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Methadone

Pronunciation

Pronunciation

(METH a done)

Index Terms

  • Methadone Hydrochloride

Dosage Forms

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

Concentrate, Oral, as hydrochloride:

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

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

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

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

Solution, Injection, as hydrochloride:

Generic: 10 mg/mL (20 mL)

Solution, Oral, as hydrochloride:

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

Tablet, Oral, as hydrochloride:

Dolophine: 5 mg, 10 mg [scored]

Generic: 5 mg, 10 mg

Tablet Soluble, Oral, as hydrochloride:

Methadose: 40 mg [scored]

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

Generic: 40 mg

Brand Names: U.S.

  • Dolophine
  • Methadone HCl Intensol
  • Methadose
  • Methadose Sugar-Free

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

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

Distribution

Lipophilic

Vd: (Mean ± SD): Children: 7.1 ± 2.5 L/kg; Adults: 6.1 ± 2.4 L/kg

Vdss: Adults: 1 to 8 L/kg

Metabolism

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

Excretion

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

Onset of Action

Oral: Analgesic: 0.5 to 1 hour; Parenteral: 10 to 20 minutes; Peak effect: Parenteral: 1 to 2 hours; Oral: Continuous dosing: 3 to 5 days

Time to Peak

1 to 7.5 hours

Duration of Action

Analgesia: Oral: 4 to 8 hours (single-dose studies), increases to 22 to 48 hours with repeated doses; slow release from the liver and other tissues may prolong duration of action

Half-Life Elimination

Terminal: Children: 19 ± 14 hours (range: 4 to 62 hours); Adults: 8 to 59 hours; may be prolonged with alkaline pH

Protein Binding

85% to 90% primarily to alpha-1 acid glycoprotein

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

Detoxification: Detoxification and maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services; injection is only for temporary treatment in patients unable to take oral medication.

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

Pain management:

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

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

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

Contraindications

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

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

Canadian labeling: Additional contraindications (not in US labeling): Diarrhea associated with pseudomembranous colitis or caused by poisoning until toxic material has been eliminated from the GI tract; concurrent use or use within 14 days of a monoamine oxidase inhibitor (Methadose product labeling)

Dosing: Adult

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse. Methadone has high interpatient variability in absorption, metabolism, and relative analgesic potency and exposure accumulates with repeated dosing, resulting in increased methadone potency. Therefore, equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals and will vary depending on baseline opioid requirements. Deaths have occurred during conversion from chronic high-dose treatment with other opioids and in patients who previously abused high doses of other opioids. Special attention is required during treatment initiation, during conversion from one opioid to another, and during dose titration. Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose and methadone has a narrow therapeutic index, especially when combined with other drugs.

Detoxification: Note: Diskets can be administered only in 10 mg increments; may not be appropriate product for initial dosing or dose reductions.

IV: Note: For use only in patients unable to take oral medication (such as during hospitalization). For dosing, convert patient's oral methadone dose to an equivalent parenteral dose using the conversions provided in Pain Management.

Oral:

Initial: 20 to 30 mg (as a single dose) when there are no signs of sedation or intoxication and patient shows symptoms of withdrawal; maximum initial dose: 30 mg. Lower doses should be considered in patients with low tolerance at initiation (eg, absence of opioids ≥5 days); an additional 5 to 10 mg may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear after 2 to 4 hours; total daily dose on the first day should not exceed 40 mg. Do not increase dose without waiting for steady-state to be achieved. Levels will accumulate over the first few days; deaths have occurred in early treatment due to cumulative effects.

Maintenance: Titrate to a dosage which prevents opioid withdrawal symptoms for 24 hours, prevents craving, attenuates euphoric effect of self-administered opioids, and tolerance to sedative effects of methadone. Usual range: 80 to 120 mg/day (titration should occur cautiously)

Withdrawal: Dose reductions should be <10% of the maintenance dose, every 10 to 14 days

Detoxification (short-term): Oral:

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

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

Withdrawal: After 2 to 3 days of stabilization at 40 mg, gradually decrease the dose on a daily basis or at 2-day intervals. Keep dose at a level sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a total daily dose decrease of 20%; ambulatory patients may require a slower reduction.

Pain management:

Manufacturer's labeling: Opioid-naive (use as the first opioid analgesic):

Oral (Dolophine only): Initial: 2.5 mg every 8 to 12 hours

IM, IV, SubQ: Initial: 2.5 to 10 mg every 8 to 12 hours; titrate slowly to effect

Alternative recommendations: Opioid-naive: Oral:

Gradual titration (for chronic noncancer pain and situations where frequent monitoring is unnecessary): Initial: 2.5 mg every 8 hours; may increase dose by 2.5 mg per dose (Va/DoD 2010) or 5 mg per day (Chou 2014) every 5 to 7 days. Once a stable dose is reached, the dosing interval may be extended to every 8 to 12 hours, or longer (Va/DOD 2010).

Faster titration (for cancer pain and situations where frequent monitoring is possible): Initial: 2.5 mg every 6 to 8 hours; may increase dose by 2.5 mg per dose as often as every day over about 4 days. Once a stable dose is reached, the dosing interval may be extended to every 8 to 12 hours, or longer (Va/DoD 2010).

Conversion recommendations:

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

Conversion from oral opioids to oral methadone:

Daily oral morphine dose <100 mg: Estimated daily oral methadone dose: 20% to 30% of total daily morphine dose

Daily oral morphine dose 100 to 300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose

Daily oral morphine dose 300 to 600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose

Daily oral morphine dose 600 to 1,000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.

Daily oral morphine dose >1,000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.

Conversion from oral morphine to parenteral methadone:

Daily oral morphine dose <100 mg: Estimated daily IV methadone dose: 10% to 15% of total daily morphine dose

Daily oral morphine dose 100 to 300 mg: Estimated daily IV methadone dose: 5% to 10% of total daily morphine dose

Daily oral morphine dose 300 to 600 mg: Estimated daily IV methadone dose: 4% to 6% of total daily morphine dose

Daily oral morphine dose 600 to 1,000 mg: Estimated daily IV methadone dose: 3% to 5% of total daily morphine dose.

Daily oral morphine dose >1,000 mg: Estimated daily IV methadone dose: <3% of total daily morphine dose.

Conversion from parenteral morphine to parenteral methadone:

Total daily parenteral morphine dose: 10 to 30 mg: Estimated daily parenteral methadone dose: 40% to 66%

Total daily parenteral morphine dose: 30 to 50 mg: Estimated daily parenteral methadone dose: 27% to 66%

Total daily parenteral morphine dose: 50 to 100 mg: Estimated daily parenteral methadone dose: 22% to 50%

Total daily parenteral morphine dose: 100 to 200 mg: Estimated daily parenteral methadone dose: 15% to 34%

Total daily parenteral morphine dose: 200 to 500 mg: Estimated daily parenteral methadone dose: 10% to 20%

Conversion from parenteral methadone to oral methadone: Initial dose: Parenteral: Oral ratio: 1:2 (eg, 5 mg parenteral methadone equals 10 mg oral methadone)

Alternative recommendations: Opioid-tolerant:

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

Titration and maintenance: May adjust dosage no more frequently than every 3 to 5 days; because of high interpatient variability, substantially longer periods between dose increases may be necessary in some patients (up to 12 days). If unacceptable adverse reactions are observed, reduce dose and/or dosing interval (ie, every 8 or 12 hours). Breakthrough pain may require a dose increase or rescue medication with an immediate-release analgesic. Some guidelines note that dose increases should not be more than 10 mg per day every 5 to 7 days (Chou 2014).

Discontinuation: Reduce dose gradually by 15% to 50% every 2 to 4 days to prevent signs or symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Critically ill patients (off-label use; Barr 2013): Note: May be used to slow development of tolerance when escalation with other opioids is required. Enteral methadone has also been used to wean prolonged continuous opioid infusions (Al Qadheeb 2012)

Oral: 10 to 40 mg every 6 to 12 hours

IV: 2.5 to 10 mg every 8 to 12 hours

Dosing: Geriatric

Refer to adult dosing. Use with caution; initiate at the low end of dosage range and titrate slowly.

Dosing: Renal Impairment

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

The following dosage adjustments have been recommended (Aronoff 2007): Adults:

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: Administer 50% to 75% of normal dose

Hemodialysis and peritoneal dialysis do not increase elimination of methadone.

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

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

QTc prolongation (Chou 2014):

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

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

Administration

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

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

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Store vials in carton until ready for use.

Oral concentrate, tablet for oral suspension: Store at 20°C to 25°C (68°F to 77°F). Protect oral concentrate from light.

Oral solution, tablet: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Metatol-D [Canadian product]: Store at 15°C to 30°C (59°F to 86°F). Protect tablets from light. Protect oral concentrate and oral solution from light and freezing. After dilution of oral concentrate in compatible diluent, may store at 2°C to 8°C (35.6°F to 46.4°F) for 7 or 14 days (refer to manufacturer labeling for specific recommendations)

Drug Interactions

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

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

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

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

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

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

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline, rasagiline, or safinamide is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: Methadone may enhance the CNS depressant effect of ARIPiprazole. ARIPiprazole may enhance the QTc-prolonging effect of Methadone. Monitor therapy

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benzodiazepines: May enhance the CNS depressant effect of Methadone. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: May increase the serum concentration of Methadone. Boceprevir may decrease the serum concentration of Methadone. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May increase the metabolism of Methadone. Consider therapy modification

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

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

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

Cobicistat: May increase the serum concentration of Methadone. Management: No increased monitoring appears necessary if the cobicistat regimen also contains elvitegravir. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Didanosine: Methadone may decrease the serum concentration of Didanosine. Management: If use of methadone with didanosine is necessary, enteric coated didanosine is preferred. Avoid using didanosine powder for solution with methadone. Increased monitoring of clinical response to didanosine (including viral load) is necessary. Consider therapy modification

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

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Methadone. Monitor therapy

Fluconazole: May enhance the QTc-prolonging effect of Methadone. Fluconazole may increase the serum concentration of Methadone. Management: Monitor patients closely for evidence of methadone toxicities, including but not limited to respiratory depression and QT-prolongation/torsades de pointes, if combined with fluconazole. Methadone dose reductions may be required. Consider therapy modification

FluvoxaMINE: Methadone may enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Methadone. Monitor therapy

Fosamprenavir: Methadone may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be reduced. This effect has been demonstrated with Amprenavir alone but not with Fosamprenavir / Ritonavir. The potential impact on Fosamprenavir alone has not been investigated. Fosamprenavir may decrease the serum concentration of Methadone. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Methadone. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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

Hydroxychloroquine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

Itraconazole: May increase the serum concentration of Methadone. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Lofexidine: May enhance the QTc-prolonging effect of Methadone. Avoid combination

Lopinavir: Methadone may enhance the QTc-prolonging effect of Lopinavir. Lopinavir may decrease the serum concentration of Methadone. More specifically, the combination of Lopinavir and Ritonavir may decrease Methadone serum concentrations. Avoid combination

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

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

MAO Inhibitors: Methadone may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Monitor therapy

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

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

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

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

PHENobarbital: May decrease the serum concentration of Methadone. Monitor therapy

Phenytoin: May decrease the serum concentration of Methadone. Monitor therapy

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

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

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

Primidone: May decrease the serum concentration of Methadone. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

QUEtiapine: Methadone may enhance the QTc-prolonging effect of QUEtiapine. QUEtiapine may increase the serum concentration of Methadone. Avoid combination

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Exceptions: Delavirdine; Etravirine. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Methadone. Management: Seek alternatives when possible. If used concomitantly, monitor closely for symptoms of methadone withdrawal upon rifamycin derivative initiation, and for excess sedation upon rifamycin derivative discontinuation. Exceptions: Rifabutin. Consider therapy modification

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

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

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

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

Saquinavir: Methadone may enhance the QTc-prolonging effect of Saquinavir. Saquinavir may decrease the serum concentration of Methadone. Management: Use methadone and saquinavir cautiously in combination, seeking alternatives when possible due to the potential for excessive QT interval prolongation and associated arrhythmias. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy

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

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

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Telaprevir: May decrease the serum concentration of Methadone. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Voriconazole: May increase the serum concentration of Methadone. Management: Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor patients closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Consider therapy modification

Xipamide: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

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

Test Interactions

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Adverse Reactions

Frequency not defined. During prolonged administration, adverse effects may decrease over several weeks; however, constipation and sweating may persist.

Cardiovascular: Bigeminy, bradycardia, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, edema, extrasystoles, flushing, hypotension, inversion T wave on ECG, orthostatic hypotension, palpitations, peripheral vasodilation, phlebitis, prolonged Q-T interval on ECG, shock, syncope, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia

Central nervous system: Agitation, confusion, disorientation, dizziness, drowsiness, drug dependence (physical dependence), dysphoria, euphoria, habituation, hallucination, headache, insomnia, sedation, seizure

Dermatologic: Diaphoresis, hemorrhagic urticaria (can occur locally with intravenous administration [rare]), localized erythema (intravenous/subcutaneous), pruritus, rash at injection site (intravenous), skin rash, urticaria, urticaria at injection site (intravenous)

Endocrine & metabolic: Amenorrhea, antidiuretic effect, decreased libido, hypokalemia, hypomagnesemia, weight gain

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

Genitourinary: Impotence, urinary hesitancy, urinary retention

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

Local: Local pruritus (intravenous), local pain (intravenous/subcutaneous), local swelling (intravenous/subcutaneous)

Neuromuscular & skeletal: Weakness

Ophthalmic: Miosis, visual disturbance

Respiratory: Pulmonary edema, respiratory arrest, respiratory depression

<1% (Limited to important or life-threatening): Hypogonadism (Brennan 2013; Debono 2011), increased serum prolactin (transient increase with chronic use; Molitch 2008)

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Methadone exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing methadone, and monitor all patients regularly for the development of these behaviors and conditions.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur; has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and methadone should only be prescribed by health care providers who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period.

Life-threatening QT prolongation:

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

Accidental ingestion (oral formulations):

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

Neonatal opioid withdrawal syndrome:

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

Conditions for distribution and use of methadone products for the treatment of opioid addiction:

For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration.

When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone should be dispensed only by opioid treatment programs (and agencies, or practitioners or institutions by formal agreement with the program sponsor) certified by the substance abuse and mental health services administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of drug supply, revocation of program approval, and injunction precluding program operation.

Cytochrome P450 interaction:

The concomitant use of methadone with all cytochrome P450 (CYP-450) 3A4, 2B6, 2C19, 2C9, or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used CYP450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Warnings/Precautions

Concerns related to adverse effects:

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

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

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

• QT prolongation: [US Boxed Warning]: QT interval prolongation and serious arrhythmias (torsades de pointes) have occurred during treatment. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of QT interval (eg, cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone. QT interval prolongation and torsades de pointes may be more commonly associated with, but not limited to, higher dose treatment >200 mg/day. QT prolongation has been reported in patients with no prior cardiac history who have received high doses of methadone. Only initiate therapy in patients for whom anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias. Other agents should be used in patients with a baseline QTc interval ≥500 msec (Chou 2014).

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur; has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and methadone should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St. John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

Disease-related concerns:

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

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

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

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

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

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

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

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

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

• Opioid addiction: [US Boxed Warning]: When used for detoxification and maintenance of opioid addiction, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration. When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone should be dispensed only by opioid treatment programs (and agencies, or practitioners or institutions by formal agreement with the program sponsor) certified by the substance abuse and mental health services administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of drug supply, revocation of program approval, and injunction precluding program operation. Regulatory exceptions to the general requirements for certification to provide opioid agonist treatment include inpatient treatment of other conditions and emergency period (not >3 days) while definitive substance abuse treatment is being sought.

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

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

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

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

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

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

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

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

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

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

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

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or addiction. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

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

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Methadone exposes patients and other users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors and conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use.

• Accidental ingestion: Oral formulations: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of methadone.

• Addiction involving opioid use: When switching patients from methadone to buprenorphine, patients should preferably be on low doses of oral methadone (<30 to 40 mg/day) prior to the switch to lessen discomfort. Patients switching from methadone to naltrexone (oral or extended release IM) require complete withdrawal from methadone or other opioids before naltrexone initiation (typically achieved in 7 days but up to 14 days may be necessary). A naloxone challenge test may be helpful to confirm patient is opioid-free prior to therapy (Kampman [ASAM 2015]).

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]). Should only be prescribed by health care professionals who are knowledgeable in the use of potent opioids for chronic pain management.

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

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

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs of misuse, abuse, and addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013). Also evaluate constipation, nausea, pruritus, and sedation (Chou 2014).

Obtain baseline ECG (evaluate QTc interval) prior to therapy in patients with risk factors for QTc interval prolongation, a prior ECG with a QTc >450 msec, or a history suggesting prior ventricular arrhythmia. If an ECG was obtained within the previous 3 months and it showed a QTc interval <450 msec, it can be used as a baseline for patients without new risk factors. Repeat ECG 2 to 4 weeks after initiating therapy and after significant dose increases; follow-up ECG should also be done if new risk factors present or signs/symptoms of arrhythmia occur. Repeat ECG when the methadone dose reaches 30 to 40 mg per day (when started at lower doses) and again at 100 mg per day (Chou 2014).

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Methadone crosses the placenta and can be detected in cord blood, amniotic fluid, and newborn urine.

Methadone is considered the standard of care when treating opioid addiction in pregnant women. Women receiving methadone for the treatment of addiction should be maintained on their daily dose of methadone in addition to receiving the same pain management options during labor and delivery as opioid-naive women; maintenance doses of methadone will not provide adequate pain relief. Opioid agonist-antagonists should be avoided for the treatment of labor pain in women maintained on methadone due to the risk of precipitating acute withdrawal (ACOG 2012; Dow 2012).

Data is available related to fetal/neonatal outcomes following maternal use of methadone during pregnancy. Information collected by the Teratogen Information System is complicated by maternal use of illicit drugs, nutrition, infection, and psychosocial circumstances. However, pregnant women in methadone treatment programs are reported to have improved fetal outcomes compared to pregnant women using illicit drugs. Fetal growth, birth weight, length, and/or head circumference may be decreased in infants born to opioid-addicted mothers treated with methadone during pregnancy. Growth deficits do not appear to persist; however, decreased performance on psychometric and behavioral tests has been found to continue into childhood. Abnormal fetal nonstress tests have also been reported.

[US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Withdrawal symptoms in the neonate may be observed up to 2 to 4 weeks after delivery and should be expected (ACOG 2012). Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow 2012; Hudak 2012). Monitoring is recommended for neonates born to mothers receiving methadone for neonatal abstinence syndrome (Chou 2014).

Methadone clearance in pregnant women is increased and half-life is decreased during the 2nd and 3rd trimesters of pregnancy; the dosage of methadone may need increased or dosing interval decreased during pregnancy to avoid withdrawal symptoms in the mother. Dosage may need decreased following delivery (ACOG 2012).

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013). Amenorrhea may also develop secondary to substance abuse; pregnancy may occur following the initiation of buprenorphine or methadone maintenance treatment. Contraception counseling is recommended to prevent unplanned pregnancies (Dow 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, or sweating a lot. Have patient report immediately to prescriber difficulty breathing, slow breathing, shallow breathing, abnormal heartbeat, signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of low magnesium (mood changes; muscle pain or weakness; muscle cramps or spasms; seizures; tremors; lack of appetite; severe nausea or vomiting; or an abnormal heartbeat), signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), severe dizziness, passing out, angina, tachycardia, bradycardia, confusion, severe constipation, severe loss of strength and energy, sexual dysfunction (males), amenorrhea, decreased libido, infertility, hallucinations, mood changes, seizures, severe abdominal pain, severe headache, shortness of breath, excessive weight gain, swelling of arms or legs, insomnia, difficult urination, bruising, bleeding, vision changes, menstrual changes, severe fatigue, or severe injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.