In utero exposure to ADHD medication and long-term offspring outcomes.

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.

[Alpha-2 adrenoreceptor agonists for the intensive care physician]. / Les agonistes α2-adrénergiques pour l'intensiviste.

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.

En pratique clinique, l'intensiviste dispose de deux α2-agonistes, à savoir la clonidine et la dexmédétomidine. L'affinité de la dexmédétomidine pour les récepteurs α2-adrénergiques est huit fois plus importante que celle de la clonidine. Leur principal effet est la sédation. Cet effet est obtenu par inhibition de la libération de noradrénaline dans le locus cœruleus du tronc cérébral. Ces molécules sont surtout utilisées pour la sédation, l'analgésie et la prise en charge du delirium chez le patient critique. Le recours à la dexmédétomidine augmente actuellement et montre une bonne sécurité de la molécule. Les effets indésirables les plus fréquents sont la bradycardie et l'hypotension.

Clonidine Versus Midazolam Premedication and Postoperative Negative Behavioral Changes in Younger Children: A Randomized Controlled Trial.

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.

Topical clonidine for neuropathic pain in adults.

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.

Intracranial hemorrhage after a single dose of Yohimbine in a chronic user of clonidine.

INTRODUCTION: Yohimbine, an alpha-2 adrenoreceptor antagonist found in a variety of supplements, has been historically used to treat libido, erectile dysfunction, xerostomia, and as a weight loss enhancement. Yohimbine toxicity causes a sympathomimetic syndrome as demonstrated by the case below of a female who developed an intracranial hemorrhage (ICH) following an ingestion of yohimbine. CASE: This case follows a 39-year-old female who presented to the emergency department (ED) with complaints of nausea, emesis, and flushing following the ingestion of a female sexual enhancement supplement labeled to contain yohimbine (BioXgenic Nature's Desire) one hour prior. The patient took her prescribed 0.1 mg clonidine when the symptoms commenced. Upon arrival, the patient's blood pressure was 198/93. She developed neurological sequelae including a left-sided facial droop and weakness of her right extremities. A computed tomography scan demonstrated an acute basal ganglia hemorrhage with mild mass effect and mild subarachnoid hemorrhage. She was transferred to a regional referral hospital and discharged 16 days later to a rehabilitation center with persistent neurological sequelae. DISCUSSION: This patient exhibited sympathetic toxicity temporally associated with yohimbine ingestion. Our patient also had a variety of risk factors that increased the likelihood of a poor outcome with yohimbine. Chronic use of clonidine is known to down-regulate alpha-2 receptors. This leads to dependence of clonidine to maintain adrenergic homeostasis and could potentiate the effects of yohimbine. To compound effects, our patient was also taking bupropion and desvenlafaxine, which inhibit norepinephrine reuptake, likely worsening our patient's sympathomimetic response. Despite the temporal relationship of our patient's ICH and ingestion of yohimbine, a definitive relationship cannot be inferred due to our lack of confirmatory testing of yohimbine content and possibility of adulterants. The U.S. Food and Drug Administration (FDA) does not regulate the supplement market strictly, with multiple studies illustrating variation among ingredients of supplements despite stated quantities on the labels. CONCLUSION: Dietary supplements are not required by the FDA to undergo efficacy or safety testing, necessitating clear post-marketing communication regarding potential adverse events from various supplements. Users should be aware of yohimbine-containing products and the possible side effects of toxicity. It is crucial that physicians and patients be aware of possible drug-supplement interactions of yohimbine and the presentation of sympathomimetic syndromes.

Risk of tizanidine-induced adverse events after concomitant exposure to ciprofloxacin: A cohort study in the U.S.

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.

The Safety and Efficacy of Clonidine in Hemodialysis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Clonidine is a frequently prescribed long-term antihypertensive medication in hemodialysis (HD) patients in the USA, but its safety and efficacy has not been clearly established in the HD population. OBJECTIVE: To evaluate, we conducted a systematic review and meta-analysis on the safety and efficacy of clonidine in HD patients. METHODS: Keyword search of "clonidine" and "dialysis" was conducted through April 2021 in PubMed, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov databases. Inclusion criteria were as follows - study design: randomized controlled trials, cohort studies, prospective studies, retrospective studies, or case series; subjects: adult HD patients; main outcome: blood pressure (BP) and safety; language: English; and article type: peer-reviewed publications. Studies that examined the effects of clonidine in populations other than adult HD patients were excluded. Meta-analysis was performed on BP reduction outcomes. RESULTS: Eight studies met the inclusion criteria for the systematic review, including prospective pre-post studies (2), double-blind controlled trial (1), single-blinded placebo-controlled trial (1), crossover open-label clinical trial (1), retrospective analysis (1), and case report series (2). Three studies included in the meta-analysis ranged from 2 to 12 weeks duration, with a collective sample size of 24 (ages 12-77 years). Risk of bias, assessed using the ROBINS-1 tool, was high for all included studies. Significant adverse effects reported included hypotension, light-headedness, drowsiness, dry mouth, rebound hypertension, and contact dermatitis from patch application. Short-term clonidine use was associated with significant improvement in systolic BP (pooled effect: -12.985 mm Hg, 95% CI [-7.878, -18.092], p < 0.001), while changes in diastolic BP were not statistically significant (-11.119 mm Hg, 95% CI [-22.725, 0.487], p = 0.060). No data currently support the long-term efficacy of clonidine in HD patients. This study was unfunded and was developed using PRISMA guidelines and registered on PROSPERO (CRD42018112042). CONCLUSIONS: There is no evidence supporting the long-term use of clonidine in the HD population and a significant side-effect profile. There is low-quality evidence demonstrating the efficacy of clonidine in lowering BP in HD patients in short-term use, but significant safety concerns remain. Fluid removal strategies and other antihypertensives should be used over clonidine for long-term BP control in the HD population.

Safety of clonidine used for long-term sedation in paediatric intensive care: A systematic review.

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.

Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database.

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.

Pharmacological and neurosurgical interventions for individuals with cerebral palsy and dystonia: a systematic review update and meta-analysis.

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.

High-versus low-dose clonidine for sedation and analgesia in critically ill adults: A retrospective cohort study.

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.

One-year Results of a Factorial Randomized Trial of Aspirin versus Placebo and Clonidine versus Placebo in Patients Having Noncardiac Surgery.

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.

Clonidine Compounding Error: Bradycardia and Sedation in a Pediatric Patient.

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.

Lofexidine versus clonidine for mitigation of opioid withdrawal symptoms: A systematic review.

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.

Perioperative adverse events attributed to α2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis.

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.

The impact of a transversus abdominis plane block including clonidine vs. intrathecal morphine on nausea and vomiting after caesarean section: A randomised controlled trial.

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.

Randomized clinical trial to compare the efficacy to improve the quality of surgical field of hypotensive anesthesia with clonidine or dexmedetomidine during functional endoscopic sinus surgery.

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.

Clonidine in pediatric anesthesia: the new panacea or a drug still looking for an indication?

PURPOSE OF REVIEW: Clonidine, an α2-receptor agonist is a widely used drug in pediatrics with a large scope of indications ranging from prevention of postoperative emergence agitation, analgesia, anxiolysis, sedation, weaning to shivering. In the era of 'opioid-free' medicine with much attention be directed toward increasing problems with opioid use, clonidine due to its global availability, low cost and safety profile has become an even more interesting option. RECENT FINDINGS: Increasing evidence from randomised clinical trials support the use of clonidine in healthy children in the perioperative setting. Clonidine appears to significantly reduce postoperative emergence agitation, opioid consumption, shivering, nausea and vomiting. In addition, emerging evidence support the use of clonidine for sedation of critically ill children in ICUs. In this review, the current evidence for clonidine in pediatrics is described and analyzed including a meta-analysis for prevention of emergence agitation. SUMMARY: Clonidine appears a safe and beneficial drug with moderate to high-quality evidence supporting its use in pediatric anesthesia. However, for some indications and populations such as children younger than 12 months old and those with hemodynamic instability, there is an urgent need for high-quality trials.

Clonidine Effect on Pain After Cesarean Delivery: A Randomized Controlled Trial of Different Routes of Administration.

BACKGROUND: Intrathecal clonidine prolongs spinal anesthesia. We evaluated the effects of the addition of intrathecal or intravenous clonidine (75 µg) to standard cesarean delivery spinal anesthesia on postoperative pain and neonatal outcomes. METHODS: In a randomized, placebo-controlled, double-blind trial, 64 women scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated and compared among 3 groups: intrathecal clonidine 75 µg, intravenous clonidine 75 µg, and placebo. The primary outcome was acute postoperative pain. A sample size of 26 individuals per group (N = 78) was planned. RESULTS: From April 2015 to April 2016, 64 women were analyzed (14 excluded). No differences in postoperative pain scores were found (Numerical Verbal Scale for pain at movement at 24 hours of postcesarean delivery: 4.53 ± 3.0 vs 4.45 ± 2.73 vs 3.93 ± 3.07 for control, intrathecal, and intravenous, respectively, P = .771). Intrathecal and intravenous clonidine led to more sedation, in comparison to the control group, during the intraoperative period (Richmond Agitation and Sedation Scale: -0.3 ± 0.47 vs -1 ± 0.53 vs -0.73 ± 0.45 for control, intrathecal, and intravenous, respectively, overall P < .001; Dunn correction: P < .001 for intrathecal versus control; P = .021 for intravenous versus control; and P = .208 for intrathecal versus intravenous). CONCLUSIONS: Intrathecal or intravenous clonidine had no effect on postoperative pain after cesarean delivery. Both intrathecal and intravenous clonidine caused more sedation.

Pharmacological therapies for management of opium withdrawal.

BACKGROUND: Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium. OBJECTIVES: To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. SEARCH METHODS: We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials. SELECTION CRITERIA: Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). AUTHORS' CONCLUSIONS: Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.