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Single-shot peripheral nerve blocks as (i) an alternative to general anesthesia and (ii) an opioid-sparing analgesic have become a portion of standard anesthesia practice throughout the world. Although perineural catheters for postoperative analgesia for the days after surgery have increased, the majority of anesthesiologists still perform single-shot blocks. Commercially available local anesthetics have a limited duration of analgesia that frequently leaves patients complaining of pain for the first time during their first postoperative night when they are likely most vulnerable. Although there are longer acting formulations and new concepts on the horizon, there are limits to what local anesthetics alone can provide. In this review, the authors will describe both evidence and potential future directions for the use of described adjuncts with each other and with long-acting local anesthetics. The focus will be on the onset and analgesic duration of single-shot nerve blocks, along with any neurotoxic concerns or neuroprotective potential.Although epinephrine certainly has analgesic benefit when used with short-acting and intermediate-acting local anesthetics, there are limited data regarding the efficacy of epinephrine for prolonging the analgesic duration of long-acting local anesthetics (ropivacaine, bupivacaine, levobupivacaine). Some studies with long-acting local anesthetics (eg, ropivacaine) failed to show an increased duration of analgesia with coadministration of epinephrine.1 The limited available data make it impossible to assess the potential analgesic benefits for the addition of epinephrine.Epinephrine remains the most widely used adjunct for local anesthetics in peripheral nerve blockade; however, the increased use of ultrasound and potential concerns about neurotoxicity may temper the enthusiasm of its use for some anesthesiologists. A review by Neal notes the differential blood flow of the extrinsic and intrinsic systems in the peripheral nerve and questions whether epinephrine has any true impact on neurotoxicity.2 Decreases in blood flow2,3 and the increased duration of analgesia4 are due to the ∝1-adrenoceptor agonist effect of epinephrine.4 Some local anesthetics, including lidocaine and ropivacaine, will also cause vasoconstriction and are synergistic with epinephrine. Whether the effect of epinephrine is simply due to decreased systemic uptake leading to a greater effect of the local anesthetic on the peripheral nerve is still not completely understood2,5; however, perineural epinephrine alone does not cause sensory or motor blockade.4The controversy surrounding widespread use of epinephrine in combination with local anesthetics is the argument as to whether it is protective or harmful. There is no question that epinephrine can be a valuable marker for the detection of intravascular injection, and some experts believe that the early detection of intravascular injection greatly outweighs the potential neurotoxic or myotoxic effects. The increased use of ultrasound worldwide allows for visualization of the needle tip and real-time assessment of local anesthetic spread; however, unintentional intravascular injection of local anesthetic with subsequent cardiovascular collapse using ultrasound has still been reported and remains a legitimate concern. Along with other experts, however, we believe that the addition of epinephrine to local anesthetics may increase the potential neurotoxicity, which may be especially concerning in those patients at higher risk for nerve injury (ie, patients with diabetes mellitus, hypertension, and/or a history of smoking).6 We still recommend the use of epinephrine as an additive for test dose purposes in out-of-plane ultrasound blocks or nerve stimulator blocks. Beta blockade may limit the use of epinephrine as a marker of intravascular injection. Avoidance of high volume blocks, use of in-plane ultrasound guidance, slow injections, and limited sedation with constant assessment of central nervous system excitatory effects are likely equally or more important for limiting potential cardiotoxicity.