Since the 1990s, the subspecialty of ambulatory regional anesthesiology has pursued research addressing “off-label” and/or novel use of traditional medications in new, if not routine, multimodal contexts. Multimodal antiemetic prophylaxis (with 5-HT3 antagonists, dexamethasone, and a nonsedating dopaminergic antagonist) is now generally expected, whether1,2 or not3–5 based on predicted risk factors for postoperative nausea and vomiting. More recently, the use of perineural analgesic adjuvants has been explored, including agents such as dexmedetomidine,6,7 clonidine, buprenorphine, and dexamethasone (C-B-D).8–10 The goals of multimodal perineural analgesia include the potential to extend nerve block analgesic duration while potentially reducing the needed concentration of local anesthetics to provide meaningful analgesia, while simultaneously reducing the potential need for a perineural continuous infusion catheter. Dexamethasone is a common denominator in both multimodal pursuits of antiemesis and perineural analgesia and is also frequently explored as a meaningful coanalgesic for systemic use.11–13
The article by Rahangdale et al.14 in the current issue of Anesthesia & Analgesia compares IV versus perineural dexamethasone (8 mg dosage used in each treatment), versus saline control. Specifically, postoperative analgesia after foot-ankle surgery is addressed. In this editorial, we will describe 2 specific major concerns regarding the methodology and outcome of this study. First, we will address a potentially important safety issue9 with respect to perineural dexamethasone, which was both cited by Rahangdale et al., 14 and published before Rahangdale et al. 14 enrolled patients for the present study. Then, we will address how the absence of dexamethasone in the saphenous nerve block treatment protocol for perineural dexamethasone patients, an anatomic limitation that the authors openly acknowledged, potentially invalidates the finding of this investigation. The net effects of this investigation are that we now have further basis to eliminate future study of perineural dexamethasone at dosages 8 mg or greater (if not ≥4 mg), and fundamentals in the anatomy of perineural analgesia should be fully acknowledged when perineural pharmacology strategies are being compared.
Perineural Safety of Dexamethasone Plus Local Anesthetic, and Possible Augmentation of Rebound Pain by Perineural Dexamethasone Plus Local Anesthetic
Rahangdale et al.14 use a prospective, double-blind, randomized controlled trial. Although frequently used as an IV dose, 8 mg dexamethasone well exceeds the extrapolated perineural dose range of 1 of 2 mg (which extrapolates to the 66 mcg/mL that was less likely to be associated with local anesthetic-induced worsening of cytotoxicity in cultured neurons).9 The clinical dosing methodology of Rahangdale et al.14 raises ethical concerns because the 8 mg perineural dose has not yet been shown to be more effective than smaller doses of perineural dexamethasone in the presence of basic science evidence of perineural toxicity (i.e., dexamethasone augmenting neuronal cytotoxicity of local anesthetics).9 Therefore, it is our opinion that use of the same dose intravascularly and perineurally inherently has different analgesic properties (and likely differing dose-response curves yet to be determined).
Mechanistically, there may be “rebound hyperalgesia” induced by local anesthetics (mediated by heat-sensitive pain fibers) that may be further worsened by coadministered dexamethasone. So in the present study, dosages of 8 mg dexamethasone given IV prove to be analgesic, while 8 mg given perineurally (in combination with local anesthetics) may actually be hyperalgesic. In a recent translational-bench study, Kolarczyk and Williams15 reported on transient heat hyperalgesia 3 hours after ropivacaine sciatic nerve block in rats, when compared with saline vehicle controls. We postulated15 that local anesthetics may be implicated in a clinical phenomenon that we previously described as “rebound pain.”16 In rat experiments that occurred simultaneously,17 ropivacaine-clonidine-buprenorphine was not associated with any difference in heat hyperalgesia from plain ropivacaine, but dexamethasone (6 mcg in 200 μL added to ropivacaine-clonidine-buprenorphine) not only showed heat hyperalgesia 3 hours after block, but also at 5 hours after block (P = 0.016), when compared with saline vehicle control rats. So we not only have a potential basic science foundation of rebound pain as the effects of local anesthetic effects dissipate, but we may also have a similar rebound pain/heat hyperalgesia phenomenon worsened with perineural dexamethasone at low-to-moderate doses, coadministered with local anesthetics.
The absence of clinical neurotoxicity after perineural dexamethasone treatment in the current study by Rahangdale et al.14 is underpowered, given the small sample size. In addition, we have no basis to declare that “higher-concentration” ropivacaine-dexamethasone neuronal cytotoxicity in vitro9 in rat primary sensory neurons is mechanistically related to potential heat-induced hyperalgesia in vivo in rat sciatic nerve.
Another point to bring to focus regarding use of dexamethasone for multimodal analgesia effects is the possible risks with any type of dexamethasone use. Being a potent and lipid-soluble corticosteroid, numerous effects from systemic use are possible: ranging from blood glucose derangements to severe immunosuppresion. In relation to this study, the high concentration dexamethasone injected perineurally is likely to have clinically meaningful absorption systemically. No studies (of which we are aware) have shown a specific dose where local (perineural) effect is maximized, yet few systemic effects are seen. This factor should also call for the termination of research on the use of 8 mg (or 4 mg) perineural dexamethasone.
The Clinical Significance of a Sustained Motor Block of the Great Toe When the Sensory Block of the Great Toe Is Separately Innervated
When analyzing the difference between sensory and motor innervations of the great toe (i.e., motor innervation by sciatic branches and sensory innervation including saphenous branches), the clinical context of the study must be considered. Rahangdale et al.14 performed a sensory block of the saphenous nerve without dexamethasone and a great toe motor block with perineural sciatic dexamethasone plus local anesthetic. The dual innervation of the great toe would therefore require consistent blocks between both saphenous and sciatic nerves to properly evaluate perineural dexamethasone combined with local anesthetics. The IV dexamethasone treatment may have improved analgesia by other means, that is, systemic analgesic effects in both the saphenous and sciatic distributions (without distinct perineural effects). In other words, perineural dexamethasone dosages should have been separated. For example, 5 to 6 mg dexamethasone could have been used at the sciatic nerve, and 2 to 3 mg at the saphenous nerve, to make the treatments meaningfully comparable.
Guidance for Future Research on Perineural Adjuvants
Rahangdale et al.14 made a clear distinction of IV versus perineural treatment groups. However, for clinical research moving forward, dexamethasone use should not focus on one route of administration versus another. In all cases, the lowest possible clinically useful dose should be explored, and not at the exclusion of other potentially useful coadjuvants (such as ondansetron and perphenazine4,5,18 as antiemetics, or clonidine and buprenorphine as perineural analgesic adjuvants,17,19 in what we call “multimodal perineural analgesia”). At our clinical facility, our care protocol is to use dexamethasone via both routes while tailoring dosing to the specific patient. For example, if using 1 mg dexamethasone in a peripheral block (in combination9,19 with bupivacaine, clonidine, and buprenorphine), the anesthesia team may logically decrease the IV dexamethasone dosage given for antiemetic purposes to 2 to 4 mg IV intraoperatively based on 1 versus 2 mg total dexamethasone used in 1 versus 2 separate blocks. We decide that both IV and perineural routes have great use for both antiemesis and analgesia, respectively, and should be within a multimodal approach for both patient-oriented objectives concurrently.
In our institution’s hip and knee replacement patients,19 and in our institution’s diabetic patients (with our patients being primarily male veterans,),19 we do not use IV dexamethasone, relying instead on perphenazine, ondansetron, and propofol for antiemetic prophylaxis (while avoiding volatile agents, and minimizing opioids beyond perineural buprenorphine). As for these patients’ single-injection blocks (at L2-L4 and at L4-S3, acknowledging that knee and hip pain are mediated by both plexi), we use the multimodal perineural analgesia strategy in a good-faith effort to (1) optimize nerve block duration, (2) minimize rebound pain, and (3) achieve motor block resolution before physical therapy on the morning after surgery. In a recent editorial,19 we presented observational duration data from n = 102 such veterans regarding the use of bupivacaine-C-B-D in combination, as part of a comprehensive analgesia plan that also included a scheduled regimen of oral multimodal analgesics. The L2-L4 blocks used bupivacaine 0.20% to 0.25%, and the L4-S3 blocks used bupivacaine 0.100% to 0.125% (with the lower listed concentrations being used for diabetics). The observed nerve block mean duration estimations (based on time from nerve block to nurse-documented time of peak rebound pain score) were 40 hours.19 Since this report, our subsequent trends have indicated favorable rebound pain trends with lower perineural dexamethasone dosages (e.g., 1 mg per plexus instead of 2 mg) and with higher buprenorphine dosages (e.g., 300 mcg buprenorphine per plexus instead of 150 mcg), with no apparent differences in perineural analgesic duration. Currently, we are collating these more recent observational data en route toward generating hypotheses for appropriate prospective clinical trials.
As a clinical research community, the era of high-dose single perineural adjuvants (especially related to dexamethasone at doses >2 mg per nerve or plexus) needs to be relegated to legacy status. Our specialty must avoid the temptation to incorporate high-dose perineural dexamethasone into routine practice based on cursory skimming of the current article by Rahangdale et al.14 and the recent meta-analysis by Choi et al.20 To continue to incorporate high-dose perineural dexamethasone in our nerve blocks would be a significant setback in both patient care and in clinical research. When basic cytotoxicity research shows more neuronal death in a dose-response curve with higher concentrations of dexamethasone combined with clinically relevant concentrations of local anesthetics,9 then our patients and our health care colleagues of all disciplines need to trust that we incorporate such basic science findings in our drug selection for off-label use.
In recent in vivo sciatic perineural injections in rats (in our Department of Defense-funded laboratory), the combination of bupivacaine (2.5 mg/mL), clonidine (3 mcg/mL), buprenorphine (18 mcg/mL), and dexamethasone (66 mcg/mL) was not associated with either sciatic nerve damage or damage to primary sensory neurons in vivo (personal communication, 2013, Mark T. Butt, DVM, DAVCP, Tox Path Specialists, LLC, Frederick, MD; manuscript in review).
To summarize, the new report by Rahangdale et al.14 describes the off-label use of dexamethasone as an adjuvant for augmenting regional anesthesia, in comparison with analgesic effects achieved with IV use. Rahangdale et al.14 indeed accomplished the objective of questioning the practice of using 8 mg dexamethasone perineurally.
Meanwhile, we are on the precipice6–10,15,17,19 of potentially useful discovery in the context of multimodal perineural analgesia, similar to the clinical advances of multimodal antiemesis dating back to the 1990s. Local anesthetics, low-dose dexamethasone, and other perineural analgesic adjuvants (such as buprenorphine and either clonidine or dexmedetomidine) may hold great promise. This likely vital research avenue may also ultimately offset the current complexity of continuous perineural catheters with simpler perineural single injections. This perineural multimodal analgesic strategy may ultimately identify the “holy grail” for improving patient care by capitalizing on the benefits and minimizing the risks associated with large doses of each additional single drug at a time.
Name: Brian A. Williams, MD, MBA.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Brian A. Williams approved the final manuscript.
Name: Nicholas J. Schott, MD.
Contribution: This author helped write the manuscript.
Attestation: Nicholas J. Schott approved the final manuscript.
Name: Michael P. Mangione, MD.
Contribution: This author helped write the manuscript.
Attestation: Michael P. Mangione approved the final manuscript.
Name: James W. Ibinson, MD, PhD.
Contribution: This author helped write the manuscript.
Attestation: James W. Ibinson approved the final manuscript.
This manuscript was handled by: Terese T. Horlocker, MD.
1. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer NIMPACT Investigators. . A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–51
2. Gan TJ, Meyer TA, Apfel CC, Chung F, Davis PJ, Habib AS, Hooper VD, Kovac AL, Kranke P, Myles P, Philip BK, Samsa G, Sessler DI, Temo J, Tramèr MR, Vander Kolk C, Watcha MSociety for Ambulatory Anesthesia. . Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2007;105:1615–28
3. Glass PS, White PF. Practice guidelines for the management of postoperative nausea and vomiting: past, present, and future. Anesth Analg. 2007;105:1528–9
4. Williams BA, Kentor ML, Skledar SJ, Orebaugh SL, Vallejo MC. Routine multimodal antiemesis including low-dose perphenazine in an ambulatory surgery unit of a university hospital: a 10-year history. Supplement to: Eliminating postoperative nausea and vomiting in outpatient surgery with multimodal strategies including low doses of nonsedating, off-patent antiemetics: is “zero tolerance” achievable? ScientificWorldJournal. 2007;7:978–86
5. Skledar SJ, Williams BA, Vallejo MC, Dalby PL, Waters JH, Glick R, Kentor ML. Eliminating postoperative nausea and vomiting in outpatient surgery with multimodal strategies including low doses of nonsedating, off-patent antiemetics: is “zero tolerance” achievable? ScientificWorldJournal. 2007;7:959–77
6. Brummett CM, Padda AK, Amodeo 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
7. Brummett CM, Hong EK, Janda AM, Amodeo FS, Lydic R. Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology. 2011;115:836–43
8. Williams BA, Murinson BB, Grable BR, Orebaugh SL. Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus. Reg Anesth Pain Med. 2009;34:445–57
9. Williams BA, Hough KA, Tsui BY, Ibinson JW, Gold MS, Gebhart GF. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med. 2011;36:225–30
10. Yilmaz-Rastoder E, Gold MS, Hough KA, Gebhart GF, Williams BA. Effect of adjuvant drugs on the action of local anesthetics in isolated rat sciatic nerves. Reg Anesth Pain Med. 2012;37:403–9
11. Salerno A, Hermann R. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am. 2006;88:1361–72
12. Waldron NH, Jones CA, Gan TJ, Allen TK, Habib AS. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth. 2013;110:191–200
13. De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2011;115:575–88
14. Rahangdale R, Mark C, Kendall MC, McCarthy RJ, Antoun Nader A, Tureanu L, Doty R, Weingart A, De Oliveira DS Jr. Effects of Perineural versus Intravenous Dexamethasone on Sciatic Nerve Blockade Outcomes: A Randomized, Double-Blind, Placebo-Controlled Study. Anesth Analg.
15. Kolarczyk LM, Williams BA. Transient heat hyperalgesia during resolution of ropivacaine sciatic nerve block in the rat. Reg Anesth Pain Med. 2011;36:220–4
16. Williams BA, Bottegal MT, Kentor ML, Irrgang JJ, Williams JP. Rebound pain scores as a function of femoral nerve block duration after anterior cruciate ligament reconstruction: retrospective analysis of a prospective, randomized clinical trial. Reg Anesth Pain Med. 2007;32:186–92
17. Williams BA. Forecast for perineural analgesia procedures for ambulatory surgery of the knee, foot, and ankle: applying patient-centered paradigm shifts. Int Anesthesiol Clin. 2012;50:126–42
18. Henao JP, Peperzak KA, Lichvar AB, Orebaugh SL, Skledar SJ, Pippi MA, Williams BA. Extrapyramidal symptoms following administration of oral perphenazine 4 or 8 mg: An 11-year retrospective analysis. Eur J Anaesthesiol. 2014;31:1–5
19. Ibinson JW, Mangione MP, Williams BA. Local anesthetics in diabetic rats (and patients): shifting from a known slippery slope toward a potentially better multimodal perineural paradigm? Reg Anesth Pain Med. 2012;37:574–6
20. Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anesth. 2014;112:427–39