Recidivism with Opiate Addicted Patients on Buprenorphine Substitution Treatment : Case Report

Introduction: Opiate dependence is a serious, chronic and recurrent psychiatric disorder, whose prevalence reach epidemic proportions. This also contributes to a signifi cant increase in mortality, associated with overdose with opiates, as well as the rise in other health and social problems of the society. The methods and availability of treatment do not correspond to increased treatment needs, and treatment success is limited by the characteristics of the disorder, or numerous risk factors, which contribute to a high percentage of recidivism. Good clinical practice guidelines have defi ned treatment recommendations that include high and low-demanding programs. The personalized and integrative approaches are emphasized. Case report: The patient aged 41 years, intravenous-use opiate addict from his adolescences, with numerous psychological, health and social complications of addiction, is a participant in institutional treatment, following a court order as a measure of obligatory treatment, due to criminal off enses related to addiction. The history of the disease refers to numerous unsuccessful attempts to heal and short-term abstinence in the past, mainly in penal institutions. The patient meets all the criteria defi ned by the guidelines for inclusion in the buprenorphine maintenance program started in the year 2013. During the four-year treatment, the doses of the drug were adapted as needed; two heroin relapses and many in-risk situations for relapse were registered. The treatment continuated with close monitoring of the patient’s condition and, with appropriate psychosocial interventions, contribute to keeping the patient in treatment and preventing the development of new complications of addiction, as well an improving the quality of his life. Discussion: Pharmacological treatment of opioid dependence relies on agents belonging to groups of antagonists, agonists and partial agonists of opiate receptors. The earlier programs with abstinence as a treatment goal have signifi cantly allocated the place to “harm reduction” programs, where the therapeutic goals are less demanding and defi ned as the harm-reduction of opiate dependence on the individual and the society. Treatment guidelines defi ne the principles and types of treatment regimens with agonists and partial agonists of opiate receptors and most commonly used are methadone and buprenorphine. The high risk of relapses despite treatment is defi ned and a comprehensive approaches and inclusion of Cognitive Behavior Therapy /CBT/, family and social therapy are needed.


INTRODUCTION
Opiates and opioids are natural and medicinal substances, which due to their analgesic activity are applied primarily in the treatment of pain.Th rough the centuries, abuse and dependence on opiates is also known, and recognized as a severe psychiatric disorder, characterized by chronicity and recidivism, regardless of the diff erent treatment options.DSM-5 defi nes opioid dependence as a "problematic form of opiate use, which leads to clinically signifi cant incompetence and distress".It is characterized by craving, increasing tolerance, abstinence syndrome and continuous abuse despite personal and social problems, as well as other behavioral changes.Similar criteria include ICD-10: strong desire or compulsive need to take substance, diffi culties in controlling behavior, abstinence crisis when use is interrupted, increased tolerance, progressive neglect of other interests and pleasures, persisting abuse of the substance despite the presence of obvious harmful consequences.
Opioid dependence caused by the use of illicit drugs or opiates and opioids prescribed, has been increased in the past 20 years [1].It is estimated that 26 to 36 million people worldwide abuse opiates, of which 2.1 million in the United States, contributed by more than three times the number of opioid prescriptions that were issued from 1990 to 2015 [2].Opportunities and treatment availability are insuffi cient for increased treatment needs.Th is is accompanied by increase in opiate overdoses and deaths, and in the United States data on a tenfold increase since the year 1999 are reported, and epidemic proportions are discussed [3].By contrast, in Europe, there is a certain decline in the number of opioid addicts, starting from 2011 e.g.data for 2014th indicate the average prevalence of high-risk opiates 0,4% in the adult population aged 18-64 years, which is still 1.3 million of high-risk consumers.Number of new opiate users in Europe decreased by almost half -from 36% in 2007 to 17% in the 2013 [4].Th e situation in Serbia, estimated in year 2005, 2011 and 2015 in samples in the general population of adults aged 18-64 years and the young population of high-school students at the age of 16.In adult population the lifetime prevalence is 7-8% for all illegal drugs and 0.9% for heroin, and 12.8% for all illegal drugs and 0.6-0.9 for heroin, in the younger population.Th ese percentages were stable in observed periods and similar as in the region of the West Balkan countries, but lower then in developed Western European countries [5][6][7][8].Mortality rates in Europe, associated with opiates overdose in 2014 accounted 6800 deaths, [4] while for Serbia this number is decreasing-41 deaths due to overdose of illegal drugs, 18 due to opiates in 2015, compared to 53 in 2007, 62 in 2008, 119 in 2009 [8].
In addition to the negative impact of the use of opiates on the psychological state and way of life, many health problems are associated with this dependence, e.g.serious cardiac abnormalities, increased risk of HIV infection and its complications, Hepatitis C, tuberculosis, etc.
Nowadays diff erent therapeutic options for treatment of opiate dependence are defi ned [9,10].Depending on the therapeutic goals, treatment programs can be divided into highly demanding, which means complete and long-lasting abstinence and low demanding, "harm-reduction programs", that involve prolonged substitution therapy.One pharmacotherapy program can be replaced by another depending on the circumstances.In addition to pharmacotherapy, an integrative approach, which provides psychotherapeutic and social therapeutic support, is considered as the most successful.Th e World Health Organization in 2009 published Guidelines for the Psychosocial Supported Pharmacological Treatment of Opioid Dependence [4], where the basic recommendations for therapeutic programs were set at the national levels and there was a signifi cant place occupied with "harm-reduction" orientation.
Following the guidelines of the World Health Organization in the countries of the European Community, national guidelines have been formulated and they recommend the implementation of substitution therapy for opiate addicts as part of public health institutions in the form of long-term intervention, similar to other chronic diseases (cardiovascular diseases, Diabetes mellitus, infectious diseases).Also, at the European Union level, eff orts are being made to ensure that regulations and professional attitudes are harmonized in all countries in relation to the application of these programs.Th e national strategy in Serbia is defi ned in the National Guidelines for the treatment of opiate and opioid addicts [10], published in April 2010, where the expert framework for the application of substitution therapy is defi ned.
It has already been emphasized that dependence on opiates is considered as severe and chronic disease.Th e National Institute on Drug Abuse in the United States has stated that about 40-60% of addicts are relapsed, while for heroin addicts that percentage goes up to 80 to 91%, with 59% being relapsed during the fi rst week aft er the treatment is completed, and 80% during the fi rst month of abstinence [11].Th is high percentage of relapse is similar to other chronic diseases, such as Diabetes mellitus, arterial hypertension, asthma, and similar treatment is proposed in the treatment.Th e experience of the Special Hospital for Addiction in Belgrade also indicates a high percentage of relapses among treated opiate addicts, a large number of unsuccessful treatments in drugfree programs and a signifi cant percentage of health, psychological and social complications of this addiction [10].

CASE REPORT
Patient aged 41 years old, heroin addict, has been treated in the specialized institution for addiction since 2010 and currently involved in the day hospital mandatory treatment by a court order since 2013 due to criminal off enses related to opiate addiction.Attended secondary school, unemployed, unmarried, having a 10 year old son from previous partnership relation, now living with a new partner.

Addiction anamnesis:
Th e fi rst contact with psychoactive substances was at the age of 15, with marijuana, out of curiosity, indiff erent, but still continues to consume it until mid 2013.He was also using alcohol, Trodon and Bensedin tablets, "speed", LSD, cocaine and ecstasy.
First contact with heroin was at the age of 17, affi rmative experience, and immediately started intravenous usage.
Addictive pattern of abuse existed since he was 21, daily intravenous taking of the drug until the fi rst hospitalization in the year of 2010, abstinences were short 3-6 months, mostly in penal institutions.
Patient overdosed with heroin on two occasions.
Virus status: HCV positive, HIV negative.
Patient served the prison sentences twice for opiate dependence related crimes: at the age of 20, a year in prison, and at the age of 27 in a prison hospital.Currently, a judicial process is under way for a similar criminal offense; it is presumed that the mandatory treatment of addiction will be imposed again.

Personal history:
Patient is the second born child , the early psychomotor development was neat, went to elementary school and graduated on time, enrolled in a secondary school, graduated, served his entire military service.Previous partner relationship, with a 10 year old child now, was confl icting and discontinued due to dependency problems.Current partner relationship is satisfi ed, they live together in his own fl at.
When the patient was 19 years old he underwent the lower jaw fracture, in the 2009, suff ered from right leg thrombosis and in the 2010 left leg thrombosis (in both cases the result thereof was the intravenous taking of drugs), rehabilitated.No allergies.Smoker.

Family history:
Parents are in their 60's, retired, healthy, their marriage is good, older sister is healthy, has her own family.Th ere is no psychiatric illnesses history in the family.

In the present mental status:
Adequate appearance, medium communicative, right oriented in all directions, no perceptive disturbances, attention and memory preserved, average intelligence, adequate ideation form and content, Th ere is slightly lowered mood , anxiety is a bit elevated, emotional resonance is established .Th e depressive aff ect is observed when confronting with their ineffi ciency and poor "problem solving" abilities.Th e initial insomnia and diminished volition are present.Th ere are no suicidal ideas or plans.Th e frustration tolerance is extremely low, impulsivity and acting out are observed at the minimum pressure.Critical judgment and insight are partially preserved, but the value system is completely inverted and negative Although the motivation for treatment is imposed by mandatory treatment, there is a motive for participation in the treatment and respecting of the program.

Treatment of opiate dependence:
Th e institutional treatment started in 2010 and diagnosed F 11.2, Status post phlebotrombosis femoropoplitealis lat sin, St post phlebotrombosis lat.dex., Oedema femoris et cruris lat.Dex, for the purpose of detoxifi cation.He left the treatment on his own initiative.
Patient in 2013 is back on treatment for the purpose of implementing the court order of mandatory treatment, due to crimes related to his addiction.He was admitted to the Day Hospital unit, substitution therapy with Buprenorphine was suggested, Buprenorphine maintenance program started on October 2013.Th e dose of Buprenorphine was 6mg, with additional medication with antidepressants and anti-anxiety agents, as well as a complete psychosocial program.Th e urine test for the opiates was negative.By the end of 2013, the dose of buprenorphine was 8mg, and he stopped using marijuana as well.
During the treatment in 2014, his mood was more stable, with better impulse controlling, but presence of sleep inversion despite of medication was observe, and patient does not accept signifi cant obligations in real life.
He continued with substitution therapy within primary care and aft er two months he made a relapse with heroin, registered after infectious complications on the skin due to needle sticking in November 2014., when he was again sent to the institution aft er the court's remark, because the treatment was interrupted on his own initiative.Detoxifi cation from heroin with buprenorphine was performed, and he was back to the buprenorphine maintenance program at a daily dose of 6 mg to the competent Health Center, with controlling and social therapy program at the institution.By the end of 2014, the urine tests for opiates were negative, with the proper administration of the prescribed dose of buprenorphine.Th e dose of buprenorphine was adjusted to 8 mg in April 2015.with additional anti-anxious medication.He made a relapse with heroin in May 2015 that he concealed, did not use adequate therapy.Aft er facing the facts that he relapsed because of non compliance with the program and the treatment was endangered, with adequate monitoring of the program, he abstained until October, with the reduction of anxiety and progress in the program.In October 2015, crises were reported on screening, a return to old patterns of behavior was observed, and a dose of buprenorphine was increased in order to prevent relapse, and a satisfactory condition was maintained by the end of 2015.During 2016 he was stable, no crisis, with better integration in society, which he changed, found a more adequate partner, and intensifi ed his relationship with his child.At the beginning of 2017 the situation is satisfactory, but soon there is a crisis with inadequate behavioral patterns, which he did not recognize.Th e risk of a new recurrence is currently resolved with intensive counseling and taking a prescribed dose of medication.Now he is planning employment and advantage in treatment is observed.

DISCUSSION
Th e recurrence of opiate dependence is explained by the profound and long-lasting changes in the functioning of certain brain regions, especially those pertaining to the reward mechanism of the Central Nervous System (CNS), which is the basic pathogenetic mechanism of the disease dependence in general [12].Th e reward mechanism of the CNS is a complex neural network, which includes mostly dopaminergic neurotransmitter centers and pathways, but also their links to serotonergic and other neurotransmitter systems.Opiate and opioid administration triggers direct opioid μ receptors in the mid brain, with consecutive activation of the neuron of the ven-tral tegmentary area of the medulla oblongata, which, with its projections toward the nucleus accumbens, is the origin of the mesolimbic dopaminergic neuronal network.Its connection with the amygdala nuclei provides the experience of satisfaction and pleasant emotions, but also the process of learning and fi xing the learned positive emotional experience.Chronic use of opiates leads to biochemical and structural changes in these structures and leads to the anticipation of experienced pleasure-craving.Also, connection with the mezocortical dopaminergic pathways, allows the compulsive behavior of purchasing and taking drugs, without the possibility of a signifi cant infl uence of will, the processes of logical thinking, possible risk and damage assessment, behavior control.At later stages, structural disorders are deepening; there is a reduction in the number of dopamine receptors, leading to even more intense cravings and an increase in tolerance [13].
Th ere are also a number of risk factors, related to the person himself, his genetic characteristics, personality traits, and acquired patterns of behavior related to addiction and from the environment, which can contribute to increasing the likelihood of recurrence.
If opiate dependence is considered as a chronic, severe and widespread disease and advocates a therapeutic approach similar to other chronically illnesses, the principles of pharmacological treatment must fi rst be defi ned by the already mentioned guidelines of Good Clinical Practice (GCP) the world-wide and at national level.
Th e pharmacotherapeutic approach relies on four groups of psychopharmaceuticals related to their affi nity for opiate receptors in the central nervous system [10]: 1. Opioid receptor agonists-methadone 2. Partial opioid receptor agonists-buprenorphine 3. Opioid receptor antagonists-naltrexone 4. Symptomatic-clonidine, tramadol Th e "gold standard" of the treatment of opioid dependence is antagonist therapy, which implies a detoxifi cation phase and maintenance phase with a certain stable dose of naltrexone (the usual daily dose is 50 mg).Th ese programs oft en represent a hard-reaching goal, with the problem of recidivism, and numerous unsuccessful treatments.
Th erapeutic requirements and goals, defi ned by the recommendations for the treat-ment of opioid dependence, have become less rigid [9].Th e ultimate goal of the treatment does not have to be a "drug free" patient, but a longer stay in treatment, better health and social functioning, reducing the use of illegal drugs, reducing mortality associated with drug abuse, controlling the risk of transmittable diseases -HIV infection, hepatitis B and C, tuberculosis, crime prevention, cost reduction caused by the problem of dependence in society.
Its goals can be reached by the "harm reduction" programs, where basic recommendations for opiate substitution therapy were set.Th at is defi ned as a strategy of controlling, rather than the prevention of opiate use.It implied prescribing and controlled administration of opioids with prolonged action with less euphoric eff ect, in order to reduce craving and to prevent abstinence symptoms.
One of the fi rst, starting from 1965, and the most commonly used opioids in the replacement-maintenance therapy, is methadone, which, in its pharmacological activity, is the complete opioid μ receptor agonist.It is characterized by a slow increase in maximal blood concentrations (4 hours), long half-life (25 hours), which supports its therapeutic efficacy, but also the cumulative eff ect aft er repeated dose and increased tolerance, indicating its addictive potential.Numerous of clinical studies [15,16] have shown its eff ectiveness, both on the underlying clinical symptoms of addiction, and on social and health implications, such as reducing the risk for HIV, reducing the addiction-related crime.Th e eff ectiveness of methadone therapy in terms of treatment retention and recidivism varies from study to study [16], from 20% to 70%, with a number of factors being aff ected as a genetic variability, specifi c metabolic characteristics, other medication, the use of other psychoactive substances, etc. [17].Pharmaco-economic studies support its use, but several recent studies show the occurrence of cardiac side eff ects, such as QT prolongation, indicating the need for medical supervision of patients in methadone maintenance treatment [18].Its negative characteristics, high addictive potential, are oft en the cause of abuse, addiction, and overdose.
Th e data suggest that about 20-25% of opiate addicts in the United States use methadone in maintenance therapy [14], compared to other forms of therapy and those who are not on therapy at all.In Europe, 70% of opiwww.hophonline.orgate addicts are on substitution therapy use methadone, combined with psychosocial interventions.According to the data in the year of 2015 in Serbia there are about 1.430 users of substitution therapy with methadone in civilian institutions, and 487 in prisons, which is increase compared to the data in 2011 [8].
In early 2007, there has been an increase in other types of substitution therapy, including buprenorphine, a partial agonist of opiate receptors.Its application was initiated between 1990 and 2000 in some European Union countries and in Australia, and since 2002 in the United States also.Buprenorphine has a slower onset and a longer duration of action, which allows dosing ones per day or once per every second or third day.It has a lower risk of over-dosage due to specifi c action -in larger doses it blocks itself leading to an antagonistic eff ect.High doses have milder opiate activity than complete agonists, but also lower maximum effi cacy in severe addicts.Symptoms of buprenorphine abstinent crises are milder and buprenorphine more easily switches to naltrexone than methadone if detoxifi cation is planned.Its recommended maximum dose is 32 mg, compared to 60-100 mg of methadone [10].Numerous clinical studies confi rm its effi cacy in relation to placebo; also studies on the use of buprenorphine in primary care and in private practice [20] confi rm that its application leads to a reduction in mortality due to overdose, a reduction in the number of heroin addicts, an improvement in the social and medical status of addicts, and a longer patient retention in treatment.It emphasizes its convenience in home care, good compliance, less impact on psychomotor abilities (driving, work).
Studies of the effi cacy of buprenorphine and methadone give inconsistent results, depending on various factors, such as dose height and application fl exibility [15,16,21] Also, the age, sex, length of heroin using, the severity of the symptoms of dependence, have an impact on the eff ectiveness of treatment by one or the other drug, so there are diff erent recommendations for the "fi rst line" in the treatment.Th e higher market price of buprenorphine restricts its widespread use compared to methadone.In Serbia, the data of 2015.indicate 852 users of buprenorphine substitution therapy, compared to only 79 in 2011 [8].
It should be noted that buprenorphine is the therapy of choice in specifi c groups of opiate addicts, such as HIV positive, pregnant women, adolescents [21].
Guidelines for substitution therapy in opioid addicts also defi ned criteria for inclusion in these programs [5]: -Th e age limit of at least 18 years -Length of opiate addiction at least 5 years -Clearly met the criteria of MKB 10 / DSM 5 for the opiate dependence -More unsuccessful attempts at treatment in the past -Opiate dependence associated with other chronic psychiatric disorders -Opiate dependence associated with criminal behavior -Opiate dependence associated with HIV infection and other transmissible infections -Motivation to enter the program Also, a detailed dose regimen, urine tests on psychoactive substances and drugs, rules of behavior for patients and staff of the medical institution are defi ned.
It has already been noted that in addition to neurobiological factors, which are responsible for the occurrence of recidivism in opiate dependence, there are many other psychological, social and other factors that come from the person and the environment, which can have a signifi cant impact on increasing the risk of relapse and maintaining dependence [22].Th e assessing these factors for each patient is a signifi cant part of the therapeutic process, followed by appropriate therapeutic actions, which includes the elements of the psychotherapeutic and social therapeutic approaches, in order to support the results of the pharmacotherapy treatment and as much as possible reduce the risk of relapse [23].It is emphasized that opiate dependence aff ects the whole person, both the biochemistry of her brain, and her psychological and social functioning.So, the treatment modalities should be the approach to all the mentioned aspects of the disorder.It is emphasized that, within the framework of an integrative treatment, relapses are not a sign of failure of treatment, but are the reason for the therapy to continue, as well as to change therapeutic modality.Relapses are oft en disappointing for patients themselves, they lead to negative emotions, depression, hopelessness, isolation, which activates old maladaptive behavioral patterns and leads to return to drug use.Th erefore, the existence of a social network and social therapy interven-tions, post-pharmacological treatment, prolonged treatment, and all forms of support for continued treatment are very important.

CONCLUSION
Opiate dependence is a diffi cult, chronic and highly recurrent psychiatric disorder, which over the past decades has reached epidemic proportions on a global scale.In addition to the detrimental impact on the individual's mental and physical health, many public health and social burdens are associated with this addiction, such as an increased risk of spreading transmission diseases-HIV, TB, Hepatitis C, high crime rates, economic burden on society, increased mortality rates due to overdose.Opportunities and treatment availability are not suffi cient for increased treatment needs.In addition to highly demanding therapeutic programs, which include long-term abstinence in protected conditions, the World Health Organization and the correspondingly most healthcare institutions in the European Union and other countries have developed harm -reduction programs, substitution therapy with agonists and partial agonists of opiate receptors.Th e proclaimed treatment objectives are patient retention in the program, restriction of the use of illegal drugs, intravenous drug use, mortality rates from overdose, control of the risk of spreading transmission diseases, and criminal drug-related behavior.
Pharmacological agents used in substitution therapy programs are most commonly methadone and, more rarely, other opiate agonists, and recently buprenorphine, a partial opiate agonist, which is the therapy of choice in outpatient treatment, as well as the treatment of special categories of addicts.Antagonist maintenance programs are also present, i.e.Naltrexone, or a combination of naloxone and buprenorphine / suboxone /, as well as the possibility of replacing one program with others.
Due to the problem of recidivism, which has numerous neurobiological, psychological and environmental causes and risk factors, a personalized and integrative approach to the treatment of opiate addicts is required, which includes a pharmacological treatment, combined with psychosocial and other support programs.It is emphasized that relapse is not a reason for termination of treatment, but for continuation, with adjustment or change program of treatment [22,24].