Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach

Objective: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. Methods: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. Results: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. Conclusion: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. Systematic review registry number: CRD42017054440.

Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach.

OBJECTIVE: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. METHODS: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. RESULTS: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. CONCLUSION: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. SYSTEMATIC REVIEW REGISTRY NUMBER: CRD42017054440.

A Novel Research Method for Determining Sedative Exposure in Critically Ill Patients.

BACKGROUND: Although potent sedative and opioid drugs are some of the most commonly used medications to manage pain, anxiety, and discomfort in critically ill patients, conducting clinical trials where sedative and opioid medications are outcome variables within a longitudinal research design can be a methodological challenge. OBJECTIVES: The purpose of this article is to provide in detail a conceptual discussion of the concept and analysis of sedative exposure: A novel research analysis method for aggregating sedative and opioid medication doses from disparate drug classes commonly administered to critically ill patients and used by our team in several clinical research studies. METHODS: Comparing the dose of each sedative and opioid administered to an individual patient (within a defined time interval) to all other patients in a research study receiving the same medications allows for ranking of dosages for each medication by quartiles. Rank values for all sedatives and opioids received can be summed to a single value resulting in a Sedation Intensity Score. In addition, a simple count of how many hours at least one dose of a sedative or opioid medication has been administered can determine sedation frequency. RESULTS: This method can allow for comparison of sedative exposure with medications from disparate drug classes and for analysis of estimates of change in medication use over time. DISCUSSION: This novel research analysis method can overcome the challenges and limitations of determining changes in sedative and opioid medication regimens in cohort and clinical trial study designs.

Diversity of Alkylproline Moieties in Pyrrolobenzodiazepines Arises from Postcondensation Modifications of a Unified Building Block.

Anticancer pyrrolobenzodiazepines (PBDs) are one of several groups of natural products that contain unusual 4-alkyl-l-proline derivatives (APDs) in their structure. APD moieties of PBDs are characterized by high structural diversity achieved through unknown biosynthetic machinery. Based on LC-MS analysis of culture broths, feeding experiments, and protein assays, we show that APDs are not incorporated into PBDs in their final form as was previously hypothesized. Instead, a uniform building block, 4-propylidene-l-proline or 4-ethylidene-l-proline, enters the condensation reaction. The subsequent postcondensation steps are initiated by the introduction of an additional double bond catalyzed by a FAD-dependent oxidoreductase, which we demonstrated with Orf7 from anthramycin biosynthesis. The resulting double bond arrangement presumably represents a prerequisite for further modifications of the APD moieties. Our study gives general insight into the diversification of APD moieties of natural PBDs and provides proof-of-principle for precursor directed and combinatorial biosynthesis of new PBD-based antitumor compounds.

Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized?

Benzodiazepine drugs are controversial because of safety and abuse liability concerns, although they have clinically relevant pharmacological differences. The current article reviews studies pertaining to the pharmacology, safety, and abuse liability of oxazepam. Compared to other benzodiazepine drugs, oxazepam has a favorable safety and abuse liability profile, which may be related to its pharmacology. Oxazepam is more slowly absorbed and enters the brain more slowly than other benzodiazepine drugs; it does not have active metabolites and does not accumulate with chronic dosing; its metabolism is not affected by age or by mild/moderate liver disease; and it is not prone to drug-drug interactions. Oxazepam also binds to the translocator protein, which stimulates the synthesis of neurosteroids, and this effect may contribute to its reduced abuse liability.

A Way of Conceptualizing Benzodiazepines to Guide Clinical Use.

Benzodiazepines are medications that are widely used for a number of different therapeutic indications and in a wide range of patients in terms of age and health status. Presented here is a simple 2 by 2 way of classifying all of the most commonly used benzodiazepines. This conceptualization is based on the most clinically relevant ways of differentiating these drugs: (a) their affinity for their common and predominant mechanism of action, the benzodiazepine-binding site of the γ-aminobutyric acid (GABA)-A iontropic receptor (ie, the chloride ion channel); and (b) their pharmacokinetics (ie, their half-lives and metabolism). The science underlying this conceptualization is presented and then its clinical applicability is discussed. This system can help clinicians select the most appropriate benzodiazepine for their patients and better understand how to switch between these medications to minimize withdrawal symptoms; it also provides a rational basis for cautiously using these agents in combination when necessary, in a manner analogous to the combined use of short-acting and long-acting forms of insulin.

Associations between Benzodiazepine Use and Neuropsychological Test Scores in Older Adults.

Benzodiazepines are widely prescribed for anxiety, although use of this class of medications has been associated with dependency and cognitive changes. This article describes the study in which we investigated the relationship between the class of benzodiazepine available for use and associated performance on neuropsychological tests in a community sample of 1,754 older Canadians from the Canadian Study of Health and Aging. Benzodiazepines were classified as short-, intermediate-, and long-acting. Associations were calculated between each class of benzodiazepine and eight neuropsychological measures, using multiple regression analysis and controlling for demographic variables. Results showed different effects of the co-variates across the three drug classes, and short half-life benzodiazepines were not associated with any neuropsychological measure. Intermediate half-life and long half-life benzodiazepine use were each associated with two measures. Increased focus on specific domains of cognitive function is needed to improve our understanding of how benzodiazepine use influences cognition.

Chronic use of benzodiazepines among older adults / Uso crônico de benzodiazepínicos entre idosos

OBJECTIVE To analyze the perception of and motivation for the chronic use of benzodiazepine among older adults. METHODS A qualitative study was conducted on 22 older adults living in Bambuí, MG, Southeastern Brazil, who were taking benzodiazepines and had the clinical and cognitive ability to respond to interview questions. The collected data were analyzed on the basis of the “signs, meanings, and actions” model. RESULTS The main reasons pointed out for the use of benzodiazepines were “nervousness”, “sleep problems”, and “worry” due to family and financial problems, everyday problems, and existential difficulties. None of the interviewees said that they used benzodiazepines in a dose higher than that recommended or had been warned by health professionals about any risks of their continuous use. Different strategies were used to obtain the prescription for the medication, and any physician would prescribe it, indicating that a bond was established with the drug and not with the health professional or healthcare service. Obtaining and consuming the medication turned into a crucial issue because benzodiazepine assumes the status of an essential food, which leads users to not think but sleep. It causes a feeling of relief from their problems such as awareness of human finitude and fragility, existential difficulties, and family problems. CONCLUSIONS Benzodiazepine assumes the characteristics of polyvalence among older adults, which extrapolate specific clinical indications, and of essentiality to deal with life’s problems in old age. Although it relieves the “nerves”, the chronic use of benzodiazepines buffers suffering and prevents older adults from going through the suffering. This shows important difficulties in the organization and planning of strategies that are necessary for minimizing the chronic use in this population. .

OBJETIVO Analisar a percepção e motivação do uso crônico de benzodiazepínicos entre idosos. MÉTODOS Estudo qualitativo desenvolvido com 22 idosos residentes em Bambuí, MG, sob uso de medicação benzodiazepínica e em condições clínicas e cognitivas para responder à entrevista. Os dados coletados foram analisados com base no modelo de “signos, significados e ações”. RESULTADOS As principais razões apontadas para o uso dos benzodiazepínicos foram “nervosismo”, “problemas de sono” e “preocupação”, decorrentes de problemas familiares, financeiros, dificuldades cotidianas e existenciais. Nenhum dos entrevistados referiu utilizar benzodiazepínicos acima das doses recomendadas nem foi alertado pelos profissionais acerca de quaisquer riscos sobre o seu uso continuado. Houve diversidade de estratégias na obtenção da prescrição do medicamento e qualquer médico fornecia a receita, o que indica que o vínculo é estabelecido com o medicamento e não com o profissional ou serviço de saúde. A obtenção e o consumo do medicamento tornam-se uma questão crucial, pois o benzodiazepínico assume a importância de um alimento essencial, que lhes permite não pensar e dormir. Oferece um alívio dos seus problemas, que incluem a consciência da finitude e da fragilidade humanas, dificuldades existenciais e familiares. CONCLUSÕES O benzodiazepínico assume características de polivalência entre os idosos, que extrapolam as indicações clínicas mais precisas, e de essencialidade para lidar com problemas da vida na velhice. Embora alivie o “nervoso”, o uso crônico de benzodiazepínicos tampona o sofrimento e impede a pessoa idosa de enfrentar o que ele representa. ...

Electrophoretic fingerprinting of benzodiazepine tablets in spike drinks.

Over the last few years, there has been an increase in the reports of drug-facilitated crimes. The list of drugs associated with these crimes is extensive and benzodiazepines constitute one of the groups of substances more commonly used. The sedative properties, which characterize benzodiazepines, are enhanced when such drugs are combined with alcohol, being more attractive for committing these types of crimes. In this work, a capillary electrophoresis method was applied to the analysis of 63 different samples of club drinks spiked with benzodiazepine tablets. The resulting electropherograms were processed and analyzed with the chemometric multivariate techniques: principal component analysis (PCA) and soft independent modeling of class analogies (SIMCA) classification. The PCA results allowed a clear differentiation of each drug class in a 3D plot. In addition, the SIMCA classification model (5% significance level) showed that eight out of nine test samples were automatically assigned by software to their proper sample class. The conflicting sample was correctly classified in the Coomans' plot (95% confidence). This novel approach based on the comparison of electrophoretic profiles of spiked drinks by chemometric tools allows determining the benzodiazepine used for drink spiking without the use of drug standards. Moreover, it provides an opportunity for the forensic laboratories to incorporate the identification capability provided by the electrophoretic fingerprinting of benzodiazepine solutions in existing or new databases.

Chronic use of benzodiazepines among older adults.

OBJECTIVE To analyze the perception of and motivation for the chronic use of benzodiazepine among older adults. METHODS A qualitative study was conducted on 22 older adults living in Bambuí, MG, Southeastern Brazil, who were taking benzodiazepines and had the clinical and cognitive ability to respond to interview questions. The collected data were analyzed on the basis of the "signs, meanings, and actions" model. RESULTS The main reasons pointed out for the use of benzodiazepines were "nervousness", "sleep problems", and "worry" due to family and financial problems, everyday problems, and existential difficulties. None of the interviewees said that they used benzodiazepines in a dose higher than that recommended or had been warned by health professionals about any risks of their continuous use. Different strategies were used to obtain the prescription for the medication, and any physician would prescribe it, indicating that a bond was established with the drug and not with the health professional or healthcare service. Obtaining and consuming the medication turned into a crucial issue because benzodiazepine assumes the status of an essential food, which leads users to not think but sleep. It causes a feeling of relief from their problems such as awareness of human finitude and fragility, existential difficulties, and family problems. CONCLUSIONS Benzodiazepine assumes the characteristics of polyvalence among older adults, which extrapolate specific clinical indications, and of essentiality to deal with life's problems in old age. Although it relieves the "nerves", the chronic use of benzodiazepines buffers suffering and prevents older adults from going through the suffering. This shows important difficulties in the organization and planning of strategies that are necessary for minimizing the chronic use in this population.

Tolerance to benzodiazepines among long-term users in primary care.

BACKGROUND: Tolerance towards the effects of benzodiazepines is observed in various animal and human studies. Therefore, it is assumed that patients who use benzodiazepines for a longer period of time need to increase their dose over time to experience the same effect. OBJECTIVE: To observe whether long-term benzodiazepine users increase their dose over time. METHODS: From the Dutch National Information Network of Family Practices, a group of long-term benzodiazepine users was identified. This group was divided into an incident long-term benzodiazepine users group (N = 113) and a prevalent long-term benzodiazepine users group (N = 992). Long-term use of benzodiazepines was defined as usage for at least 6 months. The main outcome was a change in prescribed dose from baseline until 24 months after baseline. Linear regression analysis was performed to evaluate dose change. RESULTS: Neither incident long-term benzodiazepine users nor prevalent long-term benzodiazepine users were prescribed increasing dosages during follow-up. CONCLUSION: There is no increase in prescribed dose among long-term users, as might be expected due to the development of tolerance to the effects of benzodiazepines.

Prevalence of benzodiazepines misuse in Ubon Ratchathani province Thailand.

BACKGROUND: Benzodiazepines misuse, abuse, and dependence is becoming a new problem in medicine used in Thailand. OBJECTIVE: Study the prevalence of benzodiazepines use, misuse, abuse, and dependence in Ubon Ratchathani province Thailand. MATERIAL AND METHOD: A cross-sectional household survey was conducted between October 2008 and June 2009. The target population were the people age 15 and above. A sample size of 2280 was selected from three stage stratified random sampling. Benzodiazepines were identified with generic name and drug characteristics. The DSM-IV questionnaires were used to define misuse, abuse, and dependence. Dependence was interpreted with judgment of a psychiatric nurse. For statistical analyses, prevalence was estimated with weight adjustment, variances estimated by Teylor Series Linearization method, and interpreted with 95% CI. RESULTS: There were 46,805 current users [3.9% (95% CI: 2.2-6.4)], 26,404 misuser [2.2% (95% CI: 1.6-6.2)], 7203 abuser [0.6% (95% CI: 0.1-4.1)] and 2402 dependent [0.2% (95% CI: O. 1-9.2)]. When considering the group of current user, the results showed that 57.2% of this group misused, 16.6% abused and 5.9% were dependent. CONCLUSION: Prevalence of use was higher than previously reported in Thailand while more than half of the current users misused Surveillance ofmisuse should be done in the group of current user Medical professional should give recommendations to patients, focusing on harm of misuse. Furthermore, they should limit the amount of medicine when it is necessary to dispense.

[Treatment strategies in anxiety disorders--an update]. / Aktuelle Therapiemöglichkeiten von Angststörungen.

Anxiety disorders are persistent impairing diseases, with often chronic course and suffering from symptoms throughout a life-span. The medication with the most evidence of efficacy is the benzodiazepines having a low incidence of side effects but may cause physical dependence, withdrawal and sedation. The use of these drugs should be limited to the acute treatments during the first several weeks in combination with an SSRI or and SNRI for the treatment of the acute phase. After three to four weeks, when antidepressants become effective, benzodiazepine dose should be tapered over a one week period. Among the antidepressants, the SSRI and the SNRI are considered a first-line therapy because of their favourable side effect spectrum compared to tricyclic antidepressants. However, the association with side effects such as nausea, sweating, sexual dysfunction and gastrointestinal problems and insomnia may be intolerable for a number of patients. Combining antidepressants and benzodiazepine therapy or medication treatment and psychotherapy may lead to an increase in improvement in patients not responding to one treatment approach alone. The most effective treatment for managing the recurrent symptoms of this chronic disorder are still unknown and other studies and approaches are in need as remission rates are still only about 40%.

Considerations for the use of enteral sedation in pediatric dentistry.

Treating an uncooperative, uncontrollable child can be unpleasant for all parties involved. Despite the dentist's best efforts to employ traditional techniques, the behavioral management of challenging pediatric dental patients often requires more than "tell, show, do". Consequently, pre-operative pharmacological intervention may be necessary. Enteral sedation may be the optimal adjunct for the dental treatment of such a challenging patient population. However it must be utilized with caution and is not an appropriate treatment modality for all. This paper will present various considerations for the safe, appropriate and effective use of enteral sedation in contemporary pediatric dentistry. With the strong demand for this service, properly trained practitioners can broaden their practice and provide a win-win scenario for themselves and their patients.

Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: maternal characteristics.

BACKGROUND: Use of benzodiazepine (BZD) drugs or hypnotic benzodiazepine receptor agonists (HBRAs) during pregnancy may represent a hazard for the foetus. In order to analyse this in an adequate way, knowledge of maternal characteristics as putative confounders is needed. METHODS: In the Swedish Medical Birth Register, 2149 pregnant women using BZDs or HBRAs were identified, 1944 of them in early pregnancy. These women were compared with other women (n = 859 455) giving births during the same period (1 July 1995-31 December 2004). The following maternal characteristics were studied: age, parity, smoking habits, education, previous miscarriages, years of involuntary childlessness as an estimate of subfertility, concomitant drug use and some pregnancy complications. RESULTS: Use and/or reporting of BZDs or HBRAs increased with maternal age. It was higher at first and 4+ parity and increased markedly with maternal smoking. Women with low education reported a higher use than women with high education. Previous miscarriage or subfertility had little impact on the use of these drugs. Preterm birth and caesarean section (also at term birth) were more common than expected. In women using BZDs or HBRAs, other types of psychoactive drugs were used in excess. CONCLUSIONS: Women using BZDs or HBRAs differ in many aspects from women not using those drugs. These differences may act as confounders in the analysis of pregnancy outcome.

LC-MS-(TOF) analysis method for benzodiazepines in urine samples from alleged drug-facilitated sexual assault victims.

In recent years there has been an increase in the number of reports in the U.S. of the use of drugs to commit sexual assault. In 1994, a nationwide urine testing program was developed to assess the incidence of the use of drugs to facilitate sexual assault and provide information for use in the investigation of these crimes. Urine samples were collected from victims of suspected drug-induced sexual assault by law enforcement agencies, emergency rooms, and rape crisis centers. The most implicated drug class was benzodiazepines, either alone or in combination with alcohol. In this report, a procedure was developed for the screening of 22 benzodiazepines in human urine by liquid chromatography-time of flight-mass spectrometry [LC-MS-(TOF)]. The limit of quantitation for all benzodiazepines ranged from 2 to 10 ng/mL, and the limit of detection was 0.5 to 3.0 ng/mL. These results suggest that the method sensitivity is suitable to screen for all 22 benzodiazepines in human urine at low levels. The method was used to analyze samples previously reported to have screened positive for benzodiazepines by immunoassay at 50 ng/mL cut off but failed to confirm by a gas chromatography-MS method. The results of reanalysis of these samples using this LC-MS method are reported.

Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists.

Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development.

Review of benzodiazepine use in children and adolescents.

Clinically, benzodiazepines are used in adult populations much more frequently than in children and adolescents. There may be a number of reasons for this disparity including a dearth of well controlled clinical studies and the issue of dependence associated with long term use. However, over a ten year span there has been nearly a three fold increase in the use patterns for these agents in the child population. In open studies much of the literature has indicated potentially useful results, but these findings have not been replicated when more refined methodological studies have been conducted. The lack of encouraging results in these later studies may be attributable to a number of factors such as modest sample sizes and less than optimal patient selection. Nonetheless, with increasing prescriptions being written for these agents it is not clear what is compelling clinicians to use them. In this paper we will review the available literature on benzodiazepine use in the child and adolescent population, focusing primarily on psychiatric applications.