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Heroin maintenance treatment. From idea to research to practice

Uchtenhagen, A A

http://www.ncbi.nlm.nih.gov/pubmed/21375613.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Uchtenhagen, A A (2011). Heroin maintenance treatment. From idea to research to practice. Drug and AlcoholReview, 30(2):130-137.

http://www.ncbi.nlm.nih.gov/pubmed/21375613.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Uchtenhagen, A A (2011). Heroin maintenance treatment. From idea to research to practice. Drug and AlcoholReview, 30(2):130-137.

Heroin maintenance treatment: From idea to research to practicedar_266 130..137

AMBROS A. UCHTENHAGEN

Research Institute for Public Health and Addiction, aWHO Collaborating Centre, affiliated with Zurich University,Zurich, Switzerland

AbstractMaintaining opiate addicts on opiates has a long history.The idea to prescribe pharmaceutical morphine as a substitute forstreet heroin started in USA and was abolished on the basis of prohibitionist legislation. A new approach to maintain opiateaddicts on substitution therapy was initiated in USA in 1963, with the prescription of methadone. This approach found,although slowly, increasing acceptance, and is nowadays considered to be a cornerstone in the management of opiate dependenceand for the prevention of HIV/AIDS in opiate injectors. Since 1975, the concept of heroin maintenance treatment wasre-activated in order to reach out to treatment-resistant heroin addicts. Research projects were performed in Switzerland, theNetherlands,Germany,Spain,Canada and in England,another one is planned in Belgium.Based on the unanimously positiveoutcomes, heroin maintenance has become routine treatment for otherwise untreatable heroin addicts in Switzerland, theNetherlands,Germany and England,and Denmark has set up heroin maintenance without new research trials. [UchtenhagenAA. Heroin maintenance treatment: From idea to research to practice. Drug Alcohol Rev 2011;30:130–137]

Key words: heroin dependence, heroin maintenance treatment, opioid substitution treatment, drug policy.

The origins

Prescribing and using opiates as an effective medica-tion for a range of ailments goes back to the origins ofChinese, Sumeric and Egyptian medicine, and prob-ably beyond. In Homeric times, opium in wine(‘Nepenthes’) was offered against all evils, and theopium-made ‘Theriak’ was still considered to be themost essential drug at the dawn of modern medicineby Paracelsus. It was inevitable that its addictivepotential had to become manifest, but we do notknow when and where opiate addiction was firstobserved and when the use of opiates as a mainte-nance regime started. We do know however, that theRoman emperor Marcus Aurelius was maintainedon opium by the eminent Galenus, and that theMughal emperor Jahangir received opium mainte-nance. And far into the 20th century, opium dispens-ing was practised in some countries like Pakistan andLaos, providing dependent people with their dailydose.

Once heroin (diacetylmorphine) was developed in1874, it was again used as an effective medication formany conditions, frequently prescribed as ‘patent medi-cines’. In Europe, it was also considered to be a cure formorphine, cocaine and opium dependence, until itsown addictive potential became obvious. In the USA,44 narcotic clinics were set up, most of them after theHarrison Act, which left the dependent persons withoutsupply, and introduced tapering off morphine fordetoxification purposes. But then, the maintenanceconcept was re-invented, based on the frequency ofrelapses (the ‘Tennessee system’ of 1914, see [1]).Whilethe southern clinics, treating mainly iatrogenic mor-phine dependents, were quite successful, the NewYorkclinics failed in maintaining young heroin addicts fromminority groups [1,2].

Prohibition against maintenance

While all US narcotic clinics, successful or not, wereclosed by law in 1923, a few doctors continued to

Ambros A. Uchtenhagen MD, PhD, Chair of the Board. Correspondence to Professor Ambros A. Uchtenhagen, Research Institute for PublicHealth and Addiction, a WHO Collaborating Centre, affiliated with Zurich University, Konradstrasse 32, CH-8031 Zurich, Switzerland.Tel: +4144 4481160; Fax: +41 44 4481170; E-mail: [email protected]

Received 15 November 2008; accepted for publication 4 October 2010.

R E V I E W

Drug and Alcohol Review (March 2011), 30, 130–137DOI: 10.1111/j.1465-3362.2010.00266.x

© 2011 Australasian Professional Society on Alcohol and other Drugs

prescribe heroin or morphine to addicts until the SingleConvention of 1961, when heroin became a controlledsubstance and its use restricted to scientific purposes[2]. The concept of maintaining patients on an other-wise illegal or unwelcome consumption was incompat-ible with the puritan idea of prohibition.

The one country resisting the temptation of a strictprohibition in Europe was the UK where the RollestonCommittee in 1926 recommended heroin prescribingfor chronic addicts (which at the time were mainlysocially integrated iatrogenic morphine dependents).During the late 1950s, the number of heroin addictsincreased and their characteristics changed. As a con-sequence, drug dependence clinics were opened inLondon, and addicts receiving prescriptions had to benotified to the Home Office. The much debated objec-tives were medical care and at the same time socialcontrol of addicts. For many reasons, heroin prescrib-ing was more and more replaced by methadoneprescribing, until the AIDS epidemic led to a reconsid-eration and new experimentation with injectable andsmokable heroin, now in a perspective of public healthinterests [3].

The failure of prohibition to change habits in use ofa preferred substance became obvious in the case ofalcohol prohibition; it took much longer to realise thatthe heroin epidemic in the second half of the 20thcentury could not be stopped by prohibitive lawenforcement.

The revival of agonist prescribing: ‘fighting firewith fire’

It was again in North America where agonist mainte-nance treatment of opiate addicts was re-introduced,using methadone instead of diamorphine, on the basisof its advantages (oral application, longer half-life).According to the needs of the new target population—mainly marginalised urban heroin injectors—a compre-hensive health and social support program went alongwith methadone prescribing, in contrast to just handingout prescriptions for unsupervised use. The model waspioneered by Halliday in Canada in 1959 [4], followedin 1964 with a much better known trial by Dole andNyswander in New York [5].

The positive effects of this new approach, especiallyon the health and delinquency of patients, as was con-firmed by an increasing number of evaluation studies,led to a slowly growing acceptance of the maintenanceconcept, in spite of ‘abstinence-only’ arguments andopposition. But the decisive factor to speed up metha-done (and buprenorphine) maintenance was theadvent of the HIV epidemic. Drug injecting was rec-ognised as one major factor for transmitting the virusinfection (for hepatitis C as well).Throughout Europe,

the idea of maintaining heroin addicts on opioidsbecame increasingly acceptable, instead of restrictingtreatment to ‘abstinence-only’ approaches. In 2003,there were 462 412 patients in substitution treatment[6], and the number increased to an estimated 650 000in 2007 [7]. By 2007, substitution treatment is avail-able in all Member States of the EU; in nine countries,it is open to nearly all heroin addicts, and in sevenmore countries to the majority of them [7]. Finally, in2006 the World Health Organisation (WHO) suc-ceeded in putting methadone and buprenorphine onthe list of essential medicines. While earlier the mainobjective had been to reduce criminality and to curbthe illegal heroin market, this was replaced by a majorpublic health concern [8].

The quest for prescribing the ‘original drug’:new research

The increasing number of methadone patients ledinevitably to an increased though still smaller numberof ‘methadone-resistant’ patients who continued toinject heroin in spite of the availability of adequatemethadone dosages and care. At the same time, theHIV epidemic made it a priority to increase coverage,that is, to reach out to as many injectors as possible. Inthis circumstance, the ides of prescribing heroin asthe original and preferred substance of addicts wasraised.

Even if the AIDS epidemic is at the origin of allinitiatives to prescribe heroin in Switzerland, theNetherlands, Germany, Canada and Spain, the revivalof the idea of heroin maintenance had come up beforeand was ready to be taken up again. The debatestarted in Canada in the early 1950s and again in the1970s in the Netherlands and in the USA. The argu-ments mainly focused on heroin addiction as achronic condition and the need to restrict its negativehealth and social consequences. Three attempts tostart heroin prescribing in US cities have not suc-ceeded [3]. Non-medical options providing heroin toaddicts in the Netherlands (tolerated ‘home dealers’and ‘heroin bars’) were started, but then considered tobe failures [3]. The only project under medical controlwas a compromise between new thinking and politicalconcerns: the Amsterdam morphine prescriptionexperiment for highly problematic heroin addicts,starting 1983 [9].

In the UK, where pharmaceutical diamorphine as asubstitute for street heroin was gradually replaced bymethadone after the early 1970s, and where a firstrandomised trial comparing injectable heroin withmethadone had produced ambiguous results [10], anew experiment in prescribing heroin ‘reefers’ was suc-cessfully implemented [11]. Feasibility studies on

Heroin maintenance treatment 131


heroin prescribing were initiated in Australia [12,13].Large scale experimental studies were finally set up inSwitzerland (1994–1996), the Netherlands (1995–1997), Germany (2002–2005), in Spain (2003–2004),in England (2005–2009) and in Canada (2005–2008).Belgium decided to start a trial. One has also beenprepared but not started in France, and Denmarkimplemented heroin-assisted treatment in 2009without a research project of its own.

The Swiss cohort study and the WHOexpert report

Serious attempts to engage in new scientific research onthe feasibility and effects of heroin prescribing startedas a response to the challenge of unmanageable andintolerable open drug scenes (‘needle parks’) in majorSwiss cities.The project of heroin-assisted treatment foraddicts who failed in conventional treatments, includ-ing methadone maintenance, was one element in a newnational drug policy, aiming at investing massively inprevention, treatment, harm reduction and law enforce-ment. Restoring public order, curbing drug-relateddelinquency and prostitution were as important asrelieving the misery of addicts living in these publicplaces. However, the idea was not only to engage in newinitiatives, but also to gain solid scientific evidence, as abasis for future policy decisions. Evidence-based policywas asked for, in a context of controversial ideologicaldebates.

The Swiss 3 year project was originally designed as arandomised controlled study comparing injectableheroin to injectable morphine and methadone. Becauseof frequent histamine-like side effects, patients couldnot be recruited for the morphine and methadone armsas planned. The design of the main study had to beadapted to a prospective cohort study, but including anumber of randomised controlled sub-studies compar-ing i.v. (intravenous) heroin to i.v. morphine, compar-ing patients receiving i.v. heroin to patients on a waitinglist, pilot studies on diverse diamorphine preparationsfor alternative routes of administration [14] and studiescomparing self-report data on delinquency with policedata [15,16].The study results were first published as amonograph in 1999 [17]. A more recent study testedthe safety and effectiveness of oral (slow release andinstant release) diamorphine tablets, as a replacementof heroin reefers for patients unable or unwilling toinject [18].

The detailed positive results, acknowledged by aninternational expert committee set up by WHO [19],could nevertheless not separate the effects of heroinprescribing from the effects of concomitant care. Thisbecame the starting point for the randomised con-trolled trials, thereby adding essential new findings to

the already established positive outcomes. In the UK asimilar new approach has started, in contrast to theearlier practice of handing out prescriptions without anevaluation.

The randomised controlled trials

In the Netherlands, a randomised controlled studyco-prescribing injectable or inhalable heroin in addi-tion to oral methadone, in comparison with oralmethadone alone, started in 1995.The inhalable appli-cation (‘chasing the dragon’) had to be consideredbecause the majority of Dutch heroin users prefer itover injecting.

Trial participants were recruited from existingmethadone maintenance programs, attending theirprogram regularly and receiving at least 50 mg (inhal-ing trial) or 60 mg (injecting trial) methadone per day.The number of participants in the trials was 549, with375 receiving inhalable heroin and 174 receiving inject-able heroin. Altogether, 237 were randomised into thecontrol groups and 119 into a comparison group start-ing out with oral methadone and transferred to inhal-able heroin after 12 months [20].

The co-prescription of heroin in the two experimen-tal groups lasted for 12 months.The dose of heroin wasa maximum of 1000 mg per day, plus a maximum of150 mg of oral methadone in the experimental groups,and a maximum of 150 mg of oral methadone per dayin the control group. After termination of theco-prescription of heroin, all patients received oralmethadone only. All groups were provided with ancil-lary standard psychosocial treatment [20,21].

Treatment response was significantly (P = 0.0001)higher in the experimental groups than in the controlgroups. Results from those who completed the studywere similar to those from the intention-to-treat analy-sis. Treatment responders showed relevant improve-ments in all outcome domains [20]. The only patientcharacteristic predicting a positive outcome was pastabstinence-oriented treatment [21].

Eighty-two per cent of the responders in the experi-mental groups deteriorated substantially during the2 months following cessation of heroin co-prescription,and the mean outcome scores returned to those beforeentering the program [20].

The positive outcome of the study led to a parlia-mentary decision in 2004 to increase the number oftreatment slots to 1000, to be situated in 11–15 cities.However, only about 300 treatment slots in six citieswere actually set up, mainly because of financial prob-lems. By 2008 there were eight specialist clinics pre-scribing heroin to approximately 350 patients. Thecentres have 25–70 treatment slots each. A further

132 A. A. Uchtenhagen


increase is intended, mainly with smaller centres having25–30 slots.

Injectable and inhalable heroin were registered as asubstitution drug in the treatment of heroin dependencein December 2006 by the Dutch Medicines EvaluationBoard. Heroin-assisted treatment is authorised forchronic, treatment-resistant heroin addicts who couldnot be stabilised satisfactorily in a methadone mainte-nance program. New patients can be admitted. Theindication criteria are practically unchanged. In 2007heroin-assisted treatment became acknowledged as aregular treatment under special conditions.

In Germany, the largest randomised study onheroin-assisted treatment started in 2002 and ended in2005. Clinics were set up in seven cities and a total of1032 patients were enrolled in the program (515 onheroin maintenance). All received an intensive psycho-social care program. The average daily dose of heroinwas 442 mg; after the induction phase dosage wasstable [22].

The design was a 4 ¥ 2 randomised multicentrestudy with two target groups (methadone patients whocontinue to inject heroin, and heroin addicts out oftreatment for at least 6 months) and four arms for eachtarget group (heroin vs. methadone, psychoeducationvs. case management with motivational interviewing).

The study was divided into two phases:

Phase 1: in the first 12 months, a stratified 4 ¥ 2 ran-domised controlled trial in order to examine the effectsof heroin prescribing as compared with methadone pre-scribing under similar conditions.Phase 2: follow-up study over 12 months in order toinvestigate the long-term effects in the experimentalgroup; a randomly selected group of control patientsreceives heroin prescription, the rest leave the study andare offered regular treatment.

Special studies addressed criminological aspects,economic aspects, neuropsychological issues, psychoso-cial interventions, acceptability and implementation ofthe project.

The findings showed better results for the heroingroup in regard to the criteria (improvement in somaticor mental health of at least 20%; a major reduction ofstreet heroin use and no increase in cocaine consump-tion). The differences are statistically significant. Theimprovements from heroin-assisted treatment wereequal for both target groups (refractory methadonepatients, patients out of treatment) and for both typesof psychosocial intervention (psychoeducation, casemanagement) [22].

After 2 years, the heroin group showed highly signifi-cant improvements in physical and mental health, while

illicit heroin and cocaine use also decreased signifi-cantly [23].

Based on the evaluation results, the RegistrationAuthority (Bundesinstitut für Arzneimittel und Mediz-inprodukte BfArM) decided in favour of a continuationof heroin-assisted treatment on a routine basis, andParliament agreed to provide the necessary new legalbasis for a continuation in 2008.

In Spain, initiatives to set up trials with diamorphinewere taken in two of the Autonomous Regions—inAndalusia and in Catalonia. During 2000–2001, theseinitiatives were discussed in the Central Agency forDrug Addiction. The authorities decided to allow thetrials, with the expectation that they would generatenew scientific insights, and to get approval of the Drugand Pharmaceutical Control Office for registration ofdiamorphine as a medicine. A clinical trial of heroinmaintenance therapy was authorised in 2001 [24].

A randomised controlled trial started in 2003 inGranada and was completed in 2004. Sixty-two heroinaddicts were recruited, 31 in each group. The averagedaily dose of heroin was 274.5 mg plus 42.7 mg metha-done in the experimental group, while 105 mg metha-done was prescribed in the control group. Both groupsreceived comprehensive clinical, psychological, socialand legal support.

The results showed significantly better results in theexperimental group, in regard to physical health, reduc-tion of risk behaviour, reduction of drug use and ofinvolvement in crime [25].

The Council of Andalusia requested continued com-passionate use for the 36 patients who participated intheir clinical trial. The Spanish Agency for Medicine(an organisation under the Ministry of Health) gave itsconsent and authorised these patients to receive heroinfor life.

In the UK, the Randomised Injecting Opioid Treat-ment Trial recruited 127 opiate addicts who continuedto frequently inject illegal heroin despite being pre-scribed substitute oral opiate-type drugs. These 127patients were randomly allocated either to injectablemethadone or heroin for 6 months, or to continue onoral methadone. If necessary doses were individuallyadjusted to high levels (to 300 mg of oral methadone, to200 mg of injectable methadone, to 900 mg of inject-able heroin per day) to achieve maximal comfort andsuppression of illicit opiate use. Patients receivedregular psychosocial support if needed. After the6 months of the trial, patients were reassessed for themost appropriate treatment, including possible inject-able prescribing for those previously allocated to oralmethadone.

There was better retention in the groups receivinginjectables (88% in the heroin group, 81% in themethadone group), in contrast to the group receiving



oral methadone (69%), and a significantly better reduc-tion in illegal heroin use in the heroin group. Afteradjusting for other factors, 66% of the heroin group hada good response to treatment (vs. 30% in the i.v. metha-done group and 19% in the oral methadone group).These findings were based on urine analysis differenti-ating illegal heroin use from prescribed heroin [26].

In Canada, 251 heroin injectors who had not prof-ited from at least two previous treatments were ran-domised to injectable heroin (n = 115), oral methadone(n = 111) or injectable hydromorphone (n = 25), andassessed after 12 months; main outcome criteria wereretention and use of illicit drugs or other illegal activity.The intention-to-treat analysis resulted in a signifi-cantly better retention in the heroin group (88% vs.54% in the methadone group) and reduction in illegaluse or activity (67% vs. 48%).There were some adverseevents, but limited to non-fatal overdoses and seizuresafter injections [27].

A summary of findings on feasibility, outcomeand impact

The results from all the studies have been publishedextensively, including 2 year and 6 year follow-upresults from the Swiss cohort [28,29], 2 year follow-upresults from Germany [23] and 4 year follow-up resultsfrom the Netherlands [30]. Recent reviews providedetails [31,32]. A monograph on heroin-assisted treat-

ment is in preparation at EMCDDA, the EuropeanCentre on Drugs and Drug Addiction in Lisbon.

Feasibility

Heroin-assisted treatment can be implemented withgood acceptance by patients, by law enforcementauthorities and—in the case of Swiss nationalreferenda—by the general public. The target group ofchronic, marginalised and treatment-resistant heroinaddicts could successfully be reached (for admissioncriteria see Table 1)

Safety

Heroin-assisted treatment can be implemented withoutundue risks for patients, staff and public order; underthe control conditions of the studies discussed here, nodiversion of prescribed substances to the illicit marketand no fatal overdose from prescribed heroin could befound. Serious adverse effects occur, and can be wellmanaged. Cerebral undersaturation of oxygen, causingconvulsions and respiratory depression, was foundmore frequently in heroin maintenance than in controlgroups (in Switzerland, Germany, the UK andCanada), but staff and patients learned to avoid this bypromoting physical activity after injections. Annualmortality rates from all causes are below those of

Table 1. Admission criteria for heroin maintenance treatment

Criteria Switzerland Netherlands Germany Spain UK Canada

Minimal age (years) 18 25 25 18 18 25Local residency

requiredYes >3 years >5 years — Yes >1 year

Diagnostic assessment ICD-10 DSM-IV ICD-10 ICD-10 DSM-IVR DSM-IVDuration heroin

dependence>2 years >5 years >5 years — >3 years >5 years

Daily heroin use Yes Yes Yes Yes (last 30 days) >50% of days inlast 3 months

Former treatments Minimal2 (any)

any MMT Min. 2 (incl.1 MMT)

Health and/or socialdeficits

Yes Yes Yes Yes

If in MMT Min. 12 months(39–59 visitslast 6 months),>50 mg day-1

>6 months

If out of treatment >6 monthsInformed consent Yes Yes Yes Yes Yes YesRandomisation

acceptedNo Yes Yes Yes Yes Yes

Sources: Switzerland: 17, Netherlands: 19, Germany: 21, Spain: 24, UK: 25, Canada: 26. DSM-IV, Diagnostic Statistical Manual4th edition; DSM-IVR, Diagnostic Statistical Manual revised 4th edition; ICD-10, International Classification of Diseases 10thedition; MMT, Methadone Maintenance Treatment.



untreated heroin addicts and of those in other treat-ments [33].

Treatment effects

All treatment effects indicate an improvement in physi-cal and mental health, a reduction of risk-taking behav-iour (especially needle sharing), a reduction of crimeinvolvement and some improvement in social integra-tion (although the stigma of heroin dependence is amajor obstacle). Significant positive effects are docu-mented from all studies, at different time points(Table 2). Positive effects persist over time after leavingthe program.

Patient satisfaction

Satisfaction is generally high; there were some com-plaints concerning organisational details, but not thetreatment or the substance per se.

Impact on other treatment approaches

No negative effects on other treatment approachescould be observed.Where data are available, they showan overall increase in treatment availability, utilisationand quality for heroin addicts during the implementa-tion of heroin-assisted treatment.

Impact on public health and public order

Heroin-assisted treatment reduces the risk of blood-borne infectious diseases and their transmission toothers. It reduces the role of heroin addicts in recruitingnew addicts, by a reduction of their involvement in drugtrafficking. Heroin-assisted treatment reduces the

crime involvement of patients, and the nuisance for thepublic in general caused by addicts not in treatment.

Cost–benefit

The Swiss, the Dutch and the German experimentshave been evaluated economically; all with favourablecost–benefit ratios [34–36].

Implications for drug policy

All these scientific projects had and have some featuresin common: the model of maintaining heroin addicts onsupervised injections (or inhalation or oral applica-tions) of pharmaceutical diamorphine, in the frame-work of a comprehensive assessment and care program,targeting specifically heroin addicts who are out oftreatment or who continued to use illicit heroin whilebeing on other treatments, including methadone main-tenance. The idea is not to reach out to heroin addictsin general, but to those otherwise not reachable, in aperspective of public health and public order priorities[37,38]. The treatment modality is not conceived asreplacing other forms of treatment.

Heroin prescription has moved from idea to experi-mental project to routine treatment and is part of anoverall treatment network for heroin addiction in Swit-zerland, the Netherlands, Germany and Denmark,without known negative effects on other approachesand on prevention. WHO made a cautious assessmentof this approach, in view of the limited experience andthe safety risks, especially when set up in less resourcedand well-organised health systems [39,40]. An earlyCochrane review came to similar conclusions [41],while a recent one is still under discussion [42].

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Table 2. Comparing selected outcomes over time across studies (significant changes only)

Domain 6 months 9 months 12 months 18 months 24 months 4 years

6 years(patientsstill in

treatment6 years

(ex-patients)

Health statusimprovements

CH E BRD, CH, NL CH BRD NL

Reduction in illicitheroin use

BRD, CH E BRD, CH, NL,E, CA

CH BRD NL CH CH

Increased employmentrate

CH BRD, CH CH BRD

Reduction in crime BRD, CH E BRD, CH, NL,CA

CH BRD NL CH CH

BRD, Germany; CA, Canada; CH, Switzerland; E, Spain; NL, the Netherlands; UK, England.



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