Conditions for Distribution and Use for the Treatment of Opiate Dependence
When used for the treatment of opiate dependence in detoxification or maintenance programs, methadone should be dispensed only by programs certified by the Substance Abuse and Mental Health Services Administration (SAMHSA) and approved by the designated state authority (consult Federal Standards for regulatory exceptions). Certified treatment programs should dispense only oral methadone products as outlined in the Federal Opioid Treatment Standards (42 CFR 8.12).
Failure to follow the requirements outlined in the regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program certification, and injunction precluding operation of the program.
Serious Adverse Effects
Death and life-threatening adverse effects (i.e., respiratory depression, cardiac arrhythmias) reported in patients receiving methadone. These events have been reported in patients initiating methadone therapy for pain and in patients transferring to methadone from other opiate therapy; death reported in patients initiating methadone therapy for opiate dependence. Interactions with other drugs (legal and illicit), respiratory and cardiac effects of methadone, or rapid dose titration may have contributed to these events. Consider pharmacokinetic and pharmacologic properties of methadone when initiating therapy, transferring patients from other opiate therapy, and during dose titration. (See Pharmacokinetics.)
Respiratory depression is the major toxicity associated with methadone. Peak respiratory depressant effect occurs later and persists longer than peak analgesic effect, particularly during the early dosing period. These properties can contribute to inadvertent overdosage, especially during treatment initiation and dose titration. (See Respiratory Depression under Cautions.)
Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes. Most cases have occurred in patients receiving relatively high dosages (>200 mg daily) for the treatment of chronic pain, but also reported in patients receiving lower dosages for maintenance treatment of opiate dependence. (See Cardiac Effects under Cautions.)
For pain management, initiate only if potential benefits outweigh risks of methadone therapy.
A strong analgesic used for the relief of moderate to severe pain that has not responded to nonopiate analgesics.
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).
Although considered by some clinicians to be second-line therapy in the management of chronic malignant pain, clinical studies suggest that efficacy may be similar to that of morphine and other opiates in this population.
Benefits associated with use for management of chronic pain include the commercial availability of multiple dosage forms of the drug, good oral bioavailability, rapid onset of action, reduced dosing frequency (because of the drug’s long half-life), low cost, and lack of active metabolites.
Disadvantages associated with use include increased potential for accumulation with repeated doses (which may result in toxicity), considerable interindividual variability in pharmacokinetic parameters, potential for drug interactions, challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists, and commercial availability and relative ease of use of extended-release preparations of other opiate agonists.
Detoxification and Maintenance of Opiate Dependence
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.
Success of treatment is dependent on the selection of properly motivated patients and on availability of social, psychologic, vocational, and educational as well as medical supportive services.
Dosage and Administration
General
Individualize dosage carefully; repeated doses may result in substantial accumulation of the drug, prolonging its duration of action and possibly resulting in adverse effects. There is considerable interindividual variability in absorption, metabolism, and relative analgesic potency of the drug.
Carefully monitor patients during initiation of therapy, dosage titration, and conversion from one opiate agonist to another.
Consider the specific characteristics of methadone (i.e., half-life is longer than duration of analgesic effect, peak respiratory depressant effects occur later and persist longer than peak analgesic effects, full analgesic effect not attained for several days) when making treatment decisions regarding use of the drug.
Conversion from Other Opiate Analgesic Therapy
Consider 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.
A high degree of opiate tolerance does not preclude the possibility of unintended methadone overdosage.Failure to individualize dosage has resulted in serious adverse effects, including death, in opiate-tolerant patients during conversion to methadone therapy.
Select dosage carefully when transferring patients from chronic therapy with another oral or parenteral opiate to therapy with oral or parenteral methadone, since cross-tolerance between methadone and other opiate agonists is incomplete, dosage conversion ratios are imprecise, and substantial interindividual variability exists. (See Conversion from Other Opiate Therapy under Dosage.)
Published equianalgesic dosage conversion ratios between methadone and other opiate agonists generally are based on single-dose studies in patients who are not opiate tolerant. These single-dose equivalency tables may overestimate dosage requirements during chronic therapy, since methadone may accumulate with repeated doses secondary to the long elimination half-life (see Elimination under Pharmacokinetics). Therefore, estimates of methadone dosage that are based on single-dose studies should not be used for conversion in patients receiving chronic opiate therapy.
Detoxification and Maintenance Treatment
Administer or dispense only in an oral form (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.
Hospitalized patients unable to take oral medication may receive parenteral methadone on a temporary basis. If at any time during detoxification or maintenance treatment the patient cannot tolerate oral medication because of nausea or vomiting associated with acute complicating illness, hospitalize the patient and continue methadone by the parenteral route.
Short-term detoxification: Administer in decreasing doses under close observation over a period of ≤30 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.
Long-term detoxification: Administer in decreasing doses over a period of >30 but ≤180 days to alleviate physical and psychologic effects of opiate withdrawal and to reach a drug-free state.
Maintenance treatment: Administer at a stable dosage for >21 days in the treatment of opiate dependence.
Patients with ≥2 unsuccessful detoxification episodes within a 12-month period should be assessed for alternative forms of treatment. An opiate treatment program may not admit a patient for >2 detoxification treatments within 1 year.
Patients undergoing short-term detoxification are not eligible for unsupervised administration.
Any patient in a comprehensive maintenance treatment program, including long-term detoxification treatment, may receive 1 dose to take at home for a day that the clinic is closed. Decisions to allow additional unsupervised administration by these patients 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 patient’s home environment and social relationships, length of time in the program (see below), assurance that the drug can be safely stored in the patient’s home, and assessment of whether the rehabilitative benefit derived from decreased clinic attendance outweighs potential risks of diversion.
Patients 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 1st 90 days of treatment, 2-day supply during the 2nd 90 days, and 3-day supply during the 3rd 90 days (each in addition to the 1 dose allowed for clinic closure). All other doses must be administered while the patient is closely observed.
During the remainder of the 1st year of treatment, the patient may receive a maximum 6-day supply of the drug and must visit the clinic once weekly.
After 1 year of continuous treatment, the patient may receive a maximum 2-week supply and must make twice monthly visits. After 2 years of continuous treatment, the patient may receive a maximum 1-month supply of the drug and must make monthly visits.
Substantial deviations from the FDA-approved labeling for methadone (e.g., concerning dose, frequency of administration, or conditions of use) must be documented in the patient’s medical record.
Restricted Distribution
Distribution of 40-mg dispersible tablets restricted to authorized opiate-dependency treatment programs and to hospitals. Distribution restricted in response to reports of serious adverse effects (see Serious Adverse Effects in Boxed Warning).
Administration
Administer orally or by sub-Q, IM, or IV injection.
Oral Administration
Tablets, dispersible tablets, and oral concentrate solution are for oral administration only and must not be injected.
Dispersible Tablets
Disperse in 120 mL of a liquid (e.g., water, orange juice, citrus Tang®, citrus flavors of Kool-Aid®, other acidic fruit beverages) prior to oral administration. Complete tablet dispersion occurs within 1 minute; dispersion time is slightly increased when a cold and/or acidic vehicle is used.
Each 40-mg dispersible tablet can be divided in half to yield two 20-mg doses or into quarters to yield four 10-mg doses.
The 40-mg dispersible tablets are used in detoxification and maintenance of opiate dependence; this preparation should not be used for the treatment of pain.
Dispersible tablets contain insoluble excipients and must not be used to prepare solutions for injection.
Oral Concentrate Solution
Dilute the dose with water or other suitable liquid (e.g., Kool-Aid®, Tang®, apple juice, Crystal Light® [with aspartame]) to ≥30 mL prior to administration.
IM or Sub-Q Administration
Absorption following sub-Q or IM injection may be unpredictable and has not been fully characterized; local tissue reactions may occur.
IV Administration
Administer by IV injection.
For solution and drug compatibility information, see Compatibility under Stability.
When selecting an initial dosage, consider 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 Interactions); and the acceptable balance between pain relief and adverse effects.
Give the smallest effective dose in order to minimize development of tolerance and physical dependence.
Oral
Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours. Titrate dosage to provide adequate analgesia; increase dosage slowly to avoid accumulation and potential toxicity.
Dosage interval 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. Use caution to avoid overdosage.
Patients being switched from parenteral methadone: Initiate oral methadone at a parenteral:oral dosage ratio of 1:2 (e.g., 10 mg of oral methadone hydrochloride in patients previously receiving 5 mg of parenteral methadone hydrochloride).
IV
Opiate-naive patients: Initially, 2.5–10 mg every 8–12 hours. Titrate dosage to provide adequate analgesia; increase slowly to avoid accumulation and potential toxicity. More frequent administration may be required during initiation of therapy to maintain adequate analgesia; however, use caution to avoid overdosage.
Patients being switched from oral methadone: Initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Conversion from Other Opiate Therapy
For patients being transferred from therapy with other opiate agonists, dosage may be estimated based on comparisons with morphine sulfate. Select dosage carefully (see General: Conversion from Other Opiate Analgesic Therapy under Dosage and Administration).
For patients being transferred from therapy with opiate agonists other than morphine, a comparative opiate agonist dosage table may be consulted to determine the equivalent morphine dosage.
Oral
Dosage estimates obtained from Table 1 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).
Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.
Table 1. Conversion from Oral Morphine Sulfate to Oral Methadone Hydrochloride (for Chronic Administration)
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%
IV
Dosage estimates obtained from Table 2 and Table 3 must be individualized (e.g., based on prior opiate use, medical condition, concurrent drug therapy, anticipated use of analgesics for breakthrough pain).
Administer the total daily dosage in divided doses (e.g., at 8-hour intervals) based on individual patient requirements.
Table 2. Conversion from Oral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)
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%
Table 3. Conversion from Parenteral Morphine Sulfate to IV Methadone Hydrochloride (for Chronic Administration)
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%
Derived from Table 2 assuming a 3:1 oral:parenteral morphine ratio.
Detoxification and Maintenance of Opiate Dependence
Detoxification
Oral
Initiate when there are substantial opiate-agonist abstinence symptoms.
A single dose of 20–30 mg will often suppress withdrawal symptoms. Initial dose should not exceed 30 mg; use lower initial dose in patients whose tolerance is expected to be low. Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear. If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose. If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg. Total daily dose for the first day generally should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.
During the first week, adjust dosage based on control of withdrawal symptoms at times of expected peak activity of methadone (2–4 hours after a dose). Use caution to avoid overdosage.
Usual stabilizing dosage is 40 mg daily in divided doses. When the patient has been stabilized (i.e., substantial symptoms of withdrawal are absent) for 2 or 3 days, gradually decrease dosage daily or at 2-day intervals. Individualize and adjust dosage to keep withdrawal symptoms at a tolerable level. In hospitalized patients, reduce dosage by 20% daily; a more gradual reduction may be required in ambulatory patients.
Parenteral
Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria. Patients being switched from oral methadone usually initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Maintenance
Oral
A single dose of 20–30 mg will often suppress withdrawal symptoms. Initial dose should not exceed 30 mg; use lower initial dose in patients whose tolerance is expected to be low. Additional doses may be necessary if withdrawal symptoms are not suppressed or if they reappear. If same-day dosage adjustments are to be made, reevaluate the patient 2–4 hours after the previous dose. If an additional dose is needed to suppress withdrawal symptoms, administer an additional 5–10 mg. Total daily dose for the first day generally should not exceed 40 mg unless it is documented that this total dose does not suppress withdrawal symptoms.
During the first week, adjust dosage based on control of withdrawal symptoms at times of expected peak activity of methadone (2–4 hours after a dose). Use caution to avoid overdosage.
Titrate dosage to a level at which opiate withdrawal symptoms are prevented for 24 hours, drug craving is reduced, euphoric effects of self-administered opiates are blocked or attenuated, and patient is able to tolerate the sedative effects of methadone. Usual stabilizing dosage is 80–120 mg daily. Review maintenance dosage requirements regularly and reduce as indicated.
Once-daily dosing usually is adequate; there generally is no apparent advantage to divided doses. However, rapid metabolizers may not maintain adequate plasma concentrations with usual dosing regimens.
Withdrawal from methadone maintenance: Considerable variability in appropriate rate of dosage reduction; one regimen involves reducing the dose by <10% of established tolerance or maintenance dosage at intervals of 10–14 days. 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.
Parenteral
Patients unable to receive methadone orally: Hospitalize patient and convert oral dose to parenteral dose using accepted criteria. Patients being switched from oral methadone usually initiate parenteral methadone at an oral:parenteral dosage ratio of 2:1 (e.g., 5 mg of parenteral methadone hydrochloride in patients previously receiving 10 mg of oral methadone hydrochloride).
Special Populations
Hepatic Impairment
Reduce initial dosage in patients with severe hepatic impairment.
Renal Impairment
Reduce initial dosage in patients with severe renal impairment.
Geriatric and Debilitated Patients
Reduce dosage in poor-risk and in very old patients.
Cautions
Contraindications
Known hypersensitivity to methadone or any ingredient in the formulation.
Respiratory depression in the absence of resuscitative equipment or in unmonitored settings.
Possible prolongation of the QT interval and serious cardiac arrhythmias, including torsades de pointes.(See Boxed Warning.)
Use 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 relatively high methadone dosages or receiving concomitant therapy with a drug that may cause electrolyte disturbances or prolong the QT interval [see Specific Drugs under Interactions]).
Use in patients with known prolongation of the QT interval not systematically evaluated.
If prolongation of the QT interval occurs, evaluate the patient’s drug regimen to identify drugs that may prolong the QT interval, cause electrolyte abnormalities, or inhibit metabolism of methadone.
Use for the treatment of acute or chronic pain only when the potential benefits outweigh the possible risk of QT-interval prolongation reported with higher methadone dosage.
Incomplete Cross-Tolerance
Patients who are tolerant to other opiate agonists may have incomplete tolerance to methadone. Overdosage (including fatalities) reported when dosage has not been carefully adjusted in patients being transferred from chronic, high-dose therapy with other opiate agonists to therapy with methadone.
Use methadone with caution and at appropriately adjusted dosages in patients being transferred from other opiate therapy. Carefully consider pharmacokinetic parameters during initiation and titration of methadone therapy in patients who previously received chronic opiate agonist therapy.(See General: Conversion from Other Opiate Analgesic Therapy and also see Dosage: Conversion from Other Opiate Therapy, under Dosage and Administration.)
Drug Abuse and Dependence
Abuse liability similar to that of morphine. Clinicians should consider abuse potential when prescribing or dispensing methadone in situations where they are concerned about an increased risk of misuse, abuse, or diversion. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Physical and psychic dependence and tolerance may develop with repeated administration; use with caution.
Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms. After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.
Contact the state professional licensing board or controlled substance authority for information about prevention and detection of abuse or diversion.
Increased Intracranial Pressure or Head Trauma
Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.
Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.
Use with caution, if at all, in patients with head trauma.
Acute Abdominal Conditions
Administration may complicate assessment of patients with acute abdominal conditions.
Contraindicated in patients with known or suspected paralytic ileus.
Hypotensive Effects
Like all opiate analgesics, may cause severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).
May produce orthostatic hypotension in ambulatory patients.
CNS Effects
May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery. Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.
Concomitant use with other CNS depressants may cause profound sedation, coma, respiratory depression, or hypotension. Deaths associated with illicit methadone use frequently have involved concomitant benzodiazepine abuse.
General Precautions
Acute Pain Management in Patients Receiving Maintenance Treatment
Patients maintained on a stable dose of methadone who experience trauma or acute (e.g., postoperative) pain should not be expected to derive adequate analgesia from their stable methadone regimen.
Such patients should receive analgesics, including opiates, appropriate for other patients experiencing similar nociceptive stimulation. Opiate doses may be somewhat higher or dosing intervals somewhat shorter than those in nontolerant patients.
Anxiety
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.
Hypothyroidism
Use with caution and in reduced dosage in patients with hypothyroidism.
Prostatic Hypertrophy or Urethral Stricture
Use with caution and in reduced dosage in patients with prostatic hypertrophy or urethral stricture.
Addison’s Disease
Use with caution and in reduced dosage in patients with Addison’s disease.
Specific Populations
Pregnancy
Category C.
Use for obstetric analgesia is not recommended, since neonate may be at increased risk of respiratory depression because of the long duration of effect.
Short- or long-term detoxification treatment is not recommended during pregnancy. However, pregnant women, regardless of age, are eligible for admission into a comprehensive maintenance treatment program 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.
If methadone maintenance treatment is deemed necessary during pregnancy, undertake such treatment with caution and at the lowest possible effective dosage.
Clearance may be increased during 2nd and 3rd trimesters, resulting in the need for higher doses or shorter dosing intervals in order to avoid withdrawal symptoms.
Lactation
Distributed into milk. Discontinue nursing or the drug.
Women receiving high-dose maintenance therapy who are already nursing should be instructed to discontinue nursing gradually to prevent withdrawal (neonatal abstinence syndrome) in the infant.
Pediatric Use
Safety and efficacy as analgesic not established in children <18 years of age.
Short- or long-term detoxification treatment using methadone is not subject to any age limitation. However, the effects of prolonged use on the physiologic and psychologic development of children are not known; therefore, do not initiate maintenance treatment with the drug indiscriminately in children <18 years of age.
Children <18 years of age are eligible to receive maintenance treatment provided they have undergone ≥2 documented attempts at detoxification or drug-free treatment in a 12-month period and the program physician has documented that the child continues to be, or is again, physiologically dependent on opiates. 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).
Geriatric Use
Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution in this age group and select dosage at the lower end of the dosage range.
Hepatic Impairment
Not studied extensively in patients with hepatic impairment. However, risk of accumulation with multiple doses because the drug is metabolized in the liver. Use with caution and in reduced dosage in patients with severe hepatic impairment.
Renal Impairment
Not studied extensively in patients with renal impairment. Use with caution and in reduced dosage in patients with severe renal impairment.
Metabolized principally by CYP3A4, CYP2B6, and CYP2C19, although other isoenzymes, including CYP2C9, and CYP2D6, also may be involved.
Drugs Affecting Hepatic Microsomal Enzymes
Possible pharmacokinetic interaction with drugs that are inhibitors or inducers of CYP3A4 and other CYP isoenzymes (i.e., 2B6, 2C19, 2C9, 2D6) with possible alteration of the metabolism of methadone.
Drugs that Prolong the QT Interval
Potential pharmacologic interaction (prolongation of the QT interval; potential for severe and/or life-threatening cardiac arrhythmias). Use with extreme caution.
Drugs that May be Associated with Electrolyte Abnormalities
Potential pharmacologic interaction (potential for electrolyte disorders that may cause severe and/or life-threatening cardiac arrhythmias). Use with caution.
Severe reactions (e.g., agitation, bizarre behavior, headache, hypertension, hypotension, rigidity, convulsions, hyperpyrexia, coma) reported in some patients receiving MAO inhibitors with meperidine; similar reactions not reported with methadone
If concomitant use is necessary, administer methadone in small, incremental doses over several hours with careful monitoring
Maintenance dosage of methadone probably does not need to be adjusted when zidovudine therapy is initiated in patients receiving long-term methadone treatment; monitor patients for dose-related zidovudine toxicity
Pharmacokinetics
Absorption
Bioavailability
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%).
Onset
Full analgesic effects generally are not achieved until completion of 3–5 days of therapy.
Peak respiratory depressant effects occur later than analgesic effects, particularly during the early dosing period.
Duration
Approximately 4–8 hours after a single dose.
Approximately 22–48 hours following oral administration in patients on methadone maintenance.
Respiratory depressant effects persist longer than analgesic effects, particularly during the early dosing period.
Food
Effect of food on bioavailability not established.
Plasma Concentrations
Trough plasma methadone concentrations exceeding 100–200 ng/mL may be necessary to optimize the success of methadone maintenance, particularly during the first 6 months of treatment.
Distribution
Extent
Highly lipophilic and is widely distributed in body tissues. With repeated administration, methadone is stored in the liver and other tissues and is slowly released, prolonging the duration of effect despite low plasma concentrations.
Methadone crosses the placenta and is distributed into milk.
Plasma Protein Binding
85–90% (mainly α1-acid glycoprotein).
Elimination
Metabolism
Extensively metabolized, principally by CYP3A4, CYP2B6, and CYP2C19 in the liver and/or intestine, although other isoenzymes, including CYP2C9 and CYP2D6, also may be involved.
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.
Elimination Route
Excreted to varying degrees in urine and feces as metabolites and unchanged drug.
Half-life
Considerable interindividual variability in terminal elimination half-life; generally reported as 8–59 hours, but values have ranged 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.
Special Populations
Elimination half-life is decreased during 2nd and 3rd trimesters of pregnancy.
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).
Tablets, Dispersible
15–30°C.
Oral Solution and Concentrate Solution
15–30°C.
Parenteral
Injection
25°C (may be exposed to 15–30°C).
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
A potent analgesic; shares the actions of the opiate agonists.
Opiate agonists alter perception of and emotional response to pain.
Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.
Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).
Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.
Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.
Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.
Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).
Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.
May also act as antagonist at N-methyl-D-aspartate (NMDA) receptors. Not known whether NMDA antagonism contributes to efficacy of methadone. Other NMDA antagonists have produced neurotoxic effects in animals.
May depress the cough reflex by a direct effect on the cough centers in the medulla.
Advice to Patients
Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
Importance of informing patients that methadone should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).
Importance of advising patients to seek immediate medical attention if symptoms suggestive of an arrhythmia (e.g., palpitations, dizziness, lightheadedness, syncope) occur.
Importance of informing patients that the duration of analgesia will increase with repeated dosing. Importance of patients taking the drug only as prescribed and of not increasing the dose or abruptly discontinuing therapy without consulting a clinician.
Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.
Importance of informing patients that this medication should never be given to anyone other than the individual for whom it was prescribed.
Importance of informing patients to keep this and all medications in a secure location and out of the reach of children.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug; also subject to the Substance Abuse and Mental Health Services Administration (SAMHSA) regulations (42 CFR 8) for drugs that require special studies, records, and reports when used for detoxification and maintenance of opiate dependence.
Distribution of 40-mg dispersible tablets is restricted. (See Restricted Distribution under Dosage and Administration.)
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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