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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’ 1 1 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 2 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]. 3 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. 4 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 5 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 6 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 8 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 9 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]. 10 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 11 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 12 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 13 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 14 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] 16 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]. 17 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 18 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. 19 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. 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