Neurotoxicity of common peripheral nerve block adjuvants

Abstract

Purpose of review: This review outlines the analgesic role of perineural adjuvants for local anesthetic nerve block injections, and evaluates current knowledge regarding whether adjuvants modulate the neurocytologic properties of local anesthetics.

Recent findings: Perineural adjuvant medications such as dexmedetomidine, clonidine, buprenorphine, dexamethasone, and midazolam play unique analgesic roles. The dosing of these medications to prevent neurotoxicity is characterized in various cellular and in-vivo models. Much of this mitigation may be via reducing the dose of local anesthetic used while achieving equal or superior analgesia. Dose-concentration animal models have shown no evidence of deleterious effects. Clinical observations regarding blocks with combined bupivacaine-clonidine-buprenorphine-dexamethasone have shown beneficial effects on block duration and rebound pain without long-term evidence of neurotoxicity. In-vitro and in-vivo studies of perineural clonidine and dexmedetomidine show attenuation of perineural inflammatory responses generated by local anesthetics.

Summary: Dexmedetomidine added as a peripheral nerve blockade adjuvant improves block duration without neurotoxic properties. The combined adjuvants clonidine, buprenorphine, and dexamethasone do not appear to alter local anesthetic neurotoxicity. Midazolam significantly increases local anesthetic neurotoxicity in vitro, but when combined with clonidine-buprenorphine-dexamethasone (sans local anesthetic) produces no in-vitro or in-vivo neurotoxicity. Further larger-species animal testing and human trials will be required to reinforce the clinical applicability of these findings.

Figure 1

Cell death as a function of treatment after 24 hours exposure to ropivacaine alone (RPV) and clonidine(C)-buprenorphine(B)-dexamethasone(D)-midazolam(MDZ) adjuvant combinations. Panel A shows all RPV-M combinations. Panel B shows the cytotoxicity outcomes in clinical concentrations with and without RPV 2.5mg/mL. Source: Figure 3A, Williams, BA, Hough, KA, Tsui BY et al. Neurotoxicity of Adjuvants Used in Perineural Anesthesia and Analgesia in Comparison with Ropivacaine. Reg Anesth Pain Med. 2011 May–Jun;36(3):225–230

Figure 2

Behavioral response to single injection treatments. B = buprenorphine, BPV = bupivacaine, C = clonidine, D = dexamethasone, MDZ = midazolam, VEH = vehicle (saline) Source: Table 3, Williams BA, Butt MT, Zeller JR et al. Multimodal Perineural Analgesia with Combined Bupivacaine-Clonidine-Buprenorphine-Dexamethasone: Safe In Vivo and Chemically Compatible in Solution. Pain Med. 2015 Jan;16(1):186–198

Figure 3

Data highlights regarding the described combined drugs used in MMPNA. L2-L4: femoral nerve analgesic MMPNA blocks for knee replacement surgery, and lumbar plexus psoas compartment (“Lum”) analgesic MMPNA blocks for hip replacement surgery, coadministered with spinal (“Spi”) anesthesia. L4-S3: gluteal approach sciatic nerve (“Sci”) analgesic MMPNA blocks for knee replacement surgery, and parasacral plexus analgesic MMPNA blocks for hip replacement surgery coadministered with spinal anesthesia. IQR = interquartile range; SEM = standard error of the mean. Source: Table 1, Williams BA, Ibinson JW, Mangione MP et al. Research Priorities Regarding Multimodal Peripheral Nerve Blocks for Postoperative Analgesia and Anesthesia Base on Hospital Quality Data Extracted from Over 1300 Cases (2011–2014). Pain Med. 2015 Jan;16(1):7–12