Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics.

AIMS: The aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients in order to develop a dosing regimen for sedation. METHODS: We included 24 adult mechanically ventilated, sedated patients from a mixed medical and surgical ICU. Intravenous clonidine was added to standard sedation in doses of 600, 1200 or 1800 µg/d. Within each treatment group, 4 patients received a loading dose of half the daily dose administered in 4 hours. Patients gave an average of 12 samples per individual. In total, 286 samples were available for analysis. Model development was conducted with NONMEM and various covariates were tested. After modelling, doses to achieve a target steady-state plasma concentration of >1.5 µg/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients. RESULTS: A 2-compartment model was the best fit for the concentration-time data. Clearance (CL) increased linearly with 0.213%/h; using allometric scaling, body weight was a significant covariate on the central volume of distribution (V1). Population PK parameters were: CL 17.1 (L/h), V1 124 (L/70 kg), intercompartmental CL 83.7 (L/h), and peripheral volume of distribution 178 (L), with 33.3% CV interindividual variability on CL and 66.8% CV interindividual variability on V1. Simulations revealed that a maintenance dose of 1200 µg/d provides target sedation concentrations of >1.5 µg/L in 95% of the patients. CONCLUSION: A population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 µg/d provided a target sedation concentration of >1.5 µg/L.

Using ecological momentary assessment to examine the relationship between craving and affect with opioid use in a clinical trial of clonidine as an adjunct medication to buprenorphine treatment.

BACKGROUND: In a recent clinical trial (NCT00295308), we demonstrated that clonidine decreased the association between opioid craving and moderate levels of stress and affect in patients receiving buprenorphine-based opioid agonist therapy. OBJECTIVES: To examine the relationship between illicit opioid use and craving and affect during the evaluation of clonidine as an adjunct medication in buprenorphine treatment for opioid use disorder. Secondarily, to examine whether those relationships are driven by within- or between-participant factors. METHODS: This was a secondary data analysis from our original trial. Participants (N = 108, female: n = 23, male n = 85) receiving buprenorphine were randomized to receive adjunct clonidine or placebo. Participants used portable electronic devices to rate stress, mood, and craving via ecological momentary assessment (EMA) four times randomly each day. To associate the EMA data with illicit opioid use, each EMA report was linked to participants' next urine drug screen (thrice weekly). We used generalized linear mixed models to examine the interaction between treatment group and illicit opioid use, as well as to decompose the analysis into within- and between-participant effects. RESULTS: Craving for opioids and cocaine was increased when participants were using illicit opioids; this effect was greater in the clonidine group. For affect, mood was poorer during periods preceding opioid-positive urines than opioid-negative urines for clonidine-treated participants, whereas there was no difference for placebo participants. CONCLUSION: This secondary analysis provides evidence that for participants maintained on opioid agonist therapy, clonidine minimized the behavioral impact of moderate levels of negative affect and craving.

Perineural Dexmedetomidine Is More Effective Than Clonidine When Added to Local Anesthetic for Supraclavicular Brachial Plexus Block: A Systematic Review and Meta-analysis.

BACKGROUND: Clonidine, an α-2 agonist, has long been used as a local anesthetic adjunct with proven efficacy to prolong peripheral nerve block duration. Dexmedetomidine, a newer α-2 agonist, has a more favorable pharmacodynamic and safety profile; however, data comparing its efficacy as an adjunct to that of clonidine are inconsistent. We sought to compare the clinical efficacy of these 2 α-2 agonists by examining their effects on peripheral nerve block characteristics for upper extremity surgery. METHODS: A preliminary search found that the overwhelming majority of randomized controlled trials comparing perineural dexmedetomidine to clonidine for upper extremity surgery were in the setting of supraclavicular brachial plexus block (SCB). Therefore, we performed a systematic review and meta-analysis of randomized controlled trials comparing dexmedetomidine with clonidine as perineural adjuncts to single-injection SCB. Sensory and motor block duration and onset, analgesic duration, α-2 agonist side effects, and block complications were analyzed. Sensory block duration was designated as a primary outcome. Data were combined using random-effects modeling, and ratio-of-means was used to analyze the results. RESULTS: A total of 868 patients from 14 clinical studies were included in the analysis. Compared with clonidine, dexmedetomidine prolonged the duration (ratio of means [95% confidence interval {CI}]) of sensory block by an estimate of 1.2 (1.2-1.3; P< .00001). It also prolonged the duration (ratio of means [99% CI]) of motor block by an estimate of 1.2 (1.1-1.3; P < .00001), and analgesia by an estimate of 1.2 (1.1-1.3; P < .00001). It also hastened the onset of sensory block by an estimate of 0.9 (0.8-1.0; P < .00001) and motor block by an estimate of 0.9 (0.9-1.0; P = .002). Dexmedetomidine was associated with an increased odds ratio (99% CI) of transient bradycardia by an estimate of 7.4 (1.3-40.8; P = .003) and postoperative sedation by an estimate of 11.8 (1.9-73.6; P = .0005). There were no differences in other α-2 agonist-related side effects or block-related complications. CONCLUSIONS: Compared with clonidine as a local anesthetic adjunct for single-injection SCB, perineural dexmedetomidine enhances sensory, motor, and analgesic block characteristics. These benefits should be weighed against the increased risk of transient bradycardia.

Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study.

INTRODUCTION: Enteral clonidine represents a potentially less costly alternative to dexmedetomidine for sedation in intensive care unit (ICU) patients. This study describes our practice of transitioning selected adult ICU patients from dexmedetomidine to clonidine with a focus on efficacy, safety, and drug acquisition costs. METHODS: We conducted a single-center prospective observational pilot study from January through March 2014. Consecutive patients 18 years and older treated with dexmedetomidine and transitioned to clonidine were followed. The transition was assessed in five phases: dexmedetomidine maintenance, transition, clonidine maintenance, clonidine taper, and post clonidine. Efficacy data included any occurrence of significant pain, excessive agitation or oversedation, delirium, and need for ancillary psychoactive medications. Safety data included any occurrence of bradycardia, hypotension, new second- or third-degree atrioventricular node blockade, and clonidine withdrawal syndrome. Drug acquisition cost avoidances were estimated using average wholesale price. RESULTS: Twenty patients were evaluated. Fifteen (75%) were successfully transitioned from dexmedetomidine within 48 hours of starting clonidine. The initial and maintenance clonidine regimens were 0.3 mg every 6 hours. Clonidine was the sole α2A -receptor agonist administered for 45 hours while in the ICU and for 54 hours outside the ICU. Fentanyl requirements were lower when clonidine was administered as the sole α2A -receptor agonist as compared to dexmedetomidine alone (387 vs. 891 µg/day, p = 0.03). Otherwise, there were no statistically significant differences in efficacy data during the dexmedetomidine and clonidine maintenance phases. No statistically significant differences in safety data were observed. Clonidine withdrawal syndrome criteria were met in one patient. The potential drug acquisition cost avoidance was $819-$2338 per patient during the 3-month study. CONCLUSIONS: Transitioning from dexmedetomidine to clonidine may be an efficacious, safe, and less costly method of maintaining α2A -receptor agonist therapy in critically ill adults; these results warrant confirmation in expanded studies.

Efectividad y seguridad de Risperidona comparada con Haloperidol, Olanzapina, Clozapina, Quetiapina, Aripiprazol, Clonidina, Placebo en personas con diagnóstico de trastorno del espectro autista - TEA / Effectiveness and Safety of Risperidone compared to Haloperidol, Olanzapine, Clozapine, Quetiapine, Aripiprazole, Clonidine, Placebo in People with Autism Spectrum Disorder - ASD

Introducción: Los trastornos del espectro autista (TEA) son un grupo de discapacidades del desarrollo, de características crónicas y que afectan de manera distinta a cada paciente. Los TEA se definen como una disfunción neurológica crónica con fuerte base genética que desde edades tempranas se manifiesta en una serie de síntomas basados en la tríada de Wing que incluye: la comunicación, flexibilidad e imaginación e interacción social. No existe tratamiento curativo para el TEA, las terapias están dirigidas al control de los síntomas. Debido a la heterogeneidad de los síntomas, las terapias deben adaptarse al caso individual del paciente. Las intervenciones para los pacientes con diagnóstico de TEA pueden incluir educación, terapia conductual, o manejo farmacológico. Objetivo: realizar una revisión, apreciación crítica y síntesis de la evidencia disponible sobre la efectividad y seguridad de la risperidona para el tratamiento de personas con diagnóstico de trastorno del espectro autista. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, LILACS y Google, sin restricciones de idioma, fecha de publicación y tipo de estudio. Las búsquedas electrónicas fueron hechas en octubre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por dos revisores de forma independiente y los desacuerdos fueron resueltos por consenso. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad predefinidos. Las características y hallazgos de los estudios fueron extraídos a partir de las publicaciones originales. Resultados: Se identificó evidencia proveniente de 4 revisiones sistemáticas de moderada y alta calidad, que compraban risperidona con placebo, se encontró que risperidona fue superior a placebo en los desenlaces de impresión global de salud, irritabilidad, hiperactividad, estereotipias. Conclusiones: La risperidona comparada con placebo sugiere efectividad en relación a mejoría de síntomas como irritabilidad, hiperactividad y estereotipias, así como, de la impresión clínica global. No se puede establecer con la evidencia actual el perfil de seguridad de la risperidona, solo se evidenció que los pacientes que reciben risperidona tienen mayor riesgo de aumento de peso y de presentar síndrome de extrapiramidalismo.

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study.

BACKGROUND: Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful. OBJECTIVE: Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam. DESIGN: Multicentre, double-blind, randomised equivalence trial. SETTING: Ten UK PICUs. PARTICIPANTS: Children (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours. INTERVENTIONS: Clonidine (3 µg/kg loading then 0-3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0-200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine. MAIN OUTCOME MEASURES: Primary end point Adequate sedation defined by COMFORT score of 17-26 for ≥ 80% of the time with a ± 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data. RESULTS: The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61). CONCLUSIONS: Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02639863. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information.

Repeated assessment of cardiovascular and respiratory functions using combined telemetry and whole-body plethysmography in the rat.

INTRODUCTION: As the currently recommended laboratory techniques for assessing cardiovascular and respiratory functions are telemetry and plethysmography, we therefore combined both in a single rodent model. The purpose of the present work was to assess the potential influence of body growth on the recorded parameters, to verify the sensitivity of the system to detect well known pharmacological effects of reference drugs, and to determine their reproducibility over time. METHODS: Telemetry instrumented rats were enrolled in successive experiments over a total of 5 months. In each run, they were placed in individual plethysmography chambers for 6h, and received a single intraperitoneal injection of vehicle or test compound. Heart rate, blood pressure, body temperature and respiratory parameters were measured in real time. Six of these 16 rats were submitted 5 times at one month intervals to a vehicle injection, and six rats received theophylline (30 mg/kg) twice at 4 months interval. Nine other reference compounds were also tested at a single dose. RESULTS: Analysis of baseline data mainly showed correlations between body weight or age and heart rate, as well as tidal volume. In the five successive runs, handling-induced perturbations were noted in all the parameters during 60 to 90 min. The effects of the different reference drugs were consistent with data published in animals and man. The response to theophylline was qualitatively similar at 4 months interval. DISCUSSION: We established a combined model of telemetry and plethysmography in the conscious rat, allowing the reuse of the animals over several successive pharmacodynamic studies. Although a shift of some parameters, particularly heart rate and tidal volume, was noted with age and body weight, this can easily be managed by appropriate design measures. We showed that the combined system can detect negative or positive effects on both cardiovascular and respiratory functions with enough sensitivity.

Induced hypothermia for infants with hypoxic- ischemic encephalopathy using a servo-controlled fan: an exploratory pilot study.

OBJECTIVE: Several trials suggest that hypothermia is beneficial in selected infants with hypoxic-ischemic encephalopathy. However, the cooling methods used required repeated interventions and were either expensive or reported significant temperature variation. The objective of this pilot study was to describe the use, efficacy, and physiologic impact of an inexpensive servo-controlled cooling fan blowing room-temperature air. PATIENTS AND METHODS: A servo-controlled fan was manufactured and used to cool 10 infants with hypoxic-ischemic encephalopathy to a rectal temperature of 33 degrees C to 34 degrees C. The infants were sedated with phenobarbital, but clonidine was administered to some infants if shivering or discomfort occurred. A servo-controlled radiant warmer was used simultaneously with the fan to prevent overcooling. The settings used on the fan and radiant warmer differed slightly between some infants as the technique evolved. RESULTS: A rectal temperature of 34 degrees C was achieved in a median time of 58 minutes. Overcooling did not occur, and the mean temperature during cooling was 33.6 degrees C +/- 0.2 degrees C. Inspired oxygen requirements increased in 6 infants, and 5 infants required inotropic support during cooling, but this was progressively reduced after 1 to 2 days. Dehydration did not occur. Five infants shivered when faster fan speeds were used, but 4 of the 5 infants had hypomagnesemia. Shivering was controlled with clonidine in 4 infants, but 1 infant required morphine. CONCLUSIONS: Servo-controlled fan cooling with room-temperature air, combined with servo-controlled radiant warming, was an effective, simple, and safe method of inducing and maintaining rectal temperatures of 33 degrees C to 34 degrees C in sedated infants with hypoxic-ischemic encephalopathy. After induction of hypothermia, a low fan speed facilitated accurate temperature control, and warmer-controlled rewarming at 0.2 degrees C increments every 30 minutes resulted in more appropriate rewarming than when 0.5 degrees C increments every hour were used.

Avaliação da Densidade dos anestésicos locais e da combinação com adjuvantes: estudo em laboratório / Assessment of the densities of local anesthetics and their combination with adjuvants: an experimental study / Evaluación de la densidad de los anestésicos locales y de la combinación con adyuvantes: estudio en laboratorio

JUSTIFICATIVA E OBJETIVOS: Uma das mais importantes propriedades físicas que afetam o nível da analgesia obtida após a injeção subaracnoidea de um anestésico local é sua densidade relativa à densidade do líquido cefalorraquidiano (LCR) a 37ºC. O objetivo deste trabalho foi determinar a densidade das soluções de anestésicos locais com e sem glicose e a combinação de anestésico local com adjuvantes a 20ºC, 25ºC e 37ºC em avaliação laboratorial. MÉTODO: A densidade (g.mL-1) foi medida como auxílio de um densímetro DMA 450, sensível a ± 0,00001 g.mL-1. A densidade e suas variações com a temperatura foram obtidas de todos os anestésicos locais e suas combinações com opioides a 20ºC, 25ºC e 37ºC. A solução é hiperbárica se sua densidade excede a 1,00099, a solução é hipobárica quando a densidade está abaixo de 1,00019 e é isobárica quando a densidade é maior que 1,00019 e menor que 1,00099. RESULTADOS: Ambos, anestésicos locais e adjuvantes, exibem diminuição da densidade quando se aumenta a temperatura. A 37ºC, todas as soluções que contêm glicose são hiperbáricas. Na ausência de glicose, todas as soluções são hipobáricas. A 37ºC, morfina, fentanil, sufentanil e clonidina são hipobáricas. CONCLUSÕES: A densidade dos anestésicos locais e adjuvantes diminui com o aumento da temperatura e aumenta com a adição de glicose. O conhecimento da baricidade, densidade relativa, ajuda na seleção do anestésico local mais adequado e dos adjuvantes para uso subaracnoideo.

BACKGROUND AND OBJECTIVES: The relative density of a local anesthetic in relation to that of the cerebrospinal fluid (CSF) at 37º C is one of the most important physical properties that affect the level of analgesia obtained after the subarachnoid administration of the drug. The objective of this study was to determine the density of local anesthetic solutions, with and without glucose, and the combination of the local anesthetic with adjuvants at 20º C, 25º C, and 37º C. METHODS: The density (g.mL-1) was determined by using a DMA 450 densimeter with a sensitivity of ± 0.00001 g.mL-1. The densities, and variations, according to the temperature were obtained for all local anesthetics and their combination with opioids at 20ºC, 25ºC, and 37ºC. The solution is hyperbaric if its density exceeds 1.00099, hypobaric when its density is lower than 1.00019, and isobaric when its density is greater than 1.00019 and lower than 1.00099. RESULTS: The densities of both local anesthetics and adjuvants decrease with the increase in temperature. At 37º C, all glucose-containing solutions are hyperbaric. In the absence of glucose, all solutions are hypobaric. At 37ºC, morphine, fentanyl, sufentanil, and clonidine are hypobaric. CONCLUSIONS: The densities of local anesthetics and adjuvants decrease with the increase in temperature and increase when glucose is added. The knowledge of the relative density helps select the most adequate local anesthetic to be administered in the subarachnoid space.

JUSTIFICATIVA Y OBJETIVOS: Una de las más importantes propiedades físicas que afectan el nivel de la analgesia obtenida después de la inyección subaracnoidea de un anestésico local, es su densidad relativa a la densidad del líquido cefalorraquídeo (LCR) a 37ºC. El objetivo de este trabajo fue determinar la densidad de las soluciones de anestésicos locales con y sin glucosa y la combinación de anestésico local con adyuvantes a 20ºC, 25ºC y 37ºC en evaluación laboratorial. MÉTODO: La densidad (g.mL-1) se midió con la ayuda de un densímetro DMA 450 sensible a ± 0.00001 g.mL-1. La densidad y sus variaciones con la temperatura se obtuvieron de todos los anestésicos locales y de sus combinaciones con opioides a 20ºC, 25ºC y 37ºC. La solución es hiperbárica si su densidad excede a 1.00099, la solución es hipobárica cuando la densidad está por debajo de 1,00019 y es isobárica cuando la densidad es mayor que 0,00019 y menor que 1,00099. RESULTADOS: Ambos anestésicos locales y los adyuvantes, arrojan una reducción de la densidad cuando se aumenta la temperatura. A 37ºC, todas las soluciones que contienen glucosa son hiperbáricas. Con la falta de glucosa, todas las soluciones son hipobáricas. A 37ºC, morfina, fentanil, sufentanil y clonidina son hipobáricas. CONCLUSIONES: La densidad de los anestésicos locales y adyuvantes se reduce con el aumento de la temperatura y aumenta con la adición de glucosa. El conocimiento de la baricidad, densidad relativa, ayuda a la selección del anestésico local más adecuado y de los adyuvantes para uso subaracnoideo.

Randomised controlled study-efficacy of clonidine versus carbamazepine in children with ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorder with a prevalence of 8-12%. Even though psychostimulants remain the treatment of choice, its cost and availability in developing countries limits the usage of the drug. In view of free availability and low cost, a Randomized controlled study was carried out using two second line drugs (clonidine and carbamazepine) in a tertiary care hospital, Pondicherry, South India. OBJECTIVE: To compare the efficacy of clonidine and carbamazepine in children with ADHD. METHOD: With approval of ethics committee, a prospective, Double-blind, Randomized controlled study of clonidine and carbamazepine was conducted with 50 children with ADHD (age group 4-12 years), over a period of 2 years (2005-07) in a tertiary care hospital, Pondicherry, South India. RESULTS: Clonidine was effective in improving the hyperactivity and impulsivity symptoms in children with ADHD as compared to carbamazepine. Statistical significant improvement was not noted with respect to inattention symptoms and other comorbid conditions. CONCLUSION: Clonidine can be a safer and cheaper alternative in treatment of children with ADHD, with a predominant effect on their hyperactivity and impulsivity symptoms.

An optimised methodology for the neurobehavioural assessment in rodents.

INTRODUCTION: The most widely used test to identify undesired effects of drugs on the central and the peripheral nervous system is the neurobehavioural observation battery adapted from that first described by Irwin in mice. As a neurobehavioural assessment is based on observations; thus, all factors involved need to be controlled and standardised to make the data collected objective, reproducible, reliable and predictive of safety liabilities. METHODS: An observation battery comprising 58 signs with assigned full details of numerical scores was defined, and a standard design with associated recording, presenting and analysing data system was established. Validation studies were conducted with chlorpromazine, amphetamine, diazepam or clonidine given orally to rats or mice, in order to assess if this methodology could clearly differentiate the profile of effects produced by these compounds. The analysis of data from 80 control rats allowed for the assessment of the normal behaviour in order to characterise the inter-individual, daytime-related variability and the habituation of animals to the procedure. RESULTS: The reference compounds induced their typical and expected transient effects on neurobehaviour, observed both in the home cage and open-arena, and on body temperature. In particular, amphetamine induced a stimulation of the nervous system activities and marked hyperthermia. Chlorpromazine, diazepam and clonidine induced depressive, anxiolytic or sedative effects associated with hypothermia. The analysis of data collected in control animals allowed for the identification of 6 signs which scored differently from the assigned normality at the first handling occasion due to the characteristic fear reactions to the unknown, and 9 signs at 8 h post-dose due to the animal's habituation to experimental conditions and handling. DISCUSSION: The neurobehavioural changes expected by reference compounds administration were detected. These results confirm that by using this methodology the normal behaviour of the rat and the mouse, the daytime-related variability and the habituation of animals can be characterised, allowing a refined, reliable and reproducible neurobehavioural assessment of test substances in rodents.

Assessment of clonidine orally disintegrating tablet for pre-anesthetic medication in pediatric surgery.

The purpose of this study is to assess orally-disintegrating (OD) tablet of clonidine hydrochloride (CL) for a pre-operative sedation in pediatric surgery. Sedation score and plasma CL concentration of OD formulation was compared with original preparation, CL lollipop, in pediatric patients. Fourteen patients (age: 3.9+/-2.3 years, weight: 16.9+/-5.0 kg) for OD group and 9 patients (age: 4.4+/-3.1 years, weight: 17.2+/-7.0 kg) for lollipop group received 4 microg/kg of CL preparation. Pre-operative sedation was evaluated by 5-point scoring systems at entering the operating room. Plasma CL concentrations were determined 120 min after administration of CL preparation. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were also assessed before and after administration of CL preparation. Every patient in OD group had satisfactory sedation (sedation score: 2 and 3), whereas, 3 (33%) in lollipop group had unsatisfactory sedation (sedation score: 0 and 1). Plasma CL concentration in OD group was significantly higher than those in lollipop group (0.75+/-0.15 vs. 0.42+/-0.21 ng/ml, p<0.01). There was no significant difference in hemodynamic parameters (SBP, DBP and HR) between before and after administration of CL preparation in both OD and lollipop group. We conclude that OD is superior preparation of CL for pre-operative sedation in pediatric surgery.

Transdermal clonidine: therapeutic considerations.

Transdermal clonidine was approved by the US Food and Drug Administration in 1984 for the treatment of mild-to-moderate hypertension alone or in combination with a diuretic. Clonidine is released from the patch at a constant rate and thus displays a pharmacokinetic pattern not dissimilar to that of infusion therapy. Transdermal clonidine, like oral clonidine, is effective first- or second-line therapy for most forms of hypertension. More recently, transdermal clonidine has found alternative uses in the areas of smoking cessation, posttraumatic stress disorder, menopausal hot flashes, and alcohol and opiate withdrawal syndromes. The not infrequent development of a dermatitis, together with a substantially greater cost than oral clonidine, have been the major undoings for transdermal clonidine.

Comparative assessment of the effects of alfentanil, esmolol or clonidine when used as adjuvants during induction of general anaesthesia.

BACKGROUND AND OBJECTIVE: This randomized, double-blinded, prospective study compared the effects of clonidine, esmolol or alfentanil on the level of hypnosis and haemodynamic responses to intravenous induction of anaesthesia and endotracheal intubation. METHODS: Forty-five patients scheduled for elective surgery were allotted to one of three groups. They were given either alfentanil 3 microg kg(-1) min(-1) (n = 15); esmolol 1 mg kg(-1) min(-1) (n = 16) or clonidine 3 microg kg(-1) (n = 14) as a 10 min infusion. The infusions of alfentanil and esmolol, but not of clonidine, were maintained during endotracheal intubation. Anaesthesia was induced with midazolam (2 mg) and thiopental as required to suppress the eyelash reflex. Atracurium (0.5 mg kg(-1)) was given to produce neuromuscular block. Mean arterial pressure, heart rate, and bispectral index were recorded on arrival (baseline), after study drug infusion, after injecting midazolam and thiopental, as well as after endotracheal intubation. ANOVA and chi2-test were used for analysis. RESULTS: Blood pressure, heart rate and the bispectral index were unaltered by the study drugs, but thiopental requirements were reduced by alfentanil and clonidine (P < 0.014). Mean arterial pressure values (mean +/- standard error of mean) in the alfentanil, esmolol and clonidine groups were: baseline: 107.8 +/- 3.8; 106.6 +/- 3.9; 103.4 +/- 3.7 mmHg; after thiopental: 74.0 +/- 4.2; 85.6 +/- 4.3; 94.2 +/- 4.1 mmHg and after endotracheal intubation: 91.7 +/- 5.3; 114.1 +/- 6.9; 123.6 +/- 5.6 mmHg, respectively (two-way ANOVA, P < 0.001). Mean arterial pressure changed significantly after intubation from baseline (P < 0.001) after alfentanil (-15%) and clonidine (+20%) but not after esmolol (+7%), while the changes between pre- and postintubation values were similar in all groups (24-33% increase). The bispectral index indicated that all patients had an adequate level of hypnosis, but the variability was higher in the esmolol group (P < 0.002). CONCLUSIONS: None of the study drugs blocked the increase in mean arterial pressure induced by endotracheal intubation, but esmolol provided better overall haemodynamic stability. All groups had an adequate level of hypnosis.

Predicting completion of outpatient opioid detoxification with clonidine.

Completion rates for outpatient opioid detoxification with clonidine generally range from 20-40%, but few studies have examined the correlates of successful completion. Of 29 consecutive patients, we compared those who completed detoxification with clonidine (n=12) to those who did not (n=17). Patients who completed treatment were significantly (p< 0.05) more likely to depend on opioids other than heroin, have private health insurance, and report low levels of subjective withdrawal symptoms. Patients with two or three of these characteristics were about seven times more likely to complete treatment than patients with none or one. Although it may not detoxify most opioid-dependent patients, clonidine will likely play a continued role in selected patients when a non-narcotic agent is desirable. The study findings may help target patients who could benefit the most from outpatient clonidine detoxification.

Clinical assessment of clonidine in the treatment of new-onset rapid atrial fibrillation: a prospective, randomized clinical trial.

PURPOSE: The role of digoxin and verapamil in the control of ventricular response in rapid atrial fibrillation is well established. This study investigates how clonidine compares with these standard therapies in rate control for new-onset rapid atrial fibrillation. We set out to test the hypothesis that clonidine effectively reduces heart rate in patients with new-onset rapid atrial fibrillation. SUBJECTS AND METHODS: Forty patients were seen in the emergency department with new-onset (< or =24 hours' duration), stable, rapid atrial fibrillation. Eligible patients were randomized to receive either clonidine, digoxin, or verapamil. Changes in heart rate and blood pressure over 6 hours, as well as frequency of conversion to sinus rhythm were recorded and analyzed. RESULTS: The mean reduction in heart rate over 6 hours was 44.4 beats/min (95% confidence interval [CI] 28.4-60.4 beats/min) in the clonidine group, 52.1 beats/min (95% CI 40.8-63.4 beats/min) in the digoxin group, and 41.8 beats/min (95% CI 22.5-61.0 beats/min) in the verapamil group. Analysis of variance of the heart rate changes in the 3 groups after 6 hours was not significant (P =.55). At 6 hours, 7 of 12 clonidine patients, 8 of 15 digoxin patients, and 7 of 13 verapamil patients remained in atrial fibrillation (P =.962 on chi(2)). CONCLUSION: Clonidine controls ventricular rate in new-onset atrial fibrillation with an efficacy comparable to that of standard agents.