Methadone Hydrochloride

Opiate agonist; a synthetic diphenylheptane derivative.217 222 a

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

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

• Known or suspected paralytic ileus.217

Warnings/Precautions

Warnings

Respiratory Depression

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

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

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

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

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

Cardiac Effects

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

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

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

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

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

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

Drug Abuse and Dependence

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

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

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

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

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

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

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

Inadvertent Exposure

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

Other Warnings/Precautions

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

Incomplete Cross-Tolerance

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

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

Serotonin Syndrome

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

Serotonin syndrome may occur at usual dosages.400 Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400

Adrenal Insufficiency

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

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

Chronic Pulmonary Disease

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

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

Cachectic or Debilitated Patients

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

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

Increased Intracranial Pressure or Head Trauma

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

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

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

Acute Abdominal Conditions

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

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

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

Hypotensive Effects

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

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

CNS Effects

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

Concomitant use with other CNS depressants may cause profound sedation, coma, respiratory depression, or hypotension.217 222 (See Specific Drugs under Interactions.) Deaths associated with illicit methadone use frequently have involved concomitant benzodiazepine abuse.217 222

Seizures

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

May induce seizures in some clinical settings.217

Acute Pain Management in Patients Receiving Maintenance Treatment

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

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

Anxiety

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

Hypothyroidism

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

Prostatic Hypertrophy or Urethral Stricture

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

Addison’s Disease

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

Hypogonadism

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

Specific Populations

Pregnancy

Category C.217 222

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

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

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

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

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

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

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

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

Lactation

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

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

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

AAP states that methadone is usually compatible with breast-feeding.279

Manufacturers of oral methadone recommend that the drug be used with caution.217 (See Advice to Patients.)

Manufacturer of methadone injection recommends discontinuing nursing or the drug, since information on parenteral use and on safety of high-dose therapy for chronic pain in nursing women is lacking.222

Pediatric Use

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

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

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

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults;217 222 however, geriatric patients may be at greater risk for respiratory depression217 222

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

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Lightheadedness, dizziness, sedation, nausea, vomiting, sweating.217 222

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

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

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

Methadone Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	5 mg/5 mL*	Methadone Hydrochloride Oral Solution (C-II)
		10 mg/5 mL*	Methadone Hydrochloride Oral Solution (C-II)
	Solution, concentrate	10 mg/mL*	Methadone Hydrochloride Intensol (C-II)	Roxane
			Methadone Hydrochloride Oral Concentrate (C-II)
			Methadose Oral Concentrate (C-II)	Mallinckrodt
	Tablets	5 mg*	Dolophine Hydrochloride (C-II; scored)	Roxane
			Methadone Hydrochloride Tablets (C-II)
			Methadose (C-II; scored)	Mallinckrodt
		10 mg*	Dolophine Hydrochloride (C-II; scored)	Roxane
			Methadone Hydrochloride Tablets (C-II)
			Methadose (C-II; scored)	Mallinckrodt
	Tablets, dispersible	40 mg*	Methadone Hydrochloride Diskets (C-II; scored)	Roxane
			Methadose (C-II; scored)	Mallinckrodt
Parenteral	Injection	10 mg/mL*	Methadone Hydrochloride Injection (C-II)