Substitution therapy for opioid addicts

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An opioid replacement therapy (ger .: opioid maintenance treatment (OMT); colloquially: drug substitution or drug replacement therapy ) is a treatment of subjects suffering from a dependence on opioids - mostly heroin  - suffer. The treatment is carried out with drugs that are prescribed in accordance with the law and guidelines , the aim being to achieve permanent freedom from substances ( abstinence ) in the (more or less) foreseeable time or to strive for damage minimization in the sense of permanent substitution and thus the state of health and the social situation of the Significantly improve patients and at the same time avert harm to society. Both goal orientations are to be regarded as equivalent and are not mutually exclusive. Proven better results can be shown if the substitution agent is administered with simultaneous social work and psychoeducational - much less often also psychotherapeutic  - support. A so-called substitution program includes this very psychosocial care . In addition, substitution programs offer the opportunity to clarify the participants about common comorbidities (such as hepatitis C ), to refer them to treatment here as well and to offer vaccinations against hepatitis A and B, for example .

The substances used contain the specified amount of active ingredient and no impurities. The complications of intravenous drug use , such as injection abscesses and the transmission of hepatitis C and B, and HIV can thus be avoided. Those affected are also relieved of time and money, and prostitution and criminal acquisitions can be reduced or avoided. The attending physician and the psychosocial counseling center try together with the patient to identify emerging crises as early as possible or to deal with them in the sense of crisis intervention and to maintain the job (taking up a job; beginning or completing training) and establishing social contacts to work outside the drug milieu. Day structuring or overnight accommodation is also offered in various advice centers.

history

As early as 1949, heroin addicts at the United States Public Health Service Hospital in Lexington , the largest drug rehab facility in the United States opened in 1935, were gradually treated with methadone, which was then the best withdrawal substance, for usually seven to ten days.

From the mid-1950s it became apparent that the Federal Bureau of Narcotics , which had been under the US Treasury Department and had existed since 1930, had failed with its rigid policy of prohibiting all use, passing on and supplying of opioids. In 1955, the American Bar Association (a professional association of lawyers ) and the American Medical Association merged to write a joint paper on the continued prevalence of narcotics . The committee's interim report published in 1958 recommended the establishment of an outpatient facility for prescribing narcotics on an experimental basis. The paper also criticized the intimidation of medical professionals prescribing opioids and suggested that maintenance therapy could lower drug crime rates.

The actual beginning of the scientific examination of the (long-term successful) drug treatment of opioid dependence can be determined by the publication of the research by Vincent Dole and Marie Nyswander in 1965. Opioid receptors were still unknown at the time; first indications for their existence were not published until 1973. Nor was there any knowledge of the existence of endogenous opioids , which were not discovered until 1975. Methadone, for example, was selected on the basis of careful clinical observation of pain patients and addicts because the long half-life as well as the ability to take it orally were seen as great advantages.

Dole and Nyswander administered high doses of 50 to 150 mg methadone as one of the components of a long-term therapy that was designed for an indefinite period with regard to methadone administration. In 1966 they published their work on the blockade of the “narcotic” effect of intravenously consumed opioids after methadone doses of 60–120 mg. This means that the additional intake of street heroin (or other opioids) cannot trigger an euphoric effect and thus there is no temptation to take it. They expressly refused an uncontrolled delivery. This original concept was quickly received, first in the US and then around the world.

Unfortunately, the concept of long-term support was abandoned again and the goal of abstinence was placed in the foreground, the methadone dose was reduced and the patient was thrown out of the program "as a punishment" (or for educational reasons, in any case: zero tolerance ) if they relapsed or did not adhere to the treatment contract and co- use could be proven. A partly emotionally tinged, violent dispute still takes place today between the representatives of these two directions. Here is the view that it is at a dependence on opioids is a chronic condition IN QUESTION, relapse to disease belong and measures to minimize damage ( harm minimization ) or reduction of the company of benefit is, international currently playing more attention.

Methods

Methadone reduction (detoxification, withdrawal) and methadone maintenance methods (permanent substitution) are offered simultaneously in many countries today. There are also treatment strategies that are known as “maintenance therapy for withdrawal” or “abstinence-oriented maintenance therapy”.

Long-term treatment of opioid addicts is also referred to as “medical maintenance therapy”; this is seen as a specific treatment for a metabolic disorder and compared with the administration of insulin for diabetes or the long-term therapy for arterial hypertension . This contrasts it with the temporary “short-term” or “psychotherapeutic maintenance therapy”, where it is assumed that with the decreasing opioid tolerance with tapering treatment and psychosocial support, a permanent normal state can be established. The latter objective is questioned by the proponents of medical maintenance therapy and, in addition to laboratory studies, reference is made to the high relapse rate after all forms of withdrawal treatment . However, many factors can lead to relapses and the clinical relevance of the laboratory studies is still unclear, so that to this day the dispute over the direction remains undecided.

The authors of the UK National Treatment Outcome Research Study (NTORS) found that patients on abstinence-oriented maintenance therapy did not differ significantly from patients on traditional maintenance therapy with regard to their methadone dosage after one year. After two years it was found that the faster methadone was reduced, the more heroin was consumed. The authors concluded, among other things, that the specific form of methadone reduction therapy and the corresponding treatment goals should be better communicated not only to the patient but also to the treatment team.

effectiveness

Substitution therapy for opioid addicts is now considered so effective that it is often difficult for the treating physician to sanction a violation of the treatment contract by discontinuing therapy. In a study with 1,544 patients, twice as many deaths occurred after methadone substitution than during substitution and the rate of deaths from opioid use was 51 times higher. An 8-fold increase in mortality was also observed with substitution for diseases acquired before the start of treatment, but this was significantly lower than the 63-fold increase in mortality of addicts without therapy or the 55-fold increase in mortality of addicts who had to leave a substitution program because of rule violations .

The cost-benefit analysis of substitution therapy with a conservative consideration of health and social care costs and the consequences of criminal behavior in England results in a ratio of 1: 9.5 to 1:19. According to the results of the National Treatment Outcome Research Study (NTORS), this is primarily the result of a significantly reduced crime rate, even if a Cochrane study, taking into account all evaluable existing studies, could not prove any significant advantage here. In addition to the cost criteria mentioned, the effects on the family burden of addiction to opioids, society's fear of an increase in crime or the effects of a change in consumer behavior are more difficult to grasp and are therefore usually included in cost-benefit analyzes of substitution programs not included.

Substances

The most commonly used substitute is methadone , and buprenorphine is also increasingly used and, due to the increased formal requirements, dihydrocodeine / codeine is rarely used. The substances are taken orally under supervision (by the prescribing doctor or in the pharmacy). After a certain period of time, the doctor can decide whether to take the substitute home with him (so-called take-home prescription , e.g. racemate methadone).

Because of its proven effectiveness, methadone was added to its list of essential medicines by the World Health Organization (WHO) in 2005. Buprenorphine should be used when its use has advantages over treatment with methadone. Methadone is significantly cheaper - a fact that must be taken into account when treating opioid addicts (as in all other areas of medicine).

Methadone

There is verifiable evidence for the effectiveness of methadone especially for patients in permanent substitution. This evidence decreases the shorter the methadone is administered, and to some extent also the more the treatment concept deviates from the original concept developed by Dole, Nyswander and Kreek .

In addition, the level of the administered dose is of crucial importance. The limit between a low and a high dose is somewhere between 60 and 100 mg / day. Patients usually only want the dosage with which they feel “comfortable”, that is, the dosage that prevents withdrawal symptoms from occurring. Medium to high doses also suppress substance cravings - not just for heroin - and high doses lead to complete opioid block . Patients usually do not want such high doses because they do not want to give up the goal of being completely free of substances. For opioid blockade, due to the large interindividual differences in the metabolism of methadone ( genetic polymorphism with regard to the genes coding for the breakdown enzymes , transport proteins and µ-receptors ) 55 mg / day may be sufficient, on the other hand up to 921 mg / day may be required. In the latter case (in patients who can break down the active ingredient very quickly, i.e. so-called fast or ultra-fast metabolizers ), taking it twice a day can help. In summary, a methadone dose of more than 60 mg / day supports the continuation of the substitution process significantly and leads to less heroin consumption; conversely, more than 100 mg / day in the majority of cases have no additional benefit and there are no controlled studies that would justify routine dosing at this level.

Methadone is remarkably safe on long term prescription. While Justo emphasized in 2006 that routine cardiological work-up was not necessary, the new (US) guidelines further increase the safety with regard to the occurrence of potentially life-threatening cardiac arrhythmias ( see article : Methadone ). Often patients have to be made aware of this fact, as methadone is sometimes seen as a harmful drug in the drug scene and is rejected. Many heroin addicts buy methadone on the drug scene because the effects last much longer than that of heroin. However, methadone is known for the fact that patients may have a QT prolongation on the EKG with long-term use . This problem can, however, be solved in patients at risk by switching to levomethadone , as this active ingredient does not have this side effect.

The summary of 52 large studies with a total of 12,075 participants showed that methadone-supported substitution therapy succeeds better than with all other methods (retarded morphine, for which there are only a few studies, were not investigated) in keeping the patient in a substitution program; With regard to the co-consumption of heroin, it does not differ from the heroin-supported substitution and is only inferior to the therapy with LAAM .

High doses of methadone can also lead to a significant decrease in cocaine use, assuming common mechanisms of addiction development. Methadone substitution increases the likelihood of pregnancy in women.

Buprenorphine

The combination of buprenorphine and intensive psychosocial care is safe and highly effective, in contrast to intensive psychosocial care alone. Thanks to its property as a partial antagonist , there is a saturation effect with regard to the respiratory depressive effect. However, it can also be done with buprenorphine, v. a. when benzodiazepines are used, unwanted overdoses and deaths occur. If hepatitis C is also present, buprenorphine can lead to an increase in the liver enzymes aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) and in individual cases to acute liver necrosis . Therefore, before starting a buprenorphine substitution, an existing hepatitis B and C must be examined and the liver function parameters (enzymes, bilirubin , INR , and albumin ) should be determined and these should be checked periodically at the discretion of the practitioner. The consumption of alcohol should be avoided. Methadone is better used if there is also problematic alcohol consumption.

Diamorphine

Heroin (diamorphine) was previously not marketable in Germany, i. H. it was not allowed to be sold or used medicinally. Because it has been reported repeatedly about seriously ill patients whose dependence could not be treated satisfactorily by heroin replacement drug, there was along the lines of other countries ( Switzerland , Netherlands ) under the supervision of the Federal Opium Agency from 2002 to 2006, a pilot project "heroin-assisted treatment," where the Cities of Hamburg , Karlsruhe , Bonn , Hanover , Cologne , Munich and Frankfurt am Main took part. Results were presented in March 2006: The health status of about 500 with diamorphine (heroin) substituted was significantly better than in the comparison group substituted with methadone, illegal parallel consumption and related crime low. On the basis of these results, the inclusion of diamorphine-supported treatment in the normal substitution program was demanded by all parliamentary groups with the exception of the CDU / CSU and by several Union-governed countries; the diamorphine-assisted treatment was meanwhile continued with special federal approval.

Patients in heroin programs are more likely than participants in other programs to ask for a dose increase. In such cases, it is recommended to point out that it is for this very reason that methadone is generally not recommended as a substitute drug, but rather methadone, as the dosage can be kept stable for years with the latter.

Retarded morphine

Retarded morphines are available in Switzerland, Austria, Australia, Bulgaria, France, Slovenia and, since 2015, in Germany for the treatment of opioid addiction. Disadvantages are that a Heroinbeikonsum in urine tests can not be seen and the dosage in substitution programs after the poor oral bioavailability directed and non-intended at one and never excludable iv -Use may be unintentional, fatal overdoses. When taking it, care must be taken that the capsules are not chewed, as this can cancel out the delay or prolongation of the effect. In Austria, retarded morphines are only considered from the outset as an alternative for those patients who are intolerant to methadone or buprenorphine, who are undergoing antiretroviral therapy for an HIV infection or who have a prolonged QT time in the ECG .

In an early Austrian study, 16 of 146 patients in a long-term methadone program were switched to the retarded opioid morphine sulfate due to serious side effects, after which the side effects regressed and the patients were satisfied with the change.

In a later Austrian study with a total of 240 patients, the study participants stated that the quality of life was lower with retarded morphines than that with methadone and buprenorphine, while in a much smaller Australian study with 14 participants, 78% of the participants switched from methadone to retarded morphine. was experienced as positive. However, it must be mentioned that with such a small number of participants, percentages should be viewed with caution. The authors of both papers are in favor of further studies.

Overall, retarded morphines are more euphoric than methadone and buprenorphine, so that some opioid addicts are very keen to have them prescribed, and some also emphasize the inadequate effect or side effects of other substitution drugs. In view of the disadvantages, the treatment goals must be specified more precisely, the controls for compliance with the agreements must be intensified, the intake must be carried out more precisely under visual control and the transfer regulations must be handled more restrictively.

LAAM

Levacetylmethadol (LAAM) is currently not available as a substitute because the manufacturer has discontinued marketing due to an increased risk of cardiac arrhythmias . However, due to its very long half-life, which would allow it to be taken every third day, it would be an ideal means for substitution treatment. The authors of a European multicenter study come to the conclusion that a discussion should take place regarding the introduction of LAAM in the EU.

Controls

Substitution therapy without urine controls can be compared with diabetes treatment without measurements of blood sugar levels or therapy for hypertensive disease without regular blood pressure measurements . This applies even if studies have shown that the self-reports of clients / patients on substance use and the test results obtained agree quite well.

The usual urine controls do not meet forensic requirements, but in practice they allow a sufficiently objective statement on therapy compliance , the consumption of illegal substances or benzodiazepines and provide additional information for decision-making in the event of therapy changes. A parallel consumption can thus be reduced or omitted although there is little evidence that urinalysis a deterrent with respect to an unauthorized Beikonsums. Temperature measuring strips that can be stuck to the urine cup increase the informative value of the urine tests, so that under certain circumstances there is no need to pass urine under visual control, which is degrading for the patient and the staff. Urine tests can give false positive and false negative results, the results of scientific studies suggest that additional substance use cannot be reliably ruled out and the level of knowledge of opioid prescribers regarding the informative value of urine tests leaves much to be desired. Mandatory urine tests lead to more contact with the caregivers and enable statements to be made about the efficiency of a program.

Oral mucosal swabs also provide accurate results for the detection of methadone and opioids. The acceptance of this method on the part of the client / patient is much higher than that of urine delivery under visual control. Further, important advantages are that the required unambiguous assignment is guaranteed without further ado and the test can be carried out at any time, i. This means that you don't have to wait until the bladder that you have just emptied is filled again - provided you want to insist on the test in individual cases. Checks are therefore also possible more frequently. However, the concentrations in oral fluid and blood vary from substance to substance, from person to person and within the individual. Since the specificity for benzodiazepines is probably comparable, but the sensitivity is significantly worse, this method is currently unsuitable for the detection of an additional consumption of benzodiazepines.

Only chromatographic detection methods (preferably gas or liquid chromatography coupled with a mass spectrometer ) are forensically meaningful , as these are suitable for detecting individual substances and distinguishing them from effective and ineffective metabolic products and determining the required concentrations. The urine must be obtained under visual inspection.

Consumption

Consumption of other psychotropic substances , primarily benzodiazepines , alcohol and cocaine , but also antidepressants , is one of the biggest problems for addicts in and outside of substitution programs, especially in relation to fatal overdoses. In addition, the consumption of benzodiazepines u. a. to a significant deterioration in working memory . As far as possible, substitution therapy with the substitution agent alone should be done without other substances. Nicholas Seivewright cites as a theoretical basis for this requirement that many of the studies that have led to the evidence-based proof of effectiveness of methadone were carried out with study participants without any co-consumption. Additional treatment with benzodiazepines cannot be avoided in the case of accompanying psychiatric illnesses (primarily anxiety disorders ), inadequate response to psychoeducational measures, unwillingness of the patient to increase the dose of the substitution drug, and insufficient effectiveness of alternative drugs. The more uncritical their prescription, the more likely it is to be used in a harmful way and passed on or sold.

Pain management

That pain is often inadequately treated in all populations, is a known issue, adequate pain therapy but performed less frequently in individuals with an addiction disorder in prehistory and patients in substitution treatment. The reasons that stand in the way of effective pain treatment are varied and complex.

pregnancy

Pregnancies in drug addicts must be seen by obstetricians and gynecologists as high-risk pregnancies. The treatment is tailored to the pregnant woman according to the symptoms that arise. Heroin-dependent women who become pregnant should be included in a substitution program. This should be continued for women in a substitution program. The (careful) withdrawal by means of naloxone is currently not a standard procedure. The consumption of street heroin or illegally acquired substitutes often leads to a change from overdose and withdrawal symptoms, which can endanger the health of mother and child. The controlled delivery of a substitution agent prevents these fluctuations. In addition, acceptance into a substitution program enables the social work support that is particularly important during pregnancy.

The metabolism of methadone is accelerated by the influence of progesterone on the enzyme cytochrome P450 , which is mainly responsible for the breakdown , so that withdrawal symptoms can occur and a correspondingly higher dose must then be taken. Methadone may be taken twice a day.

Since buprenorphine can be prescribed by practitioners in France without further training, up to 70,000 addicts are hired accordingly. Although field studies there as well as occasional data from the USA seem to confirm the safety of BUP from the second trimester of pregnancy, a prospective Finnish study showed an increased risk of opioid withdrawal syndrome in the newborn, a high need for opioid replacement therapy in the newborn, and a higher than expected occurrence of sudden infant death syndrome . The substitution therapy of a pregnant woman goes hand in hand with the substitution of the fetus , i. H. the unborn child consumes the substitution medication via the placenta . These have toxic and / or teratogenic pharmacological potency that affect the newborn .

Follow-up care for women is also necessary after childbirth, since a significantly increased long-term morbidity , mortality and loss of productivity can be demonstrated with early retirement. Therefore, a precise analysis of the existing disturbance pattern is necessary. All information available in the standard must be taken into account in terms of its expressiveness in order to be able to guarantee care for mother and child. Examples include: maternity record, U-booklet, all medical statements, excerpts from criminal records, diagnoses of cost and service providers.

An estimated 7,000 children are born to opioid addicts each year in the United States.

Discontinuation of therapy

It may be necessary to end the therapy immediately or faster than originally planned if there is assault, bodily harm or threats of violence against staff or fellow patients, damage to property, theft or drug trafficking on site or near the substitution facility, as well as repeated passing on of the substitution drug. In higher-threshold facilities, the consumption of psychotropic substances can lead to the (contractually agreed) discontinuation of treatment. Discontinuation of therapy is a risk factor for opioid intoxication, v. a. for fatal overdoses. In an Italian study, opioid addicts had an 8-fold increased risk of dying in the first 12 months after leaving the substitution program compared to those who remained in the program. In addition, substitution therapy was identified as a risk factor for a (non-fatal) overdose in the 12 months prior.

Country-specific facts

Differences in the treatment of opioid addicts are mainly due to the legislative framework. The situation in the German-speaking countries is presented below.

Germany

The legal basis for legal substitutions in Germany is the Narcotics Act and the Narcotics Prescription Ordinance . There, the permitted substances, indications and time periods are specified in detail. The Federal Committee of Doctors and Health Insurance Funds has laid down specific implementing provisions for statutory health insurance (i.e. they only apply to contracted doctors or those insured by statutory health insurance and social assistance recipients). The guideline of the German Medical Association for the implementation of substitution-based treatment of opioid addicts provides the generally recognized state of the art of medical science, in particular for the therapeutic goals of substitution-based treatment of opioid addicts, the general requirements for the initiation and continuation of substitution and the creation of a therapy concept in accordance with Section 5, Paragraph 12 the Narcotics Prescription Ordinance. (For the consequences of not observing the legal framework, see the article on Hannes Kapuste , an early substitution doctor in Germany.)

Both guidelines are now largely identical. They demand proof of a special qualification ( specialist knowledge of basic addiction medicine ) of the participating doctors and limit the number of addicts who can be looked after in a practice at the same time. In addition, they stipulate that psychotherapeutic and social treatment is an indispensable part of substitution, because of the risk of uncontrolled co-consumption (patient also takes other drugs) blood and urine tests should be carried out unannounced .

Access to the programs has now been made easier. According to the applicable guidelines, however, only addicts who cannot be treated drug-free are still eligible, i. H. Substitution should remain the exception. This applies, for example, if several weaning treatments were unsuccessful, during pregnancy, in the case of serious concomitant diseases, especially cancer , AIDS or chronic hepatitis. Every substitution must be reported to the Federal Institute for Drugs and Medical Devices and also documented to the responsible association of statutory health insurance physicians . This is to prevent addicts from receiving substitute drugs from multiple doctors at the same time. In the case of minors and persons whose addiction has existed for less than two years, the treatment is reviewed by a commission, limited in time and particularly strictly committed to the goal of complete abstinence . Persons who are predominantly dependent on substances other than opiates (such as alcohol or cocaine ) may not be substituted under these programs.

According to Bundestag printed paper 16/2294, the following data were reported to the substitution register of the Federal Institute for Drugs and Medical Devices on July 1, 2006:

  • 42 187 patients treated with methadone
  • 11 506 patients treated with levomethadone
  • 11 171 patients treated with buprenorphine
  • 577 patients treated with dihydrocodeine
  • 118 patients treated with codeine .

As of July 1, 2007, a total of 69,300 people were in substitution treatment.

Austria

In Austria, according to § 23c of the Narcotics Act in substitution treatment "methadone and buprenorphine, each appropriate in a for oral ingestion and intravenous use of this drug aggravating preparation method of first choice. Other substitution drugs may only be prescribed if these drugs are intolerant. ”Methadone is also preferred for reasons of cost. In addition to the above substances, the slow-release morphines morphine hydrochloride and morphine pentasulphate may also be prescribed in the event of documented intolerance to other substitution agents. Dihydrocodeine is not approved for substitution treatment.

According to current estimates, a total of approx. 22,000 to 33,000 people in Austria are affected by problematic opiate use (i.e. use of “hard” drugs with addiction and health, social and legal consequences, in Austria primarily multiple substance use with the participation of opioids) , with 11,119 people registered in substitution treatment in 2008 and, taking other factors into account, 17,000 people were in long-term drug-specific care.

On the situation of substitution treatment in the Austrian penal system, see the investigation report on behalf of the executive directorate of the Federal Ministry of Justice (May 2008) and the Court of Auditors report to the Stein prison 2007.

Switzerland

As part of harm reduction, substitution therapy is one of the four pillars of Swiss drug policy . The aim is to reduce the negative consequences of drug use for both the users and society. The substitution therapy is based on the Narcotics Act .

In 2009 around 17,000 people received substitution therapy, around two thirds of those treated for heroin addiction. In 60%, treatment was provided through basic medical care , otherwise in specialized centers. Methadone was used in around 90%, otherwise mainly buprenorphine. If neither methadone nor buprenorphine allow successful therapy, pure heroin is also given. In Switzerland, around 1,400 patients were treated with heroin in 2014 , which corresponds to around 8% of all people in substitution therapy. The release takes place as a long-term therapy with no time limit. The heroin is available in normal as well as in retarded pill form, whereby in special clinics the patients can also inject liquid heroin under supervision.

Medical heroin dispensing

In Switzerland, heroin-assisted treatment (HeGeBe) was introduced in 1995 in a pilot trial in the canton of Zurich , mainly to combat the open drug scene on the Latvian site . Pure heroin is given to addicts under medical supervision. The pilot project was anchored in 1999 as an integral part of the four-pillar policy at federal level. Since 2010, medical heroin has been anchored in the Narcotics Act. The drug is sold under the name Diaphin and is available in three versions: Diaphin 200 mg IR (releases active ingredient immediately), Diaphin 200 mg SR (retarded) and a solution for injection. The conditions for taking diaphine pills (so-called "take-homes") were tightened last year, which is why patients are currently only allowed to take an additional daily dose with them under special conditions, although a looser regulation was previously tolerated. Injection solutions are excluded from taking Diaphin to the delivery points is subject to the highest security precautions and is comparable to a gold transport protected with armored delivery vans and armed personnel.The drug is produced by the company DiaMo Narcotics GmbH, which has received the order for production from the Swiss Confederation.

Web links

Individual evidence

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  2. ↑ a b c d e f g h i j k l Nicholas Seivewright, assisted by Mark Parry: Community Treatment of Drug Misuse. More than methadone. 2nd edition. Cambridge University Press, Cambridge u. a. 2009, ISBN 978-0-521-69183-3 .
  3. ↑ Enno Freye: Opioids in medicine. 8th, updated edition. Springer, Heidelberg 2010, ISBN 978-3-540-88796-6 .
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  5. ↑ Ralf Gerlach: Methadone in a historical context: From the discovery of the substance to maintenance treatment . ( Memento of the original from December 20, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. INDRO e. V., Münster 2004 (PDF; 88 kB). @1@ 2Template: Webachiv / IABot / www.indro-online.de
  6. ^ Herman Joseph, Sharon Stancliff, John Langrod: Methadone Maintenance Treatment (MMT): A Review of Historical and Clinical Issues. ( Memento of the original from December 16, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: The Mount Sinai Journal of Medicine. Volume 67, No. 5/6, October / November 2000, ISSN 0027-2507 , pp. 347-364, (PDF; 178 kB). @1@ 2Template: Webachiv / IABot / www.drugpolicy.org 
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  15. ↑ Leif Grönbladh, Lennart S. Öhlund, Lars M. Gunne: Mortality in heroin addiction: impact of methadone treatment. In: Acta Psychiatrica Scandinavica. Volume 82, No. 3, September 1990, ISSN  0001-690X , pp. 223-227, PMID 2248048 , doi : 10.1111 / j.1600-0447.1990.tb03057.x .
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  41. ↑ Gerald A. Bennett, Eleanor Davies, Peter Thomas: Is oral fluid analysis as accurate as urinalysis in detecting drug use in a treatment setting? In: Drug and Alcohol Dependence. Volume 72, No. 3, December 2003, pp. 265-269, PMID 14643943 , doi : 10.1016 / j.drugalcdep.2003.08.001 .
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  59. ↑ Announcement of the guideline according to § 5 paragraph 12 sentences 1 to 3 of the Narcotics Prescription Ordinance of September 26, 2017 ( BAnz AT 02.10.2017 B1 )
  60. ↑ On the situation of substitution treatment in the German penal system, see Heino Stöver, Christine Kluge Haberkorn (Red.): Further development of substitution treatment in custody ( memento of the original from December 19, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . accept e. V. - Federal Association for Accepting Drug Work and Humane Drug Policy , Berlin 2010, ISBN 978-3-981 3890 . (PDF; 2.2 MB) @1@ 2Template: Webachiv / IABot / www.gesundinhaft.eu
  61. ↑ Entire legal provision for the Narcotics Ordinance, version of December 20, 2009
  62. ↑ Report on the Drug Situation in Austria 2009. Health Austria GmbH
  63. ↑ Substitution in the Austrian penal system.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. (PDF; 651 kB)@1@ 2Template: Toter Link / www.shh.at  
  64. ↑ Stein Prison. (PDF; 627 kB)
  65. ^ Substitution-based treatments for opioid addiction. (No longer available online.) Federal Office of Public Health (FOPH), archived from the original on January 15, 2011 ; Retrieved March 15, 2011 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.bag.admin.ch
  66. ↑ Federal Office of Public Health - Substitution-based treatment with diacetylmorphine (heroin) . Archived from the original on March 13, 2016. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.bag.admin.ch
  67. ^ Substitution-based treatments for opioid addiction. (PDF) Recommendations of the Federal Office of Public Health (FOPH), the Swiss Society for Addiction Medicine (SSAM), the Association of Cantonal Doctors in Switzerland (VKS). (No longer available online.) Federal Office of Public Health (FOPH), October 2009, archived from the original on November 19, 2015 ; Retrieved March 15, 2011 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.bag.admin.ch
  68. ↑ Thanks to the medical dispensing of heroin, around 1,400 addicts can legally consume - some make the connection to society: Heroin addicts in the middle of life - NZZ .
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