265}

• Substantial deviations from the FDA-approved labeling for methadone (e.g., concerning dose, frequency of administration, or conditions of use) must be documented in the patient’s medical record.²⁶³

• Strongly consider prescribing naloxone concomitantly for all patients receiving medications for treatment of OUD.⁷⁵⁰ Also consider prescribing naloxone when patients receiving opiates (e.g., methadone) for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.⁷⁵⁰ (See Respiratory Depression under Cautions.)

Restricted Distribution

• Distribution of 40-mg dispersible tablets restricted to authorized opiate-dependency treatment programs and to hospitals.^{271 272 273} Distribution restricted in response to reports of serious adverse effects (see Boxed Warning).^{270 272 273}

Administration

Administer orally or by sub-Q, IM, or IV injection.^{217 222 225 226 261 262}

Oral Administration

Tablets, dispersible tablets, oral solution, and oral concentrate solution are for oral administration only and must not be injected.^{217 225 226 261 262}

Dispersible Tablets

Disperse dose in 120 mL of water, orange juice, Tang, citrus-flavored Kool-Aid, or other acidic fruit beverage immediately prior to oral administration.^{261 262} Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used.^a If any residue remains in cup after initial administration, add a small amount of liquid and administer the resulting mixture.^{261 262}

The 40-mg dispersible tablets are used in detoxification and maintenance of opiate dependence;^{261 262 271} this preparation should not be used for the treatment of pain.^{261 262 270 271}

Dispersible tablets contain insoluble excipients and must not be used to prepare solutions for injection.^{261 262}

Each 40-mg dispersible tablet can be divided in half or in quarters.^{261 262}

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.^{261 262}

Oral Concentrate Solution

Dilute the dose with water or other suitable liquid (e.g., Kool-Aid, Tang, apple juice, Crystal Light [with aspartame]) to ≥30 mL prior to administration.^{255 256}

Sub-Q Administration

Absorption following sub-Q or IM injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.²²²

IM Administration

IM administration of opiate analgesics is discouraged; IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent analgesia.⁴³⁰

IV Administration

Administer by IV injection.²²²

For solution and drug compatibility information, see Compatibility under Stability.

Dosage

Available as methadone hydrochloride; dosage expressed in terms of the salt.^{217 222 225 226 261 262 263}

Careful dosage selection and titration are essential to avoid overdosage.²¹⁷

Pediatric Patients

Neonatal Opiate 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).^{352 355 359}

Treatment generally initiated at a dose of 0.05–0.1 mg/kg (as oral solution) based on Finnegan score (e.g., score ≥8 on 2 or 3 occasions, 1 score or 2 consecutive scores ≥12).^{294 352 355 365 368} However, protocols vary in initial dosing frequency, incremental changes and thresholds for dosage adjustment, and tapering strategies.^{293 294 352 353 355 357 361 365 368} In general, increase dosage if Finnegan score remains elevated (e.g., 2 consecutive scores ≥8, 1 score ≥12),^{352 355 361 365} and taper dosage once patient is stable (e.g., average score <8 or no score >8 for 24 hours).^{355 365} Further study needed to define optimal dosing strategies.²⁹³

Some protocols based on pharmacokinetic modeling utilize a stepwise approach to dosage escalation and tapering.^{293 294 365} Some such protocols use 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;^{293 294 365} drug is then discontinued.^{293 294} Such protocols increase early exposure to the drug;^{293 294} limited experience suggests shorter treatment durations and hospital stays with this approach.²⁹³

Other clinicians recommend initial dosage of 0.05–0.1 mg/kg every 12 hours;^{355 357 368} dosage increases, when indicated, in increments of 0.02–0.05 mg/kg per dose^{352 353 357 368} or 10%;³⁵⁵ maximum dosage of 1 mg/kg daily;^{355 357} and/or tapering schedules of 10–20% per week.^{368 369}

Monitor neonate for 48–72 hours after methadone is discontinued.^{352 365}

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 drug therapy (see Interactions); and the acceptable balance between pain relief and adverse effects.^{217 222}

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.^{411 413 431 432 435}

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.^{700 703} (See Specific Drugs under Interactions.)

Oral

Opiate-naive patients: Initially, no more than 2.5–10 mg every 8–12 hours.²¹⁷ Titrate dosage to provide adequate analgesia; increase dosage slowly to avoid accumulation and potential toxicity.²¹⁷

Dosage interval may range from 4–12 hours, since the duration of analgesia is relatively short during the first days of therapy but increases substantially with continued administration.^{217 223 227} Use caution to avoid overdosage.²¹⁷

Patients being switched from parenteral 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).²¹⁷

Adjust dosage at intervals of 1–2 days with close monitoring.²¹⁷ If breakthrough pain occurs, adjust dosage or administer small dose of rescue (immediate-release) analgesic.²¹⁷ If adverse effects are excessive, reduce the next dose; if adverse effects are intolerable, adjust dose or dosing interval.²¹⁷

If discontinuance of opiates is required, taper dosage every 2–4 days to avoid manifestations of abrupt withdrawal.²¹⁷

IV

Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours.²²² Titrate dosage to provide adequate analgesia; increase slowly to avoid accumulation and potential toxicity.²²² More frequent administration may be required during initiation of therapy to maintain adequate analgesia; however, use caution to avoid overdosage.²²²

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).²²²

Conversion from Other Opiate Therapy

For patients being transferred from therapy with other opiate agonists, dosage may be estimated based on comparisons with morphine sulfate.^{217 222} Select dosage carefully (see General: Conversion from Other Opiate Analgesic Therapy under Dosage and Administration).^{217 222}

For patients being transferred from therapy with opiate agonists other than morphine, a comparative opiate agonist dosage table may be consulted to determine the equivalent morphine dosage.^{217 222}

Oral

Dosage estimates obtained from Table 1 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).^{217 222}

Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.^{217 222}

IV

Dosage estimates obtained from Table 2 and Table 3 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).²²²

Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.²²²

Derived from Table 2 assuming a 3:1 oral-to-parenteral morphine ratio.²²²

Detoxification and Maintenance of Opiate Dependence

Detoxification

Oral

Initiate when there are substantial opiate-agonist abstinence symptoms.²¹⁷

A single dose of 20–30 mg will often suppress withdrawal symptoms.²¹⁷ Initial dose should not exceed 30 mg;^{217 263} use lower initial dose in patients whose tolerance is expected to be low.²¹⁷ Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.²¹⁷ If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.²¹⁷ If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.²¹⁷ Total daily dose for the first day generally should not exceed 40 mg^{217 263} unless it is documented that this total dose does not suppress withdrawal symptoms.²⁶³

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).²¹⁷ Use caution to avoid overdosage.²¹⁷ With continued dosing, symptoms are suppressed for a longer time.²¹⁷

Usual stabilizing dosage is 40 mg daily in divided doses.²¹⁷ 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.²¹⁷ Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level.²¹⁷ In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.²¹⁷

Parenteral

Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria.^{217 222 a} 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).²²²

Maintenance

Oral

A single dose of 20–30 mg will often suppress withdrawal symptoms.²¹⁷ Initial dose should not exceed 30 mg;^{217 263} use lower initial dose in patients whose tolerance is expected to be low.²¹⁷ Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear.²¹⁷ If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose.²¹⁷ If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg.²¹⁷ Total daily dose for the first day generally should not exceed 40 mg^{217 263} unless it is documented that this total dose does not suppress withdrawal symptoms.²⁶³

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).²¹⁷ Use caution to avoid overdosage.²¹⁷ With continued dosing, symptoms are suppressed for a longer time.²¹⁷

Titrate dosage to a level at which opiate withdrawal symptoms are prevented for 24 hours, drug craving is reduced, euphoric effects of self-administered opiates are blocked or attenuated, and patient is able to tolerate the sedative effects of methadone.²¹⁷ Usual stabilizing dosage is 80–120 mg daily.²¹⁷ Review maintenance dosage requirements regularly and reduce as indicated.^a

Once-daily dosing usually is adequate; there generally is no apparent advantage to divided doses.^a However, rapid metabolizers may not maintain adequate plasma concentrations with usual dosing regimens.^{206 207 208 210}

Withdrawal from methadone maintenance: Considerable variability in appropriate rate of dosage reduction; one regimen involves reducing the dose by <10% of established tolerance or maintenance dosage at intervals of 10–14 days.²¹⁷ All patients in a maintenance program should be given careful consideration for discontinuance of methadone therapy, especially after reaching a dosage of 10–20 mg daily.^a

Parenteral

Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria.^{217 222 a} 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).²²²

Prescribing Limits

Adults

Pain

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages.⁴¹¹ Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.^{423 431}

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).^{411 420 421 423}

Special Populations

Hepatic Impairment

Reduce initial dosage;^{217 222} titrate dosage slowly while monitoring for respiratory and CNS depression.²¹⁷

Renal Impairment

Use smaller initial doses and longer dosing intervals;^{217 222} titrate dosage slowly while monitoring for respiratory and CNS depression.²¹⁷

Geriatric and Debilitated Patients

In geriatric patients, select dosage at the lower end of the dosage range.^{217 222} Reduce dosage in poor-risk and in very old patients.^a

Cautions for Methadone

Contraindications

• Known hypersensitivity (e.g., anaphylaxis) to methadone or any ingredient in the formulation.^{217 222}

• Oral therapy: Substantial respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.²¹⁷

• Parenteral therapy: Respiratory depression in the absence of resuscitative equipment or in unmonitored settings, acute asthma or hypercarbia (hypercapnia).²²²

• Known or suspected paralytic ileus.²¹⁷

Warnings/Precautions

Warnings

Respiratory Depression

The major toxicity associated with methadone.^{217 222} (See Respiratory Depression in Boxed Warning.)

Serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases.²¹⁷

Deaths reported during transfer to methadone from chronic high-dose therapy with other opiate analgesics and during initiation of maintenance treatment for opiate dependence in individuals previously taking high doses of other opiates.²¹⁷

Geriatric, cachectic, or debilitated patients and those with conditions accompanied by hypoxia or hypercapnia are at increased risk.^{217 222} (See Contraindications, Other Warnings/Precautions, and Geriatric Use, under Cautions.)

Appropriate dosage selection and titration are essential to prevent overdosage.²¹⁷ (See General and also Dosage, under Dosage and Administration.) Should be prescribed only by clinicians knowledgeable about methadone's pharmacokinetic and pharmacodynamic properties and use of potent opiates for chronic pain management.²¹⁷

Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized opiate prescriptions for pain management or new or reauthorized prescriptions for medications for treatment of OUD.⁷⁵⁰

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose); strongly consider prescribing naloxone for all patients receiving medications for treatment of OUD.^{411 431 750} Also consider prescribing naloxone when patients receiving opiates for pain management or for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.⁷⁵⁰ Even if patients are not receiving an opiate for pain management or medication for treatment of OUD, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).⁷⁵⁰

Cardiac Effects

Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes.^{217 222 223 234} (See QT-Interval Prolongation in Boxed Warning.)

Closely monitor for changes in cardiac rhythm during initiation of therapy and dosage adjustment.²¹⁷

Use with caution and careful monitoring in patients who may be at risk for development of prolonged QT syndrome (e.g., those with cardiac hypertrophy, hypokalemia, or hypomagnesemia; those receiving relatively high methadone dosages or receiving concomitant therapy with a drug that may cause electrolyte disturbances or prolong the QT interval [see Specific Drugs under Interactions]).^{217 222}

Use in patients with known prolongation of the QT interval not systematically evaluated.^{217 222}

If prolongation of the QT interval occurs, evaluate the patient’s drug regimen to identify drugs that may prolong the QT interval, cause electrolyte abnormalities, or inhibit metabolism of methadone.^{217 222}

Use for pain management only when the potential benefits outweigh the possible risk of QT-interval prolongation reported with higher methadone dosage.^{217 222}

Drug Abuse and Dependence

Abuse liability similar to that of other opiates.^{217 222} Clinicians should consider abuse potential when prescribing or dispensing methadone in situations where they are concerned about an increased risk of misuse, abuse, or diversion.²¹⁷ However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.^{217 222}

Increased risk for abuse in patients with a personal or family history of substance abuse (e.g., drug or alcohol abuse or addiction) or mental illness (e.g., major depression).²¹⁷ Intensive monitoring for signs of misuse, abuse, and addiction required in those at increased risk for abuse.²¹⁷

Methadone abuse in combination with other CNS depressants may result in serious risk.^{217 222} (See CNS Effects under Cautions.)

Dependence and tolerance may develop with repeated administration; use with caution.^{217 222}

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.^{217 222} After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.^{217 222}

In patients receiving methadone maintenance treatment for opiate dependence, abrupt discontinuance can result in withdrawal symptoms and may increase risk of relapse to illicit drug use.^{217 222}

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome.²⁹² (See Pregnancy under Cautions.)

Contact the state professional licensing board or controlled substance authority for information about prevention and detection of abuse or diversion.^{217 222}

Inadvertent Exposure

Inadvertent ingestion, especially by children, may result in fatal overdosage.²¹⁷

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including methadone, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.^{416 417 418 700 701 702 703} Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.^{416 417 418 435 700 701}

Reserve concomitant use of methadone for analgesia and other CNS depressants for patients in whom alternative treatment options are inadequate.^{700 703} (See Specific Drugs under Interactions.)

Morbidity and mortality associated with untreated opiate addiction can outweigh the serious risks associated with concomitant use of opiates and benzodiazepines or other CNS depressants.⁷⁰⁶ FDA states that methadone treatment for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be withheld from patients receiving benzodiazepines or other CNS depressants.⁷⁰⁶ Taper and discontinue these drugs, if possible; however, excluding or discharging patients from MAT because of benzodiazepine or CNS depressant use is not likely to prevent such concomitant use and may lead to use outside the treatment setting, which could result in more severe outcomes.⁷⁰⁶

FDA states benzodiazepines are not the treatment of choice for anxiety or insomnia in patients receiving methadone for opiate addiction; consider other pharmacologic or nonpharmacologic therapies.⁷⁰⁶

FDA also states that current evidence does not support dose limitations or other arbitrary limits on methadone as a strategy for addressing concomitant benzodiazepine or other CNS depressant use in patients receiving MAT.⁷⁰⁶ However, if patient is sedated at the time of a scheduled methadone dose, evaluate the cause of sedation; omission or reduction of the methadone dose may be appropriate.⁷⁰⁶

Careful management can reduce the risks associated with concomitant use of benzodiazepines or other CNS depressants in patients receiving MAT.⁷⁰⁶ FDA recommends:

• Educating patients upon initiation of MAT regarding risks associated with such concomitant use;

• Developing strategies upon initiation of MAT for managing any prescribed or illicit use of benzodiazepines or other CNS depressants;

• Verifying diagnosis in any patient receiving prescribed benzodiazepines or other CNS depressants for anxiety or insomnia, and considering other treatment options for these conditions;

• Recognizing that MAT may be required indefinitely and should be continued for as long as the patient benefits and MAT contributes to treatment goals;

• Coordinating care to minimize risks and ensure other prescribers are aware that patient is receiving methadone; and

• Performing toxicology tests for prescribed or illicit drug use.⁷⁰⁶

Other Warnings/Precautions

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.^a

Incomplete Cross-Tolerance

Patients who are tolerant to other opiate agonists may have incomplete tolerance to methadone.^{217 222 253} Overdosage (including fatalities) reported in patients being transferred to methadone from chronic high-dose therapy with other opiate analgesics and during initiation of maintenance treatment for opiate dependence in individuals previously taking high doses of other opiates.^{217 222}

Use methadone with caution and at appropriately adjusted dosages in patients being transferred from other opiate therapy.^{217 222 253} Carefully consider pharmacokinetic parameters during initiation and titration of methadone therapy in patients who previously received chronic opiate agonist therapy.^{217 222} (See General: Conversion from Other Opiate Analgesic Therapy and also see Dosage: Conversion from Other Opiate Therapy, under Dosage and Administration.)

Serotonin Syndrome

Serotonin syndrome reported during concurrent use of opiate agonists, including methadone, and serotonergic drugs or drugs that impair serotonin metabolism (e.g., MAO inhibitors).⁴⁰⁰ (See Interactions.)

Serotonin syndrome may occur at usual dosages.⁴⁰⁰ 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).⁴⁰⁰

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.⁴⁰⁰ Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.⁴⁰⁰

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.⁴⁰⁰ If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.⁴⁰⁰ In some patients, switching to a different opiate improved symptoms.⁴⁰⁰

Chronic Pulmonary Disease

Even usual therapeutic doses may decrease respiratory drive to the point of apnea in patients with COPD, cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.^{217 222}

Closely monitor these patients for respiratory depression, particularly during initiation of therapy and dosage titration.^{217 222} Consider use of nonopiate analgesics if possible.^{217 222}

Cachectic or Debilitated Patients

Increased risk of respiratory depression, since methadone clearance may be decreased and reduced fat stores or muscle wasting may alter the drug’s pharmacokinetics.²¹⁷

Closely monitor for respiratory depression, especially when other respiratory depressants are used concomitantly and during initiation of therapy and dosage titration.²¹⁷

Increased Intracranial Pressure or Head Trauma

Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.^{217 222} Monitor susceptible patients for sedation and respiratory depression, particularly during initiation of therapy.²¹⁷

Adverse effects of opiates may obscure the clinical course of intracranial pathology.^{217 222}

Use with caution, if at all, in patients with head trauma.²²² Avoid use in patients with impaired consciousness or coma.²¹⁷

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.²²²

May cause spasm of the sphincter of Oddi.²¹⁷ Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.²¹⁷ Opiates may increase serum amylase.²¹⁷

Contraindicated in patients with known or suspected paralytic ileus.²¹⁷ Avoid use in patients with other GI obstruction.²¹⁷

Hypotensive Effects

May cause severe hypotension (e.g., orthostatic hypotension and syncope) in ambulatory patients.^{217 222}

Increased risk in patients whose ability to maintain their BP is compromised by reduced blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).^{217 222} Monitor these patients for hypotension during initiation of therapy and dosage titration.²¹⁷

CNS Effects

May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery.^{217 222} Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.^{217 222}

Concomitant use with other CNS depressants may cause profound sedation, coma, respiratory depression, hypotension, or death.^{217 222 700 703} (See Specific Drugs under Interactions.) Deaths associated with methadone use, either therapeutically or illicitly, frequently have involved concomitant benzodiazepine use or abuse.^{217 222 416 417 418 435 700 701} (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions.)

Seizures

May aggravate preexisting seizure disorder.²¹⁷ Monitor for worsened seizure control.²¹⁷

May induce seizures in some clinical settings.²¹⁷

Acute Pain Management in Patients Receiving Maintenance Treatment

Patients receiving methadone maintenance treatment who experience physical trauma or acute (e.g., postoperative) pain should not be expected to derive adequate analgesia from their stable methadone regimen.^{217 222}

Such patients should receive analgesics, including opiates, appropriate for other patients experiencing similar nociceptive stimulation.^{217 222} Opiate doses may be somewhat higher or dosing intervals somewhat shorter than those in nontolerant patients.^{217 222}

Anxiety

Anxiety in a patient receiving methadone maintenance treatment should not be confused with withdrawal syndrome and should not be treated with an increase in methadone dosage.²²²

Hypothyroidism

Use with caution and in reduced dosage in patients with hypothyroidism.²²²

Prostatic Hypertrophy or Urethral Stricture

Use with caution and in reduced dosage in patients with prostatic hypertrophy or urethral stricture.²²²

Addison’s Disease

Use with caution and in reduced dosage in patients with Addison’s disease.²²²

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;^{400 401 402 403 404} causality not established.⁴⁰⁰ Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.⁴⁰⁰ Perform appropriate laboratory testing in patients with manifestations of hypogonadism.⁴⁰⁰

Specific Populations

Pregnancy

Category C.^{217 222}

Use for obstetric analgesia is not recommended, since neonate may be at increased risk of respiratory depression because of the long duration of effect.²²²

The recommended treatment of opiate dependence in pregnant women is maintenance treatment with methadone or buprenorphine.^{350 372 373 374} Untreated opiate addiction is associated with adverse obstetrical outcomes (e.g., preeclampsia, fetal growth restriction, preterm birth, spontaneous abortion, fetal death) and often results in continued or relapsing illicit opiate use and engagement in high-risk behaviors.^{371 372 374}

Short- or long-term detoxification treatment is not recommended during pregnancy.²⁰¹ However, pregnant women, regardless of age, are eligible for admission into a comprehensive maintenance treatment program if they have a history of documented opiate dependence and are considered at risk of possibly returning to such dependence (and all its attendant risks) during pregnancy.^{201 213}

Clearance may be increased during 2nd and 3rd trimesters, resulting in the need for higher doses or shorter dosing intervals in order to avoid withdrawal symptoms.^{217 222}

Pregnant women in methadone maintenance programs receive better prenatal care, with fewer obstetric and fetal complications and reduced neonatal morbidity and mortality, compared with women using illicit drugs.^{217 222} Maternal use of methadone during pregnancy as part of a supervised therapeutic regimen is considered unlikely to pose a substantial teratogenic risk; however, data are insufficient to fully exclude such risk.^{217 222 280}

In a controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]) comparing neonatal outcomes following maternal use of either methadone or buprenorphine for treatment of opiate dependence during pregnancy (from average gestational age of 18.7 weeks until delivery), similar outcomes (proportion of neonates requiring treatment for opiate withdrawal syndrome, peak severity of the syndrome, head circumference, birth weight and length, preterm birth, gestational age at delivery, Apgar scores, serious adverse event rates) observed with maternal use of either drug, but buprenorphine-exposed neonates received a lower total morphine dosage for treatment of withdrawal, had shorter hospital stays, and required shorter duration of treatment for withdrawal compared with methadone-exposed neonates.^{370 371} However, rate of treatment discontinuance prior to delivery was higher for buprenorphine-treated women; this complicates interpretation of results.^{370 371}

Use in opiate-dependent women during pregnancy results in decreased fetal growth (reduced birth weight, length, and/or head circumference), but growth deficit does not appear to persist into later childhood.^{217 222 280 281}

Mild but persistent deficits in psychometric and behavioral test performance observed in children exposed to methadone in utero.^{217 222}

Possible increased risk of visual developmental anomalies in children born to opiate-dependent women who received methadone during pregnancy.²¹⁷

Unclear whether maternal use during pregnancy is associated with higher incidence of sudden infant death syndrome.^{217 222}

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome;²⁹² in contrast to adults, the withdrawal syndrome in neonates may be life-threatening²⁹² and requires management according to protocols developed by neonatology experts.^{350 352 353 358} Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.²⁹² Onset, duration, and severity vary depending on specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.^{355 357} Ensure availability of appropriate treatment.²⁹² (See Neonatal Opiate Withdrawal under Uses.)

Lactation

Distributed into milk.^{217 222 280 285} Peak concentrations in milk reportedly occur approximately 4–5 hours after an oral dose.^{217 222} Based on average milk consumption of 150 mL/kg daily, dose ingested by infant would be about 2–3.5% of oral maternal dose.^{217 222 285}

Detected in very low plasma concentrations in some infants whose mothers were receiving methadone.^{217 222} Sedation and respiratory depression reported in some infants exposed to methadone through breast milk.²¹⁷

Discontinuance of nursing should be gradual (not abrupt) to prevent withdrawal (neonatal abstinence syndrome) in the infant.^{217 222}

Experts recommend that women who are stable on methadone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, encourage women receiving methadone to continue treatment during the postpartum period.^{350 374 376} Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate.^{350 374 375}

The manufacturers state that benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.²⁹² (See Advice to Patients.)

Pediatric Use

Manufacturers state that safety, efficacy, and pharmacokinetics not established in pediatric patients <18 years of age.^{217 222}

Short- or long-term detoxification treatment using methadone is not subject to any age limitation.^{201 263} However, the effects of prolonged use on the physiologic and psychologic development of children are not known; therefore, do not initiate maintenance treatment with the drug indiscriminately in children <18 years of age.^{201 213}

Children <18 years of age are eligible to receive maintenance treatment provided they have undergone ≥2 documented attempts at detoxification or drug-free treatment in a 12-month period and the program physician has documented that the child continues to be, or is again, physiologically dependent on opiates.²⁶³ Signed informed consent must be obtained from a parent, legal guardian, or responsible adult designated by the appropriate local (e.g., state) authority (e.g., via emancipated minor laws).²⁶³

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults;^{217 222} however, geriatric patients may be at greater risk for respiratory depression^{217 222}

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution in this age group and select dosage at the lower end of the dosage range.^{217 222}

Closely monitor for respiratory and CNS depression, especially during initiation of therapy and dosage titration and when used concomitantly with other respiratory depressants.²¹⁷

Hepatic Impairment

Not studied extensively in patients with hepatic impairment.^{217 222} However, risk of accumulation with multiple doses because the drug is metabolized in the liver.^{217 222} Use with caution and in reduced dosage.^{217 222} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied extensively in patients with renal impairment.^{217 222} Use with caution and in reduced dosage.^{217 222} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Lightheadedness, dizziness, sedation, nausea, vomiting, sweating.^{217 222}

Drug Interactions

Metabolized principally by CYP isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by 2C9 and 2D6.^{217 222 232 235 251} .

Appears to be a P-glycoprotein substrate, but pharmacokinetics not substantially altered by P-glycoprotein inhibition.²¹⁷

Drugs Affecting Hepatic Microsomal Enzymes

CYP inducers: Possible increased metabolism and decreased plasma concentrations of methadone.^{217 222 232 235} Use with caution and careful monitoring.^{217 222 232 235}

CYP3A4 and/or CYP2C9 inhibitors: Possible decreased metabolism and increased plasma concentrations of methadone.^{217 222 232 235} Use with caution and careful monitoring.^{217 222 232 235}

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (prolongation of the QT interval; potential for severe and/or life-threatening cardiac arrhythmias).^{217 222} Use with extreme caution.^{217 222}

Drugs that May be Associated with Electrolyte Abnormalities

Potential pharmacologic interaction (potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias).^{217 222} Use with caution.^{217 222}

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs.⁴⁰⁰ May occur at usual dosages.⁴⁰⁰ Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.⁴⁰⁰ (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.⁴⁰⁰

If serotonin syndrome is suspected, discontinue methadone, other opiate therapy, and/or any concurrently administered serotonergic agents.⁴⁰⁰

Specific Drugs

Methadone Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.^a

Following oral administration, bioavailability is approximately 80%;^{223 232 235} however, there is considerable interindividual variability in oral bioavailability (range: 36–100%).²¹⁷ Peak concentrations occur 1–7.5 hours after oral administration.²¹⁷

Onset

Full analgesic effects generally are not achieved until completion of 3–5 days of therapy.^{217 222}

Peak respiratory depressant effects occur later than analgesic effects, particularly during the early dosing period.^{217 222}

Duration

Approximately 4–8 hours after a single dose.^{217 222 270 a}

Approximately 22–48 hours following oral administration in patients on methadone maintenance.^a

Respiratory depressant effects persist longer than analgesic effects, particularly during the early dosing period.^{217 222}

Food

Effect of food on bioavailability not established.²¹⁷

Plasma Concentrations

Trough plasma methadone concentrations exceeding 100–200 ng/mL may be necessary to optimize the success of methadone maintenance,^{205 206 207 208 209} particularly during the first 6 months of treatment.²⁰³

Distribution

Extent

Highly lipophilic and is widely distributed in body tissues.^{217 222 232 235} 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.^{217 222}

Methadone crosses the placenta and is distributed into milk.^{217 222 235}

Plasma Protein Binding

85–90% (mainly α₁-acid glycoprotein).^{217 222 232 235}

Elimination

Metabolism

Extensively metabolized, principally by CYP isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by 2C9 and 2D6.^{217 222 232 235 251}

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.^{217 222 232}

Appears to be a P-glycoprotein substrate, but pharmacokinetics not substantially altered by P-glycoprotein polymorphism or inhibition.²¹⁷

Elimination Route

Excreted to varying degrees in urine and feces as metabolites and unchanged drug.^{217 222 232 235}

Half-life

Considerable interindividual variability in terminal elimination half-life;^{217 222} generally reported as 8–59 hours,^{217 222} but values have ranged from 9–87 hours in postoperative patients, from 8.5–75 hours in opiate-dependent patients, and up to 120 hours in outpatients receiving therapy for chronic malignant pain.²³²

Special Populations

Elimination half-life is decreased during 2nd and 3rd trimesters of pregnancy.^{217 222}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).²¹⁷

Tablets, Dispersible

25°C (may be exposed to 15–30°C).^{261 262}

Oral Solution and Concentrate Solution

25°C (may be exposed to 15–30°C).^{225 226}

Parenteral

Injection

25°C (may be exposed to 15–30°C).²²²

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• A potent analgesic; shares the actions of the opiate agonists.^{217 222 262}

• Opiate agonists alter perception of and emotional response to pain.^c

• Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.^c

• Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).^c

• Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.^c

• Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.^c

• Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.^c

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

• Respiratory depression may be mediated by μ-receptors, possibly μ₂-receptors (which may be distinct from μ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.^c

• May also act as antagonist at N-methyl-D-aspartate (NMDA) receptors.^{217 222} Not known whether NMDA antagonism contributes to efficacy of methadone.^{217 222} Other NMDA antagonists have produced neurotoxic effects in animals.^{217 222}

• May depress the cough reflex by a direct effect on the cough centers in the medulla.^c

• Inhibits cardiac potassium channels and prolongs the QT interval.^{217 222}

Advice to Patients

• Importance of providing patient a copy of the manufacturer's patient information (medication guide) if required.²¹⁷

• Risk of respiratory depression, particularly following initiation of therapy and dosage increases.²¹⁷ Importance of recognizing respiratory depression and seeking immediate medical attention if breathing difficulty occurs.²¹⁷ Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.⁷⁵⁰

• Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.^{217 222}

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly; avoid concomitant use unless supervised by clinician.^{700 703} Importance of informing patients that methadone should not be combined with alcohol.^{217 222 700}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.^{217 222}

• Importance of advising patients to seek immediate medical attention if symptoms suggestive of an arrhythmia (e.g., palpitations, dizziness, lightheadedness, syncope) occur.^{217 222}

• Importance of informing patients that the duration of analgesia will increase with repeated dosing.²¹⁷ Importance of patients taking the drug only as prescribed and of not increasing the dose without consulting a clinician.²¹⁷

• Risk of orthostatic hypotension and syncope.²¹⁷ Importance of rising slowly from a seated or supine position.²¹⁷

• Importance of not abruptly discontinuing methadone following prolonged opiate therapy.^{217 222}

• Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.²¹⁷

• Importance of informing patients that methadone should never be given to anyone other than the individual for whom it was prescribed.²¹⁷

• Importance of storing methadone in a secure location and of properly disposing of any unused drug.²¹⁷ Accidental exposure, especially in children, may result in serious harm or death.²¹⁷

• Potential risk of serotonin syndrome with concurrent use of methadone and other serotonergic agents.⁴⁰⁰ Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.⁴⁰⁰

• Potential risk of adrenal insufficiency.⁴⁰⁰ Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.⁴⁰⁰

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.⁴⁰⁰ Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.⁴⁰⁰

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{217 222} Advise women of childbearing potential that prolonged use of opiates during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.²⁹² Advise women who are breast-feeding or wish to breast-feed that the drug distributes into milk, instruct them to recognize respiratory depression and sedation in infants and to know when to seek medical care, and advise them to discontinue nursing gradually (not abruptly) to prevent withdrawal symptoms in the infant.^{217 222}

• Importance of informing clinician of any breakthrough pain or adverse effects (e.g., constipation) that occur during therapy, so that therapy may be adjusted based on individual patient requirements.²¹⁷

• Potential for severe constipation.²¹⁷

• Importance of seeking immediate medical attention if anaphylaxis occurs.²¹⁷

• Importance of informing patients of other important precautionary information.^{217 222} (See Cautions.)

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.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug; also subject to the Substance Abuse and Mental Health Services Administration (SAMHSA) regulations (42 CFR 8) for drugs that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.

Distribution of 40-mg dispersible tablets is restricted.²⁷¹ (See Restricted Distribution under Dosage and Administration.)

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

Frequently asked questions

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