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11 Articles in Volume 15, Issue #2
Chronic Headache Management: Outpatient Strategies
Magnesium Sulfate Helpful in Treatment of Acute Migraines
New Guide to Migraine Rx Garners Mixed Reviews
Pain Education Across VA Clinics
12 Classes Offered at VA Pain School
Practical Guide to the Safe Use of Methadone
Chronic Pain Patients Who Fail Standard Treatment
Balancing State Opioid Policies With Need for Access to Pain Therapies
New Mexico’s Approach to Improving Pain and Addiction Management
Editor's Memo: Prescription Opioid Abuse is Declining
Ask the Expert: Lupus and Suicidal Ideation

Practical Guide to the Safe Use of Methadone

Methadone is an inexpensive, long-acting opioid that may be particularly beneficial in patients with neuropathic pain or opioid-induced hyperalgesia. However, methadone is challenging to use. This guide describes Methadone’s unique characteristics.

Methadone’s unique pharmacokinetic and pharmacodynamic properties render it distinguishable from other opioids. While methadone can be more challenging than other opioids to use clinically, it also is potentially more helpful. Methadone’s pharmacokinetics and mechanism of action are more complex than those of other opioids. In addition, it carries risks, such as the potential for prolongation of the QTc interval, that are not associated with other opioids.

On the other hand, methadone’s low cost and unique mechanism of action make it more accessible, and potentially more beneficial, to patients. These characteristics enable methadone to be used in cases in which other opioids fail, whether due to patient allergy and intolerance, or lack of efficacy.

Why is Methadone Dosing So Challenging?

Methadone’s complex pharmacokinetics require close attention to detail to allow appropriate patient selection, initial dosing and titration, and monitoring. However, an understanding of these pharmacokinetics can allow practitioners to use methadone safely and take advantage of its therapeutic potential. Perhaps the most challenging aspect of methadone’s pharmacokinetics is its long and variable half-life.1-4 The half-life of methadone typically is between 15 and 60 hours, although it has been reported to be as long as 120 hours in some patients.1,3 Other pharmacokinetic considerations for methadone include its absorption, distribution, metabolism, and elimination.

Conversions from other opioids to methadone are non-linear, and patients who are stable on a dose of another opioid often show incomplete tolerance to methadone.3 Methadone also has the potential to interact with many other medications, so patients’ medication regimens must be reviewed carefully before and during methadone therapy.

Lastly, methadone is associated with potential cardiac toxicity. Specifically, methadone can cause prolongation of the QTc interval, which can lead to Torsades de pointes, a potentially fatal cardiac arrhythmia.1-3,5,6 Since 2000, methadone has been second to dofetilide in cases of drug-related arrhythmia reported to the US FDA Adverse Event Reporting System.1

Is It Worth It? The Benefits of Safe Methadone Use

Like all other opioids, methadone is an agonist at the µ opioid receptor, making it a strong analgesic through modulation of the perception of pain. In addition to modulating pain via the µ opioid receptor, methadone also exerts analgesia by blocking the reuptake of the neurotransmitters serotonin and norepinephrine in the synaptic cleft.7 Increasing the availability of serotonin and norepinephrine in the central nervous system (CNS) has been proposed as a mechanism of providing analgesia, particularly for neuropathic pain.7 Methadone also acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.2-4,7 Activation of the NMDA receptor has been implicated in the development of opioid-induced hyperalgesia and central sensitization, both of which perpetuate chronic neuropathic pain.2,4,7,8 Methadone’s complex mechanism of action makes it particularly useful in patients with neuropathic pain or opioid-induced hyperalgesia.

While challenging to use in practice, methadone has great potential to relieve pain. Methadone’s low cost and long duration of action make it a therapeutic option for patients without access to other, more expensive, long-acting opioids formulations.4,7-10 As a synthetic opioid with a distinct chemical structure, methadone is also safe for use in patients with a true allergy to morphine and other phenanthrenes.2 Methadone is available in oral tablets, oral solution, and intravenous formulations.2,7 It is the only long-acting opioid available as an oral solution, including a highly concentrated (10 mg/mL) oral solution; this formulation makes long-acting therapy available to patients unable to use tablets or capsules.2,7

Compared to other opioids, methadone has been proposed to have a lower incidence of some adverse events (AEs), including myoclonus, constipation, and nausea.7,8 In patients with renal failure, methadone is considered one of the safest opioids, because only about 20% of a dose is eliminated unchanged by the kidneys and it does not have active metabolites.2,4,7

How to Use Methadone Safely

To use methadone safely, a clinician must have a thorough understanding of all its unique characteristics. To ensure patients receive maximum benefit with minimum risk of harm, clinicians must identify appropriate candidates for methadone therapy and monitor patients diligently.

Patient Selection

Methadone’s unique characteristics make it potentially beneficial for many patients, particularly patients who have a true morphine allergy or have experienced intolerable AEs with other opioids, as well as patients with neuropathic pain, pain that is not controlled with other opioids, and renal insufficiency or failure.2 Methadone also is a good option for patients who need low cost, long-acting opioid therapy.2 However, due to methadone’s long half-life and the resulting prolonged time to maximal therapeutic efficacy, patients with a very limited life expectancy
(ie, <1 week), may not receive the full therapeutic benefit of methadone.

Methadone’s unique pharmacokinetics also require patients to take their medications reliably, without self-adjusting their doses. Patients with questionable adherence to therapy or lacking social support are at greater risk of methadone AEs, and, therefore, are not good candidates for methadone therapy.1,2 When considering prescribing any opioid, clinicians should assess patients for their risk of substance misuse, abuse, and addiction.1,11 In addition, patients who take interacting drugs or other QTc-prolonging agents, or who have a history of syncope or cardiac arrhythmias, also are at greater risk of methadone-associated AEs.2

Patient Education

When initiating methadone therapy, clinicians should counsel patients on methadone’s indications and alternative therapy options, possible AEs, plans for monitoring therapy, and strategies for minimizing the risk of AEs.1 In addition, patients should be taught that adhering to therapy and not taking extra doses will help patients avoid AEs.1 Providers should inform patients specifically about the potential for drug interactions with methadone and the need to alert other health care providers about their use of methadone. Patients can ask their community pharmacist to ensure there are no significant drug interactions between methadone and the other drugs they are taking, including nonprescription medications. Information about methadone’s propensity to prolong the QTc interval also should be discussed.1 Patients must be instructed not to take their methadone dose and to call the prescriber if they experience increased sedation or changes in breathing.1 Health care providers also should alert patients about the need to reduce the dose during upper respiratory infections or asthma exacerbations, and provide patients with instructions if this occurs.11

Initiating Methadone In Opioid-Naïve Patients

Multiple methods for initiating methadone in opioid-naïve patients have been described. Patients who have not previously taken strong opioids, or those who have not received opioid therapy during the previous 1 to 2 weeks, are considered to be opioid naïve.1 A 2004 study of methadone vs morphine as a first-line opioid for cancer pain evaluated 103 patients, 49 of whom were randomized to receive methadone.4 Patients received oral methadone in a dosage of 7.5 mg every 12 hours, with an additional 5 mg every 4 hours as needed.4 However, at the end of 1 week, 6 of 49 patients (12%) in the methadone group had dropped out of the study due to opioid AEs, compared to none of the patients receiving morphine. This difference was statistically significant, and the authors hypothesized that the initial methadone dose, which they calculated using a methadone to morphine ratio of 1:2, was too high. The authors also suggested that when used for breakthrough pain, methadone might be more toxic than morphine.4

In 2006, the FDA issued a safety warning to health care professionals regarding the risks of cardiac arrhythmias and death associated with methadone.12 The FDA also revised methadone’s prescribing information to recommend an initial dose of 2.5 mg orally every 8 to 12 hours for opioid-naïve patients.12 The 2014 Clinical Practice Guideline from the American Pain Society and College of Problems of Drug Dependence in collaboration with the Heart Rhythm Society recommends that opioid-naïve patients receive an initial methadone dose of 2.5 mg orally every 8 hours.1 This is in agreement with a 2009 guideline from the American Pain Society and the American Academy of Pain Medicine, which recommends an initial methadone dose of 2.5 mg orally every 8 hours.13 More conservative initial dosing, such as 1 mg orally daily, is recommended for opioid-naïve patients who are elderly or frail.2

Switching to Methadone From Other Opioids

The 2014 Clinical Practice Guideline recommends that patients maintained on up to 60 mg of oral morphine daily (or its equivalent) should receive an initial dose of methadone 2.5 mg orally three times daily.1 If opioid-tolerant patients are receiving greater than 60 mg of oral morphine (or its equivalent), methadone should be initiated at a dose that is 75% to 90% less than the calculated equianalgesic dose.1

Because the potency of methadone increases as the dose of other opioids increases, it is safest to use different conversion ratios, depending on the dose of the previous opioid, as described by McPherson (Figure 1).2 When converting a patient already maintained on opioids to methadone, first calculate the total daily dose of opioids in oral morphine equivalents. It is crucial to include the average use of as needed or breakthrough opioids. If a patient is receiving less than 1,000 mg of oral morphine (or its equivalent) daily, and is younger than 65 years of age, a conversion ratio of 10:1 oral morphine:oral methadone is recommended.2 If a patient is receiving less than 1,000 mg of oral morphine (or its equivalent) daily and is over age 65 years, or regardless of age is receiving between 1,000 and 2,000 mg of oral morphine (or its equivalent), a conversion ratio of 20:1 is appropriate.2 Regardless of the method used to convert other opioids to methadone, the initial dose of oral methadone should not exceed 30 to 40 mg per day.1,2 The American Academy of Pain Management suggests a more conservative approach, recommending that the initial dose of methadone not exceed 15 mg orally per day.13 Initial doses also should be decreased for elderly or frail patients, as well as those with comorbidities such as chronic obstructive pulmonary disease (COPD).13


Providing Breakthrough Analgesia

Unless patients have a true morphine allergy and are unable to receive other opioids, methadone should not be used for breakthrough pain.1,2 However, in the uncommon case that a patient truly must use methadone for breakthrough pain, use 50% of the scheduled methadone dose every 3 to 4 hours as needed.2 After 5 to 7 days, the breakthrough doses used can be incorporated into the patient’s scheduled methadone regimen and the dose may be titrated up to minimize the breakthrough requirement.2 If patients are able to use other short-acting opioids, a breakthrough dose equivalent to 10% to 15% of the total daily morphine equivalent dose can be provided as needed.2


For opioid-naïve patients, the total daily dose of methadone should be increased by 2.5 to 5 mg per day no more frequently than once every 5 to 7 days.1,2 After patients have reached a dose of 30 to 40 mg of methadone per day and have tolerated dose increases of 5 mg, the 2014 Clinical Practice Guidelines recommend increasing the total daily methadone dose by increments of 10 mg per day once every 5 to 7 days.1 Similarly, the American Academy of Pain Medicine recommends methadone doses be increased by no more than 10 mg orally, and no more frequently than once per week.13 However, if a patient requires methadone doses greater than 30 to 40 mg daily, they should be re-evaluated with respect to the risks and benefits of therapy.1 In opioid-tolerant patients (those taking ≥60 mg oral morphine or its equivalent for ≥1 week), dose increases can be made by 10 mg per day once every 5 to 7 days.1

Drug Interactions

One of the more challenging aspects of using methadone is its numerous drug interactions. Because methadone is metabolized by cytochrome P 450 (CYP)3A4, CYP2C19, and CYP2B6, concomitant use with a medication that inhibits any of these enzymes can result in higher methadone levels and increased risk of toxicities such as sedation and respiratory depression.1,2 Patients who are undergoing concomitant therapy with a medication that strongly inhibits one of these enzymes should have their methadone dose reduced by 25%.2 Due to the long half-life of methadone, the impact of an enzyme inhibitor on methadone serum levels may not be evident for 4 to 6 days after the initial combination (Table 1).7,14-18 On the other hand, patients undergoing concomitant therapy with a CYP3A4, CYP2C19, or CYP2B6 inducer may experience decreased methadone levels and reduced efficacy or withdrawal.1,2,14-18 These patients should have liberal access to breakthrough doses of opioid to ensure adequate analgesia while the appropriate methadone dose is determined.2 In addition to these interactions, P-glycoprotein inhibitors or drugs that decrease gastric acidity, such as proton pump inhibitors, can interact with methadone, increasing its absorption.7

Pharmacodynamic drug interactions also can occur, and they are particularly worrisome when methadone is used in combination with benzodiazepines.1,11 Benzodiazepines generally should be avoided in patients taking methadone due to the risk of oversedation and respiratory depression. However, for a patient who has been stable on low doses of a benzodiazepine and methadone, the risks and benefits of continuing concomitant therapy should be considered and therapy should be patient-specific.1 If benzodiazepine therapy is required in combination with methadone, avoid combination therapy during sleep.11

Because methadone can prolong the QTc interval, caution should be used when combining methadone with other QTc-prolonging agents (Table 2).1,19 Concomitant use of other QTc-prolonging agents is an established risk factor for an adverse cardiac event in patients receiving methadone.3,6 Prior to initiating methadone therapy, review the patient’s medication regimen and consider discontinuation or dose reduction of interacting medications.1


Monitoring Methadone Therapy

Because of methadone’s long half-life, patients should not expect immediate pain relief upon the initiation of methadone. In fact, if patients do report immediate pain relief 1 or 2 days after starting methadone, the informed clinician should be worried. Rather than expecting immediate relief, clinicians should inform patients that full therapeutic efficacy will not be achieved for about 5 days and should provide plenty of breakthrough medication for use in the meantime.2,13

Respiratory depression, perhaps the most severe and concerning methadone adverse effect, always is preceded by sedation. Therefore, patients and their families or caregivers should be instructed to monitor for excessive drowsiness, slurred speech, difficulty thinking, and changes in respiratory rate or pattern.2 The risk of methadone overdose and AEs is greatest after initiating methadone or increasing the dose; therefore, patients must be closely monitored for 5 to 7 days following initiation or dosing changes.1,2 Recent initiation of methadone, larger starting doses, rapid dose escalation, concomitant use of interacting medications, and medical or psychiatric comorbidities all increase the risk of methadone toxicity, and should prompt the clinician to provide more intensive methadone monitoring.2,3 If sedation occurs, patients should be instructed to stop taking methadone until it resolves, at which point methadone may be restarted with a dose reduction of 20%.1 Because sleep apnea can increase the risk of opioid-induced AEs such as respiratory depression, patients should be monitored for sleep apnea.1

The STOP-Bang Questionnaire (Table 3) can be used to identify patients at high risk of having obstructive sleep apnea.20 Increasing STOP-Bang scores correlate with an increasing odds ratio of moderate to severe obstructive sleep apnea.21 Patients with a history of sleep disordered breathing or those receiving more than 50 mg per day of methadone should be evaluated for sleep apnea.11 In patients with pre-existing sleep apnea, adherence to sleep apnea therapy should be a condition of methadone therapy.11

Like other opioids, methadone can cause AEs such as constipation, nausea, sedation, hypogonadism (with chronic use), respiratory depression, and pruritus.1


Cardiac Monitoring


Due to methadone’s propensity to prolong the QTc interval, cardiac monitoring is an important component of safe methadone use. The risk of Torsades de pointes increases with increased QTc interval, and this arrhythmia primarily is seen in patients with a QTc >500 ms.1,6 However, the risk of Torsades de pointes begins to increase once the QTc interval reaches 450 ms.1 In fact, each 10 ms increase in the QTc interval is associated with a 5% to 7% increased risk of Torsades de pointes. While some degree of QTc interval prolongation is common among methadone-treated patients, QTc intervals >500 ms or prolongations >60 ms are uncommon, making clinical consequences infrequent.5 A 2013 retrospective study found that among 1,246 patients using methadone for pain management who had at least one ECG, the rate of QTc prolongation was 49.4%, but only 2.4% of patients experienced an adverse cardiac event, and no patients died of methadone-related cardiac causes.6

The 2014 Clinical Practice Guideline recommends obtaining a baseline ECG prior to initiating methadone therapy in patients who have risk factors for QTc prolongation, a prior ECG with a QTc >450 ms, or a history suggestive of prior ventricular arrhythmia.1 For patients with a baseline QTc of >450 ms, consider alternative opioids, correct any reversible causes of QTc prolongation, and obtain a follow up ECG in 2 to 4 weeks.1 Patients with a baseline QTc >500 ms should not receive methadone. Similarly, the American Academy of Pain Medicine recommends QTc interval assessment in patients receiving more than 100 mg oral methadone daily who have a history of cardiovascular disease or are at risk for electrolyte abnormalities, and those who are taking concomitant QTc interval–prolonging medications.13

Follow-up ECGs should also be obtained when the methadone dose reaches 30 to 40 mg per day and again if a dose of 100 mg methadone per day is reached.1,13 If patients have symptoms suggestive of arrhythmia or syncope, or new risk factors for QTc prolongation, and are maintained on methadone doses >100 mg per day, or are using other QTc prolonging drugs, ECG monitoring might need to be performed more frequently.1,2,7 A QTc interval >500 ms on a follow up ECG should prompt discontinuation of methadone, correction of reversible causes, and repeat ECG after methadone discontinuation.1


Methadone is an inexpensive, long-acting opioid that may be particularly beneficial in patients with neuropathic pain or opioid-induced hyperalgesia. Methadone’s unique mechanism of action and pharmacokinetics contribute to both its efficacy and challenges regarding safe use. Safe use of methadone requires an understanding of its pharmacokinetics, appropriate patient selection, proper dosing initiation and titration, consideration of drug interactions, and persistent monitoring. When used safely, methadone has the potential to be an effective tool in the pain management practitioner’s toolkit, with great benefit to patients.

Last updated on: April 14, 2015

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