REMS: FDA approved a REMS for methadone under a shared REMS system (Opioid Analgesic REMS) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of methadone and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]). |
Methadone hydrochloride is a synthetic diphenylheptane-derivative opiate agonist and an N -methyl-D-aspartate (NMDA) receptor antagonist.1, 2, 3, 4, 5, 6, 757
Methadone hydrochloride is used in the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options (e.g., nonopioid analgesics, immediate-release opioid analgesics) are inadequate.1, 2, 4 The medication is commercially available in various dosage forms and formulations including oral tablets, oral solution, and an injection for IV, IM, or subcutaneous administration.1, 2, 4 Because of the risks of addiction, abuse, and misuse with opioids, which can occur with any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, use of methadone should be reserved for patients in whom alternative treatment options (e.g., nonopioid analgesics or immediate release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.1, 2, 4 Methadone is not indicated as an as-needed analgesic.1, 2, 4
When considering the use of methadone for chronic pain management, the benefits and risks of the drug should be carefully considered given its unique pharmacologic properties and adverse effects.414, 757 Clinical practice guidelines from the American Pain Society and other experts have been published to guide safe use of methadone and mitigate potential risks associated with the medication, including serious risks related to overdose and cardiac arrhythmias.295, 414 Experts generally agree that methadone should be prescribed for pain management only by clinicians knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetics,410, 412, 413, 414, 415 and should not be the first choice for an extended-release or long-acting opiate analgesic.415 Benefits associated with the use of methadone for management of chronic pain include the commercial availability of multiple dosage forms,232, 757 excellent oral bioavailability,228, 229, 757 rapid onset of action,228, 229 reduced dosing frequency (because of its long half-life),228, 232 low cost,228, 229, 232, 235, 757 and lack of active metabolites.228, 229, 232, 757 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.229, 231, 232, 235, 757 This incomplete cross-tolerance may allow for successful pain relief in patients who previously were refractory to or experienced adverse effects from increasing dosages of other opiate agonists.232, 235, 251 However, the unique pharmacologic and pharmacokinetic properties of methadone may result in safety issues such as an increased potential for accumulation with repeated doses (which may result in toxicity),228, 254 considerable interindividual variability in pharmacokinetic parameters,228, 229 potential for drug interactions,228, 232, 757 and challenges associated with methadone dosage titration and the transfer of patients from therapy with other opiate agonists to therapy with methadone.228, 757
Pain needs to be appropriately and effectively treated, regardless of whether opioids are part of the treatment regimen.760 Treatment should be individualized and patient-centered, and include multimodal approaches.760 There are multiple nonpharmacologic treatments (e.g., exercise, physical therapy, psychological therapies) and nonopioid medications (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, nonsteroidal anti-inflammatory agents [NSAIAs]) that have been shown to be at least as effective as opioids for many types of common pain conditions.760 These nonopioid treatments are generally preferred to opioids in most situations.760 If opioids are used, clinicians should carefully evaluate the risk of opioid-related harms and work with the patient to incorporate appropriate risk mitigation strategies into the treatment plan, including offering naloxone.760
The Centers for Disease Control and Prevention (CDC) clinical guideline for prescribing opioids for pain provides recommendations for the management of acute (duration <1 month), subacute (duration 1-3 months), and chronic (duration >3 months) pain in adults in the outpatient setting.760 The CDC guideline addresses the following areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use.760 Other clinical practice guidelines provide recommendations for the management of specific types of pain such as cancer-related pain and pain associated with palliative care; although specific recommendations for the management of opioid therapy vary across the guidelines, common elements include risk mitigation strategies, careful dosage titration, and consideration of risks and benefits.295, 759, 761
CDC guidelines state that in patients with chronic or subacute pain not associated with active cancer treatment, palliative care, or end-of-life care (also referred to as chronic noncancer pain), nonopioid therapies are preferred.760 There is insufficient evidence to determine the long-term benefits of opioid therapy for chronic pain, and there is an increased risk for serious harms related to long-term opioid therapy that appears to be dose dependent.760 Use of opioid analgesics for the management of chronic noncancer pain increased 4-fold in the US from 1999 to 2010, along with a parallel increase in overdose deaths, despite uncertainty over the long-term benefits of such therapy.760 In addition, evidence that opioid analgesics are superior to other pharmacologic or nonpharmacologic treatments for chronic pain generally is lacking.760 Opioid analgesics should be considered only if other pain management strategies (nonpharmacologic [e.g., exercise, physical therapy] and nonopioid drugs [e.g., NSAIAs for musculoskeletal pain; select antidepressants or anticonvulsants, gabapentinoids, lidocaine and capsaicin patches for neuropathic pain]) have been maximized as appropriate for the specific condition and patient, and the expected benefits of opioid analgesics are anticipated to outweigh the risks.760 If opioid analgesics are used, they should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies.760 The lowest effective dosage of an immediate-release preparation should be used.760 Clinicians should work with patients to establish treatment goals and also consider how opioid therapy will be discontinued if the benefits do not outweigh the risks.760
The benefits and risks of opioid analgesic therapy should be evaluated within 1-4 weeks following initiation of therapy or an increase in dosage, and reevaluated on an ongoing basis.760 Monitoring should include documentation of pain intensity and level of functioning, assessment of progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.423, 760 Common opioid-related adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment) should be anticipated and appropriately managed.415, 760
If opioids are continued for chronic or subacute pain, clinicians should use caution when prescribing opioids at any dosage and should generally avoid dosage increases when possible.760 Many patients do not experience benefit in pain or function from increasing opioid dosages to ≥50 morphine mg equivalent/day but are exposed to progressive increases in risk as dosage increases.760
Patients should be closely monitored for adverse effects and other risks of therapy, including opioid use disorder.760 Various strategies for managing risks associated with opioid therapy for chronic noncancer pain have been recommended, including written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state prescription drug monitoring program (PDMP) data, and risk assessment and monitoring tools.414, 415, 423, 760 Clinicians should offer or arrange treatment for patients with opioid use disorder.760
The American Society of Clinical Oncology (ASCO) guideline states that opioids should be offered to patients with moderate-to-severe pain associated with cancer or active cancer treatment, unless contraindicated.759 Prior to initiating opioid therapy, it is useful to assess the mechanism for the pain syndrome, the response to nonopioid analgesics (e.g., acetaminophen or NSAIAs), and the presence of risk factors such as a history of misuse of alcohol, recreational substances, or prescription drugs.759 Opioids should be initiated as an immediate-release formulation and as needed to establish an effective dosage.759 The lowest possible dosage should be used to achieve acceptable analgesia and patient goals, and patients should be assessed early with frequent dosage titration.759 In patients receiving opioids around the clock, an immediate-release opioid at a dose of 5-20% of the regular morphine equivalent daily dose should be prescribed for breakthrough pain.759 When opioids are no longer indicated, they should be weaned or tapered to discontinuation.759
Selection of the most appropriate opioid should be based on factors such as pharmacokinetic properties, including bioavailability, route of administration, half-life, neurotoxicity, and cost of the differing medications.759 Methadone has some potential clinical advantages, including potency, efficacy in neuropathic pain, use as a long-acting agent after crushing (for enteral feeding tube delivery), relative safety in patients with renal impairment, and low cost.759 However, because of its unique pharmacokinetic and pharmacodynamic properties, the ASCO guideline states that the medication should only be prescribed as a first- or second-line opioid by experienced clinicians.759 Clinicians with limited experience with methadone prescribing should consult palliative care or pain specialists when initiating or switching to methadone.759
Palliative care is defined as care that provides relief from pain and other symptoms, supports quality of life, and is focused on patients with serious advanced illness and their families.761 Palliative care may begin early in the course of treatment for a serious illness and be delivered in a number of ways across the continuum of health care settings, including in the home, nursing homes, long-term acute care facilities, acute care hospitals, and outpatient clinics.761 Palliative care guidelines address the use of opioids for pain management in this setting.761 The ongoing care of patients being treated with opioids for physical symptoms, such as pain and dyspnea, includes documentation of treatment goals, ongoing risk assessments for opioid misuse, and frequency of re-assessments.761 The interdisciplinary care team should regularly conduct pain assessments and evaluate the effectiveness of treatments after initiation and upon any changes to the therapeutic regimen.761 The guidelines also recommend that palliative care clinicians receive training on safe and appropriate use of opioids and how to assess risk for opioid use disorder, monitor for signs of opioid abuse and diversion, and manage pain in patients at risk for substance abuse.761 An expert consensus document developed by a panel of interprofessional hospice and palliative care experts provides specific guidance on the safe and effective management of methadone therapy in the hospice and palliative care setting, which includes recommendations on selection of appropriate candidates, dosing, titration, and monitoring.295
Methadone is used for opioid withdrawal management (e.g., detoxification) and maintenance treatment in individuals with opioid use disorder.1, 2, 3, 4, 5, 6, 264, 372 The medication is used to suppress withdrawal symptoms in patients who are dependent on short-acting opioids such as heroin, morphine, and codeine.1, 2, 3, 4, 5, 6, 264 Opioid withdrawal management refers to the process of withdrawing an individual from a specific psychoactive substance in a safe and effective manner, which includes management of intoxication states (e.g., detoxification).372 Maintenance treatment involves the use of an opioid agonist or partial agonist to mitigate the pathological pursuit of reward and/or relief and allows for remission of overt addiction-related problems; such therapy may be given on a temporary basis or continued lifelong.372 When used for the treatment of opioid use disorder, methadone should be used as a component of a comprehensive treatment plan that includes counseling and other behavioral therapies, and should be administered in accordance with federal regulations.1, 2, 3, 4, 5, 6, 372
Methadone is commercially available in various dosage forms and formulations for the treatment of opioid use disorder, including oral tablets, dispersible tablets, an oral solution (1 mg/mL or 2 mg/mL), and a 10 mg/mL oral concentrate; a parenteral formulation also is available for IV, IM, or subcutaneous administration when temporary treatment of opioid dependence is needed in patients unable to take oral medications.1, 2, 3, 4, 5, 6, 372 Methadone can only be dispensed in the US in oral form by an opioid treatment program (OTP) certified by SAMHSA, but may be provided in acute care settings under limited circumstances.1, 2, 3, 4, 5, 6, 372
Medications used in the treatment of opioid use disorder have been associated with reduced risk of overdose and deaths.760 Evidence-based treatment with these medications should be offered to all patients who meet criteria for opioid use disorder.372, 760 FDA-approved medications for the treatment of opioid use disorder include methadone (a full opioid agonist), buprenorphine (a partial opioid agonist), and naltrexone (an opioid antagonist).263, 760 These treatments differ based on the evidence supporting their use, requirement for withdrawal from opioids prior to treatment initiation, and treatment setting (e.g., opioid treatment program, or office-based or home-based setting).760 While methadone and buprenorphine are more widely used than naltrexone, do not require full withdrawal from opioids, and have stronger evidence for better outcomes, naltrexone can be an option for highly motivated persons who have completed or are able to complete withdrawal.760 Alpha-2 adrenergic agonists (e.g., lofexidine, clonidine) have been shown to be safe and effective for the management of opioid withdrawal; however, methadone and buprenorphine are more effective in reducing the symptoms of opioid withdrawal, in retaining patients in withdrawal management, and in supporting the completion of withdrawal management.372 When determining whether to use methadone, buprenorphine, or naltrexone, clinicians should consider the patient's preferences, past treatment history, current clinical condition, and treatment setting.372, 760 The American Society of Addiction Medicine (ASAM) recommends the use of methadone in patients who may benefit from daily dosing and supervision in an OTP, or for patients who do not respond to buprenorphine for the treatment of opioid use disorder.372
Methadone has been used to manage manifestations of neonatal opioid withdrawal† in neonates exposed to opioids in utero.350, 352, 353, 355, 357, 359, 771 Opioids 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, 368 Approximately 60-80% of neonates with neonatal opioid withdrawal may require pharmacologic treatment for symptoms.352, 359 While morphine has been used more extensively than other opiates for this condition,352, 357, 359, 360 some studies suggest that use of methadone or buprenorphine may be associated with shorter treatment duration and hospital stay compared with morphine.360, 361, 362, 363 However, additional studies are needed to establish optimal dosage schedules and preferred opiate medication 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 is recommended since this has been shown to improve overall response, including shorter hospital stay and duration 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 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
Dispensing and Administration Precautions
Methadone hydrochloride may be administered orally as tablets, solution, concentrated solution, or dispersible tablets.2, 3, 4, 5, 6 Methadone also may be administered parenterally by IV, IM, or subcutaneous injection.1
Abuse or misuse of methadone tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of methadone and can result in overdose and death.2 Preparations labeled for oral administration must not be injected.2, 3, 4, 5, 6
Methadone also has been administered rectally†235, 252 and by epidural injection†.235
Methadone hydrochloride is administered orally as a solution, a concentrated solution, immediate-release tablets, or dispersible tablets.2, 3, 4, 5, 6
Store tablets and oral solution at 20-25°C (excursions permitted between 15-30°C).2, 4, 5, 6 Store oral concentrate at 20-25°C.5 Store dispersible tablets at 25°C (excursions permitted between 15-30°C).3
Do not crush, chew, dissolve, snort, or inject the tablets, which can result in uncontrolled delivery of methadone and potentially overdose and death.2
Methadone hydrochloride dispersible tablets are intended for dispersion in a liquid prior to oral administration.3 The tablets should not be chewed or swallowed before dispersion.3 The dispersible tablets contain insoluble ingredients and must not be injected.3 The 40-mg dispersible tablets are used for detoxification and maintenance of opioid dependence.3 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, or other acidic fruit beverage immediately prior to administration.3 If any residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered.3 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.3
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 to at least 30 mL prior to administration.5, 6
Methadone hydrochloride injection may be administered IV, IM, or subcutaneously.1
Absorption of methadone following IM or subcutaneous injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.1
Store methadone injection at 20-25°C (excursions permitted between 15-30°C); protect from light.1
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, 151 For additional information on S4S (including updates that may be available), see [Web].151
Patient Population | Concentration Standards |
|---|---|
Adults | 1 mg/mL |
When selecting an initial dosage of methadone for management of pain, consideration should be given to the type, severity, and expected duration of the patient's pain; age, general condition, and medical status of the patient; concurrent medication therapy; and the acceptable balance between pain relief and adverse effects.1, 2, 4 In addition, in patients who are being transferred to methadone from other opioid therapy, consideration should be given to the daily dosage, potency, and specific characteristics (e.g., elimination half-life) of the previously administered opioid; adverse effects of and response to the previous regimen; degree of opioid tolerance; and the relative potency estimate used to calculate an equianalgesic dosage of methadone.1, 2, 4 Appropriate dosage selection and titration are essential to prevent overdosage.1, 2, 4
A high degree of opioid tolerance does not preclude the possibility of unintended methadone overdosage.1, 2, 4 Failure to individualize dosage has resulted in serious adverse effects, including death, in opioid-tolerant patients during conversion to methadone therapy.1, 2, 4 Overestimation of the methadone dosage when transferring patients from other opioids to methadone therapy can result in fatal overdosage with the first dose.1, 2, 4
Published equianalgesic dosage conversion ratios between methadone and other opioid agonists are imprecise.1, 2 Dose equivalencies that are obtained from commonly used tables generally are based on single-dose studies in patients who are not opioid-tolerant.1, 2 When transferring patients to methadone from other opioid agonist therapy, use of single-dose equivalency tables may overestimate dosage requirements for methadone during chronic therapy because methadone has a long elimination half-life and may accumulate with repeated doses.1, 2 Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opioid therapy.1, 2 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 opioid therapy at a lower morphine sulfate dosage and higher in those receiving prior therapy at a higher morphine sulfate dosage.1, 2
Regardless of the strategy employed to determine initial methadone dosage, methadone therapy is most safely initiated using small initial doses and gradual dosage adjustments.1, 2 Some clinicians recommend a transition period of at least 3 days for patients being transferred from therapy with another opioid agonist to therapy with methadone; during the transition period, the dosage of the previous opioid agonist is gradually tapered while the dosage of methadone is slowly increased.228, 236, 257, 258
As an analgesic, methadone should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.413, 431, 432, 435, 760 Reduced dosage is indicated in high-risk patients such as the very young, very old, or debilitated.1, 2, 3, 4, 5, 6 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, 760
When opioid 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.760 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423, 431
For the relief of moderate to severe pain, the manufacturer recommends a usual initial methadone dosage in opiate-nontolerant adults of 2.5-10 mg administered IV every 8-12 hours.1 Dosage may be increased as necessary to provide adequate analgesia, but should be increased slowly to avoid accumulation of the medication and potential toxicity.1 More frequent administration may be required during initiation of therapy in order to maintain adequate analgesia, but caution is necessary to avoid overdosage.1
In patients being switched from oral to parenteral methadone, parenteral methadone 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).1
When patients are transferred from chronic therapy with another oral or parenteral opioid to therapy with parenteral methadone, dosage must be selected carefully, since cross-tolerance between methadone and other opioid agonists is incomplete, dosage conversion ratios are imprecise, and substantial interindividual variability exists.1 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 sulfate.1 The manufacturer states that these estimates provide a safe starting point for opioid conversion; however, the IV methadone dosage obtained from these comparisons must be individualized (e.g., based on prior opioid use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).1 The total daily dosage should be administered in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.1 For patients being transferred from therapy with opioid agonists other than morphine, a comparative opioid agonist dosage table may be consulted to determine the equivalent morphine dosage.1
Baseline Total Daily Oral Morphine Sulfate Dosage | Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage) |
|---|---|
<100 mg | 10-15% |
100-300 mg | 5-10% |
300-600 mg | 4-6% |
600-1000 mg | 3-5% |
>1000 mg | <3% |
Baseline Total Daily Parenteral Morphine Sulfate Dosage | Estimated Daily IV Methadone Hydrochloride Dosage (as % of Total Daily Morphine Sulfate Dosage) |
|---|---|
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 sulfate ratio.
When oral methadone is used for severe, persistent pain in opioid-nontolerant adults who require a daily opioid analgesic for an extended period of time, therapy should be initiated with 2.5 mg every 8-12 hours.2 Dosage must be carefully individualized according to patient response.2 Dosage may be titrated to provide adequate analgesia, but should be increased slowly (no more frequently than every 3 to 5 days) to avoid accumulation of the drug and potential toxicity.2
In patients being switched from parenteral to oral methadone, oral methadone 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).2
When patients are transferred to oral methadone from chronic therapy with other oral or parenteral opioids, dosage must be selected carefully because cross-tolerance between methadone and other opioid agonists is incomplete, dosage conversion ratios are imprecise, and considerable interindividual variability exists.2 The dosage conversion method shown in Table 4 is based on comparison with morphine sulfate.2 The oral methadone hydrochloride dosage obtained from this comparison must be individualized (e.g., based on prior opioid use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).2 The total daily dosage should be administered in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.2 For patients being transferred from therapy with opioid agonists other than morphine, a comparative opioid agonist dosage table may be consulted to determine the equivalent morphine dosage.2
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 3-5 days with close monitoring to achieve adequate analgesia with minimal adverse effects.2 However, because of individual variability in the pharmacokinetic profile, some patients may require substantially longer periods between dose increases (up to 12 days).2 Patients who experience breakthrough pain may require dosage adjustment or rescue therapy with a small dose of an immediate-release analgesic.2 If excessive opiate-related adverse effects are observed, the next dose of methadone may be reduced; if adverse effects are intolerable, either the dose or dosing interval of the drug may be adjusted.2
If discontinuance of opiates is required, gradual tapering of the dosage is recommended to avoid manifestations of abrupt withdrawal.2 For patients on methadone tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks.2 Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.2
Detoxification and Maintenance of Opioid Dependence
For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.1, 2, 3, 4, 5, 6
For the treatment of opioid use disorder, methadone 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 accidental ingestion.263 Hospitalized patients being treated for a medical or surgical condition may receive methadone parenterally if necessary.1 The dosage of methadone used for detoxification or maintenance treatment should be adjusted to control abstinence symptoms without causing respiratory depression or marked sedation.2, 3, 4, 5, 6
If at any time during detoxification or maintenance the patient cannot tolerate oral medication because of nausea or vomiting associated with acute complicating illness, the patient should be hospitalized and methadone may be continued by the parenteral route.1 The patient's oral methadone dose should be converted to an equivalent parenteral dose.1
The initial methadone dose should be administered under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal.2, 3, 4, 5, 6 The initial dose of methadone should be based on the level of physical dependence of the patient.372 A single oral dose of 20-30 mg of methadone will often suppress withdrawal symptoms.2, 3, 4, 5 The initial dose should not exceed 30 mg.2, 3, 4, 5, 6 Initial doses should be lower (i.e., 2.5 to 10 mg) for patients whose tolerance is expected to be low at treatment initiation (e.g., patients transitioning from naltrexone, patients re-entering the community after residential treatment or incarceration [with no agonist treatment], patients re-initiating methadone after relapse).2, 3, 4, 5, 6, 372 Loss of tolerance should be considered if more than 5 days have elapsed since the patient took an opioid.2, 3, 4, 5, 6 Initial doses should not be based on those used during prior treatment episodes or on the patient's expenditures for illicit drugs or medication abuse/misuse.2, 3, 4, 5, 6 Additional doses of methadone may be necessary if withdrawal symptoms are not suppressed or if they reappear.2, 3, 4, 5, 6 If same-day dosage adjustments are to be made, the patient should be reevaluated 2-4 hours after the previous dose, when peak plasma concentrations of methadone will have been attained.2, 3, 4, 5, 6 If an additional dose is required to suppress withdrawal symptoms, an additional 5-10 mg of methadone may be administered.2, 3, 4, 5, 6 The total daily dose on the first day should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.2, 3, 4, 5, 6
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 dose).2, 3, 4, 5, 6 Dosage adjustments should be cautious, in order to avoid overdosage.2, 3, 4, 5, 6 With continued dosing, symptoms will be suppressed for longer periods of time as the drug accumulates in body tissues.2, 3, 4, 5, 6 For short-term detoxification, when the patient has been stabilized (i.e., substantial symptoms of withdrawal are absent) for 2 or 3 days, dosage of methadone can be gradually decreased daily or at 2-day intervals.2, 3, 4, 5, 6 Dosage must be individualized and adjusted to keep withdrawal symptoms at a tolerable level.2, 3, 4, 5, 6 In hospitalized patients, dosage can usually be reduced by 20% daily, but a more gradual reduction may be required in ambulatory patients.2, 3, 4, 5, 6
Dosage should be titrated to a level at which opioid 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.2, 3, 4, 5, 6 Some clinicians state that trough and peak plasma levels of methadone (or methadone blood levels) may be used in addition to clinical evaluation to assess the safety and adequacy of a patient's dose, particularly in patients who may be rapid metabolizers and may need a split dose.372 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.2, 3, 4, 5, 6 Although a few patients may respond to a maintenance dosage of 30-60 mg daily, most patients have better outcomes if their initial dose is gradually increased to a maintenance dosage of 60-120 mg daily, which typically creates sufficient tolerance to minimize a euphoric response if patients self-administer additional opioids.372 A single dose of methadone daily usually adequately maintains the patient and there generally is no apparent advantage to divided doses.2, 3, 4, 5, 6 However, rapid metabolizers of methadone may not maintain adequate plasma methadone concentrations with usual dosing regimens.206, 207, 208, 210
Maintenance dosage requirements should be reviewed regularly and reduced as indicated.2, 3, 4, 5, 6 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.2, 3, 4, 5, 6
For the management of neonatal opioid withdrawal†, use standardized protocols that base initiation, adjustment, and tapering of methadone dosage on standardized patient assessments performed at regular intervals.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.294, 352, 355, 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, 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 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
Some protocols are based on pharmacokinetic modeling of methadone in neonates and utilize a stepwise approach for dosage escalation and tapering.293, 294 Under such protocols, methadone 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 medication has been reduced to 0.01 mg/kg once daily.293, 294 The medication may then be discontinued.293, 294 Such protocols increase early exposure to the medication,293, 294 and limited experience suggests that such an approach may allow for shorter treatment duration and hospital stay.293 Other clinicians have recommended administration of methadone 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 Specialized protocols should be consulted for further information on methadone dosage and monitoring of Finnegan scores in neonates with opioid withdrawal syndrome. Further studies are needed to define optimal dosing strategies.293
Methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency.1, 2, 3, 4, 5, 6 Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing.1, 2, 3, 4, 5, 6 Initiate these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and CNS depression.1, 2, 3, 4, 5, 6
Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency.1, 2, 3, 4, 5, 6 Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, initiate these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and CNS depression.1, 2, 3, 4, 5, 6
Elderly patients (65 years of age or older) may have increased sensitivity to methadone.1, 2, 3, 4, 5, 6 In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.1, 2, 3, 4, 5, 6
Respiratory depression is the primary risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respirations.1, 2, 3, 4, 5, 6 Titrate the dosage of methadone slowly in geriatric patients and frequently reevaluate the patient for signs of CNS and respiratory depression.1, 2, 3, 4, 5, 6
Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this medication may be greater in patients with impaired renal function.1, 2, 3, 4, 5, 6 Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.1, 2, 3, 4, 5, 6
As an opioid agonist, methadone exposes users to the risks of addiction, abuse, and misuse.1, 2, 3, 4, 5, 6 A boxed warning about this risk has been included in the prescribing information for methadone.1, 2, 3, 4, 5, 6 Although the risk of addiction in any individual is unknown, it can occur in patients with appropriate prescribing.1, 2, 4
Abuse or misuse of methadone tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of methadone and can result in overdose and death.2 Preparations labeled for oral administration must not be injected.3, 5, 6
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing methadone and reassess all patients receiving the medication for the development of these behaviors or conditions.1, 2, 4 Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).1, 2, 4 The potential for these risks should not, however, prevent the proper management of pain in any given patient.1, 2, 4 Patients at increased risk may be prescribed opioids such as methadone but use in such patients necessitates intensive counseling about the risks and proper use along with frequent reevaluation for signs of addiction, abuse, and misuse.1, 2, 4
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use; consider these risks when prescribing or dispensing methadone.1, 2, 4 Strategies to reduce these risks include prescribing the medication in the smallest appropriate quantity and advising the patient on careful storage during treatment and proper disposal of unused medication.1, 2, 4 Contact state professional licensing boards or state-controlled substances authority for information on how to prevent and detect abuse or diversion.1, 2, 4
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.1, 2, 3, 4, 5, 6 A boxed warning about this risk has been included in the prescribing information for methadone.1, 2, 3, 4, 5, 6 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.1, 2, 3, 4, 5, 6 Accidental ingestion of even one dose of methadone, especially by children, can result in respiratory depression and death due to an overdose.2, 3, 4, 5, 6 Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status.1, 2, 3, 4, 5, 6 Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.1, 2, 3, 4, 5, 6
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone, the risk is greatest during initiation of therapy or following a dosage increase.1, 2, 3, 4, 5, 6 The peak respiratory depressant effect of methadone occurs later and persists longer than the peak pharmacologic effect, especially during the initial dosing period.1, 2, 3, 4, 5, 6 The full analgesic effect usually is not attained for 3-5 days and may take longer in some patients.2, 4
Monitor patients closely for respiratory depression, especially when initiating therapy and following dosage increases.1, 2, 3, 4, 5, 6 To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential.1, 2, 3, 4, 5, 6 Overestimating the dosage when converting patients from another opioid agonist can result in a fatal overdose with the first dose.1, 2, 3, 4, 5, 6 Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical assistance immediately in the event of a known or suspected overdose.2, 3, 4, 5, 6 Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone.2, 3, 4, 5, 6
Opioid agonists can cause sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia.1, 2, 3, 4, 5, 6 Opioid use increases the risk of central sleep apnea in a dose-dependent fashion.1, 2, 3, 4, 5, 6 In patients with central sleep apnea, consider decreasing the methadone dosage using best practices for an opioid taper.1, 2, 3, 4, 5, 6
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from concomitant use of methadone with benzodiazepines and/or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).1, 2, 3, 4, 5, 6 A boxed warning regarding this risk has been included in the prescribing information for methadone.1, 2, 3, 4, 5, 6 Because of these risks, reserve concomitant prescribing of these medications for use in patients for whom alternative treatment options are inadequate.1, 2, 4
Clinical studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increased the risk of drug-related mortality compared to use of opioid analgesics alone.1, 2, 3, 4, 5, 6 Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.1, 2, 4
If concomitant use of a benzodiazepine or other CNS depressant with methadone is necessary for patients being treated for pain, prescribe the lowest effective dosages and minimum duration of concomitant use.1, 2, 4 In patients already receiving methadone, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.1, 2, 4 If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.1, 2, 4 In clinical settings, monitor patients closely for signs and symptoms of respiratory depression and sedation.1 For ambulatory use, inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).2, 4 If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.2, 4 Advise both patients and caregivers about the risks of respiratory depression and sedation when methadone is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).2, 4
For patients treated for opioid addiction, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol as a routine part of orientation to methadone treatment.2, 3, 4, 5, 6 Medication-assisted treatment of opioid use disorder should not be categorically denied to patients taking these medications as prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.2, 3, 4, 5, 6 Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment.2, 3, 4, 5, 6 There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients.2, 3, 4, 5, 6 However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation, and delays or omits the methadone dose if appropriate.2, 3, 4, 5, 6 Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.2, 3, 4, 5, 6 In some cases, monitoring in a higher level of care for taper may be appropriate while in others, gradually tapering a patient off a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.2, 3, 4, 5, 6 For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia.2, 3, 4, 5, 6 Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia.2, 3, 4, 5, 6 Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's methadone treatment and coordinate care to minimize the risks associated with concomitant use.2, 3, 4, 5, 6 If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose2, 3, 4, 5, 6 In addition, confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs via toxicology screening.2, 3, 4, 5, 6
Life-threatening QT Prolongation
Cases of QT interval prolongation and serious arrhythmias, including torsades de pointes, have been observed during treatment with methadone and a boxed warning has been included in the prescribing information for the medication about this risk.1, 2, 3, 4, 5, 6, 233, 234 These cases appear to be more commonly associated with, but not limited to, higher dose treatment (>200 mg/day).1, 2, 3, 4, 5, 6 Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.1, 2, 3, 4, 5, 6 In most patients on lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors.1, 2, 3, 4, 5, 6 However, evidence strongly suggests methadone possesses the potential for adverse cardiac conduction effects in some patients.1, 2, 3, 4, 5, 6 The effects of methadone on the QT interval have been confirmed in vivo , and methadone has been shown to inhibit cardiac potassium channels in vitro .1, 2, 3, 4, 5, 6
Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction.1, 2, 3, 4, 5, 6 QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.1, 2, 3, 4, 5, 6
Evaluate patients who develop QT prolongation while on methadone treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, medications that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism.1, 2, 3, 4, 5, 6
Only initiate methadone therapy for pain or opioid addiction in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone.1, 2, 3, 4, 5, 6
The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.1, 2, 3, 4, 5, 6
Neonatal Opioid Withdrawal Syndrome
Use of methadone for an extended period of time during pregnancy can result in withdrawal in the neonate. 1, 2, 3, 4, 5, 6 A boxed warning about this risk has been included in the prescribing information for methadone.1, 2, 3, 4, 5, 6 Unlike opioid withdrawal syndrome in adults, neonatal opioid withdrawal syndrome may be life-threatening if not recognized and treated in the neonate.1, 2, 3, 4, 5, 6 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.1, 2, 3, 4, 5, 6 Advise pregnant females using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.1, 2, 3, 4, 5, 6
The risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone therapy may differ based on the risks associated with the mother's underlying condition, pain or addiction, and the risks of alternative treatments.1, 2, 3, 4, 5, 6
When methadone is used for the treatment of pain, prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options.1, 2, 3, 4, 5, 6
Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.1, 2, 3, 4, 5, 6 Methadone is recommended as a treatment of opioid use disorder during pregnancy.350
Risks of Concomitant Use or Discontinuation of Cytochrome P450 Inhibitors and Inducers
Concomitant use of methadone with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors may increase plasma concentrations of methadone, prolong opioid adverse reactions, and cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of methadone is achieved.1, 2, 3, 4, 5, 6 Discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression.1, 2, 3, 4, 5, 6 A boxed warning about these risks has been included in the prescribing information for methadone.1, 2, 3, 4, 5, 6 Consider dosage reduction of methadone when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and evaluate patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.1, 2, 3, 4, 5, 6
The addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with methadone may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone.1, 2, 3, 4, 5, 6 When using methadone with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, assess patients for signs or symptoms of opioid withdrawal and consider increasing the methadone dosage as needed.1, 2, 3, 4, 5, 6
Risk of Accidental Overdose and Death due to Medication Errors
Accidental ingestion of even one dose of methadone, especially by children, can result in fatal overdosage.2, 3, 4, 5, 6 The prescribing information for methadone contains a boxed warning regarding this risk.2, 3, 4, 5, 6
Dosing errors can result in accidental overdose and death.4 Avoid dosing errors that may result from confusion between mg and mL and with methadone solutions of different concentrations, when prescribing, dispensing, and administering methadone oral solution.4 Ensure that the dose is communicated clearly and dispensed accurately.4
Instruct patients and caregivers on how to measure and administer the correct dose of methadone hydrochloride oral solution and to use extreme caution when measuring the dose.4 Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices.4
Other Warnings and Precautions
Opioid-Induced Hyperalgesia and Allodynia
Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain; however, this condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.1, 2, 3, 4, 5, 6 Symptoms of OIH may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).1, 2, 3, 4, 5, 6 Evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior should be ruled out to suggest a diagnosis of OIH based on these symptoms.1, 2, 3, 4, 5, 6
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.1, 2, 3, 4, 5, 6 Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.1, 2, 3, 4, 5, 6 There is evidence suggesting a strong biologic plausibility between opioid analgesics and OIH and allodynia.1, 2, 3, 4, 5, 6 If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or safely switch the patient to a different opioid medication.1, 2, 3, 4, 5
Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of methadone with serotonergic drugs.1, 2, 3, 4, 5, 6 Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, medications that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and medications that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).1, 2, 3, 4, 5, 6 This may occur within the recommended dosage range.1, 2, 3, 4, 5, 6
Serotonin syndrome symptoms 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).1, 2, 3, 4, 5, 6 The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later.1, 2, 3, 4, 5, 6 Discontinue methadone if serotonin syndrome is suspected.1, 2, 3, 4, 5, 6
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of methadone in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.1, 2, 3, 4, 5, 6 Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression receiving methadone are at increased risk of decreased respiratory drive including apnea, even at recommended dosages.2, 3, 4, 5, 6
Life-threatening respiratory depression is also more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.2, 3, 4, 5, 6
Regularly evaluate or monitor patients, particularly when initiating and titrating methadone and when given concomitantly with other medications that depress respiration; consider patient access to naloxone as well.2, 3, 4, 5, 6 Alternatively, consider the use of non-opioid analgesics in these patients.2, 4
Cases of adrenal insufficiency have been reported with opioid use, generally after more than 1 month of use.1, 2, 3, 4, 5, 6 Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.1, 2, 3, 4, 5, 6 If adrenal insufficiency is suspected, confirm the diagnosis as soon as possible.1, 2, 3, 4, 5, 6 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.1, 2, 3, 4, 5, 6 Wean the patient from methadone to allow adrenal function to recover and continue corticosteroid treatment until recovery.1, 2, 3, 4, 5, 6 Use of opioids other than methadone may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.1, 2, 3, 4, 5, 6 Current evidence does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.1, 2, 3, 4, 5, 6
Methadone may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.1, 2, 3, 4, 5, 6 There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant medications (e.g., phenothiazines, general anesthetics).1, 2, 3, 4, 5, 6 Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of methadone.1, 2, 3, 4, 5, 6 In patients with circulatory shock, methadone may cause vasodilation that can further reduce cardiac output and blood pressure; avoid use in such patients.1, 2, 3, 4, 5, 6
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure or brain tumors), methadone may reduce respiratory drive, and the resultant carbon dioxide retention can further increase intracranial pressure.1, 2, 3, 4, 5, 6 Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy.1, 2, 3, 4, 5, 6
Opioids may also obscure the clinical course in patients with head injuries.1, 2, 3, 4, 5, 6 Avoid the use of methadone in patients with impaired consciousness or coma.1, 2, 3, 4, 5, 6
Risks of Use in Patients with GI Conditions
Methadone is contraindicated in patients with GI obstruction, including paralytic ileus, as the medication may cause spasm of the sphincter of Oddi.1, 2, 3, 4, 5, 6 Opioids may cause increases in serum amylase.1, 2, 3, 4, 5, 6 Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.1, 2, 3, 4, 5, 6
Increased Risk of Seizures in Patients with Seizure Disorders
Methadone may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures.1, 2, 3, 4, 5, 6 Regularly evaluate patients with a history of seizure disorders for worsened seizure control during methadone therapy.1, 2, 3, 4, 5, 6
Do not abruptly discontinue methadone in a patient physically dependent on opioids, but rather gradually taper the dosage.1, 2, 3, 4, 5, 6 Rapid tapering in a physically dependent patient may lead to withdrawal symptoms and return of pain.1, 2, 3, 4, 5, 6 Avoid use of mixed opioid agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial opioid agonist (e.g., buprenorphine) analgesics in patients receiving a full opioid agonist analgesic, such as methadone.1, 2, 3, 4, 5, 6 In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.1, 2, 3, 4, 5, 6
Risks of Driving and Operating Machinery
Methadone may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.1, 2, 3, 4, 5, 6 Advise patients not to drive or operate dangerous machinery unless they are tolerant to the effects of methadone and know how they will react to the medication.1, 2, 3, 4, 5, 6
Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization.1, 2, 3, 4, 5, 6 In many cases, patients had predisposing risk factors (e.g., diabetes).1, 2, 3, 4, 5, 6 The relationship between methadone and hypoglycemia is not fully understood but may be dose dependent.1, 2, 3, 4, 5, 6 If hypoglycemia is suspected, monitor blood glucose levels, and manage the patient as clinically appropriate.1, 2, 3, 4, 5, 6
False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.1, 2, 3, 4, 5, 6
Most available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone.1, 2, 3, 4, 5, 6 Based on findings from animal studies, advise pregnant females of the potential risk to a fetus.1, 2, 3, 4, 5, 6
Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome (SIDS) have been inconsistent.1, 2, 3, 4, 5, 6 Children who were exposed to methadone in utero have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities.1, 2, 3, 4, 5, 6
Untreated opioid addiction during pregnancy is associated with adverse obstetrical outcomes, including preeclampsia, fetal growth restriction, preterm birth, spontaneous abortion, and fetal death.1, 2, 3, 4, 5, 6 In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use and engagement in high-risk behaviors.1, 2, 3, 4, 5, 6 Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs.1, 2, 3, 4, 5, 6 Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure in these studies appears to occur after the first trimester of pregnancy.1, 2, 3, 4, 5, 6
In a double-blind, randomized controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]), opioid withdrawal effects were assessed in neonates born to females who received methadone or buprenorphine treatment for opioid dependence during pregnancy.1, 2, 3, 4, 5, 6, 370, 371 Enrollment in the study occurred at an average gestational age of 18.7 weeks.1, 2, 3, 4, 5, 6, 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.1, 2, 3, 4, 5, 6, 370, 371 No difference was observed between methadone- and buprenorphine-exposed neonates in the proportion of neonates requiring treatment for opioid withdrawal syndrome or the peak severity of the syndrome.1, 2, 3, 4, 5, 6, 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.1, 2, 3, 4, 5, 6, 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.1, 2, 3, 4, 5, 6, 370, 371 The imbalance in treatment discontinuance rates between methadone- and buprenorphine-treated women complicate interpretation of the study findings.1, 2, 3, 4, 5, 6, 371
Pharmacokinetic data from a limited number of pregnant females suggest that methadone clearance may be increased, trough plasma concentrations of the medication may be lower, and half-life of the medication may be decreased during the second and third trimesters of pregnancy compared with pharmacokinetic values determined for the same females postpartum or for nonpregnant opioid-dependent females.1, 2, 3, 4, 5, 6 If methadone is used during pregnancy, dosage adjustment (i.e., increased dose or decreased dosing interval) may be necessary.1, 2, 3, 4, 5, 6
Methadone has been detected in umbilical cord plasma and amniotic fluid.1, 2, 3, 4, 5, 6
Opioid-dependent females on methadone maintenance therapy may require additional analgesia during labor.1, 2, 3, 4, 5, 6 Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.1, 2, 3, 4, 5, 6
Prolonged maternal use of opioid agonists during pregnancy can result in neonatal opioid withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.1, 2, 3, 4, 5, 6 Females who require prolonged opioid agonist therapy during pregnancy should be advised of the risk of neonatal opioid withdrawal syndrome, and availability of appropriate treatment should be ensured.1, 2, 3, 4, 5, 6 The onset, duration, and severity of the syndrome vary depending on the specific opioid agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.1, 2, 3, 4, 5, 6, 355, 357 Withdrawal signs and symptoms should be closely monitored in a newborn and managed accordingly.1, 2, 3, 4, 5, 6
Methadone is distributed into human milk.1, 2, 3, 4, 5, 6, 280, 285 Peak concentrations in milk reportedly occur approximately 4-5 hours after an oral dose of the medication.1, 2, 3, 4, 5, 6 In 2 studies in 22 nursing females who were receiving methadone maintenance treatment, methadone was present in low concentrations (delivering approximately 2-3% of the maternal dose to the breast-fed infant) in milk, but no adverse effects on breast-fed infants were observed.1, 2, 3, 4, 5, 6 Methadone has been detected in very low plasma concentrations in some infants whose mothers were receiving methadone.1, 2, 3, 4, 5, 6, 285 Cases of sedation and respiratory depression in infants exposed to methadone through breast milk have been reported rarely.1, 2, 3, 4, 5, 6
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, 760 In individuals receiving methadone for opioid use disorder and considering breastfeeding, CDC recommends that breastfeeding be supported if there has been no return to drug use for ≥90 days and there are no other contraindications; considered if there has been no return to drug use within 30-90 days; and discouraged if there is active substance use or a return to drug use within the last 30 days.760
The manufacturers state that the benefits of breast-feeding should be considered along with the mother's clinical need for the medication and any potential adverse effects on the breast-fed infant from either the medication or the underlying maternal condition.1, 2, 3, 4, 5, 6 Females who are receiving methadone and are breast-feeding or wish to breast-feed should be advised that the medication 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 in the infant.2, 4, 5, 6
Females and Males of Reproductive Potential
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential.1, 2, 3, 4, 5, 6 It is not known whether these effects on fertility are reversible.1, 2, 3, 4, 5, 6 In animal studies, methadone administration produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring.1, 2, 3, 4, 5, 6
The manufacturers state that safety, efficacy, and pharmacokinetics of methadone in pediatric patients younger than 18 years of age have not been established.1, 2, 3, 4, 5, 6
Patients 65 years of age or older may have increased sensitivity to methadone.1, 2, 3, 4, 5, 6 In general, use caution when selecting dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other medication therapy.1, 2, 3, 4, 5, 6
Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after administration of large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other medications that depress respiration.1, 2, 3, 4, 5, 6 Titrate the dosage of methadone slowly in geriatric patients and frequently reevaluate the patient for signs of CNS and respiratory depression.1, 2, 3, 4, 5, 6 Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this medication may be greater in patients with impaired renal function.1, 2, 3, 4, 5, 6 Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; regular evaluation of renal function should occur.1, 2, 3, 4, 5, 6
The pharmacokinetics of methadone have not been extensively evaluated in patients with hepatic impairment.1, 2, 3, 4, 5, 6 Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing.1, 2, 3, 4, 5, 6 Initiate treatment with lower doses and titrate slowly while carefully monitoring for signs of CNS and respiratory depression.1, 2, 3, 4, 5, 6
The pharmacokinetics of methadone have not been extensively evaluated in patients with renal impairment; however, unmetabolized methadone and its metabolites are excreted in urine to a variable degree.1, 2, 3, 4, 5, 6 Initiate treatment with lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of CNS and respiratory depression.1, 2, 3, 4, 5, 6
Pharmacogenomic Considerations
Genetic variations in CYP2D6 , OPRM1 (the gene coding the mu opioid receptor mu1), and COMT (the enzyme responsible for the methylconjugation of catecholamines) can influence the clinical effect or adverse effects of some opioid analgesics.774 The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines for selected opioid analgesics based on these genotypes.774 Although methadone is metabolized by CYP2D6 to some extent, CYP2D6 genotype does not appear to affect adverse effects, dosing requirements, or analgesic effects of the medication.774 CPIC states that there is insufficient evidence and confidence to provide a recommendation to guide clinical practice at this time for methadone based on CYP2D6 genotype.774 In addition, there is insufficient evidence to support any therapeutic recommendations for dosing opioids, such as methadone, based on either OPRM1 or COMT .774
Common adverse effects reported in adults receiving methadone include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.1, 2, 3, 4, 5, 6
Methadone is metabolized principally by the cytochrome P-450 (CYP) microsomal enzyme system, mainly by isoenzymes 3A4, 2B6, 2C19, 2C9 and 2D6.1, 2, 3, 4, 5, 6, 232, 235, 251
Methadone appears to be a P-glycoprotein (P-gp) substrate, but pharmacokinetics are not substantially altered by P-gp inhibition.2, 3, 4
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of methadone with medications that induce CYP isoenzymes may result in increased metabolism and decreased plasma concentrations of methadone.1, 2, 3, 4, 5, 6 After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.1, 2, 3, 4, 5, 6 If concomitant use is necessary, consider increasing the methadone dosage until stable drug effects are achieved.1, 2, 3, 4, 5, 6 Monitor for signs of opioid withdrawal.1, 2, 3, 4, 5, 6 If a CYP3A4, CYP2B6, CYP2C19, orCYP2C9 inducer is discontinued, consider methadone dosage reduction and monitor for signs of respiratory depression and sedation.1, 2, 3, 4, 5, 6 Medications that induce CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 include rifampin, carbamazepine, phenytoin, St. John's Wort, and phenobarbital.1, 2, 3, 4, 5, 6
Conversely, administration of methadone with medications that inhibit CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 may result in decreased metabolism and increased plasma concentrations of methadone.1, 2, 3, 4, 5, 6 After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease, resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.1, 2, 3, 4, 5, 6 If concomitant use is necessary, consider dosage reduction of methadone until stable medication effects are achieved.1, 2, 3, 4, 5, 6 Monitor patients for respiratory depression and sedation at frequent intervals.1, 2, 3, 4, 5, 6 If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone dosage until stable medication effects are achieved.1, 2, 3, 4, 5, 6 Medications that inhibit CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 include macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), and some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine).1, 2, 3, 4, 5, 6
Numerous drug interactions have been reported in patients receiving antiretroviral agents concomitantly with methadone due to CYP3A4 inhibition.1, 2, 3, 4, 5, 6, 243 Clinicians should monitor patients carefully for potential adverse effects when antiretroviral agents are used concomitantly with methadone.1, 2, 3, 4, 5, 6
Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir/ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir, has resulted in increased clearance or decreased plasma levels of methadone.1, 2, 3, 4, 5, 6, 243, 244, 245, 247, 249 This may result in reduced efficacy of methadone tablets and could precipitate a withdrawal syndrome.1, 2, 3, 4, 5, 6 Monitor methadone-maintained patients receiving any of these antiretroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly.1, 2, 3, 4, 5, 6
Pharmacokinetic evidence demonstrated that methadone increased the exposure of zidovudine, which could result in toxic effects.1, 2, 3, 4, 5, 6
Some evidence indicates that cigarette smoking increases CYP1A2 activity and may reduce plasma methadone concentrations.235, 773
Concomitant use of opiate agonists and CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.235, 700, 701, 702, 703
Concomitant use of anticholinergic medications may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.1, 2, 3, 4, 5, 6
Evaluate patients for signs of urinary retention or reduced gastric motility when methadone is concomitantly with anticholinergic medications.1, 2, 3, 4, 5, 6
Benzodiazepines and Other CNS Depressants
Concomitant use of opioid agonists, including methadone, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.1, 2, 3, 4, 5, 6 Concomitant use of opiate analgesics and other CNS depressants for the management of pain 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.1, 2, 3, 4, 5, 6 Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments.1, 2, 3, 4, 5, 6
In patient being treated for opioid addiction, cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.1, 2, 3, 4, 5, 6 In some cases, monitoring in a higher level of care for taper may be appropriate.1, 2, 3, 4, 5, 6 In others, gradually tapering a patient from a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.1, 2, 3, 4, 5, 6
Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments.1, 2, 3, 4, 5, 6 If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose.1, 2, 3, 4, 5, 6
Opioids such as methadone can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.1, 2, 3, 4, 5, 6 Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.1, 2, 3, 4, 5, 6
Medications 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 (TCAs), 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).1, 2, 3, 4, 5, 6, 400 Serotonin syndrome may occur within the recommended dosage ranges for these medications.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).1, 2, 3, 4, 5, 6, 400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.1, 2, 3, 4, 5, 6, 400
If concurrent therapy with opiate agonists and serotonergic medications is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.1, 2, 3, 4, 5, 6, 400 If serotonin syndrome is suspected, treatment with methadone, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.1, 2, 3, 4, 5, 6, 400
Medications that Prolong QT Interval
Medications known to prolong the QT interval (e.g., class I or III antiarrhythmic agents, calcium-channel blocking agents, and some antipsychotic agents and TCAs) should be used with extreme caution in patients receiving methadone because of the risk of severe and potentially life-threatening cardiac arrhythmias.1, 2, 3, 4, 5, 6 Methadone also should be used with caution in patients receiving medications (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.1, 2, 3, 4, 5, 6 If used concomitantly, monitor patients closely for cardiac conduction changes.1, 2, 3, 4, 5, 6
Monoamine Oxidase Inhibitors (MAOIs)
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).1, 2, 3, 4, 5, 6 The use of methadone is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.1, 2, 3, 4, 5, 6
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist and partial agonist opioid analgesics such as butorphanol, nalbuphine, pentazocine, and buprenorphine may reduce the analgesic effect of methadone and/or precipitate withdrawal symptoms.1, 2, 3, 4, 5, 6 Avoid concomitant use.1, 2, 3, 4, 5, 6
Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression.1, 2, 3, 4, 5, 6
Because respiratory depression may be greater than otherwise expected, decrease the dosage of methadone and/or the muscle relaxant as necessary.1, 2, 3, 4, 5, 6 Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose.1, 2, 3, 4, 5, 6
Methadone is a synthetic diphenylheptane-derivative opioid agonist.757 Methadone is selective for the mu-receptor and may also act as an antagonist at the N -methyl-d-aspartate (NMDA) receptor.1, 2, 3, 4, 5, 6, 757
Methadone has multiple actions qualitatively similar to those of morphine, the most prominent of which involves the CNS and organs composed of smooth muscle.1, 2, 3, 4, 5, 6 The principal therapeutic action of methadone is analgesia; methadone is also used therapeutically for detoxification and maintenance in opioid addiction.1, 2, 3, 4, 5, 6 Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of the medication.1, 2, 3, 4, 5, 6 The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that onset is slower, course is more prolonged, and symptoms are less severe.1, 2, 3, 4, 5, 6
Methadone is well absorbed from the GI tract; peak plasma concentrations occur 1-7.5 hours after oral administration.2, 3, 4, 5, 6 There is considerable interindividual variability in oral bioavailability (range: 36-100%) of methadone.2, 3, 4, 5, 6 The effect of food on bioavailability has not been established.2, 3, 4, 5, 6 Steady-state plasma concentrations and full analgesic effects usually are not attained until completion of 3-5 days of therapy.2, 3, 4, 5, 6 With repeated methadone dosing, storage in and slow release of the medication from the liver and other tissues may prolong the duration of action of methadone despite the presence of low plasma concentrations.1, 2, 3, 4, 5, 6 Peak respiratory depressant effects of methadone typically occur later and persist longer than peak analgesic effects, particularly during the early dosing period.1, 2, 3, 4, 5, 6 Methadone is highly lipophilic and is widely distributed in body tissues.1, 2, 3, 4, 5, 6 Methadone is bound (85-90%) to α1-acid glycoprotein.1, 2, 3, 4, 5, 6 Methadone is extensively metabolized by N -demethylation, principally by cytochrome P-450 (CYP) isoenzymes 3A4, 2B6, 2C19, 2C9 and 2D6 to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP).1, 2, 3, 4, 5, 6 The terminal elimination half-life of methadone ranged from 8-59 hours.1, 2, 3, 4, 5, 6 Methadone and its metabolites are excreted to varying degrees in urine and feces.1, 2, 3, 4, 5, 6
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.
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 FDA regulations (21 CFR 291.505) for medications that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.1, 2, 3, 4, 5, 6
Distribution of methadone hydrochloride 40-mg dispersible tablets is restricted to authorized opioid detoxification and maintenance treatment programs and to hospitals.270
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 5 mg/5 mL* | ||
10 mg/5 mL* | Methadone Hydrochloride Oral Solution (C-II) | |||
Solution, concentrate | 10 mg/mL* | |||
Methadose® Oral Concentrate (C-II) | ||||
Tablets | 5 mg* | |||
10 mg* | Methadone Hydrochloride Tablets (C-II) | |||
Tablets, dispersible, for oral suspension | 40 mg* | Diskets® Dispersible Tablets (C-II; scored) | Hikma | |
Methadone Hydrochloride Dispersible Tablets (C-II; scored) | Hikma | |||
Methadose® Dispersible Tablets (C-II; scored) | SpecGx | |||
Parenteral | Injection | 10 mg/mL* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Mylan Institutional LLC. Methadone hydrochloride injection, solution prescribing information. Morgantown, WV; 2023 Dec.
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