Dexmedetomidine: A look at a promising new avenue of use.

Alpha (α)-2-adrenergic receptor (α2-AR) agonists have been utilized in a host of clinical scenarios secondary to the hemodynamic-stabilizing properties, sedative, analgesic, and sympatholytic pharmacologic effects of the agent.[1] In addition, α2-AR medications such as dexmedetomidine have demonstrated a dose-dependent increase in the duration of thermal antinociception and analgesia in some animal studies.[23] Therefore, many of these advantageous effects of adding dexmedetomidine to local anesthetics during regional anesthesia and peripheral nerve blockade procedures may also prove efficacious for the surgical patient. This editorial examined the study performed by Mahmoud et al., entitled “Ultrasound-guided single-injection infraclavicular brachial plexus block using bupivacaine alone or combined with dexmedetomidine for pain control in upper limb surgery[4]” (reference the article here). Assessment of this investigation looked to provide an overview and critique of the article's current clinical status along with any potential new therapeutic avenues it may suggest. Can adding dexmedetomidine to local anesthetics provide for perioperative anesthetic-sparing and reduced postoperative rescue opioid requirements?

Dexmedetomidine is a selective α2-AR agonist with evidence of an increased ratio of α2-to-α1 activity of 1620:1, as compared to 220:1 when contrasted against clonidine. The mechanism by which α2-AR agonists produce analgesia and sedation is not fully understood, but is likely to be multi-factorial. Dexmedetomidine possesses analgesic properties and many other advantageous influences, but also lacks respiratory depression[56] that may make it a useful and safe adjunct in many diverse clinical applications. Both hypnotic and supraspinal analgesic effects of dexmedetomidine are mediated by noradrenergic neurons (via hyperpolarization). This mechanism of action: 1) causes inhibition of norepinephrine release and its associated activity in the descending medullo-spinal noradrenergic pathway (secondary to activation of central α2-ARs) and 2) suppresses neuronal firing in the locus coeruleus.[27] Suppression of these inhibitory controls causes release of mediators and neurotransmitters that in turn decrease the secretion of histamine and produce hypnosis (very similar to normal sleep), all without evidence of depression of ventilation.[8] In addition, suppression of activity along the descending noradrenergic pathway (responsible for modulation of nociceptive neurotransmission) terminates propagation of pain signals, resulting in analgesia or decreased awareness of noxious stimuli.

In neurons of the superficial dorsal horn of the spinal cord, dexmedetomidine suppresses and reduces pain transmission/conduction 1) by inhibiting the release of glutamate and substance P (nociceptive transmitters) from primary afferent terminals and 2) with G-protein-mediated activation of potassium channels causing hyperpolarization of inter-spinal neurons. The stress response to surgery can be attenuated by sympatholytic effects caused by postsynaptic activation of central α2-ARs, leading to reductions in blood pressure and slowing of the heart rate.[910]

Dexmedetomidine administered intravenously has been used for sedation and anxiolysis in the intensive care unit, as the sole agent during procedural sedation, and as a host of additional perioperative uses: premedication, to reduce emergence delirium and postoperative pain, to attenuate the stress responses associated with surgery and anesthesia (intubation, extubation, emergence), and for numerous other indications. When used as an adjunct to general anesthesia, dexmedetomidine can reduce both the minimum alveolar concentration (MAC) requirement of inhalation agents and provide opiate-sparing properties up to 90%.[11] This property enables an advantage in situations where high anesthetic concentration is undesirable, such as with certain neurosurgical procedures, minimally invasive endoscopic procedures, outpatient surgery, etc.

However, an emerging application is the role of dexmedetomidine in facilitating acute and chronic pain management. The α2-AR agonist, selectivity of dexmedetomidine, enhances the therapeutic window during treatment of pain, along with opiate-sparing effects important in the management of acute postoperative pain and chronic pain states (neuropathic pain, sympathetically maintained pain such as complex regional pain syndrome (CRPS) and chronic headaches). Dexmedetomidine is also transitioning as an adjuvant analgesic for intravenous and intrathecal infusion, during placement of peripheral nerve blockade, in the treatment of cancer pain, and in synergy with local anesthetics resulting in prolonged epidural anesthesia and analgesia.

Animal studies have not shown any evidence of neurotoxicity when administering dexmedetomidine (even at high concentrations) directly to sciatic nerves in a rat model investigation.[12] Brummett and colleagues[1314] showed that adding dexmedetomidine to ropivacaine resulted in a dose-dependent increase in the duration of both sensory and motor blockade in a similar rat model study. There have been a few clinical studies evaluating the effect of mixing dexmedetomidine with local anesthetics during placement of peripheral nerve blockade. Peripheral analgesic effects of dexmedetomidine have enabled an overall improved blockade quality when added to local anesthetics in a peripheral nerve block model and are thought to be mediated by α2-AR binding.[15] In a randomized double-blind trial performed by Esmaoglu et al.,[16] dexmedetomidine added to levobupivacaine for axillary brachial plexus blockade shortened the block onset time, prolonged the duration of motor and sensory effects, and extended postoperative analgesia. In addition, dexmedetomidine mixed with lidocaine has been reported to decrease tourniquet pain, improve block quality, and prolong postoperative analgesia during intravenous regional anesthesia.[17]

Results of some of the recent research identified above have indicated that α2-AR agonists may dose dependently enhance local anesthetic effectiveness and prolong its duration. However, additional possible mechanisms associated with dexmedetomidine that need further investigation to examine its actions in the periphery could be: 1) vasoconstriction around the site of injection (resulting in a delay of the absorption of local anesthetic); 2) prolonged local anesthetic effect possibly by α2-AR agonists interfering with absorption of local anesthetics injected by vasoconstriction since α2-ARs are involved in the control of arterial blood pressure; and 3) nonselective α2-AR agonists create a biphasic arterial blood pressure response (short hypertensive phase and subsequent hypotension). In addition, other investigators have supported another mechanism for the action of α2-AR agonists rather than vasoconstriction, such as a direct effect on peripheral nerve activity.[18] Clonidine has been shown to directly interrupt peripheral nerve action; therefore, the effect of α2-AR agonists may be induced by a direct action toward peripheral blood vessels or peripheral nerves or some component of each.[19]

Studies have demonstrated that dexmedetomidine and clonidine enhance local anesthetic action (by peripheral α2-AR). Dexmedetomidine has some advantageous pharmacological characteristics compared with similar sedative medications: 1) hemodynamic stability achieved with dexmedetomidine compared to clonidine is related to the fact that it is more selective for α2-AR and 2) both baroceptor reflex and heart rate response to a pressor are well preserved with dexmedetomidine. These important findings may suggest that dexmedetomidine has enhanced safety as an adjunct to local anesthetics in patients with cardiovascular disease, compared with other vasoconstrictors (e.g. epinephrine). Dexmedetomidine can result in adverse side effects like hypotension and bradycardia with increased dosage in addition to its effects of sedation and anxiolysis, and further studies are needed to better understand these side effects and the safe optimal dose of dexmedetomidine.

Dexmedetomidine is a potent α2-AR agonist and has widespread actions on the mammalian brain (sedation), in the neuraxial space (sympatholytic properties), and in the periphery during regional anesthesia with peripheral nerve blockade (anesthetic-sparing and postoperative analgesia). A large body of work and supporting fund of knowledge supports its favorable profile in improving the outcome and long-term function without evidence of destructive neurologic impact. Sources of such benefits are seen in the neuroprotective properties that are evident in experimental animal models as well as in the clinical setting. However, it will be necessary to explore the pharmacological mechanisms for the actions of α2-AR agonist in more detail. Dexmedetomidine may continue to be a valuable adjuvant when regional anesthesia is incorporated, but further research should focus on establishing the safe dose response requirements and optimal risk/benefit ratio when used with regional anesthesia techniques.