Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care.

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literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated.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.

Efficacy and safety of clonidine for the treatment of impulse control disorder in Parkinson's disease: a multicenter, parallel, randomised, double-blind, Phase 2b Clinical trial.

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.

[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.

Efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder.

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.

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.

Cardiac Safety of Clonidine and Quetiapine in Post-Cardiac Surgery Intensive Care Unit Patients.

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.

Efficacy and safety of epidural clonidine by continuous infusion or patient-controlled analgesia in labor: A meta-analysis of randomized controlled trials.

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.

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.

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.

Continuous clonidine infusion: an alternative for children on mechanical ventilation.

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.

Use of clonidine in the treatment of Irukandji syndrome: A 4-year retrospective cohort study on safety, efficacy and clinical utility.

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.

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.

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.

Safety And Efficacy of Clonidine for Acute Hypertensive Urgency in an Older and Hospitalized Population.

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.

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.

Oral clonidine as a pre-anesthetic medication in hair transplantation surgery-A pilot study.

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.

Excessive Blood Pressure Response to Clonidine in Hospitalized Patients With Asymptomatic Severe Hypertension.

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.

Use of continuous infusion of clonidine for sedation in critically ill infants and children.

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.

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.

Potassium wasting nephropathy in the setting of tizanidine overdose: a case report.

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.