METHADONE HCL (Generic for DISKETS)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-When given as part of a methadone maintenance program, methadone may only be administered in an oral form and according to the requirements outlined in the Narcotic Addict Treatment Act (NATA) [21USC 823(g)].
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of therapy initiation or dose escalation.
-Storage: Store methadone securely in a location not accessible by others.
-Disposal: Flush unused methadone down the toilet when it is no longer needed if a drug take-back option is not readily available.
Oral Liquid Formulations
Oral solution
-Carefully check dose before administering medication as multiple concentrations of methadone oral solution are available, including a concentrated version.
-Measure dosage using a calibrated measuring device.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Intravenous methadone is typically administered intermittently; however, it has also been administered for patient-controlled analgesia (PCA) via a rate controlled device as a continuous infusion and bolus dose in both pediatric and adult oncology patients.

Intramuscular Administration
-Inject deeply into a large muscle (e.g., anterolateral thigh or deltoid [children and adolescents only]).
-The absorption of intramuscular (IM) methadone has not been well characterized and appears to be unpredictable.
-Local tissue reactions may occur with IM use.

Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.
-The absorption of subcutaneous methadone has not been well characterized and appears to be unpredictable.
-Local tissue reactions may occur with subcutaneous use and are more common with continuous subcutaneous infusions.

Opioids have been shown to have a variety of effects on components of the immune system in both in vitro and animal models; however, the clinical significance of these findings is unknown. The effects of opioids appear to be modestly immunosuppressive.

Pharmacologic tolerance to the analgesic effects of opiate agonists, including methadone, has been reported. Tolerance is the need for increasing opioid doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required, contributing factors may be multi-factorial including tolerance, progression of disease, or psychological distress. Methadone is not fully cross-tolerant with other opiate agonists. Switching from one opiate agonist to methadone should be done cautiously as the equianalgesic dose ratio is not well established in opiate-tolerant patients; deaths have been reported during conversion.

The most significant adverse effects associated with opiate agonist use are respiratory depression (hypoventilation), respiratory arrest, dyspnea, and apnea. These result from a decreased sensitivity to both carbon dioxide and electrical stimulation in the brainstem respiratory centers. Respiratory depression is more common in cachectic or debilitated patients, after large initial doses in non-opioid tolerant patients, or when opioids are given with other central nervous system (CNS) depressants. Use with caution in patients with hypoxia, hypercapnia, or decreased pulmonary reserve. In addition, pulmonary edema has been reported in patients receiving methadone. The peak respiratory depressant effects of methadone occur later and persist longer than the peak analgesic effect, making the drug particularly hazardous during the early stages of treatment. Extreme caution is recommended during treatment initiation, conversion from 1 opiate to another, and dose titrations. Deaths due to respiratory arrest have been reported during these situations. When methadone is appropriately titrated, the risk of respiratory depression is generally small as tolerance rapidly develops to this effect. Patients may also develop respiratory depression through sub-acute overdose of an opiate agonist in which sedation builds up slowly leading to a decreased respiratory rate and then respiratory failure. This is more common with methadone compared to some other agents due to its extended half-life. Respiratory depression may persist for a significant period after discontinuation of methadone; monitor patients closely until their respiratory rate has stabilized. Medical management consists of holding 1 to 2 doses of methadone and then restarting methadone at 25% of the previous dose and slowly increasing the dose once the symptoms have resolved. Treat symptomatic respiratory depression cautiously with an opioid antagonist such as naloxone. In individuals physically dependent on opioids, administer opioid antagonists with extreme care; titrate the antagonist dose by using smaller than usual doses. Concomitant use of a CYP3A4 inhibitor or discontinuation of a concurrently used 3A4 inducer may result in excessive methadone plasma concentrations that could produce respiratory depression.

Sedation is among the most frequently observed adverse reactions with methadone. Advise patients and their caregivers that activity requiring mental alertness can be affected since central nervous system (CNS) depression, including drowsiness, confusion, and dizziness, can occur. Tolerance to the CNS depression usually develops within a few days; serious or life-threatening CNS depression can occur with rapid dose titration, excessive doses, and concomitant CNS depressant use. Headache, asthenia, agitation, nervousness, sleep disturbances (insomnia), anxiety, restlessness, visual disturbances, and congenital oculomotor disorders (nystagmus, strabismus) have been reported with methadone therapy. Dysphoria, euphoria, lightheadedness, alterations of mood (feelings of floating, disorientation, apprehension), and hallucinations are less commonly seen with methadone than other opioid agonists. Seizures have been reported in patients receiving high doses of opioid agonists. In addition, decreased respiratory drive and resultant carbon dioxide (CO2) retention can increase intracranial pressure; use methadone with caution in patients with head trauma, intracranial mass, or brain tumor. Flushing and sweating occur during methadone therapy; tolerance develops slowly to these effects.

Methadone may cause a variety of effects on the gastrointestinal (GI) system, most commonly nausea/vomiting and constipation. Nausea and vomiting are most commonly seen at the initiation of therapy or when switching agents. Opiate agonists affect the vestibular system and may cause more nausea/vomiting in ambulatory patients than bedridden patients. Antiemetics may be utilized until tolerance develops; however, care should be taken to avoid concomitant agents associated with QT interval prolongation. Constipation due to decreased GI motility and secretions is common during opiate agonist therapy. In some cases, patients can develop ileus or GI obstruction. Tolerance rarely develops to the constipating effect of methadone; therefore, a bowel regimen consisting of increased fluid and fiber intake, a stool softener, and/or a mild laxative should be employed throughout opioid therapy. Other GI adverse events reported with methadone in adults include abdominal pain, anorexia, and glossitis.

Opiate agonists, such as methadone, have been associated with biliary spasms at the sphincter of Oddi. Hyperamylasemia, secondary to drug-induced spasm of the sphincter of Oddi, has been associated with various opiate agonists. While serum amylase and lipase concentrations can rise as a result of biliary obstruction or spasm, overt pancreatitis is rare with opiate analgesics.

Methadone, like morphine, can cause miosis even in total darkness. Although miosis is a sign of opioid overdose, it is not a specific characteristic and can be seen at therapeutic doses. Marked mydriasis rather than miosis may be seen in overdose situations due to hypoxia.

Anticholinergic effects occur infrequently with methadone. Patients may experience xerostomia (dry mouth), blurred vision, antidiuretic effect (oliguria), and urinary retention or hesitancy.

Methadone is reported to cause pruritus. Opiate agonist-induced pruritus is thought to be mediated through stimulation of central opiate receptors since opiate antagonists (i.e., nalmefene or naloxone) have been shown to ameliorate pruritus associated with cholestasis. Use of H1-blockers or changing to a different opioid may lessen the pruritus. Urticaria, rash (unspecified), phlebitis, and edema have also been associated with methadone. Rarely, anaphylactoid reactions and hemorrhagic urticaria have been reported. Administration of intramuscular or subcutaneous methadone may cause an injection site reaction (e.g., pain, erythema, swelling); these reactions are more common with subcutaneous administration.

Opioid agonists can interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH), and by stimulating secretion of prolactin, growth hormone (GH), insulin, and glucagon. Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression). Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, persons could experience amenorrhea or infertility in males and females of reproductive potential. Other various medical, physical, lifestyle, and psychological stressors may influence gonadal hormone concentrations; these stressors have not been adequately controlled for in clinical studies with opioids. Persons presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation. Opioid agonists can inhibit the release of thyrotropin, leading to a decrease in thyroid hormone. Morphine and related compounds can stimulate the release of vasopressin (ADH). Hyponatremia can occur as a result of SIADH. Hypokalemia, hypomagnesemia, and weight gain have also occurred in persons taking methadone. Electrolyte abnormalities may increase the risk of subsequent adverse events. The clinical relevance of these effects during methadone therapy is not known. Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization. Most reports of hypoglycemia occurred in persons with at least 1 predisposing risk factor, such as diabetes. The relationship between methadone and hypoglycemia is not fully understood but may be dose-dependent. If hypoglycemia is suspected, monitor blood glucose concentrations and manage as clinically appropriate.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH) and cortisol. Rarely, adrenocortical insufficiency has been reported in association with opioid use, usually after more than 1 month of use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenal insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenal insufficiency. It is unclear which, if any, opioids are more likely to cause adrenal insufficiency.

Methadone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients as a result of peripheral vasodilation. Patients at increased risk include those whose ability to maintain blood pressure is already compromised by reduced blood volume or concurrent administration of certain central nervous system depressants (e.g., phenothiazines, general anesthetics); monitor these patients carefully. Flushing, red eyes, and sweating may also manifest as a result of histamine release and/or peripheral vasodilation. Other cardiovascular reactions associated with methadone use include arrhythmias, bigeminal rhythms, extrasystoles, ECG abnormalities, ST-T wave changes (T-wave inversion), sinus tachycardia, sinus bradycardia, palpitations, ventricular fibrillation, ventricular tachycardia, prolongation of QT interval, hypertension, and diaphoresis. Cases of cardiomyopathy and heart failure have been reported in patients taking methadone. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur.

Methadone inhibits cardiac potassium channels, which may lead to significant QT prolongation and torsade de pointes. Although the risk of QT prolongation appears to be dose-related, with greatest incidence occurring in patients receiving large doses for pain management (more than 200 mg/day in adult patients), smaller doses have also been implicated. Clinical practice guidelines for methadone safety recommend an ECG be obtained when the methadone dose reaches an adult equivalent of 30 to 40 mg/day in patients started at lower doses and again at 100 mg/day. In addition, if signs and symptoms of arrhythmia develop or the patient develops new risk factors for QT prolongation, an ECG should be obtained. A risk/benefit evaluation and consideration of alternative therapy is prudent for patients with risk factors for QT prolongation. Methadone should be used with caution, if at all, in patients with congenital or acquired QT prolongation syndromes, a personal or family history of QT prolongation or torsade de pointes, or unexplained syncope. Closely monitor patients with structural heart disease, cardiac hypertrophy, hypokalemia, hypomagnesemia, cardiac conduction abnormalities, and/or concomitant use of medications associated with QT prolongation, electrolyte imbalance, and/or cytochrome P450 enzyme inhibition. An ECG should be obtained prior to methadone initiation in patients with risk factors for QT prolongation, any prior ECG demonstrating a QTc more than 450 ms, or a history suggestive of ventricular arrhythmia. In patients not known to be at risk for QT prolongation and those who have had an ECG with a QTc less than 450 ms within the past year with no new risk factors, an ECG may be considered. Do not use methadone in patients with a baseline QTc more than 500 ms. For those with a QTc 450 to 499 ms, alternative opioids should be considered; if methadone is utilized in such patients, evaluation, correction of reversible contributing factors, and close monitoring should occur. For patients with risk factors, any prior ECG with a QTc more than 450 ms, or a history of syncope, a follow-up ECG should be performed 2 to 4 weeks after methadone initiation and after any significant dose increase. Prescribers and pharmacists should take special care to monitor for methadone drug interactions.

Routine use of opioid agonists, such as methadone, by an expectant mother can lead to depressed respiration in the newborn and neonatal opioid withdrawal syndrome (NOWS); NOWS is estimated to occur in up to 50% of neonates born to opioid-dependent mothers. Withdrawal symptoms in a newborn generally occur 1 to 4 days after birth and include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Monitor exposed neonates closely; NOWS can be life-threatening if not recognized and treated. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Late withdrawal can occur at 2 to 3 weeks of age and subacute withdrawal may persist until 6 months of age. As with other opioid agonists, use of methadone presents the potential for abuse. Physiological dependence will occur during chronic opioid agonist therapy as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug in these patients. While physiological and psychological dependence as a result of abuse is a concern with opioids, dependence in pediatric patients is more likely to occur in the setting of prolonged infusions in critically ill patients or as a result of chronic pain management. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. The withdrawal syndrome with methadone is less intense but more prolonged compared to morphine. Initial symptoms may not occur for up to 3 to 4 days after the last dose of methadone. Peak effects occur by day 6 and most symptoms resolve within 10 to 14 days; however, there appears to be a secondary or chronic abstinence syndrome which may last 2 to 6 months, characterized by insomnia, irritability, and muscle aches. It is important to differentiate physiological dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug, from psychological dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug, and other drug-related behaviors such as drug selling and seeking the drug from multiple sources.

In utero methadone exposure is not without risk. Neonates born to mothers taking methadone are at risk for low birth weights caused by symmetric fetal growth retardation. Seizures attributed to both drug accumulation and withdrawal may occur. Some evidence suggests that thrombocytosis may develop at 4 to 10 weeks of age in methadone-exposed infants. This may persist for 6 to 10 months. Hyperthyroidism, including elevated levels of T3 and T4 during the first week of life, may occur. The rate of sudden infant death syndrome is 3 to 4 times higher among opiate-exposed infants than the general population.

Osteoporosis, bone fractures, and decreased muscle mass have been reported with methadone use.

Methadone is a weak serotonin re-uptake inhibitor (SRI), and serotonin syndrome has been reported in patients taking methadone. Patients taking opioids concomitantly with a serotonergic medication should seek immediate medical attention if they develop symptoms such as agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Symptoms generally present within hours to days of taking an opioid with another serotonergic agent, but may also occur later, particularly after a dosage increase. If serotonin syndrome is suspected, either the opioid and/or the other agent should be discontinued.

Cases of opioid-induced hyperalgesia (OIH) have been reported, both with short-term and longer-term use of opioids. OIH occurs when an opioid paradoxically causes an increase in pain or an increase in sensitivity to pain. Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Data suggests a strong biologic plausibility between opioids and OIH and allodynia. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching to a different opioid).

Methadone use is contraindicated in patients with a hypersensitivity to methadone or any excipient in a specific dosage form. If hypersensitivity occurs, it may be possible to treat the patient with an opioid agonist from another subclass (e.g., phenanthrene, phenylpiperidine, phenylpropylamine).

False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.

Patients who are taking methadone may be safely continued on the drug after surgery or dental work, if appropriate dosage adjustments are made considering the procedure, other drugs given, and temporary changes in physiology caused by the surgical intervention. Monitor for decreased bowel motility in postoperative patients receiving opiate agonists. Additional analgesia may be warranted for acute postoperative pain; if another opioid is used, opioid tolerance must be considered when dosing. Methadone is not indicated for acute or postoperative pain.

Methadone can produce cholinergic side effects causing decreased heart rate and histamine release, which can result in peripheral vasodilation and hypotension. Use caution when administering methadone to any patient who is hemodynamically fragile or has pre-existing hypotension. Exercise extreme caution when using methadone in patients with hypovolemia or in those receiving central nervous depressants such as phenothiazines or general anesthetics, which may alter the capacity to sustain adequate pressures. Avoid methadone in patients with circulatory shock as drug-induced vasodilation may further reduce cardiac output and blood pressure. Decreased heart rate and vasodilation may aggravate cardiac arrhythmias and heart failure; methadone should be used with caution in patients with cardiac disease, angina, low serum potassium, and low serum magnesium. Opiate agonists can induce vasovagal syncope or orthostatic hypotension; use caution in patients with pre-existing orthostatic hypotension.

Methadone is associated with an increased risk for QT prolongation and torsade de pointes. Although the risk of QT prolongation appears to be dose-related, with greatest incidence occurring in patients receiving large doses for pain management (i.e., more than 200 mg/day in adult patients), it is important to note that smaller doses have also been implicated. Risk/benefit evaluation and consideration of alternative therapy is prudent in patients with risk factors for QT prolongation. Methadone should be used with caution, if at all, in patients with congenital long QT syndrome or acquired QT prolongation syndromes, a personal or family history of QT prolongation or torsade de pointes, or unexplained syncope. Closely monitor patients with structural heart disease (e.g., congenital heart defects, history of endocarditis), cardiac hypertrophy, hypokalemia, hypomagnesemia, cardiac conduction abnormalities, and/or concomitant use of medications associated with QT prolongation, electrolyte imbalance, and/or cytochrome P450 enzyme inhibition. Use methadone with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, or hypocalcemia. Females, patients with diabetes mellitus, thyroid disease, malnutrition, a history of alcohol abuse, or hepatic impairment may also be at increased risk for QT prolongation. Practitioners should discuss the risk of arrhythmia with patients and caregivers, obtain a complete cardiac history, and physically examine each patient prior to methadone initiation. Clinical guidelines for methadone safety recommend that clinicians obtain an ECG prior to initiation in patients with risk factors for QT prolongation, any prior ECG demonstrating a QTc more than 450 ms, or a history suggestive of ventricular arrhythmia. Clinicians may consider obtaining an ECG prior to methadone initiation in patients not known to be at risk for QT prolongation and those who have had an ECG with a QTc less than 450 ms within the past year and have no new risk factors. Methadone should not be used in patients with a baseline QTc more than 500 ms. Alternative opioids should be considered in those with a baseline QTc 450 to 499 ms; if methadone is utilized in such patients, evaluation and correction of reversible contributing factors and close monitoring should occur. For patients with risk factors, any prior ECG with a QTc more than 450 ms, or a history of syncope, a follow-up ECG should be performed 2 to 4 weeks after methadone initiation and after any significant dose increase. In any patient, an ECG should be performed when the methadone dose reaches an adult equivalent of 30 to 40 mg/day in patients started at lower doses and again at 100 mg/day. If signs and symptoms of arrhythmia develop or the patient develops new risk factors for QT prolongation, an ECG should be obtained. Clinicians should be aware of and carefully monitor for drug interactions that may slow methadone elimination or result in QT interval prolongation.

Do not abruptly discontinue methadone in patients who may be physically dependent on opioids. Abrupt discontinuation of methadone in physically opioid-dependent patients has resulted in serious withdrawal symptoms, uncontrolled pain, suicide, and drug-seeking behavior. Consider the opioid dose, duration of therapy, type of pain being treated, and physical and psychological attributes of the patient when decreasing the opioid dose or discontinuing therapy. Ensure ongoing care of the physically opioid-dependent patient, including a multimodal approach to pain management, and devise an appropriate tapering schedule and follow-up plan so that patient and provider goals are clear and realistic. When discontinuing therapy due to suspected substance abuse, evaluate and treat the patient or refer for evaluation and treatment of the substance abuse disorder. For physically opioid-dependent patients, decrease the methadone dose by no more than 10% to 25% of the total daily dose every 2 to 4 weeks. Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper. Reassess patients frequently to manage pain and withdrawal symptoms, if they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. If withdrawal symptoms arise, pause the taper or increase the opioid dose to the previous dose, then proceed with a slower taper. Monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. Avoid use of partial agonists (e.g., buprenorphine), mixed agonists/antagonists (e.g., nalbuphine), or pure antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the opioid antagonist. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial agonists or mixed agonist/antagonists in patients who have received or are receiving opioid agonist analgesia may reduce the analgesic effects of methadone.

Methadone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Methadone causes decreased gastrointestinal (GI) motility and delayed digestion; patients with pre-existing GI disease may be at increased risk for adverse events. Due to the effects of opiate agonists on the GI tract, use methadone cautiously in patients with inflammatory bowel disease including ulcerative colitis or or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdomen. Monitor abdominal distention and loss of bowel sounds in critically ill newborn babies and other pediatric patients receiving methadone.

The opiate agonist morphine is well recognized to increase the tone of the biliary tract causing spasms (especially in the sphincter of Oddi) and increasing biliary tract pressure. Biliary effects due to opiate agonists have resulted in plasma amylase and lipase concentrations up to 2 to 15 times the normal values. The clinical significance of these effects during methadone therapy is not known. Nevertheless, methadone should be used with caution in patients with biliary tract disease, including acute pancreatitis, or in patients undergoing biliary tract surgery.

Methadone is contraindicated in patients with significant respiratory depression and/or acute or severe bronchial asthma (e.g., status asthmaticus) in unmonitored settings or in the absence of resuscitative equipment. Additionally, avoid coadministration with other CNS depressants when possible as this significantly increases the risk for respiratory depression, low blood pressure, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting the daily methadone dose. Careful monitoring is also required with concomitant use of drugs that may inhibit or induce the metabolism of methadone; an increase in methadone concentrations could cause potentially fatal respiratory depression. The potential risk of serious adverse effects with concomitant use of methadone and other CNS depressants should not preclude the appropriate treatment of opioid addiction with methadone, but requires more intensive counseling and monitoring. Methadone may significantly decrease respiratory drive and cause hypoventilation. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Serious or fatal respiratory depression can occur at any time during the use of methadone; however, the risk is greatest during the first 24 to 72 hours after therapy initiation or dose titration. It is important to note respiratory depressant effects occur later and persist longer than peak analgesic effects. Extreme caution is recommended during initiation of therapy, conversion from 1 opioid to another, and dose titrations; dose overestimation may lead to fatal overdose. Only healthcare professionals who are knowledgeable about methadone pharmacokinetics and pharmacodynamics should prescribe the drug, particularly during conversions to methadone from other opioids and in the use of methadone for chronic pain. Methadone should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use as a "prn" or "as needed" analgesic, for acute pain, or if the pain is mild or not expected to persist for an extended period of time. In patients with pulmonary disease such as chronic lung disease (CLD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to methadone, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with cachexia, debilitation, severe obesity, or sleep apnea are at an increased risk for the development of respiratory depression associated with methadone; monitor these patients closely. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in patients with CSA. Respiratory depression may persist for a significant period of time after discontinuation of methadone and patients require close monitoring until their respiratory rate has stabilized. Management of respiratory depression should include observation, necessary supportive measures, and careful use of an opioid antagonist (e.g., naloxone) if appropriate.

Patients with CNS depression, head trauma, intracranial mass, brain tumor, or increased intracranial pressure should be given methadone with extreme caution. Decreased respiratory drive and hypoventilation can cause carbon dioxide (CO2) retention which can further increase intracranial pressure. In addition, opiate agonists may interfere with the evaluation of neurologic parameters. Avoid use in patients with impaired consciousness or coma.

Methadone and other opiate agonists can cause urinary retention and oliguria due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, urethral stricture, pelvic malignancy, or renal disease. Caution is recommended in patients with renal disease or hepatic disease. Methadone is hepatically metabolized and undergoes variable renal elimination; drug accumulation or prolonged duration of action may occur in hepatic or renal impairment. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver disease or renal disease may require lower doses and less frequent dosing intervals; titrate doses gradually with care in patients with hepatic or renal impairment.

Seizures can be precipitated by opiate analgesics, particularly if used in high-doses and during opiate withdrawal. Methadone should be used cautiously in patients with a seizure disorder.

Use methadone with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenal insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenal insufficiency. It is unclear which, if any, opioids are more likely to cause adrenal insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

Neonates and infants younger than 6 months of age have highly variable clearance of opiate agonists, including methadone. Therefore, infants younger than 6 months of age may be given opiate agonists but must be closely monitored for apnea for an extended period after their last dose. Clinical practice guidelines suggest close monitoring of children up to 1 year of age.

Opiate agonists, such as methadone, may cause sedation. Patients and their caregivers should be advised to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle or operating a vehicle).

Opioid use requires an experienced clinician who is knowledgeable about the use of opioids, including the use of extended-release/long-acting opioids, and how to mitigate the associated risks. Opioids expose users to the risks of addiction, abuse, and misuse, which can occur at any dosage or duration. Although the risk of addiction in any individual is unknown, it can occur in persons appropriately prescribed opioids. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each individual's risk for opioid addiction, abuse, or misuse before prescribing an opioid, and monitor for the development of these behaviors or conditions. Risks are increased in persons with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given individual. Persons at increased risk may be prescribed opioids, but use in such persons necessitates intensive counseling about the risks and proper use of the opioid along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; persons with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and persons with addiction disorders and are subject to criminal diversion. Abuse of opioids has the potential for overdose or poisoning and death. Consider these risks when prescribing or dispensing an opioid. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Abuse or misuse of methadone tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of methadone and can result in overdose and death. Dosing errors may result from confusion between mg and mL when prescribing, dispensing, and administering methadone oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients on how to measure the dose and to use a calibrated oral dosing device. Keep opioids out of the reach of pediatric persons, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose. Accidental exposure of even a single dose of an opioid, especially by younger persons, can result in a fatal overdose. Because the risk of overdose increases as opioid dose increases, reserve titration to higher doses of an opioid for persons in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Long-acting opioids are not intended for use in the management of acute pain or on an as-needed basis but rather only for the management of severe and persistent pain that requires an extended treatment period with a daily opioid and for which alternative treatment options are inadequate. Discuss the availability of naloxone with all patients and consider prescribing it in persons who are at increased risk of opioid overdose, such as those who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental exposure or opioid overdose.

All patients of an appropriate age should be warned to avoid ethanol ingestion while taking methadone; the combination can result in fatal respiratory depression. Use of an opioid agonist while under the influence of other central nervous system (CNS) depressants or ethanol intoxication will increase risk of CNS and respiratory depressant effects.

Methadone should be avoided in patients treated with monoamine oxidase inhibitor therapy (MAOI therapy), due to the potential risk for serotonin syndrome. The use of methadone is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. with MAOI therapy. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of methadone with many types of serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), serotonin-receptor agonists "triptans", 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAOIs - those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue methadone and other serotonergic agents if serotonin syndrome is suspected and institute appropriate medical treatment.

Prolonged in utero exposure to methadone may lead to signs and symptoms of drug withdrawal in the newborn. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the exposed neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, excessive or high-pitched crying, tremor, vomiting, diarrhea, poor feeding, weight loss, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Of note, methadone has been detected in very low plasma concentrations in breast-fed infants whose mothers were taking methadone. Although breast-feeding may help mitigate withdrawal symptoms in the neonate, in some cases when methadone maintenance was used during pregnancy, the amount of methadone in breast milk may not be enough to fully avoid withdrawal in the infant. For example, of 8 breast-fed babies born to women maintained on methadone 50 to 105 mg/day, 1 required pharmacotherapy for NOWS, whereas 4 of 8 formula-fed babies needed treatment for the event. Withdrawal symptoms may occur in infants whose mothers are taking methadone and abruptly stop breast-feeding or discontinue methadone therapy. Gradual breast-feeding discontinuation may prevent NOWS.

Chronic use of opioids may pose a reproductive risk in females and males of reproductive potential. Long-term use of opioids may influence the hypothalamic-pituitary-gonadal axis, resulting in androgen deficiency that may manifest as amenorrhea or infertility. It is not known whether effects on fertility are reversible. Patients should inform their health care professional if they experience symptoms of decreased sex hormones. Laboratory evaluation should be conducted in patients presenting with such symptoms.

Description: Methadone is a potent synthetic opioid agonist of the phenylheptylamine class. It used for prevention of opioid withdrawal in both neonatal abstinence syndrome and iatrogenic opioid dependency in the pediatric intensive care unit. Methadone is also used in chronic pain; it is an alternative strong opioid to morphine for pain associated with cancer. Equianalgesic dosing of chronic methadone and other opiate agonists is unclear; an understanding of methadone pharmacokinetics is critical for drug initiation, conversion, and titration. Benefits of methadone in the treatment of opioid withdrawal and chronic pain include good oral bioavailability, lack of active metabolites, incomplete cross tolerance, long half-life, and low cost. Potential risks of methadone use include drug accumulation (secondary to a long half-life), life-threatening respiratory depression, and increased potential for QT prolongation, torsades de points, and sudden cardiac death. Methadone is not FDA-approved for pediatric use; however, it is commonly used for prevention of opioid withdrawal in pediatric patients as young as neonates.

-Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
-When used for analgesia, methadone should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would otherwise provide inadequate pain management. Discontinue all other around-the-clock opioid drugs upon methadone initiation.
-Dosages should be slowly titrated to the desired effect. Individualize dosing for each patient; consider opioid-tolerance, the physical and medical status of the patient, the degree of analgesia desired, patient response, clinical environment, and risk factors for addiction, abuse, and misuse. Reduced initial dosages should be used in those at increased risk for respiratory depression, including patients receiving other central nervous system (CNS) depressants.
-There is no maximum dose of methadone; however, careful titration is required until tolerance develops to some of the side effects (i.e., sedation and respiratory depression).
-Monitor patients closely for CNS and respiratory depression, especially within the first 24 to 72 hours after initiation and after dosage increases. Patients should be continually evaluated. If intolerable adverse effects occur, the dose and/or interval should be adjusted.
-More frequent administration may be needed during the first few days, but extreme caution to avoid overdosage is needed due to the long half-life of methadone. Although the half-life of methadone averages about 24 hours, there is great interpatient variability; half-life has been reported to range from 8 to 150 hours in adult patients. Due to the potential for delayed toxic effects (e.g., respiratory depression), FDA-approved labeling suggests slow titration with dosage increases occurring no more frequent than every 3 to 5 days; however, some experts recommend dosage adjustments occur no more frequent than every 5 to 7 days. Because of methadone's highly variable half-life, some patients may require substantially longer periods between dose increases (up to 12 days).
-For conversion between opioids, assessment of individual clinical response is necessary. Published tables vary in suggested equianalgesic doses. Because there is not complete cross-tolerance among these agents, it is recommended to lower the equianalgesic dosing when changing agents and then titrate to response. It is safer to underestimate the patient's 24-hour methadone requirements and provide rescue medication as needed than to overestimate the opioid requirements and manage adverse reactions. Refer to the Opioid Agonists Drug Class Overview for approximate equianalgesic doses.
-Do not abruptly stop methadone. When the patient no longer requires methadone, gradually taper the dose and interval to prevent withdrawal in the physically-dependent patient.
-FDA-approved labeling recommends an initial 1:2 dose ratio to convert from parenteral to oral methadone.

Methadone/Opiate Agonist Equianalgesic Dosing:
Published tables vary in suggested equianalgesic doses; population-based equianalgesic conversion ratios between methadone and other opioids are imprecise and cannot be consistently applied to all patients. High interpatient variability in absorption, metabolism, and relative analgesic potency exists. The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies), while the plasma elimination half-life ranges from 4 to 62 hours in children; these characteristics may lead to delayed toxic effects with unintentional overdose. Further, the potency of methadone increases over time with repeated dosing, and many conversion ratios do not apply in the setting of repeated methadone dosing. When methadone is used in patients tolerant to opiate agonists (e.g., patients with chronic cancer pain), dosage should be individualized based on response and tolerance; methadone is most safely initiated and titrated using small initial doses and gradual dose adjustments. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists.
-Morphine (chronic oral dosing) - Adults and Children weighing 50 kg or more:-Individualize dosing for each patient: at a minimum, consider the patient's degree of opioid tolerance, the age and medical status of the patient, concurrent non-opioid analgesics and medications with CNS activity, and the type and severity of the patient's pain.
-For patients previously receiving morphine less than 100 mg/day PO: estimated oral methadone requirement is 20% to 30% of the total daily oral morphine dose.
-For patients previously receiving morphine 100 to 300 mg/day PO: estimated oral methadone requirement is 10% to 20% of the total daily oral morphine dose.
-For patients previously receiving morphine 300 to 600 mg/day PO: estimated oral methadone requirement is 8% to 12% of the total daily oral morphine dose.
-For patients previously receiving morphine 600 to 1,000 mg/day PO: estimated oral methadone requirement is 5% to 10% of the total daily oral morphine dose.
-For patients previously receiving morphine more than 1,000 mg/day PO: estimated oral methadone requirement is less than 5% of the total daily oral morphine dose.


For the management of chronic severe pain* in opioid-tolerant patients who require daily, around-the-clock, long-term opioid treatment:
Oral dosage:
Children and Adolescents: Initially, 0.1 mg/kg/dose PO every 6 to 8 hours. Max initial dose: 5 mg/dose. Hold methadone dose if there is evidence of sedation. Although the World Health Organization suggests a higher potential starting dose (0.1 to 0.2 mg/kg/dose PO every 4 to 12 hours [Max initial dose: 10 mg/dose]) and some experts recommend loading with 0.1 mg/kg/dose PO every 4 hours for 2 to 3 doses before extending interval out to every 6 to 12 hours, guidelines for methadone safety emphasize more cautious initiation (particularly in non-hospital settings). Titrate slowly (i.e., once every 5 to 7 days, based on breakthrough pain medication requirements and by no more than 50% of the current methadone dose) to effective pain control. An increase in dosage should occur no more frequent than every 3 days; because of high variability in half-life, some patients may require substantially longer periods between dose increases (up to 12 days). Use short-acting opioids for breakthrough pain or if more rapid initial pain control is needed. Attempt to identify the source of increased pain before increasing the methadone dose. Monitor patients closely for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation.
Intravenous, Intramuscular, or Subcutaneous dosage:
Children and Adolescents: Initially, 0.1 mg/kg/dose IV/IM/subcutaneous every 6 to 8 hours. Max initial dose: 5 mg/dose. Hold methadone dose if there is evidence of sedation. Although the World Health Organization suggests a higher potential starting dose (0.1 mg/kg/dose IV/IM/subcutaneous every 4 to 12 hours [Max initial dose: 10 mg/dose]) and some experts recommend loading with 0.1 mg/kg/dose IV/IM/subcutaneous every 4 hours for 2 to 3 doses before extending interval out to every 6 to 12 hours, guidelines for methadone safety emphasize more cautious initiation. Titrate slowly to effective pain control. Use short-acting opioids for breakthrough pain or if more rapid initial pain control is needed. Monitor patients closely for respiratory depression.

For the management of neonatal abstinence syndrome*:
Oral dosage:
Neonates: 0.1 to 0.3 mg/kg/dose PO every 8 hours, initially, based on Finnegan Score. In a randomized, controlled trial, patients treated with methadone had better short-term outcomes such as decreased length of hospital stay, length of stay attributable to NAS, and length of drug treatment compared to those receiving morphine. 0.05 to 0.1 mg/kg/dose PO every 6 to 24 hours, initially, has also been reported. Titrate by 0.025 to 0.05 mg/kg/dose until symptoms are controlled. Once symptoms are controlled, taper dosage incrementally (10% to 20% of initial dose every 12 to 48 hours), lengthening interval (e.g., every 12 to 24 hours instead of every 6 hours) prior to discontinuation. Dosage, interval, length of treatment, and taper schedule are variable and must be individualized to control symptoms of withdrawal. Weaning may take several weeks to months. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation.

For the management of iatrogenic opiate agonist dependence*:
Oral dosage:
Neonates*, Infants*, Children*, and Adolescents*: Initially, 0.05 to 0.1 mg/kg/dose PO every 6 hours. Titrate by 0.05 mg/kg/dose until symptoms are controlled. Once symptoms are controlled, taper dosage incrementally (10% to 20% of initial dose every 1 to 2 days), lengthening interval (e.g., every 12 to 24 hours) prior to discontinuation; most patients can be tapered to off within 10 days. Dosage, interval, length of treatment, and taper schedule must be individualized based on patient's previous opioid dose and symptoms of withdrawal. Various dosing regimens have been reported and some practitioners suggest the daily dosage of opioid infusion (e.g., fentanyl) be converted to an equipotent daily dosage of methadone, however this may lead to unnecessarily high doses. Monitor patients frequently for CNS and respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation.

Maximum Dosage Limits:
Safety and efficacy in pediatric patients has not been established. However, methadone is used off-label in these populations. With appropriate dosage titration, there is no maximum dose of methadone.

Patients with Hepatic Impairment Dosing
Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and CNS depression. Adjust dosage based upon clinical response; no specific quantitative recommendations are available.

Patients with Renal Impairment Dosing
Dosage and/or interval adjustments may be necessary in patients with renal impairment; guide adjustments based on clinical response.
The following initial interval adjustments have been recommended for pediatric patients (normal dose interval every 4 to 12 hours):
CrCl 30 to 50 mL/minute: Administer dosage every 6 to 8 hours.
CrCl 10 to 30 mL/minute: Administer dosage every 8 to 12 hours.
CrCl less than 10 mL/minute: Administer dosage every 12 to 24 hours.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Methadone is a potent mu-opioid receptor agonist. Opioid receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C (PLC)-inositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2). The optical isomers of methadone differ in their binding affinities for opioid receptors. The R-isomer of methadone has a higher affinity for mu1 and mu2 receptors than S-methadone or the racemate. It appears that R-methadone has a receptor binding pattern similar to morphine and S-methadone does not contribute to the opioid effects of the racemic methadone. Methadone isomers and the racemate have low affinities for delta and kappa receptors. Methadone is considered a weak serotonin re-uptake inhibitor and has been implicated in serotonin syndrome toxicity reactions.

Opioids do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (mu2-, delta-, kappa-receptors) and higher levels in the CNS (mu1- and kappa3-receptors). There is no ceiling effect of analgesia for opioids. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (mu and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opioid stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin, and glucagon.

The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms include differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

Clinically, stimulation of mu-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Methadone has a blunted euphoric effect due to its long duration of action and slow onset of action. The decreased euphoric effects of methadone make it unattractive as a drug of abuse and an appropriate agent for the management of opioid dependence. During addiction, the functioning of the opioid receptor is altered due to repeated opioid exposure. Methadone treatment normalizes neurologic and endocrine process. Methadone suppresses opiate 'craving' and produces a blockade of the euphoria induced by morphine-like opioid agonists. Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Respiratory depression is caused by direct action of opioid agonists on respiratory centers in the brain stem. Opioid agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opioid agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opioid agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opioid agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention.

Several other clinical effects occur with opioid agonists including cough suppression, hypotension, and nausea/vomiting. The antitussive effects of opioid agonists are mediated through direct action on receptors in the cough center of the medulla. Cough suppression can be achieved at lower doses than those required to produce analgesia. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor center in the medulla. Induction of nausea and vomiting possibly occurs from direct stimulation of the vestibular system and/or the chemoreceptor trigger zone.

Pharmacokinetics: Methadone may be administered orally, intravenously, subcutaneously, or intramuscularly. Methadone is 85% to 90% bound to alpha-1-acid-glycoprotein in adults. Disease states such as cancer and other medications that affect the serum concentrations of alpha-1-acid-glycoprotein may alter the response to methadone. It is widely distributed into tissues due to its basic (pKa = 9.2) and lipophilic properties; mean volume of distribution (Vd) is 7.1 +/- 2.5 L/kg in pediatric patients and 6.1 +/- 2.4 L/kg in adults. Plasma clearance is faster in pediatric patients (5.4 mL/kg/minute) than in adults (3 mL/kg/minute). Methadone undergoes N-demethylation in the liver by CYP450 microsomal isoenzymes, and with chronic dosing, methadone may induce its own metabolism via CYP3A4. Fecal elimination accounts for the majority of methadone excretion. Urinary excretion of methadone and inactive metabolites, which is considered a minor route, is pH-dependent and increases at urinary pH less than 6. In general, elimination half-life is shorter in pediatric patients (mean: 19 hours; range: 4 to 62 hours) compared to adults (mean: 35 hours; range: 8 to 150 hours).

It is important to note that because of its pharmacokinetic profile, methadone differs from other opioids in many ways. Methadone may exhibit large interpatient variability in plasma concentrations at the same dosage, necessitating an individualized approach to therapy. After a single dose, methadone's duration of analgesic action is similar to morphine (4 to 8 hours); however, the elimination half-life is much longer. Steady-state plasma concentrations and full analgesic effects are usually not obtained until days 3 to 5 of dosing. The peak respiratory depressant effects typically occur later and persist longer than its peak analgesic effects, especially during the early dosing period. In addition, after repeated dosing methadone may persist in the liver and other tissues, prolonging the pharmacological effect despite low serum concentrations.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4, CYP2B6, CYP2C9, CYP2D6, and P-glycoprotein (P-gp)
Methadone is metabolized primarily by the cytochrome P450 isoenzymes CYP2C19, CYP3A4, and CYP2B6, and to a lesser extent, by CYP2C9 and CYP2D6. Methadone also is a substrate of P-glycoprotein. Methadone should be administered cautiously in patients receiving inducers or inhibitors of these enzymes.


-Route-Specific Pharmacokinetics
Oral Route
Methadone is well-absorbed (36% to 100%) after oral administration, and peak serum concentrations occur 1 to 7.5 hours after a dose. Onset of action occurs within 30 to 60 minutes of oral dose administration. Methadone undergoes first-pass metabolism in the gastrointestinal tract where it is a substrate for P-glycoprotein. The transport of methadone across the gut wall may be increased in the presence of P-glycoprotein inhibitors (e.g., verapamil or quinidine). After administration of daily oral doses (dosage range 10 to 225 mg/day) during clinical trials, peak concentrations ranged from 124 to 1,255 ng/mL. The effect of food on methadone bioavailability has not been studied.

Intravenous Route
Onset of action occurs within 10 to 20 minutes of parenteral administration. As compared to oral administration, intravenous administration results in a higher concentration to dose ratio of R-methadone, the active isomer; this is due to a decreased first-pass effect in the liver and the by-passing of methadone gut metabolism.

Intramuscular Route
Absorption after intramuscular administration of methadone has not been well characterized but appears to be unpredictable.

Subcutaneous Route
Absorption after subcutaneous administration of methadone has not been well characterized but appears to be unpredictable.


-Special Populations
Pediatrics
Neonates
Methadone is lipophilic and highly protein bound. Neonates (and even more so premature neonates) have a lower percentage of body fat and decreased protein-binding capacity, leading to a lower Vd for lipid-soluble drugs, such as methadone, and an increased amount of unbound drug. Unbound drug can potentially lead to an increased physiologic response and increased elimination. In addition, delayed and therefore increased drug absorption may affect the bioavailability of oral methadone. Reduced hepatic enzyme activity and reduced renal excretion during the neonatal period may also affect the neonate's response to methadone. Though pharmacokinetic studies are lacking, monitoring serum concentrations of methadone in neonates born to addicted mothers has provided rough estimates of neonatal metabolism. In a study of neonates (gestational age 34 to 43 weeks), the relationship between maternal doses of methadone and the incidence of neonatal withdrawal symptoms was unpredictable. Neonatal withdrawal symptoms appeared to be related to interpatient variability of maternal metabolism, placental transfer, and neonatal rate of excretion. Neonatal elimination half-life ranges from 16 to 41 hours.

Infants, Children, and Adolescents
Ontogeny may play a role in the pharmacokinetics of methadone in infants, children, and adolescents. Practitioners should keep in mind physiologic differences between infants, children, and adolescents; pharmacokinetic data presented has not been differentiated. The mean Vd in pediatric patients (7.1 +/- 2.5 L/kg) is larger than that of adults (6.1 +/- 2.4 L/kg). In addition, patients aged 1 to 18 years have a higher plasma clearance of methadone (5.4 mL/kg/minute) compared to adults (3 mL/kg/minute), leading to a shorter elimination half-life. Substantial variation in methadone's pharmacokinetic parameters is prevalent in all age groups; half-life in pediatric patients is 19.2 +/- 14 hours (range: 4 to 62 hours) while adults is 35 +/- 22 hours (range: 9 to 87 hours). The wide range of variability suggests some pediatric patients may metabolize methadone as adults do.

Hepatic Impairment
Pharmacokinetic data from patients with hepatic disease are limited. As methadone is metabolized by the liver to inactive metabolites, patients with hepatic impairment could have drug accumulation.

Renal Impairment
Pharmacokinetic data from patients with renal disease are limited. In patients with normal renal function, glomerular filtration and urinary excretion of methadone and inactive metabolites is considered a minor but variable route. Urinary excretion is pH-dependent and increases at urinary pH less than 6. As the pH of the urine decreases, this route of elimination may become clinically significant.