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Background: This analysis is a systematic literature review assessing efficacy and adverse effects of three alpha-2 agonists for the symptomatic management of autism spectrum disorder (ASD)., Methods: The present investigation involved an extensive systematic search for eligible studies in PubMed, Embase, Cochrane Library, and Google Scholar. Nine studies, collectively incorporating 226 patients, were assessed., Results: The results demonstrated promising indications for use of alpha-2 agonists in the symptomatic management of autism spectrum disorders, including improvement of hyperactivity, impulsivity, attention deficit symptoms, irritability, and stereotypies in many of the participants studied., Conclusion: The present investigation encourages physicians to consider treatment outcomes of clonidine, guanfacine, and lofexidine to determine the most effective management of ASD-related symptoms and to minimize adverse effects. However, our review cannot provide definitive treatment protocols related to various study limitations., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: Local infiltration analgesia is commonly used for postoperative pain control after several surgical procedures including intra- and peri-articular as well as wound infiltration. Even though, various adjuvants injected with the local anesthetic have been studied in pairwise comparison or compared to peripheral nerve blocks, the question which adjuvant or combination of adjuvants is the most effective in prolonging the duration of different types of local infiltration analgesia (LIA) has not been answered conclusively., Objective: The objective of this network meta-analysis was to determine the analgesic effectiveness and safety of adjuvants in local infiltration analgesia., Design: Systematic review of randomized controlled trials with network meta-analyses., Data Sources: A comprehensive literature search in Embase, CENTRAL, MEDLINE and Web of Science was performed up to March 2023., Results: The best interventions to prolong the duration of analgesia were dexamethasone (Ratio of Means (ROM) 3.33) followed by the combinations of clonidine + morphine (ROM 3.35) and morphine + magnesium sulfate (ROM 2.92), fentanyl (ROM 2.27), ketorolac (ROM 2.26), buprenorphine (ROM 2.04), morphine (ROM 1.93), magnesium sulfate (ROM 1.91), clonidine (ROM 1.89), dexmedetomidine (ROM 1.74) and tramadol (ROM 1.58). Serious adverse events were not reported with either investigated adjuvant., Conclusion: There is moderate evidence that dexamethasone is the most effective adjuvant to prolong the duration of analgesia in LIA. The evidence for the alpha-2 agonists dexmedetomidine and clonidine is also moderate, but their effectivity to prolong analgesia stays behind dexamethasone. Clonidine and dexmedetomidine had a small detectable effect on pain scores, yet below clinical relevance, but the largest effect on MEQ consumption. The effects of different opioids were homogenous for all endpoints. The prespecified subgroup analysis of LIA of the knee did not show significantly different results than the pooled analysis., Study Registration: PROSPERO 2020 CRD42020176154 (28.04.2020)., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This review highlights adverse effects of baclofen and tizanidine in older community-dwelling adults., Data Sources: A literature search was conducted, including search terms of "adverse effect," "baclofen," "elderly," "falls," "fractures," and "tizanidine." Studies were included if they described community-dwelling adults aged 50 years and older who received oral baclofen or tizanidine. The Federal Drug Administration Adverse Event Reporting System (FAERS) data were compiled for adverse effect incidence., Study Selection and Data Extraction: The literature search was completed in July 2019 and updated in June 2023. Reviews performed by 2 independent reviewers yielded 15 records. FAERS identified 486 (baclofen) and 305 (tizanidine) adverse effects of interest., Data Synthesis: Two retrospective cohort studies evaluating baclofen use in older adults showed increased hospitalizations for encephalopathy in chronic kidney disease (7.2% vs 0.1%) and end-stage renal disease (daily dose 20 mg or more; relative risk [RR] 19.8, 95% CI = [14.0-28.0]). Other articles were case reports; 10 articles reported dyskinesias, encephalopathy or disorientation, and drowsiness associated with baclofen, and 5 articles reported bradycardia and/or hypotension with tizanidine. The FAERS Public Dashboard revealed 12.1% and 28.7% overall incidence of adverse effects of interest, with a 27.8% and 29.2% incidence of falls for baclofen and tizanidine, respectively. Baclofen and tizanidine are associated with concerning adverse effects in older adults. Alternative agents should be considered, but, if necessary, providers should start at lower doses and increase slowly., Conclusions: This review highlights the importance of using baclofen and tizanidine with caution in older adults., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Clonidine is an α-adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction in sympathetic outflow and release of certain neurotransmitters. Clonidine has multiple uses across various medical conditions. One of its uses is as adjuvant to anaesthetic and analgesic agents specially opioids, mostly administered through intravenous and epidural routes. The opioids, effective in cancer pain management, are associated with various side effects such as sedation, pruritus, constipation, nausea, respiratory depression, tolerance and dependence. Combination of clonidine with opioids seems to help to achieve better pain management and less need of opioids. Use of clonidine in palliative care has been less common, but it is gradually gaining recognition for its potential benefits in managing symptoms like cancer pain and agitation. This combination approach has been explored in palliative care settings, including cancer pain and agitation, where patients experience complex and refractory symptoms. It seems to be well tolerated and gives better symptom relief. The available literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated. Therefore, the optimal dosing, safety profile and overall effectiveness of subcutaneous clonidine requires further exploration through prospective research studies., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Objectives: To investigate the efficacy and safety of subcutaneous clonidine for refractory symptoms in the palliative setting., Methods: A retrospective chart review of the use of subcutaneous clonidine in a single palliative care centre. We reviewed the use of clonidine since it was introduced in our locality 2½ years ago. All clinical notes, medication administration records and infusion monitoring documentation were examined to ascertain therapeutic aim, efficacy and tolerability., Results: Subcutaneous clonidine was administered to 113 patients. Recipients were generally frail (median Karnofsky Score 20%) and in the last weeks of life (median survival 6 days). The the most common indications were opioid poorly responsive pain (59), agitation refractory to antipsychotics and/or benzodiazepines (18) or both (35). Symptoms appeared to improve in the majority (85/113, 75%). Some (36, 32%) required no further medication changes once clonidine was commenced. Clonidine appeared well tolerated although blood pressure was not monitored in the majority, in line with our practice to discontinue such observations in those who are nursed in bed and receiving symptom-focused care., Conclusions: Subcutaneous administration of clonidine appears to be a promising alternative option for refractory symptoms in the last weeks of life. We suggest some possible next steps for further research., Competing Interests: Competing interests: PH is an editor for the neuropharmacology sections of the Palliative Care Formulary, and has contributed to updating the clonidine monograph., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Impulse control disorders (ICDs) are frequently encountered in Parkinson's disease (PD)., Objectives: We aimed to assess whether clonidine, an α2-adrenergic receptor agonist, would improve ICDs., Methods: We conducted a multicentre trial in five movement disorder departments. Patients with PD and ICDs (n = 41) were enrolled in an 8-week, randomised (1:1), double-blind, placebo-controlled study of clonidine (75 μg twice a day). Randomisation and allocation to the trial group were carried out by a central computer system. The primary outcome was the change at 8 weeks in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) score. A reduction of the most elevated subscore of the QUIP-RS of more than 3 points without any increase in the other QUIP-RS dimension defined success., Results: Between 15 May 2019 and 10 September 2021, 19 patients in the clonidine group and 20 patients in the placebo group were enrolled. The proportion difference of success in reducing QUIP-RS at 8 weeks, was 7% (one-sided upper 90% CI 27%) with 42.1% of success in the clonidine group and 35.0% in the placebo group. Compared to patients in the placebo group, patients in the clonidine group experienced a greater reduction in the total QUIP-RS score at 8 weeks (11.0 points vs. 3.6)., Discussion: Clonidine was well tolerated but our study was not enough powerful to demonstrate significant superiority compared to placebo in reducing ICDs despite a greater reduction of total QUIP score at 8 weeks. A phase 3 study should be conducted., Trial Registration: The study was registered (NCT03552068) on clinicaltrials.gov on June 11, 2018., (© 2023. The Author(s).)

Background: Epidural clonidine improves analgesia but may induce adverse effects in labor., Objective: To evaluate the efficacy and safety of epidural clonidine as local anesthetics (LA) adjuvant by continuous infusion or patient-controlled epidural analgesia (PCEA) in labor., Search Strategy: PubMed, Embase, Web of Science, and CENTRAL were searched from inception to May 10, 2022 without language restriction; references of the retrieved studies were hand searched., Selection Criteria: Randomized controlled trials (RCTs) comparing epidural LA with and without clonidine using continuous infusion or PCEA in labor were included., Data Collection and Analysis: A random effects model was used to pool the data on analgesia and adverse effects., Main Results: Eight RCTs were included. Clonidine did not reduce the incidence of parturients requiring additional epidural boluses but reduced LA consumption and pain scores without increasing adverse effects, except for a higher incidence of instrumental delivery when clonidine was combined with LA and opioid (risk ratio 2.38, 95% confidence interval 1.26-4.50). Clonidine offered similar analgesia to opioids but had reduced opioid-related adverse effects. Trial sequential analysis showed that the evidence was insufficient., Conclusions: Epidural clonidine by continuous infusion or PCEA does not increase significant adverse effects and offers similar analgesia to opioids in labor. PROSPERO registration no. CRD42022306565., (© 2022 International Federation of Gynecology and Obstetrics.)

We report a case of posterior reversible encephalopathy syndrome (PRES) during treatment for alcohol withdrawal syndrome with gabapentin and clonidine. The patient developed severe hypertension, confusion and tremor, culminating in bilateral vision loss and a seizure. Imaging revealed posterior cerebral edema. Treatment with benzodiazepines, antihypertensives, and anti-seizure medications led to resolution. One year later, imaging showed resolution of the findings. We review the associated literature and propose the recognition of a PRES sub-entity, Alcohol-Related PRES (ARPRES), which can appear in the setting of alcohol withdrawal syndrome, chronic alcohol use, and acute alcohol intoxication, with or without hypertension.

Clonidine and dexmedetomidine are two α2-adrenoreceptors agonists available for the intensivist in the clinical practice. The affinity of dexmedetomidine is eight times greater than clonidine affinity for the α2 receptors. Their main effect is sedation. They act by inhibition of noradrenaline release in the locus coeruleus in the brainstem. α2-agonists are used primarily for sedation, analgesia, and management of delirium. Nowadays, dexmedetomidine application is increasing in critically ill patients showing a good safety. Most frequent side effects include bradycardia and hypotension., Competing Interests: N. Ben-Hamouda a reçu des honoraires des laboratoires ORIONPHARMA pour une conférence (Congrès suisse de médecine intensive). Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: The current research was designed to assess the efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder., Patients and Methods: A total of 154 children with tic disorder co-morbid with attention deficit hyperactivity disorder admitted to our hospital from July 2019 to July 2022 were recruited and assigned to receive either methylphenidate hydrochloride plus haloperidol (observation group) or clonidine (experimental group), with 77 cases in each group. Outcome measures included clinical efficacy, Yale Global Tic Severity Scale (YGTSS) scores, Conners Parent Symptom Questionnaire (PSQ) scores, and adverse events., Results: Clonidine was associated with markedly higher clinical efficacy vs. methylphenidate hydrochloride plus haloperidol (p<0.05). Clonidine offered more significant mitigation of the tic disorder vs. methylphenidate hydrochloride plus haloperidol, as evinced by the lower kinetic tic scores, vocal tic scores, and total scores (p<0.05). Children exhibited markedly milder tic symptoms after clonidine monotherapy vs. those with dual therapy of methylphenidate hydrochloride and haloperidol, suggested by the lower scores of character problems, learning problems, psychosomatic disorders, hyperactivity/impulsivity, anxiety index, and hyperactivity index (p<0.05). Clonidine features a higher safety profile than methylphenidate hydrochloride plus haloperidol by reducing the incidence of adverse events (p<0.05)., Conclusions: Clonidine effectively alleviates tic symptoms, reduces attention deficit and hyperactivity/impulsivity in children with tic disorder co-morbid attention deficit hyperactivity disorder, and features a high safety profile.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Clonidine and quetiapine are frequently used medications in the cardiac surgery intensive care unit (ICU). Objective: The purpose of this study is to assess the impact of clonidine compared to quetiapine on cardiac safety outcomes in adult cardiac surgery ICU patients. Methods: This was a single-center, retrospective observational analysis at a tertiary care, academic medical center. Results: One hundred and sixty-one cardiac surgery patients who were administered clonidine or quetiapine during their ICU stay were included between June 2015 and May 2017. The major endpoint of this study was a cardiac safety composite of bradycardia, hypotension, and QTc prolongation. Minor endpoints included ICU and hospital length of stay, and in-hospital mortality. There were 115 patients included in the clonidine arm and 46 patients in the quetiapine arm. There was no difference between groups with regard to the major endpoint (30.43% vs 33.15%; P < .8). There was a shorter ICU and hospital length of stay in the clonidine arm compared to quetiapine P < .0001. All other endpoints were not statistically significant. Conclusion: Patients who received clonidine tended to have undergone less complex procedures, be younger, and have a lower APACHE II score than patients who received quetiapine. The incidence of composite cardiac safety outcomes was not different in clonidine compared to quetiapine in cardiac surgery ICU patients.

Background: Hair transplantation (HT) is a safe and rewarding procedure for a patient as well as the surgeon. Clonidine may be a good adjuvant in HT because of its analgesic, anxiolytic, and sedative effects., Objective: To study efficacy of Clonidine as a preoperative medication in HT., Methods & Materials: The study was a prospective trial of 46 consecutive patients who underwent HT between January and May 2017. Patients with normal vital parameters on arrival were given Tab clonidine (0.1 mg) 30 min before starting of the procedure [Clonidine group (n = 30)]; rest were included in the control group (n = 16). Vitals were monitored every 30 min during surgery until the end. Patients were assessed for pain, level of sedation during surgery and for postoperative analgesia., Result: All patients who received clonidine, except one, were comfortable and experienced no pain throughout the duration of surgery; nine went into deep sleep. Of the 16 patients in the control group, no patients reported deep sleep, 3 felt restless, and 4 had mild pain. There were no untoward effects in both groups., Conclusion: Our study suggests that clonidine is useful as a pre-anesthetic medication in HT. However, this is a pilot study and further larger studies are needed., (© 2022 Wiley Periodicals LLC.)

Background: Postoperative negative behavioral changes (NBCs) are common among children, but risk for this is thought to be reduced with premedication. Midazolam has for many years been a standard premedication for children. More recently, the alpha-2 adrenergic agonist clonidine has also become popular as a preanesthetic sedative. We hypothesized that clonidine was superior to midazolam for limiting new NBCs in children as assessed using the Post Hospital Behavior Questionnaire (PHBQ)., Methods: This was a prospective, randomized, controlled, blinded study, including 115 participants aged 24 to 95 months and their parents. The participants underwent ear, nose, or throat outpatient surgery and were randomly allocated to premedication with oral midazolam 0.5 mg/kg or oral clonidine 4 µg/kg. Participants were anesthetized by protocol. At home, later, parents were asked to complete the PHBQ assessment instrument for postoperative NBCs for the participants 1 week, 1 month, and 6 months after the surgery. A secondary outcome, preinduction anxiety, was assessed using modified Yale Preoperative Anxiety Scale (mYPAS)., Results: The primary outcome, more than 3 NBCs in an individual case at 1 week, showed no difference in proportions between treatment in the clonidine group compared to the midazolam group, (12/59 or 20% vs 7/56 or 13%, respectively, odds ratio 1.39, 95% confidence interval [CI], 0.75-2.58; P = .32). A secondary result showed a higher preinduction anxiety level in the clonidine compared to the midazolam group (mYPAS >30, 43/59 or 71% vs 12/56 or 21%, respectively; P < .001)., Conclusions: These results did not show a clinical or statistically significant difference, with respect to the primary outcome of behavior changes at 1 week, between the cohorts that received midazolam versus clonidine as a premedication., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Objective: Irukandji syndrome (IS) is an extremely painful condition that causes a significant catecholamine surge and sympathetic autonomic response related to the envenomation from certain types of jellyfish. Current management involves intravenous fluids, magnesium sulphate and large doses of opioids for symptom control. Clonidine, a centrally acting alpha-2 agonist, is often used as an analgesic adjunct to reduce opioid requirements in acute pain. The present study explores the safety and efficacy of clonidine in reducing opioid requirements in IS., Methods: All patients diagnosed with IS at Cairns Hospital between 1 March 2016 and 30 April 2020, and participants from the Magnesium in Irukandji Study Trial, were included in this retrospective study (n = 114). Cases were separated into two groups depending on whether or not they received clonidine, and subsequently analysed according to pre- and post-intervention opioid requirements, clonidine dose administered and adverse effects., Results: Notably, 39 patients with IS received ≥1 mcg/kg clonidine and the remaining 75 did not. There was no difference in oral morphine equivalent daily dose (oMEDD) between groups before clonidine administration; however, there was a significant reduction in oMEDD required after patients received clonidine (26.1 mg; 95% CI 4.6-47.7) compared with those who did not (66.6 mg; 95% CI 56.9-86.1) (F = 8.722, df = 1 × 224, P = 0.003). One episode of hypotension occurred following the intervention., Conclusion: Patients with IS who received clonidine required significantly lower opioid requirements than those who did not receive clonidine. Clonidine was safe to administer and should be considered early when treating IS. The optimal clonidine dose remains unclear and requires prospective studies to validate our findings., (© 2022 Australasian College for Emergency Medicine.)

Objective: This study aimed to assess the clonidine infusion rate in the first 6 h, as maintenance dose (first 24 h), and in the pre-extubation period (last 24 h), as well as the cumulative dose of other sedatives and the hemodynamic response., Methods: This is a retrospective cohort study., Results: Children up to the age of 2 years who were admitted to the pediatric intensive care unit of a tertiary referral hospital in the south region of Brazil, between January 2017 and December 2018, were submitted to mechanical ventilation, and received continuous clonidine infusions were included in the study. The initial, maintenance, and pre-extubation doses of clonidine; the vasoactive-inotropic score; heart rate; and systolic and diastolic blood pressure of the study participants were assessed. A total of 66 patients with a median age of 4 months who were receiving clonidine infusions were included. The main indications for mechanical ventilation were acute viral bronchiolitis (56%) and pneumonia associated with acute respiratory distress syndrome (15%). The median of clonidine infusion in the first 6 h (66 patients) was 0.53 μg/kg/h (IQR 0.49-0.88), followed by 0.85 μg/kg/h (IQR 0.53-1.03) during maintenance (57 patients) and 0.63 μg/kg/h (IQR 0.54-1.01) during extubation period (42 patients) (p=0.03). No differences were observed in the doses regarding the indication for mechanical ventilation. Clonidine infusion was not associated with hemodynamic changes and showed no differences when associated with adjuvants., Conclusion: Clonidine demonstrated to be a well-tolerated sedation option in pediatric patients submitted to mechanical ventilation, without relevant influence in hemodynamic variables.

Background: Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015., Objectives: The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain., Search Methods: For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021., Selection Criteria: We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain., Data Collection and Analysis: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model.  The review primary outcomes were: participant-reported pain relief of 50% or greater; participant-reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow-up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables., Main Results: We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double-blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double-blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant-reported pain relief of 30% or greater during longest follow-up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow-up period (12 weeks) or very much improved on PGIC during the longest follow-up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow-up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow-up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence).  TC compared to active comparator There was no evidence of a difference in the number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported., Authors' Conclusions: This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: There are limited and nonconcordant data on the rapidity and safety of blood pressure response to clonidine in the setting of asymptomatic severe hypertension. We evaluated the blood pressure response to clonidine in hospitalized patients with asymptomatic severe hypertension., Methods: We performed a review of hospitalized, noncritically ill patients receiving clonidine within 6 hours of developing asymptomatic severe hypertension (systolic blood pressure [SBP] >180 or diastolic blood pressure [DBP] >110 mm Hg in the absence of acute hypertension-mediated target organ damage). The incidence of mean arterial pressure (MAP) reduction by ≥30% at 4 hours after clonidine was the primary endpoint., Results: We identified 200 relevant patient encounters (median age 63 years, 48.5% women). Median time to clonidine following asymptomatic severe hypertension was 2.8 hours. A total of 20 (10%) patients had ≥30% MAP reduction within 4 hours after clonidine, and 32 (16%) patients had ≥30% reduction in either SBP, DBP, or MAP. Older age, female sex, and preexisting vascular disease were associated with ≥30% MAP reductions (P < 0.05). Only patient sex and clonidine dose of 0.3 mg were significant in multivariable models. There were 14 adverse events observed within 24 hours of administration of clonidine; most (9) were acute kidney injury. There were no ischemic (myocardial, cerebrovascular) events., Conclusions: A substantial minority of hospitalized patients with asymptomatic severe hypertension experience precipitous blood pressure decline with clonidine, and though blood pressure declines more precipitously in women and those receiving higher doses (0.3 mg specifically), the response to clonidine is generally not predictable on clinical grounds., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tizanidine's potent muscle relaxant properties and short onset of action makes it desirable for pain management. However, concomitant use of tizanidine with ciprofloxacin, a strong inhibitor of the P450-CYP1A2 cytochrome metabolic pathway of tizanidine, can result in increased tizanidine plasma levels and associated adverse outcomes, particularly hypotension. The aim of this study was to assess the risk of hypotension with coadministration of tizanidine and ciprofloxacin., Methods: An observational nested cohort study of patients 18 years or older on tizanidine was conducted using data from electronic health records from 2000 to 2018 in the US. We estimated the prevalence and risk of hypotension associated with the DDI between tizanidine and ciprofloxacin using multivariable logistic regression models., Results: Our analysis included 70,110 encounters of patients on tizanidine across 221 hospitals. Most encounters included females (65.7%), whites (82.4%), with an average age of 56 years (SD 14.9) and an Elixhauser comorbidity index mean of 1.6 (SD 2.3). Ciprofloxacin was co-administered with tizanidine in 2487 encounters (3.6%). Compared to patients who did not receive ciprofloxacin, co-administration of tizanidine and ciprofloxacin was associated with an increased likelihood of hypotension (adjusted odds ratio: 1.43, 95% Confidence Intervals:1.25-1.63, p-value<0.001)., Conclusions: Our findings suggest that the concomitant use of tizanidine and ciprofloxacin is associated with an elevated risk of hypotension. The prevalence of co-administration of drugs with a documented interaction highlights the need for continuous education across providers to avoid the incidence of DDI related adverse events and further complications and to improve patient outcomes., Competing Interests: Declaration of Competing Interest All the authors report no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective To describe the use of clonidine in hospitalized older people for acute management of hypertension. Methods This was an observational retrospective cross-sectional chart review study. Older people hospitalized between November 2017 and November 2018, with a one-time or as-needed clonidine order were eligible, and a random sample of these patients were included. Hospitalized patients could be admitted for hypertensive urgency or emergency, or for other reasons. Results During the 12-month study period, 546 charts were identified as having at least one clonidine prescription, 248 were screened and 205 were included. The mean age was 75 years of age ± 8 years of age and men made up 53% (n = 109) of the group. One hundred fifty-one patients (74%) received at least one dose of clonidine and the remaining patients has a clonidine prescription but did not reach the blood pressure threshold for clonidine administration. The mean number of doses per patient was 1.8 ± 2.0. Twenty-nine percent of clonidine doses were given when systolic and diastolic blood pressure was below 180 mmHg and 120 mmHg respectively. A total of 25 patients (17%) had a potential adverse reaction following clonidine administration. One patient had a stroke and two patients fell. Sixty-eight patients had evidence of target organ dysfunction related to hypertension prior to clonidine administration. Conclusions Clonidine remains widely prescribed in hospitalized older people. It is possibly due to its rapid onset and little need for dosing adjustment. Clinical interventions should be designed and implanted to reduce its prescription.

Background: Adequate sedation and analgesia are required for critically ill children in order to minimize discomfort, reduce anxiety, and facilitate care. This is commonly achieved through a combination of opioids and benzodiazepines. Prolonged use of these agents is associated with tolerance and withdrawal. Clonidine as an adjunctive sedative agent may reduce sedation-related adverse events., Objective: Our first aim was to describe the indication for clonidine administration and its secondary effects in a mixed cohort of critically ill children. Our secondary aim was to measure the consumption of sedatives during two study periods: before and after the use of clonidine in our pediatric intensive care unit (PICU)., Methods: This was a single-center study conducted in a tertiary PICU and encompassed retrospective chart review of patients who received clonidine between November 2013 and April 2015. We collected data on clonidine dosage, duration of administration, indication for the prescription, and potential side effects. We analyzed the total consumption of sedatives over 18 months, before and after the introduction of clonidine in our sedation protocol., Results: A total of patients received clonidine, with a mean age of 2.2 ± 2.8 years. The primary reason for intensive care admission was respiratory failure (48%). The main indication for clonidine administration was increasing requirement for morphine and midazolam (60%). The mean duration of clonidine infusion was 9 ± 7.3 days. Bradycardia and hypotension occurred in five patients (11.6%) and nine patients (21%), respectively. These side effects did not result in any major intervention. Younger age was a risk factor for clonidine-associated bradycardia. We observed a significant decrease in morphine and midazolam consumption with clonidine as a comedication. Compared with the pre-study period, consumption decreased by 19.7% for morphine and by 59% for midazolam (calculated as milligram/admission)., Conclusion: Continuous infusion of clonidine in critically ill children is safe and effective. Clonidine is a sedative-sparing agent and this can help reduce complications associated with prolonged use of opioids and benzodiazepines., Competing Interests: Declaration of Competing Interest The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

What Is Known and Objective: Limited data suggest clonidine may be useful for sedation and analgesia in critically ill patients. Our objectives were to describe clonidine dosing regimens used for sedation and analgesia in critically ill adults, the associated adverse effects (i.e., hypotension), and whether clonidine dose was associated with dosage reductions of traditional sedatives and analgesics., Methods: We conducted a retrospective cohort study of all critically ill adults who received enteral clonidine for sedation and analgesia during a five-year study period (2011-2016). We categorized patients as low-dose (LD ≤0.4 mg/day) or high-dose (HD >0.4 mg/day) based on the maximum total daily clonidine dose., Results and Discussion: In total, 166 patients received clonidine for sedation analgesia; the median age was 56 years, 36% were female, and 96% were mechanically ventilated (median 10 days). Eighty-eight patients (53%) received HD clonidine. There were no significant differences in hypotension, bradycardia, rebound hypertension or tachycardia between groups. The HD group had a greater reduction in mean daily opioid requirements throughout clonidine use compared with the LD group (-218.8 mcg vs. -42.5 mcg fentanyl equivalents, p = 0.049), while antipsychotic doses increased (5.7 mg vs. 0 mg olanzapine equivalents, p = 0.04) and sedative doses did not differ., What Is New and Conclusions: Clonidine doses >0.4 mg/day were associated with a decrease in patients' opioid but not sedative requirements without causing significant adverse effects. Antipsychotic doses increased in conjunction with HD clonidine use., (© 2021 John Wiley & Sons Ltd.)

Clonidine is a centrally acting alpha-2 selective adrenergic receptor agonist used to treat hypertension and to control or prevent withdrawal in patients with opioid and alcohol use disorders. Case reports describe abuse of clonidine alone or in combination with benzodiazepines, methadone, codeine, or heroin. Clonidine reportedly boosts and extends the opioid-related euphoria and reduces the amount of psychoactive drug needed. In this case report, we describe clonidine abuse and withdrawal management in an elderly patient with concurrent opioid use disorder. The usage of clonidine in the treatment of opioid detoxification remains controversial. Clonidine abuse is underestimated and requires more attention among health-care providers who concurrently prescribe clonidine and opioids. With the opioid epidemic becoming increasingly prevalent, physicians and other health-care providers must be vigilant in their opioid prescribing as well as concurrent prescribing of other psychoactive pharmacologic agents.

Aim: To update a systematic review of evidence published up to December 2015 for pharmacological/neurosurgical interventions among individuals with cerebral palsy (CP) and dystonia., Method: Searches were updated (January 2016 to May 2020) for oral baclofen, trihexyphenidyl, benzodiazepines, clonidine, gabapentin, levodopa, botulinum neurotoxin (BoNT), intrathecal baclofen (ITB), and deep brain stimulation (DBS), and from database inception for medical cannabis. Eligible studies included at least five individuals with CP and dystonia and reported on dystonia, goal achievement, motor function, pain/comfort, ease of caregiving, quality of life (QoL), or adverse events. Evidence certainty was evaluated using GRADE., Results: Nineteen new studies met inclusion criteria (two trihexyphenidyl, one clonidine, two BoNT, nine ITB, six DBS), giving a total of 46 studies (four randomized, 42 non-randomized) comprising 915 participants when combined with those from the original systematic review. Very low certainty evidence supported improved dystonia (clonidine, ITB, DBS) and goal achievement (clonidine, BoNT, ITB, DBS). Low to very low certainty evidence supported improved motor function (DBS), pain/comfort (clonidine, BoNT, ITB, DBS), ease of caregiving (clonidine, BoNT, ITB), and QoL (ITB, DBS). Trihexyphenidyl, clonidine, BoNT, ITB, and DBS may increase adverse events. No studies were identified for benzodiazepines, gabapentin, oral baclofen, and medical cannabis., Interpretation: Evidence evaluating the use of pharmacological and neurosurgical management options for individuals with CP and dystonia is limited to between low and very low certainty. What this paper adds Meta-analysis suggests that intrathecal baclofen (ITB) and deep brain stimulation (DBS) may improve dystonia and pain. Meta-analysis suggests that DBS may improve motor function. Clonidine, botulinum neurotoxin, ITB, and DBS may improve achievement of individualized goals. ITB and DBS may improve quality of life. No direct evidence is available for oral baclofen, benzodiazepines, gabapentin, or medical cannabis., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Study Objective: The primary goal of this study was to determine if the addition of clonidine to ropivacaine prolonged periumbilical numbness compared to ropivacaine alone in pediatric patients receiving ultrasound guided rectus sheath nerve blocks for laparoscopic appendectomy. The secondary goals were to evaluate differences in perioperative pain scores, analgesic consumption, sedation, anxiolysis, and hemodynamic effects from clonidine., Design: This was a single center, randomized, double-blinded prospective study., Setting: This study was conducted within the pediatric operating rooms at the Children's Hospital of Pittsburgh, a large university-based academic medical center., Patients: Fifty pediatric patients (ages 10-17 years old) without pre-existing cognitive impairment, developmental delay or chronic pain undergoing laparoscopic appendectomy during weekday hours were enrolled and randomized to control versus intervention groups., Intervention: Ultrasound guided rectus sheath nerve block injections were performed at the beginning of surgery with either ropivacaine 0.5% plus normal saline or ropivacaine 0.5% plus clonidine (2 mcg/kg, maximum of 100 mcg)., Measurements: The duration of periumbilical numbness, Numeric Pain Rating Scale scores, University of Michigan Sedation Scale, State-Trait Anxiety Inventory for Children, analgesic consumption, heart rate, blood pressure, and mean arterial pressures, were recorded for each patient at several time points in the perioperative setting., Main Results: There were no significant differences in demographic characteristics between groups. The median duration of periumbilical numbness did not significantly differ between the ropivacaine only and the ropivacaine plus clonidine groups 540.0 minutes [360.0 -1015.0] (median [interquartile range (IQR)]) versus 823.5 minutes [509.5- 1080.0], p = 0.451. There were no significant differences in perioperative analgesic consumption, pain and anxiety scores, PACU sedation, or hemodynamic instability., Conclusions: The addition of clonidine did not significantly prolong rectus sheath nerve block duration and was well tolerated in pediatric patients. Perioperative analgesia, hemodynamics, anxiety, and PACU sedation did not differ between groups., Trial Registration: Clinical Trials NCT02439281., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue., Methods: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication., Results: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported., Conclusion: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Background: Hypokalemia has been rarely attributed to tizanidine, although the precise mechanism is unclear. Severe hypokalemia is a well-established cause of abnormalities involving cardiac conduction. Given this agent's well-known cardiac arrhythmogenic potential, awareness of potential concomitant electrolyte abnormalities is important., Case Presentation: Electrolyte disorders, including hypokalemia, are rare complications of the antispasmodic medicine tizanidine when taken in doses as outlined by the manufacturer's prescribing instructions. Although cases of severe hypokalemia have also been described in the literature in association with this agent, such reports are few. We report a Caucasian case of an intentional overdose involving a very large ingestion of tizanidine. In addition to the characteristic abnormalities on the electrocardiogram, our patient developed electrolyte derangements as well as self-limited acute kidney injury. These biochemical abnormalities included profound hypokalemia that was refractory to aggressive replacement over the ensuing several days, before eventually dissipating. A thorough assessment of the etiology of this hypokalemia was consistent with a defect in renal potassium handling., Conclusion: In our patient with intentional tizanidine overdose, severe and refractory hypokalemia appears to have been due to a transient potassium wasting nephropathy.

Aim: Although not approved, the α-adrenoceptor agonist clonidine is considered an option for long-term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication., Methods: Relevant literature was systematically identified from PubMed and Embase. We included interventional and observational studies on paediatric patients admitted to intensive care units and systemically long-term sedated with clonidine-containing regimes. In duplicates, we conducted standardised and independent full-text assessment and extraction of safety data., Results: Data from 11 studies with 909 patients were analysed. The studies were heterogeneous regarding patient characteristics (age groups, comorbidity, or comedication) and sedation regimes (dosage, route, duration, or concomitant sedatives). Just four randomised controlled trials (RCTs) and one observational study had comparison groups, using placebo or midazolam. For safety outcomes, our validity evaluation showed low risk of bias only in three studies. All studies focused on haemodynamic problems, particularly bradycardia and hypotension. Observed incidences or subsequent interventions never caused concerns. However, only two RCTs allowed meaningful comparisons with control groups. Odds ratios showed no significant difference between the groups, but small sample sizes (50 and 125 patients) must be considered; pooled analyses were not reasonable., Conclusion: All evaluated studies concluded that the use of clonidine in paediatric intensive care units is safe. However, a valid characterisation of the safety profile remains challenging due to limited, biased and heterogeneous data and missing investigation of long-term effects. This evaluation demonstrates the lack of data, which prevents reliable conclusions on the safety of clonidine for long-term sedation in critically ill children. For an evidence-based use, further studies are needed., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Clonidine is a central alpha-2 agonist well known to produce a syndrome of bradycardia and hypotension in overdose. However, few examples of overt clinical clonidine toxicity secondary to cutaneous absorption have been reported. We report a case of unintentional systemic clonidine toxicity in an adult because of a compounded preparation of clonidine applied to a degraded skin barrier. A 35-year-old male suffered a motorcycle accident 48 hours before presentation resulting in an abrasion to his distal left leg. On the day of presentation, he self-treated the wound by repeated application of a family member's pain-relieving cream. Later he was found confused and unable to stand by a family member. The family member recognized the thick visible coat of cream as the likely cause and decontaminated the patient while calling 911. Prehospital vitals were notable for a blood pressure of 80/30 mm Hg and heart rate of 38 beats per minute. In the emergency department, the patient was resuscitated with intravenous fluids with resultant normalization of blood pressure. Upon later review, the cream was determined to have been created by a local compounding pharmacy for the use in neuropathic pain and was labeled to contain clonidine, lidocaine, ketamine, and gabapentin. Cutaneous absorption of the pain cream was greatly increased because of loss of skin integrity. Military physicians and compounding pharmacies should ensure that patients are aware of the proper application of compounded creams and the potential risk for systemic toxicity with overuse or degraded skin., (© The Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients., Methods/design: This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950 ., Discussion: The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain., Trial Registration: This trial has been registered with ClinicalTrials.gov owned by NIH's US National Library of Medicine. ClinicalTrials.gov NCT03342950 . Registered on November 1, 2017 (trial was prospectively registered)., Protocol Version and Identifiers: This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.

Background: Clonidine is a centrally-acting α-2 agonist used in the treatment of hypertension and attention-deficit/hyperactivity disorder, among other off-label uses. In overdose, it can cause sedation, bradycardia, and hypotension. Clonidine can be compounded as a liquid formula for patients who are unable to take pills, however, this can add to the risk of dosing errors., Case Report: A 12-year-old boy diagnosed with autism, prescribed buspirone and clonidine, presented to the emergency department for altered mental status. His examination revealed generalized sedation, bradycardia (heart rate 30-40 beats/min), and hypotension (blood pressure 82/48 mm Hg). Resuscitation included i.v. crystalloids and multiple doses of atropine. Over the next 24 h, his vital signs and mental status normalized. He displayed no infectious symptoms or focal neurologic deficits. His parents noted that his medications had been refilled recently at the compounding pharmacy; because he was unable to take pills, his medications were in liquid formulation. Because his signs and symptoms were suspicious for a central α-2 agonist overdose, his clonidine preparation was sent to a reference laboratory for analysis. This analysis revealed the concentration was approximately eight times higher than indicated on its label. WHY SHOULD AND EMERGENCY PHYSICIAN BE AWARE OF THIS?: Compounding pharmacy errors can be a source of toxicity, even if there is no known history of an overdose. Recognizing the toxidrome of sedation, respiratory depression, bradycardia, hypotension, and miosis will lead to appropriate treatment of the patient and should prompt an investigation of the medication error to prevent further harm., (Published by Elsevier Inc.)

Study Objective: Postoperative delirium occurs in 20-50% of elderly patients undergoing cardiac surgery and increases morbidity and mortality. We investigated whether prophylactic dexmedetomidine could reduce delirium incidence in elderly patients after coronary artery bypass grafting (CABG), compared with clonidine., Design: Prospective observational trial., Setting: Academic university hospital., Participants: Patients (60-70 years old) who underwent CABG and received either dexmedetomidine or clonidine infusion postoperatively., Interventions: Patients were randomly allocated to dexmedetomidine or clonidine groups. In the dexmedetomidine group, patients received an initial infusion of 0.7-1.2 μg/kg/h; sedation and analgesia were evaluated after 45-60 min. If the Richmond assessment sedation score (RASS) increased from +1 to +4, the infusion rate was increased by 0.1-0.2 μg/kg/h every 30 min, up to 1-1.4 μg/kg body-weight/h. Dexmedetomidine infusion was not discontinued pre-extubation; thereafter, infusion was reduced by 0.1 μg/kg/h until 0.2 μg/kg/h. The maximum infusion duration was 72 h. In the clonidine group, patients received an initial infusion of 0.5 μg/kg, followed by 1-2 μg/kg/h, if the RASS changed from +1 to +4. This was continued throughout mechanical ventilation., Measurements: Patients were followed up to 5 days post-surgery. Delirium incidence, extubation time, lengths of intensive care unit (ICU) and hospital stay, need for inotropic support or vasopressors, mean arterial blood pressure and heart rate, hospital mortality rate, total postoperative morphine dose, number of patients receiving haloperidol, and adverse events were recorded., Main Results: Two-hundred-and-eighty-six patients (dexmedetomidine, 144; clonidine, 142) were studied. Dexmedetomidine was associated with lower risk and duration of delirium, shorter mechanical ventilation duration and ICU stay, lower mortality rate, and lower morphine consumption than the clonidine group. Dexmedetomidine significantly decreased heart rates after ICU admission., Conclusions: Postoperative infusion of dexmedetomidine provides a feasible option for postoperative control of delirium after CABG in adult patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown., Methods: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h., Results: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1)., Conclusions: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.

Purpose: Oral mucositis (OM) is a frequent and painful sequela of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in patients with HNC., Methods and Materials: Patients with HNC undergoing adjuvant radiation therapy (60-66 Gy; 5 × 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 μg (n = 56), 100 μg (n = 65), or placebo (n = 62) via a topical mucobuccal tablet starting 1 to 3 days before and continuing during treatment. The primary endpoint was the incidence of severe OM (severe OM [SOM], World Health Organization grade 3/4)., Results: SOM developed in 45% versus 60% (P = .06) of patients treated with clonidine compared with placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; hazard ratio, 0.75 [95% confidence interval, 0.484-1.175], P = .21); median time to onset was 45 versus 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% versus 98.4%, nausea in 49.6% versus 71.0%, dysphagia in 32.8% versus 48.4%, and reversible hypotension in 6.7% versus 1.6% of patients on clonidine versus placebo, respectively., Conclusions: Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably affect the course and severity of CRT-induced SOM and support further evaluation., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: The U.S. Food and Drug Administration recently approved lofexidine, an α-2-adrenergic agonist, as the first non-opioid medication for mitigation of opioid withdrawal symptoms. Clonidine, an α-2-adrenergic agonist, historically was used off-label for this indication. This review aimed to evaluate the effectiveness of lofexidine versus clonidine for mitigation of opioid withdrawal symptoms and to discuss the current role of lofexidine in the management of patients at risk of experiencing opioid withdrawal., Data Sources: MEDLINE/PubMed, EBSCO, and CENTRAL were searched using the terms "lofexidine," "clonidine," and "opioid withdrawal.", Study Selection: The literature search included English-language studies involving administration and prescription of lofexidine and clonidine for the management of opioid withdrawal symptoms in adults. Data sources were searched to include articles published between October 1993 and May 2019., Data Extraction: Three independent reviewers analyzed the title and abstract of studies to identify studies involving comparisons of lofexidine with clonidine for mitigation of opioid withdrawal symptoms. Reviewers were initially blinded to the individual determinations. Results were then unblinded and discussed among reviewers., Results: Of the 110 citations screened, 5 articles were included. One study demonstrated a statistically significant reduction in opioid withdrawal symptom severity with lofexidine compared with clonidine, whereas the other 4 studies showed no significant difference. Three studies reported the completion of opioid detoxification treatment, with no significant differences seen. In 1 study that compared lofexidine with placebo, lofexidine caused significant hypotension, bradycardia, and pupillary constriction. Three studies showed significant adverse effects of hypotension and symptoms of feeling unwell with clonidine compared with lofexidine., Conclusion: Lofexidine appears equivalent in efficacy to clonidine, with fewer adverse effects, and it may have a limited role in the management of opioid withdrawal symptoms. However, cost, detoxification venue, and value of other preferred treatment modalities may affect the comparative efficacy of lofexidine to other agents., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Tizanidine hydrochloride is a skeletal muscle relaxant used for the treatment of spasm, a sudden involuntary muscle contraction leading to pain. The presently available oral dosage form has limitations such as high first pass metabolism resulting in low oral bioavailability. The short half-life necessitates its frequent administration to maintain the required plasma concentration. Transdermal delivery of drug avoids its first pass hepatic metabolism and gives controlled release, making it possible for reduction in dosing frequency. Drug delivery through transdermal route is severely limited by the presence of a tough stratum corneum barrier. A penetration enhancement approach is often necessary to achieve desired plasma concentrations. Microneedles are very short and sharp needles which do not cause pain. Thus, in the present investigation, preparation and evaluation of a transdermal delivery system for tizanidine hydrochloride based on microneedles are described.

Objective: To establish the prevalence of delirium and its subsyndrome in intensive care and to associate it with the use of sedative and analgesia, severity and mortality., Method: Carried out in two intensive care units of adult patients, this is a quantitative and transversal study, with 157 patients, using the Richmond Agitation-Sedation Scale to assess the level of sedation and the Intensive Care Delirium Screening Checklist for delirium. The T test and Chi-square test were applied for statistical analysis., Results: The prevalence of delirium was 22.3%, and 49.7% of the subsyndrome. Associations of the use of midazolam with the presence of delirium (p=0.05) and subsyndromal delirium (p<0.01), use of clonidine with the appearance of delirium (p<0.01) and of fentanyl with subsyndromal delirium (p=0.09). There were no significant differences between the mortality of patients with delirium (p=0.40) and subsyndromal delirium (p=0.86), as well as association with the mortality score., Conclusion: The use of sedoanalgesia is associated with the presence of delirium and subsyndromal delirium. No significant statistical associations were found between the severity and mortality scores.

Background: Several systematic reviews have reported the benefits of perioperative α2-adrenoceptor agonist use for various conditions, but safety evidence is poorly documented., Methods: We performed a systematic review focusing on adverse events. We searched the MEDLINE, Embase, LILACS, Cochrane, and Clinical Trials Register databases for RCTs comparing the effects of α2-adrenoceptor agonists and placebo during non-cardiovascular surgery under general anaesthesia, for any indication, in patients not at risk of cardiovascular events. The primary outcome was the incidence of severe adverse events during or after α2-adrenoceptor agonist administration. The secondary endpoints were other adverse events. A meta-analysis was carried out on the combined data. Evidence quality was rated by the Grading of Recommendations Assessment, Development and Evaluation method., Results: We included 56 studies (4868 patients). Our review, based on moderate-quality evidence, revealed that hypotension occurred frequently during the preoperative and postoperative periods, for both clonidine and dexmedetomidine. Bradycardia was reported only with dexmedetomidine. In contrast, dexmedetomidine seemed to protect against intraoperative hypertension and tachycardia. Subgroup analysis suggested that the risk of hypotension and bradycardia persisted after cessation of treatment. Interestingly, intraoperative hypotension and postoperative bradycardia were not observed with a bolus dosage of dexmedetomidine less than 0.5 μg kg -1 or with continuous administration alone., Conclusions: Pooled data for the incidence of adverse events associated with use of α2-adrenoceptor agonists in various perioperative contexts provide high-confidence evidence for a risk of hypotension and bradycardia, and protective effects against hypertension and tachycardia., Protocol Registration: CRD42017071583., (Copyright © 2019. Published by Elsevier Ltd.)

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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

INTRODUCTION: Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in military pilots, but there is little research directed at civilian pilots who may have medications or medical conditions not permitted in military pilots. METHODS: In this case-control study, we identified 89 fatal high-G aerobatic accidents and 4000 fatal control accidents from 1995 through 2018 from the NTSB accident database and the FAA autopsy database. We retrieved medications and medical conditions from the FAA's pilot medical databases. Logistic regression models were used to explore the associations of drugs, medical conditions, height, and medical waivers with high-G accidents. RESULTS: Seven drugs (alprazolam, clonidine, ethanol, meclizine, phentermine, triamterene, and zolpidem) reached statistical significance in our models, but had such small case counts that we consider these findings to be uncertain, except for ethanol, which was found in seven cases. Of these, only triamterene was known to the FAA. Statistically significant medical predictors included only alcohol abuse (seven cases) and liver disease (only two cases). DISCUSSION: Our analysis found that the drug ethanol and the condition alcohol abuse are significantly associated with high-G accidents. Seven other factors were statistically significant, but should only be considered as hypothesis generating due to very low case counts. Our study does not suggest that restricting pilots with otherwise permissible medications or medical conditions from aerobatics is warranted. Mills WD, Greenhaw RM, Wang JMP. A medical review of fatal high-G U.S. aerobatic accidents . Aerosp Med Hum Perform. 2019; 90(11):959-965.

Purpose: Intense bleeding of the surgical field is a potential factor influencing success of functional endoscopic sinus surgery (FESS). Hypotensive anesthesia with α2 intravenous agonists reduces intraoperative bleeding, but which is the best agent is unknown. The main objective of this trial was to compare the current standard adjuvant drug for hypotensive anesthesia, clonidine, with the recently available alternative dexmedetomidine., Methods: A randomized clinical trial compared the efficacy of clonidine and dexmedetomidine during FESS. Treatment was open label for the anesthesiologist and operating surgeon, but blind for an external evaluator who evaluated video-recorded surgeries. A Boezaart scale was assessed every 30 min during FESS until surgery completion. Main end-point was the proportion of patients with mean Boezaart scores > 2 (heavy bleeding) by external blinded evaluator. Secondary end-points included other bleeding parameters, surgery duration, hemodynamic measures and surgical complications., Results: 94 patients were randomized. There were no significant differences in the proportion of patients with mean Boezaart scores > 2 in clonidine (42.6%) and dexmedetomidine (42.6%). Consistently, no differences were observed in secondary variables of bleeding, duration or complications. Small differences in mean heart rate were observed that might reflect different pharmacological profiles of the products, but are of uncertain clinical relevance., Conclusions: No significant differences were observed between clonidine and dexmedetomidine when used as anesthetic adjuvants in the reduction of surgical bleeding in FESS. A longer experience with clonidine and its lower costs suggest it may be a preferable option as an adjuvant for hypotensive anesthesia.

Background: Intrathecal morphine (ITM) is a widely used technique for postcaesarean section analgesia but entails a high risk of postoperative nausea and vomiting (PONV). The transversus abdominis plane (TAP) block is an alternative., Objective: We tested the hypothesis that a TAP block including clonidine reduces the incidence of PONV after caesarean section when compared with ITM., Design: A randomised, controlled, double-blinded study., Setting: Geneva University Hospitals, Switzerland, from October 2013 to February 2017., Patients: A total of 182 patients undergoing elective caesarean section were studied. Reasons for noninclusion were complicated pregnancy, contraindication to spinal anaesthesia or TAP block, extreme weight or height, allergy to any medication or previous median abdominal incision., Interventions: Patients were allocated randomly to one of two groups (quadruple blinded): 100 μg of morphine added to the spinal local anaesthetic or a bilateral TAP block with 20 ml of ropivacaine 0.375% + 75 μg of clonidine on each side., Main Outcome Measures: The primary outcome measure was the total number of patients presenting with PONV at 24 h. Secondary aims were to compare other adverse effects (pruritus, respiratory depression, hypotension, bradycardia, sedation), analgesic efficacy and the quality of postoperative recovery., Results: At 24 h, there was no significant difference between ITM and TAP groups in the total number of patients presenting with PONV: 17/92 patients (18.5%, 95% confidence interval 11.1 to 27.9) and 27/88 patients (30.7%, 95% confidence interval 21.3 to 41.4) in TAP and ITM groups, respectively (P = 0.065). Pain scores at 6 h and cumulative morphine consumption at 24 h were lower in the ITM group (P < 0.0001 for morphine consumption at 24 h). The incidence of hypotension was higher in the TAP group (54.3 vs. 29.2%, P = 0.0006). Maternal satisfaction was high and not different between groups., Conclusion: A TAP block with clonidine and local anaesthetic does not reduce significantly the incidence of PONV compared with ITM. We confirm the superiority of ITM on acute postcaesarean section analgesia compared with a TAP block, even with clonidine as an adjunct., Trial Registration: ClinicalTrials.gov identifier: NCT01931215.

Compared with the general population, rates of pheochromocytoma are higher in neurofibromatosis type 1 (NF1) patients. However, pheochromocytoma testing is often plagued by false positive results. Here we present a patient with NF1, elevated urinary metanephrine levels, and an indeterminate adrenal nodule. Clonidine suppression testing aided diagnosis and led to definitive surgical treatment that confirmed a pheochromocytoma. Pheochromocytoma screening and clonidine suppression testing can both aid in the evaluation for catecholamine-secreting tumours., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)