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    Agents for Opioid Dependence
    Agents for Opioid Withdrawal
    Opioid Agonists

    BOXED WARNING

    Angina, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, orthostatic hypotension, QT prolongation, thyroid disease

    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.

    Alcoholism, depression, opioid overdose, opioid use disorder, substance abuse

    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. Discuss the availability of naloxone with all patients and consider prescribing it in patients who are at increased risk of opioid overdose, such as patients 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 ingestion or opioid overdose.
     

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    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. [61143] 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.[33136] 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.[62374] 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. 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.[33136] [51312]

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    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.

    Accidental exposure, opioid-naive patients, potential for overdose or poisoning

    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.

    Requires an experienced clinician

    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.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    A phenylheptylamine synthetic opiate agonist; is structurally unrelated to morphine
    Used in medically supervised opiate withdrawal and maintenance programs; effective for the relief of severe or chronic pain
    For the treatment of opiate dependence, prescriber must register and comply with the Narcotic Addict Treatment Act (NATA) [21USC 823(g)]

    COMMON BRAND NAMES

    Dolophine, Methadose

    HOW SUPPLIED

    Dolophine/Methadone Hydrochloride Intramuscular Inj Sol: 1mL, 10mg
    Dolophine/Methadone Hydrochloride Intravenous Inj Sol: 1mL, 10mg
    Dolophine/Methadone Hydrochloride Subcutaneous Inj Sol: 1mL, 10mg
    Dolophine/Methadone Hydrochloride/Methadose Oral Tab: 5mg, 10mg, 40mg
    Methadone Hydrochloride/Methadose Oral Sol: 1mL, 5mL, 5mg, 10mg
    Methadone Hydrochloride/Methadose Oral Tab for Susp: 40mg

    DOSAGE & INDICATIONS

    For the treatment of opiate agonist withdrawal during detoxification treatment.
    NOTE: Patients need to show withdrawal symptoms but no signs of sedation or intoxication.
    NOTE: For the treatment of narcotic addiction in detoxification programs, methadone may be dispensed only by pharmacies and clinics approved by the FDA and state authorities according to treatment requirements stipulated in the Federal Methadone Regulations.
    NOTE: Detoxification shall not exceed 21 days or be repeated earlier than 4 weeks after completion of a preceding course.
    NOTE: Loss of opioid tolerance should be considered for a patient who has not taken opioids for more than 5 days.
    Withdrawal of methadone following detoxification treatment.
    Oral dosage
    Adults

    Medical withdrawal from methadone should be done in decrements as tolerated by the patient on a daily basis or at 2-day intervals. The dose should be sufficient to keep withdrawal symptoms at a tolerable level. Many hospitalized patients may tolerate a daily dosage reduction of 20%. In ambulatory patients, a somewhat slower schedule may be required. Patients should be allowed to discontinue withdrawal at anytime, for any reason, without feelings of guilt. They should then be placed into a methadone maintenance program at an appropriate dose. Any decrease in methadone dosage could precipitate a relapse to drug use. Methadone use is preferable to the use of illegal street drugs.

    Pregnant women

    Medical withdrawal of methadone maintenance is generally not recommended during pregnancy. If required, methadone withdrawal is done in decrements of 2 to 2.5 mg every 7 to 10 days. This should be done in conjunction with an obstetrician who can monitor the effects on the fetus.

    Oral dosage
    Adults, including pregnant women

    20 to 30 mg PO initially unless low opioid tolerance is expected; use a lower initial dose for these patients. Additional doses of 5 to 10 mg of methadone PO may be given 2 to 4 hours after the initial dose if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily oral dose on Day 1 should not ordinarily exceed 40 mg. Dosage adjustments on subsequent days should be based on withdrawal symptom control at the time of expected peak methadone activity (2 to 4 hours after dosing). Due to the extended half-life of methadone, it may take up to 5 days to achieve a steady-state dose that controls symptoms of opiate withdrawal. Prior to achieving steady state, adequate total daily doses may not hold patients for a full 24 hours. Deaths have occurred in early treatment due to the cumulative effects of methadone. The stabilizing dose is continued for 2 to 3 days.

    Intravenous, Subcutaneous or Intramuscular dosage

    NOTE: Intravenous methadone should only be used on a temporary basis for patients who cannot take oral medication, such as hospitalized inpatients.

    Adults

    Initially, use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone) when converting from oral to parenteral methadone. Conservative dose selection is recommended for opioid-tolerant patients due to dose conversion ratio uncertainty and incomplete cross-tolerance.

    For the maintenance treatment of opiate agonist dependence.
    For the management of iatrogenic opiate agonist dependence in pediatric patients†.
    Oral dosage
    Neonates†, Infants†, Children†, and Adolescents†

    Initially, 0.05 to 0.1 mg/kg 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.

    Oral dosage
    Adults

    Following induction therapy and detoxification, titrate patients to a dose that prevents opioid withdrawal symptoms for a full 24 hours, reduces drug craving, and blocks/attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Clinical stability is usually achieved at doses between 80 to 120 mg/day PO. Pregnant women may require dose adjustments during pregnancy to provide effective dosing. MAINTENANCE: In the U.S., administer in accordance with the Code of Federal Regulations (CFR), Title 42, Section 8.12. Continue as long as desired by the patient and continued benefit is derived; maintenance programs are effective retaining patients in treatment and suppressing opiate use. DISCONTINUATION: Avoid abrupt discontinuation due to the potential for opioid withdrawal symptoms and relapse of addiction. There is considerable individual variation in the rate of taper tolerated. Dose reductions should generally be less than 10% of the established maintenance dose, with 10 to 14-day intervals between dose reductions. A relapse to illicit drug use is a risk upon discontinuation.

    Intravenous, Subcutaneous, or Intramuscular dosage
    Adults

    Initially, use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone) when converting from oral to parenteral methadone. Conservative dose selection is recommended for opioid-tolerant patients due to dose conversion ratio uncertainty and incomplete cross-tolerance. NOTE: Intravenous methadone should only be used on a temporary basis for patients who cannot take oral medication, such as hospitalized inpatients. Injectable methadone is not approved for the outpatient treatment of opioid dependence.

    For the treatment of moderate pain or severe pain.
    For the treatment of chronic severe pain in patients who require daily, around-the-clock, long-term opioid treatment.
    NOTE: Methadone tablets or oral solution 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 initiation of methadone.
    Oral dosage
    Adults

    Initially, 2.5 mg PO every 8 to 12 hours in the opioid-naive patient; titrate to pain relief. For the relief of severe, chronic pain in opioid-tolerant patients, convert the current total daily dose of all opioids to an oral morphine equivalent dose, then multiply the morphine equivalent dose by the corresponding percentage in the dose conversion table provided in the FDA-approved labeling. Divide the total daily methadone dose into an appropriate daily regimen. Clinical guidelines suggest that methadone should be initiated at a dose that is 75% to 90% lower than the calculated equianalgesic dose and no higher than 30 to 40 mg/day in patients with opioid tolerance. If patients experience breakthrough pain, dose adjustment or a small rescue dose of an immediate-release analgesic should be considered. Use extreme caution to avoid overdosage; it is safer to underestimate a patient's daily oral methadone requirement. Due to the potential for delayed toxic effects (e.g., respiratory depression), clinical guidelines recommend dose titration every 5 to 7 days , although the manufacturer suggests adjustments may be made every 3 to 5 days. Titrate the dosage by no more than 5 mg/day in patients on relatively low doses of other opioids prior to methadone treatment (less than 40 to 60 mg/day of oral morphine equivalent) and by no more than 10 mg/day in patients taking higher doses of morphine equivalent. Patients previously prescribed methadone who have not taken opioids for 1 to 2 weeks should be considered opioid-naive for the purposes of methadone reinitiation. Monitor patients closely for respiratory depression, especially during the first 24 to 72 hours after initiation or dosage increase. When the patient no longer requires methadone, taper the dose gradually every 2 to 4 days to prevent withdrawal in the physically-dependent patient.

    For the treatment of moderate to severe pain not responsive to non-narcotic analgesics.
    Intravenous, Intramuscular, or Subcutaneous dosage
    Adults

    2.5 to 10 mg IV, IM, or subcutaneously every 8 to 12 hours, as needed for opioid-naive patients. In opioid-tolerant patients, convert the current total daily dose of all opioids to an oral morphine equivalent dose, then multiply the morphine equivalent dose by the corresponding percentages in the dose conversion table provided in the FDA-approved labeling. FDA-approved labeling recommends an initial 2:1 dose ratio to convert from oral to parenteral methadone. Clinical guidelines suggest that methadone should be initiated at a dose that is 75% to 90% lower than the calculated equianalgesic dose. Use extreme caution to avoid overdosage; it is safer to underestimate a patient's daily oral methadone requirement. Due to the potential for delayed toxic effects (e.g., respiratory depression), clinical guidelines recommend dose titration every 5 to 7 days, although the manufacturer suggests adjustments may be made every 3 to 5 days. When the patient no longer requires methadone, taper the dose gradually every 2 to 4 days to prevent withdrawal in the physically-dependent patient.

    MAXIMUM DOSAGE

    With appropriate dosage titration, there is no maximum dose of methadone. Safety and efficacy in pediatric patients have not been established; however, methadone is used off-label in these populations.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    Adults:
    Dosage adjustments may be necessary in adult patients with renal impairment; guide adjustments based on clinical response. Methadone has not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and CNS depression. For example, for CrCl less than 10 mL/minute, one source recommends that the adult initial dose be reduced by 50 to 75%.
     
    Pediatrics:
    Methadone has not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and CNS depression.
    The following initial interval adjustments have been recommended for pediatric patients (normal 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.

    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.[33136]

    Oral Solid Formulations

    Dispersible tablets (Diskets)
    Do not chew or swallow the tablets before dispersing in liquid. Disperse the desired dose of tablets in approximately 120 mL of water, orange juice, or other acidic fruit beverages before administration.
    Insoluble excipients will be present after tablets are dissolved; they will not completely dissolve. If residue remains in cup after initial administration, add a small amount of liquid and administer the resulting admixture to the patient.[51313]

    Oral Liquid Formulations

    Oral solution
    Carefully check dose before administering medication as multiple concentrations of methadone oral solution are available, including a concentrated version.[31280]
    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, methadone has also been administered intravenously for patient-controlled analgesia (PCA) via a rate controlled device as a bolus dose and as a continuous infusion.[31283]

    Intramuscular Administration

    Inject into a large muscle mass.
    The absorption of intramuscular (IM) methadone has not been well characterized and appears to be unpredictable.
    Local tissue reactions may occur with IM use.[51312]

    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.[51312]

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Dolophine:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Methadose:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Dental work, pain, surgery

    Methadone treatment for acute or chronic pain management should only be initiated if the potential analgesic or palliative care benefits outweigh the risks. Of particular concern are respiratory and cardiac related complications, including death, which may occur during treatment with the drug. Patients with cancer-related pain may have decreased clearance of methadone as compared to patients with chronic, benign pain. Patients receiving opioid dependance maintenance therapy with methadone are often under-treated or denied pain treatment. With long-term methadone therapy for opiate addiction, nearly complete tolerance develops to any analgesic effects of the medication. If a patient is taking methadone and experiences acute pain such as postoperative pain, analgesia may not be provided by the existing methadone dose; administration of another analgesic may be warranted. If another opioid is used, consider opioid tolerance induced by methadone. Whenever possible, pain management should be discussed with health care providers before any surgery or dental work takes place.

    Angina, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, orthostatic hypotension, QT prolongation, thyroid disease

    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.

    Alcoholism, depression, opioid overdose, opioid use disorder, substance abuse

    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. Discuss the availability of naloxone with all patients and consider prescribing it in patients who are at increased risk of opioid overdose, such as patients 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 ingestion or opioid overdose.
     

    Anxiety

    Methadone, as used in the treatment of opiate-dependent patients, does not have antianxiety effects. Patients who are maintained on methadone will react to life problems and stresses with the same anxiety symptoms as other individuals. Health care professionals should not confuse such symptoms with those of opiate abstinence and should not treat anxiety by increasing the dosage of methadone. The action of methadone in maintenance treatment is limited to the control of opiate withdrawal symptoms and is not effective in the treatment of anxiety.

    Biliary tract disease, constipation, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, pancreatitis, ulcerative colitis

    Due to the effects of opiate agonists on the gastrointestinal tract, methadone is contraindicated in patients with known or suspected paralytic ileus. Use with caution in patients with GI disease including GI obstruction, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Patients with acute ulcerative colitis (UC) or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated. Morphine is well recognized to increase the tone of the biliary tract causing spasms (especially in the sphincter of Oddi) increasing biliary tract pressure. Biliary effects due to opiate agonists have resulted in plasma amylase and lipase concentrations up to 2—15 times the normal values. The clinical significance of these effects during methadone therapy specifically 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.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    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. [61143] 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.[33136] 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.[62374] 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. 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.[33136] [51312]

    Brain tumor, CNS depression, coma, head trauma, increased intracranial pressure, intracranial mass

    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.

    Bladder obstruction, hepatic disease, oliguria, prostatic hypertrophy, renal disease, urethral stricture, urinary retention

    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, prostatic hypertrophy, urethral stricture, or renal disease. Due to the absence of data regarding methadone use in patients with renal impairment, caution is recommended. Renal elimination is usually a minor elimination pathway, but methadone does undergo some renal elimination (see Pharmacokinetics). Drug accumulation or prolonged duration of action can occur in patients with hepatic disease. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver disease may require less frequent dosing intervals.

    Seizure disorder, seizures

    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.

    Geriatric

    Use methadone with caution in geriatric or debilitated patients. Geriatric or debilitated patients are more susceptible to adverse reactions, especially sedation and respiratory depression, probably as a result of the altered distribution of the drug or decreased elimination. Initial doses may need to be reduced, and doses should be carefully titrated, taking into account analgesic effects, adverse reactions, and concomitant conditions and drugs that may increase CNS depression and depress respiration.[33136] According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except in the setting of severe acute pain, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. In patients receiving palliative care or hospice, the balance of benefits and harms of medication management may differ from those of the general population of older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). OBRA cautions that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. The initiation of longer-acting opioids is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.[60742]

    Adrenal insufficiency, hypothyroidism, myxedema

    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 adrenocortical 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 adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical 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.

    Infants, neonates

    The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. Methadone maintenance therapy has been an option for selected adolescents and is used off-label, though most methadone maintenance programs are aimed at adult patients. Methadone is not a drug of choice for pain management in opiate-naive pediatric patients, but off-label use of methadone has been described for children and adolescents who are opiate-experienced. Use in neonates and infants must be approached with caution. Neonates and infants younger than 6 months of age have highly variable clearance of opiate agonists. 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 for acute pain management suggest close monitoring of children up to 1 year of age.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    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.

    Breast-feeding

    Methadone is excreted in breast milk. According to the American Academy of Breastfeeding Medicine and previous American Academy of Pediatrics recommendations, therapeutic methadone use is usually compatible with breast-feeding. Consider the benefits of breast-feeding along with the mother's clinical need for methadone and any potential adverse effects on the breast-fed child from methadone or the underlying maternal condition. Women who received methadone maintenance therapy for opioid dependence during pregnancy who are stable may be encouraged to breast-feed, unless another contraindication (e.g., street drug abuse) is present. Other drugs (e.g., morphine) are preferable for pain control during breast-feeding. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported. In most samples, the milk concentrations were lower than maternal serum drug concentrations at steady state. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day, which is approximately 2% to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some 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. Of 8 breast-fed babies born to women maintained on methadone 50 to 105 mg/day, 1 required pharmacotherapy for neonatal opioid withdrawal syndrome, whereas 4 of 8 formula-fed babies needed treatment for the event. Advise breast-feeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulty. There are rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk.

    Driving or operating machinery

    Patients receiving methadone should be warned about the possibility of sedation occurring during methadone administration and to use caution when driving or operating machinery.

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction should not receive methadone. It is possible to treat these patients with an opioid agonist from the phenylpiperidine subclass (fentanyl or meperidine) or the phenanthrene subclass (codeine, hydromorphone, and oxycodone).

    Accidental exposure, opioid-naive patients, potential for overdose or poisoning

    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.

    Abrupt discontinuation

    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.[33136] [51312]

    MAOI therapy

    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.

    Requires an experienced clinician

    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.

    Infertility, reproductive risk

    Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Monitor patients for symptoms of opioid-induced endocrinopathy. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    ADVERSE REACTIONS

    Severe

    pulmonary edema / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    SIADH / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    neonatal opioid withdrawal syndrome / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    biliary obstruction / Delayed / Incidence not known

    Moderate

    psychological dependence / Delayed / 10.0
    tolerance / Delayed / Incidence not known
    hypoventilation / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    hypoxia / Early / Incidence not known
    dysphoria / Early / Incidence not known
    confusion / Early / Incidence not known
    euphoria / Early / Incidence not known
    hallucinations / Early / Incidence not known
    glossitis / Early / Incidence not known
    constipation / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    urinary retention / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    edema / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    physiological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    hyperthyroidism / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    agitation / Early / Incidence not known
    flushing / Rapid / Incidence not known
    drowsiness / Early / Incidence not known
    weakness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    restlessness / Early / Incidence not known
    headache / Early / Incidence not known
    insomnia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    nausea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    miosis / Early / Incidence not known
    xerostomia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    amenorrhea / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
    Abacavir; Dolutegravir; Lamivudine: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
    Abacavir; Lamivudine, 3TC: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known. (Moderate) Methadone increases exposure zidovudine, ZDV. Patients should be monitored for zidovudine toxicity during concurrent methadone treatment; however, the manufacturer of zidovudine states that routine dosage adjustment of zidovudine is not required during coadministration of methadone. Patients who receive both methadone and zidovudine may experience symptoms characteristic of opiate withdrawal and attribute the cause to decreased methadone levels due to zidovudine. However, it is more likely patients are actually experiencing zidovudine side effects due to increased levels since zidovudine has no effect on methadone metabolism. In one pharmacokinetic study (n=9), coadministration of methadone increased the AUC of zidovudine by about 43% (range: 16-64%). It appears methadone inhibits zidovudine glucuronidation and, to a lesser extent, decreases zidovudine renal clearance.
    Abarelix: (Severe) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation, such as methadone.
    Abiraterone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of abiraterone is necessary. If abiraterone is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2D6 substrate, and coadministration with CYP2D6 inhibitors like abiraterone can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If abiraterone is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Acetaminophen; Butalbital: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Acetaminophen; Butalbital; Caffeine: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone. (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of methadone with another CNS depressant like dihydrocodeine can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Codeine: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Oxycodone: (Major) Concomitant use of methadone with another CNS depressant, such as oxycodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also, consider a using a lower dose of the CNS depressant; use an initial dose of oxycodone at one-third to one-half the usual dosage. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as methadone. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Propoxyphene: (Major) Propoxyphene is a weak mu-opiate receptor agonist. As other opiate agonists bind to mu-opiate receptors, concurrent use of an opiate agonist with propoxyphene is not desirable. Also, propoxyphene will only partially suppress the withdrawal syndrome in patients physically dependent on narcotics. The choice of one mu-opiate receptor agonist needs to be made to avoid duplicate therapy and possible adverse effects. Concomitant use of methadone with propoxyphene can lead to additive respiratory depression, hypotension, profound sedation, or coma. Propoxyphene in combination with other CNS depressants is a major cause of drug-related death. Fatalities within the first hour of overdosage are not uncommon. Extreme caution is needed during concomitant use of any CNS-depressant drug and propoxyphene. Prior to concurrent use of methadone in patients taking a propoxyphene, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    Acetohydroxamic Acid: (Minor) As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.
    Acidifying Agents: (Minor) As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.
    Acrivastine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with acrivastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with acrivastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
    Alfentanil: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and methadone should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Aliskiren; Amlodipine: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering methadone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amifampridine: (Moderate) Carefully consider the need for concomitant treatment with opioid agonists and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Opioid agonists may increase the risk of seizures.
    Amiloride: (Moderate) Diuretics can cause electrolyte disturbances such as hypomagnesemia and hypokalemia, which may prolong the QT interval. As methadone may also prolong the QT interval, cautious coadministration with diuretics is needed. Also opiate agonists may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Diuretics can cause electrolyte disturbances such as hypomagnesemia and hypokalemia, which may prolong the QT interval. As methadone may also prolong the QT interval, cautious coadministration with diuretics is needed. Also opiate agonists may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Amiodarone: (Major) The need to coadminister methadone with amiodarone should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day in adult patients. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes, such as amiodarone, may result in increased serum concentrations of methadone.
    Amitriptyline: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of QT prolongation and serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of methadone with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression, QT prolongation, and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of QT prolongation and serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of methadone with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression, QT prolongation, and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amlodipine: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Atorvastatin: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Benazepril: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Celecoxib: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of celecoxib is necessary. If celecoxib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2D6 substrate, and coadministration with CYP2D6 inhibitors like celecoxib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If celecoxib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Olmesartan: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Telmisartan: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Amlodipine; Valsartan: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Ammonium Chloride: (Minor) As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.
    Amobarbital: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Amoxapine: (Major) Concomitant use of opioid agonists with amoxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with amoxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clarithromycin, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with clarithromycin, an inhibitor of CYP3A4 and P-gp, may result in increased serum concentrations of methadone.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clarithromycin, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with clarithromycin, an inhibitor of CYP3A4 and P-gp, may result in increased serum concentrations of methadone.
    Amphetamine: (Moderate) If concomitant use of methadone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amphetamine; Dextroamphetamine: (Moderate) If concomitant use of methadone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amphetamines: (Moderate) If concomitant use of methadone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amprenavir: (Major) Coadministration of amprenavir with methadone can decrease the plasma concentrations and efficacy of both drugs. When possible, alternatives to amprenavir therapy should be strongly considered in patients receiving methadone, in order to avoid loss of virologic response and possible viral resistance to amprenavir. If amprenavir and methadone must be coadministered, the patient's HIV status should be closely followed and the dosage of methadone may need to be increased. Observe the patient for symptoms of methadone withdrawal or other indicators of the need for methadone dosage adjustment.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include methadone.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when methadone is used concomitantly with an anticholinergic drug. The concomitant use of methadone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apalutamide: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with apalutamide is necessary; these effects may be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If apalutamide is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a substrate of CYP2C9, CYP2C19, and CYP3A4. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering methadone with apomorphine. The need to coadminister these drugs should be done with extreme caution and a careful assessment of treatment risks versus benefits. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Methadone is associated with an increased risk for QT prolongation and TdP, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Additionally, apomorphine and methadone can cause significant somnolence which may be additive. A dose reduction of one or both drugs may be warranted.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Aprepitant, Fosaprepitant: (Major) Use caution if methadone and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in methadone-related adverse effects, including excess sedation, for several days after administration of a multi-day aprepitant regimen. Methadone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of methadone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and methadone is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aripiprazole: (Major) Aripiprazole should be used cautiously and with close monitoring with methadone due to the potential for increased risk of QT prolongation, torsade de pointes (TdP), and additive CNS depressant effects. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include methadone. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor of and methadone is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased methadone concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as methadone, should be avoided. Consider ECG monitoring if methadone must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Major) Avoid coadministration of asenapine and methadone due to an additive risk of QT prolongation. Concomitant use of opioid agonists with asenapine may also cause excessive sedation and somnolence. Limit the use of opioid pain medications with asenapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Asenapine has been associated with QT prolongation. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone. (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of methadone with another CNS depressant like dihydrocodeine can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of methadone with orphenadrine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of methadone with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Concomitant use of methadone with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of methadone with another CNS depressant, such as oxycodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also, consider a using a lower dose of the CNS depressant; use an initial dose of oxycodone at one-third to one-half the usual dosage. Monitor patients for sedation and respiratory depression.
    Atazanavir: (Moderate) Caution is advised with the coadministration of atazanavir and methadone as concurrent use may result in increased concentrations of methadone. Methadone is primarily metabolized by CYP3A4; atazanavir is a CYP3A4 inhibitor. No clinically significant drug interaction was observed when atazanavir was coadministered with a stable maintenance dose of methadone. However, if coadministered, patients should be regularly monitored for excessive methadone-related side effects, as the theoretical possibility for atazanavir to inhibit methadone metabolism does exist.
    Atazanavir; Cobicistat: (Moderate) Caution is advised with the coadministration of atazanavir and methadone as concurrent use may result in increased concentrations of methadone. Methadone is primarily metabolized by CYP3A4; atazanavir is a CYP3A4 inhibitor. No clinically significant drug interaction was observed when atazanavir was coadministered with a stable maintenance dose of methadone. However, if coadministered, patients should be regularly monitored for excessive methadone-related side effects, as the theoretical possibility for atazanavir to inhibit methadone metabolism does exist. (Moderate) The plasma concentrations of methadone may be elevated when administered concurrently with cobicistat. When initiating methadone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest methadone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on methadone, an adjustment of methadone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. 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 (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include methadone.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of methadone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Azelastine: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Azelastine; Fluticasone: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Azithromycin: (Major) Avoid coadministration of azithromycin with methadone due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Baclofen: (Major) Concomitant use of methadone with baclofen may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with baclofen to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Barbiturates: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with methadone. The need to coadminister these drugs should be done with extreme caution and a careful assessment of treatment risks versus benefits. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Methadone is also considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Belladonna; Opium: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract; severe constipation or paralytic ileus is possible, especially with chronic use. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with benzhydrocodone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of benzhydrocodone with opioid agonists to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking methadone, reduce initial dosage and titrate to clinical response. If methadone is prescribed in a patient taking benzhydrocodone, use a lower initial dose of methadone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and methadone because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of methadone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
    Benzphetamine: (Moderate) If concomitant use of methadone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Bepridil: (Severe) Bepridil administration is associated with a well-established risk of QT prolongation and torsades de pointes. Patients receiving other drugs which have the potential for QT prolongation, such as methadone, have an increased risk of developing proarrhythmias during bepridil therapy. According to the manufacturer, bepridil is contraindicated for use with drugs that prolong the QT interval due to the risk of TdP.
    Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include methadone. (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include methadone. (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering methadone with boceprevir due to the potential for decreased methadone efficacy. The dose of methadone may need to be adjusted during therapy. If methadone dose adjustments are made, they should be re-adjusted upon completion of boceprevir treatment.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including methadone.
    Brexpiprazole: (Major) Concomitant use of opioid agonists with brexpiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brexpiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brigatinib: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of methadone as needed. If brigatinib is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brompheniramine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Bumetanide: (Moderate) Diuretics can cause electrolyte disturbances such as hypomagnesemia and hypokalemia, which may prolong the QT interval. As methadone may also prolong the QT interval, cautious coadministration with diuretics is needed.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Methadone has a possible risk for QT prolongation and TdP and use with buprenorphine should be avoided if possible. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as methadone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Methadone has a possible risk for QT prolongation and TdP and use with buprenorphine should be avoided if possible. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as methadone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Major) Naloxone can antagonize the therapeutic efficacy of methadone in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including methadone. Naloxone should only be administered when clinically significant respiratory or cardiovascular depression are present. If therapy with an naloxone is indicated, repeat doses may be needed due to methadone's prolonged duration of action.
    Bupropion: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as methadone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7-10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur. (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as methadone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Buspirone: (Moderate) Concomitant use of CNS depressants, such as buspirone, can potentiate the effects of methadone, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If concurrent use of codeine and buspirone is imperative, reduce the dose of one or both drugs.
    Butabarbital: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
    Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as methadone. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Butorphanol may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of butorphanol with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, increased methadone exposure is possible. Methadone is a CYP2C9 substrate. In vitro data predicts inhibition of CYP2C9 by cannabidiol potentially resulting in clinically significant interactions.
    Capecitabine: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of capecitabine is necessary. If capecitabine is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2C9 substrate, and coadministration with weak CYP2C9 inhibitors like capecitabine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If capecitabine is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. If concomitant use of methadone and metaxalone is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Carbamazepine: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with carbamazepine is necessary; consider increasing the dose of methadone as needed. If carbamazepine is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Carbetapentane; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbonic anhydrase inhibitors: (Moderate) Carbonic anhydrase inhibitors can cause electrolyte disturbances such as hypomagnesemia and hypokalemia, which may prolong the QT interval. As methadone may also prolong the QT interval, cautious coadministration with diuretics is needed.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of methadone with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carvedilol: (Moderate) Increased concentrations of methadone may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and methadone is a P-gp substrate.
    Celecoxib: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of celecoxib is necessary. If celecoxib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2D6 substrate, and coadministration with CYP2D6 inhibitors like celecoxib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If celecoxib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Cenobamate: (Moderate) Concomitant use of methadone with cenobamate may cause excessive sedation and somnolence. Limit the use of methadone with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with cenobamate is necessary; these effects may be more pronounced with cenobamate as it can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If cenobamate is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a substrate of CYP3A4 and CYP2B6; cenobamate is a moderate CYP3A4 inducer and weak CYP2B6 inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ceritinib: (Major) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary; carefully assess the benefits of treatment with the risks of therapy, including QT prolongation. Periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. If ceritinib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If ceritinib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Additionally, concentration-dependent QT prolongation has been reported with ceritinib therapy. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Cetirizine: (Moderate) Concomitant use of opioid agonists with cetirizine/levocetirizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cetirizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cetirizine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with cetirizine/levocetirizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cetirizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chloral Hydrate: (Major) Concomitant use of opioid agonists with chloral hydrate may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chloral hydrate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorcyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlordiazepoxide: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlordiazepoxide; Clidinium: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with methadone due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Codeine: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of methadone with another CNS depressant like dihydrocodeine can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of methadone with another CNS depressant like dihydrocodeine can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpromazine: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP and inhibits CYP2D6. In addition, concomitant use of methadone with another CNS depressant, such as chlorpromazine, can also lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Chlorzoxazone: (Major) Concomitant use of methadone with chlorzoxazone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with chlorzoxaz