methadone

ROUTE	ONSET	PEAK	DURATION
PO	30–60 min	90–120 min	4–12 hr
IM, IV, SUBQ	10–20 min	60–120 min	8–12 hr

Contraindicated in:

Hypersensitivity;
Significant respiratory depression;
Acute or severe bronchial asthma;
Paralytic ileus;
Known alcohol intolerance (some oral solutions);
Concurrent MAO inhibitor therapy.

Use Cautiously in:

Personal or family history of substance use disorder or mental illness (for pain management);
Structural heart disease, concomitant diuretic use, hypokalemia, hypomagnesemia, history of arrhythmia/syncope, or other risk factors for arrhythmias;
Concurrent use of drugs that prolong the QT interval or are CYP3A4 inhibitors;
Head trauma;
Seizure disorders;
↑intracranial pressure;
Severe renal impairment;
Severe hepatic impairment;
Severe pulmonary disease;
Hypothyroidism;
Adrenal insufficiency;
Undiagnosed abdominal pain;
Prostatic hyperplasia or ureteral stricture;
OB: Use during pregnancy only if the potential maternal benefit justifies the potential fetal risk. Prolonged use of methadone during pregnancy can result in neonatal opioid withdrawal syndrome;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Geri: risk of respiratory depression in older adults (dose suggested).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension, bradycardia, QT interval prolongation, TORSADES DE POINTES

Derm: flushing, sweating

EENT: blurred vision, diplopia, miosis

Endo: adrenal insufficiency

GI: constipation, nausea, vomiting

GU: urinary retention

Neuro: confusion, sedation, dizziness, dysphoria, euphoria, floating feeling, hallucinations, headache, unusual dreams

Resp: RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA)

Misc: allodynia, opioid-induced hyperalgesia, physical dependence, psychological dependence, tolerance

Interactions ⬆ ⬇

Drug-drug:

Use with extreme caution in patients receiving MAO inhibitors (may result in severe, unpredictable reactions; ↓ initial dose of methadone to 25% of usual dose).
Use with extreme caution with any drug known to potentially prolong QT interval, including class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
Use with extreme caution with CYP3A4 inhibitors, including ketoconazole, itraconazole, erythromycin, clarithromycin, calcium channel blockers, or voriconazole.
Concurrent use with laxatives, diuretics, or mineralocorticoids may ↑ risk of hypomagnesemia or hypokalemia and ↑ risk of arrhythmias.
Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SSRIs, SNRIs, MAO inhibitors, TCAs, tramadol, trazodone, mirtazapine, 5-HT3 receptor antagonists, linezolid, methylene blue, and triptans, ↑ risk of serotonin syndrome.
Concurrent use of CYP3A4 inhibitors, CYP2C9 inhibitors, CYP2C19 inhibitors, or CYP2D6 inhibitors, including ritonavir, ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, nefazodone, diltiazem, verapamil, nelfinavir, fosamprenavir, and fluvoxamine, ↑ levels and risk of opioid toxicity; careful monitoring during initiation, dose changes, or discontinuation of the inhibitor is recommended.
Concurrent use with CYP3A4 inducers, CYP2C9 inducers, or CYP2C19 inducers, including barbiturates, carbamazepine, efavirenz, corticosteroids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, or rifampin, may ↓ levels and analgesia; if inducers are discontinued or dosage ↓, patients should be monitored for signs of opioid toxicity and necessary dose adjustments should be made.
Use with benzodiazepines or other CNS depressants, including other opioids, nonbenzodiazepine sedative/hypnotics, anxiolytics, general anesthetics, muscle relaxants, antipsychotics, and alcohol, may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
Administration of agonist/antagonist opioids may precipitate opioid withdrawal in physically dependent patients.
Nalbuphine may ↓ analgesia.
Interferons (alpha) may ↓ metabolism and ↑ effects.
May ↑ blood levels and effects of zidovudine and desipramine.
Concurrent abuse of methadone with benzodiazepines has resulted in death.
Mixed agonist/antagonist analgesics, including nalbuphine or butorphanol, and partial agonist analgesics, including buprenorphine, may ↓ methadone's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.

Drug-Natural Products:

St. John’s wort↑ metabolism and ↓ blood levels; concurrent use may result in withdrawal.
Kava-kava, valerian, or chamomile can ↑ CNS depression.

Route/Dosage ⬆ ⬇

Moderate to Severe Pain

PO (Adults and Children ≥50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients: 2.5 mg every 8–12 hr.
PO (Adults and Children <50 kg): 0.1 mg/kg/dose every 4 hr for 2–3 doses, then every 6–8 hr as needed; maximum: 10 mg/dose.
PO IV (Neonates ): Initial 0.05–0.2 mg/kg/dose every 12–24 hr or 0.5 mg/kg/day divided every 8 hr; taper dose by 10–20% per wk over 1–1.5 mo.
IV IM SC (Adults and Children ≥50 kg): 10 mg every 6–8 hr.
IV IM SC (Adults and Children <50 kg): 0.1 mg/kg every 6–8 hr; maximum: 10 mg/dose.

Opioid Detoxification

PO (Adults and Children ≥50 kg): 15–40 mg once daily or amount needed to prevent withdrawal. Dose may be ↓ every 1–2 days; maintenance dose is determined on an individual basis.
PO (Adults and Children <50 kg): 0.05–0.1 mg/kg/dose every 6 hr; ↑ by 0.05 mg/kg/dose until withdrawal symptoms controlled; after 1–2 days, lengthen dosing interval to every 12–24 hr; taper by ↓ dose by 0.05 mg/kg/day.
IV IM SC (Adults and Children ≥50 kg): 15–40 mg once daily or amount needed to prevent withdrawal. Dose may be ↓ every 1–2 days; maintenance dose is determined on an individual basis.

Availability ⬆ ⬇

(Generic available)

Tablets: 1 mg; 5 mg; 10 mg; 25 mg
Tablets for oral suspension: 40 mg (available only to licensed detoxification/maintenance programs)
Oral concentratecherry and unflavored: 10 mg/mL
Oral solution (contains alcohol)citrus: 5 mg/5 mL; 10 mg/5 mL
Solution for injection: 10 mg/mL

Assessment ⬆ ⬇

Pain: Assess type, location, and intensity of pain prior to and 1–2 hr (peak) following administration. When titrating opioid doses, ↑ of 25–50% should be administered until there is either a 50% ↓ in the patient’s pain rating on a numeric or visual analogue scale or the patient reports satisfactory pain relief. Dose ↑ should be made no more frequently than every 3–5 days because of variability in half-life between patients. Cumulative effects of this medication may require periodic dose adjustments.
- Doses of methadone for patients on methadone maintenance only prevent withdrawal symptoms; no analgesia is provided. Additional opioid doses are required for treatment of pain.
An equianalgesic chart (see Equianalgesic Dosing Guidelines) should be used when changing routes or when changing from one opioid to another.
Assess BP, HR, and respiratory rate before and periodically during administration. If respiratory rate <10/min, assess level of sedation. Dose may need to be ↓ by 25–50%. Initial drowsiness will ↓ with continued use. Monitor for respiratory depression, especially during initiation or following dose ↑; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia).
Assess bowel function routinely. Prevention of constipation should be instituted with ↑ intake of fluids and bulk and with laxatives to minimize constipating effects. Stimulant laxatives should be administered routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid-induced constipation.
Prolonged use may lead to physical and psychological dependence and tolerance, which should not prevent patient from receiving adequate analgesia. Patients who receive methadone for pain rarely develop psychological dependence. Progressively higher doses may be required to relieve pain with long-term therapy.
Assess for history of structural heart disease, arrhythmia, and syncope. Obtain a pretreatment ECG to measure QTc interval and follow-up ECG within 30 days and annually. Additional ECGs recommended if dose >100 mg/day or if patients have unexplained syncope or seizures. If QTc interval >450 msec but <500 msec, discuss potential risks and benefits with patients and monitor more frequently. If the QTc interval >500 msec, consider discontinuing or ↓ dose; eliminating contributing factors (drugs that promote hypokalemia) or using an alternative therapy.
Assess risk for opioid addiction, abuse, or misuse prior to administration. Abuse or misuse by crushing, chewing, snorting, or injecting dissolved product will result in uncontrolled delivery of methadone and can result in overdose and death.
Assess for opioid-induced hyperalgesia, which can appear as ↑ levels of pain on increasing the dose of the opioid, ↓ levels of pain on decreasing the dose of the opioid, or pain from ordinarily nonpainful stimuli (allodynia). This condition is different from tolerance. If a patient is suspected to be experiencing opioid-induced hyperalgesia, consider ↓ the dose of the current opioid or switching to a different opioid analgesic.
Opioid Detoxification: Assess patient for signs of opioid withdrawal (irritability, runny nose and eyes, abdominal cramps, body aches, sweating, loss of appetite, shivering, unusually large pupils, trouble sleeping, weakness, yawning). Methadone maintenance is undertaken only by federally approved treatment centers. This does not preclude maintenance for addicts hospitalized for other conditions and who require temporary maintenance during their care.

Lab Test Considerations:

May ↑ plasma amylase and lipase levels.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For children and patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 2 min. Titrate dose to avoid withdrawal, seizures, and severe pain.

Implementation ⬆ ⬇

Do not confuse methadone with dexmethylphenidate, ketorolac, memantine, methylphenidate, or metolazone.
When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone is dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration approved by the designated state authority.
The initial dose for patients receiving detoxification treatment should be administered under medical supervision.
Explain therapeutic value of medication prior to administration to enhance the analgesic effect.
- Regularly administered doses may be more effective than as needed administration. Analgesic is more effective if administered before pain becomes severe. For patients in chronic severe pain, the oral solution containing 5 mg/5 mL or 10 mg/5 mL is recommended on a fixed dose schedule.
- Coadministration with nonopioid analgesics may have additive analgesic effects and may permit lower doses.
- Avoid the use of mixed agonist/antagonist (nalbuphine, butorphanol) or partial agonist (buprenorphine) analgesics in patients taking methadone; may cause withdrawal.
- Medication should be discontinued gradually after long-term use to prevent withdrawal symptoms. For patients on long-acting agents who are physically opioid-dependent, initiate the taper by a small enough increment (less than 10% of total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2–4 wk. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. Monitor frequently to manage pain and withdrawal symptoms (restlessness; lacrimation; rhinorrhea; yawning; perspiration; chills; myalgia; mydriasis; irritability; anxiety; backache; joint pain; weakness; abdominal cramps; insomnia; nausea; anorexia; vomiting; diarrhea; or ↑ BP, respiratory rate, or HR). If withdrawal symptoms occur, pause the taper for a period of time or ↑ the dose of opioid analgesic to the previous dose, and then proceed with a slower taper. Also, monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.
PO: Doses may be administered with food or milk to minimize GI irritation.
- Dilute each dose of 10 mg/mL oral concentrate with ≥30 mL of water or other liquid prior to administration.
- Diskettes (dispersible tablets) are to be dissolved and used for detoxification and maintenance treatment only. Available only to licensed detoxification/maintenance programs.
SC: IM: IM is the preferred route for repeated doses. SUBQ administration may cause tissue irritation.
FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain, available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com.
Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.

IV Administration:

Administer undiluted.
Rate: Inject slowly.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of methadone to patient. Instruct them to take medication as directed and when to ask for pain medication. Advise patient to read Patient Informationbefore starting and with each Rx refill in case of changes.
Instruct patient to take methadone exactly as directed. If dose is less effective after a few wk, do not ↑ dose without consulting health care professional. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide is available at www.fda.gov/OpioidAnalgesicREMSPCG.
Advise patient that methadone is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (Rx, direct from pharmacist, or state programs). OTC naloxone nasal spray is available at pharmacies nationwide for overdose or accidental ingestion.
Medication may cause drowsiness or dizziness. Advise patient to call for assistance when ambulating and to avoid driving or other activities that require alertness until response to the medication is known.
Inform patient of the potential for arrhythmias and emphasize the importance of regular ECGs.
Advise patient to notify health care professional if pain control is not adequate or if side effects occur.
Caution patient to notify health care professional if signs of overdose (difficult or shallow breathing; extreme tiredness or sleepiness; blurred vision; inability to think, talk, or walk normally; and feelings of faintness, dizziness, or confusion) occur. Methadone has a prolonged action, causing ↑ risk of overdose.
Advise patient to change positions slowly to minimize orthostatic hypotension.
Advise patient to tell health care professional what medications they are taking and to avoid taking new Rx, OTC, vitamins, or herbal products without consulting health care professional. Caution patient to avoid concurrent use of alcohol or other CNS depressants, including other opioids, with this medication.
Encourage patient to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
Emphasize the importance of aggressive prevention of constipation with the use of methadone.
Rep: Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal (irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, failure to gain weight); usually occur the first days after birth. Monitor infants exposed to methadone through breast milk for excess sedation and respiratory depression. Chronic use may fertility in females and males. During pregnancy, a woman’s methadone dose may need to be or the dosing interval due to clearance.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆ ⬇

Canadian Brand Names ⬆ ⬇

Contr. Subst. Schedule ⬆