Dexmedetomidine as a preanaesthetic agent ‐ Phase I‐III studies with a novel, specificα 2 ‐adrenoceptor agonist

For more than two decades,α 2 ‐adrenoceptor agonists have been used in veterinary practice as sedative‐analgesics, although their mechanism of action was defined as being linked to activation of centralα 2 ‐adrenoceptors as late as 1981. Medetomidine is the latestα 2 ‐adrenoceptor agonist approved to be used as a small animal sedative‐anaesthetic agent. Medetomidine possesses more potency and efficacy atα 2 ‐adrenoceptors than any of the previousα 2 ‐agonists. In animals, the characteristic effects of medetomidine include sedation, muscle relaxation, analgesia, bradycardia, reduction of blood pressure and diuresis. In the last 10 years, clonidine, the prototype ofα 2 ‐adrenoceptor agonists and an antihypertensive agent, has gained much attention among anaesthesiologists. Clonidine has several clinically desirable effects, such as sedation, anxiolysis, anaesthetic sparing and cardiovascular stabilizing properties. In addition, analgesia, reduced intraocular pressure, decreased salivary secretion and sympatholytic effects of clonidine have been confirmed in clinical studies. Thus,α 2 ‐adrenoceptor agonists represent a novel group of drugs in anaesthetic practice. Clonidine has been the only clinically available preparation ofα 2 ‐agonists for humans and that is the reason why almost all studies evaluating their anaesthesiological usefulness have been conducted with clonidine. Alpha 2 ‐adrenoceptor agonists are considered to provide analgesia without sensory or motor blockade associated with local anaesthetics or without the dose‐limiting side‐effects of opioids (i.e. nausea, pruritus, uinary retention, or potential respiratory depression). Furthermore,α 2 ‐agonists may offer an alternative in patients developing tolerance to opioids or in those forms of pain with poor response to opioid analgesics, like sympathetically maintained neuropathic pain. Dexmedetomidine, the pharmacologically active dextroisomer of medetomidine, is a more potent and selective agonist towards theα 2 ‐adrenoceptors than clonidine. Dexmedetomidine acts as a full agonist in some pharmacological test models, where clonidine displays only a partial agonistic effect. In animal studies, dexmedetomidine has reduced the MAC of inhalational anaesthetics in a dose‐dependent manner almost to zero. It has even been suggested that dexmedetomidine may act as an anaesthetic agent itself. One of the significant benefits of the perioperative use of dexmedetomidine may be increased adrenergic and hence cardiovascular stability. The central sympatholytic effect of dexmedetomidine attenuates the responses to noxious stimuli of anaesthesia and surgery and reduces plasma catecholamine concentrations. Previously, dexmedetomidine has been investigated in patients undergoing gynaecological surgery. The present study was carried out to assess the analgesic effects of dexmedetomidine and to evaluate the efficacy of dexmedetomidine premedication in patients undergoing different types of surgery. Studies involved 5 healthy male volunteers and 272 ASA physical status I‐II patients undergoing abdominal hysterectomy, cholecystectomy, intraocular surgery or minor day‐case hand surgery. In healthy volunteers, the analgesic effect of dexmedetomidine was not clearly dose‐dependent and was inferior to the effect of a potent opioid, fentanyl, but differed significantly from placebo. In hand surgery patients, dexmedetomidine premedication reduced the need for intraoperative fentanyl supplementation to alleviate pressure of the tourniquet when compared with the placebo control group. A single intravenous dose of dexmedetomidine before regional or general anaesthesia was not associated with postoperative opioid potentiation or significant analgesic effect. The analgesic treatment schedule of the study was not, however, optimal to assess this effect Dexmedetomidine effectively induced sedation and anxiolysis in subjective VAS estimates when administered as a single i.v. bolus before intravenous regional anaesthesia or as an i.m. premedication before general anaesthesia. Sedation and anxiolysis were comparable with the effects of i.m. midazolam premedication. Dexmedetomidine reduced the induction dose of thiopentone by 23% and the intraoperative fentanyl requirements by nearly 60%. Similarly, the need for additional isoflurane supplementation was reduced after dexmedetomidine. Thus, dexmedetomidine seems to have potentiating effects on volatile as well as on opioid anaesthetics. In the first outpatient study which evaluated the sympathoadrenal responses after dexmedetomidine, a more than 2‐fold increase in the plasma concentrations of adrenaline induced by a tourniquet was effectively inhibited by dexmedetomidine. Otherwise, dexmedetomidine induced up to 75% decreases in plasma noradrenaline concentrations both in outpatients with regional anaesthesia as well as in patients treated with general anaesthesia One of the major findings of the study was that a single dose of dexmedetomidine possesses significant cardiovascular activity. Generally, dexmedetomidine reduced systemic blood pressure and heart rate by approximately 15–20%, which mostly subsided within 2–4 h postoperatively. Dexmedetomidine attenuated the haemodynamic response to anaesthesia and surgery, but was associated with an increased incidence of hypotension and bradycardia. Therefore, anticholinergic treatment is indicated as a supplement to dexmedetomidine. Due to its haemodynamic side‐effects, dexmedetomidine may not be recommended as a routine premedication. The cardiovascular stabilizing effects of dexmedetomidine should, however, be investigated in those patients most vulnerable to acute haemodynamic changes, e.g. patients with hypertension and/or with an already compromised cardiovascular system undergoing major surgery. Intraocular pressure was reduced by 34% within 10 min after a single i.v. dose of dexmedetomidine. Similarly, dexmedetomidine effectively prevented the rise of intraocular pressure in response to tracheal intubation. In conclusion, dexmedetomidine has potentially many desirable properties in the perioperative setting: sedation, anxiolysis, analgesia and reduced dose requirements of anaesthetic and analgesic drugs probably without major respiratory depression. Furthermore, dexmedetomidine induces good control of haemodynamic and adrenergic responses to noxious stimuli, which results in a more favourable cardiovascular profile and thus may improve the myocardial oxygen supply/demand ratio. It seems evident, however, that dexmedetomidine is insufficient in producing clinically adequate anaesthesia by itself, because the haemodynamic side‐effects may prevent the administration of anaesthetic doses. Development of new, better targetedα 2 ‐subtype selective agents may allow separation of wanted (sedation, analgesia) from unwanted (haemodynamic) clinical effects. Thus, according to our present knowledge, dexmedetomidine will remain mainly as an anaesthetic adjuvant to be used in combination with other agents for balanced anaesthesia and analgesia.