Peter R. Martin: Historical Vocabulary of Addiction, Vol. II

Methadone

According to the electronic version of the Oxford English Dictionary (OED), the noun methadone was formed within English by compounding multiple elements.  The components of the word include:  meth- (a combining form used for forming names of organic compounds or radicals with the sense “containing, derived from, or analogous to the methyl radical”) + a- (a combining form of the noun amine used specifically in names of chemical compounds containing the group NH2 combined with a non-acid radical) + d‑ (a combining form di- used as an enteringinto numerous English words, mostly technical, as dichromic, dicotyledon…) + -one (originally: a suffix forming unsystematically the names of organic compounds derived from other compounds; later, on the model of acetone: forming the names of ketones). 

The definition of methadone in OED is: “A synthetic opioid analgesic with longer-lasting and less sedative effects than those of morphine, which can be given orally and is used also in the treatment of opioid addiction;

6-dimethylamino-4,4-diphenyl-3-heptanone, (CH3)2N·CH(CH3)·CH2·C(C6H5)2·CO·CH2·CH3.”

The first reported use of the word methadon (subsequently methadone) in the English language according to OED was in a report of the Council on Pharmacy and Chemistry of the American Medical Association (1947): “The Council voted to recognize the word Methadon as the generic designation for 6-dimethylamino-4,4-diphenyl-3-heptanone.”  The Council indicated that this decision was “In view of the fact that the term Amidone, which has been applied to the chemical 6-dimethylamino-4,4-diphenyl-3-heptanone, seems to have proprietary restriction, the Council in cooperation with several interested pharmaceutical manufacturers and investigators gave consideration to the coining of a generic or nonproprietary name for the compound.”

In the early 1930s, scientists in Germany in the laboratories of what was to become Hoechst AG began research on new synthetic atropine-like spasmolytics to potentially treat asthma and renal/biliary colic (Dodds, Lawson and Williams 1943; Defalque and Wright 2007).  In 1939, Gustav Ehrhart (1894-1971) a German chemist working at Hoechst laboratories started animal pharmacological studies with one of these newly identified compounds VA 10820 (6 dimethyl amino-4,4 diphenyl-3-hepatone) and found marked analgesic (5-10 times as potent as meperidine) but weak spasmolytic activities (Schaumann 1952).  On 11 September 1941, the Hoechst chemist Max Bockmühl (1882-1949) together with Ehrhart filed an application for a patent in Germany for the synthesis of a series of compounds, among them VA 10820, newly designated as Polamidon (Bockmühl and Ehrhart 1949).  Despite the potent opioid pharmacological actions of Polamidon its structure was not related to morphine or to other naturally occurring opioids or their congeners (Martin 2019).  Compound VA 10820 was also provided to the German military for additional testing under the code name Amidon but use was abandoned due to side effects from improper dosing (Preston 1996).  Although the drug was brought to market in 1943 in Germany as a substitute for morphine it was little used during WWII.

German patents, including the one for Polamidon, were surrendered as spoils of war to the occupying forces of the victorious nations after WWII.  The US Foreign Economic Management Department sent a “Technical Industrial Intelligence Committee” team to investigate the war-time work at the Hoechst factory which was in the US occupation zone.  The report of this committee included the findings of Bockmühl and Ehrhart on Polamidon (Kleiderer, Rice, Conquest et al. ).  The report indicated that methadone was potentially addictive, but it produced less euphoria, sedation, and respiratory depression than morphine at equianalgesic doses.  The foundational research by the Hoechst scientists involved in drug development could not be published before the formula for Polamidon had been made available to many pharmaceutical companies around the world (Bockmühl and Ehrhart 1949).  

United States university, government and pharmaceutical scientists initiated extensive basic and human studies of methadone shortly after the drug became available to them (Scott and Chen 1946; Eddy 1947; Isbell, Eisenman, Wikler et al. 1948; Troxil 1948; Way, Sung and McKelway 1949; Wikler and Altschul 1950; Wikler 1952). Commercial production of the new drug was soon implemented for the primary indication of treatment of chronic pain (Bryan and Smyth 1947).  Eli Lily and Company became the pharmaceutical company to spearhead development of methadone under the trade name Dolophine in the United States and compiled and published the extensive literature on methadone that had accumulated (Lilly Research Laboratories 1971a, 1971b).

Soon after the war, it was established that methadone was a racemic compound that could be resolved to d and l optical isomers with distinctly different profile of pharmacologic properties (Thorp, Walton and Ofner 1947).  The l-isomer was found to cause significantly greater analgesic effect (>20-fold) and respiratory suppression (>30-fold) compared to the d-isomer.  

Extensive neuropsychopharmacologic research has been conducted to differentiate the isomers.  For example, the antagonist activity of the isomeric forms at the N-methyl-d-aspartate (NMDA) receptor, which is involved in various central nervous system functions such as memory, long-term potentiation and processing of nociceptive information, have been determined (Gorman, Elliott and Inturrisi 1997).  The authors proposed that a non-opioid NMDA receptor antagonist, such as d-methadone, may improve the efficacy of morphine by attenuating the development of tolerance.  More recently, uses for the d-isomer in rapid treatment of depression have been suggested (Fogaça, Fukumoto, Franklin et al. 2019).  Importantly, it was shown that the d-isomer of methadone per se had no meaningful abuse potential in recreational drug users, which would have compromised clinical use of this novel uncompetitive NMDA receptor antagonist (Shram, Henningfield, Apseloff  et al. 2023).

Although early studies of methadone in rhesus monkeys suggested little addiction potential (Woods, Wyngaarden and Seevers 1947), U.S. government scientists at the Addiction Research Center in Lexington Kentucky (Kosten and Gorelick 2002) summarized and interpreted the available findings on methadone up to that time and concluded (Isbell, Wikler, Eddy et al. 1947):

“It is the unanimous opinion of all who have been concerned with the evaluation of the addiction liability that methadon, like morphine, is dangerous with respect to habituation. Since persons with known narcotic experience get a satisfactory subjective reaction from the drug, since the drug suppresses completely the morphine abstinence syndrome, since it can be substituted satisfactorily for morphine in cases of known morphine addiction and since it produces, in our opinion, a real, however mild, withdrawal picture, methadon must be classed as an addicting drug. We believe that unless the manufacture and use of methadon are controlled addiction to it will become a serious public health problem.”

In addition to the analgesic effects of methadone, the possibility for its use to manage opioid use disorder emerged in the 1960s as addiction to heroin became more prevalent and challenging to treat.  Initially, treatment of heroin use disorder could only be accomplished by prescribing the patient’s drug of choice or other opioids (Myers 1933; Haasen, Verthein, Degkwitz et al. 2007).  However, methadone emerged on the basis that it was more therapeutic to prescribe a noninjectable drug that because of its long half-life could be taken once daily rather than every few hours.  These underlying principles motivated research from the Rockefeller Institute and other New York City hospitals (Dole and Nyswander 1965; Dole, Nyswander and Kreek 1966; Dole, Waymond, Orraca et al. 1969).  In the introduction of their first paper, Dole and Nyswander (1965) identified the challenges of this line of research:

“The question of ‘maintenance treatment’ of addicts is one that is often argued but seldom clearly defined.  If this procedure is conceived as no more than an unsupervised distribution of narcotic drugs to addicts for self-administration of doses and at times of their choosing, then few physicians could accept it as proper medical practice.  An uncontrolled supply of drugs would trap confirmed addicts in a closed world of drug taking, and tend to spread addiction.  This procedure certainly would not qualify as ‘maintenance’ in a medical sense.  Uncontrolled distribution is mentioned here only to reject it, and to emphasize the distinction between distribution and medical prescription. The question at issue in the present study was whether a narcotic medicine, prescribed by physicians as part of a treatment program, could help in the return of addict patients to normal society.

“The present study… has yielded encouraging results; patients who before treatment appeared hopelessly addicted are now engaged in useful occupations and are not using diacetylmorphine (heroin). As measured by social performance, these patients have ceased to be addicts. It must be emphasized that this paper is only a progress report, based on treatment of 22 patients for periods of 1 to 15 months. Such limited study obviously does not establish a new treatment for general application. The results, however, appear sufficiently promising to justify further trial of the procedure on a larger scale.”

The paradigm shift (Kuhn 1964) in treating opioid use disorder as “a metabolic disease” (Dole and Nyswander 1967) with introduction of methadone maintenance has stood the test of time (Johnson, Chutuape, Strain et al. 2000).   There have been newer medicines synthesized and deployed for maintenance of patients with opioid use disorder.  The first modification was the introduction of levo-alpha-acetylmethadol (LAAM), a synthetic congener of methadone hydrochloride with a 72- to 96-hour duration of action, in the treatment of long-term compulsive heroin users (Jaffe, Schuster, Smith et al. 1970).  LAAM is no longer available for clinical use (Jaffe 2007) because it was found in a controlled trial to induce electrocardiogram QTc-prolongation to a higher degree than methadone (Wieneke, Conrads, Wolstein et al. 2009).

Other approaches employed a partial opioid agonist buprenorphine (Jasinski, Pevnick and Griffith 1978) and an opioid antagonist naltrexone (Martin, Jasinski and Mansky 1973) administered orally or in depot preparations for longer dosing intervals and less diversion.  The goal with all pharmacological agents has remained abstinence from out-of-control and problematic use of illicit opioids through the replacement of the opioid or tuning opioid receptors in the addicted individual in combination with psychosocial interventions to accomplish recovery and attain balanced lives (Martin, Weinberg and Bealer 2007). 

References:

Bockmühl M, Ehrhart G. Über eine neue Klasse von spasmolytisch und analgetisch wirkenden Verbindungen, I. Justus Liebigs Ann Chem 1949;561(1):52–86.

Bryan DI, Smyth CJ. A study of the analgesic and toxic properties of dolophine (6-dimethyl-amino-4, 4-diphenyl 3-heptanone hydrochloride). A preliminary report. Am J Med 1947;3(1):122.

Council on Pharmacy and Chemistry. Methadon, generic term for 6-dimethylamino-4,4-diphenyl-3-heptanone. J Am Med Assoc 1947;134(17):1483–1483.

Defalque RJ, Wright AJ. The early history of methadone. Myths and facts. Bull Anesth Hist 2007;25(3):13–6.

Dodds EC, Lawson W, Williams PC. Morphine-like properties of diphenylethylamine and related compounds. Nature 1943;151(3839):614–5.

Dole VP, Waymond RJ, Orraca J, Edward T, Paul S, Eric C. Methadone treatment of randomly selected criminal addicts. N Engl J Med 1969;280(25):1372–5.

Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA 1965;193(8):646–50.

Dole VP, Nyswander ME. Heroin Addiction—A Metabolic Disease. Arch Intern Med 1967;120(1):19–24.

Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med 1966;118(4):304–9.

Eddy NB. A new morphine-like analgesic. J Am Pharm Assoc Pract Pharm Ed 1947;8(11):536–40.

Fogaça MV, Fukumoto K, Franklin T, Liu R-J, Duman CH, Vitolo OV, Duman RS. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology 2019;44(13):2230–8.

Gorman AL, Elliott KJ, Inturrisi CE. The d- and l- isomers of methadone bind to the non-competitive site on the N-methyl-d-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997;223(1):5–8.

Haasen C, Verthein U, Degkwitz P, Berger J, Krausz M, Naber D. Heroin-assisted treatment for opioid dependence: Randomised controlled trial. Br J Psychiatry 2007;191(1):55–62.

Isbell H, Eisenman AJ, Wikler A, Frank K. The effects of single doses of 6-dimethylamino-4,4-diphenyl-3-heptanone (amidone, methadon, or ‘10820’) on human subjects. J Pharmacol Exp Ther 1948;92(1):83.

Isbell H, Wikler A, Eddy NB, Wilson JL, Moran CF. Tolerance and addiction liability of 6-dimethylamino-4,4-diphenyl-3-heptanone (Methadon). J Am Med Assoc 1947;135(14):888–94.

Jaffe JH. Can LAAM, like Lazarus, come back from the dead? Addiction 2007;102(9):1342–3.

Jaffe JH, Schuster CR, Smith BB, Blachley PH. Comparison of Acetylmethadol and Methadone in the Treatment of Long-Term Heroin Users: A Pilot Study. JAMA 1970;211(11):1834–6.

Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 1978;35(4):501–16.

Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence. N Engl J Med 2000;343(18):1290–7.

Kleiderer EC, Rice JB, Conquest V, Williams JH. Pharmaceutical Activities at the I.G. Farbenindustrie Plant, Hoechst-am-Main, Germany. Washington, D.C.: U. S. Department of Commerce; Report No.: 981. London(?): Combined Intelligence Objectives Sub-Committee; 1945(?).

Kosten TR, Gorelick DA. The Lexington Narcotic Farm. Am J Psychiatry 2002;159(1):22–22.

Kuhn ST. The Structure of Scientific Revolutions. Chicago: The University of Chicago Press; 1964.

Lilly Research Laboratories. Methadone: A Bibliography, 1929-1971, Part 1. Int J Addict Taylor & Francis; 1971a;6(2):329–45.

Lilly Research Laboratories. Methadone: A Bibliography, 1929–1971, Part 2. Int J Addict. Taylor & Francis; 1971b;6(4):677–92.

Martin PR. Opium. Historical Vocabulary of Addiction. inhn.org.ebooks. July 4, 2019.

Martin PR, Weinberg BA, Bealer BK. Healing Addiction: An Integrated Pharmacopsychosocial Approach to Treatment. Hoboken, New Jersey: John Wiley & Sons, Inc.; 2007.

Martin WR, Jasinski DR, Mansky PA. Naltrexone, an antagonist for the treatment of heroin dependence: effects in man. Arch Gen Psychiatry 1973;28(6):784–91.

Myers GN. Substitutes for morphine and heroin. Br Med J 1933;1(3778):980.

Preston A. The Methadone Briefing. London: ISDD; 1996.

Schaumann O. Die neuen synthetischen Analgetika. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1952;216(1–2):48–77.

Scott CC, Chen KK. The action of 1,1-Diphenyl-1-(Dimethylaminoisopropyl)-Butanone-2, a potent analgesic agent. J Pharmacol Exp Ther 1946;87(1):63.

Shram MJ, Henningfield JE, Apseloff G, Gorodetzky CW, De Martin S, Vocci FL, Sapienza FL, Kosten TR, Huston J, Buchhalter A, Ashworth J, Lanier R, Folli F, Mattarei A, Guidetti C, Comai S, O’Gorman C, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users. Transl Psychiatry 2023;13(1):192.

Thorp RH, Walton E, Ofner P. Optical isomers of Amidone, with a note on isoAmidone. Nature 1947;160(4070):605–6.

Troxil EB. Clinical evaluation of the analgesic methadon. J Am Med Assoc 1948;136(14):920–3.

Way EL, Sung C-Y, McKelway WP. The absorption, distribution and excretion of d,l methadone. J Pharmacol Exp Ther 1949;97(2):222.

Wieneke H, Conrads H, Wolstein J, Breuckmann F, Gastpar M, Erbel R, Scherbaum N. Levo-α-acetylmethadol (LAAM) induced QTc-prolongation - results from a controlled clinical trial. Eur J Med Res 2009;14(1):7.

Wikler A. Reactions of dogs without neocortex during cycles of addiction to morphine and methadone. AMA Arch Neurol Psychiatry 1952;67(5):672–84.

Wikler A, Altschul S. Effects of methadone and morphine on the electroencephalogram of the dog. J Pharmacol Exp Ther 1950;98(4):437.

Woods LA, Wyngaarden JB, Seevers MH. Addiction potentialities of 1, 1-Diphenyl-1-(β-Dimethylaminopropyl)-Butanone-2 Hydrochloride (Amidone) in the monkey. Proc Soc Exp Biol Med 1947;65(1):113–4.

April 4, 2024