Traditionally used as an antihypertensive agent since the late 1960s, clonidine has emerged in recent years as an adjuvant to commonly used medications for analgesia [1,2]. Given its potent sedative, anxiolytic, and analgesic properties, clonidine has gained popularity among anesthesiologists for clinical use [2].

Clonidine is available as tablets, injections, and transdermal patches [2]. It reaches its peak plasma concentration within 60-90 minutes and has a bioavailability of 75-95% [2]. As clonidine is lipid soluble, it can penetrate the blood-brain barrier to reach the hypothalamus and medulla [2]. It does not require transformation into another substance to become metabolically active [2]. Clonidine primarily stimulates alpha-2 adrenergic inhibitory neurons in the medullary vasomotor center [2]. As a result, there is less sympathetic nervous system outflow from the central nervous system to the peripheral tissues [2]. Adverse effects of clonidine are drowsiness, dry mouth, bradycardia, orthostatic hypotension, and impotence [2].

At present, there are many human studies examining the effect of clonidine as a booster for local anesthetics in peripheral nerve blockade [4]. A 2007 systematic review of clonidine as an adjunct to peripheral nerve blocks found that the literature supports its effect on prolonging the duration of analgesia and reducing postoperative analgesic requirements in adults [1,3,4]. When added to intermediate-acting local anesthetics, such as mepivacaine and lidocaine, clonidine extended analgesia primarily by increasing the duration of sensory block with no increase in onset time [4]. The ability of clonidine to modify the potassium channels in the central nervous system and therefore hyperpolarize cell membranes is thought to be the mechanism for the decrease in anesthetic requirements caused by clonidine administration [2].

A more recent 2016 study sought to evaluate clonidine as an adjuvant for propranolol on the quality and duration of cutaneous analgesia [1]. Propranolol, a beta-adrenergic receptor antagonist, has been used in the clinical environment for topical anesthesia [1]. The researchers concluded that clonidine is useful in assisting the production of complete pain sensation block without affecting the potency of propranolol [1]. Clonidine increased the depth of cutaneous analgesia produced by propranolol and increased its potency [1]. These results suggest that clonidine exerts a predominantly peripheral action in extending local anesthetic duration, as opposed to a systematic effect [1].

A few studies have investigated the dose response relationship of clonidine [4]. There is evidence that increasing the dose of clonidine prolongs analgesic effect but also increases the number of adverse events [4]. Doses as low as 30 μg have been shown to be effective in providing effective analgesia [4]. The majority of studies have reviewed a dose of 150 μg of clonidine with minimum adverse effects reported in the adult population [4].

Clonidine can also be used to premedicate the pediatric population [2]. A 2014 systematic review examined 11 trials investigating a total of 742 children to determine the effect of clonidine in reducing postoperative pain in the pediatric population [5]. The study found evidence that when clonidine is given at an adequate dose (4 μg/kg) before surgery, it is effective in reducing the analgesic requirements after surgery for children when compared to standard treatment [5]. Caudal clonidine may have a large margin of safety in healthy children as reported in three case studies where 100 times the dose for a single shot caudal was administered [2]. Apart from excessive transient somnolence, these children did not show respiratory depression or hemodynamic instability [2].

Clonidine is associated with several beneficial effects in clinical use, especially in the pediatric demographic [2]. It can provide a calm patient preoperatively, stable intraoperative hemodynamics, and a prolonged postoperative sedation without respiratory depression [2]. Due to these properties, clonidine is assuming a greater role as an anesthetic adjuvant for anesthesiologists [2].

References 

1. Hung, C., Chiu, C., Liu, K., Wang, J., & Chen, Y. (2016). Clonidine as an adjuvant for propranolol enhances its effect on infiltrative cutaneous analgesia in rats. Neuroscience letters, 616, 70-74. doi:10.1016/j.neulet.2016.01.054 

1. Basker, S., Singh, G., & Jacob, R. (2009). Clonidine in paediatrics–a review. Indian journal of anaesthesia, 53(3), 270. PMID:20640134 

1. Van Elstraete, A., Pastureau, F., Lebrun, T., & Mehdaoui, H. (2000). Caudal clonidine for postoperative analgesia in adults. British journal of anaesthesia, 84(3), 401-402. doi:10.1093/oxfordjournals.bja.a013448 

1. McCartney, C., Duggan, E., & Apatu, E. (2007). Should we add clonidine to local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature. Regional anesthesia and pain medicine, 32(4), 330-338. doi:10.1016/j.rapm.2007.02.010 

1. Lambert, P., Cyna, A., Knight, N., & Middleton, P. (2014). Clonidine premedication for postoperative analgesia in children. Cochrane Database of Systematic Reviews, (1). doi:10.1002/14651858.CD009633.pub2