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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. [DSC] = Discontinued product

Concentrate, Oral, as hydrochloride:

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

Methadose: 10 mg/mL (1000 mL) [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]

Methadose: 10 mg [DSC]

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 weak N-methyl-D-aspartate (NMDA) receptor antagonism (Callahan, 2004).

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, and CYP2C19 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: 35 ± 22 hours (range: 9 to 87 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 function impairment.

Use: Labeled Indications

US labeling:

Chronic pain (except for oral soluble tablets for suspension): 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: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioids, reserve methadone for use in patients for whom alternative analgesic treatment options (eg, nonopioid analgesics, immediate-release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Methadone is not for use as an as-needed analgesic.

Detoxification: Detoxification and maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.

Canadian labeling:

Detoxification: Detoxification and maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.

Contraindications

Hypersensitivity to methadone or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma (in the absence of resuscitative equipment or in an unmonitored setting) or hypercarbia; known or suspected paralytic ileus; concurrent use of selegiline (Emsam product labeling)

Methadone is not to be used on an as-needed basis; it is not for pain that is mild or not expected to persist; it is not for acute pain or postoperative pain.

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

Dosing: Adult

Regulations regarding methadone use may vary by state and/or country. Obtain advice from appropriate regulatory agencies and/or consult with pain management/palliative care specialists. Note: These are guidelines and do not represent the maximum doses that may be required. Consider total daily dose, potency, prior opioid use, degree of opioid experience and tolerance, conversion from previous opioid, patient’s general condition, concurrent medications, and type and severity of pain during prescribing process. Other factors to consider:

• Interpatient variability in absorption, metabolism, and relative analgesic potency.

• Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.

• Duration of analgesic action is much shorter than plasma elimination half-life.

• Steady-state plasma concentrations and full analgesic effects are not attained until at least 3 to 5 days after initiation, and may take longer in some patients.

• Methadone has a narrow therapeutic index, particularly when used concomitantly with other medications.

Chronic pain:

Manufacturer’s labeling: Opioid-naive: Use as the first opioid analgesic:

Oral: Initial: 2.5 mg every 8 to 12 hours

IV: Initial: 2.5 to 10 mg every 8 to 12 hours; titrate slowly to effect; may also be administered by SubQ or IM injection (manufacturer’s labeling)

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:

Conversion from oral opioids to oral methadone: 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 oral 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. 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 in the table 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 in table are only for the conversion from another oral opioid analgesic to methadone. Table 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 is not a table of equianalgesic doses.

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 1000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.

Daily oral morphine dose >1000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.

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: Manufacturer's labeling: May adjust dosage every 3 to 5 days to a dose providing adequate analgesia and minimal adverse reactions. However, because of high interpatient variability, substantially longer periods between dose adjustments may be necessary in some patients (up to 12 days). 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: Manufacturer's labeling: When pain management is no longer required, do not abruptly discontinue. Reduce dose every 2 to 4 days to prevent signs or symptoms of withdrawal.

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

Detoxification: Oral:

Initial: A single dose of 20 to 30 mg is usually sufficient to suppress symptoms. Should not exceed 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 of methadone 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. Reassure the patient that duration of effect will increase as methadone accumulates.

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 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.

Dosage adjustment during pregnancy: Methadone dose may need to be increased or the dosing interval decreased when chronic doses are used during the second or third trimesters. Use is not appropriate for short term analgesia during labor and delivery.

Dosing: Geriatric

Oral, IM: 2.5 mg every 8 to 12 hours; refer to adult dosing.

Dosing: Renal Impairment

Off-label dosing (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. Avoid in severe liver disease.

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 msecs: 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 msecs during treatment.

QTc ≥500 msecs: Alternative therapies for opioid addiction or chronic pain are recommended. If QTc ≥500 msecs 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

Oral dose for detoxification and maintenance may be administered in fruit juice or water. Dispersible tablet should not be chewed or swallowed; add to liquid and allow to dissolve before administering. May rinse if residual remains. Injectable solution can be administered IM, SubQ, or IV; rate of IV administration not defined.

Compatibility

Stable in NS.

Y-site administration: Incompatible with phenytoin.

Storage

Injection: Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Oral concentrate, oral solution, tablet: Store at 25°C (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 or rasagiline 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

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 (Systemic): 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

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

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

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

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. 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

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

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 [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. 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

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

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

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)

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse (tablet, oral concentrate):

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 or conditions.

Life-threatening respiratory depression (tablet, oral concentrate):

Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase.

Life-threatening QT prolongation (tablet, oral concentrate):

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 for changes in cardiac rhythm during initiation and titration of methadone.

Accidental exposure (tablet, oral concentrate):

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

Neonatal opioid withdrawal syndrome:

Prolonged use of methadone during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management 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.

Treatment of opioid addiction (tablet, oral concentrate):

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.

Appropriate use (injection):

To treat narcotic addiction in detoxification or maintenance programs, methadone should be dispensed only by hospitals, community pharmacies, and maintenance programs approved by the FDA and designated state authorities. Approved maintenance programs shall dispense and use methadone in oral form only and according to treatment requirements stipulated in Federal Methadone Regulations. 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.

Methadone, used as an analgesic, may be dispensed in any licensed pharmacy.

Cardiac conduction effects (injection):

Laboratory studies, in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (greater than 200 mg/day). 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.

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 which require mental alertness (eg, operating machinery or driving).

• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).

• QT prolongation: [US Boxed Warning]: QTc interval prolongation and serious arrhythmias (eg, torsades de pointes) have occurred during treatment. Most cases involve patients being treated for pain with large, multiple daily doses. Closely monitor patients during initiation and titration for changes in cardiac rhythm. Patients should be informed of the potential arrhythmia risk, evaluated for any history of structural heart disease, arrhythmia, syncope, and for existence of potential drug interactions including drugs that possess QTc interval-prolonging properties, promote hypokalemia, hypomagnesemia, or hypocalcemia, or reduce elimination of methadone (eg, CYP3A4 inhibitors). Obtain baseline ECG for all patients and risk stratify according to QTc interval (see Monitoring Parameters). Use with caution in patients at risk for QTc prolongation, with medications known to prolong the QTc interval, promote electrolyte depletion, or inhibit CYP3A4, or history of conduction abnormalities. QTc interval prolongation and torsades de pointes may be associated with doses >200 mg/day, but have also been observed with lower doses. Other agents should be used in patients with a baseline QTc interval ≥500 msecs (Chou, 2014).

• Respiratory depression: [US Boxed Warning]: May cause serious, life-threatening, or fatal respiratory depression. Monitor closely for respiratory depression, especially during initiation or dose escalation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Peak respiratory depressant effect of methadone occurs later and persists longer than the peak analgesic effect, particularly during the initial dosing phase. Misuse or abuse (chewing, swallowing, snorting, or injecting the dissolved product) causes uncontrolled medication delivery resulting in a significant risk of overdose and death.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Avoid use in patients with obstruction. Use is contraindicated with known or suspected paralytic ileus.

• Adrenal 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 of methadone in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Drug abuse: Use opioids for chronic pain with caution in patients at increased risk for misuse; factors associated with increased risk include previous substance use disorder, younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Head injury or increased intracranial pressure (ICP): Use with extreme caution in patients with head injury, brain tumor, or elevated ICP; reduced respiratory drive and resultant CO2 retention can increase ICP.

• Hepatic impairment: Use with caution in patients with hepatic impairment; avoid with severe 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 treatment of opioid addiction (detoxification or maintenance), may only be dispensed by certified opioid treatment programs. These programs must be certified by the designated state authority; exceptions include inpatient treatment of other conditions and emergency period (not >3 days) while definitive substance abuse treatment is being sought.

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

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

• Respiratory disease: Contraindicated in patients with significant respiratory depression or conditions that increase the risk of life-threatening respiratory depression, acute or severe bronchial asthma, and hypercarbia. Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, or preexisting respiratory depression, particularly when initiating therapy and titrating with methadone; even therapeutic doses may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure disorders: Use with caution in patients with seizure disorders; may induce or aggravate seizures. Monitor for seizure control.

• 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:

• 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.

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

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.

• Elderly: Use with caution in the elderly; 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]).

• Neonates: Neonatal withdrawal syndrome: Oral formulations: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. 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.

• Soluble tablets (diskets): [US Boxed Warning]: For oral administration only; excipients to deter use by injection are contained in tablets.

Other warnings/precautions:

• Abuse/misuse/diversion: Oral formulations: [US Boxed Warning]: Users are exposed to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Risk of opioid abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness.

• Accidental exposure: 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 non-opioid 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.

• 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. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms. Gradually taper dose.

Monitoring Parameters

Assess efficacy of pain control; vital signs and mental status; signs of drug abuse, addiction, or diversion; signs or symptoms of hypogonadism or hypoadrenalism (Brennan, 2013). Also evaluate constipation, nausea, pruritus, respiratory depression, 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 msecs, or a history suggesting prior ventricular arrhythmia. If an ECG was obtained within the previous 3 months and it showed a QTc interval <450 msecs, 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

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Pregnancy Considerations

Adverse events were 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-naïve 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 maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. 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, arrhythmia, signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe dizziness, passing out, angina, tachycardia, bradycardia, illogical thinking, severe constipation, loss of strength and energy, sexual dysfunction, decreased libido, 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 irregularities, 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 healthcare 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.

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