With the term “drug addiction”, the WHO (World Health Organization) defines a “chronic and relapsing disease that pushes the individual, in a forced manner, to take substances at increasing or constant doses to have temporary subjective beneficial effects, whose persistence is inextricably linked to the continuous intake of the substance”. In the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders), the category “addictive and substance use-related disorders” has experienced substantial changes from previous editions of the DSM: The categories of “substance abuse” and “substance dependence” have been reunified into a single disorder, measured on a continuum mild to severe, whose criteria for diagnosis (almost identical to the previous criteria) were merged into a single list of 11 symptoms. The DSM-5 sets the following conditions for the diagnosis of a substance use disorder (DUS) [1]:

1. Tolerance: A phenomenon for which it is necessary to intensify the behavior of use (for example, by increasing the amount of drug to be used or frequency of intakes), in order to achieve the same effects on the body.
2. Withdrawal: characterized by the presence of emotional or physical symptoms that occur when the subject cannot implement the behavior of intake.
3. Interruption or reduction of social, work, or recreational activities: The use of drugs and onset of the disorder cause a series of damage to the functioning of the person who uses it (conflicts with affectively important people, work problems, influences on self-esteem, etc.) that increase in intensity, progressively harming the patient.
4. Unsuccessful attempts to reduce and control use: it is frequent that the patient, before formally seeking help from the psychologist or services, has tried on his own to reduce the use or “control” it. Generally, a phase is observed, in which the patient is firmly convinced that he can limit his conduct on his own by creating a mode of use that can be reconciled (but only ideally) with the rest of his life, commitments, and duties.
5. Expenditure of time: when the disorder is established, or being established, a criterion to look at is that of the time that the patient devotes to research, use, or recovery from the effects of the substance. The more the addiction is over, the greater the time that is dedicated to the substance in a day, until it becomes the only activity present in the most serious cases.
6. Loss of control over use: The pathological behavior of use of the substance tends to occur, despite the negative consequences that it has brought over time and person’s awareness of it (the behavior of use becomes “compulsive”).
7. Continuous use despite the awareness that the drug is a problem: many patients do not stop, even in the face of the onset of serious health risks or clear family crises.
8. Recurrent use with the inability to fulfill their duties: many patients lose their jobs due to drug intake, interrupt the course of study, or become unable to perform their family or parental duties.
9. Use in situations at risk: over time, the ability to estimate the risk associated with hiring is progressively reduced; becoming compulsive assumptions, it can happen to feel “forced” to make abuse, despite having to drive or perform precision tasks that cannot be “rationally” reconciled with the state of alteration given by the substances of abuse.
10. Recurrent use despite this causes social or interpersonal problems: As previously stated, drug use becomes salient, even to the detriment of one’s effective relationships.
11. Craving: urgent desire for the substance.

Recently, it has been reported that about 62 million people used opioids for non-medical purposes in 2019, corresponding to 1.2% of the world’s population. North America (3.6%) has the highest prevalence rate, and Europe the lowest (0.8%). The illegality of opioids, such as heroin, precludes the accurate assessment of how many people use these drugs [2]. Illicit opioid addiction is a significant public health problem, especially when you consider that heroin use is also associated with the spread of infectious diseases (e.g., HIV, hepatitis B, and C) and overdose deaths [3]. Drug use in Europe compromises of a wide range of substances. Among the people who use drugs, poly abuse is common, but difficult to estimate, and individual patterns of use range from experimental to habitual to addiction. The prevalence of high-risk opioid use among adults (15–64 years) in 2019 is estimated to represent 0.35% of the EU population, equivalent to 1 million high-risk opioid users. In 2019, in the European Union, there were 510,000 users in substitution therapy for opioid addiction. Opioid users account for 26% of drug treatment claims. Opioids resulted in 76% of the overdose deaths reported in the European Union in 2019. National prevalence estimates range between less than one and more than seven high-risk opioid users per 1000 inhabitants aged 15 to 64. Overall, this translates to around 0.35% of the European population, or 1 million high-risk opioid users in 2019. The four most populous countries in the European Union (Germany, Spain, France, and Italy) account for more than two-thirds (68%) of this estimate. In 2019, opioid use was reported as the main reason for access to specialist drug treatments by 84,000 users, accounting for 27% of all those who underwent treatment in Europe. Of these, about 20,000 were accessing treatment for the first time. Heroin was the primary drug for 13,600 (79%) of the 17,300 new users taken in charge who had reported the opiate, a relatively stable number, compared to the previous year [4]. In Italy, during 2020, the Ser.D. (Servizi Dipendenze) assisted a total of 125,428 drug addicts, for which 12% were new users. A total of 86% of Ser.D. patients were male, with an average age of 41 years. Female users, on the other hand, have an average age of 40 years. New users are younger (on average 9 years) than those already in charge. On average, the subjects present in treatment at the socio-rehabilitative structures, surveyed in 2020, were 13,781 per day. A total of 35% of users were in treatment for the primary use of cocaine/crack, with an equal share for heroin/opiates. At the end of 2020, there were 14,148 drug-addicted prisoners in prison, equal to 26% of the entire prison population—a decrease, compared to the previous two years. The main activity provided by the services is individual counseling on the risks of infectious diseases, followed by hepatitis screening campaigns and the distribution of information material [5].

All this is in collaboration and synergy with therapeutic communities, municipal administrations, and volunteering. Alongside these services, there is the work carried out at the Dual Diagnosis Operating Unit.

The term double diagnosis has been adopted to indicate a particular clinical condition, in which the picture of drug addiction or abuse (e.g., heroin, cocaine, alcohol, or drugs) and a psychiatric disorder coexist [6].

Double diagnosis is defined by the WHO as the “coexistence in the same individual of a disorder due to the consumption of psychoactive substances and another psychiatric disorder”

The condition of patients with double diagnosis is particularly serious and requires networking between local psychiatric services, hospital services, and possibly private specialists. The patient shows, compared to others:

1. a higher relapse rate;
2. more frequent hospitalizations;
3. more likely to commit crimes and end up in prison;
4. higher risk of contracting infectious diseases, such as HIV and hepatitis.

In this group, a reference is made to types of patients who are also very different from each other. Some develop a psychiatric disorder, secondary to substance abuse. They may be patients who have developed anxiety and mood disorders, secondary to the condition of abuse or consequences of abuse (loss of work, social and family relationships, etc.). In addition, as well-documented by neuroimaging studies, the use of drugs can create irreversible damage to the central nervous system, with consequent psychic and behavioral problems, often very serious. The second group of patients may have a primary psychiatric diagnosis before substance abuse. The state of psychic suffering can, in these patients, represent a risk factor for developing a pathological addiction. The use of substances can also be interpreted as an attempt, by these patients, to self-care for the primary psychiatric disorder [7]. A third group, on the other hand, has a psychiatric disorder and substance abuse or addiction in parallel. In these cases, it is “as if” the patient develops the two disorders independently. Dual diagnosis treatment is necessarily an integrated multi-step treatment that provides both detoxification/withdrawal and prevention of the risk of withdrawal and craving, and treatment of the psychiatric disorder in comorbidities.

Drug replacement therapy is considered the most effective treatment for opiate-dependent patients. However, issues related to substance abuse addiction, such as psychiatric comorbidities, infectious diseases, psychological distress, and stigmatization, can make treatment largely challenging and often requires a multidimensional approach to therapy [8].

Morphine receptor agonists and partial agonists represent the most recognized drug treatment in opiate-dependent patients worldwide [9]. Numerous clinical studies and evaluation programs demonstrate its effectiveness in reducing the illicit use, related mortality, and transmission of blood viruses, human immunodeficiency viruses (HIV), hepatitis C (HCV), and hepatitis B (HBV). Therapy also improves physique, psychological health, and quality of life and promotes social functioning and reintegration [10,11]. However, side effects can affect the patient’s response and reduce the maintenance rate [12].

Rac-methadone is the reference drug in the treatment of opioid dependence. It is considered the most effective of the drugs available in flexible-dose, in combination with psycho-social interventions, resulting in better retention in treatment. The prescription of these drugs is based on physical examination and clinical, drug, and psychological history. Rac-methadone is proposed in patients with a double diagnosis of addiction and maniacal psychosis, even borderline, who need sedation. However, the interindividual response to rac-methadone is strongly variable, ranging from a minimum initial dose per os of 15–20 mg/day for the treatment of abstinence symptoms to a dose of 40 mg/day in methadone-dependent patients, at average doses of 50–120 mg/day, up to prescribed doses, in off-label, of 300 mg/day, in the maintenance of severely dependent patients in some areas of Puglia. The response is influenced by various factors. One of them is related to molecular structure. Methadone is, in fact, a racemic mixture, in which the levo enantiomer is responsible for most of the therapeutic effects, while there are side effects [13]. Other factors that come into play are environmental ones and those related to the concomitant use of substances of abuse and drugs, which interfere with the metabolism and pharmacodynamics of the methadone itself. Highly effective doses of raceme methadone and long-term therapy, in patients in maintenance, expose them to adverse reactions, such as QT tract lengthening, respiratory depression, liver disease, infections, fatigue, constipation, hypertension, and hypotension, increased moderate-to-severe intracranial pressure, and sudden death.

Buprenorphine, on the other hand, has a well-known, different pharmacological profile, compared to methadone. It is a partial agonist of the opioid μ receptor: it mimics the pharmacological effect of an opioid, but to a much lesser extent, thus preventing opioid withdrawal symptoms. However, it has a slow rate of dissociation from the receptor, thus having a prolonged duration of action, compared to other opioids. Instead, it has antagonistic activity on k receptors, which contributes to the dysphoric and psychotomimetic effects of opioids. Buprenorphine reduces these effects. The partial competition of opiate receptors makes the molecule a valid alternative to methadone, as the μ risk of respiratory depression from overdose is greatly reduced [14,15,16,17,18]. This is especially important in the drug addict population. It is also administered sublingually, in combination with the antagonist naloxone, in a single administration/day, at doses even greater than 2 mg/day. The average daily maintenance dose is 8 mg. The majority of patients do not require doses greater than 16 mg/day. The efficacy and safety of buprenorphine tablets have been demonstrated in clinical trials at doses of up to 24 mg/day. Recent reports propose buprenorphine as the drug of choice in subgroups of dual-diagnosed patients with severe opioid dependence, tolerance, and major depression [19].

The clinical activity of buprenorphine/naloxone is mainly based on the different pharmacodynamic properties of the two drugs contained therein. In particular, when taken correctly, and this is sublingually, only the absorption of buprenorphine occurs with consequent clinical efficacy (naloxone is poorly absorbable enterally), while, if taken incorrectly intravenously, in addition to buprenorphine, naloxone is also absorbed, which acts as a receptor antagonist, generating a clinical situation of discomfort and/or mild withdrawal in the patient, such as to discourage its use by this route. Naloxone has long been known as a short-acting opioid receptor antagonist. It binds to receptors with high affinity in a competitive manner. It is administered in low doses and can reverse the side effects of opioids, such as respiratory depression, sedation, and hypotension, without significantly affecting analgesia. At high doses, however, naloxone can block opioid analgesia, causing withdrawal. However, it presents clinical activities only for parenteral administration.

The levomethadone-based drug is 10 times more active, in vitro and in vivo, on opioid receptors than methadone raceme in pre-registration studies. This is the latest drug in this therapeutic to be available in Italy in 2015. The effects, related to the elimination of opioid symptoms and compulsive desire to search for the substance, as well as the analgesic effect, are attributed to the levomethadone enantiomer [20]. In contrast, dextro-methadone is responsible for adverse effects, including cardiotoxic effects. This drug shows stereoselective pharmacodynamics and pharmacokinetics that justify its use, instead of rac-methadone, in patients at high cardiological risk. The effective maintenance dose of levomethadone hydrochloride may be up to 60 mg/day. In patients already receiving methadone, the dose indicated for substitution from the racemate to the R enantiomer is expected to be −50% [21].

Opioid receptors can form hetero-multimeric complexes, with receptors for cannabinoids CB1, or glutamate N-Methyl-D-Aspartate (NMDA) receptors with important functional implications of cross-talk between systems. Methadone inhibits NMDA receptors in an enantio-selective manner, with relevant implications in neuroprotection, pain control, and depression. NMDA receptors, such as NR1/2A and NR1/2B, show a higher affinity for levomethadone than morphine and dextro-methadone [22,23].

Rac-methadone undergoes a significant first-pass effect after absorption with hepatic metabolism, which transforms it by N-demethylation by the cytochrome P450 enzyme system (CitP) and, in particular, by CitP3A4 into EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), the inactive metabolite, and EMDP (2-ethyl-5-methyl-3, 3-diphenylpyrroline). In addition, CitP2D6 and CitP1A2 (inducible by Smoke) [24] are involved in the metabolism of rac-methadone raceme. The enzyme system of CitP2C19 metabolizes levomethadone, while dextro-methadone is metabolized by CitP2B6. Serious adverse reactions from rac-methadone overdose, such as respiratory depression and ventricular arrhythmia, are associated with gene polymorphisms [25]. CitP2D6 gene variants 3, 4, and 5 are associated with the slow metabolization of rac-methadone, resulting in accumulation. The polymorphism of the CitP2B6 *6/*6 gene is associated with respiratory depression and death from rac-methadone overdose. On the CitP2B6 *6/*6 slow metabolizers, the risk from dextro-methadone is significantly increased, compared to levomethadone. Gene polymorphisms of KCNH2, encoding the hERG potassium channel, are associated with QTc tract prolongation [25,26,27].

To date, limited data on the effectiveness of levomethadone are available in clinical practice at the national level and Apulian reality. There are no national and regional guidelines or shared indications that help the clinician in prescribing these drugs to patients in maintenance therapy. The success of drug therapy depends on psycho-social support, which is, in turn, regionalized so foreign experiences cannot be easily transferred to the site. The phenomenon of immigration has then exacerbated the medical–social problem. The prescription of these drugs and dosage is empirically based on the experience of the clinician, as well as the patient’s condition: mild, moderate, or severe tolerance to opioids, as well as from psychiatric and psychological supportive care. Although the supporting data indicate that the best treatment of drug addiction requires an integrated approach, in case of double diagnosis, these patients are followed in psychiatry and at drug addiction centers, as well as in the case of adverse reactions in internal medicine departments with loss of dose control and low quality of intervention. The resulting data will be compared with the international reality.