methadone

What Is Methadone?

According to the pharmaceutical encyclopedia Drugs.com [1], methadone is “an opioid medication” that “reduces withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the ‘high’ associated with the drug addiction.” It is also “used as a pain reliever and as part of drug addiction detoxification and maintenance programs.”

Brand names: Dolophine, Methadose, Methadose Sugar-Free, Diskets, Methadone Intensol

Forms: According to Healthline [2], “Methadone comes as an oral tablet, oral dispersible tablet (tablet that can be dissolved in liquid), oral concentrate solution, and oral solution. Methadone also comes in an intravenous (IV) form, which is only given by a healthcare provider.”

Methadone: History

In 1936, Hitler announced a Four-Year Plan for Nazi Germany that would establish German independence through economic and industrial means that would negate the country’s need for outside resources — including opium, at the time most widely produced in Southeast Asia and used for morphine. According to a German nonprofit and non-government harm reduction advocacy organization [3], “methadone was first synthetized in 1939 at the pharmaceutical laboratories of the I.G. Farbenkonzern … the product of a long and continuous research chain in the area of synthetic antipyretics and analgetics that had already been initiated in the early 1880s.”

Their research, which began at the end of the 1920, led to the discovery of Pethidin/pethidine, “an effective opioid analgesic drug which was launched in Germany in 1939 under the trade name Dolantin.” Additional research led to the discovery of another compound that became known as Amidon, but after the war, “all German patents, trade names and research records were requisitioned and expropriated by the allied forces.” The Council on Pharmacy and Chemistry of the American Medical Association called Amidon “methadone,” and the U.S. company Eli-Lilly purchased rights to commercial production of the formula, which was given the trade name Dolophine and first introduced in 1947, approved by the Food and Drug Administration (FDA) as a cough preventative and suppressant.

Over the next decade, however, researchers began to see that methadone, while similar to morphine in its effects, seemed to be longer-acting, and “clinical research showed that opiate withdrawal syndrome could be treated effectively by substituting methadone for morphine and slowly reducing the dose over a 7–10 day period,” according to the book Federal Regulations of Methadone Treatment [4]. “Its primary use in addiction treatment was to withdraw addicts from heroin, well before methadone maintenance treatment was developed.”

This research was widely disseminated, leading to the involvement of the FDA, which clashed with researchers in New York who were experimenting with methadone’s effectiveness among heroin addicts in the city. From 1970 to 1974, the government hammered out “standards of treatment for narcotic addiction treatment,” the goal of which was initially an “eventual drug free state” before acknowledging “that for some patients the drug may be needed for long periods of time.” However, these methadone treatment programs were to provide “minimum program services,” which “in addition to the dispensing of methadone, were to include counseling, rehabilitation, and other social services to help the patient ‘become a well-functioning member of society.’”

methadoneIn 1974, the Narcotic Addict Treatment Act codified existing methadone treatment laws by separating the dispensation of methadone into two categories: “detoxification treatment,” involving less than 21 days, in decreasing doses “sufficient to prevent withdrawal symptoms ‘as a method of bringing the individual to a drug free state,’” and maintenance treatment, which would involve “the dispensing, for a period in excess of twenty-one days, of a narcotic drug in the treatment of an individual for dependence upon heroin or other morphine-like drugs." The new law required a separate, annual registration with the Drug Enforcement Agency for practitioners distributing methadone by either method, thus tying government approval to methadone maintenance in both long- and short-term settings.

In the 1980s, the rules governing the use of methadone were further defined:

  • “Mandatory urine testing for methadone maintenance patients of at least eight tests in the first year of treatment, at least quarterly tests for the second and successive years, and monthly tests for each six-day take-home patient.”
  • The standard requirement of two years of addiction to qualify for maintenance was reduced to one year (and lowered to 16 years of age), if clinical evaluation showed that the individual was physically dependent.
  • The minimum ratio of one counselor for every 50 patients was spelled out (although the initial screening process could thereafter be carried out by a “well-trained program counselor” rather than a mental health professional).
  • “The initial dosage was limited to 30 mg per day, with an additional 10 mg allowable in the 4 to 8 hours after initial administration if needed to suppress withdrawal symptoms.” And
  • “The final rule restricted take-home methadone to a liquid form for ‘responsible’ patients.”

Over the next several decades, further revisions have fine-tuned the regulations governing methadone maintenance, especially as the concern over diversion — the selling or over-consumption of take-home doses — has become more pressing. In addition, with methadone maintenance in use as an opioid treatment therapy for almost 50 years now, the long-term health risks are coming into clearer focus, and as a result, “there are a variety of recommendations on the use of electrocardiograms (EKG) in patients receiving methadone,” according to the Substance Abuse and Mental Health Services Administration [5]. “Patient-specific risk minimization strategies such as careful patient monitoring; obtaining electrocardiograms as indicated by a particular patient's risk profile; and adjusting the methadone dose, as needed, for patients with identified risk factors for adverse cardiac events should also be included.”

How Does Methadone Work?

According to the National Institute on Drug Abuse (NIDA) [6], “Methadone is a synthetic opioid agonist that eliminates withdrawal symptoms and relieves drug cravings by acting on opioid receptors in the brain — the same receptors that other opioids such as heroin, morphine, and opioid pain medications activate.” The NIDA goes on to add that “although it occupies and activates these opioid receptors, it does so more slowly than other opioids and, in an opioid-dependent person, treatment doses do not produce euphoria,” but that’s debatable among the addiction treatment community.

“With methadone, and to a lesser extent Suboxone (buprenorphine), you’re still using a mood-altering substance, even if it’s for long-term maintenance,” says Travis Pyle, director of medical services at the drug and alcohol treatment center Cornerstone of Recovery. “You’re still using a substance that can be abused, and as addicts, we can’t use substances that can be abused without abusing them at some point in time, because the risk and the opportunity are too great. Chronic opiate use changes the neurochemistry of your brain, which most experts believe is reversible over time if the opiates are discontinued, but the brain is not healing if you’re on methadone, because you’re still giving it the agonist that activates those opioid receptors.”

As an opioid agonist, methadone sits on those opioid receptors in the brain and activates them at a different, more sustained level than an opiate like heroin does. This was discovered in studies of methadone in the 1960s, which found that “a single daily dose of methadone could suppress withdrawal symptoms for 24 hours.” [7] In addition, methadone was demonstrated to produce a “blockade” effect, meaning that with appropriate doses, addicts who used heroin were unable “to get any euphoria or any other perceived or observable opiate effects. This lack of any override effect has been established in the clinical research laboratory and subsequently on the street. Studies have demonstrated that the double-blind administration of heroin, morphine, hydromorphone — all administered in typical ‘street’ doses to methadone-maintained patient subjects — produced no narcotic-like effects.”

NIDA points [8] to a repetitive cycle that’s often repeated several times a day that’s typical of addiction and the “severe behavioral disruption” that accompanies it. The high — the euphoria — is rapid when a drug like heroin is introduced into the body, where it activates opioid receptors in the brain. However, it’s a short-acting effect, which leads to a crash of dopamine released by those receptors, and the biological craving for more. “As a result,” according to NIDA, “methadone and buprenorphine have gradual onsets of action and produce stable levels of the drug in the brain. As a result, patients maintained on these medications do not experience a rush, while they also markedly reduce their desire to use opioids.”

That stability is what makes methadone, despite its role as an agonist, so attractive: According to a paper in the Western Journal of Medicine [9], “The aim is to substitute methadone, a legal, oral opiate with a long half-life, for the illicit, parenterally administered heroin, which is associated with a high risk of morbidity and mortality. Methadone maintenance therapy offers a reprieve from the daily life associated with the procurement and use of heroin and allows a person to reintegrate as a functional member of society. Methadone therapy achieves this by preventing opiate withdrawal symptoms, blocking the euphoric effects of heroin, and minimizing the craving for heroin.”

Methadone: Pros

methadoneAccording to the publication Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings [10], “methadone has been included on the World Health Organization's List of Essential Medicines. This highlights its importance as a treatment for heroin dependence.” The publication goes on to tout that methadone maintenance treatment (MMT) “significantly reduces drug injecting; because it reduces drug injecting, MMT reduces HIV transmission; MMT significantly reduces the death rate associated with opioid dependence; (and) MMT reduces criminal activity by opioid users.”

Other studies have been shown to give credence to these claims:

  • A Chinese review of data [11] from that country’s nationwide MMT program from 2004 to 2014 found that “MMT has significantly reduced criminal activity, and improved employment rate and social well-being, of clients of the MMT programme.”
  • While studies in the early 1990s demonstrated that “the use of methadone maintenance treatment is known to reduce the incidence of HIV in people who use drugs by reducing the frequency of injecting,” new research unveiled at the 22nd International AIDS Conference [12] demonstrated that “people on methadone maintenance treatment spent less time with a detectable viral load above 1500 copies/ml, potentially reducing the risk of HIV transmission.”
  • A 2017 study [13] of the relationship between methadone maintenance and crime found “rates of violent and non‐violent offending were lower during periods when individuals were dispensed methadone compared with periods in which they were not dispensed methadone.”
  • Methadone has shown promise in reducing the potential for overdose: According to a 2018 National Institute of Health paper [14], “during treatment with methadone, people were 59% less likely to die of an opioid overdose than people who didn’t receive medication for opioid-use disorder.”

Around the world, various studies have demonstrated that methadone can play a positive role in the treatment of opioid addiction:

  • One study of Hong Kong patients showed that a methadone program “reduced levels of drug injecting and HIV risk behaviours.” [10]
  • In Australia, methadone maintenance treatment was introduced into the prison population, 80 percent of which had used heroin in the previous month [10]. After four months of MMT, only 25 percent of inmates were still using heroin.
  • As part of an HIV prevention strategy in prisons, Indonesia introduced an MMT pilot program in 2005 [10] that demonstrated “it is feasible to introduce methadone maintenance treatment in resource-poor settings.”

In general, most of those studies come to the same generalized conclusions through controlled studies and under specific scientific conditions — “that long-term methadone use in patients who are dependent on opiates has substantial societal benefits, including diminishing illicit opiate use, reducing the transmission of HIV and hepatitis, and decreasing criminal activity and healthcare costs in this population.” [9]

Methadone: Cons

However, as Cornerstone of Recovery Clinical Director Dr. Scott Anderson points out, methadone alone isn’t the silver bullet that slays the beast of opioid addiction.

“I think that almost without fail, these drugs that are intended to fix addiction problems don’t actually fix them; the person just ends up becoming addicted to a new substance,” Anderson says. “Having worked in the field for so long, I have a skepticism about any drug that’s touted as a ‘cure’ for addiction, because our experience and my belief is that addiction involves a lot more than just a physiological process.”

Without fail, every medical and scientific body that hails methadone as an aid to addiction recovery says the same thing. The American Society of Addiction Medicine, for example, says as much in its National Practice Guideline [15]: “Psychosocial treatment, though sometimes minimally needed, should be implemented in conjunction with the use of methadone in the treatment of opioid use disorder.”

However, that’s not always the case, as a 2002 article in the journal Science and Practice Perspectives points out [16]: “Simply intensifying routine drug abuse counseling improves outcomes for patients receiving methadone, and even better response can be achieved with more specialized interventions. This work has led to a critical principle in the treatment of drug abuse: Providing appropriate intensities of proven psychological interventions enhances patients’ response to medications. Yet many programs deliver only limited counseling. Inadequate funding, large caseloads, and overextended counseling staff partially account for this problem.

“However, even when sufficient counseling is available, even in well-designed and adequately funded treatment studies, patients often attend fewer than half of their scheduled sessions. The consequences are less effective therapy and reduced staff morale.” Fifteen years later, a review of literature in the Journal of Addiction Medicine [17] found that there had been little improvement in the establishment of a balance between medication maintenance and co-occurring behavioral therapy: “Perhaps the most striking aspect of the research seems to be the lack of information about the use of specific medications in combination with specific types of psychosocial interventions during all phases of treatment and among different subpopulations,” the researchers wrote. “Furthermore, there is little empirical evidence suggesting which psychosocial treatments work best in conjunction with medication-assisted treatment as there are relatively few studies comparing the differential effectiveness of various psychosocial approaches (eg, CM, MI) for individuals receiving medications for the treatment of opioid addiction.”

methadoneAnd then there are the physical ramifications of methadone maintenance. According to the U.S. National Library of Medicine [18], common side effects may include “serious or life-threatening breathing problems, especially during the first 24 to 72 hours of your treatment and any time your dose is increased.” Patients who have any sort of chronic breathing problems are at higher risk for side effects, which can be exacerbated if methadone is combined with certain medications like antipsychotics, benzodiazepines, tranquilizers, sleeping pills, muscle relaxants and other opioids. (It should go without saying that combining methadone with alcohol “increases the risk that you will experience serious, life-threatening side effects.”)

A rare side effect associated with methadone is “prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death).” Cardiac toxicity has been written about in detail over the years, and one review of papers published between 2000 and 2013 [19] found that “the main cardiac effects of methadone include prolongation of QT interval and torsade de pointes (an abnormal heart rhythm that can lead to sudden cardiac death). Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases … effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects.”

And what about changes in the very organ that methadone supposedly helps the most — the brain? There are cautionary studies about those effects as well. One 2012 study by the Norwegian Institute of Public Health [20] found that “methadone can lead to cellular changes that affect cognitive functioning after the drug has left the body, which may be cause for concern.” A 2016 study published in the journal Nature [21] found that “chronic methadone consumption has damaging effects on (white matter) integrity” in the brain, deep tissue nerve bundles that are responsible for essential connectivity. Finally, there are risks associated with pregnant women on methadone maintenance treatment, with NIDA itself highlighting a study on how methadone can affect the development of fetal brain cells in utero [22]: “The researchers found that therapeutic doses of methadone caused increases in multiple proteins found in myelin and an increase in number of neurons with mature myelin. This accelerated maturation and myelination could potentially disrupt normal connectivity within the developing brain.”

Finally, of major concern to the drug and alcohol treatment field is the same warning associated with any other addictive drug: “Methadone may be habit forming.” [18] While it is a medication that has found a niche in the treatment of opioid addiction, it is, in itself, an opioid — meaning it can be and is abused, and there are those individuals — rare though they might be — who present to a drug and alcohol treatment center with methadone as their primary drug of choice. And those individuals, according to Dr. Fred “Kip” Wenger, Medical Director at Cornerstone of Recovery, face an uphill battle indeed, mostly because of the extended half-life of methadone: According to Drugs.com [23], withdrawal “symptoms typically appear 24 to 36 hours after the last dose of methadone. The duration of methadone withdrawal varies from person to person but can last from two to three weeks to up to six months.”

“There are multiple issues around methadone,” Wenger says. “The advantage of methadone’s long half-life, which allows it to be dosed less frequently, also becomes a distinct disadvantage in that it accumulates in the body and can result in a number of frightening side effects. Methadone is a particular challenge in detoxifying the user, mostly because it has a metabolic half-life that’s measured in days, so the drug hangs out in the body forever.

“It’s very difficult to get somebody clean from methadone, because it takes a huge amount of time. It is typically a very painful, prolonged, and uncomfortable experience to withdraw from methadone, and because the half-life is somewhere between two and three days in length, a patient can be 14 days into their (residential treatment) stay before they’re basically even feeling slightly normal.”

That can vary according to dosage, and some physicians are in favor of removing dosage caps for patients who receive the drug as part of a maintenance program — even while acknowledging that “it does take longer to taper off a higher dose.” [24] And then there are geographical factors to consider: A 2018 study [25] published in the Journal of Experimental Criminology, which examined crime statistics in areas surrounding nine outpatient methadone maintenance treatment (OMMT) facilities, found that “within a 200 (mile) radius, the presence of an OMMT facility causes a significant decrease in property and total crime but a significant increase in drug and violent crime.”

“From a harm reduction model or from a M.A.T. model, and as a doctor, I would say that methadone has saved lives,” Wenger says. “Do I think methadone is evil? I don’t think any particular drug is evil, but in the wrong hands, if it’s not monitored carefully, and if it’s not used on the appropriate patient, it can be a problem.”

SOURCES

[1]: https://www.drugs.com/methadone.html

[2]: https://www.healthline.com/health/methadone-oral-tablet#about

[3]: https://indro-online.de/en/the-history-of-methadone/

[4]: https://www.ncbi.nlm.nih.gov/books/NBK232105/

[5]: https://store.samhsa.gov/sites/default/files/d7/priv/pep15-fedguideotp.pdf

[6]: https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/how-do-medications-to-treat-opioid-addiction-work

[7]: https://www.ncbi.nlm.nih.gov/books/NBK232112/

[8]: https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/frequently-asked-questions/use-medications-methadone-buprenorphine-simply-replacing

[9]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1070723/

[10]: https://www.ncbi.nlm.nih.gov/books/NBK310658/

[11]: https://bmjopen.bmj.com/content/5/1/e005997.short

[12]: https://www.aidsmap.com/news/aug-2018/people-hiv-receiving-methadone-and-hiv-drugs-spend-less-time-detectable-viral-load

[13]: https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14059

[14]: https://www.nih.gov/news-events/nih-research-matters/medications-reduce-risk-death-after-opioid-overdose

[15]: https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf

[16]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851064/

[17]: https://journals.lww.com/journaladdictionmedicine/Fulltext/2016/04000/A_Systematic_Review_on_the_Use_of_Psychosocial.4.aspx

[18]: https://medlineplus.gov/druginfo/meds/a682134.html

[19]: https://pubmed.ncbi.nlm.nih.gov/26869865/

[20]: https://www.sciencedaily.com/releases/2012/08/120815082707.htm

[21]: https://www.nature.com/articles/srep19662

[22]: https://archives.drugabuse.gov/news-events/latest-science/impact-methadone-brain-cell-development

[23]: https://www.drugs.com/medical-answers/long-methadone-withdrawal-3543797/

[24]: https://www.hcplive.com/view/methadone-dosing-in-opioid-treatment-programs-use-the-evidence

[25]: https://link.springer.com/article/10.1007/s11292-018-9347-1