Clonidine in Anesthesiology: A Brief Review

Background and Aims: The alpha-2-adrenergic mechanism has been explored for a long time in anesthesiology. Clonidine belongs to this class and has some interesting characteristics for this specialty.

Kidney Effects: Alpha-2-adrenergic receptors induce diuretic and natriuretic effects in the renal system. Αlpha-2 agonist drugs also inhibit the release of the antidiuretic hormone and antagonize its action in the renal tubule. Unlike opioids, they do not present a urinary retention effect [24,25].
Endocrine Effects: Clonidine is a powerful sympatholytic agent. It reduces the secretion of noradrenaline, adrenaline, ACTH, cortisol. It stimulates the release of growth hormone [26]. As a direct effect on the alpha-2 receptors of the pancreatic Langerhans cells, they inhibit insulin secretion, which may increase glycemia, but without relevant clinical consequences [1].

Clonidine uses in anesthesia
Systemic Use: In anesthesia, clonidine can be used by the oral, intravenous, epidural or intrathecal routes. As a premedication, a dose of 2 to 4μg/kg orally provides sedation, hypnosis and antisialogogue effect [27]; attenuates perioperative hemodynamic instability, spares need for anesthetics during surgery, and reduces the need for postoperative analgesics [1,9,10,12,[28][29][30]. It has a propofol sparing effect, reducing the needs of this venous anesthetic [8,31]. In a meta-analysis about systemic clonidine, either orally pre-anesthetic or intraoperative venous administered clonidine, showed that the use of this drug reduces opioid consumption and postoperative pain scores in the first 24 hours, and incidence of nausea in the first 8 hours, but at the expense of lower intraoperative blood pressure levels (not clinically impacting) [4]. Clonidine has been used to attenuate symptoms resulting from withdrawal of opioids, alcohol and benzodiazepines, with encouraging results [32]. Clonidine also has benefit in the treatment of postoperative tremors, with efficacy equivalent to dolantine, but without the adverse effects of this drug [33].

Epidural use
Epidural clonidine may be used at a dose of 2 to 4μg/kg and it prolongs the time and improves the quality of analgesia and motor blockade of the associated local anesthetic, with a sedative effect. It can be used continuously at the dose of 30μg/h [1]. In children, it can be used in sacral epidural block at a dose of 1 to 2μg/kg, which results in a longer duration of postoperative analgesia, without major hemodynamic changes [34]. In the treatment of chronic cancer pain, it has already been used epidurally in the dose of 10-50μg/h, when the response to opioids is no longer satisfactory [35].

Spinal use
At the dose of 1 to 2μg / kg, clonidine has its most pronounced effects when administered intrathecally [1]. As an adjunct to local anesthetics, the drug prolongs sensory and motor blockade without resulting in the typical adverse effects of opioids (urinary retention and respiratory depression, for example) [36,37]. A recent metaanalysis evaluated the efficacy of adding clonidine to morphine in spinal anesthesia in acute postoperative pain and concluded that this drug prolongs the time of analgesia, with a longer time interval for the first analgesic demand and reduces the total dose of morphine used for analgesic rescue [3]. The association of clonidine to spinal local anesthetics has also been the subject of a systematic review, showing that alpha-2-adrenergic agonists increase the duration of motor blockade, improve intraoperative analgesia, and delay motor block regression and the interval for first demand analgesic. The main adverse effect observed is intraoperative hypotension [5].
In obstetrics, the use of clonidine as an adjuvant to cesarean section anesthesia is well established, with several studies showing many benefits. In the immediate postoperative period of patients undergoing cesarean delivery under general anesthesia, 150μg of clonidine alone was administered intrathecally in the immediate postoperative period and compared with placebo, concluding that clonidine induces effective analgesia at this dose for an average of 6 hours, but not without side effects such as hypotension, sedation and dry mouth [38]. Benhamou and colleagues assigned 78 women to undergo cesarean section in groups who received spinal anesthesia with isolated bupivacaine, clonidine(75μg)-bupivacaine association or clonidine(75μg)-fentanyl (12.5μg)-bupivacaine association. After intra and postoperative analysis, the groups receiving clonidine associated with bupivacaine and clonidine associated with fentanyl and bupivacaine showed superior intraoperative analgesia, with no higher frequencies of hypotension, greater need for ephedrine or lower levels of the Apgar score in the newborns. The group receiving bupivacaine, clonidine and fentanyl had better intraoperative analgesia, longer time of postoperative analgesia, and higher sedation rates when compared to the other groups, although this sedation did not exceed moderate levels [39].
The Paech group performed a randomized clinical study on 240 patients and concluded that the subarachnoid combination of 100μg morphine with clonidine for spinal anesthesia in cesarean sections significantly improves postoperative pain relief but increases sedation. He further compared groups with different doses of clonidine, suggesting that the minimum effective dose for spinal clonidine is 30 to 60μg, combined with bupivacaine and fentanyl [40]. In Brazil, a recent study by Neves et al. demonstrated that the addition of clonidine to spinal anesthesia with 0.5% hyperbaric bupivacaine (12.5mg) and morphine (100μg) for cesarean section improved the quality of postoperative analgesia without increasing the incidence of side effects [41]. In the Netherlands, van Tuijl compared the use of bupivacaine alone to the use of bupivacaine associated with 75μg of clonidine in cesarean spinal anesthesia,

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concluding that clonidine prolonged the analgesia considerably and improved early analgesia, but there was no difference in total consumption of postoperative morphine, only in time to the first demand.
There were no maternal or neonatal side effects [42]. In 2008, Lavand'homme investigated the anti hyperalgesic effects of clonidine. She compared groups of parturients submitted to elective cesarean sections under spinal anesthesia with bupivacaine associated with fentanyl, bupivacaine associated with fentanyl and clonidine, and bupivacaine associated with clonidine. She concluded that the combination of clonidine and spinal bupivacaine had a significant effect on the reduction of the area and the incidence of peri-incisional mechanical hyperalgesia in the first 48 hours of the postoperative period, with no significant side effects [43]. In 2011, Kothari and his co-researchers demonstrated that the u se of clonidine can reduce bupivacaine doses in cesarean section, maintaining adequate motor blockade and prolonging postoperative analgesia, although the use of clonidine has been implicated in higher frequency of certain adverse effects (mild sedation) [44].

Conclusion
In patients submitted to surgeries under general anesthesia, there is evidence that perioperative use of systemic clonidine (either as a premedication or as an intraoperative adjuvant) reduces postoperative opioid consumption, pain intensity, and incidence of nausea. However, the increased risk of intra-and postoperative hypotension and bradycardia should be taken into account when deciding on the systemic use of this drug. The addition of clonidine to the neuroaxis (intrathecal or epidural) increases the duration of motor blockade, improves the quality of intraoperative analgesia, delays the regression of the sensory blockade, and prolongs postoperative analgesia with later requests for rescue. As with the systemic route, the main intraoperative adverse effect is hypotension.