[HTA and non-hormonal menopause treatment]. / HTA et traitements non-hormonaux de la ménopause.

Serotonin reuptake inhibitors, clonidine, gabapentin and pregabalin have shown moderate efficacy in menopausal disorders. The effect of phytoestrogens is reported to be modest, but the side effects are not well known.

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.

Aggregometric assessment of clonidine's impact on the efficacy of dual platelet inhibition.

BACKGROUND: Clonidine is commonly used as a calmative and antihypertensive agent in perioperative care. Due to the drug's alpha-2-agonistic effects, it has recently been hypothesised that clonidine may affect platelet aggregability. The present investigation aimed to study the potential impact of clonidine on the efficacy of dual antiplatelet therapy. METHODS: In this prospective, observational, single-centre study, patients treated with dual antiplatelet therapy were screened for eligibility. The patients were enrolled in the study if ex vivo thrombin-induced (TRAPtest), arachidonic acid-induced (ASPItest) and adenosine diphosphate-induced (ADPtest) platelet aggregation, as measured using multiple electrode aggregometry (MEA; Multiplate, Roche AG, Grenzach, Germany), confirmed efficient dual platelet inhibition. Ex vivo induced platelet aggregation was assessed before (baseline) and 3 minutes after (T1) spiking blood samples with either 1 ng/mL clonidine or sodium chloride 0.9% (control group). RESULTS: In total, 34 patients were finally enrolled in the study. Compared with baseline, platelet aggregation in the ASPItest and ADPtest was significantly increased at T1 in both groups. Platelet aggregation in the TRAPtest remained unchanged between baseline and T1 in both groups. Comparing platelet aggregation at T1, we detected no differences between blood samples that were spiked with clonidine and blood samples that were spiked with sodium chloride 0.9% in the TRAPtest, the ASPItest, or the ADPtest. CONCLUSIONS: The results of this study indicate that clonidine does not affect platelet aggregability in patients treated with dual antiplatelet therapy. The findings of the study also indicate that ex vivo induced platelet aggregation in the ASPItest and ADPtest increases with the duration between blood drawing and MEA analyses.

Eficacia y seguridad del uso de medicamentos para la cesación de la adicción al tabaco: revisión de guías de práctica clínica / Efficacy and safety of medication use for the cessation of tobacco addiction: Are view of Clinical Practice Guidelines

Objetivo Revisar la eficacia y seguridad de medicamentos para cesación del tabaquismo en el contexto de construcción de guías de práctica clínica (GPC). Métodos Revisión sistemática de GPC para adaptación mediante ADAPTE. Los desenlaces fueron cesación ≥6 meses y seguridad de las intervenciones. Las GPC se calificaron por pares con DELBI. Se extrajeron resultados de estudios agregativos incluidos en las guías seleccionadas. Resultados Los fármacos duplican la cesación comparados con placebo (tasas de 25,0 % hasta 27,0 % al combinarse con consejería). Los mayores incrementos en cesación se obtienen con ansiolíticos y antidepresivos (8,7% a 19,4%), y los menores con terapia de reemplazo nicotínico -TRN- (5,2% a 12,9%). La nortriptilina tiene eficacia similar al bupropion (aproximadamente 10,0 %). Con limitadas excepciones (parche e inhalador, tabletas y bupropion), las combinaciones de medicamentos no incrementan la abstinencia. Conclusiones TRN, vareniclina, bupropion y nortriptilina son eficaces para dejar de fumar. Las combinaciones de medicamentos requieren más evidencia y deberían restringirse a personas con alta dependencia o con falla terapéutica inicial. Serían deseables análisis de costo-efectividad para valorar implementación de programas en países en desarrollo.

Objective To review the efficacy and safety of pharmacotherapy for smoking cessation in the context of clinical practice guidelines (CPG). Methods A systematic review of CPGs was conducted, aimed at adapting recommendations for Colombia following the ADAPTE methodology. Outcomes comprised 6-months or higher smoking cessation rates and intervention safety. CPGs were peer-assessed based on DELBI. Results from aggregative studies included in selected CPGs were obtained. Results Pharmacotherapy doubles smoking cessation rates as compared with placebos (rates @25% and up to 27 % when combined with counseling). The highest efficacy was observed for ansyolitic and antidepressive drugs (8.7 % to 19.4 %), and the lowest for nicotine replacement therapy -NRT- (5.2 % to 12.9 %). Nortriptiline shows an efficacy similar to that of bupropion (@10%). With limited exceptions, combined pharmacotherapy for smoking cessation has shown no significant increase in cessation rates. Conclusions NRT, varenicline, bupropion and nortriptiline are effective treatments for smoking cessation. Combination of drugs deserves further clinical evidence and should be restricted to highly dependent smokers or initial therapeutic failure. Cost-effectiveness analyses might help to introduce smoking cessation programs in low and middle income countries.

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.

[Efficacy and safety of medication use for the cessation of tobacco addiction: A review of Clinical Practice Guidelines]. / Eficacia y seguridad del uso de medicamentos para la cesación de la adicción al tabaco: revisión de guías de práctica clínica.

OBJECTIVE: To review the efficacy and safety of pharmacotherapy for smoking cessation in the context of clinical practice guidelines (CPG). METHODS: A systematic review of CPGs was conducted, aimed at adapting recommendations for Colombia following the ADAPTE methodology. Outcomes comprised 6-months or higher smoking cessation rates and intervention safety. CPGs were peer-assessed based on DELBI. Results from aggregative studies included in selected CPGs were obtained. RESULTS: Pharmacotherapy doubles smoking cessation rates as compared with placebos (rates @25% and up to 27 % when combined with counseling). The highest efficacy was observed for ansyolitic and antidepressive drugs (8.7 % to 19.4 %), and the lowest for nicotine replacement therapy -NRT- (5.2 % to 12.9 %). Nortriptiline shows an efficacy similar to that of bupropion (@10%). With limited exceptions, combined pharmacotherapy for smoking cessation has shown no significant increase in cessation rates. CONCLUSIONS: NRT, varenicline, bupropion and nortriptiline are effective treatments for smoking cessation. Combination of drugs deserves further clinical evidence and should be restricted to highly dependent smokers or initial therapeutic failure. Cost-effectiveness analyses might help to introduce smoking cessation programs in low and middle income countries.

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.

Pediatric safety of tizanidine: clinical adverse event database and retrospective chart assessment.

BACKGROUND: Tizanidine is an imidazoline with central alpha(2)-adrenoceptor agonist activity at both spinal and supraspinal levels, which is indicated as a short-acting drug for the management of spasticity. Despite being used in pediatric populations, there is no adequate information or well controlled studies to document the safety and efficacy of tizanidine in this group. OBJECTIVE: To evaluate the safety of tizanidine in the pediatric population. We compared spontaneous adverse event reports in the Acorda Therapeutics worldwide clinical adverse event database for children (< or = 16 years; n = 99) and adults (>16 years; n = 1153) who had received tizanidine and for whom at least one adverse event was reported, and performed a retrospective chart review of the safety of tizanidine in children (< or = 16 years; n = 76) at a large US pediatric neurology practice. Causality of adverse events in our worldwide clinical adverse event database were neither assessed nor assigned by the company. RESULTS: When adverse events from the clinical adverse event database were collapsed into the 25 Medical Dictionary for Regulatory Activities (MedDRA; version 9.0) organ system classes, five classes were more frequent in adults (general disorders and administration site conditions [p = 0.0006], hepatobiliary disorders [p = 0.0031], nervous system disorders [p = 0.0108], skin and subcutaneous disorders [p = 0.0063], and vascular disorders [p = 0.0029]), while one class was more frequent in children (psychiatric disorders [p < 0.0001]). The most common adverse event classes in children were psychiatric disorders (52.5%) followed by nervous system disorders (29.3%), and gastrointestinal disorders (16.2%), whereas the most common adverse event classes in adults were nervous system disorders (42.4%), general disorders and administration site conditions (28.6%), and gastrointestinal disorders (21.3%). Serious adverse events were substantially less frequent in children than adults (19.2% vs 45.9%) in the clinical adverse event database. In the pediatric practice chart review, the incidence of adverse events in the MedDRA psychiatric disorders class was very similar (52.6%) to that for children in the clinical adverse event database, while the next most common classes were gastrointestinal disorders (14.5%), and nervous system disorders (13.2%). There were three deaths in children across the databases, including one from accidental exposure and two from cardiac events; the relationship of cardiac events in relation to tizanidine or other causes was difficult to assess with the limited available information.The major causes of death in adults were related to suicide or overdose. Minor, transient liver transaminase increases were occasionally reported; the effect of tizanidine could not be ruled out. CONCLUSION: The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.

Assessment of efficacy and psychomotor performances of thiocolchicoside and tizanidine in patients with acute low back pain.

Objectives of this study were to assess efficacy and effects on psychomotor performances of thiocolchicoside (TCC) and tizanidine (TZ) compared to placebo. Patients complaining of acute low back pain (LBP) associated with muscle spasm were enrolled in this randomised, double-blind clinical trial, comparing the effects of oral TCC, TZ and placebo on psychomotor performances assessed by a visual analogue scale of tiredness, drowsiness, dizziness and alertness and by psychometric tests after 2 and 5-7 days of treatment. The efficacy assessments, both TCC and TZ, were more effective than placebo in improving pain at rest, hand-to-floor distance, Schober test and decreased paracetamol consumption. There were significant differences among the treatment groups in favour of TCC compared to TZ in visual analog scale-parameters. TZ-induced reduction of psychomotor performances of the patients was confirmed by psychometric tests, which showed significant differences among groups. This study showed that TCC is at least as effective as TZ in the treatment of acute LBP, while it appears devoid of any sedative effect in contrast to TZ.

The quest for biological correlates of social phobia: an interim assessment.

OBJECTIVE: The primary goal of this review was to assess critically the literature concerning the ongoing search for possible biological correlates of social phobia. METHODS: In addition to manual searches, Medline, Current Contents and Psych Info databases were searched for relevant publications. RESULTS: On the evidence of an extensive body of research, so far biological correlates of social phobia remain elusive. Furthermore, the majority of studies reveal by default that the neurobiological functioning of social phobics is very much like that of normal control subjects. CONCLUSION: The conceptual and methodological foundations underpinning the current research programme are discussed critically. Its main weaknesses were found to be: lack of theory to guide research and aid the interpretation of results, static comparisons between subject groups and analysis oblivious to great individual variations. Possibilities of alternative approaches to study the neurobiology of social phobia are raised. Among others, continuous and situation-specific measurement, subjects used as their own controls and neurobiological correlates of clinical improvement following psychotherapy are considered.

Tourette's syndrome, Part II: Contemporary approaches to assessment and treatment.

Clinical assessment of a child with Tourette's syndrome (TS) includes a careful review of motor and phonic tics. In addition, commonly associated problems of such as obsessive-compulsive symptoms, or symptoms of attention deficit hyperactivity disorder (inattention, impulsiveness, and overactivity) should also be evaluated. Treatment almost always includes education of the child, family, and school personnel concerning the natural history and behavioral boundaries of the disorder. Other treatment interventions depend to a great extent on the primary source of impairment. This article, the second of two parts, presents three illustrative cases and reviews current treatment interventions for children and adolescents with TS.