Jose Martinez-Raga

Risk of Serious Cardiovascular Problems with Medications for Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and/or impulsivity. The proportion of patients diagnosed with ADHD receiving pharmacological treatments has increased enormously in recent years. Despite the well established efficacy and the good safety and tolerability profile, there is concern about the potential for rare but serious cardiovascular adverse events, as well as sudden cardiac death, with pharmacotherapies used for treating ADHD in children, adolescents and adults. The present paper aims to comprehensively and critically review the published evidence on the controversial association between medications approved for treating patients with ADHD and the risk of serious cardiovascular problems, specifically the risk of corrected QT interval (QTc) prolongation, and the risk of sudden cardiac death. A comprehensive search of relevant databases (PubMed, EMBASE and PsychINFO) was conducted to identify studies published in peer-reviewed journals until 21 July 2012. Clinical reports, as well as retrospective or prospective population-based studies with children, adolescents or adults as participants, of pharmacotherapies for ADHD reporting cardiovascular adverse events were included. Stimulant medications for ADHD, including methylphenidate and amphetamine derivatives, are generally safe and well tolerated. Small but statistically significant increases in blood pressure (BP) and heart rate (HR) are among the adverse events of stimulant treatment in all age groups. Similarly, the non-stimulant medication atomoxetine has also been associated with increased HR and BP, although as is the case with stimulants, these are generally minor, time limited and of minor clinical significance in children, adolescents or adults. Growing evidence suggests that these medications do not cause sudden and unexpected cardiac death or serious cardiovascular problems including statistically or clinically significant increases in QTc, at therapeutic doses in ADHD patients across the lifespan. Small decreases in mean systolic BP, diastolic BP and HR have been observed in studies with guanfacine-extended release (-XR) or clonidine-XR, two α2-adrenergic receptor agonists, administered alone or in combination with psychostimulants to children and adolescents with ADHD. There are also no statistically or clinically significant increases in QTc associated with clonidine or guanfacine. There are no reports of torsades de pointes clearly and directly related to medications used for treating ADHD in patients of all age groups. The risk for serious cardiovascular adverse events, including statistically or clinically significant increases in QTc, and sudden cardiac death associated with stimulants, atomoxetine or α2-adrenergic agonists prescribed for ADHD is extremely low and the benefits of treating individual patients with ADHD, after an adequate assessment, outweigh the risks. However, great caution is advised when considering stimulant and non-stimulant medications for patients of any age with a diagnosis of ADHD and a personal or family history or other known risk factors for cardiovascular disease.

Modafinil: A Useful Medication for Cocaine Addiction? Review of the Evidence from Neuropharmacological, Experimental and Clinical Studies

Cocaine addiction is a chronic relapsing disorder associated with severe medical and psychosocial complications. However, there are no approved medications for cocaine dependent individuals. Modafinil, a medication that differs chemically and pharmacologically from other central nervous system stimulants, has been suggested to be potentially useful for this complex disorder. The present paper aims to critically review the published evidence from laboratory and clinical studies on modafinil for cocaine addiction, including discussion of its pharmacological characteristics and how it may relate with cocaine neurobiology. Whilst its exact mechanism of action remains to be elucidated, different neurotransmitter systems have been implicated, including modulation on dopamine, glutamate/GABA, noradrenaline and the hypocretin/orexin system, but it is possible that modafinil acts by a synergistic combination of mechanisms. With a favourable pharmacokinetic profile, it appears to have a low abuse potential. Laboratory and clinical studies provide consistent, albeit preliminary, evidence of the potential usefulness of modafinil for cocaine dependent patients. Not only there is no evidence of pharmacokinetic interactions between modafinil and cocaine, but in addition cocaine induced euphoria and cardiovascular effects appear to be attenuated by modafinil. Furthermore, modafinil has been shown to decrease cocaine self-administration. In addition, modafinil treated patient are more likely to achieve protracted abstinence than placebo treated patients. However, further research is needed to confirm these findings.

Antipsychotic Drug Treatment of Schizophrenic Patients with Substance Abuse Disorders

Background/Aim: In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature. Methods: A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: ‘schizophrenia’, ‘substance use disorder’ and ‘antipsychotics’. Results: While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder. Conclusion: In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.

Rethinking Dual Disorders/Pathology

Objective:Comorbidity of addictive disorders and other psychiatric disorders is very common. The optimal treatment of patients with addiction disorders requires awareness of their comorbid mental disorders and vice versa. The operational and contextual definitions of the different terms used vary significantly. To address this terminology problem the present document proposes and, therefore, has chosen the term ‘dual pathology.’ Methods:The present paper aims to discuss the most current evidence regarding the multiple genetic, developmental, and environmental factors underlying the complex interactions that modulate the vulnerability and trajectories of patients with dual pathology. It, thus, goes beyond the current prevailing view of considering patients as having primarily either an addictive disorder or any other mental disorder and may have an additional comorbid psychiatric disorder. Results:It is time to rethink mental disorders, including addictive disorders and dual disorders or dual pathology, recognizing that these are disorders of brain circuits likely caused by developmental processes shaped by a complex interplay of genetics and experience, and may therefore be considered neurodevelopmental disorders. The view of dual pathology as a neurobiological systems failure should help us to develop more comprehensive interventions for optimizing the ways in which we prevent and treat a complex, multifactorial, likely neurodevelopmental disorder such as dual pathology. Conclusions:Despite the scientific evidence, there are beliefs and, as a result, certain resistance or barriers that have hindered the recognition and acceptance of dual pathology in daily clinical practice or in research. Twelve of these common barriers are addressed and discussed.

Suboxone (Buprenorphine/Naloxone) as an Agonist Opioid Treatment in Spain: A Budgetary Impact Analysis

Objective: To evaluate the economic impact of buprenorphine/naloxone (B/N) as an agonist opioid treatment for opiate dependence. Methods: A budgetary impact analysis model was designed to calculate the annual costs (drugs and associated costs) to the Spanish National Healthcare System of methadone versus B/N. Data for the model were obtained from official databases and expert panel opinion. Results: It was estimated that 86,017 patients would be in an agonist opioid treatment program each of the 3 years of the study. No increase in the number of patients is expected with the introduction of B/N combination. The budgetary impact (drugs and associated costs) for agonist opiate treatment in the first year of the study would be 89.53 million EUR. In the first year of B/N use, the budgetary impact would rise by 4.39 million EUR (4.6% of the total impact), with an incremental cost of 0.79 million EUR (0.9% of the total impact). The budgetary increase would be 0.6% (0.48 million EUR increase) and 0.6% (0.49 million EUR increase) in the second and third years of use, respectively. The mean cost per patient in the first year with and without B/N would be EUR 1,050 and 1,041, respectively. The most influential variables in the sensitivity analysis were logistics and production costs of methadone and the percentage use of B/N. Conclusion: With an additional cost of only EUR 9 per patient, B/N is an efficient addition to the therapeutic arsenal in the drug treatment of opiate dependence, particularly when considering clinical aspects of novel pharmacotherapy.

Attention-deficit hyperactivity disorder (ADHD), substance use disorders, and criminality: a difficult problem with complex solutions.

Abstract The association between attention-deficit hyperactivity disorder (ADHD) and criminality has been increasingly recognized as an important societal concern. Studies conducted in different settings have revealed high rates of ADHD among adolescent offenders. The risk for criminal behavior among individuals with ADHD is increased when there is psychiatric comorbidity, particularly conduct disorder and substance use disorder. In the present report, it is aimed to systematically review the literature on the epidemiological, neurobiological, and other risk factors contributing to this association, as well as the key aspects of the assessment, diagnosis, and treatment of ADHD among offenders. A systematic literature search of electronic databases (PubMed, EMBASE, and PsycINFO) was conducted to identify potentially relevant studies published in English, in peer-reviewed journals. Studies conducted in various settings within the judicial system and in many different countries suggest that the rate of adolescent and adult inmates with ADHD far exceeds that reported in the general population; however, underdiagnosis is common. Similarly, follow-up studies of children with ADHD have revealed high rates of criminal behaviors, arrests, convictions, and imprisonment in adolescence and adulthood. Assessment of ADHD and comorbid condition requires an ongoing and careful process. When treating offenders or inmates with ADHD, who commonly present other comorbid psychiatric disorder complex, comprehensive and tailored interventions, combining pharmacological and psychosocial strategies are likely to be needed.

Dual Diagnosis Resource Needs in Spain: A National Survey of Professionals

Objective: Since provision of integrated services for patients with dual pathology or dual disorders (coexistence of an addictive disorder and another mental health disorder) is an important challenge in mental health, this study assessed health care professionals’ perceptions and knowledge of the current state of specific resources for patients with dual pathology in Spain. Methods: We conducted a national survey of health care professionals seeing patients with dual pathology in treatment facilities throughout Spain. Participants completed a specific online questionnaire about the needs of and available resources for patients with dual pathology. Results: A total of 659 professionals, mostly psychologists (n = 286, 43.4%) or psychiatrists (n = 217, 32.9%), participated in the study. Nearly all participants who responded to these items reported that specific resources for dual pathology were needed (n = 592/635, 93.2%); 76.7% (n = 487) identified intermediate resources, 68.8% (n = 437) acute detoxification units, and 64.6% (n = 410) medium-stay rehabilitation units as particularly necessary. In the opinion of 54.0% of respondents (n = 343), integrated mental health and addiction treatment services were available. Of the participants who answered these items, only a small proportion (n = 162/605, 26.8%) reported that there were appropriate outpatient programs for dual pathology, 30.4% (n = 184/605) specific hospitalization units, 16.9% (n = 99/587) subacute inpatient units, 34.2% (n = 201/587) outpatient intermediate resources, 15.5% (n = 91/587) day hospitals, and 21.5% (n = 126/587) day centers. Conversely, 62.5% (n = 378/587) of participants reported a greater presence of specific detoxification/withdrawal units, 47.3% (n = 286/587) psychiatric acute admission units, and 41.9% (n = 246/587) therapeutic communities. In the professionals’ opinion, the presence of specialty programs was low; 11.6% of respondents (n = 68/587) reported that vocational programs and 16.7% (n = 98/587) reported that occupational rehabilitation programs were available. Employee turnover was common: 51.9% of respondents (n = 314/605) stated that employee turnover was occasional to frequent. Conclusions: According to the professionals surveyed, specific health care resources for the management of dual pathology are currently insufficient, underlining the need for additional efforts and strategies for treating individuals with comorbid disorders.

Attention deficit hyperactivity disorder and dual disorders. Educational needs for an underdiagnosed condition

Abstract A wide range of comorbid psychiatric disorders overlap with attention-deficit hyperactivity disorder (ADHD) across the life span. There is a robust and complex link between ADHD and substance use disorders (SUD). The aim of this report was to review the neurobiological and other vulnerability factors explaining the comorbidity of ADHD and an addictive disorder, as well as the key aspects of the assessment and diagnosis of dually diagnosed ADHD patients. A comprehensive and systematic search of relevant databases (PubMed, Embase, and PsychINFO) was conducted to identify studies published in peer-reviewed journals until July 31, 2012, with the aim of exploring the association of ADHD and SUD with postgraduate training and residency education. Across the life span, ADHD is associated with significant impairment and comorbidity. Data from epidemiological, clinical and epidemiological studies show a very solid link between ADHD and SUD. Therefore, it is very important to carefully and systematically assess for any substance use in patients with suspected ADHD coming to initial assessment, and vice versa. While there are various valid and reliable rating and screening scales, diagnosis cannot solely rely on any of the instruments available for both SUD and ADHD in adult patients with dual pathology. The most important and effective tool in the assessment of dually diagnosed patients with ADHD and SUD is a full and comprehensive clinical and psychosocial assessment. Hence, it is essential to actively incorporate training opportunities on the assessment, diagnosis, and management of adult ADHD and dually diagnosed ADHD patients during postgraduate education residency or specialist training.

Chronic hepatitis C and individuals with a history of injecting drugs in Spain: population assessment, challenges for successful treatment

In Spain, there is a need to improve chronic hepatitis C care among people who inject drugs (PWID). Injecting drug use is an important risk behaviour for hepatitis C virus (HCV) infection. Review of 28 sources of the relevant published literature mapped the size of the addiction-HCV population in Spain. Experts in opioid use disorder (OUD) treatment in Spain completed a consensus to define the population size, HCV prevalence and access or barriers to hepatitis C treatment for PWID populations. In Spain, over 300 000 individuals have a lifetime history of injecting drugs. Currently, 150 000 individuals in Spain have OUD; many have injected drugs. Each year, 80 000 individuals engage with treatment services for OUD. A proportion of this group continues to inject drugs. There is a high HCV prevalence in PWID – estimates of 60–80% in Spain. Uptake of hepatitis C therapy in PWID in Spain is limited; barriers include awareness of treatment pathways, advocacy for regular screening and effective joint care. There is an urgent need to address barriers to effective hepatitis C care for PWID in Spain. Practical and specific strategies including peer-led solutions, patient buddy systems and joint working models at the local level can make important short-term differences.

Budgetary impact analysis of buprenorphine-naloxone combination (Suboxone ® ) in Spain

BackgroundOpioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial μ-opiod agonist and a κ-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine-naloxone (B/N) combination.MethodsA budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (€, 2010).ResultsThe number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is €85,766,129; €79,855,471 and €79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be €86,589,210; €80,398,259 and €79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is €10.58; €6.98 and €7.34 in the first, second and third year respectively.ConclusionAddition of B/N combination would imply a maximum incremental yearly cost of €10.58 per patient compared to scenario only with methadone and would provide additional benefits.