Metabolism – Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma. In plasma, methadone is predominantly bound to α-acid glycoprotein (85% to 90%). Effect of food on the bioavailability of methadone has not been evaluated.ĭistribution – Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Dose proportionality of methadone pharmacokinetics is not known. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.Ībsorption – Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. The contribution of NMDA receptor antagonism to methadone's efficacy is unknown. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. Methadone hydrochloride is a mu-agonist a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.įailure 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. 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 8.12). 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. Methadone treatment for analgesic therapy in patients with acute or chronic pain should only be initiated if the potential analgesic or palliative care benefit of treatment with methadone is considered and outweighs the risks.Ĭonditions for Distribution and Use of Methadone Products for the Treatment of Opioid AddictionĬode of Federal Regulations, Title 42, Sec 8 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. In addition, cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids (see DOSAGE AND ADMINISTRATION). Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists.
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