CONTRAINDICATIONS / PRECAUTIONS
General Information
Methadone is contraindicated in persons with methadone hypersensitivity (e.g., anaphylaxis) or hypersensitivity to any other ingredient in the formulation.
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.
Accidental exposure, alcoholism, depression, opioid overdose, opioid use disorder, potential for overdose or poisoning, requires an experienced clinician, substance abuse
Opioid use requires an experienced clinician who is knowledgeable about the use of opioids, including the use of extended-release/long-acting opioids, and how to mitigate the associated risks. Opioids expose users to the risks of addiction, abuse, and misuse, which can occur at any dosage or duration. Although the risk of addiction in any individual is unknown, it can occur in persons appropriately prescribed opioids. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each individual's risk for opioid addiction, abuse, or misuse before prescribing an opioid, and monitor for the development of these behaviors or conditions. Risks are increased in persons with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given individual. Persons at increased risk may be prescribed opioids, but use in such persons necessitates intensive counseling about the risks and proper use of the opioid along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; persons with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and persons with addiction disorders and are subject to criminal diversion. Abuse of opioids has the potential for overdose or poisoning and death. Consider these risks when prescribing or dispensing an opioid. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Abuse or misuse of methadone tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of methadone and can result in overdose and death. Dosing errors may result from confusion between mg and mL when prescribing, dispensing, and administering methadone oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients on how to measure the dose and to use a calibrated oral dosing device. Keep opioids out of the reach of pediatric persons, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose. Accidental exposure of even a single dose of an opioid, especially by younger persons, can result in a fatal overdose. Because the risk of overdose increases as opioid dose increases, reserve titration to higher doses of an opioid for persons in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Long-acting opioids are not intended for use in the management of acute pain or on an as-needed basis but rather only for the management of severe and persistent pain that requires an extended treatment period with a daily opioid and for which alternative treatment options are inadequate. Discuss the availability of naloxone with all patients and consider prescribing it in persons who are at increased risk of opioid overdose, such as those who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental exposure or opioid overdose.
Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, respiratory depression, respiratory insufficiency, sleep apnea
Methadone is contraindicated in persons with significant respiratory depression and those with acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment. Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in persons for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor closely for signs or symptoms of respiratory depression and sedation. Persons with chronic obstructive pulmonary disease (COPD), cor pulmonale, respiratory insufficiency, hypoxemia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive even at recommended doses. Persons with advanced age, cachexia, or debilitation are also at an increased risk for opioid-induced respiratory depression. Monitor such persons closely, particularly when initiating and titrating the opioid; consider the use of non-opioid analgesics. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in persons with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Careful monitoring and dose titration is required, particularly when CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 inhibitors are used concomitantly. Concomitant use or discontinuation of CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 inhibitors may result in an increase in plasma methadone concentrations and potentiate the risk of fatal respiratory depression. Management of respiratory depression may include observation, necessary supportive measures, and opioid antagonist use when indicated.
Biliary tract disease, GI obstruction, ileus, pancreatitis
Methadone is contraindicated in persons with known or suspected GI obstruction, including paralytic ileus. Methadone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor persons with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Abrupt discontinuation
Avoid abrupt discontinuation of opioids in a physically-dependent patient. When a person who has been taking opioids regularly and may be physically dependent no longer requires therapy with an opioid, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If these signs or symptoms develop, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Consider tapering to reduced opioid dosage, or tapering and discontinuing long-term opioid therapy, when pain improves; the patient requests dosage reduction or discontinuation; pain and function are not meaningfully improved; the patient is receiving higher opioid doses without evidence of benefit from the higher dose; the patient has current evidence of opioid misuse; the patient experiences side effects that diminish quality of life or impair function; the patient experiences an overdose or other serious event (e.g., hospitalization, injury) or has warning signs for an impending event such as confusion, sedation, or slurred speech; the patient is receiving medications (e.g., benzodiazepines) or has medical conditions (e.g., lung disease, sleep apnea, liver disease, kidney disease, fall risk, advanced age) that increase risk for adverse outcomes; or the patient has been treated with opioids for a prolonged period and current benefit-harm balance is unclear. If the patient has a serious mental illness, is at high suicide risk, or has suicidal ideation, offer or arrange for consultation with a behavioral health provider before initiating a taper. In patients with opioid use disorder, offer or arrange for medication-assisted treatment. Individualize opioid tapering schedules. The longer the duration of previous opioid therapy, the longer the taper may take. Common tapers involve dose reduction of 5% to 20% every 4 weeks; a faster taper may be appropriate for some patients. Significant opioid withdrawal symptoms may indicate the need to pause or slow the taper. Opioids may be stopped, if appropriate, when taken less often than once daily. Advise patients that there is an increased risk for overdose on abrupt return to a previously prescribed higher dose; provide opioid overdose education, and consider offering naloxone. Monitor patients closely for anxiety, depression, suicidal ideation, and opioid use disorder, and offer support and referral as needed.[64906]
Brain tumor, CNS depression, coma, head trauma, increased intracranial pressure, intracranial mass
Avoid methadone use in persons with CNS depression, impaired consciousness, or coma; opioids may obscure the clinical course in a person with a head trauma injury. Monitor persons who may be susceptible to the intracranial effect of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure, brain tumor, or intracranial mass) for signs of sedation and respiratory depression, particularly when initiating methadone therapy. Methadone may reduce respiratory drive and resultant carbon dioxide retention can further increase intracranial pressure.
Driving or operating machinery
Warn persons against performing potentially hazardous activities such as driving or operating machinery unless they are tolerant to the effects of methadone and know how they will react to the medication. Methadone may impair mental or physical abilities required to perform such tasks.
Seizure disorder, seizures
Monitor persons with a history of seizure disorder for worsened seizure control during opioid therapy. Opioids may increase the frequency of seizures in persons with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.
Hepatic disease, renal failure, renal impairment
In persons with hepatic disease, renal impairment, or renal failure, start methadone at a lower dose and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression. Methadone pharmacokinetics have not been extensively evaluated in persons with hepatic or renal insufficiency. Methadone is metabolized by hepatic pathways; therefore, persons with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.
Infants, neonates
Neonates and infants younger than 6 months of age have highly variable clearance of opioids, including methadone. Therefore, infants younger than 6 months of age may be given opioids but must be closely monitored for apnea for an extended period after their last dose. Guidelines 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.
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]
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.
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.
Laboratory test interference
False positive urine drug screens (i.e., laboratory test interference) for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.
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: (Contraindicated) 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; Aspirin; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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; Caffeine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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.
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: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression.
Adagrasib: (Major) Avoid concomitant use of adagrasib and methadone due to the potential for increased methadone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Methadone is a CYP2C9, CYP2D6, and CYP3A substrate, adagrasib is a moderate CYP2C9, moderate CYP2D6, and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
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.
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.
Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with methadone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with methadone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
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.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with methadone. Amisulpride causes dose- and concentration- dependent QT prolongation. 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.
Amitriptyline: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of methadone with tricyclic antidepressants 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. 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 vs. benefits. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose therapy (elevated serum concentrations). Monitor patients closely for cardiac conduction changes. Also monitor patients for the emergence of serotonin syndrome and for signs of urinary retention or reduced gastric motility. 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. The concomitant use of opioids with anticholinergic drugs may increase risk of urinary retention or severe constipation, which may lead to paralytic ileus.
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; 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; 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; Valsartan; 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.
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; 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.
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.
Asciminib: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of asciminib is necessary. If asciminib is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; asciminib is a CYP2C9 and CYP3A inhibitor. Concomitant use with asciminib 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.
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; 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) Concomitant use of methadone and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Avacopan: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; avacopan is a weak CYP3A inhibitor. Concomitant use with avacopan 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.
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) Concomitant use of azithromycin and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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; 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.
Belumosudil: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of belumosudil is necessary. If belumosudil is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; belumosudil is a weak CYP3A inhibitor. Concomitant use with belumosudil 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.
Belzutifan: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with belzutifan is necessary. Consider increasing the dose of methadone as needed. If belzutifan is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; belzutifan is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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.
Berotralstat: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4 and CYP2D6; berotralstat is a moderate CYP3A4 and CYP2D6 inhibitor. Concomitant use with berotralstat 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.
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.
Bicalutamide: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; bicalutamide is a weak CYP3A4 enzyme inhibitor. Concomitant use with bicalutamide 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (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) Concomitant use of metronidazole and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (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.
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.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
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 a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; brigatinib is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting 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 medication 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.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Brompheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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; 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.
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.
Bupivacaine; Meloxicam: (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.
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.
Butalbital; Acetaminophen: (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.
Butalbital; Acetaminophen; 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.
Butalbital; Acetaminophen; 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.
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.
Cabotegravir; Rilpivirine: (Major) Close clinical monitoring is advised with coadministration. Use of these drugs together may cause the plasma concentration of methadone to decrease, thereby resulting in decreased methadone efficacy. No dose adjustments are required when initiating concurrent treatment; however, the maintenance dose of methadone may need to be adjusted in some patients. In addition, due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with methadone. A careful assessment of treatment risks versus benefits should be conducted prior to coadministration. When initiating concurrent treatment no dose adjustments are required; however, the dose of methadone may need to be adjusted during maintenance therapy. 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate 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. Also 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.
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 respiratory depression, profound sedation, and death. Limit the use of opioid pain medication 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. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
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.
Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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) Concomitant use of opioid agonists like methadone with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine 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.
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.
Celecoxib; 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. (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: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cetirizine; Pseudoephedrine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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; Amitriptyline: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of methadone with tricyclic antidepressants 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. 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 vs. benefits. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose therapy (elevated serum concentrations). Monitor patients closely for cardiac conduction changes. Also monitor patients for the emergence of serotonin syndrome and for signs of urinary retention or reduced gastric motility. 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. The concomitant use of opioids with anticholinergic drugs may increase risk of urinary retention or severe constipation, which may lead to paralytic ileus. (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 medication 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.
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 medication 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.
Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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 medication 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.
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 medication 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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication 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.
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: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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.
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 chlorzoxazone 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.
Cinacalcet: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of cinacalcet is necessary. If cinacalcet is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use with cinacalcet 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.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) 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. Because of the potential for TdP, use of cisapride with methadone is contraindicated.
Citalopram: (Major) Coadministration may increase the risk of serotonin syndrome, QT prolongation, or torsade de pointes (TdP). Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer of citalopram, ECG monitoring is recommended in patients receiving concurrent drugs that prolong the QT interval. 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 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. In addition, both citalopram and methadone have central serotonergic properties and serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Clarithromycin: (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.
Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine 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.
Clobazam: (Major) Concomitant 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 doses and minimum treatment durations needed to achieve the desired clinical effect. If methadone is initiated in a patient taking a benzodiazepine, reduced dosages are recommended; in opioid-naive adults, use an initial dose of methadone 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 dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clofazimine: (Major) Concomitant use of clofazimine and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of methadone with tricyclic antidepressants 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. 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 vs. benefits. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose therapy (elevated serum concentrations). Monitor patients closely for cardiac conduction changes. Also monitor patients for the emergence of serotonin syndrome and for signs of urinary retention or reduced gastric motility. 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. The concomitant use of opioids with anticholinergic drugs may increase risk of urinary retention or severe constipation, which may lead to paralytic ileus.
Clonazepam: (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.
Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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.
Clopidogrel: (Moderate) Coadministration of opioid agonists, such as methadone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
Clorazepate: (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.
Clozapine: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clozapine, 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, concomitant use of methadone with another CNS depressant, such as clozapine, 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. Consider a lower dose of the CNS depressant. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Cobicistat: (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.
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.
Codeine; Guaifenesin: (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.
Codeine; Guaifenesin; Pseudoephedrine: (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.
Codeine; Phenylephrine; Promethazine: (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) 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 considered to be associated with an increased risk for QT prolongation especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Drugs with a potential risk for QT prolongation that should be used cautiously with methadone include promethazine. Additionally, use of methadone with another CNS depressant can lead to additive sedation, respiratory depression, hypotension, or coma. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. 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; for example, 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. Monitor patients for sedation and respiratory depression.
Codeine; Promethazine: (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) 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 considered to be associated with an increased risk for QT prolongation especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Drugs with a potential risk for QT prolongation that should be used cautiously with methadone include promethazine. Additionally, use of methadone with another CNS depressant can lead to additive sedation, respiratory depression, hypotension, or coma. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants. 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; for example, 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. Monitor patients for sedation and respiratory depression.
COMT inhibitors: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Conivaptan: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; conivaptan is a moderate CYP3A inhibitor. Concomitant use with conivaptan 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.
Crizotinib: (Major) Avoid coadministration of crizotinib with methadone due to the risk of QT prolongation; exposure to methadone may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. If crizotinib 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 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. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration 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 crizotinib 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.
Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
Cyclizine: (Moderate) Concomitant use of opioid agonists with cyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cyclizine 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.
Cyclobenzaprine: (Major) Concomitant use of methadone with cyclobenzaprine may cause respiratory depression, hypotension, profound sedation, and death. Additionally, concomitant use may result in serotonin syndrome. Limit the use of opioid pain medications with cyclobenzaprine 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. 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.
Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine 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.
Dacomitinib: (Moderate) Concomitant use of methadone with dacomitinib may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
Dalfopristin; Quinupristin: (Moderate) Concomitant use of methadone with dalfopristin; quinupristin may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of dalfopristin; quinupristin could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If dalfopristin; quinupristin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP3A4. Dalfopristin; quinupristin is a weak inhibitor of CYP3A4.
Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of drugs that are CYP3A4 substrates including methadone.
Dantrolene: (Major) Concomitant use of methadone with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene 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.
Daridorexant: (Major) Concomitant use of opiate agonists with daridorexant may cause excessive sedation and somnolence. Limit the use of opiates with daridorexant 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. Avoid prescribing cough medicines that contain opiates in patients taking daridorexant.
Darifenacin: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of darifenacin is necessary. If darifenacin 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 darifenacin 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 darifenacin 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. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Darifenacin has anticholinergic actions that may produce additive effects. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Darunavir: (Moderate) Coadministration of darunavir with methadone is expected to result in decreased methadone concentrations. Patients should be monitored for opiate abstinence syndrome; an increase in methadone dosage may be considered based on clinical response.
Darunavir; Cobicistat: (Moderate) Coadministration of darunavir with methadone is expected to result in decreased methadone concentrations. Patients should be monitored for opiate abstinence syndrome; an increase in methadone dosage may be considered based on clinical response. (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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of darunavir with methadone is expected to result in decreased methadone concentrations. Patients should be monitored for opiate abstinence syndrome; an increase in methadone dosage may be considered based on clinical response. (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.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of ritonavir with methadone has resulted in decreased methadone plasma concentrations. However, because methadone is metabolized by multiple CYP450 enzymes, including CYP3A4, CYP2C19, CYP2C9, and CYP2D6, and ritonavir is known to inhibit CYP3A4 and CYP2D6 and induce CYP2C19 and CYP2C9, the potential for increased methadone exposure should also be considered with concomitant administration. Therefore, concurrent use may increase or prolong opioid effects, resulting in fatal overdose or may decrease methadone efficacy or produce onset of withdrawal symptoms in patients physically dependent on methadone. Monitor for respiratory depression, sedation, and signs of opioid withdrawal. Consider adjusting the methadone dose until stable drug effects are achieved. If ritonavir is discontinued, and its CYP450 effects decline, methadone plasma concentrations may increase or decrease. Closely monitor for increased opioid adverse effects and for evidence of withdrawal and adjust the methadone dose as necessary when ritonavir is discontinued.
Dasatinib: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and methadone should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). 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 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.
Degarelix: (Major) The need to coadminister methadone with drugs known to prolong the QT interval like degarelix 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 (greater than 200 mg/day; averaging about 400 mg/day in adults). 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. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Delavirdine: (Major) The concurrent administration of methadone and inhibitors of cytochrome P450 3A4, such as delavirdine, may result in increased concentrations of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used (e.g., 200 mg/day PO in adult patients). A decrease in methadone doses may be required.
Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desipramine: (Major) Concomitant use of methadone with tricyclic antidepressants may c