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Special Alerts
Methadone: Recommendations for QTc Interval Screening Before and During Methadone Treatment - Updated: January 2009
The Center for Substance Abuse and Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration has developed a consensus guideline statement outlining recommendations regarding ECG monitoring in patients being considered for and being treated with methadone regardless of indication. Of note, these recommendations should not supersede clinical judgment or patient preferences and may not apply to patients with terminal, intractable cancer pain.
Five recommendations have been developed:
Recommendation 1 [Disclosure]: Clinicians should inform patients of arrhythmia risk when methadone is prescribed.
Recommendation 2 [Clinical History]: Clinicians should inquire about any history of structural heart disease, arrhythmia, and syncope.
Recommendation 3 [Screening]: Clinicians should obtain pretreatment ECG for all patients to measure QTc interval, follow up ECG within 30 days, then annually (monitor more frequently if patient receiving >100 mg/day or if unexplained syncope or seizure occurs while on methadone).
Recommendation 4 [Risk Stratification]: If before or at anytime during therapy:
QTc >450-499 msecs: Discuss potential risks and benefits; monitor QTc more frequently
QTc ?500 msecs: Consider discontinuation or reducing methadone dose or eliminate factors promoting QTc prolongation (eg, potassium-wasting drugs) or use alternative therapy (eg, buprenorphine)
Recommendation 5 [Drug Interactions]: Clinicians should be aware of interactions between methadone and other drugs that either prolong the QT interval or reduce methadone elimination.
The panel also concluded that the arrhythmia risk is directly associated with methadone's ability to block the delayed rectifier potassium channel (Ikr) and prolong repolarization. The guideline further states that the use of the Bazett formula is adequate even though it is likely to overcorrect with high heart rates. The patient should remain supine for at least 5 minutes prior to obtaining ECG. In addition, screening for QTc prolongation using automated readings does not require a specialist (eg, cardiologist) and may be performed in a primary care setting. However, in cases when uncertainty exists about whether or not clinically significant QTc prolongation is present, the ECG should be repeated or interpreted by a cardiologist.
For more information, refer to: Krantz MJ, Martin J, Stimmel B, et al, “QTc Interval Screening in Methadone Treatment,” Ann Int Med, 2009, 150(1):1-10 (epub ahead of print).
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Methadone may be confused with dexmethylphenidate, Mephyton®, methylphenidate, Metadate® CD, and Metadate® ER
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(METH a done)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of moderate-to-severe pain; detoxification and maintenance treatment of opioid addiction as part of an FDA-approved program
Restrictions
C-II
When used for treatment of opioid addiction: May only be dispensed in accordance to guidelines established by the Substance Abuse and Mental Health Services Administration's (SAMHSA) Center for Substance Abuse Treatment (CSAT). Regulations regarding methadone use may vary by state and/or country. Obtain advice from appropriate regulatory agencies and/or consult with pain management/palliative care specialists.
Note: Regulatory Exceptions to the General Requirement to Provide Opioid Agonist Treatment (per manufacturer's labeling):
1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction, to facilitate the treatment of the primary admitting diagnosis.
2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility.
Pregnancy Risk Factor
C/D (prolonged use or high doses at term)
Pregnancy Considerations
Teratogenic effects have been observed in some, but not all, animal studies. Data collected by the Teratogen Information System are 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. Methadone can be detected in the amniotic fluid, cord plasma, and newborn urine. Fetal growth, birth weight, length, and/or head circumference may be decreased in infants born to narcotic-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. Withdrawal symptoms in the neonate may be observed up to 2-4 weeks after delivery. The manufacturer states that methadone should be used during pregnancy only if clearly needed. Because methadone clearance in pregnant women is increased and half-life is decreased during the 2nd and 3rd trimesters of pregnancy, withdrawal symptoms may be observed in the mother; dosage of methadone may need increased or dosing interval decreased during pregnancy.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”)
Breast-Feeding Considerations
Peak methadone levels appear in breast milk 4-5 hours after an oral dose. Methadone has been detected in the plasma of some breast-fed infants whose mothers are taking methadone. Use during breast-feeding is not recommended, and the manufacturer recommends that women on high dose methadone maintenance who already are breast-feeding be instructed to wean breast-feeding gradually to avoid neonatal abstinence syndrome. Sedation and respiratory depression have been reported in nursing infants. Unless otherwise contraindicated (concurrent medical conditions, other medications of abuse), the AAP rates methadone “compatible” with breast-feeding.
Contraindications
Hypersensitivity to methadone or any component of the formulation; respiratory depression (in the absence of resuscitative equipment or in an unmonitored setting); acute bronchial asthma or hypercarbia; paralytic ileus; concurrent use of selegiline
Warnings/Precautions
Boxed warnings:
• Opioid addiction use: See “Other warnings/precautions” below.
• QT prolongation: See “Concerns related to adverse effects” below.
• Respiratory depression: See “Concerns related to adverse effects” below.
• Tablets: See “Dosage form specific issues” below.
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).
• QTc prolongation: [U.S. Boxed Warning]: May prolong the QTc interval and increase risk for torsade de pointes. 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 torsade de pointes may be associated with doses >100 mg/day, but have also been observed with lower doses.
• Respiratory depression: [U.S. Boxed Warning]: Severe respiratory depression has occurred with administration. Use extreme caution during treatment initiation, dose titration and conversion from other opioid agonists to methadone. Peak respiratory depressant effects occur later and persist longer than peak analgesic effects possibly contributing to cases of iatrogenic overdose.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; acute pancreatitis may cause constriction of sphincter of Oddi.
• CNS depression/coma: Use with caution in patients with CNS depression or coma.
• Depression: Use with caution in patients with depression or suicidal tendencies.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with severe hepatic failure.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urethral stricture: Use with caution in patients with prostatic hyperplasia and/or urethral stricture.
• Renal impairment: Use with caution in patients with severe renal failure.
• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages. Because the respiratory effects last longer than the analgesic effects, slow titration is required.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• High potential for interactions: Use with caution in patients receiving concurrent use of medications known to inhibit CYP3A4, prolong the QTc interval, or promote hypokalemia, hypomagnesemia, or hypocalcemia; may require dosage adjustments or use of alternative therapy.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Debilitated patients: Use with caution in 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.
• Pediatrics: Safety and efficacy have not been established in children.
Dosage form specific issues:
• Tablets: [U.S. Boxed Warning]: For oral administration only; excipients to deter use by injection are contained in tablets.
Other warnings/precautions:
• Acute pain management: Patients maintained on stable doses may need higher and/or more frequent doses in case of acute pain (eg, postoperative pain, physical trauma).
• Anxiety use: Methadone is ineffective for the relief of anxiety.
• 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.
• Narcotic addiction use: [U.S. Boxed Warning]: When used for treatment of narcotic addiction: May only be dispensed by opioid treatment programs when used for treatment of narcotic addiction: 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.
• 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.
• Withdrawal: Concurrent use of agonist/antagonist 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.
Adverse Reactions
Frequency not defined. During prolonged administration, adverse effects may decrease over several weeks; however, constipation and sweating may persist.
Cardiovascular: Arrhythmia, bigeminal rhythms, bradycardia, cardiac arrest, cardiomyopathy, ECG changes, edema, extrasystoles, faintness, flushing, heart failure, hypotension, palpitation, peripheral vasodilation, phlebitis, orthostatic hypotension, QT interval prolonged, shock, syncope, tachycardia, torsade de pointes, T-wave inversion, ventricular fibrillation, ventricular tachycardia,
Central nervous system: Agitation, confusion, disorientation, dizziness, drowsiness, dysphoria, euphoria, hallucination, headache, insomnia, lightheadedness, sedation, seizure
Dermatologic: Hemorrhagic urticaria, pruritus, rash, urticaria
Endocrine & metabolic: Antidiuretic effect, amenorrhea, hypokalemia, hypomagnesemia, libido decreased
Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, constipation, glossitis, nausea, stomach cramps, vomiting, weight gain, xerostomia
Genitourinary: Impotence, urinary retention or hesitancy
Hematologic: Thrombocytopenia (reversible, reported in patients with chronic hepatitis)
Neuromuscular & skeletal: Weakness
Local: I.M./SubQ injection: Erythema, pain, swelling; I.V. injection: Hemorrhagic urticaria (rare), pruritus, urticaria, rash
Ocular: Miosis, visual disturbances
Respiratory: Pulmonary edema, respiratory depression, respiratory arrest
Miscellaneous: Death, diaphoresis, physical and psychological dependence
Metabolism/Transport Effects
Substrate of CYP2C9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP2D6 (moderate), 3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Methadone. Risk C: Monitor therapy
Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Barbiturates: May increase the metabolism of Methadone. Risk D: Consider therapy modification
CarBAMazepine: May increase the metabolism of Methadone. Risk D: Consider therapy modification
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Didanosine: Methadone may decrease the serum concentration of Didanosine. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of Methadone. Risk C: Monitor therapy
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Phenytoin: May increase the metabolism of Methadone. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Protease Inhibitors: May decrease the metabolism of Methadone. Exceptions: Atazanavir; Indinavir. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the metabolism of Methadone. Exceptions: Delavirdine; Etravirine. Risk D: Consider therapy modification
Rifamycin Derivatives: May increase the metabolism of Methadone. Exceptions: Rifabutin. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Methadone. Fluvoxamine appears to be the only interacting SSRI. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
Zidovudine: Methadone may increase the serum concentration of Zidovudine. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS effects). Watch for sedation.
Herb/Nutraceutical: Avoid St John's wort (may decrease methadone levels; may increase CNS depression). Avoid valerian, kava kava, gotu kola (may increase CNS depression). Methadone is metabolized by CYP3A4 in the intestines; avoid concurrent use of grapefruit juice.
Storage
Injection: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.
Oral concentrate, oral solution, tablet: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).
Compatibility
Stable in NS.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Onset of action: Oral: Analgesic: 0.5-1 hour; Parenteral: 10-20 minutes
Peak effect: Parenteral: 1-2 hours; Oral: continuous dosing: 3-5 days
Duration of analgesia: Oral: 4-8 hours, increases to 22-48 hours with repeated doses
Distribution: Vdss: 1-8 L/kg
Protein binding: 85% to 90%
Metabolism: Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, and CYP2C19 to inactive metabolites
Bioavailability: Oral: 36% to 100%
Half-life elimination: 8-59 hours; may be prolonged with alkaline pH, decreased during pregnancy
Time to peak, plasma: 1-7.5 hours
Excretion: Urine (<10% as unchanged drug); increased with urine pH <6
Dosage
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 in all patients. Methadone accumulates with repeated doses and dosage may need reduction after 3-5 days to prevent CNS depressant effects. Some patients may benefit from every 8-12 hour dosing interval for chronic pain management. Doses should be titrated to appropriate effects.
Children (unlabeled use):
Pain (analgesia):
Oral: Initial: 0.1-0.2 mg/kg 4-8 hours initially for 2-3 doses, then every 6-12 hours as needed. Dosing interval may range from 4-12 hours during initial therapy; decrease in dose or frequency may be required (?days 2-5) due to accumulation with repeated doses (maximum dose: 5-10 mg)
I.V.: 0.1 mg/kg every 4-8 hours initially for 2-3 doses, then every 6-12 hours as needed. Dosing interval may range from 4-12 hours during initial therapy; decrease in dose or frequency may be required (?days 2-5) due to accumulation with repeated doses (maximum dose: 5-8 mg)
Iatrogenic narcotic dependency: Oral: General guidelines: Initial: 0.05-0.1 mg/kg/dose every 6 hours; increase by 0.05 mg/kg/dose until withdrawal symptoms are controlled; after 24-48 hours, the dosing interval can be lengthened to every 12-24 hours; to taper dose, wean by 0.05 mg/kg/day; if withdrawal symptoms recur, taper at a slower rate
Adults:
Acute pain (moderate-to-severe):
Oral: Opioid-naive: Initial: 2.5-10 mg every 8-12 hours; more frequent administration may be required during initiation to maintain adequate analgesia. Dosage interval may range from 4-12 hours, since duration of analgesia is relatively short during the first days of therapy, but increases substantially with continued administration.
Chronic pain (opioid-tolerant): Conversion from oral morphine 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 100-300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose
Daily oral morphine dose 300-600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose
Daily oral morphine dose 600-1000 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.
Note: The total daily methadone dose should then be divided to reflect the intended dosing schedule.
I.V.: Manufacturers labeling: Initial: 2.5-10 mg every 8-12 hours in opioid-naive patients; titrate slowly to effect; may also be administered by SubQ or I.M. injection
Conversion from oral methadone to parenteral methadone dose: Initial dose: Parenteral:Oral ratio: 1:2 (eg, 5 mg parenteral methadone equals 10 mg oral methadone)
Detoxification: Oral:
Initial: A single dose of 20-30 mg is generally 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 5-10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear after 2-4 hours; total daily dose on the first day should not exceed 40 mg, unless the program physician documents in the patient's record that 40 mg did not control opiate abstinence symptoms.
Maintenance: Titrate to a dosage which attenuates craving, blocks euphoric effects of other opiates, and tolerance to sedative effect of methadone. Usual range: 80-120 mg/day (titration should occur cautiously)
Withdrawal: Dose reductions should be <10% of the maintenance dose, every 10-14 days
Detoxification (short-term): Oral:
Initial: Titrate to ?40 mg/day in divided doses to achieve stabilization, may continue 40 mg dose for 2-3 days
Maintenance: Titrate to a dosage which prevents/attenuates euphoric effects of self-administered opioids, reduces drug craving, and withdrawal symptoms are prevented for 24 hours.
Withdrawal: Requires individualization. Decrease daily or every other day, keeping withdrawal symptoms tolerable; hospitalized patients may tolerate a 20% reduction/day; ambulatory patients may require a slower reduction
Dosage adjustment during pregnancy: Methadone dose may need to be increased, or the dosing interval decreased; see Pregnancy Implications - use should be reserved for cases where the benefits clearly outweigh the risks
Dosage adjustment for toxicity:
QTc >450-499 msecs: Monitor QTc more frequently
QTc ?500 msecs: Consider discontinuation or reducing methadone dose
Dosage adjustment in renal impairment: Clcr <10 mL/minute: Administer 50% to 75% of normal dose
Dosage adjustment in hepatic impairment: Avoid in severe liver disease
Administration: Oral
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.
Administration: I.V. Detail
pH: 4.5-6.5
Monitoring Parameters
Obtain baseline ECG (evaluate QTc interval), within 30 days of initiation, and then annually for all patients receiving methadone. Increase ECG monitoring if patient receiving >100 mg/day or if unexplained syncope or seizure occurs while on methadone (Krantz, 2008).
If before or at anytime during therapy:
QTc >450-499 msecs: Discuss potential risks and benefits; monitor QTc more frequently
QTc ?500 msecs: Consider discontinuation or reducing methadone dose or eliminate factors promoting QTc prolongation (eg, potassium-wasting drugs) or use alternative therapy (eg, buprenorphine)
Pain relief, respiratory and mental status, blood pressure
Reference Range
Prevention of opiate withdrawal: Therapeutic: 100-400 ng/mL (SI: 0.32-1.29 ?mol/L); Toxic: >2 mcg/mL (SI: >6.46 ?mol/L)
Test Interactions
Some quinolones may produce a false-positive urine screening result for opiates 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 opiate screens by more specific methods should be considered.
Patient Education
If self-administered, use exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. Maintain adequate hydration unless instructed to restrict fluid intake. May cause hypotension, dizziness, drowsiness, impaired coordination, or blurred vision (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); loss of appetite, nausea, or vomiting (frequent mouth care, small frequent meals, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help; if unresolved, consult prescriber about use of stool softeners). Report chest pain, slow or rapid heartbeat, acute dizziness or persistent headache; changes in mental status; swelling of extremities or unusual weight gain; changes in urinary elimination; acute headache; back or flank pain or muscle spasms; blurred vision; skin rash; or shortness of breath. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. If you are breast-feeding, consult prescriber.
Geriatric Considerations
Because of it's long half-life and risk of accumulation, methadone is difficult to titrate and is not considered a drug of first choice. It should be prescribed only by physicians who are experienced in using it. Elderly may be particularly susceptible to the CNS depressant and constipating effects of narcotics.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Significant xerostomia (normal salivary flow resumes upon discontinuation) and glossitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
This drug is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”).
Prolongation of the QT interval is thought to result from delayed ventricular repolarization. The repolarization process within the myocardial cell is due to the efflux of intracellular potassium. The channels associated with this current can be blocked by many drugs and predispose the electrical propagation cycle to torsade de pointes.
Methadone is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, levonordefrin [Neo-Cobefrin®]) be used with caution.
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for additive or adverse interactions. Monitor therapeutic effectiveness and adverse reactions of overdose at beginning of therapy and at regular intervals with long-term use. May cause physical and/or psychological dependence. Monitor QTc, blood pressure, respiratory and CNS status (degree of sedation). For inpatients, implement safety measures. Assess knowledge/teach patient appropriate use (if self-administered) adverse reactions to report, and appropriate interventions to reduce side effects. Discontinue slowly after prolonged use.
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, solution, as hydrochloride: 10 mg/mL (20 mL)
Solution, oral, as hydrochloride: 5 mg/5 mL (500 mL); 10 mg/5 mL (500 mL) [contains alcohol 8%; citrus flavor]
Solution, oral, as hydrochloride [concentrate]: 10 mg/mL (946 mL)
Methadone Intensol™: 10 mg/mL (30 mL) [dye free, sugar free; contains sodium benzoate; unflavored]
Methadose®: 10 mg/mL (1000 mL) [contains propylene glycol; cherry flavor]
Methadose®: 10 mg/mL (1000 mL) [dye free, sugar free; contains sodium benzoate; unflavored]
Tablet, as hydrochloride: 5 mg, 10 mg
Dolophine®: 5 mg, 10 mg
Methadose®: 5 mg, 10 mg [DSC]
Tablet, dispersible, as hydrochloride: 40 mg
Methadose®: 40 mg
Methadone Diskets®: 40 mg [orange-pineapple flavor]
Pricing: U.S. (www.drugstore.com)
Tablet,Dispersible (Methadone HCl Diskets)
40 mg (20): $16.66
Tablets (Methadone HCl)
5 mg (20): $11.99
10 mg (20): $11.33
Tablets (Methadose)
5 mg (20): $11.33
10 mg (20): $11.99
References
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“Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain,” 5th ed, Glenview, IL: American Pain Society, 2003.
Wasserman S and Yahr MD, “Choreic Movements Induced by the Use of Methadone,” Arch Neurol, 1980, 37(11):727-8.
Wu CH and Henry JA, “Deaths of Heroin Addicts Starting on Methadone Maintenance,” Lancet, 1990, 335(8686):424.
Wunsch MJ, Stanard V, and Schnoll SH, “Treatment of Pain in Pregnancy,” Clin J Pain, 2003, 19(3):148-55.
Zacher JL and Givone DM, “False-Positive Urine Opiate Screening Associated With Fluoroquinolone Use,” Ann Pharmacother, 2004, 38:1525-28.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2009
Content last modified August 2009
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