Methadone

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

May cause constipation, which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

QT interval prolongation and serious arrhythmias (torsades de pointes) have occurred during treatment. 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. Closely monitor patients with risk factors for development of QT interval (eg, cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone. QT interval prolongation and torsades de pointes may be more commonly associated with, but not limited to, higher dose treatment >200 mg/day. QT prolongation has been reported in patients with no prior cardiac history who have received high doses of methadone. Only initiate therapy in patients for whom anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias. Other agents should be used in patients with a baseline QTc interval ≥500 msec (Chou 2014).

Respiratory depression, including fatal cases, has been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and methadone should only be prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation of methadone or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St. John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea). Disease-related concerns:

May obscure diagnosis or clinical course of patients with acute abdominal conditions. Avoid use in patients with obstruction.

Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

Avoid use in patients with impaired consciousness or coma, because these patients are susceptible to intracranial effects of CO2 retention.

Use with caution in patients with delirium tremens.

Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

Use with caution in patients with hepatic impairment.

Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, suicidal tendencies, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]). Methadone is ineffective for the relief of anxiety.

Use with caution in patients who are morbidly obese.

When used for detoxification and maintenance of opioid addiction, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration. When used for the treatment of opioid addiction in detoxification or maintenance programs, methadone should be dispensed only by opioid treatment programs (and agencies, or practitioners or institutions by formal agreement with the program sponsor) certified by the substance abuse and mental health services administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of drug supply, revocation of program approval, and injunction precluding program operation. Regulatory exceptions to the general requirements for certification to provide opioid agonist treatment include inpatient treatment of other conditions and emergency period (not >3 days) while definitive substance abuse treatment is being sought.

Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

Use with caution in patients with toxic psychosis.

Use with caution in patients with renal impairment.

Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in patients with seizure disorders; may cause or exacerbate seizures.

Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

Use with caution in patients with thyroid dysfunction. Concurrent drug therapy issues:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, is a risk factor for respiratory depression and death. Reserve concomitant prescribing of methadone and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation and consider delaying or omitting daily methadone dosing.

The concomitant use of methadone with all cytochrome P450 (CYP450) 3A4, 2B6, 2C19, 2C9, or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used CYP450 3A4, 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in elderly patients; may be more sensitive to adverse effects. Decrease initial dose and monitor closely when initiating and titrating. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

Neonatal withdrawal syndrome: [US Boxed Warning]: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or addiction. Advise the patient of the risk of neonatal opioid withdrawal syndrome so that appropriate planning for management of the neonate can occur. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn. Dosage form specific issues:

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling. Other warnings/precautions:

Methadone exposes patients and other users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors and conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use.

Oral formulations: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of methadone.

When switching patients from methadone to buprenorphine, patients should preferably be on low doses of oral methadone (• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when inc

Use caution in converting patients from other opioids to methadone. Follow appropriate conversion schedules. Patients tolerant to other mu opioid agonists may not be tolerant to methadone and at risk for severe respiratory depression when converted to methadone.

An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.