Introduction ⬇
AHFS Class:
Generic Name(s):
Associated Monographs
Notification REMS: FDA approved a REMS for methadone hydrochloride to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of methadone hydrochloride and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]). - FDA drug safety communication (4/13/2023):500 As part of its ongoing efforts to address the nation's opioid crisis, FDA is requiring several updates to the prescribing information of opioid pain medicines. The changes are being made to provide additional guidance for safe use of these drugs while also recognizing the important benefits when used appropriately. The changes apply to both immediate-release (IR) and extended-release/long-acting preparations (ER/LA).
- Updates to the IR opioids state that these drugs should not be used for an extended period unless the pain remains severe enough to require an opioid pain medicine and alternative treatment options are insufficient, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
- Updates to the ER/LA opioids recommend that these drugs be reserved for severe and persistent pain requiring an extended period of treatment with a daily opioid pain medicine and for which alternative treatment options are inadequate.
- A new warning is being added about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.
- Information in the boxed warning for all IR and ER/LA opioid pain medicines will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).
- Other changes will also be required in various other sections of the prescribing information to educate clinicians, patients, and caregivers about the risks of these drugs.
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Methadone hydrochloride is a synthetic diphenylheptane-derivative opiate agonist.
Uses ⬆ ⬇
Methadone is used in the relief of pain. Methadone also may be used in detoxification and maintenance treatment. Although the drug has antitussive activity, methadone is no longer approved by the US Food and Drug Administration for this indication.
Pain 
Methadone is a strong analgesic used parenterally for the treatment of moderate to severe pain that has not responded to non-opiate analgesics.222 Methadone is used orally for relief of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.217,225,226 Methadone is used for relief of chronic pain in both opiate-naive patients and in individuals being switched to methadone therapy from other opiate agonists because of inadequate pain relief or adverse effects from the previous drug (opiate rotation).228,232,254 Most clinical studies evaluating methadone in the management of pain have involved individuals with chronic malignant pain.228,232 The manufacturers state that oral preparations of the drug are not indicated for relief of acute (including postoperative) pain, for relief of pain that is mild or is not expected to persist for an extended period of time, or for use on an as-needed (“prn”) basis.217,225,226
Clinical studies suggest that methadone may have efficacy similar to that of morphine and other opiates in patients with chronic malignant pain.228,232 However, experts generally agree that methadone should be prescribed for chronic pain management only by clinicians knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetics,410,411,412,413,414,415 and should not be the first choice for an extended-release or long-acting opiate analgesic.411,415 Benefits associated with the use of methadone for management of chronic pain include the commercial availability of multiple dosage forms of the drug,232 good oral bioavailability,228,229 rapid onset of action,228,229 reduced dosing frequency (because of the drug's long half-life),228,232 low cost,228,229,232,235 and lack of active metabolites.228,229,232 Incomplete cross-tolerance between methadone and other opiate agonists has been reported; some patients who were previously refractory to high doses of other opiate agonists have experienced pain relief with methadone therapy.217,229,231,232,235 This incomplete cross-tolerance may allow for successful pain relief in patients who previously were refractory to or who experienced adverse effects from increasing dosages of other opiate agonists.232,235,251 Disadvantages associated with the use of methadone include its increased potential for accumulation with repeated doses (which may result in toxicity),217,228,254 considerable interindividual variability in pharmacokinetic parameters,217,228,229 the potential for drug interactions,217,228,232 challenges associated with methadone dosage titration and with the transfer of patients from therapy with other opiate agonists to therapy with methadone,217,228 and the commercial availability and relative ease of use of extended-release preparations of other opiate agonists.228 (See Cautions.)
For further information on the role of opiate analgesics in the management of chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.
Detoxification and Maintenance of Opiate Dependence
Methadone is used in detoxification treatment and maintenance treatment as an oral substitute for heroin or other morphine-like drugs to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs. The success of such treatment programs is dependent on the selection of properly motivated patients and on the availability of social, psychologic, vocational, and educational as well as medical supportive services. In detoxification treatment, methadone is administered in decreasing doses over a period not exceeding either 30 days ( short-term detoxification ) or 180 days ( long-term detoxification ) in order to withdraw use of opiate agonist(s);201,213,263 previously (prior to enactment of Public Law 98-509 in 1984), detoxification treatment with methadone could not exceed 21 days.200 Patients of any age may undergo detoxification treatment. Methadone is approved by the US Food and Drug Administration (FDA) for detoxification treatment of opiate dependence and for maintenance treatment of opiate dependence (opiate use disorder [OUD]).217,221,225,226,261,262 Buprenorphine hydrochloride is approved by the FDA for the management of opiate dependence.216 Levomethadyl acetate (LAAM, ORLAAM®) also has been approved by the FDA for the management of opiate dependence but is no longer commercially available in the US because of potentially severe adverse cardiac effects.215,221
Maintenance treatment consists of administration of stable doses of methadone or buprenorphine for relatively long periods (i.e., exceeding 21 days).212,213,216,263,267 Maintenance treatment with methadone is provided as comprehensive maintenance , which is provided in conjunction with a comprehensive range of appropriate medical and rehabilitative services, or interim maintenance , which is provided in conjunction with appropriate medical services while the patient is awaiting transfer to comprehensive maintenance.212,213,263 Maintenance treatment with buprenorphine is provided as office-based outpatient therapy.216 Office-based treatment with buprenorphine is an innovative model intended to increase access to opiate dependence treatment and may be appropriate for individuals who may not otherwise seek methadone maintenance treatment (comprehensive maintenance), do not meet enrollment criteria, do not have access to such programs, or have chosen to opt out of such programs for another reason.218 In the office-based treatment model, specially trained physicians prescribe buprenorphine as a take-home medication.218 As with detoxification treatment, the eventual goal of maintenance therapy is withdrawal of the drug.
According to federal regulations, only patients who have demonstrated current physiologic dependence on opiate drugs and at least a 1-year history of this dependence can be admitted to comprehensive maintenance programs.201,213,263 If clinically appropriate, the 1-year history of dependence can be waived for individuals released within the previous 6 months from a penal institution, pregnant women, or previously treated individuals (up to 2 years after discharge from treatment).263
Detoxification or maintenance treatment with methadone is permitted to be undertaken only by opiate-dependency treatment programs certified by the Substance Abuse and Mental Health Services Administration (SAMHSA) and approved by the designated state authority;217,222,263 however, this does not preclude detoxification or maintenance treatment of an addict who is hospitalized or is admitted to a long-term care facility for medical conditions other than addiction and who requires detoxification or maintenance treatment during his hospitalization or stay in the long-term care facility,217,263 nor does it exclude administration of opiates for up to 72 hours (emergency treatment to relieve acute withdrawal symptoms) while care in an opiate-dependency treatment program is being sought.217,222,264 For information on the use of methadone for detoxification and maintenance treatment in children younger than 18 years of age and during pregnancy, see Cautions: Pediatric Precautions and also Pregnancy and Lactation.214,215
Because of the risk of acquiring human immunodeficiency virus (HIV) infection from illicit IV drug use,202,203,211,212 the conditions for use of methadone in maintenance treatment were revised (effective January 6, 1993) to facilitate more rapid entry into treatment programs of increased numbers of opiate-dependent patients more rapidly.202,211,212 The revisions permit programs to provide minimum service ( interim ) maintenance treatment (which is aimed at helping to alleviate the human suffering of opiate-dependent individuals, including the risk of HIV infection, and to reduce the abuse of IV drugs) in addition to comprehensive maintenance treatment (which already existed).202,211,212,213 There is some evidence that the revised conditions for treatment of opiate dependence can reduce substantially the illicit use of IV drugs (and hence needles) by dependent individuals and that such reductions in IV use of these drugs will decrease the spread of HIV within this population.202,203,204,212 In addition, the revised conditions for use of methadone in detoxification and in maintenance treatment require provision of counseling for preventing HIV transmission and exposure and provision of information on the availability of, and ensuring access to, HIV testing; mandatory HIV testing is not a requirement of opiate-dependency treatment programs, but such testing must be made available, either on site or at another facility, to any patient requesting it.212,213
The minimum service program serves as interim treatment until a patient can be admitted into a comprehensive program; however, such treatment cannot exceed 120 days in any 12-month period.212,213,263,267 In general, the requirements for comprehensive maintenance treatment or detoxification treatment apply to interim maintenance treatment, although the provision of a comprehensive range of services is not required during interim maintenance treatment.212,213,263 Comprehensive medical, vocational rehabilitative, employment, educational, and counseling services (e.g., formation and periodic evaluation of treatment plans, primary counselor assignments) are not required during interim maintenance.212,213,263 However, some services are required (e.g., medical treatment referrals, prenatal care referrals, HIV counseling), and sufficient counseling staff should be available to provide such services and to respond to emergencies.212,213,263 In addition to initial drug screening, interim programs must provide a minimum of 2 additional drug screenings to assist in assessing patient needs and priorities for transfer into comprehensive programs.212,213,263 Patients admitted to an interim maintenance program are required to be administered each daily methadone dose while being closely observed; take-home medication is not permitted.212,213,263 Both admission to interim treatment programs and transfer to comprehensive treatment programs are to be provided preferentially to pregnant women.212,213,263 Interim maintenance treatment programs can be implemented by existing maintenance programs, provided the program has filed for and received federal authorization (formerly from FDA but as of May 18, 2001, from SAMHSA) and authorization from the appropriate local (e.g., state) authority.212,263
Federal regulations (effective May 18, 2001) concerning use of opiates in detoxification and maintenance programs transferred oversight for such programs from FDA to SAMHSA and altered the nature of the regulatory system from one that relied on inspection for compliance with process-oriented regulations to a system based on program accreditation and subsequent certification by SAMHSA.265,267,268 Standards for treatment programs also were modified to permit greater flexibility and professional judgment in treatment.267 The requirement that programs use only liquid oral formulations was modified to allow for use of either liquid or solid oral dosage forms.267 The requirement that treatment programs administer methadone hydrochloride dosages exceeding 100 mg daily under direct supervision at least 6 days per week regardless of length of time in the program (unless prior approval for take-home dosages exceeding 100 mg had been obtained from FDA and the state authority) was eliminated, and a more flexible schedule for unsupervised administration was allowed (see Maintenance under Dosage: Detoxification and Maintenance of Opiate Dependence, in Dosage and Administration).265,267
Other federal initiatives were undertaken in 2000 to expand access to treatment and to involve office-based physicians in the care of opiate-dependent individuals.219,220 These initiatives were taken in response to limitations in the heavily regulated comprehensive maintenance programs and the increasing heroin use and high rates of HIV and hepatitis C virus transmission among illicit users of IV drugs.220 The Drug Addiction Treatment Act (DATA) of 2000 allows qualifying physicians to prescribe and dispense opiates in schedules III, IV, and V of the Federal Controlled Substances Act that have been approved by the FDA for detoxification or maintenance treatment of opiate dependence.219 With the approval of buprenorphine and buprenorphine in fixed combination with naloxone for the management of opiate dependence, treatment of opiate dependence can be undertaken in a system that resembles care provided for other chronic medical conditions.216,220
Neonatal Opiate Withdrawal
Methadone has been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates† exposed to opiates in utero.350,352,353,355,357,359 Opiates are recommended as first-line pharmacologic therapy when environmental and supportive measures (e.g., minimization of external stimuli, maximization of mother-infant contact [e.g., parental “rooming in”], breast-feeding when not contraindicated, swaddling and gentle handling) are inadequate.350,352,353,355,357,359 Other adjunctive therapy (e.g., clonidine, phenobarbital) may be added if the response to opiates is inadequate, or phenobarbital be added if the neonate was exposed to additional substances in utero.350,352,353,355,357,358,359,365,368 Approximately 60-80% of neonates with opiate abstinence syndrome may require pharmacologic treatment for withdrawal symptoms.352,359 While morphine has been used more extensively than other opiates in the management of neonatal opiate abstinence syndrome,352,357,359,360 some studies suggest that use of methadone or buprenorphine (an opiate partial agonist) may be associated with shorter treatment durations and hospital stays compared with morphine use.360,361,362,363 However, additional study is needed to establish optimal dosage schedules and preferred opiate drugs and to evaluate longer-term (e.g., neurodevelopmental) outcomes.351,353,354,355,360 Conflicting findings to date may be related in part to differences in study design, nonpharmacologic care, concomitant in utero drug exposures, the stringency of institutional protocols for care, and optimization of dosage schedules.354,360,362
Use of standardized protocols for identification, evaluation, and treatment of neonatal opiate withdrawal syndrome is recommended since use of such protocols has been shown to improve overall response, including shorter hospital stays and durations of pharmacologic treatment.350,352,353,358,359 Some evidence suggests that use of a standardized protocol may be more important than use of a specific opiate agonist (e.g., methadone versus morphine) in improving outcomes.352,359,363 Protocols generally utilize assessment tools that were developed to quantify severity of withdrawal in term neonates (e.g., Finnegan or modified Finnegan scoring tools) to facilitate decisions regarding initiation, titration, and tapering of therapy.352,353,355,357,359
Dosage and Administration ⬆ ⬇
Administration
Methadone hydrochloride may be administered orally as tablets, solution, concentrated solution, or dispersible tablets or by subcutaneous, IM, or IV injection.
Methadone hydrochloride dispersible tablets are intended for dispersion in a liquid prior to oral administration. Dispersible tablets of the drug contain insoluble excipients and therefore must not be used to prepare solutions for injection. Each 40-mg dispersible tablet can be divided in half or in quarters; the desired dose should be dispersed in approximately 120 mL of water, orange juice, Tang®, citrus-flavored Kool-Aid®, or other acidic fruit beverage immediately prior to administration.261,262 Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used. If any residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered.261,262 Because the dispersible tablets can be administered only in increments of 10 mg, this dosage form may not be appropriate in many patients for initial dosing during detoxification and maintenance treatment or for gradual dosage reduction following short-term detoxification or a period of maintenance treatment.261,262
When the 10-mg/mL oral concentrate solution is used for the treatment of pain, the dose must be diluted with water or other suitable liquid (e.g., Kool-Aid®, Tang®, apple juice, Crystal Light® [with aspartame]) to at least 30 mL prior to administration.255,256
Absorption of methadone following subcutaneous or IM injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.222
Methadone hydrochloride also has been administered rectally†235,252 and by epidural injection†.235
Epidural Administration
Standardize 4 Safety
Standardized concentrations for epidural methadone†have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 151Multidisciplinary expert panels were convened to determine recommended standard concentrations. 151Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 151 For additional information on S4S (including updates that may be available), see [Web]151 .
Table 1: Standardize 4 Safety Epidural Standard Concentrations for Methadone as a Single Drug151
Patient Population | Concentration Standards |
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Adults | 1 mg/mL |
Restricted Distribution
Manufacturers of methadone hydrochloride 40-mg dispersible tablets and the Drug Enforcement Administration (DEA) have agreed to restrict distribution of this preparation to authorized opiate-dependency treatment programs and to hospitals.271,272,273 This restriction is in response to reports of serious adverse effects such as cardiotoxicity and death in patients receiving methadone (see Cautions).270,272,273 Methadone hydrochloride 40-mg dispersible tablets are used in detoxification and maintenance treatment of opiate addiction;261,262,271 this preparation is not labeled by the US Food and Drug Administration (FDA) for the treatment of pain.261,262,270,271
Dosage
Dosage of methadone hydrochloride must be carefully individualized because repeated doses may result in substantial accumulation of the drug, prolonging its duration of action and possibly resulting in adverse effects, and because there is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.217,222,232 Patients should be carefully monitored during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.217,222 Steady-state plasma concentrations and full analgesic effects of methadone generally are not achieved until completion of 3-5 days of therapy.217,222
Pain
When selecting an initial dosage of methadone hydrochloride for management of pain, consideration should be given to the type, severity, and expected duration of the patient's pain; the age, general condition, and medical status of the patient; concurrent drug therapy (see Drug Interactions); and the acceptable balance between pain relief and adverse effects.217,222 In addition, in patients who are being transferred to methadone from other opiate therapy, consideration should be given to the daily dosage, potency, and specific characteristics (e.g., elimination half-life) of the previously administered opiate; adverse effects of and response to the previous regimen; degree of opiate tolerance; and the relative potency estimate used to calculate an equianalgesic dosage of methadone hydrochloride.217,222,236,259 Appropriate dosage selection and titration are essential to prevent overdosage.217
A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.217,222Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.217,222,236(See Cautions.) Overestimation of the methadone dosage when transferring patients from other opiate therapy to methadone therapy can result in fatal overdosage with the first dose.217
Published equianalgesic dosage conversion ratios between methadone hydrochloride and other opiate agonists are imprecise. Dose equivalencies that are obtained from commonly used tables generally are based on single-dose studies in patients who are not opiate tolerant.217,222 When transferring patients to methadone from other opiate agonist therapy, use of single-dose equivalency tables may overestimate dosage requirements for methadone hydrochloride during chronic therapy, since methadone may accumulate with repeated doses secondary to the long elimination half-life of the drug (see Pharmacokinetics: Elimination).217,222,227 Therefore, estimates of methadone hydrochloride dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.217,222 In addition, equianalgesic dosage conversion ratios between morphine sulfate and methadone hydrochloride have been reported to vary substantially depending on the dosage of the previously administered morphine regimen; the morphine sulfate-to-methadone hydrochloride equianalgesic dosage conversion ratio has been reported to be lower in patients receiving prior opiate therapy at a lower morphine sulfate dosage and higher in those receiving prior therapy at a higher morphine sulfate dosage.217,223,232,236,257,258
Regardless of the strategy employed to determine initial methadone dosage, methadone hydrochloride therapy is most safely initiated using small initial doses and gradual dosage adjustments.222 Some clinicians recommend a transition period of at least 3 days for patients being transferred from therapy with another opiate agonist to therapy with methadone; during the transition period, the dosage of the previous opiate agonist is gradually tapered while the dosage of methadone hydrochloride is slowly increased.223,236,257,258 Other clinicians state that patients receiving low dosages of another opiate agonist may be transferred to methadone therapy in 1 day.260
As an analgesic, methadone hydrochloride should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Reduced dosage is indicated in poor-risk patients such as very young, very old, or debilitated patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)
When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431 For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Parenteral Dosage
For the relief of moderate to severe pain, the manufacturer recommends a usual initial methadone hydrochloride dosage in opiate-naive adults of 2.5-10 mg administered IV every 8-12 hours.222 Dosage may be increased as necessary to provide adequate analgesia, but should be increased slowly to avoid accumulation of the drug and potential toxicity.222 More frequent administration may be required during initiation of therapy in order to maintain adequate analgesia, but caution is necessary to avoid overdosage.222
In patients being switched from oral to parenteral methadone hydrochloride, parenteral methadone hydrochloride should be initiated at a parenteral-to-oral dosage ratio of 1:2 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).222
When patients are transferred from chronic therapy with another oral or parenteral opiate to therapy with parenteral methadone hydrochloride, dosage must be selected carefully, since cross-tolerance between methadone and other opiate agonists is incomplete, dosage conversion ratios are imprecise, and substantial interindividual variability exists.222,235 The dosage conversion methods recommended by the manufacturer for converting to IV methadone hydrochloride (See Tables 2 and 3) are based on comparisons with morphine.222 The manufacturer states that these estimates provide a safe starting point for opiate conversion; however, the IV methadone hydrochloride dosage obtained from these comparisons must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).222 The total daily dosage should be administered in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.222 For patients being transferred from therapy with opiate agonists other than morphine, a comparative opiate agonist dosage table (such as the table in the Opiate Agonists General Statement 28:08.08) may be consulted to determine the equivalent morphine dosage.222
Table 2. Conversion of Oral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)222
Baseline Total Daily Oral Morphine Sulfate Dosage | Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage) |
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<100 mg | 10-15% |
100-300 mg | 5-10% |
300-600 mg | 4-6% |
600-1000 mg | 3-5% |
>1000 mg | <3% |
Table 3. Conversion of Parenteral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)a
Baseline Total Daily Parenteral Morphine Sulfate Dosage | Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Dosage) |
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10-30 mg | 40-66% |
30-50 mg | 27-66% |
50-100 mg | 22-50% |
100-200 mg | 15-34% |
200-500 mg | 10-20% |
aDerived from Table 2 assuming a 3:1 oral-to-parenteral morphine ratio.222
Oral Dosage
When oral methadone hydrochloride is used for the relief of moderate to severe pain in opiate-naive adults who require a continuous, around-the-clock analgesic for an extended period of time, therapy should be initiated with small doses of no more than 2.5-10 mg given every 8-12 hours.217 Dosage must be carefully individualized according to patient response.217,232 Dosage may be titrated to provide adequate analgesia, but should be increased slowly to avoid accumulation of the drug and potential toxicity.217 The dosage interval during methadone therapy may range from 4-12 hours, since the duration of analgesia is relatively short during the first days of therapy but increases substantially with continued administration.223,227 Clinicians and patients must be prepared to markedly reduce the methadone hydrochloride dose and/or increase the dosing interval after the first few doses based on assessments of pain relief, sedation, and other adverse effects.227 Some clinicians experienced with the use of methadone may elect to initiate opiate therapy by administering methadone hydrochloride on an as-needed basis for the first 3-7 days and then establishing an around-the-clock dosage schedule based on the duration of action reported by the patient. Opiate therapy also may be initiated with a short-acting opiate agonist and then switched to methadone once adequate analgesia is established.227
In patients being switched from parenteral to oral methadone hydrochloride, oral methadone hydrochloride should be initiated at an oral-to-parenteral dosage ratio of 2:1 (e.g., 10 mg of oral methadone hydrochloride in patients previously receiving 5 mg of parenteral methadone hydrochloride).217
When patients are transferred to oral methadone from chronic therapy with other oral or parenteral opiates, dosage must be selected carefully because cross-tolerance between methadone hydrochloride and other opiate agonists is incomplete, dosage conversion ratios are imprecise, and considerable interindividual variability exists.217,222 The dosage conversion method shown in Table 4 is based on comparison with morphine sulfate.217,222 The oral methadone hydrochloride dosage obtained from this comparison must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).217,222 The total daily dosage should be administered in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.217,222 For patients being transferred from therapy with opiate agonists other than morphine, a comparative opiate agonist dosage table (such as the table in the Opiate Agonists General Statement 28:08.08) may be consulted to determine the equivalent morphine dosage.217,222
Table 4. Conversion of Oral Morphine Sulfate to Oral Methadone Hydrochloride (for Chronic Administration)217,222
Baseline Total Daily Oral Morphine Sulfate Dosage | Estimated Daily Oral Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage) |
|---|
<100 mg | 20-30% |
100-300 mg | 10-20% |
300-600 mg | 8-12% |
600-1000 mg | 5-10% |
>1000 mg | <5% |
Dosage adjustments may be made at intervals of 1-2 days with close monitoring to achieve adequate analgesia with minimal adverse effects.217 Patients who experience breakthrough pain may require dosage adjustment or rescue therapy with a small dose of an immediate-release analgesic.217 If excessive opiate-related adverse effects are observed, the next dose of methadone hydrochloride may be reduced; if adverse effects are intolerable, either the dose or dosing interval of the drug may be adjusted.217 If discontinuance of opiates is required, gradual tapering of the dosage every 2-4 days is recommended to avoid manifestations of abrupt withdrawal.217
Detoxification and Maintenance of Opiate Dependence
In detoxification and maintenance treatment, methadone hydrochloride may be administered or dispensed only as an oral preparation (e.g., tablet, dispersible tablet, liquid) that is formulated and packaged in such a way as to reduce potential for parenteral abuse and accidental ingestion.214,261,262,263 Hospitalized patients being treated for a medical or surgical condition may receive methadone parenterally if necessary. The dosage of methadone used for detoxification or maintenance treatment should be adjusted to control abstinence symptoms without causing respiratory depression or marked sedation. Any substantial deviations from the FDA-approved labeling for methadone hydrochloride (e.g., concerning dose, frequency of administration, or conditions of use) must be documented in the patient's medical record.263
If at any time during detoxification or maintenance the patient cannot tolerate oral medication because of nausea or vomiting associated with acute complicating illness, he should be hospitalized and methadone hydrochloride may be continued by the parenteral route. The patient should receive 2 injections daily by the subcutaneous or IM route; each dose should be about one-fourth of the total oral daily dosage.
Detoxification
Detoxification treatment is initiated when there are substantial opiate-agonist abstinence symptoms. The initial dose of methadone hydrochloride should be based on the opiate tolerance of the patient. A single oral dose of 20-30 mg of methadone hydrochloride will often suppress withdrawal symptoms. The initial dose should not exceed 30 mg.217,263 Initial doses should be lower for patients whose tolerance is expected to be low at treatment initiation.217 Loss of tolerance should be considered if more than 5 days have elapsed since the patient took opiates.217 Initial doses should not be based on those used during prior treatment episodes or on the patient's expenditures for illicit drugs.217 If there is any doubt, it is usually safer to start with a smaller dose and keep the patient under observation. Additional doses of methadone hydrochloride may be necessary if withdrawal symptoms are not suppressed or if they reappear.217 The manufacturer states that if same-day dosage adjustments are to be made, the patient should be reevaluated 2-4 hours after the previous dose, since peak plasma concentrations of methadone will have been attained.217 If an additional dose is required to suppress withdrawal symptoms, an additional 5-10 mg of methadone hydrochloride may be administered.217 The total dose on the first day should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.217,263
Dosage adjustments should be made over the first week of methadone therapy based on assessments of withdrawal-symptom suppression at times of expected peak activity (i.e., 2-4 hours after a methadone hydrochloride dose).217 Dosage adjustments should be cautious, in order to avoid overdosage.217 With continued dosing, symptoms will be suppressed for longer periods of time as the drug accumulates in body tissues.217 In most patients, a daily dosage of 40 mg of methadone hydrochloride in single or divided doses will usually constitute an adequate stabilizing dosage level, but higher dosage may be required. When the patient has been stabilized (i.e., substantial symptoms of withdrawal are absent) for 2 or 3 days, dosage of methadone hydrochloride can be gradually decreased daily or at 2-day intervals. Dosage must be individualized and adjusted to keep withdrawal symptoms at a tolerable level. In hospitalized patients, dosage can usually be reduced by 20% daily, but a more gradual reduction may be required in ambulatory patients.
For short-term detoxification, methadone must be administered daily while the patient is under close observation in reducing dosages over a period not exceeding 30 days.201,213,263 For long-term detoxification, methadone must be administered in a regimen designed to reach a drug-free state within 180 days or less.201,213,263 Take-home medication may be allowed during long-term detoxification if certain conditions are met (see Maintenance under Dosage: Detoxification and Maintenance of Opiate Dependence, in Dosage and Administration).263,264 Individuals with 2 or more unsuccessful detoxification episodes within a 12-month period should be evaluated for alternative forms of treatment.263 An opiate-dependency treatment program may not admit an individual for more than 2 detoxification treatments within one year.263
Maintenance
Interim (minimum service) maintenance treatment is that which is provided in conjunction with appropriate medical services while a patient is awaiting transfer to comprehensive maintenance treatment.212,213,263 A maintenance program that is unable to place a patient requesting treatment into a comprehensive maintenance treatment program within 14 days of application for admission and within a reasonable geographic area may place the patient in an interim maintenance treatment program until placement in a comprehensive program is possible.212,213,263 A patient may not continue in an interim treatment program for longer than 120 days in any 12-month period, and must be transferred to a comprehensive program after 120 days in an interim program if still in need of treatment.212,213,263 A patient admitted to an interim maintenance program is required to be administered each daily methadone dose while being closely observed, and take-home medication is not allowed.212,213,263 Although most requirements for comprehensive maintenance treatment apply to interim maintenance treatment, some do not apply.212,213,263 (See Uses: Detoxification and Maintenance of Opiate Dependence.)
When methadone hydrochloride is used to initiate maintenance treatment, the initial dose should be based on the opiate tolerance of the patient. A single oral dose of 20-30 mg of methadone hydrochloride will often suppress withdrawal symptoms.217 The initial dose should not exceed 30 mg.217,263 Initial doses should be lower for patients whose tolerance is expected to be low at treatment initiation.217 Loss of tolerance should be considered if more than 5 days have elapsed since the patient took opiates.217 Initial doses should not be based on those used during prior treatment episodes or on the patient's expenditures for illicit drugs.217 If there is any doubt, it is usually safer to start with a smaller dose and keep the patient under observation. Additional doses of methadone hydrochloride may be necessary if withdrawal symptoms are not suppressed or if they reappear. The manufacturer states that if same-day dosage adjustments are to be made, the patient should be reevaluated 2-4 hours after the previous dose, since peak plasma concentrations of methadone will have been attained.217 If an additional dose is required to suppress withdrawal symptoms, an additional 5-10 mg of methadone hydrochloride may be administered.217 The total dose on the first day should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.217,263
Subsequent dosage should be adjusted according to the requirements and response of the patient. Dosage adjustments should be made over the first week of methadone treatment based on assessments of withdrawal-symptom suppression at times of expected peak activity (i.e., 2-4 hours after a methadone hydrochloride dose).217 Dosage adjustments should be cautious, in order to avoid overdosage.217 With continued dosing, symptoms will be suppressed for longer periods of time as the drug accumulates in body tissues.217 Dosage should be titrated to a level at which opiate symptoms are prevented for 24 hours, drug craving is reduced, the euphoric effects of self-administered opiates are blocked or attenuated, and tolerance to the sedative effect of methadone is evident.217 It has been suggested that trough plasma methadone concentrations exceeding 100-200 ng/mL may be necessary to optimize the success of methadone maintenance,205,206,207,208,209 particularly during the first 6 months of treatment.203 Stabilization of maintenance dosage usually occurs at 80-120 mg daily,217 although higher dosage is sometimes required. A single dose of methadone daily usually adequately maintains the patient and there generally is no apparent advantage to divided doses. However, rapid metabolizers of methadone may not maintain adequate plasma methadone concentrations with usual dosing regimens.206,207,208,210 Highly motivated patients may be maintained on dosage as low as 20-30 mg daily.
Because levomethadyl acetate hydrochloride is no longer commercially available in the US, patients receiving maintenance treatment with the drug should be transferred to alternative treatments.221 Patients maintained on levomethadyl acetate hydrochloride can be transferred to methadone.215,221 Methadone hydrochloride can be initiated at a daily dose that is 80% of the levomethadyl acetate hydrochloride dose; the initial methadone dose must be given no sooner than 48 hours after the last levomethadyl acetate hydrochloride dose.215,221 Subsequent doses of methadone hydrochloride may be increased or decreased in increments of 5-10 mg daily to control manifestations of withdrawal or excess sedation according to clinical observation.215,221
Experience with the transfer of patients from methadone maintenance to buprenorphine is limited.216
Any individual in a comprehensive maintenance treatment program, including long-term detoxification treatment, may receive one daily dose of methadone to take at home for a day that the clinic is closed.263,264 Decisions to allow additional unsupervised administration by these individuals should be based on the following factors: absence of recent abuse of drugs (including alcohol), regularity of clinic attendance, absence of serious behavioral problems at the clinic, absence of known recent criminal activity, stability of the individual's home environment and social relationships, length of time in the program, assurance that the drug can be safely stored in the individual's home, and assessment of whether the rehabilitative benefit derived from decreased clinic attendance outweighs potential risks of diversion.263 Individuals meeting these criteria may be permitted to receive additional supplies of the drug to take at home each week, in the following amounts: 1-day supply during the first 90 days of treatment, 2-day supply during the second 90 days, and 3-day supply during the third 90 days (each in addition to the one dose allowed for clinic closure).263,264,265 All other doses must be administered while the individual is closely observed.263 During the remainder of the first year of treatment, individuals may receive a maximum 6-day supply of methadone and must visit the clinic once weekly.263,265 After 1 year of continuous treatment, individuals may receive a maximum 2-week supply of methadone and must make twice monthly visits.263,265 After 2 years of continuous treatment, the individual may receive a maximum 1-month supply of the drug and must make monthly visits.263,265
Maintenance dosage requirements should be reviewed regularly and reduced as indicated. In patients desiring medically supervised withdrawal from methadone maintenance treatment, there is considerable variability in the appropriate rate of methadone dosage reduction; dosage generally should be reduced at intervals of 10-14 days by an amount that is less than 10% of the established tolerance or maintenance dosage.217 All patients in a maintenance program should be given careful consideration for discontinuance of methadone therapy, especially after reaching a dosage of 10-20 mg daily.
Neonatal Opiate Withdrawal
For the management of neonatal opiate abstinence syndrome†, use of standardized protocols that base initiation, adjustment, and tapering of methadone hydrochloride dosage on standardized patient assessments performed at regular intervals is recommended.352,355,359 The most commonly used tool for assessing severity of withdrawal in term neonates is the Finnegan scoring system (original or modified versions) performed every 3-4 hours.352,355,359 Treatment with methadone hydrochloride oral solution generally is initiated at a dose of 0.05-0.1 mg/kg based on Finnegan score (e.g., score is 8 or greater on 2 or 3 occasions, a single score or 2 consecutive scores are 12 or greater).294,352,355,365,368 However, protocols vary in initial dosing frequency, incremental changes and thresholds for dosage adjustment, and tapering strategies.293,294,352,353,355,357,361,365,368 In general, dosage may be escalated if Finnegan score remains elevated (e.g., 2 consecutive scores are 8 or greater, one score is 12 or greater),352,355,361,365 and dosage is tapered once patients are stable (e.g., no score exceeds 8 or average score is less than 8 for 24 hours).355,365
Some protocols are based on pharmacokinetic modeling of methadone in neonates and utilize a stepwise approach to dosage escalation and tapering.293,294,365 Under such protocols, methadone hydrochloride may be administered at an initial dose of 0.1 mg/kg; dosing intervals are shorter during the initial steps of the protocol, but then are lengthened to and maintained at 12 hours while the dose is tapered, if tolerated, by a modest amount every 24 hours until the dosage of the drug has been reduced to 0.01 mg/kg once daily.293,294,365 The drug may then be discontinued.293,294 Such protocols increase early exposure to the drug,293,294 and limited experience suggests that such an approach may allow for shorter treatment durations and hospital stays.293 Other clinicians have recommended administration of methadone hydrochloride at an initial dosage of 0.05-0.1 mg/kg every 12 hours;355,357,368 dosage increases, when indicated, in increments of 0.02-0.05 mg/kg per dose352,353,357,368 or 10%;355 a maximum dosage of 1 mg/kg daily;355,357 and/or tapering schedules of 10-20% per week.368,369 Following discontinuance of methadone, neonates should be monitored for 48-72 hours.352,365 Specialized protocols should be consulted for further information on methadone hydrochloride dosage and monitoring of Finnegan scores in neonates with opiate abstinence syndrome. Further study is needed to define optimal dosing strategies.293
Cautions ⬆ ⬇
Methadone shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.)
Death and life-threatening adverse effects, including respiratory depression and cardiac arrhythmias, have occurred during initiation of methadone for the treatment of pain and in patients being transferred to methadone from other opiate therapy, possibly as a result of inadvertent overdosage, drug interactions, and adverse cardiac effects of the drug.217,270
While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy and following dosage increases.217 In some cases, respiratory depression has occurred when methadone was used as recommended and was not misused or abused.217 Deaths have been reported in patients being transferred to methadone from chronic therapy with high dosages of other opiate analgesics; deaths also have been reported during initiation of methadone maintenance treatment for opiate dependence (opiate use disorder [OUD]) in individuals who previously used high dosages of other opiates.217 An understanding of methadone's pharmacokinetic and pharmacodynamic properties is crucial for safe use of the drug.217,270 Methadone's elimination half-life (8-59 hours) is substantially longer than the duration of its analgesic action (4-8 hours); in addition, peak respiratory depressant effects of the drug typically occur later and persist longer than its peak analgesic effect, particularly during the early dosing period.217,270 The full analgesic effect usually is not attained for 3-5 days.217,270 These properties can contribute to inadvertent overdosage, particularly during treatment initiation and dosage adjustment.217,270 Methadone should be prescribed only by clinicians who are experienced in the use of potent opiates for the treatment of chronic pain.217 Methadone dosage should be selected carefully and titrated slowly, even in opiate-tolerant patients, and patients should be monitored carefully during treatment initiation, transfer to methadone from other opiate therapy, and dosage titration.217,270
Prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes, have been reported in patients receiving methadone.217,222,223,234 Most of the reported cases have occurred in patients receiving methadone at relatively high dosages (more than 200 mg daily) for the treatment of chronic pain, but cases also have been reported in patients receiving methadone maintenance therapy at lower dosages.217,222,233,234 In most cases involving patients receiving usual methadone maintenance dosages, concomitant drug therapy and/or conditions such as hypokalemia were identified as contributing factors.217 Methadone should be used for pain management only when the potential benefit from the drug outweighs the possible risk of QT-interval prolongation that has been reported with higher methadone dosages.217,222 Patients should be monitored closely for changes in cardiac rhythm during initiation of therapy and following increases in dosage.217 In addition, methadone should be used with caution and careful monitoring in patients who may be at risk for development of prolonged QT syndrome (e.g., those with cardiac hypertrophy, hypokalemia, or hypomagnesemia; those receiving methadone at relatively high dosages or receiving concomitant therapy with a drug that may cause electrolyte disturbances or prolong the QT interval [see Drug Interactions: Drugs that Prolong QT Interval]).217,222 If prolongation of the QT interval occurs in a patient receiving methadone, the patient's drug regimen should be evaluated to identify drugs that may prolong the QT interval, cause electrolyte abnormalities, or inhibit metabolism of methadone.217,222 Use of methadone in patients with known prolongation of the QT interval has not been systematically evaluated.217,222
Profound sedation, respiratory depression, coma, and death may occur when opiate agonists are used concomitantly with benzodiazepines or other CNS depressants.416,417,418,700,701,702,703 Concomitant use of opiate analgesics and other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Patients receiving methadone and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703 Concomitant use with alcohol should be avoided.700 (See Drug Interactions: Alcohol and also see Drug Interactions: Benzodiazepines and Other CNS Depressants.)
Because the morbidity and mortality associated with untreated opiate addiction can outweigh the serious risks associated with concomitant use of opiates and benzodiazepines or other CNS depressants, FDA states that methadone treatment for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be withheld from patients receiving benzodiazepines or other CNS depressants.706 These drugs should be tapered and discontinued, if possible, in patients receiving MAT.706 However, excluding or discharging patients from MAT because of benzodiazepine or CNS depressant use is not likely to prevent such concomitant use and may lead to use outside the treatment setting, which could result in more severe outcomes.706 Careful management can reduce the risks associated with concomitant use of benzodiazepines or other CNS depressants in patients receiving methadone treatment for opiate addiction.706 FDA states that benzodiazepines are not the treatment of choice for anxiety or insomnia in patients receiving methadone treatment for opiate addiction; other pharmacologic or nonpharmacologic therapies should be considered.706 FDA also states that current evidence does not support dose limitations or other arbitrary limits on methadone as a strategy for addressing concomitant benzodiazepine or other CNS depressant use in patients receiving MAT.706 However, in patients who are sedated at the time of a scheduled methadone dose, the cause of sedation should be evaluated and omission or reduction of the methadone dose may be appropriate.706
Precautions recommended by FDA for minimizing risks associated with concomitant use of benzodiazepines or other CNS depressants in patients receiving MAT include the following:
- Patient education upon initiation of MAT regarding the risks associated with concomitant use of benzodiazepines or other CNS depressants;
- Development of strategies upon initiation of MAT for managing any prescribed or illicit use of benzodiazepines or other CNS depressants;
- Verification of the diagnosis in any patient receiving prescribed benzodiazepines or other CNS depressants for anxiety or insomnia, and consideration of other treatment options for these conditions;
- Recognition that MAT may be required indefinitely and should be continued for as long as the patient derives benefit and MAT contributes to the intended treatment goals;
- Coordination of care to minimize risks and ensure that other prescribers are aware that the patient is receiving methadone treatment; and
- Toxicology screening to monitor for prescribed or illicit drug use.706
Because of the risks associated with opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized opiate prescriptions for pain management or new or reauthorized prescriptions for medications for treatment of OUD.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) and should strongly consider prescribing naloxone for all patients receiving medications for treatment of OUD.411,431,750 Clinicians also should consider prescribing naloxone when patients receiving opiates for pain management or for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate for pain management or medication for treatment of OUD, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)
Patients should be instructed to take methadone exactly as prescribed and advised not to initiate or discontinue use of other drugs or dietary supplements without consulting their clinician; patients also should be informed of the signs and symptoms of overdosage and symptoms suggestive of a cardiac arrhythmia, and advised to seek immediate medical attention if such manifestations occur.217,270
Serotonin syndrome has been reported during concomitant use of opiate agonists, including methadone, and serotonergic drugs at recommended dosages.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)
Patients who are tolerant to other opiate agonists may have incomplete tolerance to methadone; therefore, methadone should be used with caution and at appropriately adjusted dosages in patients being transferred to methadone from other opiate therapy.217,222,253 Overdosage of methadone (sometimes fatal) has been reported in patients being transferred from chronic, high-dose therapy with other opiate analgesics to therapy with methadone.217,222 Pharmacokinetic parameters must be carefully considered during initiation and titration of methadone therapy in patients who previously received chronic opiate agonist therapy.217,222 (See Dosage and Administration: Dosage.)
Inadvertent ingestion of methadone, particularly by children, may result in fatal overdosage.217
Deaths associated with illicit use of methadone frequently have involved concomitant abuse of benzodiazepines.217
Methadone overdosage has been reported to induce pulmonary edema. During methadone maintenance treatment, most adverse effects disappear over a period of several weeks; however, constipation and excessive sweating often persist.
In patients receiving methadone maintenance treatment for opiate dependence, abrupt discontinuance of the drug can result in withdrawal symptoms and may increase the risk of relapse to illicit drug use.217,222 Anxiety in a patient receiving methadone maintenance treatment should not be confused with withdrawal syndrome and should not be treated with an increase in methadone dosage.222
Patients receiving methadone maintenance treatment for opiate dependence who experience physical trauma or other acute (e.g., postoperative) pain should not be expected to derive adequate analgesia from their stable methadone regimen.217,222 Such patients should receive analgesics, including opiates, that would be appropriate for other patients experiencing similar nociceptive stimulation.217,222 Opiate doses may be somewhat higher or dosing intervals somewhat shorter than those used in non-opiate-tolerant patients.217,222
Use of methadone has not been extensively evaluated in patients with renal or hepatic impairment.217,222 Because methadone is metabolized in the liver, patients with hepatic impairment may be at risk for accumulation of the drug with repeated administration.217,222
Pediatric Precautions
The manufacturers state that safety, efficacy, and pharmacokinetics of methadone in pediatric patients younger than 18 years of age have not been established.217,222
Short- or long-term detoxification treatment using methadone is not subject to any age limitation.201,263 However, the effects of prolonged methadone use on the physiologic and psychologic development of children are not known; therefore, maintenance treatment with the drug should not be initiated indiscriminately in children younger than 18 years of age.201,213 Children younger than 18 years of age are eligible to receive maintenance treatment with methadone provided they have undergone at least 2 documented attempts at detoxification or drug-free treatment within a 12-month period and the program physician has documented that the child continues to be, or is again, physiologically dependent on opiates.201,213,263 In addition, signed informed consent must be obtained from a parent, legal guardian, or responsible adult designated by the appropriate local (e.g., state) authority (e.g., via emancipated minor laws).201,213,263
Pregnancy and Lactation
Pregnancy
Methadone should be used during pregnancy only when the potential benefits justify the possible risks. Because of the drug's long duration of effect, use of methadone for obstetric analgesia is not recommended since there may be an increased risk of neonatal respiratory depression.
Untreated opiate addiction during pregnancy is associated with adverse obstetrical outcomes, including preeclampsia, fetal growth restriction, preterm birth, spontaneous abortion, and fetal death.371,372,374 In addition, untreated opiate addiction often results in continued or relapsing illicit opiate use and engagement in high-risk behaviors.371,374 The recommended treatment of opiate dependence in pregnant women is maintenance treatment with methadone or buprenorphine; this approach is superior to medically supervised withdrawal (i.e., detoxification) because withdrawal is associated with high relapse rates and poorer outcomes.350,372,373,374
Short- or long-term detoxification treatment using methadone is not recommended during pregnancy.201,281 However, pregnant women, regardless of age, are eligible for admission into a comprehensive maintenance treatment program using methadone if they have a history of documented opiate dependence and are considered at risk of possibly returning to such dependence (and all its attendant risks) during pregnancy.201,213 For such women, evidence of current physiologic dependence is not necessary, provided the program physician certifies the pregnancy and considers such therapy medically justified using reasonable clinical judgment.201,213 All pregnant women admitted into a maintenance program with methadone must be given the opportunity for prenatal care either by the program or by referral to an appropriate health-care provider.201,263 Such women should be advised of the possible risks to them and their fetus from continued use of illicit drugs and from the use and withdrawal of methadone as part of maintenance or detoxification treatment.201
Pharmacokinetic data from a limited number of pregnant women suggest that methadone clearance may be increased, trough plasma concentrations of the drug may be lower, and half-life of the drug may be decreased during the second and third trimesters of pregnancy compared with pharmacokinetic values determined for the same women postpartum or for nonpregnant opiate-dependent women.217,222 If methadone is used during pregnancy, dosage adjustment (i.e., increased dose or decreased dosing interval) may be necessary.217,222
Studies of methadone use during pregnancy generally have compared benefits of methadone maintenance treatment with the risks of untreated dependence on illicit drugs; the relevance of these findings to use of methadone as an analgesic during pregnancy is unclear.217,222 Pregnant women in methadone maintenance programs receive better prenatal care, with fewer obstetric and fetal complications and reduced neonatal morbidity and mortality, compared with women using illicit drugs.217,222 Available data suggest that maternal use of methadone during pregnancy as part of a supervised therapeutic regimen is unlikely to pose a substantial teratogenic risk; however, data are insufficient to fully exclude such risk.217,222,280 Most information regarding pregnancy outcomes involves methadone exposure after the first trimester, and information on methadone dosage and duration of use during pregnancy is limited.217,222 Interpretation of available information on pregnancy outcomes also is complicated by maternal factors such as illicit drug use, nutritional status, presence of infections, and psychosocial circumstances.217,222
In a double-blind, randomized, controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]), outcomes, principally opiate withdrawal effects, were assessed in neonates born to women who received methadone or buprenorphine treatment for opiate dependence during pregnancy.370,371 Enrollment in the study occurred at an average gestational age of 18.7 weeks.370,371 Prior to the end of pregnancy, 18% of methadone-treated women and 33% of buprenorphine-treated women discontinued treatment; outcomes were evaluated for the neonates whose mothers remained in treatment until delivery.370,371 No difference was observed between methadone- and buprenorphine-exposed neonates in the proportion of neonates requiring treatment for opiate withdrawal syndrome or the peak severity of the syndrome.370,371 Buprenorphine-exposed neonates required a lower total mean morphine sulfate dosage for treatment of withdrawal (1.1 versus 10.4 mg), had shorter hospital stays (10 versus 17.5 days), and shorter duration of treatment for withdrawal (4.1 versus 9.9 days) compared with methadone-exposed neonates.370,371 The groups did not differ in other outcome measures (head circumference, weight and length at birth, preterm birth, gestational age at delivery, and 1- and 5-minute Apgar scores) or in the rates of serious maternal or neonatal adverse events.370,371 The imbalance in treatment discontinuance rates between methadone- and buprenorphine-treated women complicate interpretation of the study findings.371
A retrospective review of pregnancy outcomes for women who underwent inpatient methadone detoxification did not reveal any increase in the risk of spontaneous abortion during the second trimester or premature delivery during the third trimester,217,222 although other studies have suggested an increased risk of premature delivery in opiate-dependent women who received methadone during pregnancy.217 Several studies have suggested that use of methadone in opiate-dependent women during pregnancy results in decreased fetal growth (with reduced birth weight, length, and/or head circumference), but this growth deficit does not appear to persist into later childhood.217,222,280,281 However, mild but persistent deficits in psychometric and behavioral test performance have been observed in children who were exposed to methadone in utero.217,222 In addition, several studies have suggested that the risk of visual developmental anomalies may be increased in children born to opiate-dependent women who received methadone during pregnancy.217 There are conflicting reports on whether maternal use of methadone during pregnancy is associated with a higher incidence of sudden infant death syndrome.217,222 During late pregnancy, results of fetal nonstress tests reportedly are more likely to be abnormal when the tests are performed 1-2 hours after a maintenance dose of methadone than when they are performed in control subjects.217,222
Methadone has been detected in cord blood and amniotic fluid at concentrations proportional to maternal plasma concentrations.217,222
Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.292 In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated,292 and requires management according to protocols developed by neonatology experts.350,352,353,358 Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.292 The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.355,357 Use of standardized protocols for identification and management of opiate withdrawal syndrome has been shown to improve overall response, including reductions in hospital stay and duration of pharmacologic treatment.350,352,359 When environmental and supportive measures are inadequate, opiates (e.g., methadone) are recommended as first-line pharmacologic therapy.352,357,359 (See Uses: Neonatal Opiate Withdrawal.)
Although no teratogenic effects were observed in rats or rabbits given methadone, administration of large doses of the drug in guinea pigs, hamsters, and mice resulted in teratogenic effects including exencephaly and cranioschisis.217,222 When male rodents were given methadone prior to mating, their offspring exhibited decreased weight gain after weaning, increased neonatal mortality, reduced thymus weight (male progeny), increased adrenal weight (female progeny), and physiologic and behavioral changes; increased embryolethality and preimplantation deaths also have been reported.217 Perinatal exposure to methadone in rats has been associated with alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to other drugs.217,222 Animal data also indicate neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic, and serotonergic systems.217,222
Lactation
Methadone is distributed into human milk.217,222,280,285 Peak concentrations in milk reportedly occur approximately 4-5 hours after an oral dose of the drug.217,222 In 2 studies in 22 nursing women who were receiving methadone maintenance treatment, methadone was present in low concentrations in milk, but no adverse effects on breast-fed infants were observed.292 At maternal oral dosages of 10-80 mg daily, reported concentrations of methadone in milk were 50-570 ng/mL; in most of the milk samples, methadone concentrations were lower than maternal steady-state serum concentrations of the drug.217,222 At maternal oral dosages of 20-80 mg daily, the mean infant dosage of the drug, calculated based on an assumed average milk consumption of 150 mL/kg daily, was approximately 17.4 mcg/kg daily, which was approximately 2-3.5% of the oral maternal dosage.217,222,285 Methadone has been detected in very low plasma concentrations in some infants whose mothers were receiving methadone.217,222,285 Cases of sedation and respiratory depression in infants exposed to methadone through breast milk have been reported rarely.217,292
Experts recommend that women who are stable on methadone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, women receiving methadone should be encouraged to continue treatment during the postpartum period.350,374,376 Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate.350,374,375 The manufacturers state that the benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from either the drug or the underlying maternal condition.292 Women who are receiving methadone and are breast-feeding or wish to breast-feed should be advised that the drug distributes into human milk, should be instructed to recognize respiratory depression and sedation in infants and to know when to seek medical care, and should be informed that nursing should be discontinued gradually (not abruptly) in order to prevent withdrawal (neonatal abstinence syndrome) in the infant.217,222
Drug Interactions ⬆ ⬇
Drugs Affecting Hepatic Microsomal Enzymes
Methadone is metabolized principally by the cytochrome P-450 (CYP) microsomal enzyme system, mainly by isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by isoenzymes 2C9 and 2D6.217,222,232,235,251 Concomitant use of methadone with drugs that induce CYP isoenzymes may result in increased metabolism and decreased plasma concentrations of methadone.217,222,232,235 Conversely, administration of methadone with drugs that inhibit CYP3A4 and/or CYP2C9 may result in decreased metabolism and increased plasma concentrations of methadone.217,222,232,235 Therefore, methadone should be used with caution in patients receiving drugs that inhibit or induce these CYP isoenzymes, and patients receiving such drugs concomitantly should be monitored carefully.217,222,232,235
Alcohol
Chronic consumption of alcohol has been reported to increase metabolism of methadone and reduce serum concentrations of the drug; however, acute consumption of alcohol has been reported to increase the area under the plasma concentration-time curve (AUC) of methadone, resulting in an increased potential for adverse effects.235 Concomitant use of opiate agonists and CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.700,701,702,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)
Anticonvulsants
Administration of phenytoin, phenobarbital, or carbamazepine in patients receiving methadone may result in increased metabolism of methadone secondary to induction of CYP3A4.217,222,232,235 Concomitant use of phenytoin (250 mg twice daily for 24 hours followed by 300 mg daily for 3-4 days) in patients receiving methadone maintenance therapy reduced plasma concentrations of methadone by 50% and resulted in withdrawal symptoms.217,222,235 Withdrawal symptoms also may occur in patients receiving methadone concomitantly with phenobarbital or carbamazepine.217,222
Antidepressants
Concomitant use of certain selective serotonin-reuptake inhibitors (SSRIs) (e.g., sertraline, fluoxetine, fluvoxamine) may increase serum methadone concentrations and increase opiate effects secondary to inhibition of methadone metabolism.217,222,235
Concomitant use of desipramine with methadone may result in increased serum desipramine concentrations.217,222,235 Opiate agonists (including methadone) may potentiate the effects of tricyclic antidepressants (see Drug Interactions: Antidepressants, in the Opiate Agonists General Statement 28:08.08).222
Concomitant use of methadone and antidepressants also may result in serotonin syndrome.400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)
Antifungals
Administration of azole antifungal agents that are known to inhibit the CYP3A4 isoenzyme (e.g., fluconazole, ketoconazole, itraconazole, voriconazole) in patients receiving methadone may result in decreased clearance of methadone.217,222,232,235,278 Administration of fluconazole (200 mg daily) has been shown to increase the AUC and peak plasma concentrations of methadone by 35 and 27%, respectively.232,235 Administration of voriconazole increased steady-state peak plasma concentrations and AUC of the pharmacologically active R -isomer of methadone by 31 and 47%, respectively, in individuals receiving methadone maintenance treatment (30-100 mg daily).217,278 Because of the potential for increased or prolonged opiate agonist effects, patients receiving these agents concomitantly should be carefully monitored and methadone dosage should be adjusted as necessary.217,222,278
Antimycobacterials
Administration of rifampin in patients receiving methadone therapy has reduced serum methadone concentrations and resulted in withdrawal symptoms.217,222,232,235
Antiretrovirals
Approximately 25-30% of patients receiving methadone maintenance therapy are HIV-positive, and numerous drug interactions have been reported in HIV-positive patients receiving antiretroviral agents concomitantly with methadone.217,222,232,235 Clinicians should monitor patients carefully for potential adverse effects when antiretroviral agents are used concomitantly with methadone.217,232
Abacavir
Concomitant use of methadone and abacavir increased methadone clearance by 22%.243 Some experts state that dosage adjustment is not necessary in patients receiving the drugs concomitantly.243 The manufacturer states that patients receiving concomitant therapy with abacavir and methadone should be monitored closely for opiate withdrawal, and methadone dosage should be increased as clinically indicated.217
Atazanavir
Concomitant use of methadone and atazanavir does not substantially alter plasma concentrations of either drug.243 No dosage adjustment is necessary.243
Concomitant use of methadone and ritonavir-boosted atazanavir decreased plasma concentrations of R -methadone by about 16-18%.243 Opiate withdrawal is unlikely but may occur.243 Patients should be monitored for opiate withdrawal, and methadone dosage should be increased as clinically indicated.243
Darunavir
Concomitant use of methadone and ritonavir-boosted darunavir decreased the AUC of methadone by 16%.243,274 Opiate withdrawal is unlikely but may occur.243 Patients should be carefully monitored for opiate withdrawal, and methadone dosage should be increased as clinically indicated.217,243,274
Delavirdine
Concomitant use of delavirdine and methadone may increase plasma concentrations of methadone.243 Patients receiving concomitant delavirdine and methadone therapy should be closely monitored for methadone toxicity; methadone dosage may need to be reduced.243
Didanosine
Concomitant use of methadone and buffered didanosine preparations appears to decrease bioavailability of didanosine.222,232,248,249 In a limited number of individuals, concomitant use of methadone and buffered didanosine resulted in a 66% decrease in the peak serum concentration and 63% decrease in the AUC of didanosine; trough concentrations of methadone did not appear to be affected.217,249 Concomitant use of methadone and didanosine delayed-release capsules does not affect the pharmacokinetics of didanosine; dosage adjustments are not necessary with this preparation.243
Efavirenz
Administration of methadone hydrochloride (35-100 mg daily) and efavirenz (600 mg daily for 14-21 days) in HIV-infected individuals with a history of drug dependence decreased the peak plasma concentration and AUC of methadone by 45 and 52%, respectively, and resulted in manifestations of opiate withdrawal.222,232,246 The maintenance dosage of methadone hydrochloride was increased by an average of 22% to alleviate withdrawal symptoms.222,246
Individuals receiving concurrent methadone and efavirenz therapy should be informed of this potential interaction and closely monitored for signs of opiate withdrawal; an increase in the maintenance dosage of methadone frequently is necessary in such individuals.217,222,232,243,246,247
Elvitegravir, Cobicistat, Tenofovir, and Emtricitabine
Concomitant use of methadone and the fixed combination of elvitegravir, cobicistat, tenofovir, and emtricitabine does not substantially affect plasma concentrations of any of the concomitantly administered drugs.243 No dosage adjustment is necessary.243
Etravirine
Concomitant use of etravirine and methadone does not appear to affect plasma concentrations of either drug.243 Dosage adjustment is not needed.243
Fosamprenavir
Concomitant use of methadone and amprenavir (no longer commercially available in the US) decreased trough plasma concentrations of R -methadone by 21% but did not substantially alter the AUC of methadone.243 Because fosamprenavir is metabolized to amprenavir, interactions reported with amprenavir are expected to occur in patients receiving fosamprenavir.243 Patients receiving methadone concomitantly with fosamprenavir should be carefully monitored and methadone dosage should be adjusted as necessary.217,243,275
Concomitant use of methadone and ritonavir-boosted fosamprenavir decreased the AUC of R -methadone by 18%.243,275 Opiate withdrawal is unlikely but may occur.243 Patients should be monitored for opiate withdrawal, and methadone dosage should be increased as clinically indicated.243
Indinavir
Concomitant use of methadone and indinavir does not appear to substantially affect exposure to either drug.284
Lopinavir
Concomitant use of methadone and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) decreased the AUC of methadone by 26-53%; opiate withdrawal symptoms may occur.222,243 Patients should be monitored closely for opiate withdrawal, and methadone dosage should be increased as clinically indicated.217,243
Maraviroc
No data are available regarding concomitant use of maraviroc and methadone.243 Some experts state that maraviroc is considered safe for use in patients receiving methadone.243
Nelfinavir
Concomitant use of methadone and nelfinavir may result in decreased plasma concentrations of methadone; opiate withdrawal occurs rarely.243 Individuals receiving concomitant methadone and nelfinavir therapy should be closely monitored for signs of opiate withdrawal; an increase in the maintenance dosage of methadone may be necessary.217,243
Nevirapine
There have been reports of opiate withdrawal and subtherapeutic or decreased serum methadone concentrations following initiation of nevirapine therapy in individuals who were receiving long-term methadone treatment for opiate addiction.222,232,242,244,245 nevirapine has been reported to decrease the AUC of methadone by 37-51%.243
Individuals receiving concomitant methadone and nevirapine therapy should be informed of this potential interaction, and should be closely monitored for signs of opiate withdrawal when nevirapine therapy is initiated; an increase in the maintenance dosage of methadone frequently is necessary.217,222,232,242,243,244,245 If methadone dosage is increased during nevirapine therapy, patients should be monitored for methadone overdosage when the antiretroviral agent is discontinued.244
Raltegravir
Concomitant use of methadone and raltegravir does not substantially affect plasma concentrations of either drug.243 Dosage adjustment is not necessary in patients receiving the drugs concomitantly.243
Rilpivirine
Rilpivirine has been reported to decrease the AUC of methadone by 16%.243 No dosage adjustment is necessary, but patients should be monitored for withdrawal symptoms.243
Ritonavir
Administration of a single 5-mg dose of methadone hydrochloride and ritonavir (500 mg every 12 hours for 15 days) decreased the AUC of methadone by 36%.240 There has been at least one report of opiate withdrawal and subtherapeutic or decreased serum methadone concentrations following initiation of ritonavir therapy in an HIV-infected patient who was receiving long-term methadone treatment for opiate addiction.222,232,235,241
Methadone should be administered with caution in patients receiving ritonavir, especially when used in combination with other drugs that may decrease plasma concentrations of methadone.222 Individuals receiving concomitant methadone and ritonavir therapy should be informed of this potential interaction, and should be closely monitored for manifestations of opiate withdrawal when ritonavir therapy is initiated; an increase in the maintenance dosage of methadone may be necessary.217,240,241 If methadone dosage is increased during ritonavir therapy, patients should be monitored for methadone overdosage when the antiretroviral agent is discontinued.241
Saquinavir
Concomitant use of methadone and ritonavir-boosted saquinavir decreased the AUC of R -methadone by 19%.243 Opiate withdrawal is unlikely but may occur.243 Patients should be monitored closely for opiate withdrawal, and methadone dosage should be increased as clinically indicated.217,243
Stavudine
Concomitant use of stavudine and methadone appears to decrease bioavailability of stavudine.222,232,249 In a limited number of individuals, concomitant use of stavudine and methadone resulted in a 44% decrease in peak concentrations and a 25% decrease in the AUC of stavudine; trough concentrations of methadone did not appear to be affected.217,243,249 Dosage adjustment is not necessary in patients receiving the drugs concomitantly.243
Tenofovir
Concomitant use of tenofovir and methadone does not appear to affect plasma concentrations of either drug.243
Tipranavir
Concomitant use of methadone and ritonavir-boosted tipranavir decreased peak plasma concentrations and AUC of R -methadone by 46 and 48%, respectively.243,266 Patients should be monitored closely for opiate withdrawal, and methadone dosage should be increased as clinically indicated.217,243,266
Zidovudine
In one study in IV drug abusers with HIV infection who were receiving long-term methadone hydrochloride treatment for opiate addiction (30-90 mg daily), initiation of zidovudine therapy (200 mg orally every 4 hours) did not appear to have any clinically important effects on the pharmacokinetics of methadone and did not result in any evidence of opiate withdrawal.238,239,253 However, the AUC of zidovudine was increased about 43% in patients receiving concomitant methadone compared with those receiving zidovudine alone.222,232,239,243,253 In another study in HIV-infected individuals who had been receiving methadone treatment for approximately 2 months, concomitant use of oral or IV zidovudine increased the zidovudine AUC by 29 or 41%, respectively, and reduced the clearance of zidovudine by about 26%.237,243 While the mechanism of this interaction requires further study, limited data indicate that methadone inhibits zidovudine glucuronidation and also reduces renal clearance of zidovudine.237
Based on the results of these studies, it appears that the maintenance dosage of methadone probably does not need to be adjusted when zidovudine therapy is initiated in patients receiving long-term methadone treatment; however, the clinical importance of the increased zidovudine AUC during concomitant therapy is unclear.237,239 Patients receiving concomitant zidovudine and methadone therapy should be monitored for dose-related zidovudine toxicity.237,239,243
Macrolide Antibiotics
Administration of macrolide anti-infectives that are known to inhibit CYP3A4 (e.g., clarithromycin, erythromycin, telithromycin) may result in decreased clearance of methadone.217,222,232 Patients receiving methadone concomitantly with macrolide anti-infectives should be carefully monitored and methadone dosage should be adjusted as necessary.217,222
Smoking
Some evidence indicates that cigarette smoking increases CYP1A2 activity and may reduce plasma methadone concentrations.235
St. John's Wort
Manifestations of opiate withdrawal may occur in patients receiving methadone and St. John's wort ( Hypericum perforatum ) concomitantly, since St. John's wort may increase metabolism of methadone via induction of CYP3A4.217,222 Patients receiving methadone concomitantly with St. John's wort should be carefully monitored, and methadone dosage should be adjusted as necessary.217
Concomitant use of methadone and St. John's wort also may result in serotonin syndrome.400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)
Benzodiazepines and Other CNS Depressants.
Concomitant use of opiate agonists, including methadone, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants, in the Opiate Agonists General Statement 28:08.08.) Concomitant use of opiate analgesics and other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Concomitant use with alcohol should be avoided.700
If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving methadone for analgesia, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a benzodiazepine or other CNS depressant, methadone, if required for analgesia, should be initiated at a reduced dosage and titrated based on clinical response.700,703
Because the morbidity and mortality associated with untreated opiate addiction can outweigh the serious risks associated with concomitant use of opiates and benzodiazepines or other CNS depressants, FDA states that methadone treatment for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be withheld from patients receiving benzodiazepines or other CNS depressants.706 Clinicians should develop treatment plans that minimize the risks associated with concomitant use.706 If possible, benzodiazepines or other CNS depressants should be tapered and discontinued.706 (See Cautions.)
Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Cautions.)
Drugs Associated with Serotonin Syndrome
Serotonin syndrome has occurred in patients receiving opiate agonists, including methadone, in conjunction with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT3 receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort, tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400
If concurrent therapy with opiate agonists and serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with methadone, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.400
For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.
Drugs that Prolong QT Interval
Drugs known to prolong the QT interval (e.g., class I or III antiarrhythmic agents, calcium-channel blocking agents, some antipsychotic agents, tricyclic antidepressants) should be used with extreme caution in patients receiving methadone because of the risk of severe and potentially life-threatening cardiac arrhythmias.217,222 Methadone also should be used with caution in patients receiving drugs (e.g., diuretics, laxatives, corticosteroid hormones with mineralocorticoid activity) that may result in electrolyte disorders (e.g., hypomagnesemia, hypokalemia) that may prolong the QT interval.217,222
Risperidone
There have been reports of opiate withdrawal following the initiation of risperidone therapy in patients receiving methadone.235,250
For further information about drug interactions involving opiate agonists (including methadone hydrochloride), see Drug Interactions in the Opiate Agonists General Statement 28:08.08.
Other Information ⬆ ⬇
Laboratory Test Interferences
Chlorpromazine, clomipramine, diphenhydramine, doxylamine, quetiapine, thioridazine, and verapamil may produce false-positive results for urine screening tests for methadone.217
Pharmacology
In equianalgesic doses, methadone hydrochloride may produce a similar or slightly greater degree of respiratory depression than does morphine sulfate. A single dose of methadone may produce less sedation and euphoria than does morphine; however, because of the cumulative effect of methadone, marked sedation occurs after repeated administration. Methadone causes less constipation than does morphine. Methadone has antitussive activity. Methadone inhibits cardiac potassium channels and prolongs the QT interval.217,222
Pharmacokinetics
Absorption
Methadone is well absorbed from the GI tract. Following oral administration, bioavailability is approximately 80%; however, there is considerable interindividual variability in oral bioavailability (range: 36-100%).217,223,232,235 Following IM or subcutaneous administration of a single dose of methadone, onset and duration of analgesic effect are similar to those of morphine; duration is approximately 4-8 hours. Oral administration delays the onset as compared to parenteral administration. Peak plasma concentrations of the drug occur 1-7.5 hours following oral administration.217 Steady-state plasma concentrations and full analgesic effects usually are not attained until completion of 3-5 days of therapy.217,222
With repeated methadone dosing, storage in and slow release of the drug from the liver and other tissues may prolong the duration of action of methadone despite the presence of low plasma concentrations.217,222 Peak respiratory depressant effects of methadone typically occur later and persist longer than the drug's peak analgesic effects, particularly during the early dosing period.217,222 The drug has an extended duration of action in patients who are physically dependent on oral methadone. Duration of action increases with repeated administration and is approximately 22-48 hours following oral administration in patients on methadone maintenance. Depressant effects after overdosage may also continue for 36-48 hours.
Distribution
Methadone is highly lipophilic and is widely distributed in body tissues.217,222,232,235 Because of its lipophilicity, methadone may persist in the liver and other tissues.217,222 Slow release of methadone from these sites may prolong the duration of action of the drug despite the presence of low plasma concentrations.217,222
Methadone is highly bound (85-90%) to plasma proteins, mainly α1-acid glycoprotein.217,222,232,235
Methadone crosses the placenta and is distributed into milk.217,222,235
Elimination
In clinical studies, the terminal elimination half-life of methadone ranged from 8-59 hours.217,222 In clinical use, the elimination half-life of methadone has varied considerably, ranging from 9-87 hours in postoperative patients, from 8.5-75 hours in opiate-dependent patients, and up to 120 hours in outpatients receiving therapy for chronic malignant pain.232 In one study in 5 patients receiving 100 or 120 mg of oral methadone hydrochloride daily for maintenance treatment of opiate addiction, the drug had an apparent plasma half-life of 13-47 hours, with an average of 25 hours.
Methadone is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzymes 3A4, 2B6, and 2C19 and to a lesser extent by CYP isoenzymes 2C9 and 2D6.217,222,232,235,251 The drug undergoes N -demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP), and other metabolites with little or no pharmacologic activity.217,222,232 Although methadone appears to be a substrate of the P-glycoprotein transport system, its pharmacokinetics do not appear to be substantially altered by P-glycoprotein polymorphism or inhibition.217
Methadone and its metabolites are excreted to varying degrees in urine and feces.217,222,232,235 Methadone is excreted by glomerular filtration and undergoes renal reabsorption. Reabsorption of methadone decreases as urinary pH decreases. Urinary excretion of methadone and its metabolic end products is dose dependent and comprises the major route of excretion only in dosages exceeding 55 mg daily. Methadone metabolites are also excreted in the feces via the bile.
Chemistry and Stability
Chemistry
Methadone hydrochloride is a synthetic diphenylheptane-derivative opiate agonist. The drug occurs as colorless crystals or a white, crystalline powder and is soluble in water and freely soluble in alcohol. Dispersible tablets of methadone hydrochloride are specially formulated with insoluble excipients to deter use of the drug by injection. Methadone hydrochloride injection has a pH of 3-6.5. Methadone hydrochloride oral concentrate has a pH of 1-6.
Stability
Methadone hydrochloride preparations should be stored in tight, light-resistant containers. Methadone hydrochloride oral concentrate and oral solution should be stored at 15-30°C; the tablets and injection should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.
Methadone hydrochloride injection has been reported to be physically or chemically incompatible with solutions containing aminophylline, ammonium chloride, amobarbital sodium, chlorothiazide sodium, phenytoin sodium, heparin sodium, methicillin sodium (no longer commercially available in the US), nitrofurantoin sodium, pentobarbital sodium, phenobarbital sodium, sodium bicarbonate, and thiopental sodium (no longer commercially available in the US). Specialized references should be consulted for more specific compatibility information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Methadone hydrochloride is subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug and, in addition, is subject to US Food and Drug Administration regulations (21 CFR 291.505) for drugs that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.
Distribution of methadone hydrochloride 40-mg dispersible tablets is restricted.271 (See Restricted Distribution under Dosage and Administration: Administration.)
Methadone Hydrochloride
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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