Discontinuation of pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder: meta-analysis of 63 studies enrolling 11,788 patients.

BACKGROUND: The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear. METHODS: A systematic review and meta-analysis of randomised, placebo-controlled clinical trials (RPCCTs) investigating the efficacy of pharmacological treatment in children or adolescents with ADHD was carried out. Meta-analysis of treatment discontinuation, clinician-, parent- and teacher-rated efficacy and adverse events was performed. The effect of covariates was studied. RESULTS: Sixty-three studies were included. Ten drugs were investigated, with atomoxetine and methylphenidate the most frequently studied. RPCCTs had mostly a short duration (7.9 weeks). All-cause treatment discontinuation was lower with pharmacological treatment than placebo (OR = 0.68). Pharmacological treatment was more efficacious than placebo independently of the rater (clinician, standardised mean difference (SMD) 0.74; parent, SMD = 0.63; or teacher, SMD = 0.75). Evidence of publication bias was found for clinician-rated efficacy, especially in industry-sponsored RPCCT. Psychostimulants showed a higher efficacy and were associated with a better outcome on treatment discontinuation than non-stimulant drugs. Efficacy was smaller in RPCCTs for which a psychiatric comorbid disorder was an inclusion criterion, was larger in studies with a commercial sponsorship and showed a negative association with treatment length. CONCLUSIONS: In the short term, pharmacological treatment provides moderate-high symptom relief, is safe and shows lower treatment discontinuation than placebo, suggesting a suitable risk-benefit balance, particularly with psychostimulants. The efficacy is lower in patients with a comorbid psychiatric disorder and should be assessed periodically, as it appears to reduce over time. Publication bias of clinician-rated efficacy in studies with a commercial sponsor is suggested.

Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients.

RATIONALE: The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. METHODS: A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. RESULTS: Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95 % confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95 % CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95 % CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). CONCLUSION: Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.

Pharmacological treatment of attention deficit hyperactivity disorder with co-morbid drug dependence.

BACKGROUND: Drug dependence is frequent in patients with attention deficit hyperactivity disorder (ADHD). Nevertheless, the efficacy and safety of pharmacological treatments in this population are unclear. METHODS: A systematic review with meta-analysis was performed. Randomised placebo-controlled clinical trials investigating the efficacy of pharmacological treatment in patients with co-occurring ADHD and substance use disorder (SUD) were included. ADHD symptom severity, drug abstinence and all-cause treatment discontinuation were the primary study endpoints. The effects of patient-, intervention- and study-related covariates over the primary outcomes were investigated by means of meta-regression. RESULTS: Thirteen studies were included, enrolling a total of 1,271 patients. A small to moderate reduction of ADHD symptoms was found. Meta-regression analysis identified the presence of a lead-in period as a covariate associated with reduced efficacy. Conversely, no beneficial effect was observed either on drug abstinence or treatment discontinuation. The efficacy on ADHD symptoms was smaller in studies with a lead-in period. A positive correlation between the efficacy for ADHD and that for SUD was found. CONCLUSIONS: The efficacy of pharmacological interventions for co-occurring ADHD and SUD has been little investigated. Mixed results were obtained: while pharmacological interventions improved ADHD symptoms, no beneficial effect on drug abstinence or on treatment discontinuation was noted. The strength of the recommendation of pharmacological treatment for co-occurring ADHD and SUD is therefore modest. The study was registered with the international prospective register of systematic reviews (PROSPERO): CRD 4212003414.

Workplace bullying and psychotropic drug use: the mediating role of physical and mental health status.

OBJECTIVES: The association between workplace bullying and psychotropic drug use is not well established. This study was aimed at exploring the association between workplace bullying, and its characteristics, and psychotropic drug use and studying the mediating role of physical and mental health. METHODS: The study population consisted of a random sample of 3132 men and 4562 women of the working population in the south-east of France. Workplace bullying, evaluated using the validated instrument elaborated by Leymann, and psychotropic drug use, as well as covariates, were measured using a self-administered questionnaire. Covariates included age, marital status, presence of children, education, occupation, working hours, night work, physico-chemical exposures at work, self-reported health, and depressive symptoms. Statistical analysis was performed using logistic regression analysis and was carried out separately for men and women. RESULTS: Workplace bullying was strongly associated with psychotropic drug use. Past exposure to bullying increased the risk for this use. The more frequent and the longer the exposure to bullying, the stronger the association with psychotropic drug use. Observing bullying on someone else at the workplace was associated with psychotropic drug use. Adjustment for covariates did not modify the results. Additional adjustment for self-reported health and depressive symptoms reduced the magnitude of the associations, especially for men. CONCLUSIONS: The association between bullying and psychotropic drug use was found to be significant and strong and was partially mediated by physical and mental health.

Workplace bullying and sleep disturbances: findings from a large scale cross-sectional survey in the French working population.

STUDY OBJECTIVES: The purpose of this study was to explore the associations between workplace bullying, the characteristics of workplace bullying, and sleep disturbances in a large sample of employees of the French working population. DESIGN: Workplace bullying, evaluated using the validated instrument developed by Leymann, and sleep disturbances, as well as covariates, were measured using a self-administered questionnaire. Covariates included age, marital status, presence of children, education, occupation, working hours, night work, physical and chemical exposures at work, self-reported health, and depressive symptoms. Statistical analysis was performed using logistic regression analysis and was carried out separately for men and women. SETTING: General working population. PARTICIPANTS: The study population consisted of a random sample of 3132 men and 4562 women of the working population in the southeast of France. RESULTS: Workplace bullying was strongly associated with sleep disturbances. Past exposure to bullying also increased the risk for this outcome. The more frequent the exposure to bullying, the higher the risk of experiencing sleep disturbances. Observing someone else being bullied in the workplace was also associated with the outcome. Adjustment for covariates did not modify the results. Additional adjustment for self-reported health and depressive symptoms diminished the magnitude of the associations that remained significant. CONCLUSIONS: The prevalence of workplace bullying (around 10%) was found to be high in this study as well was the impact of this major job-related stressor on sleep disturbances. Although no conclusion about causality could be drawn from this cross-sectional study, the findings suggest that the contribution of workplace bullying to the burden of sleep disturbances may be substantial.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by inadequate blood flow through the veins, usually in the lower limbs. It can result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Sufferers may also experience swelling and ulcers. Phlebotonics are a class of drugs that are often used to treat CVI. OBJECTIVES: To assess the efficacy of oral or topical phlebotonics. SEARCH STRATEGY: We searched the Cochrane Peripheral Vascular Diseases Group trials register (April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE (January 1966 to April 2005), EMBASE (January 1980 to April 2005) and reference lists of articles. We also contacted pharmaceutical companies. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in CVI patients at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. The effects of treatment were estimated by relative risk (RR) or by standardised mean differences (SMD) by applying a random effects statistical model. Sensitivity analyses were also performed. MAIN RESULTS: Fifty-nine RCTs of oral phlebotonics were included, but only 44 trials involving 4413 participants contained quantifiable data for the efficacy analysis: 23 of rutosides, ten of hidrosmine and diosmine, six of calcium dobesilate, two of centella asiatica, one of french maritime pine bark extract, one of aminaftone and one of grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Outcomes included oedema, venous ulcers, trophic disorders, subjective symptoms (pain, cramps, restless legs, itching, heaviness, swelling and paraesthesias), global assessment measures and side effects. The results of many variables were heterogeneous. Phlebotonics showed some global benefit (i.e. oedema reduction) (relative risk 0.72, 95% confidence interval 0.65 to 0.81). The benefit for the remaining CVI signs and symptoms must be evaluated by phlebotonic group. There were no quantifiable data on quality of life. AUTHORS' CONCLUSIONS: There is not enough evidence to globally support the efficacy of phlebotonics for chronic venous insufficiency. There is a suggestion of some efficacy of phlebotonics on oedema but this is of uncertain clinical relevance. Due to the limitations of current evidence, there is a need for further randomised, controlled clinical trials with greater attention paid to methodological quality.

Consumo y gasto de fármacos antipsicóticos / Consumption and cost of antipsychotic drugs

Introducción. En los últimos años se han comercializado nuevos fármacos antipsicóticos atípicos. El objetivo del estudio es analizar la evolución del patrón de consumo y del gasto farmacéutico de los fármacos antipsicóticos durante los últimos años y el impacto que han tenido los nuevos fármacos antipsicóticos atípicos. Métodos. A partir de la base de datos ECOM del Ministerio de Sanidad y Consumo español se han seleccionado los datos de ventas de los fármacos antipsicóticos en Cataluña durante el período 1990-2001. Los fármacos se han clasificado en típicos o clásicos y atípicos. Los datos de consumo se han expresado en dosis diarias definidas (DDD) por 1.000 habitantes y por día de tratamiento (DHD) y los de gasto en euros constantes. Resultados. El consumo de antipsicóticos aumentó de 3,31 DHD en 1990 a 6,04 DHD en 2001. El consumo de los típicos disminuyó (del 100 % del consumo en 1990 a un 46 % en 2001) y aumentó el de los atípicos (del 1% del consumo en el año 1993 a un 54 % en el año 2001). Se constató un cambio en el patrón de uso de los diferentes fármacos. En el año 1990 los fármacos más consumidos fueron el flupentixol (0,86 DHD) y el haloperidol (0,67 DHD), y en el año 2001 la olanzapina (1,69 DHD) y la risperidona (1,30 DHD). Los fármacos con un mayor incremento del consumo fueron la olanzapina, que multiplicó por cinco su consumo de 1997 a 2001, y la risperidona, que multiplicó por 20 su consumo de 1994 a 2001. Durante el período de estudio el gasto aumentó unas 13 veces, sobre todo a causa del incremento del gasto de los antipsicóticos atípicos (de menos del 1% del gasto total en 1993 a un 92 % del gasto total en 2001). El coste de la DDD de los antipsicóticos se incrementó (6,48e en 1990 y 20,31e en 2001); sin embargo, el de los antipsicóticos típicos disminuyó (6,48e en 1990 y 4,62e en 2001) y el de los atípicos aumentó (2,06e en 1993 y 15,69e en 2001). Conclusión. La comercialización de los nuevos antipsicóticos atípicos ha tenido un extraordinario impacto sobre el consumo y el gasto de los medicamentos antipsicóticos. Se debería evaluar la relación coste/efectividad de los nuevos antipsicóticos atípicos en la práctica clínica para determinar los recursos económicos destinados al gasto de los diferentes fármacos antipsicóticos

Introduction. In recent years, new atypical antipsychotic drugs have been marketed. This study aims to analyze the evolution of the consumption pattern and pharmaceutical cost of the antipsychotic drugs during the last years and the impact that the new atypical antipsychotic drugs have had. Methods. Based on the ECOM database of the Ministry of Health and Consumer Affairs of Spain, the sales data of the antipsychotic drugs in Catalonia during the 1990-2001 period have been chosen. The drugs have been classified into typical or classical and atypical. Consumption data have been expressed in daily defined dose (DDD) per 1,000 inhabitants and per day of treatment (DID), and cost data in constant euros. Results. Antipsychotic consumption increased from 3.31 DID in 1990 to 6.04 DID in 2001. Typical drugs consumption decreased (from 100 % consumption in 1990 to 46 % in 2001) and that of the atypical ones increased (from 1% consumption in the year 1993 to 54% in the year 2001). A change in the use pattern of different drugs is verified. In the year 1990, the most consumed drugs were flupenthixol (0.86 DID) and haloperidol (0.67 DID), and in the year 2001 olanzapine (1.69 DID) and risperidone (1.30 DID). The drugs with a greater increase in consumption were olanzapine, which multiplied its consumption five fold from 1997 to 2001 and risperidone, which multiplied it by 20 from 1994 to 2001. During the study period, the cost increased 13 times, above all due to increase in cost of atypical antipsychotics (from less than 1 % of the total cost in 1993 to 92 % of the total cost in 2001). The DDD cost of antipsychotics increased (6.48e in 1990 and 20.31e in 2001). However, that of the typical antipsychotics decreased (6.48e in 1990 and 4.62e in 2001) and that of the atypical ones increased (2.06e in 1993 and 15.69e in 2001). Conclusion. The marketing of the new atypical antipsychotic drugs has had an extraordinary impact on antipsychotic drug consumption and cost. The cost/effectiveness ratio of the new atypical antipsychotic drugs in the clinical practice should be evaluated to determine the economic resources aimed at costs of the different antipsychotic drugs

[Consumption and cost of antipsychotic drugs]. / Consumo y gasto de fármacos antipsicóticos.

INTRODUCTION: In recent years, new atypical antipsychotic drugs have been marketed. This study aims to analyze the evolution of the consumption pattern and pharmaceutical cost of the antipsychotic drugs during the last years and the impact that the new atypical antipsychotic drugs have had. METHODS: Based on the ECOM database of the Ministry of Health and Consumer Affairs of Spain, the sales data of the antipsychotic drugs in Catalonia during the 1990-2001 period have been chosen. The drugs have been classified into typical or classical and atypical. Consumption data have been expressed in daily defined dose (DDD) per 1,000 inhabitants and per day of treatment (DID), and cost data in constant euros. RESULTS: Antipsychotic consumption increased from 3.31 DID in 1990 to 6.04 DID in 2001. Typical drugs consumption decreased (from 100 % consumption in 1990 to 46 % in 2001) and that of the atypical ones increased (from 1% consumption in the year 1993 to 54% in the year 2001). A change in the use pattern of different drugs is verified. In the year 1990, the most consumed drugs were flupenthixol (0.86 DID) and haloperidol (0.67 DID), and in the year 2001 olanzapine (1.69 DID) and risperidone (1.30 DID). The drugs with a greater increase in consumption were olanzapine, which multiplied its consumption five fold from 1997 to 2001 and risperidone, which multiplied it by 20 from 1994 to 2001. During the study period, the cost increased 13 times, above all due to increase in cost of atypical antipsychotics (from less than 1 % of the total cost in 1993 to 92 % of the total cost in 2001). The DDD cost of antipsychotics increased (6.48 euros in 1990 and 20.31 euros in 2001). However, that of the typical antipsychotics decreased (6.48 euros in 1990 and 4.62 euros in 2001) and that of the atypical ones increased (2.06 euros in 1993 and 15.69 euros in 2001). CONCLUSION: The marketing of the new atypical antipsychotic drugs has had an extraordinary impact on antipsychotic drug consumption and cost. The cost/effectiveness ratio of the new atypical antipsychotic drugs in the clinical practice should be evaluated to determine the economic resources aimed at costs of the different antipsychotic drugs.

Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug.

OBJECTIVE: Pyrithyldione, a sedative-hypnotic drug with a poor clinical pharmacological development, was associated with anecdotal cases of agranulocytosis in the 1940s in the USA, in the 1960s and 1970s in the ex-Democratic Republic of Germany and in the 1980s in Japan. We describe the estimation of the risk of agranulocytosis associated with its use in Spain, which led to its withdrawal from the market. METHODS: In collaboration with the haematology units of all the hospitals in a defined area (3.3-3.9 x 10(6) inhabitants), all cases of agranulocytosis meeting strict diagnostic criteria were identified. Each case - defined as an episode of agranulocytosis - was reviewed by a haematologist without knowledge of previous drug exposures. Cases and age-, gender- and hospital-matched controls were interviewed with a structured questionnaire about previous drug exposures. In addition, in order to estimate the risk of pyrithyldione-associated agranulocytosis through a case-population approach, its consumption among the cases was compared with its consumption among the general population. RESULTS: After a follow-up of 66.5 x 10(6) person-years, 330 cases of agranulocytosis (230 community cases) were assembled. Reliable information on previous exposures was obtained for 204 cases. They were compared with 1314 controls. Eleven patients (14 cases, 6.9%) and zero controls had been exposed to pyrithyldione. The adjusted OR was 200.11 (CI 95% 22. 62-infinity). All patients were female; none had a fatal outcome; three exhibited positive rechallenge; and all had concomitantly taken other drugs. Although pyrithyldione was a prescription-only medicine, only 8% had been dispensed with medical prescriptions. Assuming the worst case, i.e. that all the exposed cases could be attributed to pyrithyldione, the incidence was 35.6 cases per 100, 000 patient-years (95% CI, 18.9-60.9), which gives a risk ratio estimate of 109.6 (57.5-191.5) if compared with the incidence of agranulocytosis among the non-exposed population [3.26 cases (CI 95% 2.83-3.71) per 10(6) inhabitants and per year]. DISCUSSION: Pyrithyldione was viewed by pharmacists as a mild hypnotic, and apparently this had conferred to this drug an unjustified image of safety. The National Commission of Pharmacovigilance recommended to the Ministry of Health its withdrawal from the market when eight cases of agranulocytosis had been identified. However, it took more than 2 years to withdraw it, and six additional cases occurred in the study area. This illustrates the need for quick regulatory action when pharmacoepidemiological data suggest an unfavourable benefit/risk ratio.

European network for the case-population surveillance of rare diseases (Euronet). A prospective feasibility study.

OBJECTIVE: Euronet, a case-population surveillance scheme, aims to estimate the risk of certain rare conditions which are commonly iatrogenic, by comparing drug use amongst non-selective cases with overall drug use in the general population. METHODS: The method is based on three provisos: (1) all incident cases (irrespective of suspected aetiology) should be ascertained and studied; (2) a full drug history should be obtained from cases by direct interview; and (3) drug-use data for the products of interest should be available for this population from which cases are chosen. The feasibility of this problem-oriented approach for the identification of new signals of adverse drug reactions and for risk estimation will be tested in relation to agranulocytosis, Stevens-Johnson syndrome and toxic epidermal necrolysis in four defined areas in Europe, totalling 19 x 10(6) inhabitants, with these latest two outcomes being studied in only three regions. The design, methods and main limitations of this case-population surveillance approach are described.

Spontaneous reporting of adverse drug reactions to non-steroidal anti-inflammatory drugs. A report from the Spanish System of Pharmacovigilance, including an early analysis of topical and enteric-coated formulations.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the third most commonly prescribed group of drugs in Spain. We present here the profile of adverse drug reactions (ADRs) attributed to them and reported to the Spanish System of Pharmacovigilance (SSPV) between 1983 and 1991, together with a preliminary analysis of topical, slow-release (SR) and enteric-coated (EC) preparations. Out of 18,348 reports of ADRs included in the SSPV database, 1609 (8.8%) implicated an NSAID. NSAIDs ranked second after antibiotics (15.1% of all reports) among the most commonly implicated drugs. Half of the patients were more than 55 years old, and 60% were women. Diclofenac (364 reports), piroxicam (282), indomethacin (197), naproxen (155), and ketoprofen (137) were the most commonly implicated NSAIDs in reports of ADRs. The most commonly reported ADRs were gastrointestinal (39%), cutaneous (20%), and those affecting the central and peripheral nervous system (9%). Seven reactions had a fatal outcome, and 138 were considered life threatening. Forty-nine reports included previously undescribed ADRs. There were 98 reports describing ADRs attributed to topical NSAIDs; 5 of these described 11 general reactions, such as duodenal ulcer, gastrointestinal bleeding, diarrhoea, dyspnoea, facial oedema, aggravation of bronchospasm, and angioedema. One hundred and sixty-eight reports referred to SR and EC preparations. The ratio of gastrointestinal to non-gastrointestinal reactions to SR-EC diclofenac was higher in the case of SR-EC diclofenac than in the case of plain diclofenac (P = 0.037); similarly, the ratio of CNS to non-CNS reactions to SR-EC indomethacin was also higher than the corresponding ratio with plain indomethacin (P = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)