Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

One of the theories on the biology of panic disorder which received much attention is the locus coeruleus hypothesis. This hypothesis states that there exists an episodic overactivity of noradrenergic systems in panic disorder. Experiments with yohimbine form the cornerstone of this theory, and additional supporting evidence is provided by challenge studies with isoproterenol and treatment studies with clonidine. These studies are critically reviewed and it is argued that based upon the studies with yohimbine one cannot conclude that there is a specific noradrenergic abnormality in panic disorder, since yohimbine also affects dopaminergic and serotoninergic neurons in the brain.

In an alternative theory on the relationship between noradrenaline and anxiety it is postulated that increases in anxiety, irrespective of the diagnostic category, are related to increases in locus coeruleus activity.

Summary

Background and objective: An anti-inflammatory effect of α2-adrenoreceptor agonists has been suggested. Phospholipase A2 is a key enzyme in the production of precursors of inflammatory lipid mediators. The aim of the present study was to investigate the effect of clonidine on phospholipase A2 activity in an established in vitro model. Methods: Human being platelet membranes containing active phospholipase A2 were exposed to buffer control or to three increasing concentrations of clonidine. Phospholipase A2 was measured by a radioisotope technique. Results: A massive increase in phospholipase A2 activity was measured after clonidine exposure leading to final values of 92.5 ± 3.1 pmol mg protein−1 min−1 (4.5-fold higher than control values; P ≤ 0.01 vs. control). After clonidine exposure the maximal reaction velocity increased, while the Michaelis–Menten constant did not change. The Lineweaver–Burk representation suggested an interaction of clonidine with the phospholipase A2–substrate complex as well as the phospholipase A2 molecule. Conclusion: We conclude that the putative anti-inflammatory effect of clonidine was not caused by inhibition of phospholipase A2.

Summary

Background and objective: Clonidine, which is used for induction of sympatholysis and prevention or treatment of alcohol withdrawal in anaesthesia and intensive care medicine, may have deleterious effects on intestinal mucosal perfusion. This study was designed to investigate the effects of clonidine on intestinal perfusion and oxygenation. Methods: Following ethical approval 17 anaesthetized, and acutely instrumented pigs were randomly assigned to two groups: eight animals received intravenous clonidine (2 μg kg−1 bolus and 2 μg kg−1 h−1), nine animals served as a control group. Measurement points for systemic and regional haemodynamic and oxygenation parameters were 135 and 315 min after starting the clonidine application. Results: Clonidine elicited systemic haemodynamic changes (median [25–75th interquartile range]): heart rate (106 [91, 126] to 84 [71, 90] beats min−1) cardiac output (147 [123, 193] to 90 [87, 107] mL min−1 kg−1) and mean arterial pressure (77 [72, 93] to 69 [61, 78] mmHg) decreased. Despite systemic haemodynamic changes, the superior mesenteric artery blood flow did not change in the clonidine group. The vascular resistance of the superior mesenteric artery decreased. The small intestinal oxygen supply, the mucosal and the serosal tissue oxygen partial pressure did not change. Conclusions: Systemic sympatholysis induced by intravenously applied clonidine in addition to basic intravenous anaesthesia elicited a decrease in cardiac output and mean arterial pressure. However, regional macrohaemodynamic perfusion was maintained and intestinal oxygenation did not change. Clonidine does not impair intestinal mucosal and serosal oxygenation under physiological conditions.

Background and objective: The aim was to determine if the intravenous administration of sufentanil or clonidine before the induction of anaesthesia could obtund the increase of intraocular pressure associated with rapid-sequence induction.

Methods: Thirty-two ASA I—II patients with no history of eye illness scheduled for elective non-ophthalmic surgery were randomly assigned to receive either sufentanil 0.05 µg kg−1 i.v. (Group A, n = 15) or clonidine 2 µg kg−1 i.v. (Group B, n = 17) prior to induction. General anaesthesia was induced with thiopental (5 mg kg−1) followed by succinylcholine 1 mg kg−1 to facilitate tracheal intubation. The general anaesthetic technique was standardized in both groups. Intraocular pressure was measured using the Schioetz tonometer just before the succinylcholine administration (t0), just before tracheal intubation (t1) and immediately after intubation (t2). Mean arterial pressure and heart rate were recorded at the same time intervals.

Results: Intraocular pressures were similar in both groups at t0, but the sufentanil group had significantly lower values compared with the clonidine group just before (t1) and immediately after tracheal intubation (t2).

Conclusions: Sufentanil is effective in blunting the increase in intraocular pressure caused by rapid-sequence induction with succinylcholine, while clonidine did not seem to have any effect in intraocular pressures just before (t1) and just after (t2) intubation.

Background and objective: The α2-adrenoceptor agonist clonidine has potent central antinociceptive properties. The study was designed to investigate the effects of the combined subarachnoid administration of clonidine and prilocaine on spinal block and postoperative analgesia for the transurethral resection of tumours in the urinary bladder.

Methods: The controlled, prospective, double-blind study enrolled 40 patients scheduled for elective transurethral resection of bladder tumours under spinal anaesthesia with prilocaine. Patients were randomly assigned to receive an intrathecal injection of prilocaine 75 mg alone (control group) or in combination with clonidine 75 µg. We assessed haemodynamic changes (non-invasive arterial pressure, heart rate), pulse oximetry, the upper level of block, the onset and duration of sensory and motor block, postoperative analgesia and any adverse effects.

Results: There were no statistically significant differences in demographic data, heart rate, onset time or the levels of sensory or motor block. Analgesia lasted significantly longer in the clonidine group (498.4 ± 226.9 versus 187.2 ± 103.1 min; P < 0.05). The duration of motor block was longer in the clonidine group (165.5 ± 30.6 min) than in the control group (139.7 ± 40.4 min; P < 0.05) and the duration of sensory block was also longer in the clonidine group (157.3 ± 24.5 min) than in the control group (137.2 ± 31.2 min; P < 0.05). Fewer patients in the recovery room needed metamizol (dipyrone) in the clonidine group (5%) than in the control group (50%). Arterial pressure decreased significantly in the clonidine group 75-135 min after the block.

Conclusions: The addition of clonidine 75 µg to prilocaine 75 mg for subarachnoid anaesthesia increased the duration of sensory and motor block and reduced the need for additional postoperative analgesics by providing excellent analgesia for about 8 h during recovery from transurethral resection of bladder tumours.

Background and objective: The effects of clonidine and dopamine, both alone and together, on gastric tone were studied using an electronic barostat. This enabled volume changes to be measured in an intragastric bag with constant preset pressure.

Methods: Nine healthy male volunteers were each studied on two occasions in a randomized order. During each study period, a continuous infusion of dopamine was given, starting with a dose of 2.5 μg kg−1 min−1 and then increasing at 15-min intervals to 5.0 and 7.5 μg kg−1min 2 1. Clonidine 150 μg intravenously was given on one occasion during the infusion of dopamine (7.5 μg kg−1min−1) and on the other occasion 15 min before the dopamine infusion started.

Results: During dopamine infusion, the intragastric bag volume increased (gastric tone therefore decreasing) in a dose-related manner (total increase 290 6 114 mL). Clonidine given either during or before dopamine infusion did not influence the bag volume. When the dopamine infusion started 15 min after clonidine, the bag volume did not change until the infusion of dopamine reached 7.5 μg kg−1min−1(total increase 205 6 156 mL).

Conclusions: Dopamine reduced gastric tone in a dose-related manner, and clonidine did not influence gastric tone per se. If clonidine is given before dopamine, the effects of dopamine are reduced.

Background and objective This study compares the effect of oral clonidine vs. hydroxyzine on the haemodynamic and catecholamine responses to microlaryngoscopy.

Methods Thirty-five ASA II-III patients were included in this double-blind randomized trial. The patients received either hydroxyzine 1 mg kg−1 (n=18) or clonidine 3 μg kg−1 (n = 17) for their oral premedication 100 min before an intravenous induction of anaesthesia using propofol (2–3 mg kg−1) and fentanyl (2 μg kg−1). Arterial pressure and heart rate were measured before premedication, and throughout the procedure and recovery. Plasma catecholamine levels were determined before premedication, after induction, and 1.5, 30 and 120 min after laryngoscopy.

Results Mean arterial pressure was significantly lower after clonidine, whereas there was no difference in heart rate and plasma catecholamine levels between the two groups.

Conclusions Clonidine for premedication significantly decreased mean arterial pressure during microlaryngoscopy and the following recovery phase but did not modify the overall haemodynamic response to the suspension microlaryngoscopic nociceptive stimulus.

Alpha-adrenergic agonists produce pain relief through an opioid independent mechanism and may be alternatives to opioids for combination with local anaesthetics for analgesia during labour. We studied 41 pregnant women. Epidural block was performed with 75 μg clonidine (n=20) or 50 μg fentanyl (n=21) combined with 0.125% bupivacaine (10 mL). Maternal vital parameters were measured. Analgesia was evaluated using a visual analogue scale (VAS); sedation was scored using a five-point scale. There were no differences in maternal vital parameters, fetal heart rate (FHR) or Apgar scores between the groups. Analgesia lasted longer in the bupivacaine-clonidine group (139.4±31 min) compared with the bupivacaine–fentanyl group (127.9±48 min) (P=0.42). Additional analgesic requirement was more often in the fentany–bupivacaine group and total bupivacaine requirement was less in the clonidine–bupivacaine group (22.5±12.5mg vs. 30.9±12.8 mg) (P=0.04). This small study confirms that this combination of bupivacaine and clonidine provides satisfactory analgesia for first-stage labour, and of longer duration than bupivacaine–fentanyl.

The aim of this study was to evaluate whether the addition of clonidine, or sufentanil, or both, to a bupivacaine solution for a caudal block prolonged the period of analgesia after operation in children. Sixty ASA class I or II boys, aged between 8 months and 13 years, admitted for hypospadias repair were enrolled into a prospective randomised study. After induction of general anaesthesia and endotracheal intubation the children were allocated into four groups. Group I received 0.5 mL kg−1 bupivacaine 0.25% caudally, in addition group II received 1 mg kg−1 clonidine, group III 0.5 mg kg−1 sufentanil and group IV 0.5 mg kg−1 clonidine and 0.25 mg kg−1 sufentanil. The concentrations of clonidine and sufentanil in group IV were halved to reduce possible side-effects with higher dosages. Analgesia and side-effects were assessed 2, 4, 6, 8 and 12 h after operation. No significant differences were found among the four groups for the pain scores at 2, 4, 6, 8 and 12 h. All groups had a similar frequency of vomiting and a comparable appetite and quality of night rest during the first 24 h following the operation. There was no signficant difference in the requirement for additional doses of analgesics. The addition of sufentanil, or clonidine, or both, to bupivacaine for caudal administration provides no additional clinical benefit over bupivacaine alone.

Recently, it was suggested that peripherally-mediated analgesia can be accomplished by the intra-articular delivery of the mu-opioid morphine or of the a2-agonist clonidine. This clinical study assesses the potential peripheral analgesic effect of the combination of morphine and clonidine after intra-articular administration. Sixty patients (American Society of Anesthesiologists status I or II) undergoing arthroscopic repair of the knee during general anaesthesia were randomized to receive after operation, in a double-blind manner, either 1 μg morphine intra-articularly (group 1); 150 μg clonidine intra-articularly (group 2); or 1 μg morphine + 150 μg clonidine intra-articularly (group 3); or normal saline intra-articularly (group 4) in a volume of 30 mL, respectively. Visual analogue pain scores (VAS), duration of analgesia as defined by first demand for supplemental analgesics, subsequent 24 h consumption of postoperative supplementary supplementary analgesics, and patient satisfaction were evaluated. Co-administration of morphine + clonidine (group 3) resulted in a significant VAS reduction at 2 h after injection compared with the other groups. There was a tendency towards a lower need for supplementary rescue analgesia and towards a more prolonged analgesia in group 3 (211 min ± 224 min SD) compared with group 1 (173 min ± 197 min SD) and group 4 (91 min ± 21 min SD). More patients were very satisfied with the postoperative analgesic regimen receiving the combination of morphine and clonidine (group 3) at 24 h postoperatively. Thus we conclude, that the peripheral co-delivery of an opioid and an a2-agonist will result in improved postoperative pain relief, when compared with each single agent given alone.

We investigated the influence of intravenous clonidine 2, 4 and 6 μg kg−1 on the electroencephalogram and on the minimal alveolar concentration of isoflurane in 40 patients aged 20–60 years undergoing elective surgery. Minimal alveolar concentration was determined using the Dixon ‘up-and-down’ method. Thirty min after the clonidine infusion anaesthesia was induced with etomidate, 0.25 mg kg−1. Skin incision was made after stable end-tidal isoflurane concentrations had been maintained for at least 15 min. Clonidine caused significant decreases in the spectral edge (95%) and median power frequency of the electroencephalogram and in the bispectral index. The minimal alveolar concentration of isoflurane decreased in a dose-dependent manner from 1.32% (95% CI, 1.28%–1.36%) in the control group to 1.03% (0.9%–1.18%) in patients given clonidine 6 μg kg−1. Clonidine 4 and 6 μg kg−1 was associated with a moderate reduction in heart rate and arterial systolic blood pressure. We recommend the use of clonidine intravenously as an adjunct to general anaesthesia in a dose of 4 μg kg−1 given 15 min before induction of anaesthesia.

The effects of intravenous and epidural clonidine, 4 μg kg−1, combined with epidural morphine, 40 μg kg−1, on the neuro-endocrine and immune stress responses to thoracic surgery are reported. A control group received only epidural morphine. Anaesthesia was induced and maintained with propofol. Catecholamines, vasopressin, cortisol, β-endorphin concentrations and leucocyte counts were measured before drug administration, immediately after intubation of the trachea, after thoracotomy and at the end of surgery. Catecholamines did not change in any of the groups. The other stress hormones increased during surgery, the pattern being similar in the three groups. Total leucocyte and neutrophil counts were increased in all groups at the end of surgery, but the increase was least in the epidural clonidine group. The number of lymphocytes was reduced at the end of surgery in the epidural and intravenous group, compared with the control group in which the number of lymphocytes did not change. The effects are more pronounced with epidural than with intravenous administration. We conclude that clonidine can modulate the immune stress response to thoracic surgery.