Chapter 3B: Methadone (2024)

Chapter 3B provides an overview of methadone pharmacology and discussion of key methadone dosing considerations for healthcare professionals working in opioid treatment programs (OTPs).

Methadone is the most studied medication for opioid use disorder (OUD). Of all OUD pharmacotherapies, it is used to treat the most people throughout the world and has by far the longest track record (nearly 50 years).^77,78 Numerous clinical trials and meta-analyses have shown that methadone treatment is associated with significantly higher rates of treatment retention and lower rates of illicit opioid use compared with placebo and with no treatment.⁷⁹ Other research associates methadone treatment with reduced mortality, criminal behavior, and HIV seroconversion.^80,81,82 A Cochrane meta-analysis found that, at flexible doses, methadone compared with buprenorphine retains patients in treatment significantly longer and equally reduces illicit opioid use.⁸³

In the United States, OTPs can offer methadone to treat OUD, but all providers who may care for patients with OUD should be familiar with this treatment.

Formulations

There are several formulations of methadone:

•: Liquid concentrate, which is the formulation most commonly used in treatment programs.
•: Powder, which is dissolved in water and administered as a liquid.
•: Dispersible tablets, which are scored tablets that are dissolved in water.
•: Tablets, which are most commonly used outside of OTPs for analgesia.

Pharmacology

Methadone, a long-acting mu-opioid receptor full agonist, is a schedule II controlled medication. It is highly plasma–protein bound and binds to proteins within tissues throughout the body.⁸⁴ Through mu-opioid receptor binding and opioid cross-tolerance to other mu-opioid agonists, at adequate doses, methadone reduces opioid craving and withdrawal and blunts or blocks the effects of illicit opioids.

There is wide individual variability in methadone pharmacokinetics. The half-life of methadone can vary from 8 to 59 hours⁸⁵ depending on the patient. The average is 24 hours.⁸⁶

Methadone has no ceiling effect. As a full agonist, increasing doses of methadone produce maximal physiological effects at the opioid receptors. Plasma levels reach steady state in about 5 days (i.e., five half-lives). Before achievement of steady state, release from tissue reservoirs can lead to increasing serum plasma levels and toxicity, even if the daily methadone dose is not changed.

Methadone induction, thus, should begin at a low dose and increase gradually with daily monitoring over days or weeks. At stable daily doses, serum levels peak 2 to 4 hours after dosing, then slowly decrease, providing 24 hours without overmedication or withdrawal.⁸⁷

Bioavailability

Methadone is approximately 70 to 80 percent bioavailable when patients take it orally for OUD. There is notable individual variability in bioavailability, ranging from 36 to 100 percent.^88,89

The liver's CYP450 3A4 enzyme is primarily responsible for metabolizing methadone,⁹⁰ although CYP2B6 and CYP2D6 enzymes are also involved.⁹¹ At the start of methadone treatment, methadone can increase CYP3A4 activity and accelerate its own metabolism in some individuals.⁹²

Dosing must be individualized because methadone's bioavailability, clearance, and half-life can vary considerably among patients.

Providers should check for potential drug–drug interactions and monitor patients receiving concomitant medications. Some medications (e.g., benzodiazepines, anticonvulsants, antibiotics, antiretroviral agents, some antidepressants) can induce or inhibit CYP450 enzymes, resulting in potential changes in methadone serum concentration, effectiveness, and side effect profile.

Dosing Considerations

Methadone is indicated for people meeting OTP admission criteria, which for people 18 and older are:

•: Being currently “opioid-addicted”—the term the Substance Abuse and Mental Health Services Administration (SAMHSA) OTP regulations use (e.g., meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁹³ criteria for OUD). Not all patients meeting OUD criteria, particularly those with mild OUD, are appropriate candidates for methadone. This is discussed in detail in Part 2 of this Treatment Improvement Protocol (TIP).
•: Having a history of at least 1 year of opioid addiction before admission.
•: Providing voluntary, written informed consent.

OTP physicians can waive the history requirement per Code of Federal Regulations (42 CFR 8.12)⁹⁴ for:

•: Women who are pregnant.
•: Former patients (up to 2 years after discharge).
•: Patients within 6 months of release from incarceration.

For patients younger than 18, admission criteria are different. They include two documented, unsuccessful, medically supervised withdrawals or treatments without OUD medication (e.g., methadone) in a 12-month period. The parent or legal guardian must provide written informed consent.

Contraindications

Contraindications to treatment with methadone include an allergy to methadone and other instances in which opioids are contraindicated, such as acute asthma, in patients with abnormally high carbon dioxide blood levels (e.g., from pulmonary disease or sleep apnea), or paralytic ileus.

Precautions and Warnings

Respiratory depression

Methadone can cause respiratory depression, particularly during initial dosing and dose titration. The goal of methadone dosing in the first weeks of treatment (i.e., induction) is to relieve withdrawal but avoid oversedation and respiratory depression. Patients who are older or cachectic or who have chronic obstructive pulmonary disease are more susceptible to respiratory depression and should be treated cautiously with lower doses.

A standard formula for dose induction for all patients, without careful monitoring of response to treatment, and individualized dose adjustment is inadvisable. This can lead to methadone intoxication and overdose death.

Individualize dosing decisions through daily monitoring of patients' responses to treatment. Opioid tolerance cannot be accurately gauged based on patient self-reports of the type, amount, or purity of the opioids they've used or of the severity of their opioid withdrawal symptoms.

The best approach to dosing is to start low and go slow. Methadone has a relatively long half-life (24–36 hours or longer). Steady-state serum levels are generally not reached until about five half-lives. This means that patients will not feel the full effect of the initial dose for 4 or more days even if the daily dose is the same. Slow release of methadone from tissues causes serum levels to continue to increase until reaching steady state. Initially a dose may seem appropriate, but the third or fourth day of the same dose can lead to oversedation and even respiratory depression and death.⁹⁵

Use a lower-than-usual starting dose in individuals with no or low opioid tolerance (5 mg to 10 mg). Increase doses slowly and with careful monitoring for patients who:

•: Have not used opioids for 5 or more days (e.g., after leaving a controlled environment).
•: Do not use opioids daily.
•: Use weaker opioids (e.g., codeine).

Do not determine doses by analgesic equivalence dose conversion tables for patients using high doses of prescription opioids, whether by prescription or illicitly. This can lead to death owing to incomplete cross-tolerance⁹⁶ and the unique pharmacology of methadone.

Concurrent substance use disorders (SUDs) involving benzodiazepines or alcohol

Concurrent misuse of alcohol or benzodiazepines with methadone (or buprenorphine) increases respiratory depression risk. Use of alcohol and benzodiazepines (illicit and prescription) is common in patients with OUD. Managing OUD with methadone for patients with alcohol or benzodiazepine use disorders is challenging and should be undertaken with care. A 2017 Food and Drug Administration (FDA) Drug Safety Communication noted that although concomitant use of buprenorphine or methadone with benzodiazepines increases the risk of an adverse reaction, including overdose death, opioid agonist treatment should not be denied to patients solely on the basis of their taking benzodiazepines, because untreated OUD can pose a greater risk of morbidity and mortality.⁹⁷ FDA advises that careful medication management by healthcare professionals can reduce risk (see www.fda.gov/downloads/Drugs/DrugSafety/UCM576377.pdf for more information).

Strategies to manage patients with concurrent alcohol or benzodiazepine use disorders include the following (see also Exhibit 3B.1):

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EXHIBIT 3B.1. Strategies for Managing Benzodiazepine Use by Patients in OUD Treatment.

•: Obtain permission to communicate with the benzodiazepine prescriber to confirm the reason for use, adherence to treatment, and prescriber awareness of the patient's OUD. It can also help to speak (with permission) with close family members or friends to assess the extent and impact of any alcohol or benzodiazepine misuse.
•: Ensure that patients understand the risk of potential respiratory depression and unintentional overdose death when combining methadone with alcohol, benzodiazepines, or other central nervous system (CNS) depressants.
•: Determine whether patients require medically supervised withdrawal or tapering from alcohol or benzodiazepines. Patients at risk for serious alcohol or benzodiazepine withdrawal syndrome (including seizures and delirium tremens) may need inpatient medically supervised withdrawal.
•: Attempt gradual outpatient medically supervised withdrawal for benzodiazepines when indicated. Some OTPs have the staffing and capacity to provide a supervised outpatient taper from benzodiazepines. This usually requires use of a long-acting benzodiazepine, management of anxiety and sleeplessness, and careful monitoring with observed dosing and toxicology screening. It may also require lower-than-usual methadone doses. Engage in outpatient medically supervised withdrawal only with patients who are physically dependent on benzodiazepines but do not inject or binge. This may only be successful in a minority of patients. Attempt the taper while continuing treatment with methadone, subject to certain conditions that promote safety and reduce risk.
•: Consider increasing counseling frequency as appropriate.

For more information on managing benzodiazepine use, see Management of Benzodiazepines in Medication-Assisted Treatment (https://ireta.org/wp-content/uploads/2018/03/BP_Guidelines_for_Benzodiazepines.pdf).

QTc prolongation and cardiac arrhythmia

Methadone treatment has been associated with QTc prolongation, which often occurs without clinical consequences.^99,100 Since 2006, methadone has had an FDA black box warning on QTc prolongation and Torsades de Pointes. QTc intervals above 500 milliseconds can increase risk for this rare ventricular arrhythmia, which can be lethal.^101,102 The prevalence of QTc prolongation among methadone patients is not known with certainty. It has been estimated that about 2 percent of patients in methadone treatment have QTc intervals greater than 500 milliseconds.¹⁰⁵ According to methadone's FDA label, most Torsades de Pointes cases occur in patients receiving methadone for pain treatment, although some cases have occurred among those in methadone maintenance.¹⁰⁶ High methadone doses may be associated with prolonged QTc intervals.¹⁰⁷ Other risk factors include:¹⁰⁸

•: Some medications (e.g., antidepressants, antibiotics, antifungals).
•: Congenital prolonged QTc interval.
•: Hypokalemia.
•: Bradycardia.

QTc prolongation is an abnormally long time in electrocardiogram (ECG) tracing between the start of a Q wave and the end of a T wave. Various cutoffs define prolonged QTc interval, including greater than 450 milliseconds for men, greater than 460 to 470 milliseconds for women, or greater than 450 milliseconds for either gender.¹⁰³ However, the faster the heart rate, the shorter the QTc interval. Hence, correct the QTc interval for heart rate; divide the QTc interval in milliseconds by the square root of the R-R interval in seconds.¹⁰⁴

There is considerable controversy about how best to screen for QTc prolongation without creating barriers to methadone treatment entry.¹⁰⁹ Indeed, a Cochrane review of the literature was unable to draw any conclusions about the effectiveness of QTc screening strategies in preventing cardiac morbidity or mortality among methadone patients.¹¹⁰ Notwithstanding the uncertainty about the best approach, OTPs can take steps to identify patients who may be at risk for cardiac arrhythmia. The TIP expert panel concurs with the recommendations of other expert panels (which included cardiologists) that OTPs develop a cardiac risk management plan,^111,112 to the extent possible. OTPs should consider the following elements in crafting a cardiac risk management plan:

•

An intake assessment of risk factors, which can include:

-: Family history of sudden cardiac death, arrhythmia, myocardial infarction, heart failure, prolonged QTc interval, or unexplained syncope.
-: Patient history of arrhythmia, myocardial infarction, heart failure, prolonged QTc interval, unexplained syncope, palpitations, or seizures.
-: Current use of medications that may increase QTc interval (for a complete list, see https://crediblemeds.org/index.php/login/dlcheck; register for free for the most current list).
-: Patient history of use of cocaine and methamphetamines (which can prolong the QTc interval).
-: Electrolyte assessment (for hypokalemia or hypomagnesemia).

•

A risk stratification plan, which can include the following:

-

Conduct an ECG for patients with significant risk factors at admission; repeat within 30 days. Repeat once a year and if the patient is treated with more than 120 mg of methadone per day.

-

Discuss risks and benefits of methadone with patients with QTc intervals between 450 and 500 milliseconds. Adjust modifiable risk factors to reduce their risk.

Accidental ingestion

Inform patients that accidental ingestion can be fatal for opioid-naïve individuals, particularly children. Patients should safeguard take-home methadone in a lockbox out of the reach of children.

Neonatal abstinence syndrome (NAS)

Ensure awareness among pregnant patients or patients who may become pregnant that NAS can occur in newborns of mothers treated with methadone. Women receiving methadone treatment while pregnant should talk with their healthcare provider about NAS and how to reduce it. Research has shown that the dose of opioid agonist medication is not reliably related to the severity of NAS.^114,115,116 Thus, each woman should receive the dose of medication that best manages her illness.

Misuse and diversion

Alert patients to the potential for misuse and diversion of methadone.

Physical dependence

Inform patients that they will develop physical dependence on methadone and will experience opioid withdrawal if they stop taking it.

Sedation

Caution patients that methadone may affect cognition and psychomotor performance and can have sedating effects. Urge patients to be cautious in using heavy machinery and driving until they are sure that their abilities are not compromised.

Adrenal insufficiency

Adrenal insufficiency has been reported in patients treated with opioids. Ask patients to alert healthcare providers of nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.¹¹⁷

Drug Interactions

Methadone has more clinically significant drug–drug interaction than buprenorphine.¹¹⁸ Carefully monitor each patient's response to treatment if they are prescribed or stop taking a CYP450 34A inducer or inhibitor. Methadone dosages may need to be adjusted up or down depending on the medication and whether treatment is starting or stopping. Exhibit 3B.2 lists common interactions between methadone and other medications.

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EXHIBIT 3B.2. Common Potential Methadone Drug–Drug Interactions.

Medications that induce CYP450 activity can increase methadone metabolism. Patients may experience craving or opioid withdrawal symptoms between doses if they begin these medications or become sedated if they discontinue them:

•: Some antibiotics (e.g., rifampin).
•: Antiretrovirals (e.g., efavirenz, nevirapine, ritonavir).
•: Anticonvulsants (carbamazepine, phenobarbital, phenytoin).

Other medications can inhibit CYP450 activity and decrease methadone metabolism, causing symptoms of overmedication (e.g., sedation) when the medication is started and possibly withdrawal or cravings when it is stopped. Among such medications are:¹¹⁹

•: Some antibiotics (ciprofloxacin, erythromycin).
•: Antacids (cimetidine).
•: Antifungals (fluconazole).
•: Antidepressants (e.g., fluvoxamine, paroxetine, sertraline).

Methadone can affect the metabolism of other medications. For example, zidovudine levels are reported to increase significantly during methadone treatment. Monitoring for zidovudine side effects during treatment is warranted.¹²¹ Check drug–drug interactions online (www.drugs.com/drug_interactions.php).

Side Effects

Possible side effects of methadone include the following (methadone FDA labels list all potential side effects and are available at ):

•: Constipation
•: Nausea
•: Sweating
•: Sexual dysfunction or decreased libido
•: Drowsiness
•: Amenorrhea
•: Weight gain
•: Edema

Assessment

A thorough assessment will help decide whether a patient is appropriate for admission and meets federal and any state regulatory requirements for methadone treatment. (See Part 2 of this TIP for detailed discussion of screening and assessment.) Before ordering methadone:

•

Check the state PDMP for opioid or benzodiazepine prescriptions from other providers (see www.nascsa.org/stateprofiles.htm for links to state PDMPs). Note that methadone for OUD treatment will not appear in the PDMP because of confidentiality regulations regarding substance use treatment records. Obtain the patient's consent to release information and speak with treating providers to coordinate care for patient safety.

•

Take the patient's history.

-: Conduct a medical, psychiatric, substance use, and substance use treatment history.
-: Assess recent opioid use, including frequency, quantity, type, route, and recency (last day of use and use in the past 30 days).
-: Establish OUD diagnosis.
-: Assess for other SUDs, including those that involve alcohol, benzodiazepines, or stimulants.

•

Conduct a physical exam.

-

Assess for signs and symptoms of intoxication. Do not give patients who are sedated or intoxicated their first dose. Instead, assess and treat them appropriately:

•: Identify causes of sedation or intoxication.
•: Ensure the patient's immediate safety.
•: Reassess methadone induction appropriateness.
•: Develop a plan to reattempt induction or follow a different course of treatment as appropriate.

-

Assess for signs and symptoms of opioid withdrawal and physiological dependence. One approach to documenting withdrawal symptoms is to use a scale such as the Clinical Opioid Withdrawal Scale (COWS) or the Clinical Institute Narcotic Assessment (CINA) Scale for Withdrawal Symptoms (see “Resource Alert: Opioid Withdrawal Scales”). Before the first dose of methadone, confirm signs of opioid withdrawal to provide some confidence that the patient is opioid tolerant and can begin dose induction. The Naloxone Challenge should not be routinely used to determine physiologic withdrawal because withdrawal symptoms will be visible, if present, on physical exam if enough time has passed since last opioid use.¹²²

•

Obtain laboratory tests.

-: Conduct drug and alcohol tests. Use reliable urine tests for drugs, including opioids (e.g., morphine, methadone, buprenorphine, oxycodone), benzodiazepines, cocaine, and other drugs that may be commonly used in the area (e.g., methamphetamine). Obtain an opioid urine or oral fluid test before initiating treatment. A negative opioid test in the absence of clear opioid withdrawal symptoms indicates that the patient is likely no longer opioid tolerant; diagnosis should be reconfirmed. If such patients are to start taking methadone (rather than naltrexone for relapse prevention), use caution in initiating treatment (see the subsection “First dose for patients without current opioid tolerance” in the section “Initiating Methadone Treatment”). Use an alcohol breathalyzer to estimate the patient's blood alcohol content. Do not provide methadone until the alcohol reading is considerably below the legal level of alcohol intoxication.
-: Conduct a pregnancy test. Pregnant patients with OUD should be treated with methadone or transmucosal buprenorphine.^123,124 Discuss risks and benefits of treatment with methadone and alternative approaches for each patient and fetus versus the risks of continued illicit opioid use. Refer pregnant patients to prenatal care. Women should be advised that their menstrual cycle may return to normal once they are stabilized on medication, and hence they should use birth control if they wish to avoid pregnancy.
-: Conduct liver function tests. If possible, assess liver function tests. It is not necessary to wait for the results of these tests to begin treatment, because the risk of not starting methadone outweighs the benefits of having the test results. Patients with suspected cirrhosis based on history and clinical exam should be started at a lower methadone dose than typical patients, with more cautious titration. Patients who have chronic hepatitis can be treated with methadone. Have a risk/benefit discussion with patients whose liver enzymes are at or greater than five times the normal level and monitor their liver function during treatment.
-: Conduct hepatitis and HIV testing. Hepatitis B and C are common among patients who enter methadone treatment. HIV infection is also prevalent. Everyone ages 15 to 65 should be tested at least once for HIV. Persons at higher risk, such as people who use drugs by injection, should be tested annually.¹²⁵ Anyone who is injecting or has ever injected drugs, even once, no matter how long ago, should be tested for hepatitis C, regardless of their intention to seek treatment for SUD.¹²⁶ The Centers for Disease Control and Prevention recommends hepatitis B vaccination for people seeking treatment for SUDs.¹²⁷

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RESOURCE ALERT.

Patient Selection

No evidence clearly predicts which patients will respond best to methadone treatment versus alternative pharmacotherapies. Inform patients of all options and the settings in which they're available, as appropriate. (See “Treatment Planning or Referral” in Part 2 of this TIP for more on shared decision making.)

Patients who responded well to methadone in the past should be considered for this treatment.

Unsuccessful treatment experiences with methadone in the past do not necessarily indicate that methadone will be ineffective again. Motivation and circumstances change over time. Also, treatment varies by OTP, as it does for other medical illnesses. Records from previous providers can contextualize the extent of past treatment.

Pregnant women should be considered for methadone treatment.

Methadone (or buprenorphine) treatment through OTPs may be best for patients who need a higher level of outpatient structure or supervision of medication adherence. Tailor medication decisions to patients' medical and substance use histories, patient preferences, and treatment availability.

Informed Consent

Inform all patients of:

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EXHIBIT 3B.3. Key Points of Patient Education for Methadone.

Educate patients about the importance of safe storage of take-home methadone doses. Discuss with patients where they will store their take-home medication. Advise them against storing medication in common areas of the home where visitors or children would have access, such as kitchens and bathrooms. Take-home doses should be kept in their original childproof packaging in a lockbox. The key should not be left in the box. Inform patients that any portion of a dose taken by another person, a child, or pet can be deadly. If this occurs, call 9-1-1 immediately.

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RESOURCE ALERT.

Initiating Methadone Treatment

Observing patients directly when they take doses early in treatment is not just required; it's beneficial. It maximizes adherence, provides a daily opportunity to assess response to the medication, and minimizes the likelihood of medication diversion. Federal OTP regulations permit patients to receive one take-home dose per week, given routine clinic closure on weekends. Patients who demonstrate progress can earn one additional take-home dose per week for the first 90 days of treatment at the OTP medical director's discretion. All other doses are directly observed at the clinic in the first 90 days.

The goal of initiating methadone treatment is to increase the patient's methadone dose gradually and safely, stabilizing the patient and reducing his or her opioid use while recognizing that the risk of dropout or overdose from illicit opioid use may increase if induction is too slow.

Day 1

The first dose should reduce opioid withdrawal symptoms. Perform induction cautiously; it's impossible to judge a patient's level of tolerance with certainty. For patients addicted to prescription opioids, opioid conversion tables should not be relied on to determine methadone dosage.

First dose for patients with opioid tolerance

The first dose for patients tolerant to opioids is generally between 10 mg and 30 mg (30 mg is the maximum first dose per federal OTP regulations). After the first dose, patients should remain for observation for 2 to 4 hours if possible to see whether the dose is sedating or relieves withdrawal signs.

•: If withdrawal symptoms lessen, the patient should return the next day to be reassessed and to continue the dose induction process.
•: If sedation or intoxication occurs after the first dose, the patient should stay under observation at the clinic until symptoms resolve. In this case, the patient should be reassessed the following day, and the subsequent day's dose should be substantially reduced. Extremely rarely, the patient will need to be treated for overdose with naloxone. If necessary, begin rescue breathing and call 9-1-1.
•: If the patient shows neither sedation nor reduction of objective signs of opioid withdrawal during the 2- to 4-hour waiting period, administer another 5 mg dose. A final 5 mg dose after another waiting period of 2 to 4 hours can be administered if necessary. The maximum total methadone dose on the first day of treatment should not exceed 40 mg.¹²⁸ However, caution dictates against exceeding a total first day's dose of 30 mg except in rare cases. In such cases, the patient should be carefully monitored on subsequent days to rule out oversedation.
•: Patients transferring from another OTP whose methadone dose and last date of medication administration can be confirmed by the medical staff and documented in the medical record can be continued on the same methadone dose administered in the original OTP, even if the dose exceeds the maximum permitted 40 mg.

For some patients, the lower range of initial doses is best. Dose with 10 mg to 20 mg in patients who:

•

Are ages 60 and older.

•

May have lower levels of opioid tolerance based on their recent history.

•

Use sedating medications, such as benzodiazepines, antipsychotics, or antidepressants.

•

Engage in problem drinking or have alcohol use disorder.

•

Take medications that can increase methadone serum levels or are stopping medications that decrease methadone serum levels.¹²⁹

•

Have medical disorders that may cause hypoxia, hypercapnia, or cardiac arrhythmias. These include:

-: Asthma, chronic obstructive pulmonary disease, and kyphoscoliosis.
-: Obesity.
-: Sleep apnea.
-: QTc prolongation.
-: A family history of cardiac arrhythmias, fainting or dizziness, or sudden death.
-: Cor pulmonale.
-: Electrolyte abnormalities, such as hypokalemia or hypomagnesemia.

First dose for patients without current opioid dependence

In some circumstances, patients who are not currently dependent on opioids may be admitted to an OTP (e.g., individuals with a history of OUD who are returning from controlled environments).¹³⁰ In these instances, consider treatment with extended-release naltrexone (XR-NTX) to avoid establishing new physiological opioid dependence. Instead of starting methadone, consider starting with a low dose of buprenorphine because of buprenorphine's superior safety threshold.¹³¹ In one such study, 1 mg of buprenorphine was the starting dose, which was increased slowly¹³² (see Chapter 3D of this TIP). If XR-NTX and buprenorphine are not available, or the patient prefers methadone treatment, consider starting methadone at a 5 mg daily dose (as was done in one study¹³³) after discussing risks and benefits with the patient.

Titrate the dose much more slowly than for patients who are opioid tolerant. Increase initially by 5 mg about every week, based on patient response. Doses can be increased somewhat more rapidly after careful assessment of response if the patient begins to use illicit opioids. As with other methadone dosing, induction in these cases should not be based on a standing order.

Dose Titration (Weeks 1 to 2)

The goals of early dose titration for patients with current opioid dependence starting on Day 2 of the first week of treatment through stabilization are to avoid sedation at peak serum levels and to gradually extend time without opioid withdrawal symptoms and craving. When patients attend the program, before dose administration, nursing and/or medical staff members should ask patients whether they felt sedation, opioid intoxication effects, or opioid withdrawal symptoms 2 to 4 hours after their methadone administration the prior day (Exhibit 3B.4). Doses should be decreased for reports of symptoms of opioid intoxication or oversedation. Dosing must be individualized based on careful patient assessment and generally should not be increased every day, because plasma methadone levels do not reach steady state until about five methadone half-lives (Exhibit 3B.5).

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EXHIBIT 3B.4. Using Signs and Symptoms To Determine Optimal Methadone Level.

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EXHIBIT 3B.5. Steady-State Methadone Concentration Reached in About 5 Days.

Even when holding the methadone dose constant over several days, the patient's methadone serum level will rise each day until it reaches steady state (Exhibit 3B.5). For example, if the patient remains on 20 mg per day for the first few days of induction, the serum level on Day 2 would reflect the 20 mg second day's dose plus 10 mg that remained in the body from the first day's dose (for the equivalent single dose total of 30 mg). The third day would reflect the 20 mg third day's dose, plus 10 mg remaining in the body from the second day's dose, and 5 mg remaining from the first day's dose (for the equivalent single dose total of 35 mg), and so on. Patients who report relief from withdrawal 4 to 12 hours after their last dose may benefit from staying at that same dose for a few days so that their serum level can stabilize.¹³⁴

An American Society of Addiction Medicine expert panel recommended increasing the methadone dose in this phase by 5 mg or less every 5 or more days.¹³⁵ Other expert recommendations suggest somewhat faster dose increases,¹³⁶ including increases of 5 mg to 10 mg no sooner than every 3 to 4 days.^137,138

The most important principle is to individualize dose induction based on careful assessment of the patient's response to the medication.

Dose Titration (Weeks 3 to 4)

Methadone doses can be increased further in 5 mg increments about every 3 to 5 days based on the patient's symptoms of opioid withdrawal or sedation.¹⁴² Patients who miss more than four doses must be reassessed. Their next methadone dose should be decreased substantially and built back up gradually. It may be necessary to restart the dose induction process from Day 1. Be aware of any specific state requirements regarding missed doses.

Serum Levels

Dosing must be individualized because methadone's bioavailability, clearance, and half-life vary among patients, affecting their clinical responses and requiring doses to be changed. Many factors can affect serum levels and clinical responses to treatment. Along with age and diet, these factors include:

•: Other medications and herbs (e.g., St. John's wort).
•: Genetic differences in metabolizing enzymes.
•: Pregnancy.
•: Changes in urinary pH.¹⁴³

Consider measuring serum methadone levels in patients who, after being on a stable methadone dose, report feeling drowsy 2 to 4 hours after dose administration but develop craving or withdrawal symptoms before the next dose is due to be administered. This may occur in the third trimester of pregnancy, when concomitant medications interact with methadone, or when patients rapidly metabolize opioids. In such cases, consider dividing the daily methadone dose into twice-daily dosing.¹⁴⁴

To assess serum methadone levels, draw peak and trough blood specimens at about 3 hours and 24 hours, respectively, after dose administration. Serum methadone levels generally correlate with methadone dose,¹⁴⁵ but there is no defined therapeutic window based on serum methadone level because response varies widely among patients. Minimum trough methadone levels of 300 ng/mL to 400 ng/mL may be associated with reduced likelihood of heroin use,¹⁴⁶ but determining the therapeutic dose should depend on the overall patient response, not the serum plasma levels. Peak:trough ratios above 2:1 may indicate rapid metabolism.¹⁴⁷

Dose Stabilization (Week 5 and Beyond)

Once the patient achieves an adequate dose, extended continuation is possible without dose adjustment. Continuing treatment goals are to avoid sedation, eliminate withdrawal and craving, and blunt or block euphoric effects of illicit opioids.

The TIP expert panel advises against arbitrary methadone dosage caps.

There may be reasons to further adjust the dose, including:

•: Changes in health that can affect medications (e.g., acute hepatitis, exacerbation of pulmonary disease, sleep apnea).
•: Changes in patient medications.
•: Pregnancy. Increased metabolism in the last trimester may warrant dose increase or split dosing.^148,149 This may require a SAMHSA exception for daily take-home half-doses via an SMA-168 Exception Request (www.samhsa.gov/medication-assisted-treatment/opioid-treatment-programs/submit-exception-request).
•: Concurrent illicit opioid or other drug or alcohol use.

As illicit opioid use stops and stabilization is achieved, the patient may wish to lower the dose to reduce any unpleasant side effects. Typical stabilization doses of at least 60 mg are associated with greater treatment retention; 80 mg to 120 mg¹⁵⁰ is the typical daily range.¹⁵¹ However, there is wide variation, and some patients benefit from higher daily doses.

Take-Home Medication

OTPs can provide gradually increasing numbers of take-home doses to patients who discontinue illicit drug use and begin achieving treatment goals, commensurate with their tenure in the program. This provides a powerful incentive for patients to achieve treatment goals.¹⁵² It also furthers patients' recovery goals by allowing them to attend work, school, or other activities without daily OTP visits.

Federal OTP regulations describe the conditions under which take-home doses are permitted. Some states have additional regulations. OTPs should be familiar with these regulations and have written procedures to address take-home dosing.

The benefits of take-home doses must outweigh the risks and further patients' rehabilitation goals. When deciding whether patients can handle the responsibility of take-home doses of methadone or buprenorphine, OTP medical directors should consider whether patients demonstrate:

•: No recent misuse of substances.
•: Regular clinic attendance.
•: No serious behavioral problems at the clinic.
•: No recent criminal activity (e.g., selling drugs).
•: Stability at home and in social relationships.
•: Sufficient time in treatment.
•: Ability and intent to store take-home medication safely.
•: Rehabilitative benefits from decreasing the frequency of clinic attendance that outweigh the potential risks of diversion.

Federal regulations based on patients' time in treatment determine eligibility to be considered for receiving take-home doses of methadone (but buprenorphine is not bound by these limits):

•: One earned dose/week (beyond a weekly clinic closure day or federal holiday, when clinics typically close) in the first 90 days of treatment
•: Two doses during the second 90 days
•: Three doses during the third 90 days
•: Up to 6 doses during the last 90 days
•: Up to 2 weeks of doses after 1 year
•: Up to 1 month of doses after 2 years

Assessing responsible handling of take-home doses

Methadone diversion is a risk. People with OUD who are not in treatment more frequently use illicit methadone to self-medicate withdrawal symptoms than to achieve euphoria.^153,154 Still, diversion is a public health risk; people who self-medicate may not know what dose they are taking. Moreover, opioid-naïve people (including children) who ingest methadone can die of methadone intoxication.

OTPs must assess patients' adherence to responsible take-home-dose handling and have a diversion control plan. The plan may require that the OTP:

•: Remain open 7 days per week or arrange dosing at another clinic on days the clinic is closed for certain patients to avoid providing take-home doses to new or unstable patients.
•: Contact patients randomly and request that they return their take-home containers within a day or two to see whether they still have the medication in their possession or have altered the medication in any way.
•: Establish an appropriate drug testing program with policies to prevent falsification of specimens and to respond to tests that are negative for methadone.
•: Require patients to store their take-home medication in a lockbox to prevent theft or accidental use by children or others.

Duration of Methadone Treatment

Longer lengths of stay in methadone treatment are associated with superior treatment outcomes.¹⁵⁵ Leaving methadone treatment is associated with increased risk of death from overdose and other causes.^156,157 Patients should continue as long as they benefit, want to, and develop no contraindications.

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The TIP expert panel considers arbitrary time limits on OUD treatment with methadone to be medically unwarranted and inappropriate. They pose a risk to patients and the public.

Dose Tapering and Methadone Discontinuation

Discuss risks and benefits with patients who wish to discontinue treatment. Explore their reasons for wanting to discontinue and solutions for potential barriers to treatment, which may include:

•: Logistics (e.g., travel, scheduling). Transportation services, including publicly funded ride services, ride sharing, or peer support workers, may be available. If not, transferring patients to a closer OTP or to one with more suitable hours of operation may resolve the problem.
•: Costs. Providers can help patients explore publicly supported treatment options or apply for insurance.
•: Side effects. Changing the dose or treating side effects may resolve the problem.
•: Opinions of friends or family. When external pressure from family or friends drives the decision, a discussion with the patient and those individuals may help.
•: A desire to switch to buprenorphine or XR-NTX treatment. These options should be discussed.

Caution patients who are not yet stable against discontinuing treatment, because of high rates of return to illicit opioid use and increased chance of overdose death.¹⁵⁸ Discuss the alternative of switching to a different OUD medication. Give patients who stop treatment information about overdose prevention and encourage them to return to treatment. Prescribe naloxone to use in case of overdose.

Create a plan collaboratively with stable patients who wish to discontinue treatment that addresses:

•: Gradually tapering their dose.
•: Increasing psychosocial and recovery supports.
•: Discontinuing dose reduction if necessary.
•: Returning to medication treatment after discontinuation if they return to illicit opioid use.
•: Increasing dosage if destabilization occurs.

Individualize the pace of methadone dose reduction to the patient's response. One approach is to decrease the methadone dose gradually by 5 to 10 percent every 1 to 2 weeks. Once patients reach a relatively low dose, often between 20 mg and 40 mg, they may begin to feel more craving. Some patients may choose to switch to buprenorphine for a period to complete the dose reduction. They may also wish to begin XR-NTX after an appropriate period of opioid abstinence.

Encourage patients to use techniques for preventing return to use, such as participating in recovery support groups and gaining support from counseling and family. Doing so can help patients succeed in tapering off their medication.

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Methadone Dosing Summary

The initial goal is to reduce opioid withdrawal and craving safely.

•: Use the “start low and go slow” approach but increase dose at a rate that minimizes chances of continued illicit drug use, while monitoring for side effects.
•: Increase doses gradually over several weeks.
•: Assess for sedation at peak serum concentration (2–4 hours after the dose).

The eventual target is an adequate dose that:

•: Stops withdrawal symptoms for 24 hours.
•: Reduces or eliminates craving.
•: Blunts or blocks euphoria from self-administered illicit opioids.

In general, after induction is complete, higher doses are more effective than lower doses.

Enhancing Access to OUD Medication in OTPs

Individuals on waiting lists for OTPs should receive interim methadone maintenance treatment. People on waiting lists typically continue to use illicit opioids. Many never gain admission through the waiting list process. Federal OTP regulations permit use of interim methadone maintenance to address this problem by providing methadone treatment for up to 120 days to someone on an OTP waiting list. Routine counseling and treatment planning are not required during this period.

Interim methadone maintenance has been shown to be more effective than a waiting list to facilitate entry into comprehensive methadone treatment and to reduce illicit opioid use, according to two randomized trials.^159,160 Interim methadone requires approval by SAMHSA and the state opioid treatment authority. For more detailed information on interim methadone maintenance, see SAMHSA's Federal Guidelines for Opioid Treatment Programs (https://store.samhsa.gov/product/Federal-Guidelines-for-Opioid-Treatment-Programs/PEP15-FEDGUIDEOTP).

OTPs can overcome geographic barriers by opening a medication unit of the parent OTP site. Under the aegis of a certified OTP, a medication unit may provide methadone or buprenorphine administration, dispensing capacity, and urine drug testing, but not counseling. The parent clinic must provide counseling and other required services. Such arrangements can lessen the amount of time required to drive to a parent OTP location in large states with rural populations.

SAMHSA's Federal Guidelines for Opioid Treatment Programs offers more information on medication units and other OTP regulations (https://store.samhsa.gov/product/Federal-Guidelines-for-Opioid-Treatment-Programs/PEP15-FEDGUIDEOTP).

Chapter 3B Appendix

Sample Standard Consent to Opioid Maintenance Treatment Form for OTPs (PDF, 1.2M)