The perioperative scheme of clonidine administration adopted in the main RCT [13] is the following: the night before surgery, patients received a 0.2 mg oral tablet, and a transdermal patch which continuously delivers 0.2 mg per day was applied, achieving therapeutic plasma levels 2 days after its initial application; [30] therefore, they received a further oral loading dose of 0.2 mg 1 h prior to surgery. The patch was removed on postoperative day 4. There was some evidence of clonidine withdrawal phenomena on postoperative days 5 and 6 after patch removal, which suggests that the patch should be left on and allowed to auto-taper as the drug concentration in the patch falls [31].

The therapeutic antihypertensive dose ranges from 0.2 to 0.6 mg per day given in divided doses; this dosage causes dose-dependent adverse effects such as prolonged sedation (especially in the elderly), hypotension, bradycardia, dry mouth, dizziness, and constipation.

Some pharmacological interactions should be noted. Tricyclic compounds and mirtazapine antagonize α2-adrenoceptors, which may result in a decrease in or loss of effect of clonidine. Clonidine may potentiate the Central nervous system-depressive effects of alcohol, barbiturates, benzodiazepines, or other sedating drugs. Clonidine and opioids have some synergistic effects and share a similar distribution in the brain [32], but mediate analgesia through independent receptor mechanisms; however, they both activate the same transduction and intracellular effector pathways. Therefore, clonidine allows us to reduce the perioperative opioid dose, possibly decreasing their respiratory and addictive side effects [25, 33].

The potentially life-saving role of the perioperative administration of clonidine merits further investigation. However, perioperative interventions can have unintended consequences. A large international trial demonstrated that a β-blocker reduced the risk of perioperative MI but increased the risk of stroke and death [34]. Unanticipated consequences appeared to have occurred primarily as a result of clinically important hypotension and bleeding, and also raise the issue of the risk for a possibly reduced ability to afford acute blood loss in the face of variable degrees of pharmacological sympatholysis. Although one meta-analysis [35] suggests that perioperative low-dose clonidine reduces perioperative myocardial ischemia and may prevent perioperative mortality and MIs without inducing hemodynamic instability, at least two meta-analyses [16, 25] provide counterevidence. Thus, caution is warranted in view of reported episodes of hypotension and bradycardia associated with clonidine administration.