PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
methadone

2D structure

Overview

Generic Names: (+/-)-Methadone; (+/-)-Methadone hydrochloride; DL-Methadone hydrochloride; Methadon; Methadone HCL; Methadone hydrochloride; Phenadone hydrochloride; dl-Methadone
Trade Names: Adanon; Adanon hydrochloride; Adolan; Algidon; Algolysin; Algovetin; Althose hydrochloride; Amidon; Amidone; Biscuits; Butalgin; Depridol; Diaminon; Diaminon hydrochloride; Dollies; Dolly; Dolofin hydrochloride; Dolohepton; Dolophin; Dolophin hydrochloride; Dolophine; Dolophine HCL; Fenadon; Fenadone; Heptadon; Heptadone; Heptanon; Ketalgin; Ketalgin hydrochloride; Mecodin; Mephenon; Methadone HCL Intensol; Methadone M; Methadose; Methaquaione; Miadone; Moheptan; Phenadone; Physeptone; Polamidon; Polamidone; Tussol; Westadone
Brand Mixtures: (+/-)-Tussal
PharmGKB Accession Id: PA450401

Description

A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. It has actions and uses similar to those of morphine. It also has a depressant action on the cough center and may be given to control intractable cough associated with terminal lung cancer. Methadone is also used as part of the treatment of dependence on opioid drugs, although prolonged use of methadone itself may result in dependence. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1082-3) (source: Drug Bank)

Indication

For the treatment of dry cough, drug withdrawal syndrome, opioid type drug dependence, and pain. (source: Drug Bank)

ATC Therapeutic Categories

  • N02AC:Diphenylpropylamine derivatives
  • N07BC:Drugs used in opioid dependence
  • R05DA:Opium alkaloids and derivatives

Pharmacology, Interactions, and Contraindications

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. (source: Drug Bank)

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. (source: Drug Bank)

Food Interactions

Take without regard to meals. Avoid alcohol. Usually diluted in fruit juice. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

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. (source: Drug Bank)

Protein Binding

In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). (source: Drug Bank)

Absorption

Well absorbed following oral administration. The bioavailability of methadone ranges between 36 to 100%. (source: Drug Bank)

Toxicity

In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. (source: Drug Bank)

Isomeric SMILES Code:

CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c2ccccc2 (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs6277 at chr11:112788669 in DRD2
    Phenotype: The 957CC carriers were more frequently non-responders to methadone treatment (OR=2.4; p=0.02). The 957CC carriers were 25% (95% CI = 15-36%) in the non-responder group (n = 73) whereas they were only 12% (95% CI = 8-18%) in the responder group (n = 165; χ2 = 5.9; p = 0.015). No significant difference was observed for the TaqI A genotype frequency in responder and non-responder groups (p = 0.9). Study size: 238 patients. Study population: Caucasian.
    Variant Name:
    DRD2: C957T
    Related Drugs:
    methadone
    Related Diseases:
    Substance-Related Disorders
    Evidence:
    PMID:18687376
  2. rs6275 at chr11:112788687 in DRD2
    Risk or phenotype-associated allele: T. Phenotype: The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. Study size: 85. Study population/ethnicity: Caucasian. Type of association: GN.
    Related Drugs:
    methadone
    Evidence:
    PMID:19373123
  3. rs2070995 at chr21:38008835 in KCNJ6
    Risk or phenotype-associated genotype: AA. Phenotype: The average methadone dose during the first year of substitution therapy were significantly larger in AA carriers (n=4) than in the other rs2070995 genotypes (p=0.003). Study Size: 85. Study population: Caucasian.
    Related Drugs:
    methadone
    Evidence:
    PMID:20220551
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ARRB2
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP19A1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2B6
  • CO
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  •   
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Has annotations
DRD2
  •   
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
KCNH2
  •   
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ6
  •   
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
NR1I2
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
OPRM1
  •   
  • PD
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
UGT2B7
  •   
  •   
  • PK
  •   
  • GN
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
CHRNA10 Uncurated Annotation (source: Drug Bank)
GRIN3A Uncurated Annotation (source: Drug Bank)
OPRM1 Uncurated Annotation (source: Drug Bank)

PharmGKB Curated Pathways

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
ritonavir
  •   
  •   
  • PK
  •   
  •   
Publications

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
amobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
amprenavir Uncurated Annotation The protease inhibitor decreases the effect of methadone (source: Drug Bank)
aprobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
butabarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
butalbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
butethal Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
carbamazepine Uncurated Annotation Carbamazepine decreases levels of methadone (source: Drug Bank)
cimetidine Uncurated Annotation Cimetidine increases the effect of the narcotic (source: Drug Bank)
efavirenz Uncurated Annotation The antiretroviral agent decreases the effect of methadone (source: Drug Bank)
ethotoin Uncurated Annotation The hydantoin decreases the effect of methadone (source: Drug Bank)
fluvoxamine Uncurated Annotation Fluvoxamine increases the effect and toxicity of methadone (source: Drug Bank)
fosamprenavir Uncurated Annotation The protease inhibitor decreases the effect of methadone (source: Drug Bank)
fosphenytoin Uncurated Annotation The hydantoin decreases the effect of methadone (source: Drug Bank)
heptabarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
hexobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
mephenytoin Uncurated Annotation The hydantoin decreases the effect of methadone (source: Drug Bank)
methohexital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
methylphenobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
naltrexone Uncurated Annotation Naltrexone may precipitate a withdrawal syndrome in opioid-dependent individuals (source: Drug Bank)
nelfinavir Uncurated Annotation Nelfinavir decreases the effect of methadone (source: Drug Bank)
nevirapine Uncurated Annotation The antiretroviral agent decreases the effect of methadone (source: Drug Bank)
pentobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
phenobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
phenytoin Uncurated Annotation The hydantoin decreases the effect of methadone (source: Drug Bank)
primidone Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
quinidine Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
rifabutin Uncurated Annotation The rifamycin decreases the effect of methadone (source: Drug Bank)
rifampin Uncurated Annotation The rifamycin decreases the effect of methadone (source: Drug Bank)
rifapentine Uncurated Annotation The rifamycin decreases the effect of methadone (source: Drug Bank)
ritonavir Uncurated Annotation The protease inhibitor decreases the effect of methadone (source: Drug Bank)
secobarbital Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
talbutal Uncurated Annotation The barbiturate decreases the effect of methadone (source: Drug Bank)
zidovudine Uncurated Annotation Methadone increases the effect and toxicity of zidovudine (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Opioid-Related Disorders
  •   
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Pain
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Poisoning
  •   
  •   
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. Physicochemical determinants of human renal clearance

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00333
KEGG Compound ID:
C07163
PubChem Compound ID:
4095
PubChem Substance ID:
149416
IUPHAR Ligand ID:
1605

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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