Methadon

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Methadone hydrochloride/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Methadone hydrochloride/

Methadone hydrochloride preparations should be stored in tight, light-resistant containers. Methadone hydrochloride oral concentrate and oral solution should be stored at 15-30 °C; the tablets and injection should be stored at a controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C.

Keep container tightly closed in a dry and well-ventilated place. Light sensitive. Keep in a dry place. /Methadone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Methadone hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /Methadone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. /Methadone hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Methadone hydrochloride/

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Methadone hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Methadone hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Methadone hydrochloride/

Skin protection: Handle with gloves. /Methadone hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Methadone hydrochloride/

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Methadone hydrochloride/

The concentration of methadone in breast milk (BM) and serum (SR) of methadone-maintained women measured on postpartum days 1 through 4 at both trough (just before methadone dose) and peak (3 hours after dosing) and the breast milk to serum ratio (BM/SR) were reported as follows(1):[Table#4453]

Approximately 28% of methadone passes through the body unchanged, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine and 2-ethyl-5-methyl-3,3-diphenylpyrrolidine are major metabolites(1).

Methadone ... is secreted in breast milk in concentrations approaching plasma levels ...

Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person, takes a large dose of methadone, effective opioid antagonists are available to counteract the potentially lethal respiratory depression. (L1712)

Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible. Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.

Methadone maintenance patients (MMP) often abuse other drugs, including alcohol. The combined use of methadone and alcohol could impair performance and daily functioning. /The purpose of this study was/ to examine the effects of methadone in combination with alcohol, as well as acute increases in methadone, on performance outcomes. This double-blind, double-dummy, crossover study included eight opioid-dependent participants stabilized on methadone. Participants completed six inpatient sessions corresponding to methadone (100% or 150% of daily dose) and beverage (placebo, 0.25 or 0.50 g/kg alcohol). Performance tasks were completed before and after drug administration. Area under the time-course values were analyzed by a 2 (methadone dose) by 3 (alcohol dose) repeated measures analysis of variance. Main effects of methadone were observed for two attention outcomes, suggesting reduced accuracy and slowed responding at an elevated methadone dose. In addition, main effects of alcohol were observed for episodic memory (false alarms and response bias) suggesting more impulsive responding as alcohol dose increased. No robust interactions of methadone and alcohol were observed for any outcome. Study findings indicate that an acute increase in methadone (150%) and a moderate dose of alcohol (2-3 drinks) can impair distinct aspects of performance, although no significant interactive effect between methadone and alcohol was found. Future studies with larger sample sizes, larger doses, and more clinically informative tasks could expand on the present findings and further explore the cognitive consequences of concurrent opioid and alcohol use.

/The purpose of the study was/ to assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in six healthy Greyhound dogs (three male, three female) to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng/mL) and CMAX (6 ng/mL) of methadone significantly increased to 541 hours ng/mL and 47.8 ng/mL, respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment.

Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (0.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.

For more Interactions (Complete) data for Methadone (41 total), please visit the HSDB record page.

Bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur (RxList, A308). Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

Therapy with methadone has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. However, chronic hepatitis B and C are common among persons on methadone maintenance. There is no evidence that methadone maintenance worsens the course of chronic viral hepatitis. In prospective studies, transient serum enzyme elevations were not uncommon in patients on methadone maintenance; however, almost all of the abnormalities occurred in patients with underlying chronic hepatitis B or C and no clinically apparent liver injury arose anew during therapy.

TERRESTRIAL FATE: Based on a classification scheme(1), a log Koc value of 3.35(2), indicates that methadone is expected to have slight mobility in soil(SRC). The pKa of methadone is 8.94(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation from moist soil is not expected because cations do not volatilize(SRC). Methadone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). iodegradation studies of methadone are inconclusive, ranging from 100% in wastewater in a closed container over 3 days to <5% in unfiltered wastewater after 1 day; abiotic conversion was the dominant mechanism for methadone degradation(6). This suggests that biodegradation in not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a reported log Koc value of 3.35(2), indicates that methadone is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.94(3) indicates methadone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). Methadone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(5), an estimated BCF of 180(SRC), from its log Kow of 3.93(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high. Biodegradation studies of methadone are inconclusive, ranging from 100% in wastewater in a closed container over 3 days to <5% in unfiltered wastewater after 1 day; abiotic conversion was the dominant mechanism for methadone degradation(8). This suggests that biodegradation in not an important environmental fate process in water(SRC). .

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methadone, which has an estimated vapor pressure of 1.1X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase methadone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3.7 hours(SRC), calculated from its rate constant of 1.1X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase methadone may be removed from the air by wet or dry deposition(SRC). Methadone absorbs at maximum wavelength of 295 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

As with other opioid medications, the typical adverse effects of methadone stem from excessive opioid receptor activity, including, but are not limited to, diaphoresis or flushing, pruritus, nausea, dry mouth, constipation, sedation, lethargy, respiratory depression, adrenal insufficiency, hypotension, and hyperhidrosis.

Inhalation (MSDS, RxList, A308); dermal (MSDS, RxList, A308); ingestion (MSDS, RxList, A308); intravenous injection (MSDS, RxList, A308). Well absorbed following oral administration. The bioavailability of methadone ranges between 36 to 100%.

The concentration of methadone in breast milk of methadone-maintained women measured on postpartum days 1-4 at both trough (just before methadone dose) and peak (3 hours after dosing) and measured pre-feed and post-feed times was reported as follows(1):[Table#4457]

EXPERIMENTAL: Methadone ... is secreted in breast milk in concentration approaching plasma levels ...

IDENTIFICATION AND USE: Methadone is a Schedule II controlled substance. Methadone hydrochloride tablets are indicated for the detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance treatment of opioid addiction, in conjunction with appropriate social and medical services. Methadone hydrochloride tablets are also indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Methadone may be used as an alternative opioid preanesthetic or analgesic in dogs or cats. It is also being investigated for epidural use for horses. Poor oral bioavailability precludes oral dosing in dogs. HUMAN STUDIES: The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred 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. Acute overdosage produces signs of opioid toxicity, circulatory and CNS depression, lethargy, coma, respiratory depression, and decreased GI motility with ileus. Apnea, hypotension, bradycardia, noncardiogenic pulmonary edema, seizures, dysrhythmias, and death may occur with severe poisonings. Death may occur during induction of methadone maintenance when tolerance is incorrectly assessed, and during maintenance when several days' doses are combined. Death can also follow accidental ingestion. The effect of in utero exposure to drugs of abuse on certain neurological and behavioral characteristics of the newborn was studied in 10 infants of drug-dependent mothers. Fourteen newborns of mothers not receiving drugs served as matched controls. Infants exposed to drugs of abuse during fetal life exhibited a high level of arousal and irritability, and extreme muscle tone fluctuations, a predominant hypertonicity (rigidity) alternating with short periods of a very low tone (flaccidity). These newborns were also highly active, tremulous, and motorically immature, and displayed near-constant crying and disturbed sleep patterns. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. ANIMAL STUDIES: Overdosage may produce profound respiratory and/or CNS depression in most species. Newborns may be more susceptible to these effects than adult animals. Other toxic effects can include cardiovascular collapse, hypothermia, and skeletal muscle hypotonia. Methadone administered to the male rat prior to mating with methadone-naive females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals. Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. In pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased postimplantation loss and decreased live fetuses at 10 mg/kg/day or greater and decreased ossification and fetal body weight at 20 mg/kg/day or greater. Methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures.

/AQUATIC SPECIES/ Pharmaceuticals are present in low concentrations (<100 ng/L) in most municipal wastewater effluents but may be elevated locally because of factors such as input from pharmaceutical formulation facilities. Using existing concentration data, the authors assessed pharmaceuticals in laboratory exposures of fathead minnows (Pimephales promelas) and added environmental complexity through effluent exposures. In the laboratory, larval and mature minnows were exposed to a simple opioid mixture (hydrocodone, methadone, and oxycodone), an opioid agonist (tramadol), a muscle relaxant (methocarbamol), a simple antidepressant mixture (fluoxetine, paroxetine, venlafaxine), a sleep aid (temazepam), or a complex mixture of all compounds. Larval minnow response to effluent exposure was not consistent. The 2010 exposures resulted in shorter exposed minnow larvae, whereas the larvae exposed in 2012 exhibited altered escape behavior. Mature minnows exhibited altered hepatosomatic indices, with the strongest effects in females and in mixture exposures. In addition, laboratory-exposed, mature male minnows exposed to all pharmaceuticals (except the selective serotonin reuptake inhibitor mixture) defended nest sites less rigorously than fish in the control group. Tramadol or antidepressant mixture exposure resulted in increased splenic T lymphocytes. Only male minnows exposed to whole effluent responded with increased plasma vitellogenin concentrations. Female minnows exposed to pharmaceuticals (except the opioid mixture) had larger livers, likely as a compensatory result of greater prominence of vacuoles in liver hepatocytes. The observed alteration of apical endpoints central to sustaining fish populations confirms that effluents containing waste streams from pharmaceutical formulation facilities can adversely impact fish populations but that the effects may not be temporally consistent. The present study highlights the importance of including diverse biological endpoints spanning levels of biological organization and life stages when assessing contaminant interactions.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Methadone (DEA Code Number: 9250) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including methadone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Methadone hydrochloride/

Methadone (DEA Code Number: 9250) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

MEDICATION

MEDICATION (VET)

Analgesics, Opioid; Antitussive Agents; Narcotics

For the treatment of dry cough, drug withdrawal syndrome, opioid type drug dependence, and pain (A308).

Impurities: (2RS)-4-imino-N,N,2-trimethyl-3,3-diphenylhexan-1-amine (isomethadone ketimine); (4RS)-4-(dimethylamino)-2,2-diphenylpentanenitrile (didiavalo); (3RS)-4-(dimethylamino)-3-methyl-2,2-diphenylbutanenitrile (isodidiavalo); (5RS)-6-(dimethylamino)-5-methyl-4,4-diphenylhexan-3-one (isomethadone); diphenylacetonitrile /methadone hydrochloride/

Diphenylacetonitrile is condensed with 2-chloro-1-dimethylaminopropane in presence of sodamide, yielding 4-(dimethylamino)-2,2-diphenylvaleronitrile and an unwanted isomeric nitrile in approximately equal amounts. The isomers are separated and the former is subjected to Grignard addition with ethyl magnesium bromide. Subsequent hydrolysis in the presence of hydrochloric acid yields methadone hydrochloride. /Methadone hydrochloride/

Dimethylisopropanolamine + diphenylacetonitrile + ethylmagnesium bromide (alcohol chlorination/dehydrochlorination/Grignard reaction/hydrolysis).

L-Polamidon /l-Form Hydrochloride/

AN-148, Hoescht 10820, Depridol, Dolophine, Fenadone, Heptadon, Haptanon, Ketalgin, Mephenon, Methadose, Physeptone. /Methadone Hydrochloride/

Table: Methadone Hydrochloride Preparations [Table#4455]

Common street names include: Amidone, Chocolate Chip Cookies, Fizzies, Maria, Pastora, Salvia, Street Methadone, and Wafer.

For more Formulations/Preparations (Complete) data for Methadone (6 total), please visit the HSDB record page.

Pharmaceuticals

Pharmaceuticals -> Nervous System -> Anaesthetics -> Opioids