Methadone hydrochloride
FOR ORAL USE ONLY
Deaths have been reported during initiation of methadone treatment for opioid dependence. In some cases, drug interactions with other drugs, both licit and illicit, have been suspected. However, in other cases, deaths appear to have occurred due to the respiratory or cardiac effects of methadone and too-rapid titration without appreciation for the accumulation of methadone over time. It is critical to understand the pharmacokinetics of methadone and to exercise vigilance during treatment initiation and dose titration (see DOSAGE AND ADMINISTRATION). Patients must also be strongly cautioned against self- medicating with CNS depressants during initiation of methadone treatment.
Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.
Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. 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.
Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction
Code of Federal Regulations, Title 42, Sec 8
METHADONE PRODUCTS WHEN USED FOR THE TREATMENT OF OPIOID ADDICTION IN DETOXIFICATION OR MAINTENANCE PROGRAMS, SHALL BE DISPENSED ONLY BY OPIOID TREATMENT PROGRAMS (AND AGENCIES, PRACTITIONERS OR INSTITUTIONS BY FORMAL AGREEMENT WITH THE PROGRAM SPONSOR) CERTIFIED BY THE SUBSTANCE ABUSE AND MENTAL HEALTH SERVICES ADMINISTRATION AND APPROVED BY THE DESIGNATED STATE AUTHORITY. CERTIFIED TREATMENT PROGRAMS SHALL DISPENSE AND USE METHADONE IN ORAL FORM ONLY AND ACCORDING TO THE TREATMENT REQUIREMENTS STIPULATED IN THE FEDERAL OPIOID TREATMENT STANDARDS (42 CFR). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.
FAILURE TO ABIDE BY THE REQUIREMENTS IN THESE REGULATIONS MAY RESULT IN CRIMINAL PROSECUTION, SEIZURE OF THE DRUG SUPPLY, REVOCATION OF THE PROGRAM APPROVAL, AND INJUNCTION PRECLUDING OPERATION OF THE PROGRAM.
Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment:
During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis.
During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)).
DRUG DESCRIPTION
Methadose™ Oral Concentrate (methadone hydrochloride USP) is supplied as a cherry flavored liquid concentrate. Methadose™ Sugar-Free Oral Concentrate (methadone hydrochloride USP) is a dye-free, sugar-free, unflavored liquid concentrate of methadone hydrochloride. Each liquid concentrate contains 10 mg of methadone hydrochloride per mL.
Methadone hydrochloride is chemically described as 3-heptanone, 6- (dimethylamino)-4, 4-diphenyl-, hydrochloride. Methadone hydrochloride is a white, essentially odorless, bitter-tasting crystalline powder. It is very soluble in water, soluble in isopropanol and in chloroform, and practically insoluble in ether and in glycerine. It is present in Methadose as the racemic mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in octanol/water and a molecular weight of 345.91. Its molecular formula is C21H27NO•HCl.
Other ingredients of Methadose Oral Concentrate: Artificial cherry flavor, citric acid anhydrous USP, FD&C Red No 40, D&C Red No 33, methylparaben NF, polaxamer 407 NF, propylene glycol USP, propylparaben NF, purified water USP, sodium citrate dihydrate USP, sucrose NF.
Other ingredients of Methadose Sugar-Free Oral Concentrate: Citric acid anhydrous USP, purified water USP, sodium benzoate NF.
INDICATIONS
For detoxification treatment of opioid addiction (heroin or other morphine- like drugs).
For maintenance treatment of opioid addiction (heroin or other morphine- like drugs), in conjunction with appropriate social and medical services.
NOTE
Outpatient maintenance and outpatient detoxification treatment may be provided only by Opioid Treatment Programs (OTPs) certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). This does not preclude the maintenance treatment of a patient with concurrent opioid addiction who is hospitalized for conditions other than opioid addiction and who requires temporary maintenance during the critical period of his/her stay, or of a patient whose enrollment has been verified in a program which has been certified for maintenance treatment with methadone.
DOSAGE AND ADMINISTRATION
Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing.
Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.
While methadone's duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone's plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex.
The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.
Detoxification and Maintenance Treatment of Opiate Dependence
For detoxification and maintenance of opiate dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.
Induction/Initial Dosing
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. Initially, a single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days' dosing. Patients should be reminded that the dose will "hold" for a longer period of time as tissue stores of methadone accumulate.
Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use.
For Short-term Detoxification
For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.
For Maintenance Treatment
Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.
For Medically Supervised Withdrawal After a Period of Maintenance Treatment
There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
SIDE EFFECTS
Heroin Withdrawal
During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore show typical withdrawal symptoms, which should be differentiated from methadone-induced side effects.
They may exhibit some or all of the following signs and symptoms associated with acute withdrawal from heroin or other opiates: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilliness alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss.
Initial Administration
The initial methadone dose should be carefully titrated to the individual. Too rapid titration for the patient's sensitivity is more likely to produce adverse effects.
The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable.
Other adverse reactions include the following: (listed alphabetically under each subsection)
Body as a Whole - asthenia (weakness), edema, headache
Cardiovascular (also see WARNINGS: Cardiac Conduction Effects) - arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia
Digestive - abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis
Hematologic and Lymphatic - reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis
Metabolic and Nutritional - hypokalemia, hypomagnesemia, weight gain
Nervous - agitation, confusion, disorientation, dysphoria, euphoria, insomnia, seizures
Respiratory - pulmonary edema, respiratory depression (see WARNINGS: Respiratory Depression)
Skin and Appendages - pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria
Special Senses - hallucinations, visual disturbances
Urogenital - amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or hesitancy
Maintenance on a Stabilized Dose - During prolonged administration of methadone, as in a methadone maintenance treatment program, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist.
Drug Abuse And Dependence
Methadose contains methadone, a potent Schedule II opioid agonist. Schedule II opioid substances, which also include hydromorphone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.
Abuse of Methadose poses a risk of overdose and death. This risk is increased with concurrent abuse of Methadose with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV.
Since Methadose may be diverted for non-medical use, careful record keeping of ordering and dispensing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re- evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Methadose, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners or institutions by formal agreement with the program sponsor).
Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (See PRECAUTIONS; Pregnancy, Labor and Delivery).
DRUG INTERACTIONS
In vitro results suggest that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these enzymes may result in a more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone's effects. Although anti- retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, and lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy.
Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists
As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.
Anti-retroviral Agents
Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination - Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone. Methadone-maintained patients beginning treatment with these anti-retroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly.
Didanosine and Stavudine - Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.
Zidovudine- Experimental evidence demonstrated that methadone increased the AUC of zidovudine which could result in toxic effects.
Cytochrome P450 Inducers
Methadone-maintained patients beginning treatment with CYP3A4 inducers should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes:
Rifampin - In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.
Phenytoin - In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration.
St. John's Wort, Phenobarbital, Carbamazepine
Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms.
Cytochrome P450 Inhibitors
Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4, such as azole antifungal agents (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin), should be carefully monitored and dosage adjustment should be undertaken if warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon coadministration with methadone and result in increased opiate effects and/or toxicity.
Voriconazole - Repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased the Cmax and AUC of (R)- methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity, including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Others
Monoamine Oxidase (MAO) Inhibitors - Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are under careful observation.
Desipramine - Plasma levels of desipramine have increased with concurrent methadone administration.
Potentially Arrhythmogenic Agents
Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
Caution should also be exercised when prescribing Methadose concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval. These drugs include diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Interactions with Alcohol and Drugs of Abuse
Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids or CNS depressants, or with illicit drugs that cause central nervous system depression. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines.
Anxiety - Since methadone as used by tolerant patients at a constant maintenance dosage does not act as a tranquilizer, patients will react to life problems and stresses with the same symptoms of anxiety as do other individuals. The physician should not confuse such symptoms with those of narcotic abstinence and should not attempt to treat anxiety by increasing the dose of methadone. The action of methadone in maintenance treatment is limited to the control of narcotic withdrawal symptoms and is ineffective for relief of general anxiety.
Acute Pain- Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. Due to the opioid tolerance induced by methadone, when opioids are required for management of acute pain in methadone patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients.
Physical Dependence
Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence is expected during opioid agonist therapy of opioid addiction.
If a physically dependent patient abruptly discontinues use of methadone, or the dose of methadone does not adequately "cover" the patient, an opioid abstinence or withdrawal syndrome may develop and is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms may also develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS: Pregnancy, Labor and Delivery).
In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: For Medically Supervised Withdrawal After a Period of Maintenance Treatment).
Special-Risk Patients - Methadone should be given with caution, and the initial dose reduced, in certain patients such as the elderly and debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression requires added vigilance.
WARNINGS
Methadose and Methadose Sugar-Free are for oral administration only. The preparation must not be injected. Methadose and Methadose Sugar-Free, if dispensed, should be packaged in child-resistant containers and kept out of reach of children to prevent accidental ingestion.
Respiratory Depression
Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.
Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.
Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and central nervous system (CNS) depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Methadone should be used at the lowest effective dose and only under careful medical supervision.
Cardiac Conduction Effects
This information is intended to alert the prescriber to comprehensively evaluate the risks and benefits of methadone treatment. The intent is not to deter the appropriate use of methadone in patients with a history of cardiac disease.
Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment ( > 200 mg/day). Although most cases involve patients being treated for pain with large, multiple daily doses of methadone, cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most of the cases seen at typical maintenance doses, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients.
Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction abnormalities, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Patients developing QT prolongation while on methadone treatment should be evaluated for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities and drugs which might act as inhibitors of methadone metabolism.
The potential risks of methadone, including the risk of life-threatening arrhythmias, should be weighed against the risks of discontinuing methadone treatment. In the patient being treated for opiate dependence with methadone maintenance therapy, these risks include a very high likelihood of relapse to illicit drug use following methadone discontinuation.
The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. The potential risks of methadone should be weighed against the substantial morbidity and mortality associated with untreated opioid addiction.
When treating patients with methadone, an individualized benefit to risk assessment should be carried out and should include evaluation of patient presentation and complete medical history. For patients judged to be at risk, careful monitoring of cardiovascular status, including evaluation of QT prolongation and dysrhythmias should be performed.
Incomplete Cross-tolerance between Methadone and other Opioids
Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to methadone, thus making determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise.
Misuse, Abuse, and Diversion of Opioids
Methadone is a mu-agonist opioid with an abuse liability similar to that of morphine and other opioid agonists and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.
Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadose in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with other CNS Depressants
Patients receiving other opioid analgesics, general anesthetics, phenothiazines or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma (see PRECAUTIONS).
Interactions with Alcohol and Drugs of Abuse
Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Deaths associated with illicit use of methadone frequently have involved concomitant benzodiazepine abuse.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential.
Acute Abdominal Conditions
The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Hypotensive Effect
The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion).