High Doses Of Clonidine Research Articles

CONTROL OF SHIVERING UNDER SPINALANAESTHESIA- A PROSPECTIVE RANDOMIZED COMPARATIVE ANALYSIS OF BUTORPHANOL, TRAMADOL AND CLONIDINE

INTRODUCTION: Shivering that develops following spinal anaesthesia is a common problem and may occur in 40- 70% of patients .Perioperative hypothermia is the primary cause which occurs due to inhibition of thermoregulatory mechanism in the hypothalamus. It is detrimental to the patient hence effective control of shivering is mandatory. AIM: To compare the relative efcacy of Butorphanol, Tramadol and Clonidine and nd rst line of management for the control of shivering during spinal anaesthesia in lower abdominal,lower limb and open gynaecological surgeries and study their side effects MATERIALS AND METHOD:114 (38 for each drug group) ASA 1 and 2 patients of either gender, aged between 18 to 65 yrs in the above mentioned surgeries who developed shivering after spinal anaesthesia were included in the study. Tab. Diazepam 10 mg was given the night before and morning of surgery. Baseline heart rate, SpO , Blood pressure, ECG and axillary temperature were recorded. Subarachnoid block was performed with Inj. Bupivacaine 2 heavy 0.5% (3-4 ml) at L3-L4/L4-L5 interspace.Heart rate, SpO , NIBPand axillary temperature was recorded till 1 hour post operatively. For the 2 patients who developed grade 2 and above of shivering , group B received 1mg Butorphanol ,group T 1mg /kg Tramadol and group C 1 µg/kg Clonidine randomly after diluting to 5 ml.The time and temperature at onset of shivering,time taken for control of shivering ,side effects- nausea, vomiting, hypotension, bradycardia,dry mouth,skin rash,sedation score,recurrence of shivering were noted.Statistical analysis was done using One way Anova and Chi square tests .RESULTS: There was a statistically signicant difference in between the drug groups only for recurrence of shivering after drug. More recurrence was found with Clonidine. There was signicant reduction in heart rate at 1 hour in Clonidine group compared to B and T groups. ASA-ps, grade of shivering, duration, time at onset of shivering, pre-op temp, temp at onset, time to control of shivering, SBP, DBP, MAP and SpO2 differences were not statistically signicant.CONCLUSION: Clonidine caused more recurrence and more reduction in heart rate. Butorphanol had a faster control of post spinal shivering though not statistically signicant. Tramadol and Butorphanol can be used with almost no side effects for post spinal anesthesia shivering,a higher dose of Clonidine may be required.

Analgesic Efficacy of α2 Adrenergic Receptor Agonists Depends on the Chronic State of Neuropathic Pain: Role of Regulator of G Protein Signaling 4

The analgesic effect of alpha-2 adrenergic receptor (α2AR) agonists, which relieve chronic neuropathic pain, is highly variable among individuals. Here, we used a mouse model of spared nerve injury (SNI) to show that treatment time after the establishment of neuropathic pain was important for the variability in the analgesic efficacy of α2AR agonists, which was related to the activity of regulator of G-protein signaling protein 4 (RGS4). Intrathecal treatment with α2AR agonists, clonidine (0.1–1 nmol) or dexmedetomidine (0.3–1 nmol), relieved mechanical allodynia and thermal hyperalgesia on postoperative day (POD) 14, but their efficacy was weaker on POD28 and absent on POD56. The RGS4 level of plasma membrane was increased on POD56 compared to that on POD14. Moreover, in RGS4-deficient or RGS4 inhibitor (CCG50014)-treated mice, the analgesic effect of the α2AR agonists was conserved even on POD56. The increased plasma membrane RGS4 expression and the reduced level of active Gαi after clonidine injection on POD56 were completely restored by CCG50014. Higher doses of clonidine (10 nmol) and dexmedetomidine (3 nmol) relieved neuropathic pain on POD56 but were accompanied with serious side effects. Whereas, the coadministration of CCG50014 with clonidine (1 nmol) or dexmedetomidine (1 nmol) did not cause side effects. These findings demonstrated that SNI-induced increase in plasma membrane RGS4 expression was associated with low efficacy of α2AR agonists in a model of persistent, chronic neuropathic pain. Furthermore, α2AR agonist administration together with RGS4-targeted intervention represents a novel strategy for the treatment of neuropathic pain to overcome dose-limiting side effects.

Pharmacological therapies for management of opium withdrawal.

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. To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. 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. 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. We used the standard methodological procedures expected by Cochrane. 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). 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.

Pharmacopuncture With Scolopendra subspinipes Suppresses Mechanical Allodynia in Oxaliplatin-Induced Neuropathic Mice and Potentiates Clonidine-induced Anti-allodynia Without Hypotension or Motor Impairment

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of anticancerdrugs but lacks an effective treatment strategy. Scolopendra subspinipes has been used in traditional medicine to treat chronic neuronal diseases. Moreover, pharmacopuncture with S subspinipes (SSP) produces potent analgesia in humans and experimental animals. In this study, we examined the effect of SSP into the ST36 acupoint on oxaliplatin-induced mechanical allodynia in mice. Acupoint treatment with SSP (0.5%/20 μL) significantly decreased mechanical allodynia produced by a single oxaliplatin injection (10mg/kg i.p.), which was completely prevented by acupoint preinjection of lidocaine. Intrathecal treatment with yohimbine (25 μg/5 μL), an α2-adrenoceptor antagonist, prevented the anti-allodynic effect of SSP. In contrast, a high dose (0.1mg/kg i.p.) ofclonidine,an α2-adrenoceptor agonist, suppressed oxaliplatin-induced mechanical allodynia butproduced severe side effects including hypotension, bradycardia, and motor impairment. The combination of SSP with a lower dose of clonidine (0.03 mg/kg) produced a comparable analgesic effect without side effects. Collectively, our findings demonstrate that SSP produces an analgesic effect in oxaliplatin-induced pain via neuronal conduction at the acupoint and activation of spinal α2-adrenoceptors. Moreover, acombination of low-dose clonidine with SSP represents a novel and safe therapeutic strategy for chemotherapy-induced chronic pain. PerspectiveSSP can relieve oxaliplatin-induced mechanical allodynia. Moreover, SSP potentiates clonidine-induced anti-allodynia, allowing a lower dose of clonidine with no significant side effects. The combination of SSP and low-dose clonidine might provide a novel strategy for the management of chemotherapy-induced peripheral neuropathy.

Effect of adding various doses of clonidine as an adjunct in Transversus abdominis plane block in unilateral inguinal hernioplasty

Background: Transverses abdominis plane (TAP) block is a new regional anaesthetic technique for postoperative analgesia in abdominal surgeries, as a part of multimodal analgesia. We evaluated effect of two different doses of clonidine as an adjunct in TAP block in patients underwent unilateral inguinal hernioplasty.Methods: Sixty adult patients undergoing unilateral inguinal hernioplasty were randomized into two groups, Group A (n=30) received bilateral TAP block with bupivacaine 0.25% 38cc + clonidine (1cc) 150 microgram +1cc NS=40cc, Group B (n=30) received bupivacaine 0.25% 38cc+clonidine (2cc) 300 microgram=40cc, at the end of surgery. The postoperative pain was evaluated by visual analog score (VAS) for pain scoring at 2, 4, 6, 12 and at 24 hours. Subjective assessment of duration of analgesia was done.Results: The VAS score in patients who received clonidine 300 microgram Group B as an adjunct was significantly lower than who received 150 microgram Group A. Duration of analgesia was longer in Group B. 2 patients in Group B showed bradycardia treated with atropine. Sedation score was lesser in Group A.Conclusions: Clonidine showed dose dependant analgesia and adverse effect in TAP block for postoperative analgesia. Higher doses of clonidine may be used as an adjunct in TAP block.

Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration.

Clonidine is used for sedation in the paediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during paediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit. All children below the age of 18 years who received clonidine during ECMO were eligible. The pharmacokinetic analysis was conducted by nonlinear mixed effect modelling, which enables to establish the separate influences of determinants on drug blood level and to provide individualized dosing. Twenty-two patients, median age 1month (IQR 6.4) and weight at inclusion 4kg (IQR 3.1) were included of whom 90% in addition to ECMO received pre-emptive continuous venovenous hemofiltration to optimize fluid balance. The clonidine clearance rate was two-fold that measured in patients not on ECMO. Clearance increased steeply with postnatal age: at days 6, 8 and 10, respectively 30%, 50% and 70% of the adult clearance rate was reached. The use of diuretics was associated with a lower clearance. The volume of distribution increased by 55% during ECMO support. Our findings suggest that a higher dose of clonidine may be needed during ECMO. The PK parameters on ECMO and the dosing guidelines proposed hold the potential to improve sedation practices on ECMO but need to be repeated with different ECMO systems.

Evaluation of clonidine as an adjuvant to brachial plexus block and its comparison with tramadol.

Background and Aims:It has been reported that clonidine when used as an additive in a dose of 90 μg in adults increases the duration of peripheral nerve blocks. Hence, this study was conducted to evaluate the effect of clonidine in brachial plexus blocks and to compare it with tramadol.Material and Methods:Ninety patients posted for upper limb orthopedic surgery were divided randomly into three groups. 40 mL of local anesthetic solution was prepared using 15 mL of 2% lignocaine-adrenaline-sodium bicarbonate solution, 15 mL of 0.5% bupivacaine, and 10 mL distilled water. Patients received a supraclavicular brachial plexus block with 0.7 mL/kg of this solution to which either 1 mg/kg tramadol, 1 μg/kg clonidine, or 1.5 μg/kg clonidine was added. The onset and duration of sensory and motor block and the duration of postoperative analgesia were recorded. Pulse rate, blood pressure, respiratory rate, saturation, sedation, and any side effect were monitored. Results were statistically analyzed using analysis of variance F-test and unpaired t-test.Results:There was a statistically significant difference in the onset of both the sensory and motor components of the block with the fastest onset seen when clonidine was used in a dose of 1.5 μg/kg. The block also lasted statistically significantly longer with clonidine as compared with tramadol although there was no statistically significant increase in the duration of the block when a higher dose of clonidine was used. The time for rescue analgesia was the longest in patients who received 1.5 μg/kg of clonidine (491.8 ± 33.9 min). This duration was also statistically significant. Patients who received tramadol reported a statistically significant higher incidence of nausea.Conclusion:Clonidine in a dose of 1.5 μg/kg body weight provided the fastest onset of sensory as well as motor block and the longest duration of postoperative analgesia and thus is a good additive to local anesthetic solutions for brachial plexus blocks.

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination.

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

Brachial plexus block: Comparison of two different doses of clonidine added to bupivacaine

Background:The role of clonidine as an adjuvant to local anesthetic agents in brachial plexus block (BPB) has been extensively studied. However, till date there has been no consensus about the ideal dose of clonidine for this purpose. This study was carried out to evaluate two doses of clonidine-1 and 2 g/kg, added to 0.5% bupivacaine, with regard to onset and duration of sensorimotor blockade, hemodynamic effects, postoperative analgesia, and adverse effects.Materials and Methods:Sixty adult patients undergoing upper limb surgeries were randomly allocated into two groups. Thirty patients received 1 g/kg clonidine (group I) and the rest received 2 g/kg clonidine (group II) added to 30 mL of 0.5% bupivacaine through nerve stimulator-guided supraclavicular BPB. The onset and duration of sensorimotor blockade, hemodynamic variables, duration of analgesia, level of sedation, and adverse effects was assessed.Results:The onset of sensorimotor block was earlier in group II (9.9 ± 4.1 min for sensory block and 13.2 ± 6.7 min for motor block) than in group I (15.9 ± 6.8 min for sensory block and 18.5 ± 7.8 min for motor block). The duration of analgesia was also prolonged in patients receiving the higher dose (21.0 ± 2.96 h vs. 14.9 ± 3.0 h). Although hemodynamics remained comparable in both the groups, incidence of hypotension and bradycardia was higher in group II as compared to group I. The sedation was clinically and statistically more in group II patients (43% vs. 17%).Conclusion:Higher dose of clonidine in BPB hastens the onset, prolongs the duration of sensorimotor blockade and postoperative analgesia without significant hemodynamic alterations. It also causes more sedation, which although ensures patient comfort in most cases, but might be undesirable in certain situations.

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Introduction: Critically ill children in the pediatric intensive care unit (PICU) often receive multiple classes of sedatives and analgesics for comfort and safety. Dexmedetomidine is frequently added when a child proves challenging to sedate with traditional opioid and benzodiazepine regimens. Discontinuation of prolonged infusions of high dose dexmedetomidine may result in a clinical withdrawal syndrome similar to opioid withdrawal, and clonidine is utilized to treat children experiencing withdrawal. Hypothesis: We hypothesize that longer duration and higher dose of dexmedetomidine is associated with clinical withdrawal syndrome and discharge home on transdermal or oral clonidine. Methods: We performed a retrospective chart review from June 2011 to June 2012 of all children who received dexmedetomidine for sedation in the pediatric intensive care unit. Dosing variables for dexmedetomidine, concurrent administration of other sedatives, and documentation of withdrawal with the Withdrawal Assessment Tool (WAT-1) were collected. Results: 37 children received dexmedetomidine during the 12-month period studied. The average daily dose of dexmedetomidine was 1.1 mcg/kg/hour and the mean duration of administration was 12.2 days. 10 children (27%) were discharged home on clonidine. The presence of greater than two concurrent sedatives at the time of dexmedetomidine initiation was predictive of longer dexmedetomidine duration and higher average daily dose. Longer duration of dexmedetomidine was associated with increased WAT scores within 24 hours of discontinuation and higher doses of clonidine upon discharge to home. After adjustment for age, sex and duration of intubation, dexmedetomidine dose and duration were not associated with survival to discharge. Conclusions: These data support the role of dexmedetomidine as a cause of physiologic withdrawal in critically ill children receiving sedatives. As dexmedetomidine use becomes more widespread in the critically ill pediatric population, further research is necessary to determine the physiologic effects of discontinuation of this drug after prolonged duration of therapy, and long-term outcomes in children discharged home on clonidine.

Cardiovascular withdrawal effects of clonidine and tiamenidine on abrupt cessation of oral treatment in conscious cats.

In conscious renal hypertensive cats prepared with permanent indwelling arterial catheters oral administration of clonidine (0.05 mg x 3 daily) clonidine (0.0125 mg x 3 daily), or tiamenidine (0.25 mg x 3 daily) induced hypotension and bradycardia during 6 days of treatment, although these responses were not well sustained. A pronounced tachycardia was demonstrated in all cats, 16-20 h after cessation of treatment with the higher dose of clonidine, however, only two cats in this group showed increased blood pressures above pre-dose levels at this time; these 'withdrawal' effects were absent 44 h after the final dose. No evidence of tachycardia, or blood pressure overshoot was seen up to 44 h after cessation of the low clonidine treatment regime, providing evidence for a dose-withdrawal effect relationship. Significant tachycardia was demonstrated in all cats 15-19 h after cessation of treatment with tiamenidine with no evidence of blood pressure elevation; the tachycardia was absent 48 h after the final dose. In four of these same cats clonidine (0.1 mg x 2 daily), in a long-acting, sustained release formulation (LA clonidine), elicited prolonged falls in blood pressure and heart rate over a 10 day period. No evidence of withdrawal effects were obtained 14-48 h after cessation of this treatment.

Location of the mechanism of the clonidine withdrawal tachycardia in rats.

Withdrawal of chronic infusion of clonidine elicits severe tachycardia and short-lasting blood pressure elevations (upswings). Withdrawal of clonidine in low dosage (30 micrograms kg-1 day-1 i.c.v., 7 days) elicited a maximum of 10.9 +/- 0.5 upswings h-1. Cessation of s.c. infusion of clonidine (30 micrograms kg-1 day-1 7 days) evoked a maximum of 1.9 +/- 0.5 upswings h-1. After cessation of the two clonidine infusions no overshoot of heart rate occurred. Withdrawal of a higher dose of clonidine (300 micrograms kg-1 day-1 s.c., 7 days), however, induced tachycardia (from 302 +/- 8 to 433 +/- 8 beats min-1) and 7.6 +/- 1.4 upswings h-1. The administration of the alpha 2-adrenoceptor antagonist yohimbine precipitated withdrawal tachycardia in animals treated with oxymetazoline, a hydrophilic alpha-adrenoceptor agonist. Yohimbine (3 mg kg-1 i.p.) precipitated a severe rise in heart rate from 285 +/- 14 to 520 +/- 5 beats min-1 in oxymetazoline (300 micrograms kg-1 day-1 s.c., 7 days) treated rats and from 320 +/- 13 to 420 +/- 11 beats min-1 in saline-treated animals. Upswings were not induced by yohimbine treatment. It is concluded, that the blood pressure upswings after clonidine withdrawal are due to a central mechanism, whereas the mechanism of the overshoot of heart rate is located peripherally, probably at the cardiac presynaptic level.

Unexplained high fever in an elderly patient treated with clonidine, duloxetine, and atorvastatin

Background: Drug-induced fever is a clinical diagnosis and should always be considered when the fever is constant and high without a clear source of infection. Although drug-induced fever has been reported with other centrally acting antihypertensive drugs such as methyldopa, published reports of this adverse effect with clonidine in humans were not identified in a search of the literature. Case summary: A 66-year-old institutionalized white female with a history of morbid obesity (body mass index, 40 kg/m2), Alzheimer's dementia, hypertension, and depression presented to a hospital in Boston, Massachusetts (Caritas Saint Elizabeth's Medical Center) with generalized weakness and shortness of breath and was found to have a non-ST segment elevation myocardial infarction. Before hospitalization, the patient was taking memantine 10 mg PO BID, donepezil 10 mg PO once daily, duloxetine 60 mg PO once daily, clonidine 0.1 mg PO TID, metoprolol 50 mg PO BID, and amlodipine 10 mg PO once daily. On admission, the patient was initiated on aspirin 325 mg, atorvastatin 80 mg, and clopidogrel 75 mg PO daily. Her dose of clonidine was increased to 0.2 mg PO TID to optimize blood pressure control, and metoprolol and amlodipine were continued at the same doses. The patient developed fever on the third day after the cardiac catheterization. The fever ranged from 99.0°F to 102.7°F. The physical examination, laboratory data analysis, multiple blood cultures, urinalysis, chest radiograph, and a computed tomography of the head, chest, abdomen, and pelvis did not reveal any source of infection. On the sixth day after admission, clonidine was reduced to the baseline dose of 0.1 mg PO TID and on the ninth day it was stopped. The patient was afebrile on the twelfth day and remained so for the duration of her hospitalization. Naranjo scores for her newly initiated concomitant medications were as follows: aspirin, 1; atorvastatin, 3; clonidine, 6; and clopidogrel, 1. The rating of 6 for clonidine suggests that it was probably associated with the fever in this patient. Conclusion: We describe a case of drug-induced fever probably associated with clonidine administration. The higher dose of clonidine alone or in interaction with duloxetine and atorvastatin may have contributed to the development of drug-induced fever.

Acupoint Stimulation With Diluted Bee Venom (Apipuncture) Potentiates the Analgesic Effect of Intrathecal Clonidine in the Rodent Formalin Test and in a Neuropathic Pain Model

Although intrathecal (i.t.) administration of the alpha(2)-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an alpha(2)-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects. This study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.

Discrepant Antihypertensive Dose Recommendations

In 1997 and 2003 the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension (JNC VI and JNC VII) gave beginning dose recommendations for antihypertensive drugs that were lower than those found in drug package inserts and the Physicians’ Desk Reference (PDR). Popular handheld Personal Digital Assistant (PDA) programs recommended the JNC starting dose only 35% of the time and standard textbooks 34% of the time. Prescribing patterns at an academic medical center reflected PDR guidelines for the thiazide diuretics and a calcium channel blocker, but they were closer to JNC guidelines for beta adrenergic blockers. The higher thiazide doses recommended by the PDR were associated with hypokalemia. The PDR gives 2.4 mg of clonidine daily as the maximum effective dose, twice the maximum dose recommended by the JNC. High clonidine doses were used 14% of the time in inpatients and in 9% of outpatient prescriptions at an academic medical center, even though high doses of clonidine raise rather than lower blood pressure. When recommendations for high doses of antihypertensive medications in the package insert conflict with JNC recommendations, the package insert recommendations carry through to the PDR, textbooks, PDAs, and to some physician prescriptions.

Sympatho-modulatory therapies in perioperative medicine

With increasing life expectancy and improved surgical technology an ever-larger number of elderly patients with cardiovascular disease, or significant cardiovascular risk factors will undergo major surgery. More than 5% of an unselected surgical population undergoing non-cardiac surgery will suffer from perioperative cardiovascular complications including myocardial infarction and cardiac death. The incidence of adverse cardiac events may even reach 30% in high-risk patients undergoing vascular surgery causing a substantial financial burden of perioperative health care costs. 59 Thus, all therapeutic measures should be undertaken to reach the challenging goal of a lower incidence of perioperative cardiovascular complications. Gaining control over sympathetic nervous system activity, that is blunting the adrenergic response to the surgical trauma, traditionally represents an important aspect of anaesthetic practice. 21 Anaesthesiology has been regarded as the ‘practice of autonomic nervous system medicine’. While variable and moderate changes in sympathetic nervous system activity function as a servo-control mechanism and are even required to maintain and optimize cardiac performance, undue liberation of excitotoxic substances such as catecholamines and inflammatory cytokines, particularly during emergence from anaesthesia and the painful postoperative period, facilitates the occurrence of cardiovascular complications. 83 84 At this point, the life-supporting adrenergic drive (‘fight-or-flight-response’) turns into a potentially hazardous life-threatening maladaptation. In support of this concept, the beneficial effects of antiadrenergic treatment regimens in perioperative medicine have been confirmed, in observational studies, metaanalyses 55 1 66 and randomized controlled clinical trials. 43 54 59 63 80 84 However, the seemingly established concept of ‘sympatholysis’ as an effective cardioprotective treatment modality needs considerable refinement in the light of the many new experimental and clinical findings. The parlance of ‘sympatholytic’ protection erroneously equates annihilation of any type of adrenergic stimulation with cardioprotection and should be replaced by ‘sympathomodulatory’protection. The present review summarizes findings from large-scale heart failure trials and discusses basic and clinical aspects of individual sympatho-modulatory therapies, as currently used in perioperative medicine, including b-adrenergic antagonism, a2-agonism, and regional anaesthetic techniques. For limitation of space, reviews will often be cited where further references to the primary literature may be found.

Modulation of θ rhythmicity in the medial septal neurons and the hippocampal electroencephalogram in the awake rabbit via actions at noradrenergic α2-receptors ☆

The modulation of the firing discharge of medial septal neurons and of the hippocampal electroencephalogram (EEG) mediated by actions on α2-adrenoreceptors (ARs) was investigated in awake rabbits. Bilateral i.c.v. infusion of a relatively low dose (0.5 μg) of the α2-AR agonist clonidine produced a reduction in the θ rhythmicity of both medial septal neurons and the hippocampal EEG. In contrast, a high dose of clonidine (5 μg) increased the percentage and degree of rhythmicity of θ bursting medial septal neurons as well as the θ power of the hippocampal EEG. On the other hand, administration of α2-AR antagonist idazoxan produced the opposite dose-dependent effect. While a low dose of the antagonist (20 μg) produced an increase in both the θ rhythmicity of medial septal neurons and the θ power of the hippocampal EEG, a high dose (100 μg) caused a reduction of θ rhythmicity in both the medial septum and hippocampus. These results suggest that low doses of α2-ARs agents may act at autoreceptors regulating the synaptic release of noradrenaline, while high doses of α2-ARs drugs may have a predominant postsynaptic action. Similar results were observed after local injection of the α2-AR drugs into the medial septum suggesting that the effects induced by the i.c.v. infusion were primarily mediated at the medial septal level. We suggest that noradrenergic transmission via the postsynaptic α2-ARs produces fast and strong activation of the septohippocampal system in situations that require urgent selective attention to functionally significant information (alert, aware), whereas the action via the presynaptic α2-ARs allows a quick return of the activity to the initial level.

Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus

Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA3 pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1–4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT1B autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 μg/kg, i.v.), which assesses α2-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT1A receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT1A receptors might be attributable in part to a desensitization of α2-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.

Alpha 2 agonists in regional anesthesia and analgesia

Clonidine is a partial alpha 2 adrenergic agonist that has a variety of different actions including antihypertensive effects as well as the ability to potentiate the effects of local anesthetics. It can provide pain relief by an opioid-independent mechanism. It has been shown to result in the prolongation of the sensory blockade and a reduction in the amount or concentration of local anesthetic required to produce perioperative analgesia. Different routes for the administration of regional anesthesia, including intravenous, intrathecal and epidural ones, as well as the addition of clonidine for peripheral neural blockade, have been described. It has been also used for intra-articular administration. The latest articles describing the use of clonidine in regional anesthesia are discussed. Most authors agree that the use of clonidine for regional neural blockade in combination with a local anesthetic results in increased duration of sensory blockade with no difference in onset time. The addition of clonidine to the local anesthetic opioid mixtures seems to produce analgesia of longer duration, more rapid onset and higher quality. The higher doses of clonidine were associated with a more cephalad spread of the spinal blockade and increased sedation and hypertension. When clonidine is added to a fentanyl-bupivacaine mixture for epidural labor analgesia, it seems to provide satisfactory analgesia of a longer duration than that produced by the fentanyl-bupivacaine combination alone. Similar results were found when epidural analgesia using levobupivacaine with clonidine was used in patients undergoing total hip arthroplasty. Less clear results were seen when clonidine was used for caudal anesthesia in a pediatric patient population. The addition of clonidine to intravenous regional anesthesia resulted in prolongation of the tourniquet time and improvement of postoperative analgesia. However, the latter was found to be short-lived. In another study, the effects of clonidine used for intra-articular administration in combination with morphine were investigated. These authors found a significantly higher rate of satisfaction in the group of patients receiving clonidine plus morphine. Although several recent studies have shown certain benefits from the use of clonidine for regional anesthesia, further investigations are necessary to clarify its role.

Clonidine fails to modify dopaminergic neuronal activity during morphine withdrawal

Cellular substrates of opiate withdrawal syndrome involve several brain areas, in particular the mesolimbic dopaminergic and noradrenergic systems, but the interactions between the two pathways remain unclear. The aim of the present work was to investigate the effects of the alpha2-agonist clonidine on ventral tegmental area dopamine neurons during morphine withdrawal syndrome by recording their neuronal activity before and after the administration of low and relatively high doses of clonidine (from 5 to 100 microg/kg). The spontaneous neuronal activity of meso-accumbens dopaminergic neurons, identified by antidromical stimulation from the nucleus accumbens, was recorded by use of in vivo extracellular single-unit recordings in control and morphine-withdrawn rats after chronic administration (15 days). Control rats showed a mean spontaneous firing frequency of 2.47+/-0.48 Hz, percentage of burst firing of 22+/-12 and an increase in firing after the administration of cumulative doses of clonidine (5, 10, 20, 40, 100 microg/kg). Conversely, both spontaneous firing rate (1.55+/-0.25 Hz) and the percentage of burst firing (5+/-2) were found to be significantly reduced in rats abstinent for 24 h, and increasing doses of clonidine did not re-establish electrophysiological activity observed in the controls. The results indicate that: 1) clonidine did not restore the decreased firing activity of DA neurons in morphine-withdrawn rats, and 2) high doses of clonidine increased firing in control rats but not in morphine-withdrawn rats.