Perineural local anesthetic and adjuvant action: the meaning of an ex vivo data set for efficacy and safety.

A bolus of long-acting local anesthetic can provide a sensory and motor block for more than 12 hours. However, it is often desirable to further prolong the duration of the sensory block. Achievement of this aim has been sought in 3 ways. The first approach is to increase the local anesthetic concentration and/or volume (thus dose), which is limited by increased risk of systemic toxicity and an increasedVand often undesirableVdensity of sensory and/or motor effects. A second approach has been to place a catheter that permits continued exposure of the perineural space to low-dose local anesthetic, with a theoretically lower risk of systemic toxicity. A third approach has been to use drug adjuvants that can change the physicochemical properties of the local anesthetic, augment inhibition of nerve impulse transmission through a direct effect on channel function, or augment the duration of local anesthetic action through an indirect mechanism. The latter has occasioned a variety of clinical reports (cited by Yilmaz-Rastoder et al in their accompanying article in this issue) in which agents, such as clonidine (>2-adrenergic agonist), buprenorphine (K-opioid partial agonist), midazolam (benzodiazepine), or dexamethasone (steroid), have been reported to increase the effective duration of the block. With the exception of midazolam, these agents alone do not usually produce a block, and are accordingly considered to be adjuvants to local anesthetics, which indeed block the sodium channel. These previously-reported findings are intriguing, as they raise questions as to the mechanism(s) of action of local anesthetic adjuvants. First, we might consider whether the adjuvant agent acts to reduce the clearance of the anesthetic from the perineural environment, as has been long appreciated with the codelivery of vasoconstrictive agents. Alternatively, we could query as to whether there is a direct interaction of the agents with the axonal membrane or channel that increases the effects of sodium channel blocker action. If it is the former, then augmentation should be absent when there is no blood flow, that is, in an ex vivo preparation, while the latter would be present in the ex vivo model. In this issue of Regional Anesthesia and Pain Medicine, Yilmaz-Rastoder et al report their examination in an ex vivo model of the effects of several agents on the compound action potential (CAP) of an isolated rat sciatic nerve and the agents’ interaction with ropivacaine or midazolam in blocking that CAP. Within the concentration ranges examined, the 3 agents alone had little effect on the CAP of either the rapidly conducting large myelinated A fibers or slowly conducting small unmyelinated C fibers. Nor did these adjuvants alter either the potency (concentration required to produce a criterion level of block) or efficacy (the maximum achievable block) of ropivacaine or midazolam. This study was thus aimed at addressing the very specific issue raised by clinical reports that indicate these agents in combination increase the duration of the local anesthetic effects. The model usedVthe isolated sciatic nerveVis common, and by assessing the area of the curve under the rapidand slow-conducting components, it can determine the effect of agents on large myelinated and small unmyelinated axons, respectively. Because the study occurs within a bath, local concentrations can be readily defined, and the clearance of drug can be determined by the simple expedient of changing the bathing solution. Therefore, the take-home message is that these agents do not interact with membrane channels to alter conduction in these fiber classes and that they do not alter the interaction of ropivacaine (or EDITORIAL