indication

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

pharmacology

Methadone is a synthetic opioid analgesic with multiple actions quantitatively similar to those at morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. However, Methadone is more active and more toxic than morphine. Methadone is indicated for relief of severe pain, for detoxification treatment of narcotic addiction, and for temporary maintenance treatment of narcotic addiction. The principal actions of therapeutic value are analgesia and sedation and detoxification or temporary maintenance in narcotic addiction. 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.

mechanism of action

Methadone 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. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. 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. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone's efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.

toxicity

In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

biotransformation

Hepatic. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine.

absorption

Well absorbed following oral administration. The bioavailability of methadone ranges between 36 to 100%.

half life

24-36 hours

route of elimination

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.

drug interactions

Amobarbital: The barbiturate, amobarbital, decreases the effect of methadone.

Amprenavir: The protease inhibitor, amprenavir, may decrease the effect of methadone.

Aprobarbital: The barbiturate, aprobarbital, decreases the effect of methadone.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Butabarbital: The barbiturate, butabarbital, decreases the effect of methadone.

Butalbital: The barbiturate, butalbital, decreases the effect of methadone.

Butethal: The barbiturate, butethal, decreases the effect of methadone.

Carbamazepine: Carbamazepine may decrease the serum level of methadone. Monitor for changes in the therapeutic and adverse effects of methadone if carbamazepine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine, a moderate CYP3A4 inhibitor, may increase the serum concentration of metahdone, a CYP3A4 substrate. Monitor for changes in the therapeutic and adverse effects of methadone if cimetidine is initiatied, discontinued or dose changed.

Dihydroquinidine barbiturate: The barbiturate, dihydroquinidine barbiturate, decreases the effect of methadone.

Efavirenz: Efavirenz may decrease the serum concentration of methadone by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of methadone if efavirenz is initiated, discontinued or dose changed.

Ethotoin: The hydantoin decreases the effect of methadone

Fluvoxamine: Fluvoxamine increases the effect and toxicity of methadone

Fosamprenavir: The protease inhibitor, fosamprenavir, may decrease the effect of methadone.

Fosphenytoin: The hydantoin decreases the effect of methadone

Heptabarbital: The barbiturate, heptabarbital, decreases the effect of methadone.

Hexobarbital: The barbiturate, hexobarbital, decreases the effect of methadone.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephenytoin: The hydantoin decreases the effect of methadone

Methohexital: The barbiturate, methohexital, decreases the effect of methadone.

Methylphenobarbital: The barbiturate, methylphenobarbital, decreases the effect of methadone.

Nelfinavir: Nelfinavir decreases the effect of methadone

Nevirapine: The antiretroviral agent decreases the effect of methadone

Pentobarbital: The barbiturate, pentobarbital, decreases the effect of methadone.

Phenobarbital: The barbiturate, phenobarbital, decreases the effect of methadone.

Phenytoin: The hydantoin decreases the effect of methadone

Primidone: The barbiturate, primidone, decreases the effect of methadone.

Quinidine barbiturate: The barbiturate, quinidine barbiturate, decreases the effect of methadone.

Rifabutin: The rifamycin decreases the effect of methadone

Rifampin: The rifamycin decreases the effect of methadone

Rifapentine: The rifamycin decreases the effect of methadone

Ritonavir: The protease inhibitor, ritonavir, may decrease the effect of methadone.

Secobarbital: The barbiturate, secobarbital, decreases the effect of methadone.

St. John's Wort: St. John's Wort decreases levels/effect of methadone

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Talbutal: The barbiturate, talbutal, decreases the effect of methadone.

Tamoxifen: Methadone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Methadone, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Methadone is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Methadone. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Methadone if Telithromycin is initiated, discontinued or dose changed.

Thiopental: Thiopental may decrease the effect of Methadone by increasing Methadone metabolism. Methadone withdrawal may occur.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Tipranavir, co-administered with Ritonavir, decreases the Methadone concentration. Monitor for symptoms of opiate withdrawal.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Methadone may decrease the effect of Tramadol by decreasing active metabolite production.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: The CNS depressants, Triprolidine and Methadone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of methadone by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of methadone if voriconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Zidovudine: Methadone increases the effect and toxicity of zidovudine

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).