Download Heroin maintenance treatments - are the further investigation need

Heroin maintenance treatments - are the further investigation needed?
Tatjana Petrushevska, [Doctoral Student]
Ministry of Health of The Republic of Macedonia
Abstract
Drug abuse does not understand the nationalities and borders. Drugs are one of the
landmarks of the globalization of international relations, along with demographic, cultural and
economic transnational flows. Drug use affects not only individual users but also their families,
friends, associates and the community. Drugs generate crime, violence and other social problems
that are damaging to society as a whole. UNODC estimated that there are between 12 and 21
million opiates users worldwide in 2010[1].
The estimates in Europe relate to the population 15–64 years old, based on the recent data
available (surveys conducted between 2001 and 2009/10), for problem opioid users1 are between
1.3 and 1.4 million Europeans [2]. About 700 000 opioid users received substitution treatment in
2009 and Drug induce deaths were about 7 600, with opioids being found in around three
quarters [2]. NIDA defines addiction as a chronic, relapsing disease characterized by compulsive
drug seeking and use despite harmful consequences as well as neurochemical and molecular
changes in the brain [5]. Drug use contributes to the rapid spread of infectious diseases like HIV
/ AIDS and hepatitis, but also complications associated with drug dependences are malnutrition,
bacterial endocarditic, thrombophlebitis, pulmonary embolia, depression, overdose, problems
connected with motivation, but also problems with memory and concentration [6].
Drug addiction is understood as medical disorder to which contributes more factors and it
is necessary to implement the treatment in multi disciplinary manner – from pharmacological,
psychiatric, and social aspect.
In recent periods studies are underway in several countries in the European region, to
provide justification, with the scientific medical evidence, for use heroin as a pharmaceutical
dosage form, as a second-line treatment of drug addictions for previously unresponsive group.
Keywords
„Pharmaceutical Heron“, „injection“, „addiction“, „drug dependence“, „diacetylmorphine“,
„maintenance“
Problem drug use is defined as ‘injecting drug use or long-duration/regular use of opioids, cocaine
and/or amphetamines’
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1. Introduction
Heroin is semi synthetic derivate. It can be produced with process of acetylating of the
natural alkaloid morphine, which is extracted from certain varieties of the plant Papaver
somniferum. In the past, extraction of morphine and other alkaloids (tebain, codeine, papaverine,
noscapin etc.) take place by incision of the poppy straw, in a certain time of the year when it
reaches the desired maturity of the plant, and thus the accumulation of alkaloids. From the cut
parts of the poppy straw, leakage juice which under the influence of external temperature,
condense. This juice (latex) represents the concentration of alkaloids; it is collected and is known
as opium. This procedure when alkaloids are obtaining for medical purposes is now prohibited
by international legal acts[9], but still admitted to illegal acts, since it provides the highest
concentration of active components. For medical purposes, poppy are harvesting in the upper
part of the plant and is treated with chemicals to extract alkaloids - the active components, and
then evaporating the used chemicals, using known techniques for pharmaceutical synthesis. The
largest producer of illicit opium and heroin is Afghanistan in a worldwide scale [1]. According to
UNODC it is estimated 12-14 million heroin users in the world, using around 375 mt (metric
tons) of heroin [1]. Europe is one of the most important markets for heroin with an estimated 250
kg of heroin used per day [8]. So far, most of the profit with illicit production and trade of heroin
goes to international traders with illegal drugs.
In 1805 morphine was isolated by a German pharmacist, and it is the main alkaloid and
active component of opium which came to be used for treatment of pain, against coughing or
against diarrhea. Then other alkaloids of opium were isolated. Morphine was used for the
removal of pain before and after surgery, during the First World War. This resulted in
irreversible disease known as army disease. This was the reason to continuing with research in
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order to detect drug with the same or similar effect to morphine to cure of pain, but without the
tendency to develop addiction. With that intention heroin is synthesized in the 19th century, first
by a chemist who worked at the hospital St. Mary in London. After a certain number of years
active ingredients with the generic name 3,6-diacetylmorphine was re-synthesized by the
pharmaceutical company Bayer[77]. It was found that this product is 2 to 3 times more powerful
than morphine, because of its great liposolubility, which allows quickly passing the barriers and
entering the central nervous system. That is the reason why it was given the protected trade name
"heroin", precisely because of the great, heroic power which is mostly used in the treatment of
tuberculosis, for suppression of coughing. But, patients suffering from tuberculosis continued to
die, which confirms that this product only stopped the pain and worked to suppress cough but not
cure the disease. Heroin was used to combat opium dependence, but soon after introduction into
treatment it was confirmed that heroin causes greater dependence than that of morphine [77].
Opioid dependence is characterized by a range of cognitive, behavioral and psychological
disorders [13]. Addiction implies that a person needs a drug to function normally.
Cohort studies of dependent illicit opioid users show that although significant proportion
(10–40%) are abstinent at follow-up, most continue to use illicit opioids [69-72]. Contact with
treatment is one factor associated with recovery from opioid dependence; other factors include
personal motivation, religion, spirituality, family and employment [70].
A United Nations convention for drugs control includes the requirement to make
treatment available for people who are dependent upon narcotic drugs or psychotropic
substances. The two main objectives of these conventions are to make narcotic drugs and
psychotropic substances (including opioids) available for medical and scientific purposes, and to
prevent their diversion for other purposes [9].
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However, relapse to heroin use following the cessation of agonist maintenance treatment
is common [46, 47, 48] and research is lacking on when, who and how to withdraw from opioid
agonist maintenance treatment.
Heroin or diacetyl ester of morphine is classified in the first category of controlled
substances under the United Nations Convention of 1961[9]. From 1990 following the
recommendations of Health Councils, trials were conducted in few EU countries and Canada,
involving severe heroin dependent persons who did not respond sufficiently to the currently
available medical interventions treatment of drug addiction. Trials incorporate prescription of
heroin to chronic heroin addicts as an additional medical treatment for this population, with
implementation of good clinical practice.
It was expected that dependent patients could have positive effects on their physical and
mental condition, as well as on their social functioning and addictive behavior. Other expected
out come from trials was to obtain the necessary information from medical-scientific research
important to establish a positive balance between the beneficial and harmful effects associated
with such treatment.
Main aim of the review paper is to contribute to improvement of the quality of
pharmacological treatment, as well as in development of evidence based and ethical elements for
treatment of opioid dependence. While Heroin injection supervised treatment may be useful as
addition to established treatment opportunities, especially for drug addicted persons, their
families and society, it is not a solution for the heroin problem. More over, looking ahead, the
challenge is to establish different routes of administration of diacetylmorphine (oral, intranasal)
if further studies investigate and receive positive findings for longer term outcomes of treatment
with heroin.
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2. Materials and methods
This review paper was produced after comprehensive systematic review of international
literature on evidence of effectiveness of treatment of drug dependence, search for relevant
articles in: medical Lancet Journal, Journal of epidemiology & community health, Journal of
Pharmaceutical Science and Technology, British Journal of Psychiatry, British Medical Journal,
Journal of Clinical Epidemiology, Journal of Pharmaceutical Science and Technology, Journal
of Neuroscience, Journal of Substance Abuse Treatment, Journal of Addictive Diseases, Journal
of Substance Abuse Treatment, American Journal of Drug and Alcohol Abuse, as well as reports,
info facts and literature search in NIDA, SAMSHA, EMCDDA, WHO, UNAIDS, UNODC.
The objective of this literature review is to look at current trials on the implementation of
heroin treatment in the some European member states and Canada, its impact on prevention of
drug related crime.
Furthermore some statistical data on the prevalence of opioid substitution treatment in
Europ and worldwide are provided. For the overview on statistical data and policy information,
the Reitox2 National Reports were searched for information as well as the EMCDDA3 standard
tables on drug-related treatment availability (2012) and the WHO Health database (WHO 2012).
Electronic search for the existing data was carried out in: in databases (Medline/Pub Med,
Cochrane Central Register of Controlled Trials (CENTRAL), Elsevier, Google scholar, Medical
Subject Headings, DocGuide, , Psycinfo), in publications, monographs, standards and guidelines
of the EMCDDA, in the national reports of the national focal points of the REITOX-Network as
well as in activities and information of the WHO Europe, Pompidou-Group.
2
3
REITOX- European Information Network on Drugs and Addiction
EMCDDA-European Monitoring Centre for Drugs and Drug Addiction
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The literature which was reviewed was mostly in English and partially in German
langage.
Search terms which were used are: pharmaceutical heroin, diacetylmorphine,
maintenance program with heroin, supervised use of heroin, pharmacological profile of heroin.
Primarily as a method in this review is retrospective analysis, covering the period of the
first synthesis of heroin and its initial application, the reasons for its disposal fоr medical use and
classification in the group of controlled substances under UN Convention which understands
prohibited or limited application due to harmful effects on human health. Then the analysis
follow overview of proven pharmacological profile of heroin and its pharmacokinetics and
pharmacodynamics, as an exceptional important aspect for or against heroin return in medicinal
practice.
Finally analysis covered a survey of available literature and conducted trials for the
efficacy of treatment of dependence with injectible heroin.
The searches were for the period from 1990 and present, when supervised treatment with
pharmaceutical heroin was introduced initially in Switzerland.
3. Results
3.1. The principles of treatment of drug addiction
Drug addiction is compulsive drug use, regardless of the negative effect to health [14].
Drug addiction is a chronic, relapsing disease with neurological changes in the brain. Drug
addiction results in long-term anatomical and functional changes and risk for the patient and the
occurrence of other health problems [14]. The International Classification of Diseases (ICD10)[15] identifies six elements: strong desire or sense of compulsion to take opioids, difficulties
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in controlling opioid use, physiological withdrawal state, tolerance, progressive neglect of
alternative pleasures or interests because of opioid use, persisting with opioid use despite clear
evidence of overtly harmful consequences. Termination of drug abuse causes dramatic signs of
excitement, impatience, muscle aches, sweating, anxiety, nervousness, nausea, vomiting,
insomnia etc.
Opioid addiction causes significant economic costs to society, not only through direct
medical costs (treatment programs and prevention and other services for health care) but also the
impact on other budgets (the correctional system, the system for reintegration) from one side and
from the other, has an effect on productivity, through unemployment, absence, premature
mortality. Research has clearly shown the links between drug use and crime. Offences are
committed 1) in relationship to the activities of the criminal organizations involved in illicit
market, 2) with the aim of supporting with money the addictive habit, 3) under the influence of
illicit drugs provoking or aggressive-violent behavior[16].
Opioid
agonist
maintenance
treatment
is
defined
as
the
administration
of
comprehensively evaluated opioid agonists, by accredited professionals, in the framework of
recognized medical practice, to people with opioid dependence, for achieving defined treatment
aims [68].
Treatment should be designed to the needs of the target population, but based on
scientific evidence. The principles of treatment of drug addiction in accordance with World
Health Organization (United Nations and their members - 192 countries), includes availability
and affordability of treatment of disease with pharmacological therapy that has proven
effectiveness and efficiency in stabilizing the person with developed drug addiction, as well as
psychological and social interventions. Principles of treatment understands reducing of co7
morbidity (HIV/AIDS, Hepatitis), reducing the risk of mortality associated with use of drugs, to
increase physical, mental and social capabilities, re-socialization and social integration in
society or functioning in the system within normal frontiers and values.
The number of people in contact with treatment services has more than doubled over the
last decade, this suggests that the drug-treatment system has been responding effectively by
increasing numbers in treatment and improving treatment effectiveness [62].
When treating people with opioid dependence, ethical principles should be considered,
the human rights of opioid-dependent persons should always be respected and patients should be
fully inform about the risks and benefits of treatment choices [79]. Patients must give informed
consent for treatment. Confidentiality of patient records should be ensured. Treatment decisions
should be based on standard principles of medical-care ethics – providing equitable access to
treatment and psychosocial support that best meets the needs of the individual patient. Moreover,
treatment program should create supportive and coordinated approach to cure co-morbid mental
and physical disorders, and address relevant psychosocial factors[80].
A good clinical governance should ensure that treatments for opioid dependence are safe,
effective and transparent. The choice of treatment for an individual should be based on a detailed
assessment of the treatment needs and evidence based. Screening for psychiatric and somatic
comorbidity should form part of the initial assessment [10]. Psychosocial support should be
available to all opioid dependent patients, in association with pharmacological treatments of
opioid dependence. At a minimum, this should include assessment of psychosocial needs,
supportive counseling and links to existing family and community services [10].
There are two pharmacological approaches to opioid dependence treatment – those based
on opioid withdrawal -measured ending of an opioid use. In practice, most patients restart opioid
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use within six months of beginning opioid withdrawal [73, 74] and psychosocial assistance in
agonist maintenance treatment consists of daily administration of an opioid agonist (e.g.
methadone) or a partial agonist (e.g. buprenorphine). In practice, most patients beginning opioid
agonist treatment will stop heroin or use it occasionally, with only 20–30% reporting ongoing
regular heroin use [73, 75].
Keeping ahead what is said above, but taking the results from studies of treatment of drug
addiction that are implemented in the past, their goal, specific objectives included groups, risk
assessment, and assessment of possibility and effect of treatment, should be a basis to establish a
general platform for further action regarding this matter.
3.2. Description of the Reviewed Studies
In this part of the paper are presented scientific evidence for injectible treatment with
heroin, under supervision of health professional, that was accumulate through international
trials.
To date, open randomized control trials were conducted in six countries Switzerland,
Germany, Holland, England, Spain, Canada. Target groups were chronic heroin dependent
individuals, severe, treatment-resistant heroin addicts, selected by random selection, and were
aged 18 to 65. Trials were conducted for treatment with heroin under supervision, reached 1500
patients [83]. The duration of the tests varies between countries from 6 to 12 months. Positive
aspects of the conducted tests are that they were applied in the principles of Good Medicine and
Good Clinical Practice according to WHO, ICH / EU standards. Also, studies were conducted
under the provisions of the Declaration of Helsinki and Medical Ethics Manual regarding the
ethical aspects of studies, obtaining consent from patients after their informing in detail about the
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study, expected outcomes of the study, possible risks and concerning the protection of personal
data.
Trials were conducted in accordance with developed protocols [84] in compliance with the
international guidelines for Good Clinical Practice. One type of protocol was for the
investigation of the effectiveness of intravenously injected heroin, and another protocol for the
trial involving inhaled heroin [39].
The setting for treatment provision in all trials was an outpatient in supervised injecting
clinics of varied size. Studies conducted in the Netherlands are applied ideally in terms of facility
conditions, space, equipment and staff. Heroin was co-prescribed in newly established treatment
units. Each unit consisted of a lobby, a waiting-room, a dispensing-room, separate rooms for
injecting and inhaling heroin, and rooms for the physician, nurses, social worker, administrative
staff and researchers. The surface of the treatment units was approximately 300 m² [82].
Main goals of the scientific trials were: treatment of intoxication with narcotics,
achieving formal abstinence (considering that they used heroin as drug treatment), prevention of
criminal activity (which is expected when there is no need to find ways of ensuring dose of
„street“ heroin, when heroin is available, free of charge and more over in the form of injection).
Objectives of the studies were also to stabilize the addicted person and to reduce the harm.
The studies assess the efficacy of the prescribed intravenous diacetylmorphine versus oral
methadone with medical and psychosocial support, with view of improving physical and mental
health as well as social integration among socially excluded, opioid dependant individuals for
whom standard treatments have failed [90]. The studies assess also retention in treatment, illicit
drug use, HIV risk behaviour, criminal activity, social functioning, health and psychological
status as measured by self-report, urinalysis and doctor's ratings[84].
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In most of the trials for evaluation of the treatment of persons addicted to drugs, as a
medication is used heroin that enters the body by injection, and in addition, treatment with
flexible dosage of methadone, but in oral pharmaceutical dosage form. These patients are
monitored during the study, and as a control (comparison group) were persons to whom were
administered only oral form of methadone, without combining it with heroin (van den Brink et
al., 2003; March et al., 2006; Haasen et al., 2007; Oviedo-Joekes et al., 2009; Strang et al.,
2010).
In a study conducted in Switzerland, were analyzed and compare the effect of heroin,
among persons with developed drug addiction. Heroin was in pharmaceutical dosage form:
Injection. Comparison group were persons selected from the waiting lists for treatment, and they
used treatment option of their choice, available at that time in Geneva (Perneger et al., 1998).
It is interesting to point out that in the study conducted in the Netherlands, persons with
addiction were treated with heroin, but in dosage form: inhalation, complemented with
methadone in oral form[39]. As a comparison group of patients were patients to which
methadone was given in oral form.
Questionnaires, interviews, and medical examinations done at entry point to assess
somatic and mental health, social integration, and treatment outcomes were used in the
trials[88]. Measure of patient response was a reduction in illicit drug use or criminal activity as
based on the composite score of the European Addiction Severity Index (EUROP-ASI).
Outcomes were assessed at stages in the trial — at baseline and follow-up months with using a
complex score of measures of general health, self-reported ‘street’ heroin use, quality of life,
drug addiction-related problems, risk behavior for HIV and hepatitis C virus, psychological
functioning, and social and family status as based on ASI (Addiction Severity Index; McLellan
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et al., 1992), OTI (Opiate Treatment Index; Darke et al., 1992), SCL-90 (Symptom Checklist-90;
Derogatis and Cleary, 1997) and SF-12 (Short Form-12; Gandek et al., 1998).
The primary outcome measures in the trial included a reduction of self-reported drug use,
reduction of ‘street’ heroin use and improved health status and social functioning.
Secondary outcomes across trials included, but were not limited to, safety, criminal
activity, other drug use, physical health, and psychological and social functioning. Also the costeffectiveness was assessed[82].
A measure of reduction of ‘street’ heroin and/or other drug use, rather than abstinence,
was consistently used across the trials. Analysis showed that treatment with medically prescribed
heroin plus methadone was significantly more effective (51.8% response) than standard
methadone maintenance treatment (28.7%) Multivariate logistic regression analyses showed that
only one of all baseline characteristics was predictive of a differential treatment effect: patients
who had previously participated in abstinence-orientated treatment responded significantly better
to heroin-assisted treatment than to methadone treatment (61% versus 24%), while patients
without experience in abstinence-orientated treatment did equally well in heroin-assisted or
methadone maintenance treatment (39% and 38%, respectively)[85].
Randomized controlled trial comparing injected diacetylmorphine and oral methadone
was carried out in Andalusia, Spain. The subsequent follow-up study evaluated the health and
drug use status of participants, 2 years after the completion of the trial. Data collected included
information on socio-demographics, drug use, health and health-related quality of life. Compared
data collected before randomization and at 2 years for the following three groups: those currently
on heroin-assisted treatment, those who have discontinued .Patients who received on heroinassisted treatment showed better outcomes compared with those not on heroin-assisted
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treatments. The results of this study strengthen the evidence showing that on heroin-assisted
treatment can improve and stabilize the health of long-term heroin users with severe co
morbidities and high mortality [86].
Observational cohort study to describe 4-year treatment retention and treatment response
among chronic, treatment-resistant heroin-dependent patients offered long-term heroin-assisted
treatment in the Netherlands showed four-year retention 55.7% [95% confidence interval (CI):
47.6-63.8%]. It was concluded that long-term heroin-assisted treatments is an effective treatment
for chronic heroin addicts who have failed to benefit from methadone maintenance treatment.
Four years of heroin-assisted treatments is associated with stable physical, mental and social
health and with absence of illicit heroin use and substantial reductions in cocaine use [87].
Functioning across several life domains, cross-sectional study with a 6-month follow-up
assessed that the Heroin Prescribed group manifested lower levels of psychopathology and
showed greater retention in treatment. Although reduced, illicit heroin misuse was not
eliminated; the use of other illicit substances was comparable between groups but significantly
more of the Heroin Prescribed groups were using illicit cocaine. No differences in current
physical health were apparent, criminal activity appeared significantly reduced, but not
eliminated, in the Heroin Prescribed group [89].
All these findings support the hypothesis that under the supervised conditions heroin
could be safely delivered. In physical health, HIV risk behavior, street heroin use, and days
involved in crime heroin used as a medicine plus methadone was more efficacious than
methadone alone[90].
Some argument contra the thesis is that of the estimated 270 000 heroin addicts in the UK,
only about 300—400 people are prescribed heroin for their addiction, despite the fact that a
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subset of people (about 5—10% of all heroin addicts) do not respond to methadone treatment,
take methadone but continue to use heroin illegally, and refuse to try existing treatments that
might be of benefit. Some experts are skeptical about whether these clinics are really the way
forward [91].
3.1.
Qualitative analysis : pharmacological profile of heroin
Pharmacological profile of heroin is that the product is an agonist of the complex group
of receptors μ, k, d, that normally are activated by endogenous neurotransmitters such as
endorphins[68]. The opioid effects of analgesia, euphoria and sedation are mediated primarily
by the mu receptor. Opioids induce dopamine release indirectly by decreasing gammaaminobutyric acid (GABA)[66-67]. The estimated lethal dose of heroin LD50 is 200mg, but
individuals who developed dependence can tolerate 10 times more of the dose[76]. Besides
analgesia, heroin causes drowsiness, euphoria, indifference, respiratory depression, suppression
of couth reflex, hypothermia, nausea, decreased motility in the gastrointestinal tract[6].
Injecting heroin intravenously can produce a feeling of euphoria in seven to eight seconds.
After injection, heroin passes the blood - brain barrier by 20 seconds and a 70% dose arrived in
the brain. It is difficult to detect in the blood due to rapid hydrolysis, which is then followed by
slower conversation to morphine, the main active metabolite that is excreted in the urine in
conjugated form. Heroin (3,6-diacetylmorphine) in the brain is deacetylated into 6monoacetylmorphine (6-MAM) and morphine which bind to μ-opioid receptors, resulting with
euphoric, analgesic (pain relief) and anxiolytic effects. Molecular studies (Kieffer, 1999) have
highlighted μ-opioid receptors as the gate for opioid analgesia, tolerance and dependence. It is
interesting to mention that Diacetylmorphine itself exhibits relatively low affinity for the μ
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receptor.The half-life of heroin in plasma is about 3 minutes. Because of this pharmacological
performance, powerful and extremely fast pharmacokinetics, heroin or diacetylmorphine is
controlled substance which can fastest of all others, can occur overdose and poisoning with fatal
outcome. When heroin (diacetylmorphine) is administered intravenously, creates a larger
histamine release, resulting in the feeling of users typically two types of euphoric effects:
“rush” usually lasts one to two minutes, as an intense feeling that is felt throughout the body,
especially in the abdomen which occurs immediately after administration of the drug and
“high” that can last four to six hours, as well as episode of pruritus (itching) when they first start
using. The feeling “high” is described as warm and pleasant, with indifference to internal and
external stimuli [17].
The peak effects of smoking heroin are similar to those obtained from intravenous injection
[18]. When heroin is injecting intramuscularly, leads to a slower onset of euphoria, taking five
to eight minutes [16]. The peak effects of snorting heroin occur in 10 to 15 minutes[16]. Oral
administration of heroin has little effect7.
Heroin ( 3,6-Diacetylmorphine) Duration of effect: 4-5 hours; Elimination half-life: 0.5 hours,
Minimal deadly dose: 25 mg i.v.
Morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major
metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may
15
also take place in the brain and the kidneys [21]. Liver enzymes are involved in heroin
hydrolysis and glucuronidation of the heroin metabolite morphine. The kidneys are
primarily involved in the excretion of morphine and morphine glucuronides following
heroin administration[23,24]. The clinical importance of routine drug monitoring of serum
concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G)
during chronic morphine therapy is not established [22]
Other metabolites that were found in minor quantities in human urine after heroin intake are
normorphine-glucuronide,
codeine,
morphine-3-6-diglucuronide
and
morphine-3-
ethersulphate[25-29]
Figure 1: Metabolism of Heroin in the body
Source: Current Clinical Pharmacology, 2006, 1, 109-118 [31]
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4. Discussion
WHO Best Practice refers pharmacological treatment options should consist of both
methadone and buprenorphine for opioid agonist maintenance and opioid withdrawal, alpha-2
adrenergic agonists for opioid withdrawal, naltrexone for relapse prevention, and naloxone for
the treatment of overdose [81]. Methadone and buprenorphine taken on a daily basis they do not
produce the cycles of intoxication and withdrawal seen with shorter acting opioids, such as
heroin. Both methadone and buprenorphine can also be used in reducing doses to assist in
withdrawal from opioids, a process also referred to as opioid detoxification. Buprenorphine, a
partial opioid agonist, is emerging as a major alternative for opioid substitution treatment of
dependence. The usual route of administration for Buprenorphine substitution treatment is
sublingual. It is used in most of the countries. Buprenorphine is acceptable to heroin users, has
few side effects, and is associated with a low level of physical dependence and a relatively mild
withdrawal syndrome. Around three-quarters of people who enter methadone substitution
treatment respond well (Gerstein et al 1994; Gossop et al 2000). On the other hand, for various
reasons, methadone does not go well with all opioid-dependent people. For this group it is
important that alternative approaches are available to encourage their retention in treatment.
Methadone and buprenorphine have a strong evidence base for their use, and have been
placed on the WHO model list of essential medicines [78].
4.1.
Qualitative analysis 2: Comprehensive aspects of the trials, which needs to be
further explored
-In the trials heroin was supervised but self-administrated [19].
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It is strange why in the studies as a main option is self administration of intravenous heroin,
especially if treatment takes place in specialized institutions and under the supervision of
numerous staff, including nurses.
- It is unclear how long it takes to stabilize and to functioning „normally“after patient will
receive intravenous therapy with heroin? Also how many patients can be covered per time
interval, what is the optimal number of patients per team and per a specialized clinic?
-The main purpose of the studies that have been set, are inclusion in the treatment of
marginalized groups, treatment which will be intended only for a small group of people with
developed a drug addiction those who have no reaction to any other treatment available[83] But
if we look in the people involved in the trials, we will recognize that a small number of trials
included people from "waiting lists" for treatment or who had effort to fit in the treatment with
methadone, but after some time left. In most studies involved persons are on treatment with
methadone in oral pharmaceutical form, but in parallel they have practice to inject heroin.
Major assumption is that when physical dependency is satisfied, the receptors are filled with
substitution active component (methadone), it remains only desire to experience symptoms of
pleasure and euphoria.
- Also important part of the country profiles, analyzes and the reports as well as scientific
papers were identified poly drug use, or diagnosis according to ICD -F19. How to solve polydrug
use as a present health condition in patient’s on treatment with injectible heroin plus oral
methadone. What about usage in parallel of benzodiazepines, THC - Marijuana and stimulate
drugs (cocaine, synthetic drugs) and sometimes in combination also with alcohol?
- Results of the studies (trials) have indicated that treatment with methadone in oral
pharmaceutical form, but parallel with heroin in pharmaceutical form injections, follows the
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improvement of the general condition of the persons dependent on drugs, the reduction of
criminal activities, stabilization, better communication and behavior and family involvement,
maintaining the "treatment" etc. Studies are not giving answers about the pharmacological effect
of drugs on the body, especially when two medicines with very hard bio-properties are involved
in the treatment. That it is why the first part of this paper provides pharmacological profile of
heroin and its excretion through the liver and kidneys through its distribution in the brain,
pancreas, lungs, muscles. Is excreted in sweat, cross the placenta and has incompatibility and
interaction with numerous drugs and substances that means that there is very complex
mechanism of action in place, very complex pharmaco-kinetics, pharmaco-dynamic; distribution
and elimination. That is the main reason that heroin, morphine, methadone are classified in the
first category of controlled substances by the United Nations.
-Trials are not giving data for proportional increasing of the dose, due to development of the
effect of tolerance of the narcotic?
4.2. Estimated prevalence of drug dependent persons and persons included to
treatment of drug addiction worldwide
Dependence of narcotics is considered as a multifactorial disorder of the health, chronic
disease and it can be characterized with phase of relapsing, but also with neurological changes on
motivation pathways in the brain. For treatment of this health condition, broad multidisciplinary
approach which includes diversified psychological and pharmacological interventions to respond
to the patient needs to be implemented.
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Most of the countries have comprehensive system for treatment of drug dependence,
health care networks, health care facilities distributed on local and regional level, inpatient,
outpatient treatment centers, outreach services for „hidden“ population affected by drug use,
multidisciplinary professional teams, as well as evidence-based diversified pharmacological and
psychosocial interventions.
Opioid dependence and injecting drug use is a serious problem in at least 138 countries in
the world. It is estimated that 13.5 million people are using opioids, including 9.2 million using
heroin. This represents 0.2 % of the world’s total population. There have been over 100
randomized studies of opioid maintenance treatment, and these studies consistently report
benefits for those in treatment.
No single treatment is effective and fits to all individuals. Patients on treatment for opioid
dependence have different patterns of use of drugs as well as risk and protective factors that lead
to dependence, different psychological and social problems. Therefore services should be
sufficiently diverse and flexible to respond to the needs of patients, to the severity of
dependence, personal circumstances, motivation and response to interventions. There is need for
balanced combination of pharmacotherapy, psychotherapy, psychosocial rehabilitation and
reduction of risk factors.
Patients undergoing heroin treatment have experienced some improvements but heroin
treatment has not been consistently or substantially superior across studies and outcomes,
particularly the health and psychosocial functioning domains. A lot of important aspects in health
impact of the heroin to the patient body in general terms are not consider at all.
20
It was also consider necessary to provide a review of the long-term trajectories of patients
receiving heroin, as well as their perspective on this treatment and the impact of supervised
injectable maintenance clinics and service provision in local communities [83].
Figure 2: Estimated trends in the prevalence of problem opioid use — 2004 to 2009
(rate per 1 000 population aged 15 to 64): Combined estimates per country
Source: Reitox national focal points; based on Table PDU-6 of 2011 Statistical
Bulletin.http://www.emcdda.europa.eu/stats11/pdutab6b
Figure 3: Trends in reported number of new clients entering specialised treatment by primary
drug used, from 2004 to 2009
Source: Reitox national focal points; Figure TDI-1 part ii of 2011 Statistical Bulletin.
21
Table 1: International comparison of estimates of problem opioid users and numbers of clients in
opioid substitution treatment
Problem opioid users
Clients in opioid substitution
treatment
European Union
1 300 000
685 000
Australia
90 000
43 000
Canada
80 000
22 000
China
2 500 000
242 000
Russia
1 600 000
0
USA
1 200 000
660 000
NB: Year: 2009, except for Canada (reference year is 2003). All numbers are approximate.
Sources: Arfken et al. (2010), Chalmers et al. (2009), Popova et al. (2006), UNODC (2010wdr); Yin et al. (2010).
Picture 1 Supervised injecting clinics have been set up in three cities in the UK as part of a trial
Source: The Lancet, Volume 371, Issue 9612, Pages 545 - 546, 16 February 2008
22
5. References
1. UNODC (2011). World Drug Report. UNITED NATIONS OFFICE ON DRUGS AND CRIME.
2. Annual report on the state of the drugs problem in Europe, EMCDDA, Lisbon, November
2011 http://www.emcdda.europa.eu/publications/annual-report/2011
3. http://www.emcdda.europa.eu/themes/key-indicators/pdu
4. EU drugs strategy for the period 2005–2012, Council of the European Union, Brussels,
22 November 2004, 15074/04, CORDROGUE 77, SAN 187,ENFOPOL 178,RELEX 564
5. www.drugabuse.gov
6. http://www.nlm.nih.gov/medlineplus/ency/article/001522.htm
7. Joint UNODC-WHO Action Programme On Drug Dependence Treatment Scaling Up
Evidence-Based Services For Drug Dependence Treatment And Care for 2009-2013,
2008
8. UNODC World Drug Report, 2009
9. UN Convention for narcotic drugs 1961, UN Convention for psychotropic substances
1972, UN Convention against illicit production and trafficking with narcotics 1988
10. Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid
Dependence, World Health Organization 2009
11. Ferri M, Davoli M, Perucci CA.. Heroin maintenance for chronic heroin-dependent
individuals. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.:
CD003410. DOI: 10.1002/14651858.CD003410.pub4
12. Centers for Disease Control and Prevention, 2002 Annual smoking-attributable mortality,
years of potential life lost, and economic costs—United States, 1995–1999. Morbidity
and Mortality Weekly Report 51(14):300-303
13. Samet JH. Drug abuse and dependence. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed.
Philadelphia, Pa: Saunders Elsevier; 2007:chap 32.
23
14. http://www.nlm.nih.gov/medlineplus/ency/article/000949.htm
15. World Health Organization, International Classification of Diseases, 10th edition (ICD-10).
http://www.who.int/classifications/apps/icd/icd10online/
16. NIDA. Heroin: Abuse and Addiction. Rockville, MD: NIH; 2005 May.
17. Stimmel B. The facts about drug use: Coping with drugs and alcohol in your family, at work, in
your community. The Hawthorne Medical Press; 1992.
18. Cone EJ. Recent discoveries in pharmacokinetics of drugs of abuse. Toxicology Letters 1998
Dec 28;102:97-101.
19. Wim van den Brink, Vincent M. Hendriks, Peter Blanken, Ineke A. Huijsman, Jan M.
van Ree, Medical co-prescription of heroin two randomized controlled trials, Central
Committee on the Treatment of Heroin Addicts (CCBH),2002, Utrecht, The Netherlands
20. John Strang, Teodora Groshkova and Nicola Metrebian, New heroin-assisted treatment,
Recent evidence and current practices of supervised injectable heroin treatment in
Europe and beyond, European Monitoring Centre for Drugs and Drug Addiction, 2012
21. Hasselstrom J, Eriksson S, Persson A, et al. The metabolism and bioavailability of
morphine in patients with severe liver cirrhosis, Br J Clin Pharmacol 1990; 29: 289-97.
22. Christrup LL. Morphine metabolites. Department of Pharmaceutics, Royal Danish School of
Pharmacy, Copenhagen, Denmark. Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 2):116-22. PubMed
23. Klepstad P, Borchgrevink PC, Dale O, Zahlsen K, Aamo T, Fayers P, Fougner B, Kaasa
S. Routine drug monitoring of serum concentrations of morphine, morphine-3glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer
patients. Department of Anaesthesia and Medical Imaging, Norwegian University of
Science and Technology, Trondheim, Norway. [email protected] Palliat
Med. 2003 Dec;17(8):679-87.
24. Mo BP, Way EL. An assessment of inhalation as a mode of administration of heroin by
addicts. J Pharmacol Exp Ther 1966; 154: 142-51.
24
25. Elliott HW, Parker KD, Wright JA, Nomof N. Actions and metabolism of heroin
administered by continuous intravenous infusion to man. Clin Pharmacol Ther 1971; 12:
806-14.
26. Boerner U, Roe RL, Becker CE. Detection, isolation and characterization of normorphine
and norcodeine as morphine metabolites in man. J Pharm Pharmacol 1974; 26: 393-8.
27. Boerner U. The metabolism of morphine and heroin in man. Drug Metab Rev 1975; 4:
39-73.
28. Gyr E, Brenneisen R, Bourquin D, et al. Pharmacodynamics and pharmacokinetics of
intravenously, orally and rectally administered diacetylmorphine in opioid dependents, a
two-patient pilot study within a heroin-assisted treatment program. Int J Clin Pharmacol
Ther 2000; 38: 486-91.
29. Yeh SY, Gorodetzky CW, Krebs HA. Isolation and identification of morphine 3- and 6glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and
normorphine 6- glucuronide as morphine metabolites in humans. J Pharm Sci 1977; 66:
1288-93.
30. Yeh SY, Gorodetzky CW, McQuinn RL. Urinary excretion of heroin and its metabolites
in man. J Pharmacol Exp Ther 1976; 196: 249-56.
31. Elisabeth J. Rook1, Alwin D.R. Huitema , Wim van den Brink, Jan M. van Ree and Jos
H. Beijne,2006 Pharmacokinetics and Pharmacokinetic Variability of Heroin and its
Metabolites: Review of the Literature, Current Clinical Pharmacology, 2006, 1, 109-118
109 ,2006 Bentham Science Publishers Ltd.
32. Ali, R., Auriacombe, M., Casas, M., et al. (1999), Report of the external panel on the
evaluation of the Swiss scientific studies of medically prescribed narcotics to drug
addicts, World Health Organization, Geneva.
33. Altman, D. G. (1998), ‘Confidence intervals for the number needed to treat’, British
Medical Journal 317, pp. 1309–1312.
25
34. Amato, L., Davoli, M., Vecchi, S., et al. (2011), ‘Cochrane systematic reviews in the
field of addiction: What’s there and what should be’, Drug and Alcohol Dependence 113,
pp. 96–103.
35. Ashcroft, R. E. Chadwick, D. W., Clark, S. R. L., et al. (1997), ‘Implications of sociocultural contexts for the ethics of clinical trials’, Health Technology Assessment 9. Online
at: http://www.hta.ac.uk/project/htapubs
36. Blanken, P., van den Brink, W., Hendriks, V.M., et al. (2010b), ‘Heroin-assisted
treatment in the Netherlands: History, findings, and international context’, European
Neuropsychopharmacology 20, pp. 105–158.
37. Blanken, P., Hendriks, V., van Ree, J. and van den Brink, W. (2010), ‘Outcome of longterm heroin-assisted treatment offered to chronic, treatment-resistant heroin addicts in the
Netherlands’, Addiction 105, pp. 300–308.
38. van den Brink, W., Hendriks, V. M. and van Ree, J. M. (1999), ‘Medical co-prescription
of heroin to chronic, treatment-resistant methadone patients in the Netherlands’, Journal
of Drug Issues 29, pp. 587–608.
39. van den Brink, W., Hendricks, V. M., Blanken, P., et al. (2003), ‘Medical prescription of
heroin to treatment resistant heroin addicts: two randomised trials’, British Medical
Journal 327, pp. 310–316.
40. Darke, S., Ward, J., Hall, W., Heather, N. and Wodak, A. (1991), The Opiate Treatment
Index (OTI) researcher’s manual, National Drug and Alcohol Research Centre Technical
Report Number 11, National Drug and Alcohol Research Centre, Sydney.
41. Darke, S., Hall, W., Wodak, A., Heather, N. and Ward, J. (1992), ‘Development and
validation of a multidimensional instrument for assessing outcome of treatment among
opiate users: the Opiate Treatment Index’, British Journal of Addiction 87, pp. 733–742.
42. Derogatis, L. R. and Cleary, P. A. (1997), SCL-90 administration, scoring and procedure
manual for the revised version, Johns Hopkins University School of Medicine, Baltimore
(MD).
26
43. Dijkgraaf, G. W., Van der Zanden, B. P., De Borgie, A. J. M., et al. (2005), ‘Cost utility
analysis of co-prescribed heroin compared with methadone maintenance treatment in
heroin addicts in two randomised trials’, British Medical Journal 330, pp. 7503–7506.
44. Delaney, A., Bagshaw, S. M., Ferland, A., et al. (2007), ‘The quality of reports of critical
care meta-analyses in the Cochrane Database of Systematic Reviews: an independent
appraisal’, Critical Care Medicine 35, pp. 589–594.
45. Fischer, B., Rehm, J., Kirst, M., et al. (2002), ‘Heroin-assisted treatment as a response to
the public health problem of opiate dependence’, European Journal of Public Health 2,
pp. 228–234.
46. Gacond, A. (2004), ‘Analyse der Todesfälle von Juli 1996 bis Dezember 2000 während
und nach der heroingestützten Behandlung’, cited in Rehm, J., et al. (2005).
47. Gandek, B., Ware, J. E., Aaronson, N. K., et al. (1998), ‘Cross-validation of item
selection and scoring for the SF-12 health survey in nine countries: Results from the
IQOLA project. International Quality of Life Assessment’, Journal of Clinical
Epidemiology 51, pp. 1171–1178.
48. Glass, G., V. (1976), ‘Primary, secondary and meta-analysis of research’, Educational
Researcher 5, pp. 3–8.
49. Glasziou, P., Chalmers, I., Rawlins, M. and McCulloch, P. (2007), ‘When are randomised
trials unnecessary? Picking signal from noise’, British Medical Journal 334, pp. 349–
351.
50. Güttinger, F., Gschwend, P., Schulte, B., Rehm, J. and Uchtenhagen, A. (2003),
‘Evaluating long-term effects of heroin-assisted treatment: the results of a 6-year followup’, European Addiction Research 9, pp. 73–79.
51. Haasen, C., Verthein, U., Degkwitz, P., et al. (2007), ‘Heroin-assisted treatment for
opioid dependence: randomised controlled trial’, British Journal of Psychiatry 191, pp.
55–62.
52. Hartnoll, R. L., Mitcheson, M. C., Battersby, A., et al. (1980), ‘Evaluation of heroin
maintenance in controlled trial’, Archives of General Psychiatry 37, pp. 877–884.
27
53. Higgins, J. P. T. and Green, S. (2008), Cochrane Handbook for Systematic Reviews of
Interventions Version 5.0.1. (updated September 2009), The Cochrane Collaboration.
54. Jadad, A. R., Moher, M., Browman, G. P., et al. (2000), ‘Systematic reviews and metaanalyses on treatment of asthma: critical evaluation’, British Medical Journal 320, pp.
537–540.
55. Jones, S. H., Thornicroft, G., Coffey, M. and Dunn, G. (1995), ‘A brief mental health
outcome scale — reliability and validity of the Global Assessment of Functioning
(GAF)’, British Journal of Psychiatry 166, pp. 654–659.
56. Kilias, M. and Rabasa, J. (1998), ‘Does heroin prescription reduce crime? Results from
the evaluation of the Swiss heroin prescription projects’, Studies on Crime and Crime
Prevention 7, pp. 127–133.
57. Klous, M.G., Nuijen, B., van den Brink, W., Van Ree, J.M. and Beijnen, J.H. (2004a),
‘Pharmaceutical development of an intravenous dosage form of diacetylmorphine
hydrochloride’, Journal of Pharmaceutical Science and Technology 58, pp. 287–295.
58. Klous, M.G., Nuijen, B., van den Brink, W., Van Ree, J.M. and Beijnen, J.H. (2004b),
‘Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via
‘chasing the dragon’ by heroin addicts’, Drug Development and International Pharmacy
30, pp. 775–784.
59. Oviedo-Joekes, E., Brissette, S., Marsh, D., et al. (2009), ‘Diacetylmorphine versus
methadone for the treatment of opioid addiction’, The New England Journal of Medicine
361, pp. 777–786.
60. Oviedo-Joekes, E., March, J.C., Romero, M., and Perea-Milla, E. (2010), ‘The
Andalusian trial on heroin-assisted treatment: A two year follow-up’, Drug and Alcohol
Review 29, pp. 75–80.
61. Perea-Milla, E., Aycaguer, L. C., Cerda, J. C., et al. (2009), ‘Efficacy of prescribed
injectable diacetylmorphine in the Andalusian trial: Bayesian analysis of responders and
non-responders according to a multi-domain outcome index’, Trials 10, p. 70.
28
62. Perneger, T. V., Giner, F., del Rio, M. and Mino, A. (1998), ‘Randomised trial of heroin
maintenance programme for addicts who fail in conventional drug treatments’, British
Medical Journal 317, pp. 13–18.
63. Prescription of injectable diacetylmorphine (heroin) in case of opioid dependence; Rules
of guidance No 9240, 11 May 2009. Online at: http://www.emcdda.europa.eu/bestpractice/standards/treatment
64. Andrew Jones, Michael Donmall, Tim Millar, Alison Moody, Samantha Weston, Tracy
Anderson,Matthew Gittins, Varunie Abeywardana and John D’Souza The Drug
Treatment Outcomes Research Study (DTORS):Final outcomes, Research Report 24,
Key Implications
65. Johnson SW and North RA (1992). Opioids excite dopamine neurons by
hyperpolarization of local interneurons. Journal of Neuroscience. 12(2):483-488.
66. Bonci A and Williams JT (1997). Increased probability of GABA release during
withdrawal from morphine. Journal of Neuroscience. 17(2):796-803.
67. Cami J and Farre M (2003). Drug addiction. New England Journal of Medicine.
349(10):975-986.
68. Neuroscience of psychoactive substance use and dependence WORLD HEALTH
ORGANIZATION GENEVA, 2004
69. Darke S, Ross J, Mills KL, Williamson A, Havard A and Teesson M (2007). Patterns of
sustained heroin abstinence amongst long-term, dependent heroinusers: 36 months
findings from the Australian Treatment Outcome Study (ATOS). Addictive Behaviors.
32(9):1897-1906.
70. Maddux JF and Desmond DP (1992). Methadone maintenance and recovery from opioid
dependence. American Journal of Drug and Alcohol Abuse.18(1):63-74.
71. Flynn PM, Joe GW, Broome KM, Simpson DD and Brown BS (2003). Recovery from
opioid addiction in DATOS. Journal of Substance Abuse Treatment,25(3):177-186.
29
72. Hser YI (2007). Predicting long-term stable recovery from heroin addiction: findings
from a 33-year follow-up study. Journal of Addictive Diseases,26(1):51-60.
73. Teesson M, Ross J, Darke S, Lynskey M, Ali R, Ritter A and Cooke R (2006). One year
outcomes for heroin dependence: findings from the Australian Treatment Outcome Study
(ATOS). Drug & Alcohol Dependence, 83(2):174-180.
74. Gandhi DH, Jaffe JH, McNary S, Kavanagh GJ, Hayes M and Currens M (2003). Shortterm outcomes after brief ambulatory opioid detoxification with buprenorphine in young
heroin users. Addiction. 98(4):453-462.
75. Hser YI, Anglin MD and Fletcher B (1998). Comparative treatment effectiveness. Effects
of program modality and client drug dependence history on drug use reduction. Journal
of Substance Abuse Treatment, 15(6):513-523.
76. E. Leong WAY ,M. Joseph YOUNG , John W. KEMP Metabolism of heroin and its
pharmacologic implications, Department of Pharmacology, University of California
Medical Center, San Francisco, Cal.
77. Journal of epidemiology & community health http://jech.bmj.com/content/58/9/747.full
78. WHO Model List of Essential Medicines. Geneva, World Health Organization. Available
from URL: http://www.who.int/ medicines.
79. Benatar SR. Linking Moral Progress to Medical Progress: New opportunities for the
Declaration of Helsinki. World Med J 2004; 50/1: 11-13
80. World Health Organization (2005). WHO Resource Book on Mental Health, Human
Rights and Legislation. Geneva, WHO.
81. WHO Expert Committee on Drug Dependence. Geneva, Switzerland, WHO technical
report
82. Wim van den Brink, Vincent M. Hendriks, Peter Blanken, Ineke A. Huijsman, Jan M.
van Ree, Medical co-prescription of heroin two randomized controlled trials, Central
Committee on the Treatment of Heroin Addicts (CCBH),2002, Utrecht, The Netherlands
30
83. John Strang, Teodora Groshkova and Nicola Metrebian, Emcdda insights New heroinassisted treatment, Recent evidence and current practices of supervised injectable heroin
treatment in Europe and beyond, 2012
84. Metrebian N, Shanahan W, Wells B, Stimson GV Department of Social Science and
Medicine, Imperial College School of Medicine, London, United Kingdom, Feasibility
of prescribing injectable heroin and methadone to opiate-dependent drug users:
associated health gains and harm reductions. Med J Aust. 1998 Jun 15;168(12):596-600.
85. Blanken P, Hendriks VM, Koeter MW, van Ree JM, van den Brink W. Matching of
treatment-resistant heroin-dependent patients to medical prescription of heroin or oral
methadone treatment: results from two randomized controlled trials, Cochrane Database
Syst Rev. 2003;(4):CD003410
86. Oviedo-Joekes E, March JC, Romero M, Perea-Milla E. School of Population and Public
Health, University of British Columbia, Vancouver, BC, The Andalusian trial on heroinassisted treatment: a 2 year follow-up. Drug Alcohol Rev. 2010 Jan;29(1):75-80.
87. Blanken P, Hendriks VM, van Ree JM, van den Brink W Central Committee on the
Treatment of Heroin Addicts, University Medical Centre Utrecht, Utrecht, The
Netherlands. Outcome of long-term heroin-assisted treatment offered to chronic,
treatment-resistant heroin addicts in the Netherlands, 2010. [PubMed - indexed for
MEDLINE
88. Rehm J, Gschwend P, Steffen T, Gutzwiller F, Dobler-Mikola A, Uchtenhagen A
Addiction Research Institute, Zurich, Switzerland Feasibility, safety, and efficacy of
injectable heroin prescription for refractory opioid addicts: a follow-up study. Lancet.
2000;359(9309):889-90
89. McCusker C, Davies M Department of Clinical Psychology, School of Psychology,
Queen's University of Belfast, Northern Ireland. Prescribing drug of choice to illicit
heroin users: the experience of a U.K. community drug team. [PubMed - indexed for
MEDLINE
90. March JC, Oviedo-Joekes E,Perea-Milla E, Carrasco F, Andalusian School of Public
Health,Granada 18080, Spain Controlled trial of prescribed heroin in the treatment of
opioid addiction, J.Subst. abuse Treat,2006 Sept:31(2)203-11.Epub 2006 Jul.18
31
91. Priya ShettyUK Government considers supervised injecting clinics The Lancet, Volume
371, Issue 9612, Pages 545 - 546, 16 February 2008
32