"Above all, do no harm": hippocrates.

LOCAL anesthetics block voltage-gated sodium channels, thereby preventing generation of action potentials and their propagation along the nerve. However, complete sensory blockade is generally accomplished only with simultaneous sympathetic and motor blockade, thereby often leading to unwanted adverse side effects. To date, no agent or method translatable into current clinical practice has been shown to elicit usable, predominantly sensory nerve blocks. In this issue of ANESTHESIOLOGY, Brummett et al. report the approach of combining ropivacaine with an 2 agonist (dexmedetomidine), thereby dose-dependently increasing the duration of sensory blockade over motor blockade in a rat sciatic nerve block model. Logically, the questions of whether and how to progress to clinical studies arise. The clinical development of several new, promising local anesthetics had to be halted because of adverse side effects, e.g., failure in late clinical trials due to neurotoxicity. These local anesthetics, as well as local anesthetics currently in use, may cause histologically detectable toxicity in various animal models even when used in modest doses. Lidocaine and bupivacaine (approved by the US Food and Drug Administration in 1947 and 1963, respectively) are still the two most widely used local anesthetics. Two homologs of bupivacaine, ropivacaine and levobupivacaine, are available, but neither is genuinely less toxic, as evidenced by recurring case reports of their toxicity. Besides reasons of neurotoxicity, development strategies for sensory-selective nerve blockade (sensory-selective and differential block are commonly used terms and are often interchanged with pain-selective and nociceptor-selective) are plagued by simple inefficacy. A major effort has taken place to develop Na channel blockers for specific channel subtypes, because Nav 1.7, Nav1.8, and Nav1.9 are expressed exclusively on peripheral nociceptors. A “hot” target for nociceptive-specific blockade is Nav1.7, because this channel determines the ability of a nerve to transmit pain sensation. The importance of Nav 1.7 has become increasingly evident through genetic correlation of this channel with congenital abnormality of pain perception. Loss-of-function mutations of Nav1.7 are reported in patients with associated neurologic insensitivity, in which patients have isolated lack of sensory function for pain and smell. On the other hand, several gain-of-function mutations of genes related to the regulation or function of Nav1.7, resulting in overactivity of this channel, are found in patients with two painful congenital disorders, erythromelalgia and paroxysmal extreme pain disorder. Both are congenital conditions whereby patients are afflicted by severe episodic pain attacks accompanied by cutaneous flushing. Unfortunately, although Nav1.7, Nav1.8, and Nav1.9 are ideal targets for developing more effective drugs, none of the existing compounds have proven suitable for clinical use, mostly due to low bioavailability. So why does the approach of Brummett et al. of combining dexmedetomidine with ropivacaine seem to be a “fast-track” approach? Others have used very effective combination approaches, e.g., transient receptor potential vanilloid subtype 1 channel–mediated local anesthetic delivery (e.g., QX-314) into C-fibers, yielding even pain-selective nerve blockade. However, the introduction of the investigational drug QX-314 will take many years, whereas dexmedetomidine is already in clinical use, although for a different indication (approved by the US Food and Drug Administration for intravenous sedation). Although the combination of ropivacaine and dexmedetomidine certainly is not intended to achieve sensory-selective blockade, current work suggests that the combination prolongs the sensory block more than the motor block, compared with ropivacaine alone. The peripheral mechanism of dexmedetomidine is not known. Other 2 agonists, such as clonidine, have been found to enhance sensory blockade through the hyperpolarization-activated cation current (Ih current). 5 Similarly, it has been suggested that a direct inhibition of tetrodotoxin-resistant Na channels may contribute to the antinociceptive effects of clonidine and dexmedetomidine. Laboratory studies using clonidine have been limited to examining its efficacy in combination with short-acting drugs such as lidocaine or procaine. The effect of clonidine added to a long-acting local anesthetic (bupivacaine, levobupivacaine, and ropivacaine) for peripheral nerve blocks has not been studied in vitro, whereas results in human studies have been mixed. The favorable results by Brummett et al. investigating longacting local anesthetics combined with dexmedetomidine for peripheral nerve block, allow for cautious optiThis Editorial View accompanies the following article: Brummett CM, Padda A, Amadeo FS, Welch KB, Lydic R: Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. ANESTHESIOLOGY 2009; 111:1111–9.