Chapter 1

Introduction

Methadone - a synthetic opiate - was developed in Germany between the two World Wars. The lack of natural morphine to treat human war casualties necessitated the development of a synthetic analgesic. After World War II methadone was discovered in the secret German war archives and the United States continued its further analysis. Due to its opiate-like analgesic properties, the viewpoint emerged that methadone could cure morphine and heroin-dependency. However, studies showed that the addictive potency of methadone was similar to that of heroin or morphine (Isbell et al., 1948; Isbell and Vogel, 1949).

Methadone maintenance treatment
In 1965 Dole and Nyswander reported their observations on the use of methadone to treat heroin users in New York. A group of 22 male long-term heroin-dependent volunteers entered a three-phase study. in phase one, lasting six weeks, the patients were admitted to a hospital ward for a thorough physical and mental evaluation. After the first week of hospitalisation, they were free to leave the ward, usually - but not always - accompanied by a member of the staff. In phase two, patients were treated ambulatory, returning every day for methadone medication. Methadone was administered in the presence of a clinical nurse. A daily urine specimen was collected for analysis. In tl3is phase assistance was provided in obtaining jobs, housing, and education. Phase three - the goal of the treatment - comprised the achievement of social rehabilitation and stabilisation. Clinical supervison of the medication in this phase remained as carefull as in phase two.

In phase one, the volunteers were given gradually increasing oral doses of methadone. Those patients who entered the study with mild or severe abstinence symptoms were relieved promptly by one or two doses of 10 mg morphine sulphate intramuscularly, after which oral methadone treatment started with 10 or 20 mg twice daily. Over the next four weeks the methadone dose was gradually increased up to a stabilization level, ranging between 50 and 150 mg methadone daily. At the end of the stabilisation period, the methadone dose was reduced to a one-per-day schedule given in the morning. The results of the study showed that methadone possesses three beneficial effects:

1 it relieves the 'narcotic hunger' or craving for heroin,
2 it blocks the euphoric effects of additionally used heroin,
3 it has a half-life of approximately 24 hours, which enables once-daily dosing.

All subjects in the study stated that previous attempts to abstain from using heroin after following a detoxification program failed, due to their continued craving for heroin shortly after discharge from the detoxification unit. Some of the subjects experimented with heroin during the methadone maintenance. They reported that they did not experience the usual effect formerly rendered by injecting heroin. After this lack of benefit, they discontinued these experiments and discouraged the other test subjects from using additional heroin. The authors concluded that methadone maintenance is able to block the euphoria of additional heroin use. The main benefit of using methadone instead of morphine or heroin itself was its long half-life of approximately 24 hours, which allowed for a once daily oral intake instead of several parenteral administrations per day with the shorter acting morphine or heroin.

These findings marked the beginning of the use of methadone as a maintenance drug for the treatment of morphine and heroin-dependent persons (Dole and Nyswander, 1965), which would become known as methadone maintenance treatment (MMT)

Methadone maintenance in The Netherlands
The treatment of opiate-dependency with methadone in The Netherlands started in Amsterdam in 1968 by Krauweel, Geerlings and several independent general practitioners (Liefhebber, 1979). The treatment policies differed among the various providers. Methadone maintenance as well as methadone reduction programs were offered. There was no uniformity of the criteria of selection, the maintenance methadone dose level, mandatory urine monitoring or the provision of supportive therapy (Driessen, 1990). The treatment goals in MMT in The Netherlands in the last two decades have shifted from methadone reduction directed towards total abstinence to methadone maintenance aimed at the reduction of dependency related harm, (social) stabilization and reintegration of drug dependent patients (Wijngaard, 1991). The proposed methadone maintenance dose levels by Dole and Nyswander (50 to 150 mg methadone per day, mean 88 mg for phase 2 and 3 in their original study), had never been reported in studies investigating MMT programs in The Netherlands.

The mean methadone dose for maintenance in the first decade of methadone treatment in the Netherlands was low (30 - 40 mgj (Geerlings, 1982; Buisman, 1983; Wijngaart, 1990). In 1990, the year when the present study started, the mean methadone dose given to all registered patients in MMT in Amsterdam was 33.8 mg (range: 2 - 250 mg), which gradually increased to 55.6 mg (range: 2 - 250 mg) in 1995 (van Brussel and van Lieshout, 1993; van Brussel et al., 1996). Several published and unpublished explanations for the low mean methadone maintenance dose in the first two decades exist. Geerlings (1982) stated that there is a general resistance against methadone maintenance among both heroin-dependent patients and treatment providers. An investigation of the different goals among the methadone treatment providers in that period, showed that reduction of opiate abstinence symptoms was the treatment goal among all providers; however, total abstinence of heroin was a treatment goal among only 58 % of all treatment providers (Hovens et al., 1984).

Another descriptive study, investigating the different treatment policies among methadone programs, described the widespread tolerance among treatment providers towards the use of heroin among MMT patients (Buisman, 1983). Another reason for the relatively low methadone dose in The Netherlands was the belief that total abstinence is easier achieved from a low methadone dose than from a high methadone dose. The fear for unexpected complications due to opiate overdose also caused reluctance against high methadone doses (Driessen, 1996). The Amsterdam MMT program around 1975 was faced with an influx of heroin smokers, originating from Surinam, who were highly opposed to a high methadone maintenance dose. They reported a moderate heroin use and therefore desired a relatively low methadone maintenance dose, enabling them to maintain their heroin use (personal communication by G. H. A. van Brussel). The same argument was consequently mentioned by ethnic Dutch heroin dependent patients (personal communication by F. Driessen). An interesting point, raised by the Medical Service for Heroin Users, an heroin-dependency self-help and advocacy organisation in The Netherlands, against a high methadone maintenance dose is the risk of increased passivity among drug-users resulting in a greater dependence upon methadone, ultimately leading to an increased level of dependency (Mol et al.,1993).

Increased availability of cocaine on the illegal drugs market - which started in the 1980's - led to the use of this drug among heroin-dependent patients in the Netherlands. Heroin-dependent patients reduced their expenses for heroin in favour of cocaine. This made the methadone prescribed in MMT even more important for these polydrug users as a pharmacologically save basis to help them preventing opiate abstinence symptoms (Baanders,1986)

The practise and difficulties of methadone maintenance treatment
After the initially published success with methadone treatment for opiate dependency, a number of critical questions were raised with regard to the study and the practical application of the findings of Dole and Nyswander. The group of 22 subjects studied by Dole and Nyswander was not representative; the study was limited in follow-up time, as it was a progress report; the authors mentioned the exclusion of two patients from the study due to 'uncooperativeness'; and they reported patients having difficulties in spanning a 24-hour-period without withdrawal symptoms with a single methadone dose. Other questions raised were (Jaffe,1970):

- how will methadone maintenance work within a less selected group,
- can methadone maintenance be started without initial hospitalization, - how is one to deal with continued heroin use among MMT patients,
- can a long-term MMT patient eventually become totally free from the use of narcotics, and what is the essential feature of the methadone approach: (1) prevention of opiate withdrawal symptoms?, (2) the alleviation of opiate craving? or, (3) the blockade of heroin induced euphoria?

Further illustration of the questions arising around long-term treatment were findings in both the United States and The Netherlands that the enrollment in a methadone reduction program could not prevent later heroin relapse of former drug dependent patients (e.g. Ball,1988; Hartgers et al.,1992).

One of the first MMT departments in The Netherlands in which these problems with MMT were identified, was the methadone outpatient department of the Municipal Health Service in Groningen, where the staff was faced with the problem of poor performance among some MMT patients. The patients undergoing MMT continued their heroin use. The science information centre of the Faculty of Medicine at the University of Groningen (The Netherlands) was then requested to investigate this problem. About the same time, the question was put forward independently by the Royal Dutch Pharmaceutical Society (KNMP). As a result a report was presented by a group of pharmacists in Amsterdam regarding the question of pharmacokinetically adequate use of methadone in MMT. This interest in the pharmacokinetics of methadone was also displayed by the Jellinek Clinic in Amsterdam (The Netherlands). Reports from the Municipal Health Service (GG&GD) in Amsterdam had shown that policies with regard to prescription of methadone were substantially different between the various treatment centres of dependency and among the general practitioners. The development of a black market for methadone despite a low threshold for admission to MMT, indicated a dissatisfaction of the patients. It appeared that many drug-users - but certainly not all - could be compliant with one methadone dose per day.

The main discussion in the treatment of heroin-dependency with methadone maintenance emerged around the adequate methadone dose required for achieving the main goals of MMT as has already been indicated:

- alleviation and prevention of the opiate abstinence symptoms; - complete abstinence of using other opiates;
- the reduction of opiate craving;
- blocking the rewarding effects of heroin.

In analysing this discussion, several points of interest can be distinguished which lay influence the clinical outcome of MMT:

- an inadequate methadone maintenance dose,
- the (individual) pharmacokinetics of methadone,
- the pharmacodynamic effectiveness of d,l-methadone versus that of 1 methadone
- the presence and influence of psychopathological comorbidity among opiate dependent patients, and
- the effects of additional opiate use on opiate craving during MMT

A. In the American State Methadone Treatment Guidelines the required dose to prevent withdrawal symptoms is set between 20 and 40 mg methadone daily. To achieve the specific goals of MMT - reduction or elimination of opiate craving and blockade of the euphoric effects of any illicitly self-administered narcotics - a maintenance dose of 80 + 20 mg is advised (Parrino, 1993). These guidelines have been based upon the original study of Dole and Nyswander, and upon several large studies comparing different dosing schedules on long-term MMT outcome (e.g. DARP: Simpson and Sells, 1982; TOPS: Hubbard et al., 1989; Ball and Ross,1991). In The Netherlands the mean methadone maintenance dose - according to the findings presented in the above mentioned guidelines - is sufficient to prevent withdrawal symptoms, but inadequate to achieve the other MMT goals. Whereas the poor performance among MMT clients in The Netherlands plausibly could be due to a generally low mean methadone maintenance dose, in both American and Scandinavian studies the description of 'bad performance' among MMT patients is usually applied to adequately dosed MMT patients. However, these studies are not consistent. Some studies show a correlation between high methadone doses or plasma methadone concentrations and adequate MMT performance (Caplehorn et al., 1993, Strain et al., 1993a; Strain et al., 1993b; Caplehorn, 1994; Maremmani et al., 1994), whereas in other studies no correlations were observed (Handal and Lander, 1976; Madduxetal.,1991).

B. Although in MMT it is routine practice to dispense methadone doses once daily for a substantial amount of heroin-dependent patients it is difficult to achieve stabilisation using a 24-hour dose regime. In fact, when maintained on a high methadone dose, these patients nonetheless complain about their methadone dose They express that their dose does not prevent opiate abstinence symptoms or heroin craving and therefore they continue to use heroin.

These so-called 'bad performers' (Tennant et al., 1984; Bell et al., 1988) or 'therapeutic failures' (Nilsson et al., 1983), could hypothetically have a different metabolism, an increased methadone elimination rate or a diminished biological availability of methadone. A dosing schedule with a 24-hour frequency is generally accepted in MMT, but the scientific rationale for such a schedule is based only on a few ambiguous pharmacokinetic studies. Literature review reveals large differences in the pharmacokinetical parameters for methadone, such as its half-life, between individuals (Nilsson et al., 1983; Anggard et al., 1979).

C D,l-methadone chemically consists of two almost identical molecules or stereoisomers. These two molecules are mirror images of each other. They can be discerned by their ability to establish a left or right sided rotation of polarised light. Lmethadone, the methadone molecule which directs polarised light to the left, contains almost all the analgesic and opiate withdrawal suppressing properties (Scott et al., 1948; Sullivan et al., 1975; Olsen et al., 1976). Despite these facts, methadone is stili used in its d,l-methadone form, except in Germany, where 1methadone is used. Several studies have suggested pharmacokinetic differences between the two stereoisomers (Beck et al., 1991; Kristensen et al., 1996). A study investigating side effects of d,l-methadone and l-methadone did not reveal such differences (Judson et al., 1976). However, a difference between d,l-methadone and l-methadone on respiratory rate and pupillary effects was found (Olsen et al., 1976). An important issue in MMT is the possible superior clinical effectiveness of 1methadone over d,l-methadone administered in the same dose. This issue is a specific interest to the satisfaction of the patient. Journals expressing the interest of heroin-dependent patients report cases of withdrawal symptoms occurring after switching from l-methadone to (an equivalent dose of) d,l-methadone (Lang, 1994). The Medical Service for Heroin Users in

The Netherlands has stated that 1methadone possesses more euphoria- and dependency-inducing effects than d,lmethadone. They claim that using d,l-methadone invites the use of other drugs as well in order to obtain euphoria (Mol et al., 1993). In any case, this controversy, like the dosage issue, is in need of further research given the inconsistency in the literature.

D. The prevalence of psychiatric comorbidity among heroin-dependent patients is widely described and acknowledged (Weissman et al., 1976; Khantzian and Treece, 1985; Rounsaville et al., 1982; Mirin et al., 1991; Rounsaville et al., 1991

Bryant et al., 1992; van Limbeek et al., 1992). However, these studies have not shown a characteristic diagnostic profile for a drug-dependent person. There are indications in the literature that the individual dose requirements differ in relationship with the presence of both state (axis I pathology in DSM IIIR) and trait (axis 11 pathology in DSM IIIR) psychopathology. For instance: higher methadone doses are given in cases where personality disorders, marked by odd or eccentric behaviour and social withdrawal or isolation (cluster A, axis 11 in DSM lil), are present (Treece and Nicholson, 1980). In a large (n = 106) study a higher prevalence of emotional distress and anxiety (axis 1) was found in patients with a higher methadone dose (Roszell and Calsyn, 1986). It has also been postulated that drug-dependent patients who show aggressiveness, along with their psychopathological symptoms, require a higher methadone dose (Maremmani et al., 1993).

E In the search of alternatives for methadone or heroin as a maintenance substitution for illegal heroin, both injectable morphine and injectable methadone have been compared. Both have the disadvantage that they are only suitable for intravenous drug users. In a large-scale study in which both injectable morphine and methadone were prescribed to long-term heroin users in Switzerland, serious adverse reactions have been observed (Uchtenhagen et al., 1996). Furthermore, it seems that injectable morphine and methadone do not produce a similar effect as heroin injection (Derks, 1990; Jongerius et al., 1994). Apart from alternatives for methadone as a drug for maintenance (e.g. buprenorphine (Temgesic@), see Ling et al., 1996), additives to methadone maintenance have also been considered. In 1995, the Amsterdam Municipal Health Service initiated the use of dextromoramide (Palfium@) in their MMT program as an adjuvans to methadone maintenance. Dextromoramide, a synthetic opiate, was developed by Janssen in 1956 as an analgesic (Janssen, 1956). Due to its addictive properties the use as an analgesic has become obsolete (Seymour-Shove and Wilson, 1967). On a very limited scale dextromoramide has been used among heroin-dependent patients in the United Kingdom (Gossop, 1994). Due to its strong structural and pharmacological resemblance to methadone, it became a potential alternative for heroin as an adjuvans to methadone maintenance.

Craving
The assessment of the current level of satisfaction of drug-dependent patients in methadone maintenance treatment is an important and controversial issue. For longterm heroin-dependent patients easy access to opiates is of great importance to avoid mental craving and physical withdrawal symptoms due to a lack of opiates in their blood. The level of well-being for heroin-dependent patients has been clinically associated with their experience of craving for these drugs. Therefore the individual level of craving is a strong indicator of the current level of well-being of heroin dependent patients. In previous studies of dependency, the importance of the measurement of the individual (subjective) craving as compared to physiological or behavioural measures has been underlined (Edwards et al., 1981; Koziowski and Wilkinson, 1987). When withdrawal symptoms and subjective craving levels are measured among opiate-dependent patients under experimental conditions, results have shown that the subjective (self) reports of craving relate more accurately to the presence or absence of opiates in the blood than the objective reports. In a study, investigating both a subjective and an objective rating scale for opiate withdrawal among heroin users, the subjective opiate withdrawal scale (SOWS) showed an increase of craving after a naloxone challenge whereas the objective opiate withdrawal scale (OOWS) did not (Handelsman et al., 1987). In another study, examining the correlation between the objective and the subjective measurement of craving, a substantial difference in the duration of withdrawal symptoms after detoxification was seen. Whereas the objective measurements (OOWS) showed a gradual decay of withdrawal symptoms 24 hours after detoxification from opiates, the subjective opiate withdrawal questionnaire (SOWQ, Haertzen and Meketon, 1968) showed a continuation of withdrawal symptoms up to 120 hours after detoxification. The authors of this study state that the clinical assessment significantly underrated the psychological distress existing at the tail end of the assessment, therefore making observer ratings unrealistic for the design of specific treatment schedules (Loimer et al., 1991a). In a study, in which both the objective and subjective opiate withdrawal symptoms were measured simuitaneously with plasma methadone levels during MMT, a strong correlation between the subjective measurements (modified SOWS) and plasma methadone levels was established. In contrast, the objective scale (modified OOWS) showed only a few items which were correlated with the plasma methadone concentrations (Hiltunen et al., 1995).

The assessment of the individual level of opiate craving in the current study is performed using the Experience Sampling Method (ESM)(Vries et al., 1987). The ESM is a field-intensive assessment instrument that uses a self-observational strategy cued by an electronic beeper. Repeated structured observations of the mental state and the level of opiate craving are collected at a random time signal. The assessment questionnaires collect reports of cognitions, moods and behaviours, as well as the context in which they occur, within the natural setting of the research subjects. The assessments are scored on a 7-point Likert scale, which ranges from 'not at all' to 'very much'. The specific opiate craving items include:

'Did you think about using?', (also present in the SOWQ)
'Did you feel stoned?',
'Were you in control of yourself?',
'Did you feel restless?' (also present in the SOWS and SOWQ), 'Did you need dope quickly?',
'Did you feel the need to use dope?'.

These items were created in dialogue with street drug users to increase the construct validity of the self-reports. Subject assessments were sampled approximately ten times a day between Q7:30 and 23:00, running 1 to 4 days. An essential characteristic of this method is that the assessments are made by means of self reports which can be recorded at any moment during the waking hours of the test subjects. This provides an estimate of the dynamics and fluctuations in the experience of craving wh7ch are seen in drug dependent subjects (Kaplan, 1992 Delespaul, 1995).

Aims of the present study

The main research question of this study, is: are there differences in the fate of methadone pharmacokinetics between heroin-dependent patients undergoing methadone maintenance treatment, that can explain (poor) performance and the level of opiate craving during treatment? As the level of craving among heroin dependent patients during MMT can be influenced by their methadone dose, the presence of psychopathology and additional drug use, the relationship between these issues had to be considered as well.

Therefore, the purpose of this study is to reveal factors which may be involved in the clinical performance and the individual experience of craving of heroin-dependent patients in MMT. For this purpose four sources of information obtained from longterm heroin-dependent patients in MMT have been analysed:

1. pharmacokinetic parameters of different substances in plasma (methadone, its first metabolite 1,5-dimethyl-3,3-diphenyl-2-ethylidene-pyrrolidine (EDDP), I methadone and dextromoramide),
2. individual levels of craving measured simultaneously with pharmacokinetic data,
3. the presence of symptoms of psychopathology during the study period, and
4. the presence of other drugs (and their metabolites) in urine samples during the study period and the individual history of dependency.

In chapter 2 the determination and the pharmacokinetics of methadone and its primary metabolite in long-term heroin-dependent subjects are described. This first study was conducted in a closed metabolic ward in the Jellinek clinic in Amsterdam among 20 subjects. Chapter 3 describes determination and the pharmacokinetics of dextromoramide used in conjunction with methadone. This second study was performed among 6 long-term MMT subjects admitted in a closed metabolic ward in the Jellinek clinic in Amsterdam. In chapter 4 the opiate craving patterns as observed in the 20 subjects of the first study are described, and subsequently correlated with plasma concentrations of methadone.

A case report of a long-term heroin-dependent person in MMT is presented in chapter 5 showing a high level of craving while on a high methadone dose. Chapter 6 describes the craving patterns observed in the 6 MMT subjects receiving both methadone and dextromoramide in the second study.

The third study, a pharmacokinetic investigation of methadone and l-methadone among 40 long-term heroin-dependent subjects as well as the clinical comparison between the two maintenance treatment drugs, is presented in chapter 7. Chapter 8 evaluates the comorbidity of current~psychopathology and its influence on the level of craving among the study subjects from the first study.

In chapter 9 concluding remarks and recommendations for future research and methadone maintenance treatment are formulated.