The history of methadone and methadone prescribing

Responses to opiate use vary across the world and are, in many ways, as much a product of history as of anything else.

Understanding the history of responses to opiate use puts into context the prescribing policies we see today - and may help us anticipate the future.

Starting with the first organised responses to opiate use in the UK this section describes the influences on policy and practice, including those from the USA, the history of the discovery of methadone and the development of its unique role in the treatment of opiate use.

The services offering a treatment response to opiate use that are currently available in the UK are then described in the light of the historical background.

The origin of legal controls

At the turn of the century most countries had few laws restricting the possession of drugs.

Growing international concern about opiate use led to the First Opium Convention in the Hague in 1912. Britain as a signatory agreed to the principle of adopting controls over opium, morphine and cocaine.1

In July 1916, following rumours that soldiers on leave were using cocaine, a 'Defence of the Realm Regulation' was enacted making it illegal to possess cocaine unless prescribed by a doctor.

In 1920 and 1923 the list of drugs that were illegal to possess, import or sell was expanded by the Dangerous Drugs Acts to include opium and opium derivatives such as heroin. Doctors could still prescribe these drugs, but each prescription could only be for a maximum of three collections from the pharmacy.

This caused some concern among doctors because it left them unclear as to when prescribing these drugs was legitimate and was seen as Home Office interference with medical autonomy.

In 1924 the Ministry of Health set up a committee, chaired by Sir Humphrey Rolleston, to look into these issues.

The Rolleston report

This report, published in 1926, accepted the principle that all doctors could legitimately prescribe addictive drugs as part of the treatment of dependence. The report argued that abstinence should be the long-term goal of treatment, but also accepted that long-term prescribing was a legitimate way of treating people who were unable to stop taking drugs.

It recommended that two groups receive treatment with morphine or heroin, namely:

Those who are undergoing treatment for the cure of addiction by the gradual withdrawal method, and
Persons for whom, after every effort has been made for the cure of the addiction, the drug cannot be withdrawn either because:
complete withdrawal produces such serious symptoms which cannot be satisfactorily treated under the normal conditions of private practice; or the patient, while capable of leading a normal life so long as he takes a certain non-progressive quantity, usually small, of the drug of addiction, ceases to be able to do so when the regular allowance is withdrawn.
This pragmatic approach in which the care of opiate users was entrusted to doctors continued without serious review until the late 1950s. However the number of people being treated at any time was only a few hundred - and they were generally considered to be stable.

When the first statistics were compiled in 1935 they counted 700 'addicts'. About one sixth of these were medical practitioners. This size and pattern of addiction remained similar through the 1930s, '40s and '50s. In 1959 there were 454 known addicts of whom the majority (204) were addicted to morphine, 68 to heroin and 60 to methadone. 76% had become addicted following treatment for pain and 15% were health professionals.2

The discovery of methadone
The origins of the research

In 1939 Otto Eisleb and a colleague O Schaumann, scientists working for the large chemicals conglomerate I G Farbenindustrie at Hoechst-Am-Main, Germany, discovered an effective opioid analgesic drug which they numbered compound 8909 and called Dolantin.3 This was the discovery of pethidine. As with diamorphine (heroin) before, and buprenorphine (Temgesic) since, the early hopes of it being 'a new non-addictive analgesic' were not realised.

However the powerful analgesic action of pethidine was much needed during the Second World War. It was being produced commercially by 19393 and at the height of the war in 1944 annual production had risen to 1600 kg.4

Meanwhile close colleagues Max Bockmühl and Gustav Ehrhart were working on compounds with a similar structure to Dolantin in the hope of finding:

• Water-soluble hypnotic (sleep-inducing) substances5
• Effective drugs to slow the gastrointestinal tract to make surgery easier6
• Effective analgesics that were structurally dissimilar to morphine - in the hope that they would be non-addictive5 and escape the strict controls on opiates.

There is no evidence, as had been widely believed both here and in the USA, that they were working as part of a German attempt, directed by Hitler, to replace opium supplies which had been cut off by the war.

This myth has been widely expanded to attributing one of methadone's first trade names - Dolophine - to being a derivation of Adolf and even that it was called Adolophine in Germany - the 'A' being dropped after the war. In fact the name Dolophine was created for the drug as a trade name after the war by the Eli-Lilly pharmaceutical company in America. It was probably derived from the French dolor (pain) and fin (end).6

The discovery of 'Hoechst 10820': methadone

During 1937 and the spring and summer of 1938 Bockmühl and Ehrhart worked on the creation of another new substance in the group which they called 'Hoechst 10820' and, later, polamidon.

A patent application was filed on 11 September 1941 and the discovery was formally credited to Bockmühl and Ehrhart (see overleaf).7

It has been asserted that because the new compound's two-dimensional structure had no resemblance to morphine its pain-killing properties were not recognised until after the war had ended.6 But although the town of Hoechst was extensively bombed during the war the I G Farbenindustrie factory suffered only slight damage and so limited experimental work was able to continue, stopping only when supplies of coal ran out or when the rail links were broken. In the autumn of 1942, after it had been determined that the drug was both an analgesic and a spasmolytic, it was handed over to the military for further testing under the code name Amidon.8 There was no attempt to try and get polamidon production levels up to those of pethidine. Construction continued at Hoechst on a new pethidine production plant.4
An explanation for it not being exploited more fully between 1939 and 1945 was given by Dr K K Chen - an American doctor who did much of the early clinical research work after the war - who said a former employee of I G Farbenindustrie had told him in personal correspondence that they had discounted its use because of the side effects.8 Chen presumed that the doses used in the experiments had been too high, causing nausea, overdose etc.

After the war

All German patents and trade names, including those for polamidon, were requisitioned by the allies as spoils of war. The I G Farbenindustrie factory was in a US occupation zone and therefore came under American management. The US Foreign Economic Management Department sent a 'Technical Industrial Intelligence Committee' team of 4 men (Kleiderer, Rice, Conquest and Williams) to investigate the war-time work at Hoechst.

In 1945 The Kleiderer report was published by the US Department of Commerce Intelligence. For the first time in print it reported the findings of Bockmühl and Ehrhart; and that despite having a different structure, polamidon closely mimicked the pharmacological action of morphine.9

The formula was distributed around the world and exploited by many companies, which is why it has so many different trade names. As a result this production of analgesics, which was no longer commercially viable, practically stopped at Hoechst after the war. The pethidine plant, by then half finished, was instead dedicated to the production of penicillin.4 The I G Farbenindustrie empire was broken up by the allies and the plant that had developed methadone became part of a new company called Hoechst A G.

Eli-Lilly and other American and UK pharmaceutical companies quickly began clinical trials and commercial production of the new drug, polamidon.

In 1947 Isbell et al, who had been experimenting extensively with methadone, published a review of their experimental work with humans and animals and clinical work with medical patients.10 They gave volunteers up to 200mg 4 times daily, and found rapidly developing tolerance and euphoria. They had to reduce levels with patients on these high doses because of, among other things: '...signs of toxicity ... inflammation of the skin ... deep narcosis and ... a general clinical appearance of illness.' They also found that 'morphine addicts responded very positively.' They concluded that methadone had high addiction potential: 'We believe that unless the manufacture and use of methadon [methadone] are controlled addiction to it will become a serious health problem.'

There were many early studies all of which found methadone to be an effective analgesic. Bockmühl and Ehrhart were not able to submit the preliminary research results that they had given to Kleiderer on the 60 or so compounds they had discovered in the 'new class of spasmolytic and analgesic compounds' until July 1948. They were published in 1949.11

Early use in the UK

The earliest accounts of methadone use in the UK were from papers published in the Lancet in 1947 describing it as 'at least as powerful as morphine, and 10 times more powerful than pethidine' and, subsequently, a study of its use as an obstetric analgesic at the University College, London.12 This study, however, was terminated because of respiratory depression in the newborn babies.

Early advertisements claimed that Physeptone (Wellcome's trade name for methadone) carried 'little risk of addiction' and the consensus was that it was a better analgesic than morphine. It is therefore likely that the first people who became dependent on it had either been treated for pain or treated by doctors who thought it to be less dependency-forming than other opiates.

In 1955 the Home Office was aware of 21 methadone addicts; by 1960 the number had risen to 60.2 In 1968 when the present Home Office notification system was set up the first two notifications arrived on 1 January: a 19 year-old female from London SW12 and a 20 year-old male from London SE23. By the end of the year 297 people had been notified as addicted to methadone.13 In 1969, as a result of the setting up of clinics (see below) the number of people reported as using methadone had risen to 1687.14

The 1960s

In 1958, at the instigation of the Home Office, the Department of Health set up a Committee on Drug Addiction to review policy in the light of the new synthetic opiates that had come on to the market. The report, often called the 'First Brain Report', was published in 1961. Its conclusions were, effectively, an endorsement of the Rolleston report.

In the early 1960s the number of opiate addicts increased and the pattern of use began to change: there were younger people and more people taking opiates for pleasure rather than as part of medical treatment.

Heroin first overtook morphine as the most notified drug of addiction in 1962.15 Most of these 'new' addicts lived in London. All of the heroin was pharmaceutically pure and much of it was prescribed by a small number of doctors.

There was concern that, contrary to the principles of the Rolleston report, some doctors were showing little, if any, inclination to 'make every effort for the cure of addiction'. This concern led to the recall of the Committee on Drug Addiction in 1964.

The second Brain report

This report was published in 1965 and resulted in changes in policy and the law:

• The right to prescribe heroin and other specified controlled drugs for the treatment of addiction was restricted to doctors licensed by the Home Office
• Doctors were legally required to notify addicts to the new Home Office Addicts Index
• Drug clinics were set up to provide specialised medical treatment of addiction.

Contrary to the belief of many doctors methadone has never been one of the controlled drugs that can only be prescribed by specially licensed doctors.

The late 1960s

By 1966 there were 6 times more notified heroin addicts than morphine addicts.15

In 1968 the new drug clinics began operating. Their establishment attracted a large population of opiate users into contact with the service and the number of notified addicts rose to 2881 of whom 2240 were addicted to heroin. The clinics were set up to:

• Provide a legal supply of drugs
• Attract heroin users into contact with the service
• Prevent the illicit market in drugs
• Prevent the crime associated with illicit drug use
• Help people get off drugs altogether.

In the first years of the drug clinics they prescribed drugs that the clients were already taking, mostly in injectable form. Some clinics had 'fixing rooms' where injecting equipment was provided so that clients could inject their medication.

By the end of 1969, in central London, diverted supplies of injectable methadone, mostly in the form of Physeptone ampoules and 10mg diamorphine tablets, were huge. These tablets were known as 'Jacks' which is the origin of the phrase 'Jacking up'. Indeed Physeptone ampoules were so easily available on the black market that they were used:

• As a suitable sterile fluid to flush out and clean injecting equipment between 'hits' of 10mg diamorphine tablets
• Instead of water to dissolve drugs
• As a 'freebie' to encourage bulk sales of the 10mg diamorphine tablets.

These supplies came from both the clinics and a small number of doctors in central London who had large numbers of opiate users on their lists to whom they prescribed freely.

The 1970s

During the 1970s the incidence of heroin use continued to rise. For the first time this included a significant quantity of imported, illicit heroin.

The clinics started to doubt the efficacy of prescribing the client's drug of choice as a way of producing change. Clinic prescribing practice moved away from predominantly prescribing injectable heroin towards prescribing oral methadone, on the basis that it was more therapeutic to prescribe a non-injectable drug and because its long half-life meant it could be taken once daily rather than every few hours.

A landmark study from that time (and the only randomised controlled trial in this area) compared the effects of randomly allocating heroin users to either of these two treatments.16 The study, carried out by Martin Mitcheson and Richard Hartnoll between 1971 and 1976, found that methadone treatment produced more polarised effects than heroin treatment. The methadone group were more likely to leave treatment but were also more likely to achieve abstinence. The heroin group were more likely to stay as they were. The researchers concluded that:

'The provision of heroin maintenance may be seen as maintaining the status quo, although ameliorating the problems of acquiring drugs ... by contrast the refusal to prescribe heroin (and offer oral methadone instead) may be seen as a more active policy of confrontation that is associated with greater change.'

As the results of this study became available the clinics were starting to deal with a new and different client group: large numbers of working-class heroin users who were smoking rather than injecting the relatively cheap heroin that had appeared on the market from the Middle East.

In the light of the changing client group - who were not asking for injectable drugs - and the results of the study, the clinics defined their role as one of promoting change and increasingly moved towards the use of oral methadone.

The shift away from maintenance prescribing

Some clinics began to review the efficacy of maintenance prescribing. For example a small study carried out in 1975 by the Glasgow Drug Clinic found that ceasing to prescribe methadone to new patients led to them improving as much as maintained patients, except in the area of crime.17 Although weak scientifically, the publication of studies such as this in the late 1970s led to questioning of the value of maintenance prescribing, or, indeed, any prescribing.

The 1980s

In the early 1980s there was a second period of dramatic increase in the prevalence of heroin use. The numbers of notified addicts which had increased slowly through the 1970s from 509 in 1973 to 607 in 1976 and to 1110 in 1979, doubled from 1979 to 1982 and had doubled again by 1984.18

This great increase in the early 1980s differed from that of 20 years earlier, in that it was not restricted to London: it occurred all over Britain and many of these new users smoked their heroin (known as 'chasing the dragon') rather than injecting it.

The prescribing response was largely one of methadone mixture detoxification programmes - the 'gradual withdrawal method' of the Rolleston report.

However the increase in the number of opiate users meant that services had to expand and become more widely available. Prompted by this change and the Advisory Council on the Misuse of Drugs (ACMD) Report on Treatment and Rehabilitation19 the Government responded with a funding initiative which saw the development of a non-statutory drug service and/or a Community Drug Team in most health districts. Most of these new services got involved in methadone prescribing either by employing a clinical assistant or a consultant psychiatrist on a sessional basis to prescribe methadone, or through working with GPs.

AIDS and the re-emergence of maintenance prescribing

The possibility of rapid transmission of the HIV virus among intravenous drug users and reports of high HIV prevalence figures among intravenous drug users in Edinburgh prompted a fundamental review of drugs policy.

The 1988 report of the Advisory Council on the Misuse of Drugs (ACMD) on AIDS and drug misuse20 Part 1 led to the development of community-based needle and syringe exchange schemes all over Britain.

The report articulated the policy of directing treatment towards abstinence by achieving intermediate goals such as:

• Stopping injecting with unsterile equipment
• Taking drugs by mouth or inhalation
• Taking prescribed rather than illegal drugs.

The report advocated a comprehensive approach to the prevention of the spread of HIV, following its first conclusion that:

'...HIV is a greater threat to public and individual health than drug misuse. The first goal of work with drug misusers must therefore be to prevent them acquiring or transmitting the virus. In some cases this will be achieved through abstinence. In others, abstinence will not be achievable for the time being and efforts will have to focus on risk reduction. Abstinence remains the ultimate goal but efforts to bring it about in individual cases must not jeopardise any reduction in HIV risk behaviour which has already been achieved.'

This reversed the abstinence-orientated prescribing policy of the preceding years as it legitimised longer-term prescribing to enable users to stop injecting. Although there was a wider range of prescribing options supplementing short-term detoxification, most doctors continued to prescribe methadone mixture only for limited periods of time.

In time it transpired that the high HIV infection rates in Edinburgh were a local phenomenon resulting from factors such as unavailability of injecting equipment, and were not being replicated across Britain.21, 22 However the services that were set up on the assumption that these HIV prevalence rates were typical have almost certainly been instrumental in maintaining relatively low rates of HIV seroprevelance among injecting drug users.

The opposition to methadone maintenance prescribing

This shift was not universal. The prescribing clinic in Sheffield was disbanded and replaced by short-term in-patient detoxification and residential rehabilitation.23 At first in Edinburgh - where the epidemic of HIV had left half of the city's injectors HIV positive - methadone was only offered to those who were HIV positive. It took until 1988 to establish a co-ordinated prescribing service.24

In Merseyside some doctors revived the prescribing of heroin in injectable and smokeable forms.

The 1980s conflict over prescribing policy led many to regard as a cause célèbre the disciplining of Dr Anne Dally who had espoused maintenance prescribing. The General Medical Council found Dr Dally guilty of 'serious professional misconduct' because she had 'irresponsibly treated addicts privately by providing methadone in the long term without reasonable medical care.' Some saw this as punishment by the medical establishment for her policy of maintenance prescribing and prescribing of injectables as part of private practice.25, 26

The American experience

It is helpful to understand the American experience with methadone maintenance because:

• This is where the concept originated
• Of the different ways in which treatment has been delivered there
• Much of the research into methadone treatment has been carried out in the USA.

The American experience shows that treating patients with the same medication can be viewed and executed in very different ways, and that these may be as important as the drug itself in determining the effects of treatment.

From the First World War onwards American and British drug policies took very different directions. In the USA in 1914 the Harrison Act controlled the sale and possession of drugs. It contained references to the prescription of addictive drugs for 'legitimate medical purposes ... prescribed in good faith'. However in 1922 the Behrman case, in stark contrast to UK policy, determined that it was a crime for a physician to prescribe a narcotic drug to an addict.

By 1938 approximately 25000 doctors had been prosecuted on narcotics charges and 3000 had served prison sentences! Federal agents relied heavily on the testimony of drug users to secure these convictions - they secured these testimonies by supplying the users with small quantities of drugs.6 Understandably this resulted in doctors having very little to do with the treatment of addiction.

After the Second World War there were just two large drug treatment facilities providing in-patient treatment to 'help addicts abandon drug taking'. The one at Fort Worth in Texas offered a service to men who lived west of the Mississippi and the one in Lexington in Kentucky served men east of the Mississippi and women from the entire USA.

The first use of methadone in the treatment of opiate dependence

An account of the first use of methadone in the treatment of addiction given by Dr M J Kreek in 1989 is quoted by Thomas Payte.6

In the early 1960s Dr Marie Nyswander and Dr Vincent Dole, a respected American psychiatrist and research scientist, had found that they could not stabilise opiate users on morphine without continually increasing the dose. They reviewed the medical literature in search of possible alternatives and pioneered the radical step of prescribing methadone which was effective orally, and seemed from pain research and some detoxification experience to be longer acting (they were not able to measure blood levels in those days). They soon found that once they had reached an adequate treatment dose that they could maintain people on that dose for long periods of time.

Dole encountered powerful resistance from the US Bureau of Narcotics whose agents told him that he was breaking the law and that they would 'put him out of business'. In view of the past history of doctors' experiences in court he took the brave step of inviting them to prosecute so that a 'proper ruling on the matter could be made' - they declined.

Nyswander and Dole: the pioneers of American methadone maintenance

Within a year Nyswander and Dole had developed 'Methadone Maintenance Treatment'. Their experiments with this approach began with treating people in a locked ward with elaborate security procedures. The project soon discovered that this level of security was unnecessary and it was gradually abandoned by moving first to an open ward, and then having patients reside in the ward whilst they went out in the daytime to work. This innovative treatment was offered only to people with a long history of heroin use and failed treatment.

Nyswander and Dole based their approach on the theory that, once addicted, opiate addicts suffer from a metabolic disorder, similar in principle to metabolic disorders such as diabetes. Just as insulin normalises the dysfunction in diabetes, so methadone was proposed to normalise the dysfunction of opiate addiction. They argued the necessity for large doses of methadone (80mg to 150mg) to establish a 'pharmacological blockade' against the effects of heroin, that would prevent addicts from experiencing euphoria if they took it.

Even though Nyswander and Dole viewed methadone treatment as a physical treatment for a physiological disorder, their initial attempts to use methadone maintenance were combined with intensive psycho-social rehabilitation. Many of their patients clearly derived great benefit from this innovative treatment.27

The spread of methadone maintenance programmes

This new form of treatment spread rapidly in the USA but was often implemented in a rigid way that lost some of the characteristics of Nyswander and Dole's original work. Consequently few programmes have produced such good results as their early work. The ways in which it was implemented in the early 1970s were strongly affected by political and other factors, with extensive government regulation.

The medical treatment was - and is - encased in a rigid delivery system. In most programmes patients attend the programme daily to drink their methadone and are regularly monitored through testing of urine samples (the collection of which is supervised) and counselling. Some programmes offer a variety of help and psycho-social treatment from group therapy to help in finding jobs. Once patients are stabilised they are able to earn the 'privilege' of taking home doses of methadone for one or more days.

The numbers of patients receiving Methadone Maintenance Treatment (MMT) in the USA rose: in 1992 there were about 120000 patients served by around 800 programmes. There is a great deal of variation in the rehabilitation and psycho-social services that are offered in addition to methadone and also in the dosage levels employed. Over half of patients receive below 60mg daily - which is accepted in the USA as the therapeutic minimum28 - well below the level recommended by Nyswander and Dole's research.

Prescribing services available in the UK today

Methadone prescribing services in the UK could be described as a patchwork, with most areas having a service of some kind but with many variations between health districts. The titles of services can vary a lot but, in addition to GPs, there are three main types of community service:

• Street agencies
• Community drug teams
• Drug clinics.

There are also a small number of doctors who offer treatment to drug users as part of:

• Private medical practice.

General Practitioners (GPs)

Everyone has the right to have a GP. Although many refuse to treat drug dependency all GPs are entitled to prescribe methadone (and most other drugs) in order to treat addiction. GPs notify nearly half of all those treated with methadone.

They do not usually have in-house testing facilities such as urinalysis, but primary health care teams increasingly have staff such as counsellors in their surgery.

GPs vary considerably in their attitudes and practice in treating drug problems. If a GP is not inclined to prescribe methadone for an opiate user there is little that can be done to force them because doctors are able to use considerable discretion in deciding what they think is the best treatment for their patients.

Street agencies: easy-reach, often non-statutory services

Such services are often called the 'Drug Advisory Service' or similar and tend to be based in town centres, designed to be easily accessible and easy to approach. They may be staffed by a mix of paid staff and voluntary workers, usually providing a telephone helpline, advice and counselling, needle exchange and guidance on how to access residential rehabilitation and detoxification or methadone treatment. They usually serve a wide range of people with drug problems, and their families.

Community drug teams (CDT)

Statutory services are usually staffed by nurses and social workers and in some cases also by clinical psychologists, probation officers, counsellors, and/or medical practitioners. Some community drug teams play the same role as street agencies, but usually focus on a prescribing and counselling service. They may have their own doctor to prescribe, or may liaise with the patient's GP to put together a package of care involving monitoring and counselling from the CDT. CDTs tend to serve mainly opiate users, but usually have a remit to help people and their relatives with other types of drug problems.

Drug clinics

Drug clinics tend to be based in hospital and emphasise out-patient medical care; they are often headed by a consultant psychiatrist, but staffed by doctors, nurses, social workers, and possibly occupational therapists and/or clinical psychologists.

Clients may have to attend on a daily basis or several times a week to obtain their prescriptions. In some cases, usually 'low threshold methadone maintenance programmes', they may be required to drink their methadone at the clinic in front of a member of staff.

To cope with the large volume of prescription writing most clinics use a computer to generate prescriptions - see Section 5: methadone and the law, handwriting exemptions. These prescriptions may then be sent to retail pharmacies for dispensing. Alternatively, methadone may be dispensed from a local hospital pharmacy as this is often cheaper.

Drug clinics may have access to specialist in-patient facilities for detoxification and other in-patient treatments. Some clinics have facilities for dispensing methadone to patients who have to attend daily to receive their medication. Drug clinics usually offer a variety of treatment options.

Large centre prescribing is often an essential part of a service to a large number of opiate users, hence their predominance in large cities.

Private practice

Despite the experience of Dr Anne Dally (see above) there are still a small number of doctors in private practice who prescribe oral or injectable methadone to drug users. Some do it out of a belief in the need for more sympathetic, responsive services and offer a useful adjunct to the NHS. Others are not so principled, and some of these are still a source of drugs for the illicit market, and are of little therapeutic value to their patients. However, large dose, unsupervised prescribing is not confined to private practice and is a feature of a minority of all service types.

In general, private services are preferred by clients who are in full-time employment, and appreciate the shorter waiting times, increased doses and willingness to prescribe on a maintenance basis.

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