Methadone Hydrochloride

Pronunciation

Pronunciation: METH-a-done HYE-droe-KLOR-ide
Class: Opioid analgesic

Trade Names

Diskets
- Tablets, dispersible 40 mg

Dolophine Hydrochloride
- Tablets 5 mg
- Tablets 10 mg

Methadone Hydrochloride
- Injection 10 mg/mL
- Solution, oral 5 mg per 5 mL
- Solution, oral 10 mg per 5 mL

Methadone Hydrochloride Intensol
- Liquid concentrate, oral 10 mg/mL

Methadose
- Tablets 5 mg
- Tablets 10 mg
- Tablets, dispersible 40 mg
- Concentrate, oral 10 mg/mL

Metadol (Canada)

Pharmacology

Relieves pain by stimulating opiate receptors in CNS; also causes respiratory depression, peripheral vasodilation, inhibition of intestinal peristalsis, sphincter of Oddi spasm, stimulation of chemoreceptors that cause vomiting and increased bladder tone.

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Pharmacokinetics

Absorption

Following oral administration, bioavailability ranges from 36% to 100%. T max ranges from 1 to 7.5 h. After administration of oral daily doses of 10 to 225 mg, the steady-state plasma concentrations ranged from 65 to 630 ng/mL and C max ranged from 124 to 1,255 ng/mL.

Distribution

Vd at steady state ranges from 1 to 8 L/kg. Protein binding is 85% to 90%, primarily to alpha-1 acid glycoprotein. Methadone is secreted in amniotic fluid, breast milk, saliva, and umbilical cord plasma.

Metabolism

Methadone is primarily metabolized to inactive metabolites by the CYP3A4, CYP2B6, and CYP2C19 isozymes, and to a lesser extent by CYP2C9 and CYP2D6 isozymes.

Elimination

The primary route of excretion is in the urine. Apparent plasma Cl ranges from 1.4 to 126 L/h, and the terminal half-life is highly variable, ranging from 8 to 59 h. Because it is lipophilic, methadone persists in the liver and tissue. The slow release from these sites may prolong the duration of methadone action despite low plasma concentrations.

Duration

Analgesia: 4 to 8 h.

Special Populations

Renal Function Impairment

The pharmacokinetics have not been extensively evaluated in patients with renal insufficiency.

Hepatic Function Impairment

The pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. However, methadone is metabolized by hepatic pathways; therefore, there is a risk of drug accumulation after multiple dosing in patients with hepatic function impairment.

Elderly

Pharmacokinetics have not been evaluated.

Children

Pharmacokinetics have not been evaluated.

Gender

Pharmacokinetics have not been evaluated.

Race

Pharmacokinetics have not been evaluated.

Indications and Usage

Detoxification treatment of opioid addiction; maintenance treatment of opioid addiction, in conjunction with appropriate social and medical services.

Dolophine , Intensol , methadone injection, methadone oral solution, Methadose

For the treatment of moderate to severe pain not responsive to non-narcotic analgesics. Methadone injection: Temporary treatment of opioid dependence in patients unable to take oral medication.

Contraindications

Any situation in which opioids are contraindicated (eg, respiratory depression in the absence of resuscitative equipment or in unmonitored settings); patients with acute bronchial asthma or hypercarbia; patients who have or are suspected of having a paralytic ileus; hypersensitivity to any component of the product.

Dosage and Administration

Conversion From Parenteral Methadone to Oral Methadone
Adults

PO Start with 1:2 dose ratio (eg, parenteral methadone 5 mg to oral methadone 10 mg).

Detoxification and Maintenance Treatment of Opiate Dependence
Adults

IV/IM/Subcutaneous/PO For detoxification and maintenance of opiate dependence, methadone should be administered in accordance with the treatment standards cited in the Code of Federal Regulation, Title 42, Section 8.12, including limitations on unsupervised administrations.

Induction
Adults

PO Start with 20 to 30 mg to suppress withdrawal symptoms. For same-day dosing adjustments, wait 2 to 4 h for further evaluation when peak levels are reached. An additional 5 to 10 mg may be administered if withdrawal symptoms have not been suppressed or if symptoms reappear (max, 40 mg the first day). Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (eg, 2 to 4 h after dosing). Initial doses should be lower for patients whose tolerance is expected to be low at the beginning of treatment.

Initiation of Therapy in Opioid Nontolerant Patients
Adults

IV/IM/Subcutaneous/PO When used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, start with 2.5 to 10 mg every 8 to 12 h. Slowly titrate to effect. More frequent administration may be required during initiation in order to maintain adequate analgesia.

Maintenance
Adults

PO Most commonly, clinical stability is achieved at dosages between 80 and 120 mg/day. Titrate to a dose at which opioid symptoms are prevented for 24 h, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone.

Medically Supervised Withdrawal After a Period of Maintenance Treatment
Adults

PO It is generally suggested that the dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10- to 14-day intervals should elapse between dose reductions.

Short-Term Detoxification
Adults

PO Titrate patients to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilization level. Continue stabilization for 2 to 3 days, after which the dose should be gradually decreased. The rate of decrease should be determined for each patient. The dose can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.

Switching Patients to Methadone From Other Chronic Opioids
Adults

IV/PO Use the following guidelines for oral morphine to methadone conversion:

Total daily baseline oral morphine dose Morphine less than 100 mg

The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 20% to 30% (IV, 10% to 15%).

Morphine 100 to 300 mg

The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 10% to 20% (IV, 5% to 10%).

Morphine 300 to 600 mg

The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 8% to 12% (IV, 4% to 6%).

Morphine 600 to 1,000 mg

The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is 5% to 10% (IV, 3% to 5%).

Morphine more than 1,000 mg

The estimated daily oral methadone requirement as a percent of total daily oral morphine dose is less than 5% (IV, less than 3%). Published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids should be consulted.

Total daily baseline parenteral morphine dose Morphine 10 to 30 mg

The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 40% to 66%.

Morphine 30 to 50 mg

The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 27% to 66%.

Morphine 50 to 100 mg

The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 22% to 50%.

Morphine 100 to 200 mg

The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 15% to 34%.

Morphine 200 to 500 mg

The estimated daily parenteral methadone requirement as percent of total daily morphine dose is 10% to 20%.

General Advice

  • Dose adjustment should be cautious; deaths have occurred in early treatment because of the cumulative effects of the first several days dosing. Extreme caution is necessary when titrating the dose to avoid overdosage, taking into account the long elimination half-life of methadone.
  • Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days.
  • Methadone Diskets and tablets for oral suspension are intended for dispersion in a liquid immediately prior to oral ingestion of the prescribed dose.
  • Methadone Diskets and tablets for oral suspension should not be chewed or swallowed before dispersing in liquid.
  • Methadone Diskets and tablets for oral suspension are cross-scored, allowing for flexible dosage adjustment in 10 mg increments.
  • Because Methadone Diskets and tablets for oral suspension can only be administered in 10 mg increments, they may not be appropriate for initial dosing or gradual dose reduction.
  • Prior to administration, the desired dose of the Diskets or tablet for oral suspension should be dispersed in approximately 120 mL of water, orange juice, Tang , citrus flavors of Kool-Aid , or other acidic fruit beverage. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture should be ingested by the patient.

Storage/Stability

Dolophine , Intensol , methadone injection, methadone oral solution

Store at 59° to 86°F. Protect from light.

Methadone Diskets

Store at 59° to 86°F.

Methadose dispersible tablets

Store at 68° to 77°F.

Methadose oral solution, Methadose oral tablets

Store at 68° to 77°F. Protect from light.

Drug Interactions

Agents that prolong the QT interval (eg, cisapride, class I antiarrhythmic agents [eg, procainamide, quinidine], class III antiarrhythmic agents [eg, dofetilide, sotalol], isradipine, nicardipine, pimozide, thioridazine, ziprasidone)

The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased.

CNS depressants (alcohol, benzodiazepines [eg, alprazolam, diazepam], general anesthetics, hypnotics, opioid analgesics, phenothiazines, sedatives, tranquilizers)

Risk of coma, hypotension, profound sedation, and respiratory depression may be increased. Deaths have been reported.

Desipramine

Plasma concentrations may be elevated by methadone, increasing efficacy.

Didanosine, stavudine

Plasma concentrations of these drugs may be reduced by methadone, decreasing their efficacy.

Inducers of CYP3A4, CYP2B6, CYP2C19, and, to a lesser degree, CYP2C9 and CYP2D6 (examples of agents in these classes include barbiturates [eg, phenobarbital], carbamazepine, NNRTIs [eg, efavirenz, nevirapine], phenytoin, protease inhibitors [eg, lopinavir, nelfinavir, ritonavir], rifampin, St. John's wort)

May reduce methadone plasma concentrations, decreasing the efficacy, possibly resulting in opioid withdrawal symptoms. Adjust the methadone dose as needed.

Inhibitors of CYP3A4, CYP2B6, CYP2C19, and, to a lesser degree, CYP2C9 and CYP2D6 (examples of agents in these classes include azole antifungals [eg, ketoconazole, voriconazole], fluvoxamine, grapefruit juice, macrolide antibiotics [eg, erythromycin])

May increase methadone plasma concentrations, increasing the pharmacologic effects and the risk of toxicity. Adjust the methadone dose as needed.

Opioid antagonists, mixed agonists/antagonists, and partial agonists (examples of these agents include buprenorphine, butorphanol, nalbuphine, naloxone, naltrexone, pentazocine)

Opioid withdrawal symptoms may occur.

Quinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin)

Inhibition of methadone metabolism by ciprofloxacin and norfloxacin may elevate methadone plasma concentrations, increasing pharmacologic effects and adverse reactions. Gatifloxacin, levofloxacin, and moxifloxacin may increase the risk of life-threatening cardiac arrhythmias, including torsades de pointes.

Zidovudine

Plasma concentrations may be elevated by methadone, increasing the risk of toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Arrhythmias, bigeminal rhythms, bradycardia, cardiac arrest, cardiomyopathy, ECG abnormalities, edema, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, shock, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia.

CNS

Agitation; asthenia; confusion; disorientation; dizziness; dysphoria; euphoria; hallucinations; headache; insomnia; light-headedness; sedation; seizures.

Dermatologic

Hemorrhagic urticaria (rare), pruritus, skin rash, sweating, urticaria.

EENT

Visual disturbances.

GI

Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis, nausea, vomiting.

Genitourinary

Amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy.

Hematologic-Lymphatic

Reversible thrombocytopenia.

Metabolic-Nutritional

Hypokalemia, hypomagnesemia, weight gain.

Respiratory

Pulmonary edema, respiratory arrest and depression.

Miscellaneous

Edema.

Precautions

Warnings

Cardiac effects

QT interval prolongation and serious arrhythmia (eg, torsades de pointes) have occurred with methadone treatment. Most cases involve treatment with large, multiple daily methadone doses; however, cases have been reported in patients receiving commonly used doses for maintenance treatment of opioid addiction.

Distribution and use

Methadone products, used for treatment of opioid addiction in detoxification or maintenance programs, are to be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Service Administration and approved by the designated state authority, except: 1) during inpatient care, when the patient is admitted for conditions other than concurrent opioid addiction, to facilitate the treatment of the primary admitting diagnosis; and 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.

Fatalities

Deaths have been reported during initiation of methadone treatment for opioid dependence. Deaths appear to be due to drug interactions with licit and illicit drugs, or the respiratory or cardiac effects of methadone, and too-rapid titration without appreciation for the accumulation of methadone over time.

Respiratory depression

Respiratory depression is the chief hazard associated with methadone administration. Peak respiratory depressant effects of methadone occur later and persist longer than peak analgesic effects, particularly during the early dosing period.


Monitor

Monitor for evidence of withdrawal when treatment with a CYP3A4 inducer is started.


Pregnancy

Category C . Methadone Cl is increased during pregnancy. It may be necessary to increase the dose or dosing interval during pregnancy.

Lactation

Excreted in breast milk.

Children

Not recommended for children; dosage is not well defined.

Elderly

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

May need to decrease dose in patients with renal function impairment.

Hepatic Function

May need to decrease dose in patients with hepatic impairment.

Special Risk Patients

Use with caution in patients with myxedema, acute alcoholism, acute abdominal conditions, ulcerative colitis, decreased respiratory reserve, head injury or increased intracranial pressure, hypoxia, superventricular tachycardia, depleted blood volume, circulatory shock, hypothyroidism, Addison disease, prostatic hypertrophy, or urethral stricture.

Abuse

Methadone abuse poses risk of overdose and death. Methadone is a mu-agonist opioid and has abuse liability similar to morphine and other opioid agonists and is subject to criminal diversion.

Acute pain

Maintenance patients on a stable dose of methadone who experience physical trauma, postoperative pain, or other acute pain do not derive analgesia from their existing dose of methadone; treat these patients with analgesics, including opioids, in doses indicated for non–methadone-treated patients with similar painful conditions.

Debilitated patients

Use with caution because comorbidity or concurrent medications may predispose debilitated patients to dysrhythmia or reduced ventilatory drive.

Heroin withdrawal

During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical symptoms, which should be differentiated from methadone-induced side effects.

Hypotension

Severe hypotension may occur in patients whose ability to maintain normal BP is compromised (eg, severe volume depletion).

Incomplete cross-tolerance

Patients tolerant to other opioids may be incompletely tolerant to methadone, which is a concern when converting patients tolerant to other mu-opioid agonists to methadone. This makes determination of dosing conversion complex. Deaths have occurred during conversion.

Nonteratogenic effects

Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Duration of withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal.

Obstetrical analgesia

Do not use methadone for obstetrical analgesia. Its long duration of action increases the probability of neonatal respiratory depression.

Physical dependence

Physical dependence manifested by withdrawal symptoms may occur after abrupt discontinuation or administration of an antagonist.

Treatment of drug addiction

Methadone for detoxification should not be given for more than 21 days and treatment should not be repeated within 4 wk. More than 3 wk of methadone treatment for narcotic dependence is considered maintenance therapy; only approved programs can provide this therapy.

Overdosage

Symptoms

Apnea, bradycardia, cardiac arrest, circulatory collapse, cold and clammy skin, death, extreme somnolence progressing to stupor or coma, hypotension, maximally constricted pupils, respiratory depression, skeletal muscle flaccidity.

Patient Information

  • Tell patient to take methadone regularly, as prescribed. If dose is missed, tell patient to take as soon as possible. If close to next dose, wait and take next regularly scheduled dose.
  • Advise patient that drug may cause dizziness, drowsiness, or blurred vision, and to use caution while driving or performing other hazardous tasks.
  • Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (eg, dizziness, light-headedness, palpitations, syncope).
  • Caution patient to avoid intake of alcoholic beverages or other CNS depressants.
  • If constipation occurs, tell patient to increase fluids and fiber or to use fiber laxative.
  • Explain that use of methadone before pain becomes acute will allow it to alleviate pain better.
  • Caution patient to avoid sudden position changes to prevent orthostatic hypotension.
  • Explain types and potential significance of sympathomimetic side effects.

Copyright © 2009 Wolters Kluwer Health.

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