Dextromoramide

This paper begins with a brief description of the epidemiology of heroin addiction in the Netherlands and an overview of the current treatment system, with special emphasis on oral methadone maintenance. It is followed by a short history of the debate over the prescription of heroin to addicted patients. This history reveals that alternatives to methadone have been viewed as essential in the Netherlands since the early 1980s. Earlier experiments with intravenous morphine, intravenous methadone and oral dextromoramide (Pallium(R)) were not as successful as had been hoped and precluded their introduction in daily practice. Finally, recent experiences in Switzerland with the medical prescription of heroin facilitated the decision to initiate a scientific study of the medical co-prescription of heroin in the Netherlands. The paper provides a detailed description of the randomized clinical trial regarding the effectiveness of co-prescribed heroin that is now underway in the Netherlands. It concludes with a brief discussion of the likely consequences for future treatment options of different study outcomes.

INTRODUCTION

Heroin was introduced in the Netherlands in the autumn of 1972. During the first few years, its use was largely limited to the ethnic Dutch population and the route of administration was mainly through intravenous injection. A rapid upsurge in the number of heroin users was recorded around 1975 when Surinam, a former Dutch colony in the north of South-America, became independent. At that time, almost half of the Surinamese population emigrated to the Netherlands, settling mainly in Amsterdam, Rotterdam, The Hague and some other urban areas. Young Surinamese men came to play a major role in the street trade of heroin, and many of them became users themselves. In this, however, they adhered to their own way of administering the drug, i.e. not injecting but inhaling (Korf, 1995). Since then, the estimated number of heroin users has increased from 10,000 in 1977 to 20,000 in 1979 and 30,000 in 1983 (Schreuder and Broex, 1998). Since 1984, the total number of heroin addicts in the Netherlands seems to be rather stable with probably some decrease in the last few years (Hoekstra and Derks, 1991; Brussel et al., 1996). The total number of heroin addicts in the Netherlands is currently estimated to be 25,000 (Schreuder and Broex, 1998).

The general picture is one of a relatively stable population of heroin addicts with a low incidence of new cases and a low mortality rate. This is also reflected in the fact that the mean age of the methadone maintenance population in Amsterdam has been increasing by approximately 10 months each year since 1984 (the mean age in 1984 was 28.2; the mean age In 1997 was 38.8). Also, the percentage of heroin addicts in methadone maintenance who are younger than 26 years of age dropped from 28 percent in 1985, to 3 percent in 1997 (Buster and Reurs, 1998). A similar pattern emerged in Rotterdam, where 28 percent of methadone maintenance patients were under 25 years of age in 1988, while only 13 percent were in 1995 (they had a mean age of 29.3 in 1988 and 34.2 in 1995 (Toet, 1996). At the same time the ratio of injectors to inhalers has changed, with a growing proportion of addicts using heroin mainly, or exclusively, by inhaling the vapors of heroin base that has been heated on aluminum foil ("chasing the dragon").

This stable, aging population of heroin addicts is served by a comprehensive treatment and health care system that provides services free of charge and has little or no waiting lists. The system includes various kinds of abstinenceoriented treatment facilities (e.g. inpatient and outpatient detoxification, methadone reduction, residential treatment and therapeutic communities). It also provides a wide range of facilities that focus on stabilization and harm reduction (e.g. methadone maintenance, needle and syringe exchange, work projects, sheltered housing and user rooms), rather than abstinence. It is estimated that, depending on the local circumstances, 65-85 percent of all heroin addicts are currently involved in some form of contact with the treatment system (Gageldonk et al., 1997; Schreuder and Broex, 1998).

Patients often begin treatment hoping to become abstinent. In the course of their addiction and treatment careers, however, many of those who did not quit the habit switch from abstinence treatment to some kind of harm reduction. This typically occurs through participation In a methadone maintenance program, with or without the additional use of other pharmacological treatments (e.g. triple therapy for AIDS, antidepressants for a comorbid affective disorder) and psychotherapeutic (e.g. counseling, skills training) or psychosocial (e.g. budgeting, housing assistance, work projects) interventions.

The medical prescription of heroin is a final treatment option, which is intended only for those chronic heroin addicts who have repeatedly failed in other available treatments, including state-of-the-art treatment in a methadone maintenance program. It is, therefore, crucial to have an adequate understanding of methadone treatment in the Netherlands and the results that have been achieved with it.

METHADONE TREATMENT IN THE NETHERLANDS

The prescription of methadone as a treatment method began in the Netherlands in 1968. During the first few years, methadone was prescribed to morphine dependent patients, Following the introduction of heroin in the Netherlands in 1972, treatments with methadone were primarily directed towards achieving abstinence from heroin addiction. Generally, these methadone reduction programs suffered from high dropout rates, and there was a serious threat that they would lose contact with many addicts. Paralleling the rapid increase in the number of heroin addicts during the 1970s, and the introduction of HIV/AIDS in the mid 1980s, the aim of oral methadone prescription in the Netherlands shifted from achieving abstinence towards achieving stabilization and harm reduction. Prevention of risky behaviors and the provision of medical care through regular contact with the addict became the primary objectives of methadone maintenance programs for those patients that refused counseling and continued their use of illegal drugs. In this period of increasing risk of infection and increasing necessity (with regard to AIDS prevention) to at least stay in contact with the addict, the high dropout rates in the methadone programs were seen as unacceptable by both treatment agencies and policy makers.

Currently, many of the Dutch methadone efforts are referred to as lowthreshold maintenance programs. They are characterized by the absence of mandatory counseling, an absence of sanctions when urine tests reveal illegal substance use and relatively low dosages of methadone. These programs are aimed at the reduction of health risks and improvement of the quality of life of those addicts who are unable or unwilling to give up their drug use. Due to their low-threshold character, a high percentage of heroin addicts in the Netherlands (50-80 percent), including poor performers who have failed in their earlier rehabilitation efforts, are reached by these programs (Bieleman et al., 1995). In contrast, most methadone programs in the United States are 'high-threshold' programs, which target 'good performers,' are aimed at achieving abstinence, and they only reach 15-20 percent of the heroin using population (Office of National Drug Control Policy, 1998). Given the differences between the Dutch and the US methadone efforts and the populations being served by them, results from American methadone evaluations cannot simply be projected to the Dutch situation.

Although no controlled studies on the effectiveness of the methadone treatments have been conducted in the Netherlands, there is extensive clinical experience with dispensing methadone, and follow-up studies do provide some insight regarding their outcomes. In 1988, a survey was conducted on the dispensing of methadone in the Netherlands (Driessen, 1990). According to this study, the estimated number of heroin addicts in the Netherlands then was 24,000. Of these, an estimated 17,000 addicts (71 percent of the total) had been in contact with a treatment program at least once during the previous year (Figure 1). Among that group, approximately 4,500 had been in drug-free treatment and approximately 12,500 had received methadone on a regular basis, most of them for many years (mean time in program was approximately 8 years). According to the treatment staffs of the methadone maintenance programs, 36 percent of the 12,500 patients (4,500 persons) were well regulated, meaning that they exhibited little or no illegal drug use, were compliant with treatment efforts and showed some degree of social integration. Another 40 percent (5,000 persons) were not adequately regulated, meaning that they had frequently used illegal drugs, been less than fully compliant with treatment efforts and achieved low levels of social integration. Finally, 24 percent(3,000 persons)were identified as being extremely problematic. These persons used various illegal substances on a daily basis, manifested symptoms of physical and/or mental problems, exhibited high levels of criminality and showed no evidence of social integration.

Data from 1991 indicate that three-quarters (78 percent) of all methadone maintenance patients had continued using heroin and more than a third (37 percent) were still using heroin on a daily basis (Driessen, 1992). At that time, nearly all methadone maintenance programs offered the maintenance drug along with a broad spectrum of services, including psychosocial counseling, medical counseling and treatment, social work and, in some centers, psychotherapy. Despite their availability, however, only 49 percent of these clients took advantage of social work assistance, 28 percent in medical counseling, 13 percent in psychiatric counseling, 2 percent in psychotherapy, 2 percent in family therapy and 6 percent in group therapy (Driessen, 1992).

These early data are supported by a more recent Amsterdam study (Buster and van Brussel, 1996). This study found that 5,545 heroin addicts living in Amsterdam had received methadone between 1994 and 1995. Based on the results of urinalysis tests, 65-70 percent of them were found to still be using heroin regularly or even daily. This high level of illegal heroin use cannot be explained (as it sometimes has been) as being a byproduct of low dosages (less than 50 milligrams) of prescribed methadone, however, because in 1995 in Amsterdam, the average daily methadone dose was almost 60 milligrams (Brussel et al., 1996).

In addition to the 11,500 patients in methadone maintenance programs in 1995. there were more than 1,400 drug-related admissions to a general psychiatric hospital and more than 3,000 drug-related admissions to addiction treatment clinics in the Netherlands (Gageldonk et al., 1997). Finally, some outpatient drugfree treatment is provided by the Dutch Consultation Centers for Alcohol and Drugs. It should be noted that these numbers can not be simply added to obtain the figures for the nation as a whole, however, because some patients use more than one of the above services during the registration period and therefore could be counted more than once. It is, however, quite certain that the amount and the types of services, which are currently provided to heroin addicts, are very similar to those from 1988 (Driessen, 1990).

In 1993, the Netherlands Institute of Mental Health (NcGv) surveyed 1,900 patients and ex-patients from the Consultation Centers for Alcohol and Drugs (Jongerius et al., 1994). The results of this survey indicated that 62 percent of the methadone patients were very satisfied with the treatment they had received. Almost 60 percent reported a reduction in their heroin use as a result of this treatment, and nearly one third reported abstinence in terms of illicit drug use. Despite these positive outcomes, 47 percent of the patients said that methadone had made it more difficult for them to achieve abstinence, and 10 percent reported that methadone treatment had not had any positive impact on them. These data are very similar to those collected earlier by Driessen (1992) in which 47 percent reported one or more major complaints, especially regarding dispensing times, the lack of take-home dosages and the undesired contact with other drug addicts.

In the Netherlands there are many different regimes offered by methadone programs, but no data are available on the relationship between methadone dosage, the various forms of counseling provided in the programs, and the results of the treatment. However, data provided by the Amsterdam Municipal Health Service indicate that there has been an increase in the average daily methadone dosage from 43 milligrams in 1989 to 56 milligrams in 1995 (Brussel, 1996), and similar developments have been reported in other cities in the Netherlands. This average is, however, still lower than the recommended dosage used in programs in the United States (Parrrino, 1992). According to the American guidelines, the effective daily methadone dosage should be about 80 milligrams plus or minus 20 milligrams. However, a national survey in the USA showed that many programs had dose limits below these effective ranges and that many programs applied time limits regarding the maximum length of stay allowed in the program (D'Aunno and Vaughn, 1992). Given the fact that most patients who receive methadone in the Netherlands are either unable or unwilling to give up their heroin use, higher methadone doses, which would prevent them from experiencing the euphoric effects of heroin (Korf et al., 1998), are often unacceptable to the patient. Consequently, prescribing higher doses of methadone is likely to promote elevated drop-out rates, thereby undermining one of the main aims of the Dutch methadone treatment system - to reach as many addicts as possible for prevention, medical supervision and treatment.

The effectiveness of this pragmatic approach is evidenced, among other measures, by the relatively small number of injecting drug users who are AIDS patients in the Netherlands (12.4 percent) compared to the United States (24 percent) and Europe at large (38 percent) (Laar et al., 1995). In addition, deaths attributable to drug addiction (as a primary or secondary cause of death) remain quite low in the Netherlands, where only 33 drug-related deaths of Dutch residents were registered in 1995 (de Zwart and van Wamel, 1998). In Amsterdam and Rotterdam (the cities with by far the largest number of heroin users and addicts), 16 deaths occurred in the former and 14 in the latter in 1996 (de Zwart and van Wamel, 1998).

Taken together, these findings suggest that methadone maintenance treatment is widely available in the Netherlands. At least 50 percent of all heroin addicts are currently enrolled in one of these programs that serve a stable and aging population of chronic heroin addicts with long addiction and treatment careers. It was also observed that a substantial number of the methadone patients regularly use illegal heroin and other illegal drugs. Approximately 8,000 of the 12,500 methadone patients function at less than optimal levels, exhibiting low levels of medical and psychosocial functioning. About 3,000 of them are engaged in high levels of criminal behavior. There has been a growing awareness of these disappointing results, despite extensive attempts by professionals to improve the living conditions of these chronically addicted patients. There have also been repeated calls for reductions in the public nuisance that results from their criminal behavior. All of these difficulties have led to various attempts to prescribe opioids other than oral methadone for the treatment of chronic, treatment resistant heroin addicts. These efforts are briefly discussed below.

THE PRESCRIPTION OF OPIOIDS OTHER THAN ORAL METHADONE IN THE NETHERLANDS

Three small-scale experiments have been conducted in the Netherlands involving the substitution of prescription opioids for oral methadone. In the late 1970s, the consulting physician at a low threshold day-care center for chronic heroin addicts in Amsterdam began prescribing intravenous morphine and amphetamines to five patients. In 1983 he published the positive results of these interventions in the Dutch Monthly Journal of Mental Health (Havas, 1983) and negotiated with the Amsterdam Municipal Health Service (GG&GD) to extend the program (Derks, 1997). After a heated debate, and the closure of the dispensing program in the day-care center, the Minister of Health approved a morphine dispensation program for 37 patients. At the same time, the city council of Amsterdam announced plans for the initiation of a large-scale heroin dispensation program for approximately 300 drug users. That proposal was rejected by the Dutch government however, and the program was never implemented (Brussel, 1997a; Derks, 1997).

The morphine dispensation program started at the end of 1983 with a group of 37 extremely problematic heroin addicts, and was to run for an experimental period of two years. Most of these patients received a combination of intravenous morphine along with a basic dose of oral methadone. The results of the study suggested a beneficial effect, in terms of reduced levels of illegal heroin use and lower levels of criminality for approximately one half of the participants. These results could not simply be attributed to the co-prescription of intravenous morphine, however, because no control group was included in the study. Also compromising the results was the attrition of 11 participants who abandoned treatment within the first year because they were dissatisfied with morphine and/or were suffering from histamine reactions following its administration (Derks, 1984, 1990). In 1993, 10 years after the start of the project (which was supposed to have continued for only two years), seven of the original thirty-seven patients were still receiving intravenous morphine. Among the remainder, fourteen patients had returned to oral methadone maintenance treatment, one was known to be drug-free and fifteen had died (five committed suicide, six died from AIDS, two had developed lung cancer and two died of a drug overdose). These figures clearly reflect an alarming mortality rate, however, most of the deaths were not thought to have been related to the program itself, but merely reflected the severity of the patients' pathological state at the time they joined it. The experimental program demonstrated that prescriptions of injectable opioids are feasible, that very little morphine leaked to the black market and that some of the patients did show improvement. When the experiment finally ended, no new patients were recruited because, when given a choice, most patients preferred injectable methadone.

A second quasi-experiment began in 1990 when the Amsterdam Municipal Health Service began prescribing intravenous methadone to 30 unmanageable and severely addicted AIDS patients who were in very poor health. Prescriptions had to be terminated for almost half of the participants because they failed to comply with the treatment regimen. Among the remaining group, many subsequently died. Among those patients who continued in treatment, clear improvements were shown in their therapeutic relationships with the treatment staff. In addition, the heroin use of these patients decreased considerably, although it did not stop altogether. According to the patients, injectable methadone does produce a high, although it does not equal the one produced by heroin (van Brussel, 1995). Given that popular belief, it should come as no surprise that the vast majority of Dutch methadone patients are not interested in participating in a program where injectable methadone is prescribed (Jongerius et al., 1994)

A third experimental treatment program was initiated in 1995 by the Amsterdam Municipal Health Service. In this effort, oral dextromoramide (Palfium(R)) was prescribed in addition to oral methadone to 53 severely addicted, non-injecting heroin users who had average addiction careers of 21 years, and all of whom had not responded well to earlier methadone opportunities. The goal of this new treatment strategy was to alleviate the patients' suffering and to stabilize their drug intake. Unfortunately, the project was not systematically evaluated. The general impression of project staff, however, was that the treatment with Palfium resulted in improved social functioning of patients and in a better relationship with the treatment services. A clinical evaluation suggested that heroin use decreased among most of the patients and that one actually stopped using altogether. Urinalysis test results revealed no increase in cocaine use. Finally, termination of prescriptions for those patients who had not benefitted from the Palfium treatment, did not cause problems (van Brussel, 1997b).

These attempts to improve the medical and psychosocial status of chronic, treatment-resistant heroin addicts indicate an active debate on the medical prescription of opioids other than oral methadone. However, the experimental treatment programs were directed to very small groups of heroin addicts with rather specific needs, and as we have noted, the results of these experiments were not adequately documented. These limitations leave ample room for doubt regarding the effectiveness of the treatments themselves, and the generalizability of their results. Given these concerns, when discussing the desirability of the medical prescription of heroin to Dutch addicts, the Committee on Pharmacological Interventions in Drug Addiction of the Health Council of the Netherlands (1995) turned to the evaluation results of the scientific experiments with heroin in other countries. These included programs in the United Kingdom (Hartnoll et al., 1980) and in Switzerland (Uchtenhagen, 1996a). The following paragraphs summarize their findings.

THE EFFECTIVENESS OF HEROIN PRESCRIPTION

Over the past 40 years, several countries have gained experience with prescribing heroin to addicts. This began in the late 1950s and early 1960s when individual physicians in the United Kingdom started to prescribe heroin to addicts for maintenance purposes (Strang et al., 1994). In 1968 NHS (National Health Service) drug clinics took over the responsibility for prescribing injectable heroin from individual physicians who were no longer allowed to prescribe the drug to addicts. During the late 1960s and early 1970s, these clinics began to switch their prescription from injectable heroin to injectable methadone and since the mid1970s, from injected to oral methadone (Mitcheson, 1994). During this period (1972-1975), a randomized clinical trial was conducted comparing the effectiveness of a medical prescription of injectable heroin (the old standard treatment) with a medical prescription of oral methadone (the new standard treatment) (Hartnoll et al., 1980). The study population consisted of 96 patients with a mean age of 23.9 years (range 18 to 32 years), a mean addiction career of 5.9 years and a history of daily heroin injection for at least three months prior to the study. All participants were strongly committed to continuing their drug use. The prescribed heroin doses ranged from 30 to 120 milligrams and the oral methadone doses ranged from 10 to 120 milligrams daily, with most prescriptions ranging from 40 to 80 milligrams per day.

The study produced equivocal results, in that there were no clear indications that one treatment produced better results than the other. Both treatments produced positive outcomes in certain areas and negative ones in others. For example, the heroin maintenance patients attended the clinic more regularly than did their methadone counterparts and they also showed a greater reduction in their illegal heroin use and criminal activities. In both groups, no significant changes were observed in work performance, housing status, diet or physical complications arising from their drug use. While the majority of those who were refused a heroin prescription continued to inject illegal heroin and only attended the clinic when they needed a specific service, approximately one-fifth were successfully stabilized on oral methadone, and another fifth achieved abstinence (Mitcheson, 1994). According to the investigators, the results suggested that the preference for one particular approach depend on the priorities assigned to the various outcome domains. On the one hand, they could choose to help a small number of addicts to stop using drugs by means of oral methadone. On the other hand, they could choose to try to help as many addicts as possible to improve their situation by means of injectable heroin.

In this early study, most of the patients in the heroin prescription group were persuaded to convert to oral methadone. This led the investigators to believe that a maintenance dose of injectable heroin for a limited period of time does not necessarily lead to irreversible situations with potential adverse consequences for the long-term health status of the patients (Hartnoll et al., 1980). The authors noted that the findings provided no clear indication that one treatment was superior to the other. Despite, this caveat, the findings were used bv many to infer that injectable heroin maintenance should be dropped in favor of oral methadone maintenance. Following a heated debate, many of the clinics moved towards a more interventionist therapeutic approach, simply refusing to prescribe injectable drugs to new patients (Mitcheson, 1994). In 1994 only 1-2 percent of the estimated 75,000-150,000 heroin users in the United Kingdom was receiving a prescribed supply of any injectable drug, and only a small proportion of these was receiving injectable heroin (Strang et al,. 1994).

The most recent experience with the prescription of opioids other than oral methadone comes from Switzerland. In 1994, the Swiss initiated a large-scale study of the effects of prescribing injectable and inhalable heroin, injectable and oral morphine, and injectable and oral methadone. The prescription program started as a comprehensive scientific experiment and was completed on December 3 1, 1996. The evaluation indicated that there had been very positive results for the 1,146 patients who had received heroin by injection. In addition, there was considerable popular support for the project, as revealed in a national referendum on the issue (71 percent of all voters supported it, as did a majority in all 26 cantons). Consequently, the medical prescription of heroin continues to be an established treatment in Switzerland today.

According to the reports produced by the investigators (Uchtenhagen et al., 1996a, 1996b, 1997) and an independent process evaluation conducted by the World Health Organization (WHO, 1999), the results of the Swiss heroin experiment have indeed been positive. Beneficial outcomes included high treatment retention rates (89 percent after six months and 69 percent after eighteen months), dramatic reductions in the use of illegal drugs (heroin and cocaine) and substantial decreases in the level of participants' criminal activities. Study subjects also experienced substantial and stable improvements in the domains of physical health, psychological wellbeing, housing and employment, and substantial reductions in the number of contacts they sustained with drug users and the drug scene in general. It is also important to note that no public order problems were encountered and that no fatalities could be attributed to the experiment. Finally, the cost-benefit analysis revealed an overall net economic benefit of 32 US Dollars (45 Swiss Francs) per patient, per day when compared to treatment as usual (mainly methadone maintenance). These results were all based on a one group, pre-post study design. Within that format, baseline characteristics were compared with follow-up data on almost 800 patients who entered the project in 1994 and stayed in it for at least 18 months (69 percent). However, there was no possibility to compare these pre-post changes with similar changes in a randomly assigned or matched control group receiving treatment as usual. It should be noted that the Swiss study does include four rather small, randomized trials, with some of them using a double-blind procedure. Most of these studies were not intended to evaluate the long-term effects of heroin prescription, however, but rather to investigate the short-term effects associated with the different experimental substances (intravenous heroin, intravenous methadone, intravenous morphine) on recruitment, treatment retention, treatment compliance and side-effects. The only randomized trial examining the long-term effects of heroin prescription was a small study conducted in Geneva (Perneger et al.. 1998). In this study, 51 treatment-resistant heroin addicts were randomly assigned to either receive intravenous heroin and other health and psychosocial services or to some other conventional drug treatment, usually oral methadone maintenance. After six months, almost all of the patients using legal heroin had stopped their illegal heroin use and their psychological and social functioning (measured by the frequency of suicide attempts and the level of criminal activities) was much better than was true for those in the control group.

It is important to acknowledge that these recent Swiss studies made no attempt to investigate the long-term effects of the prescription of heroin alone, i.e. without obligatory counseling and other psychosocial interventions. Thus, they do not provide information about the effect of the prescription of heroin per se, but rather about the effect of a combined package of pharmacological (heroin) and psychosocial interventions. Consequently, it is possible that the benefits of the Swiss heroin maintenance programs could be at least partially attributable to the additional and often mandatory psychosocial interventions (Perneger et al., 1998).

Finally, the Swiss experiment with inhalable heroin in the form of heroin reefers (surrogate cigarettes) failed, due to the low bio-availability (10-15 percent) of the heroin from these sugarettes. Investigators found that 85-90 percent of the heroin was destroyed in the process of burning and therefore never entered the patient's body.

In summary, the medical prescription of injectable heroin appears to be both feasible and potentially effective in chronic, treatment-resistant heroin addicts. This is true, however, only when the prescription is medically controlled, no takehome heroin is allowed, and if psychosocial services are provided (e.g. Wodak, 1998). Three questions remain unanswered. The first of these is, what is the unique contribution of the heroin prescription when it is combined with various other pharmacological and psychosocial interventions? A second asks, what is the effect of participation in a scientific experiment on pre-post changes in some of the major outcome variables? The third is, can we expect a positive effect of prescription inhalable heroin if adequate levels of bio-availability can be attained? The latter question is especially pertinent for the Netherlands where only 20-40 percent of heroin addicts inject the drug and 60-80 percent are inhaling it in a process known as chasing the dragon.

The present Dutch study on the effectiveness of the medical co-prescription of heroin will attempt to answer each of these questions. This will be accomplished using the format of a randomized clinical trial that compares the effects of a standard oral methadone maintenance program with similar programs using co-prescribed injectable or inhalable heroin, with drug administration at the clinic and no take-home dosages of heroin.

THE DECISION TO START THE DUTCH HEROIN PRESCRIPTION STUDY

We noted earlier that, epidemiologically, the Netherlands features a stable, aging population of heroin addicts with long addiction and treatment careers. In addition, a substantial proportion of the Dutch heroin addicts have proven treatment-resistant, despite the existence of a comprehensive and easily accessible treatment system with many well-funded methadone maintenance programs. These circumstances, coupled with the positive reports on the Swiss experience, led the former Minister of Welfare, Health and Cultural Affairs to ask the Health Council of the Netherlands for advice about the conditions under which the prescription of heroin could be regarded as good clinical practice.

In an advisory report written in response to this request, it was concluded that the medical prescription of heroin to heroin dependent patients could have positive effects on their physical and mental condition, as well as on their addictive behavior. Medical treatment with heroin is viewed as expedient if sound medical-scientific research has established a positive balance between the effectiveness and harms associated with such treatment. In order to obtain the necessary data, the Health Council recommended that a trial should be conducted in the Netherlands with severely heroin dependent patients who have failed in, or insufficiently responded to, currently available medical interventions (Health Council of the Netherlands, 1995).

In concert with the Dutch parliament, the government subsequently decided to prepare and then carry out the study proposed by the Health Council. In December 1996, the Minister of Health, Welfare and Sport installed the Central Committee on the Treatment of Heroin Addicts (CCBH), assigning them the task of reporting the intended and adverse effects of heroin treatment. This report was to be written after the completion of a scientific study. Following extensive discussions, the CCBH developed protocols for the study of the effects of the medical prescription of heroin (either through injection or by inhalation) to severe, treatment-resistant heroin addicts. The protocols were developed in compliance with the guidelines for Good Clinical Practice, the Dutch law, and common medical-ethical standards regulating the conduct of medical-scientific research. Protocols were also developed for the development and testing of a stable and efficient inhalable form of heroin administration. These guidelines were submitted to several international experts in order to get their reactions. In addition, there was an intensive exchange of ideas and experiences between the CCBH and various members of the Swiss project. Lastly, there have been extensive discussions with the Dutch Central Committee on Medical Ethics. The results of these and other contacts were incorporated in the final protocols.

In August 1997, the final protocols were presented to the Minister of Health, Welfare and Sport. The study is designed to accomodate 750 patients and will be carried out in eight treatment units situated in several Dutch cities. In September 1997, the Dutch parliament approved a pilot period of three months during which time a total of 185 patients, 50 of whom will actually receive heroin, will be studied. If unacceptable medical or public order problems do not arise, the study will be extended to a full complement of 750 patients. In November 1997, it was determined that the pilot study would be carried out in Amsterdam and Rotterdam. In January 1998, the International Narcotics Control Board (INCB) confirmed the estimates of the amounts of heroin that are needed to sustain the study. In July 1998, the first treatment units opened in Amsterdam and Rotterdam. The final results of the study will be available in 2001.

MEDICAL CO-PRESCRIPTION OF HEROIN IN THE NETHERLANDS: A RANDOMIZED TRIAL

Below we provide a brief overview of some of the most important methodological decisions that were made during the development of the study protocols.

OBJECTIVES OF THE STUDY

The primary objective of the Dutch study is to evaluate the beneficial and harmful effects of 12 months of maintenance treatment with oral methadone and co-prescribed heroin, when compared with standard maintenance treatment with oral methadone alone. The study population consists of chronic, treatmentresistant heroin addicts who are currently enrolled in methadone maintenance programs. The effects of the medical co-prescription of heroin will not be evaluated with stable abstinence as the primary outcome parameter. Instead, investigators will measure improvements in the physical and mental status of patients, in their social integration and social functioning and in reductions in their illicit drug use. The project features several secondary study objectives. These include a comparison of the effects of co-prescribed heroin after 6 and 12 month periods, the effects of the discontinuation of co-prescribed heroin after 6 and 12 months of treatment, an evaluation of the effect of co-prescribed heroin on patient satisfaction and the generation of hypotheses for future patienttreatment matching strategies. Each of these objectives will be evaluated separately for the prescription of injectable heroin and for inhalable heroin.

TARGET POPULATION

According to the advisory report of the Health Council of the Netherlands (1995), the study should be directed to the treatment of severely addicted heroin users who have not responded at all, or only insufficiently, to currently available medical interventions. The Dutch government added the stipulation that it should be restricted to "older patients with a long addiction career whose psychosocial condition is without perspective" (please provide ref. + page number if this is a citation. Also what do they mean by being without perspective?), In the study protocol, this population.was operationally defined as the group of chronic heroin addicts who have been treated repeatedly, although unsuccessfully, in methadone maintenance programs. The decision to limit the study to this group of patients was based on the following considerations: many patients in methadone maintenance programs fit the description of the target group; the problems of methadone maintenance patients in the Netherlands are quite similar to those of heroin users currently not in contact with the treatment system (Eland-Goossensen, 1997). registration systems associated with methadone programs provide a clear sampling frame for the selection of study subjects-, and combining data from the methadone and the heroin registration system can prevent the prescription of double dosages. The decision to limit the study group to treatment-resistant methadone maintenance should help to assure higher internal validity, at the expense of only minor limitations with regard to the external validity. Table I describes the target population in terms of inclusion and exclusion criteria.

Inclusion criterion 1 (a-e) represents the severity and chronicity of the addict's problems, despite the fact that the person has received relatively high doses of methadone in the past. The cut-off point of five years in inclusion criterion lawas chosen on the basis of systematic review by Cramer and Schippers (1994) regarding the course and outcome of heroin addiction. They found that the major shift from drug use towards abstinence occurs during the first five years of the addiction career. Broadly speaking, after five years approximately 20 percent of the population of problematic drug users have achieved abstinence, and this percentage does not change much in the following 5 to 10 years. Regarding inclusion criterion 1b, it is important to note that a methadone dose of 80 milligrams plus or minus 20 milligrams per day has been recommended as an effective dose in the American State Methadone Maintenance Treatment Guidelines (Parrino, 1992). Therefore, a daily dose of 60 milligrams can be regarded to be a minimum requirement for methadone maintenance to be effective. Consequently a minimum dosage of 60 milligrams for at least four consecutive weeks was taken as a requirement for the decision whether a patient has failed in a state of the art methadone maintenance program.

With regard to the exclusion criteria 2, 3 and 4, it is important to note that these have been purposely described without being explicitly operational ized, as they are intended to exclude only those patients who are very likely to jeopardize the conduct of the study. It is expected that no more than 2 to 3 percent of recruited patients will be excluded from participation in the study. Therefore, these criteria do not constitute a serious threat to the external validity of the study. Patients meeting exclusion criterion 9 still have the potential to succeed in their abstinence attempts and will therefore be excluded from the study.

STUDY DESIGN

As noted above, the study has been designed to include 750 patients who are to be treated in eight distinct treatment units located in six Dutch cities. After an intensive debate, the Central Committee on the Treatment of Heroin Addicts (CCBH) decided that a traditional randomized clinical trial was preferred over a so-called pre-randomization or Zelen design (Central Committee on the Treatment of Heroin Addicts, 1997; Zelen, 1979, 1990). Within this randomized trial (phase II), three different treatment conditions will be distinguished: (I ) patients in group A will receive oral methadone during the first 12 months of the study in combination with a standard package of psychosocial interventions; (2) patients in group B will be offered oral methadone and heroin during the first 12 months of the study in combination with the same standard package of psychosocial interventions; (3) patients in group C will receive oral methadone and the standard package of psychosocial interventions during the first six months of the study, and a combination of methadone, co-prescribed heroin and the same standard package of psychosocial interventions during the second six months of the study (see Table 2). Patients will only be randomly assigned to one of these treatment options after successful completion of a qualification period of 4-8 weeks (phase 1).

Major outcome assessments will occur after six (phase IIa) and twelve (phase IIb) months of treatment, i.e. 6 and 12 months after randomization. Following phase IIb, all subjects will enter a follow-up period of six months (phase III). Patients who had been assigned to group A will then be given the opportunity to receive the experimental treatment of co-prescribed heroin for a period of six months. The prescription of heroin in groups B and C will be terminated at the end of phase IIb and replaced by an offer to return to the methadone maintenance program or to any other form of standard addiction treatment. This is true for both responders and non-responders to the experimental treatment with heroin. For the group of non-responders in phase II, the termination of the prescription of heroin is final. Similarly, no further heroin will be prescribed to those patients who responded positively to the experimental treatment and who did not deteriorate after termination of the heroin prescription. Heroin prescription can be reinstated in those responders to the experimental treatment who demonstrate substantial (> 20 percent of the baseline severity) deterioration in their functioning during the first two months following termination of the experimental treatment. In these cases, heroin co-prescription will be offered on the basis of a medical recommendation, and on a strictly individual basis.

TREATMENTS

The drugs prescribed in the study are heroin (hydrochloride or base) and methadone (hydrochloride). As noted above, patients in the experimental condition will be offered both methadone and heroin in combination with a standard package of psychosocial services, whereas patients in the control condition will be offered only methadone and a similar package of psychosocial services. Methadone was selected as the control compound because it constitutes the most extensively researched substitution treatment that is currently available. Heroin was chosen as the experimental compound because of its superior results when compared to most of the other opioids in terms of their appeal to clients, client retention in treatment, patient compliance and the absence of problematic side effects (Uchtenhagen et al., 1997). The rationale for utilizing a combination of methadone and (co-prescribed) heroin in the experimental condition is that methadone, with its long half-life, can prevent the occurrence of withdrawal symptoms when it is not possible or desirable to take heroin. The prescriptions of both methadone and heroin are provided free of charge to all participants. Methadone is regarded as an effective medication and is therefore fully reimbursed by the insurance system in the Netherlands. Heroin, on the other hand, is treated as an experimental medication with no proven effectiveness, so no charges can be made to the patient. In the injecting group, heroin is offered in a 20 percent solution of diacethylmorphine-hydrochloride, whereas in the inhaling group, heroin is offered as a powder consisting of diacethylmorphine-base in combination with caffeine. The latter compound is added in order to facilitate the evaporation of diacethylmorphine, resulting in an optimal bio-availability of heroin (Huizer, 1988). Dosages are individually titrated with a maximum of 400 milligrams of pure heroin per administration and a maximum of 1000 milligrams of pure heroin per day in a treatment regimen with a maximum of three administrations per day and a treatment setting that provides treatment sessions seven days per week. Patients will generally have to administer the heroin themselves, either through injection or by chasing the dragon. Patients randomly assigned to the injecting protocol are allowed to switch to inhalation as their route of administration. However, those assigned to the inhalation protocol are not allowed to switch to injection. No take-home dosages of heroin are allowed, and no other illicit drugs are prescribed to study participants.

Patients in both the experimental and control conditions are offered similar packages of psychosocial interventions, including individual counseling, group counseling, housing and budget assistance, participation in work projects and standard medical and psychiatric treatment. These additional treatments are available, although in varying degrees and combinations in the different cities, to all patients participating in existing methadone maintenance programs in the Netherlands (Lei ij and Driessen, 1998). Because of the differences between cities in terms of the availability of these additional treatments, it was decided to stratify random assignments according by city.

OUTCOME AND SUCCESS PARAMETERS

In the proposed study it is anticipated that stabilization or cessation of illicit drug use will be accompanied by improvements in physical and/or mental health status and in social functioning and integration. With regard to the primary outcome variable, however, attention must be paid to the way in which these different outcome domains are related. Two approaches have been considered. The first is based on the view that the most significant benefit from treatment in this specific population, and arguably the most difficult to achieve, is social integration and rehabilitation. Previous studies have suggested that improved social integration and rehabilitation is preceded by an initial reduction or stabilization of illicit drug use and illicit activities, as well as by improvements in physical and mental health status. In this view, social integration and rehabilitation constitutes the primary outcome variable. Improvements in illicit drug use and health are viewed as precursors of improved social integration. Changes in health and illicit drug use are therefore considered secondary outcome or process variables. Consequently, the statistical power of the study should be based on relevant goals and realistic expectations of the effect in terms of social rehabilitation.

In the second approach, no assumptions are made regarding the hierarchical or sequential order of the different outcome domains. In terms of a primary effect measure, this implies the use of a composite index score, which simultaneously refers to improvements in illicit drug use, physical and mental health status and social functioning in order to demonstrate a treatment effect. Consequently, the power analysis in this approach should be based on this composite index score. In addition, the question should be answered whether the primary outcome variable should be dimensional or categorical. The first is often expressed in terms of differences in mean levels of improvement between the experimental and control group(s), whereas the second is commonly expressed in the difference in response rates between the experimental and control groups(s). In both cases, however, the difference that is to be considered clinically relevant and the statistical analysis should be determined prior to the start of the trial. Following the consensus statement articulated by the European College of NeuropsychoPharmacology (1995), it was decided that "( ... ) a statistically significant difference between drug and placebo treatment with respect to the percentage responders defined as a pre-established degree of reduction on a pivotal scale may provide the most objective information about clinical relevance yet available". After a long debate, the Central Committee on the Treatment of Heroin Addicts (CCBH), decided that the difference in the percentage of responders between the experimental and control condition should be at least 20 percent. A responder was defined as a patient who meets the following criteria: (a) shows at least a 40 percent improvement in his or her medical condition AND/OR (b) at least a 40 percent improvement in his or her social functioning AND (c) no deterioration of 40 percent or more from baseline in medical or social functioning AND (d) no increase of more than 20 percent in illicit drug use.

DISCUSSION

This paper has provided the historical background and clinical rationale for the Dutch study on the medical co-prescription of heroin to chronic, treatmentresistant methadone patients. It should be emphasized that the medical prescription of heroin is not seen as a first line treatment for patients with an addiction to heroin and that the medical prescription of heroin is not a replacement for currently available and well established treatments such as the oral administration of methadone. Instead, heroin maintenance provides an additional, last resort treatment option in an accessible, comprehensive treatment system. The medical prescription of heroin and studies regarding its effectiveness should never be offered at the expense of effective treatments that are already available. However, it may play a beneficial role for some patients who did not respond to other treatments.

The authors contend that the Swiss study on the medical prescription of heroin has shown that such treatment is feasible, although many important questions remain unanswered. The most important of these pertain to the mechanisms of action in heroin prescription, and the feasibility and effectiveness of the medical prescription of inhalable heroin. It should be noted that a random clinical trial is not the only and perhaps not even the most appropriate, design to foster a sophisticated understanding of the psychological and social changes that occur within and between heroin addicts in the criminal and drug subcultures. Therefore, the clinical trial will be supplemented with several qualitative studies that look at the changing function of heroin among patients in the experimental condition, related changes in their lifestyles, as well as the effects of the new treatment on the drug scene as a whole.

Depending on the course and outcome of the Dutch trial, different scenarios for the future can be depicted. The frequent occurrence of insurmountable public order problems, serious adverse medical events or a failure to show clinically relevant positive effects would almost inevitably lead to the termination of this kind of treatment in the Netherlands. In contrast, positive outcomes could raise a number of additional questions. The first of these concerns whether enough data are available to implement the medical prescription of heroin as a routine treatment option within the comprehensive treatment system as a whole. Other questions will be posed with regard to the most desirable target populations for such treatment. Should it be restricted to patients who meet the inclusion criteria used in the original study, or should other heroin addicts also be considered for the medical prescription of heroin? If so, should this be done without formal scientific evaluation, or should it follow the same rigorous investigations as the random trial just described? These and other questions reveal that the Dutch trial on the medical co-prescription of heroin is just the start of an interesting new era in which innovative treatment options will become available and new studies will be conducted. Eventually these new treatments will have to be implemented and integrated in the currently available treatment system. Interesting questions regarding cost-effectiveness, patient-treatment matching and the political acceptability of certain effective interventions lie ahead. Creative discussions and innovative solutions are needed in order to exploit these opportunities for the improvement of all addicts and for society as a whole.

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Wim van den Brink, M.D. Ph.D., is professor of Psychiatry and Addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research, Amsterdam. Vincent M. Hendriks, Ph.D., is senior researcher of the Central Committee Heroin Addicts and Head of the Research Centre of the Mental Health Institute Parnassia, The Hague. Jan M. van Ree, Ph.D., is professor of Psychopharmacology at the Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht. Address correspondence and requests for reprints to W. van den Brink, Centrale Commissie Behandeling Heroineverslaafden (CCHB), Stratenum-5(e) verdieping, Universiteitsweg 100, 3584 CG Utrecht.

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