Methadone

Generic Name
Methadone
Brand Names
Diskets, Dolophine, Metadol, Metadol-D, Methadose
Drug Type
Small Molecule
Chemical Formula
C21H27NO
CAS Number
76-99-3
Unique Ingredient Identifier
UC6VBE7V1Z
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.

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. 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. Specifically by inhibiting the NMDA receptor, methadone dampens a major excitatory pain pathway within the central nervous system. Compared to other opioids, methadone's effects on NMDA inhibition may explain it's improved analgesic efficacy and reduced opioid tolerance.

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.

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.

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. 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.

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.

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.

Associated Conditions
Opioid Addiction, Severe Pain
Associated Therapies
Opioid Detoxification, Maintenance therapy

The Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome

Completed
Conditions
Interventions
First Posted Date
2012-12-21
Last Posted Date
2014-06-13
Lead Sponsor
Children's Hospital Medical Center, Cincinnati
Target Recruit Count
20
Registration Number
NCT01754324
Locations
🇺🇸

The University Hospital, Cincinnati, Ohio, United States

🇺🇸

Mercy Hospital Anderson, Cincinnati, Ohio, United States

Methadone in Post-Herpetic Neuralgia Pain

Phase 3
Completed
Conditions
Interventions
First Posted Date
2012-12-19
Last Posted Date
2013-03-18
Lead Sponsor
University of Sao Paulo
Target Recruit Count
10
Registration Number
NCT01752699

Neurocognitive Effects of Opiate Agonist Treatment

First Posted Date
2012-11-27
Last Posted Date
2022-02-11
Lead Sponsor
Albert Einstein College of Medicine
Target Recruit Count
135
Registration Number
NCT01733693
Locations
🇺🇸

Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States

🇺🇸

Fordham University, Bronx, New York, United States

Diversion to Treatment for Injection Drug Users Arrested for Possession of Heroin

First Posted Date
2012-11-08
Last Posted Date
2014-12-11
Lead Sponsor
Johns Hopkins University
Target Recruit Count
1
Registration Number
NCT01723527
Locations
🇺🇸

Center for Learning and Health, Baltimore, Maryland, United States

Treatment of Neonatal Abstinence Syndrome

First Posted Date
2012-11-08
Last Posted Date
2013-11-27
Lead Sponsor
Eastern Maine Medical Center
Target Recruit Count
40
Registration Number
NCT01723722
Locations
🇺🇸

Eastern Maine Medical Center, Bangor, Maine, United States

Pharmacogenomics of Methadone in Spine Fusion Surgery

Phase 1
Withdrawn
Conditions
Interventions
First Posted Date
2012-09-03
Last Posted Date
2015-04-22
Lead Sponsor
Northwestern University
Registration Number
NCT01677650
Locations
🇺🇸

Northwestern Memorial Hospital, Chicago, Illinois, United States

Drug Interaction Study of Isavuconazole and Methadone

First Posted Date
2012-04-20
Last Posted Date
2012-07-02
Lead Sponsor
Astellas Pharma Global Development, Inc.
Target Recruit Count
24
Registration Number
NCT01582425
Locations
🇺🇸

Parexel International, LLC, Glendale, California, United States

Efficacy Evaluation of Traditional Chinese Medicine JITAI Combined Comprehensive Model Among Heroin Addicts After Detoxification

First Posted Date
2012-04-18
Last Posted Date
2015-11-18
Lead Sponsor
Shanghai Mental Health Center
Target Recruit Count
554
Registration Number
NCT01580163
Locations
🇨🇳

National Institute on Drug Dependence,Peking University, Beijing, Beijing, China

🇨🇳

The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

Reducing Drug Use and HIV Risk in Drug-dependent Adults Arrested for Prostitution

First Posted Date
2012-03-22
Last Posted Date
2014-12-11
Lead Sponsor
Johns Hopkins University
Target Recruit Count
38
Registration Number
NCT01560221
Locations
🇺🇸

The Center for Learning and Health, Baltimore, Maryland, United States

Buprenorphine and Methadone for Opioid-dependent Chronic Back Pain Patients

Phase 4
Completed
Conditions
Interventions
First Posted Date
2012-03-21
Last Posted Date
2020-11-03
Lead Sponsor
State University of New York at Buffalo
Target Recruit Count
19
Registration Number
NCT01559454
Locations
🇺🇸

UB/MD Family Medicine, Inc., Amherst, New York, United States

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