Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP). Although the risk of QT prolongation appears to be dose-related , with most incidences of QT prolongation and torsade de pointes occurring in patients receiving large doses for pain management (i.e. > 100 mg/day), it is important to note that smaller doses for maintenance of opiate addiction have also been implicated. A public health advisory was issued concerning cardiac-related deaths, which have been reported during initiation of methadone treatment as well as during conversion to methadone from other opiates. Extreme caution is recommended during initiation of treatment, conversion from one opiate to another, and dose titrations. An understanding of methadone pharmacokinetic parameters is critical. In addition to slowing the rate of cardiac repolarization thus lengthening the QT interval, methadone may produce cholinergic side effects (by stimulating medullary vagal nuclei) causing bradycardia and induce the release of histamine causing peripheral vasodilation. Use methadone with extreme caution, if at all, in patients whose ability to maintain blood pressure has already been compromised by hypovolemia or administration of certain CNS depressant medications such as phenothiazines or general anesthetics. Monitor patients for hypotension at the initiation of therapy and during dose titration. These effects can cause problems in patients with cardiac disease (e.g., angina, heart failure). Methadone should be used cautiously in patients with cardiac arrhythmias, hypokalemia, hypomagnesemia, hypotension, hypovolemia, or orthostatic hypotension. Opiate agonists can induce vasovagal syncope or orthostatic hypotension. A risk/benefit evaluation of methadone and consideration of alternative therapy is prudent for patients with QT prolongation (congenital long QT syndrome or acquired QT prolongation syndromes), patients with a history of torsade de pointes, patients with unexplained syncope, and those with multiple risk factors for QT prolongation including family history and/or coadministration of contributing medications (i.e. drugs associated with QT prolongation and drugs that inhibit the cytochrome P450 enzymes). 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, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, a history of alcohol abuse, or hepatic impairment may also be at increased risk for QT prolongation. A 2009 clinical guideline for cardiac safety with methadone treatment recommends that prescribers: (1.) discuss the risk of arrhythmia with patients; (2.) take a complete cardiac clinical history; (3.) screen patients for QT prolongation with ECG monitoring prior to initiation of methadone, at 3 months, and annually thereafter; (4.) use the ECG findings to stratify patient risk (i.e., patients with a QTc interval of 451—499 ms should receive more frequent monitoring and discuss the potential risks vs. benefits of treatment, patients with a QTc interval of >= 500 ms should receive intervention to lower cardiac risk either by discontinuing or lowering the methadone dose or by eliminating contributing factors); and (5.) be aware of methadone-drug interactions. Drugs known to prolong the QT interval, potentiate hypokalemia, or reduce methadone elimination should be coadministered with a careful assessment of risks versus benefits.
Methadone is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain methadone illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. The misuse of methadone by crushing, chewing, snorting, or injecting the dissolved product can result in overdose and death. To discourage abuse, the smallest appropriate quantity of methadone should be dispensed, and proper disposal instructions for unused drug should be given to patients.
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 obstructive pulmonary disease (COPD), 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. 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.
There are no adequate and well-controlled studies with methadone in pregnant women. Use methadone for severe pain during pregnancy only if the potential benefit justifies the potential risk to the fetus. Medical withdrawal of pregnant, opioid-dependent women from methadone is not recommended. When methadone is used during pregnancy as part of a supervised, therapeutic regimen, it is unlikely to pose substantial teratogenic risk. Pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. Consider these risks in pregnant women treated with methadone for maintenance treatment of opioid addiction. No increased risk of miscarriage in the second trimester or premature delivery in the third trimester was noted by a retrospective review of data from 101 opioid-dependent women. Benefits of methadone therapy during pregnancy include assisting women staying free of heroin or other opioids, increasing prenatal care, lessening the possibility of fetal death, and reducing the risk of HIV and hepatitis infection. Infants born to narcotic-addicted women treated with methadone during pregnancy have been found to have decreased fetal growth with reduced birth weight, length, or head circumference. The growth deficit does not appear to persist into later childhood. Children born to mothers who received methadone during pregnancy demonstrate mild but persistent performance deficits on psychometric and behavioral tests and may have an increased risk of visual development anomalies. Administration of methadone to pregnant animals during organogenesis through lactation resulted in decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain which correlate with altered behavioral responses at exposures comparable to and less than the human daily dose of 120 mg. Methadone clearance may be increased during pregnancy. The methadone dose or interval may need to be increased as the pregnancy progresses due to changes in plasma volume and renal blood flow; due to an increased metabolism of methadone during pregnancy, close monitoring of pregnant women is recommended. Methadone is not recommended for analgesia during labor and obstetric delivery due to its long duration of action and potential for respiratory depression in the newborn. Women maintained on methadone require appropriate obstetric pain management, as methadone maintenance does not provide analgesia. Narcotics with mixed agonist/antagonist properties should not be used for pain control during labor in patients chronically treated with methadone as they may precipitate acute withdrawal. Prolonged maternal use of opioids, such as methadone, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, 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.
All forms of methadone have the potential for overdose or poisoning. Methadone is a long-acting opioid that should only be used as an analgesic in patients with pain severe enough to require daily, around-the-clock, long-term opioid treatment. When used for analgesia, methadone should be reserved for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release, short-acting opioids) are ineffective, not tolerated, or would otherwise be inadequate to provide sufficient pain management. Due to the risk of respiratory depression, use methadone with caution in opioid-naive patients. Patients tolerant to other opioids may be incompletely tolerant to methadone; use caution when converting patients from other opioids to methadone. Special care should be taken to keep it out of the reach of patients for whom it was not prescribed, particularly pediatric patients, as accidental exposure may cause fatal overdose.
Methadone therapy requires an experienced clinician skilled in the use of potent opioids for chronic pain or opioid addiction. Outpatient maintenance and outpatient detoxification treatment may be provided only by Opioid Treatment Programs (OTPs) certified by the U.S. Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). In the U.S., outpatient maintenance therapy should be administered in accordance with the treatment standards in the Code of Federal Regulations (CFR), Title 42, Section 8.12, including limitations on unsupervised administration, dispensing by authorized pharmacies, and certification of treatment programs. If clinically indicated, patients may be enrolled directly into a maintenance program without first attempting detoxification since the purpose of the maintenance program is to provide a stable dose of methadone as a substitute for illicit opiate use. Maintenance should be continued as long as desired by the patient and as long as continued benefit is derived from treatment. During chronic administration of methadone, monitor patients for persistent constipation and maintain an effective bowel regimen. Maintenance treatments are effective in retaining patients in treatment and suppressing opiate use, with or without structured psychosocial services. An exception may be made for the maintenance treatment of a patient with concurrent opioid addiction who is hospitalized for conditions other than opioid addiction and who requires temporary maintenance during the critical period of their stay, or of a patient whose enrollment has been verified in a program which has been certified for maintenance treatment with methadone.