Methadone

Identification

Summary

Methadone is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction.

Brand Names

Diskets, Dolophine, Metadol, Metadol-D, Methadose

Generic Name

Methadone

DrugBank Accession Number

DB00333

Background

Methadone is a potent synthetic analgesic that works as a full µ-opioid receptor (MOR) agonist and N-methyl-d-aspartate (NMDA) receptor antagonist. As a full MOR agonist, methadone mimics the natural effects of the body's opioids, endorphins, and enkephalins through the release of neurotransmitters involved in pain transmission. It also has a number of unique characteristics that have led to its increased use in the last two decades; in particular, methadone has a lower risk of neuropsychiatric toxicity compared to other opioids (due to a lack of active metabolites), minimal accumulation in renal failure, good bioavailability, low cost, and a long duration of action.^{22,23,24,14,19,20}

Due to its unique mechanism of action, methadone is particularly useful for the management of hard to treat pain syndromes such as neuropathic pain and cancer pain requiring higher and more frequent doses of shorter-acting opioids.^15,16,18 Compared with morphine, the gold standard reference opioid, methadone also acts as an agonist of κ- and σ-opioid receptors, as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, and as an inhibitor of serotonin and norepinephrine uptake.^2,7 Specifically by inhibiting the NMDA receptor, methadone dampens a major excitatory pain pathway within the central nervous system.¹² Compared to other opioids, methadone's effects on NMDA inhibition may explain it's improved analgesic efficacy and reduced opioid tolerance.^16,17

Methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl. However, it also has a unique pharmacokinetic profile. Compared with short-acting and even extended-release formulations of morphine, methadone displays a comparatively longer duration of action and half-life. These effects make methadone a good option for the treatment of severe pain and addiction as fewer doses are needed to maintain analgesia and prevent opioid withdrawal symptoms. However, methadone also has an unpredictable half-life with interindividual variability, which leads to an unpredictable risk of respiratory depression and overdose when initiating or titrating therapy.⁸

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis, sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. At higher doses, methadone use can result in respiratory depression, overdose, and death.^22,23,24

Treatment of opioid addiction with methadone, buprenorphine, or slow-release oral morphine (SROM) is termed Opioid Agonist Treatment (OAT) or Opioid Substitution Therapy (OST). The intention of substitution of illicit opioids with the long-acting opioids used in OAT is to prevent withdrawal symptoms for 24-36 hours following dosing to ultimately reduce cravings and drug-seeking behaviours. Use of OAT is also intended to lead to social stabilization by reducing crime rates, incarceration, use of illicit opioids such as heroin or fentanyl, and ultimately marginalization.¹³ Illegally purchased opioids present many other harms in addition to overdose as they can be injected and may be laced with other substances that increase the risk of harm or overdose. Provision of OAT is often combined with education about harm reduction including use of clean needles and injection supplies in an effort to reduce the risks associated with injection drug use such as contraction of HIV and Hepatitis C and other complications including skin infections, abscesses, or endocarditis.

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Methadone (DB00333)

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Weight

Average: 309.4452
Monoisotopic: 309.209264491

Chemical Formula

C₂₁H₂₇NO

Synonyms

• (+-)-Methadone
• (+/-)-Methadone
• (±)-methadone
• 6-Dimethylamino-4,4-diphenyl-3-heptanone
• dl-Methadone
• Metadona
• Methadone
• Methadonum

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Pharmacology

Indication

Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.²³

Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services.^22,24

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Opioid addiction		••••••••••••	•••••
Management of	Opioid addiction		••••••••••••	•••••
Management of	Severe pain		••••••••••••	•••••	•••••••••• ••••••••••• ••••••••• •••••••

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Associated Therapies

• Opioid Detoxification
• Maintenance therapy

Contraindications & Blackbox Warnings

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Pharmacodynamics

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction.

Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures.^19,20

Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone.

Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine.^22,23,24

Dependence and Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.^22,23,24

Cardiac Conduction Effects

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). 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 disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia.^22,23,24

Respiratory Depression and Overdose

Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase.

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 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. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose.

Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed.

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.^22,23,24

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.^22,23,24

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 µ-opioid agonists who are being converted to methadone, thus making the 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.^22,23,24

Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls.

Misuse, Abuse, and Diversion of Opioids

Methadone is a mu-agonist opioid with an abuse liability similar to morphine. 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 Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion.^22,23,24

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).^22,23,24

Gastrointestinal Effects

Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions.^22,23,24

Sexual Function/Reproduction

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. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility.^22,23,24

Mechanism of action

Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity.²

Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer.² The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects.

While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, 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.

Target	Actions	Organism
AMu-type opioid receptor	agonist	Humans
ANMDA receptor	antagonist	Humans
ADelta-type opioid receptor	agonist	Humans
ANeuronal acetylcholine receptor subunit alpha-7	agonist	Humans
U5-hydroxytryptamine receptor 3A	antagonist	Humans
UNeuronal acetylcholine receptor subunit alpha-3	antagonist	Humans
UNeuronal acetylcholine receptor subunit alpha-4	antagonist	Humans
UNeuronal acetylcholine receptor subunit beta-2	antagonist	Humans

Absorption

Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known.^2,22,23,24

Following 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. Effect of food on the bioavailability of methadone has not been evaluated.^2,22,23,24

Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility.^2,22,23,24

Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function.² There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study.⁸

Volume of distribution

Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L⁸ with monographs listing it between 1.0-8.0L/kg.^22,23,24 As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone.^2,24

Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels.²⁴

Protein binding

Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma.^2,24,11

Metabolism

Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive.^22,24,11

The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference.^9,11

Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP].¹⁰ The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone.¹⁰ See the pharmacogenomics section for further information.

Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval.¹⁰

Hover over products below to view reaction partners

• Methadone
  • 2-Ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP)
    • 2-Ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP)

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.

Half-life

Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours⁸ with official monographs listing it between 7-59 hours.^22,23,24

Clearance

Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours⁸ with approved monographs listing it between 1.4 to 126 L/h.^22,23,24

Adverse Effects

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Toxicity

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

Pathways

Pathway	Category
Methadone Action Pathway	Drug action
Methadone Metabolism Pathway	Drug metabolism

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
ATP-dependent translocase ABCB1	---	GG	2677G > T/A	pgx review	The ABCB1 2677G > T/A GG genotype affects methadone pharmacokinetics and was associated with a 20% reduction in CL/F.	Details
Cytochrome P450 2B6	CYP2B6*6	Not Available	516G >T	pgx review	The presence of the rs3745274 minor allele (CYP2B6 515G > T) has been found to affect methadone pharmacokinetics. It reduces CL/F by up to 20% for S-methadone only and reduces (R)- and (S)-methadone N-demethylation,	Details
Cytochrome P450 2B6	CYP2B6*4	Not Available	c.785A>G	pgx review	The presence of the rs2279343 allele (CYP2B6 785A>G) amplifies CYP2B6 activity and has been found to increase methadone metabolism and clearance.	Details
Cytochrome P450 2B6	CYP2B6*2	Not Available	c.64C > T	pgx review	The presence of the rs8192709 allele has been found to result in a lower metabolic ratio of [Methadone]/[EDDP] in heterozygotes.	Details
Cytochrome P450 2B6	CYP2B6*5	Not Available	1459C > T	pgx review	There is conflicting evidence for the effects of the presence of the rs3211371 allele (CYP2B6 1459C>T). Some studies show it results in increased CYP2B6 activity and ultimately reduced (S)-methadone plasma levels and increased clearance[A184661] while others have demonstrated the opposite effects. [A184658]	Details
Cytochrome P450 2B6	CYP2B6*9	Not Available	516G>T		The presence of the rs3745274 allele (CYP2B6 516G>T) has been shown to reduce CYP2B6 activity, increase (R,S)-methadone plasma levels, and reduce (R)- and (S)-methadone N-demethylation.	Details
Cytochrome P450 2B6	CYP2B6*11	Not Available	136A > G	pgx review	The presence of the rs35303484 allele (CYP2B6 135A>G) has been shown to increase (S)-methadone plasma levels and decrease clearance.	Details
Cytochrome P450 2B6	CYP2B6 3′UTR	Not Available	c.*1355A > G	pgx review	The presence of the rs707265 allele (CYP2B6 c.*1355A>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Cytochrome P450 2B6	CYP2B6 3′UTR	Not Available	c.*1277A > T	pgx review	The presence of the rs1038376 allele (CYP2B6 c.*1277A > T) has been shown to increase the [(S)-MTD/MTD Dose] plasma ratio and reduce (S)-MTD clearance.	Details
Cytochrome P450 2B6	CYP2B6 intron 1	Not Available	c.172–468 T > G	pgx review	The presence of the rsl0403955 allele (c.172–468 T>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Cytochrome P450 2B6	CYP2B6 intron 5	Not Available	c.923–197T > C		The presence of the rs2279345 allele (CYP2B6 c.923–197T>C) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Cytochrome P450 3A4	CYP3A4*1B	Not Available	−392A > G	pgx review	The presence of the rs2740574 allele (CYP3A4 −392A>G) has been shown to increase (S)-methadone plasma levels.	Details

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	1,2-Benzodiazepine may increase the central nervous system depressant (CNS depressant) activities of Methadone.
Abacavir	The therapeutic efficacy of Abacavir can be decreased when used in combination with Methadone.
Abametapir	The serum concentration of Methadone can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Methadone can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Methadone.

Food Interactions

• Avoid alcohol.
• Take with or without food. Food does not significantly affect absorption.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Methadone hydrochloride	229809935B	1095-90-5	FJQXCDYVZAHXNS-UHFFFAOYSA-N

International/Other Brands

Adolan / Depridol / Heptadon / Heptanon / Ketalgin / Mephenon / Physeptone

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Diskets	Tablet	40 mg/1	Oral	Hikma Pharmaceuticals USA Inc.	1973-03-14	Not applicable
Dolophine	Tablet	5 mg/1	Oral	West-Ward Pharmaceuticals Corp.	1947-08-13	Not applicable
Dolophine	Tablet	10 mg/1	Oral	West-Ward Pharmaceuticals Corp.	1947-08-13	Not applicable
Metadol	Tablet	5 mg	Oral	Paladin Labs Inc.	2003-07-29	Not applicable
Metadol	Solution	10 mg / mL	Oral	Paladin Labs Inc.	2000-05-05	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Apo-methadone	Tablet	1 mg	Oral	Apotex Corporation	Not applicable	Not applicable
Apo-methadone	Tablet	10 mg	Oral	Apotex Corporation	Not applicable	Not applicable
Apo-methadone	Tablet	5 mg	Oral	Apotex Corporation	Not applicable	Not applicable
Apo-methadone	Tablet	25 mg	Oral	Apotex Corporation	Not applicable	Not applicable
Jamp Methadone Oral Concentrate	Solution	10 mg / mL	Oral	Jamp Pharma Corporation	2020-10-30	Not applicable

Categories

ATC Codes

N07BC02 — Methadone

• N07BC — Drugs used in opioid dependence
• N07B — DRUGS USED IN ADDICTIVE DISORDERS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

N02AC52 — Methadone, combinations excl. psycholeptics

• N02AC — Diphenylpropylamine derivatives
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

Drug Categories

• Analgesics
• Anticholinergic Agents
• Antidepressive Agents
• Antitussive Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C18 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 CYP3A7 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Diphenylpropylamine Derivatives
• Drugs that are Mainly Renally Excreted
• Drugs Used in Addictive Disorders
• Drugs Used in Opioid Dependence
• High-risk opioids
• Ketones
• Moderate Risk QTc-Prolonging Agents
• Narcotics
• Nervous System
• Nicotinic Antagonists
• NMDA Receptor Antagonists
• Opiate Agonists
• Opioid Agonist
• Opioids
• P-glycoprotein inhibitors
• Peripheral Nervous System Agents
• QTc Prolonging Agents
• Respiratory System Agents
• Sensory System Agents
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin Agents
• Serotonin Modulators
• Thyroxine-binding globulin inducers

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Diphenylmethanes

Direct Parent

Diphenylmethanes

Alternative Parents

Aralkylamines / Gamma-amino ketones / Trialkylamines / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives

Substituents

Amine / Aralkylamine / Aromatic homomonocyclic compound / Carbonyl group / Diphenylmethane / Gamma-aminoketone / Hydrocarbon derivative / Ketone / Organic nitrogen compound / Organic oxide

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

tertiary amine, benzenes, ketone (CHEBI:6807)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

UC6VBE7V1Z

CAS number

76-99-3

InChI Key

USSIQXCVUWKGNF-UHFFFAOYSA-N

InChI

InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3

IUPAC Name

6-(dimethylamino)-4,4-diphenylheptan-3-one

SMILES

CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

References

Synthesis Reference

Charles J. Barnett, "Modification of methadone synthesis process step." U.S. Patent US4048211, issued August, 1952.

US4048211

General References

1. Kell MJ: Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting. J Addict Dis. 1994;13(1):5-26. [Article]
2. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [Article]
3. Joseph H, Stancliff S, Langrod J: Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med. 2000 Oct-Nov;67(5-6):347-64. [Article]
4. Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor RS: Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess. 2007 Mar;11(9):1-171, iii-iv. [Article]
5. Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL: Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction. 2005 Oct;100(10):1496-509. [Article]
6. Haroutiunian S, McNicol ED, Lipman AG: Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012 Nov 14;11:CD008025. doi: 10.1002/14651858.CD008025.pub2. [Article]
7. Codd EE, Shank RP, Schupsky JJ, Raffa RB: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70. [Article]
8. Bart G, Lenz S, Straka RJ, Brundage RC: Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study. Drug Alcohol Depend. 2014 Dec 1;145:185-93. doi: 10.1016/j.drugalcdep.2014.10.014. Epub 2014 Oct 24. [Article]
9. Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, Tan HK, Lin L, Wu CS, Su LW, Huang CL, Yang YH, Liu ML, Lin KM, Chen CY, Liu SC, Wu HY, Chan HW, Tsai MH, Lin PS, Liu YL: CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011 Aug;31(4):463-9. doi: 10.1097/JCP.0b013e318222b5dd. [Article]
10. Ahmad T, Valentovic MA, Rankin GO: Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics. Biochem Pharmacol. 2018 Jul;153:196-204. doi: 10.1016/j.bcp.2018.02.020. Epub 2018 Feb 16. [Article]
11. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [Article]
12. Deng M, Chen SR, Pan HL: Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain. Cell Mol Life Sci. 2019 May;76(10):1889-1899. doi: 10.1007/s00018-019-03047-y. Epub 2019 Feb 20. [Article]
13. Ferri M, Minozzi S, Bo A, Amato L: Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD009879. doi: 10.1002/14651858.CD009879.pub2. [Article]
14. Toombs JD, Kral LA: Methadone treatment for pain states. Am Fam Physician. 2005 Apr 1;71(7):1353-8. [Article]
15. Kahan M, Wilson L, Mailis-Gagnon A, Srivastava A: Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians. Part 2: special populations. Can Fam Physician. 2011 Nov;57(11):1269-76, e419-28. [Article]
16. Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer. 1993 Oct 1;72(7):2266-72. doi: 10.1002/1097-0142(19931001)72:7<2266::aid-cncr2820720734>3.0.co;2-p. [Article]
17. Hewitt DJ: The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000 Jun;16(2 Suppl):S73-9. [Article]
18. Bruera E, Neumann CM: Role of methadone in the management of pain in cancer patients. Oncology (Williston Park). 1999 Sep;13(9):1275-82; discussion 1285-8, 1291. [Article]
19. Mercadante S: Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain. 1998 Jan;74(1):5-9. [Article]
20. Sarhill N, Davis MP, Walsh D, Nouneh C: Methadone-induced myoclonus in advanced cancer. Am J Hosp Palliat Care. 2001 Jan-Feb;18(1):51-3. doi: 10.1177/104990910101800113. [Article]
21. FDA Approved Drug Products: DISKETS (methadone hydrochloride) tablets, for oral suspension CII [Link]
22. FDA Label - Methadone [File]
23. Health Canada Label - Metadol [File]
24. Health Canada Label - Methadose [File]

External Links

Human Metabolome Database

HMDB0014477

KEGG Drug

D08195

KEGG Compound

C07163

PubChem Compound

4095

PubChem Substance

46505722

ChemSpider

3953

BindingDB

82507

RxNav

6813

ChEBI

167309

ChEMBL

CHEMBL651

Therapeutic Targets Database

DAP000267

PharmGKB

PA450401

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Methadone

FDA label

Download (327 KB)

MSDS

Download (60 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Adverse Drug Reaction (ADR) / Arrhythmia / Effect of Drugs	1
4	Completed	Health Services Research	Human Immunodeficiency Virus (HIV) Infections / Opioid Use Disorder (OUD)	1
4	Completed	Prevention	Chronic Pain / Postoperative pain	1
4	Completed	Prevention	Post Operative Nausea and Vomiting (PONV) / Postoperative pain	1
4	Completed	Treatment	Acquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections / Opiate Addiction / Substance Dependence	1

Pharmacoeconomics

Manufacturers

• Roxane laboratories inc
• Vistapharm inc
• Mallinckrodt chemical inc
• Bioniche pharma usa llc
• Sandoz inc
• Mallinckrodt inc
• The pharmanetwork llc

Packagers

• AAIPharma Inc.
• Bioniche Pharma
• Blenheim Pharmacal
• Bryant Ranch Prepack
• D.M. Graham Laboratories Inc.
• Direct Dispensing Inc.
• Dispensing Solutions
• Diversified Healthcare Services Inc.
• Eon Labs
• Lake Erie Medical and Surgical Supply
• Mallinckrodt Inc.
• Nucare Pharmaceuticals Inc.
• Physicians Total Care Inc.
• Redpharm Drug
• Roxane Labs
• Stat Rx Usa
• Vistapharm Inc.
• Xanodyne Pharmaceuticals Inc.

Dosage Forms

Form	Route	Strength
Solution	Parenteral	10.000 mg
Tablet	Oral	40.000 mg
Solution	Oral	1.000 g
Syrup	Oral	5 mg/ml
Injection, solution	Parenteral	10 MG/1ML
Syrup	Oral	1 MG/ML
Syrup	Oral	10 MG/20ML
Syrup	Oral	20 MG/20ML
Syrup	Oral	5 MG/20ML
Tablet	Oral	1 mg
Tablet	Oral	10 mg
Tablet	Oral	25 mg
Tablet	Oral	5 mg
Solution	Oral	1 mg / mL
Solution	Oral	10 mg/mL
Solution	Oral
Solution	Oral	1 MG/ML
Solution	Oral	5 MG/ML
Injection, solution, concentrate	Oral	10 mg/ml
Injection, solution	Intravenous	10 mg/1mL
Syrup	Oral
Tablet	Oral	40 mg/1
Concentrate	Oral	10 mg/1mL
Injection, solution	Intramuscular; Intravenous; Subcutaneous	10 mg/1mL
Powder	Oral	1 g/1g
Solution	Oral	10 mg/5mL
Solution	Oral	5 mg/5mL
Tablet	Oral	10 mg/1001
Tablet	Oral	10 mg/1
Tablet	Oral	5 mg/1001
Tablet	Oral	5 mg/1
Solution	Oral	10 mg / mL
Tablet, soluble	Oral	40 mg
Syrup	Oral	2 mg/ml
Tablet	Oral	20 mg
Tablet	Oral	40 mg
Tablet	Oral	60 mg
Solution, concentrate	Oral

Prices

Unit description	Cost	Unit
Methadone hcl 10 mg/ml vial	7.48USD	ml
Methadone hcl powder	5.91USD	g
Metadol 25 mg Tablet	1.69USD	tablet
Metadol 10 mg Tablet	0.9USD	tablet
Methadone intensol 10 mg/ml	0.85USD	ml
Metadol 5 mg Tablet	0.56USD	tablet
Methadone hcl 10 mg tablet	0.37USD	tablet
Metadol Concentrate 10 mg/ml Liquid	0.37USD	ml
Methadone hcl 5 mg tablet	0.34USD	tablet
Dolophine hcl 10 mg tablet	0.21USD	tablet
Metadol 1 mg Tablet	0.17USD	tablet
Methadose 5 mg tablet	0.16USD	tablet
Methadose 10 mg tablet	0.14USD	tablet
Dolophine hcl 5 mg tablet	0.13USD	tablet
Metadol 1 mg/ml Solution	0.1USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	235.0 °C	Not Available
logP	3.93	HANSCH,C ET AL. (1995)
pKa	9.2	A497

Predicted Properties

Property	Value	Source
Water Solubility	0.0059 mg/mL	ALOGPS
logP	4.14	ALOGPS
logP	5.01	Chemaxon
logS	-4.7	ALOGPS
pKa (Strongest Acidic)	19.79	Chemaxon
pKa (Strongest Basic)	9.12	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	20.31 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	97.27 m3·mol-1	Chemaxon
Polarizability	36.28 Å3	Chemaxon
Number of Rings	2	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9968
Blood Brain Barrier	+	0.9772
Caco-2 permeable	+	0.7841
P-glycoprotein substrate	Substrate	0.6224
P-glycoprotein inhibitor I	Inhibitor	0.7627
P-glycoprotein inhibitor II	Non-inhibitor	0.9101
Renal organic cation transporter	Non-inhibitor	0.5851
CYP450 2C9 substrate	Non-substrate	0.7822
CYP450 2D6 substrate	Non-substrate	0.7743
CYP450 3A4 substrate	Substrate	0.66
CYP450 1A2 substrate	Inhibitor	0.5312
CYP450 2C9 inhibitor	Non-inhibitor	0.864
CYP450 2D6 inhibitor	Inhibitor	0.5449
CYP450 2C19 inhibitor	Non-inhibitor	0.8177
CYP450 3A4 inhibitor	Non-inhibitor	0.5507
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.6586
Ames test	Non AMES toxic	0.946
Carcinogenicity	Carcinogens	0.6315
Biodegradation	Not ready biodegradable	0.9888
Rat acute toxicity	3.5250 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.947
hERG inhibition (predictor II)	Inhibitor	0.7606

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0uk9-9080000000-1cd26d01442b30c05512
GC-MS Spectrum - EI-B	GC-MS	splash10-00di-9310000000-d71659ee33e210178a79
GC-MS Spectrum - CI-B	GC-MS	splash10-03di-0009000000-c583dd769bf5998ac160
Mass Spectrum (Electron Ionization)	MS	splash10-00di-9210000000-7542d8c3f742c7713c13
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-03di-0029000000-43d5c8da88c1aa260682
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-014i-0090000000-31b8655a24b30962bd8c
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-01b9-0590000000-9894da52e88d32034318
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-014i-0940000000-fedb75bd4c80c6c4fea9
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-0gb9-0940000000-a27b5f75aab7fac8931d
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-014i-0090000000-1d4283f6dffa11b765e7
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-03di-0019000000-416fca50b212d00b968c
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-014i-0090000000-ad95925610aed55afe91
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0aor-1980000000-6d4d0adc4c8db177eaad
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-1920000000-0548504791642aa3b2e0
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-2920000000-dd2ce03c02a54aa24f83
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-3910000000-1af5f56241eabde05700
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-03di-0019000000-015df6e52b9d5ebe5cb2
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-014i-0091000000-b328f3740a7ca4485324
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0aor-0980000000-24074e0b5c722d7279c0
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-1920000000-5477eb89abafab290dd1
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-2920000000-b4ffdf7888e464422c0c
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-0a4i-3910000000-6053da2e4586dbcae300
LC-MS/MS Spectrum - LC-ESI-ITFT , positive	LC-MS/MS	splash10-014i-0090000000-0863c3130ca5df5f25b6
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03di-2049000000-e4dc57c9820c45a073f6
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0195000000-9ceca80e6194b023ef37
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0aor-1590000000-acdafc2b8098d3d28d12
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0mvl-5091000000-bedeea2c566c5eed9730
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00b9-1910000000-27eccf3db1d5c07158a4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014i-2940000000-7725c672d6932f42dc70
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	189.3222635	predicted	DarkChem Lite v0.1.0
[M-H]-	174.8972	predicted	DeepCCS 1.0 (2019)
[M+H]+	189.7020635	predicted	DarkChem Lite v0.1.0
[M+H]+	177.2552	predicted	DeepCCS 1.0 (2019)
[M+Na]+	189.6602635	predicted	DarkChem Lite v0.1.0
[M+Na]+	184.34584	predicted	DeepCCS 1.0 (2019)

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	4.1	N/A	N/A	A18240

Details

Binding Properties1. Mu-type opioid receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

Curator comments

Full agonist.

General Function

Voltage-gated calcium channel activity

Specific Function

Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...

Gene Name

OPRM1

Uniprot ID

P35372

Uniprot Name

Mu-type opioid receptor

Molecular Weight

44778.855 Da

References

1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
3. Shi J, Hui L, Xu Y, Wang F, Huang W, Hu G: Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat. 2002 Apr;19(4):459-60. [Article]
4. Kakko J, von Wachenfeldt J, Svanborg KD, Lidstrom J, Barr CS, Heilig M: Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence. Biol Psychiatry. 2008 Jan 15;63(2):172-7. Epub 2007 Sep 11. [Article]
5. Kvam TM, Baar C, Rakvag TT, Kaasa S, Krokan HE, Skorpen F: Genetic analysis of the murine mu opioid receptor: increased complexity of Oprm gene splicing. J Mol Med (Berl). 2004 Apr;82(4):250-5. Epub 2004 Jan 9. [Article]
6. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [Article]
7. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11. [Article]

Details2. NMDA receptor (Protein Group)

Kind

Protein group

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Voltage-gated cation channel activity

Specific Function

NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...

---

Components:

Name	UniProt ID
Glutamate receptor ionotropic, NMDA 1	Q05586
Glutamate receptor ionotropic, NMDA 2A	Q12879
Glutamate receptor ionotropic, NMDA 2B	Q13224
Glutamate receptor ionotropic, NMDA 2C	Q14957
Glutamate receptor ionotropic, NMDA 2D	O15399
Glutamate receptor ionotropic, NMDA 3A	Q8TCU5
Glutamate receptor ionotropic, NMDA 3B	O60391

References

1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
3. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11. [Article]
4. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [Article]
5. Hanania T, Manfredi P, Inturrisi C, Vitolo OV: The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats. Exp Clin Psychopharmacol. 2019 Aug 1. pii: 2019-44083-001. doi: 10.1037/pha0000310. [Article]
6. Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H: Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol. 1998 Sep 1;56(5):553-9. doi: 10.1016/s0006-2952(98)00088-4. [Article]
7. FDA Label - Methadone [File]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
Ki (nM)	1000	N/A	N/A	A27621

Details

Binding Properties3. Delta-type opioid receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Opioid receptor activity

Specific Function

G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...

Gene Name

OPRD1

Uniprot ID

P41143

Uniprot Name

Delta-type opioid receptor

Molecular Weight

40368.235 Da

References

1. Gross ER, Hsu AK, Gross GJ: Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion. Anesth Analg. 2009 Nov;109(5):1395-402. doi: 10.1213/ANE.0b013e3181b92201. [Article]
2. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [Article]

Details4. Neuronal acetylcholine receptor subunit alpha-7

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Toxic substance binding

Specific Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The cha...

Gene Name

CHRNA7

Uniprot ID

P36544

Uniprot Name

Neuronal acetylcholine receptor subunit alpha-7

Molecular Weight

56448.925 Da

References

1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [Article]
2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [Article]

Details5. 5-hydroxytryptamine receptor 3A

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Voltage-gated potassium channel activity

Specific Function

This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gate...

Gene Name

HTR3A

Uniprot ID

P46098

Uniprot Name

5-hydroxytryptamine receptor 3A

Molecular Weight

55279.835 Da

References

1. Deeb TZ, Sharp D, Hales TG: Direct subunit-dependent multimodal 5-hydroxytryptamine3 receptor antagonism by methadone. Mol Pharmacol. 2009 Apr;75(4):908-17. doi: 10.1124/mol.108.053322. Epub 2009 Jan 8. [Article]

Details6. Neuronal acetylcholine receptor subunit alpha-3

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Ligand-gated ion channel activity

Specific Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Gene Name

CHRNA3

Uniprot ID

P32297

Uniprot Name

Neuronal acetylcholine receptor subunit alpha-3

Molecular Weight

57479.54 Da

References

1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [Article]
2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [Article]

Details7. Neuronal acetylcholine receptor subunit alpha-4

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Ligand-gated ion channel activity

Specific Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...

Gene Name

CHRNA4

Uniprot ID

P43681

Uniprot Name

Neuronal acetylcholine receptor subunit alpha-4

Molecular Weight

69956.47 Da

References

1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [Article]
2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [Article]

Details8. Neuronal acetylcholine receptor subunit beta-2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Antagonist

General Function

Ligand-gated ion channel activity

Specific Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...

Gene Name

CHRNB2

Uniprot ID

P17787

Uniprot Name

Neuronal acetylcholine receptor subunit beta-2

Molecular Weight

57018.575 Da

References

1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [Article]
2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [Article]

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Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55