Copyright @ 2009 . Unauthorized reproduction of this article is prohibited. American Society of Regional Anesthesia and Pain Medicine Future Considerations for Pharmacologic Adjuvants in Single-Injection Peripheral Nerve Blocks for Patients With Diabetes Mellitus Brian A. Williams, MD, MBA,* Beth B. Murinson, MD, MS, PhD,Þ Benjamin R. Grable, MD,þ and Steven L. Orebaugh, MD* Abstract: As the epidemics of obesity and diabetes expand, there are more patients with these disorders requiring elective surgery. For surgery on the extremities, peripheral nerve blocks have become a highly favorable anesthetic option when compared with general anesthesia. Peripheral blocks reduce respiratory and cardiac stresses, while potentially mitigating untreated peripheral pain that can foster physiologic conditions that increase risks for general health complications. However, local anesthetics are generally accepted to be a rare but possible cause of nerve damage, and there are no evidence-based recommendations for dosing local anesthetic nerve blocks in patients with diabetes. This is important because anesthesiologists do not want to potentially accelerate peripheral nerve dysfunction in diabetic patients at risk. This translational vignette (i) ex- amines laboratory models of diabetes, (ii) summarizes the pharmacology of perineural adjuvants (epinephrine, clonidine, buprenorphine, midazo- lam, tramadol, and dexamethasone), and (iii) identifies areas that warrant further research to determine viability of monotherapy or combination therapy for peripheral nerve analgesia in diabetic patients. Conceivably, future translational research regarding peripheral nerve blocks in diabetic patients may logically include study of nontoxic injectable analgesic adjuvants, in combination, to provide desired analgesia, while possibly avoiding peripheral nerve toxicity that diabetic animal models have exhibited when exposed to traditional local anesthetics. (Reg Anesth Pain Med 2009;34: 445Y457) T he underlying mechanisms of insulin resistance in obesity, 1 anesthesia care considerations for patients with diabetes mellitus and/or metabolic syndrome, 2 and chronic pain in the setting of diabetes 3,4 have all recently been reviewed. Interest- ingly, little has been written regarding the implications of diabetes for peripheral nerve blocks used for surgical anesthesia- analgesia. Nonetheless, increases in the incidence and preva- lence of diabetes and metabolic syndrome mean that specialists in regional anesthesia need to reevaluate and potentially improve anesthesia care for diabetic patients undergoing surgery on the extremities. In a recent editorial, 5 a call was issued for a shift in peripheral nerve block research to address (i) the specific peri- neural pathophysiology associated with hyperglycemia and dia- betes mellitus and (ii) the effects of local anesthetics, perineural analgesic adjuvants, and their potential combinations. This editorial 5 also introduced some basic science concepts regarding research models in diabetic neuropathy that may be potentially relevant for creating a model related to peripheral nerve blocks. The editorial was authored in response to a recent publication detailing altered perineural stimulation responses in a dog model with streptozotocin (STZ)Yinduced hyperglycemia. 6 It is clear that the specific details of research models in diabetic neuropa- thy are critically relevant for selecting bench science methods that best model peripheral nerve blocks. 5 This translational vignette will first review recent developments in laboratory models of diabetes then discuss the clinical challenges asso- ciated with peripheral nerve blocks in diabetic patients, followed by a literature summary (Table 1) regarding the use of adjuvants in peripheral nerve blocks in (heretofore) nondiabetic patients. It will conclude with recommendations for future research. EVOLVING MODELS OF DIABETES AND POTENTIAL APPLICATIONS An ‘‘Ideal’’ Animal Model for Diabetic Neuropathy At present, there is no consensus regarding diabetic animal models that best replicate the human condition, neither for endocrinology-metabolism considerations nor for the develop- ment of neuropathy. The aforementioned editorial 5 described type 2 diabetes in primates (rhesus monkeys 7 ) that are overfed for a protracted period. It seems unlikely that this model will be cost-effective in addressing diabetic polyneuropathy and peripheral nerve blockade. Diabetic rat strains include BB/W and Zucker diabetic fatty rats 8,9 ; there are also nonobese diabetic mouse models that bear the phenotype of severe combined immunodeficiency. These nonobese diabetic/severe combined immunodeficiency animals 10 are derived by selective breeding. As a result of inbreeding, some of these strains have particular characteristics, independent of diabetes, that may complicate implementation as a model of human diabetes. As noted, there are diabetes-induction models that entail treating normal animals with the pancreatic beta cell toxin, STZ. The effect of STZ is quite rapid, and the potential for preparing littermate animals in a parallel study (ie, treated vs vehicle con- trol) represents significant advantages in experimental design. A wide range of species have been induced diabetic with STZ. 11,12 A disadvantage of STZ is hepatotoxicity and/or nephrotoxicity at higher doses. 13 Importantly, STZ-animal models develop peripheral neuropathy, as demonstrated recently in dogs by Rigaud et al, 6 as well as in the classic rat study by Kalichman TRANSLATIONAL VIGNETTE Regional Anesthesia and Pain Medicine & Volume 34, Number 5, September-October 2009 445 From the *Department of Anesthesiology, University of Pittsburgh Medical Center South Side, University of Pittsburgh, Pittsburgh, PA; †Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; and ‡Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA. Accepted for publication November 4, 2008. Address correspondence to: Brian A. Williams, MD, MBA, Department of Anesthesiology, UPMC South Side, Suite 2302 2000 Mary St, Pittsburgh, PA 15203 (e-mail: williamsba@anes.upmc.edu). Dr. Williams is supported by departmental sources and by National Institutes of Health grant 1K01DA025146. Dr. Murinson is supported by departmental sources and by National Institutes of Health grant 5K08NS48146. Drs. Grable and Orebaugh are supported by departmental sources. Reprints will not be available from the authors. Copyright * 2009 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0b013e3181ac9e42