Cite as: Fettiplace M, Soffin E. Pros and cons: mixing local anesthetics: best of both worlds or playing with fire?. ASRA Pain Medicine News 2026;51. https://doi.org/10.52211/asra020126.007.

Pro-Con

Introduction

Since the identification of cocaine as a local anesthetic (LA) by Karl Koller in 1884, clinicians have endeavored to identify an “ideal” LA that combines rapid onset and prolonged analgesia. The predominant limitation of LAs has been their duration of action; therefore, this search primarily focused on extending pain relief. What followed was the progression from ester-linked to amide-linked LAs and the development of extended-release formulations including liposomal bupivacaine. However, longer durations are accompanied by longer onset times, and no single agent provides the rapid onset of lidocaine with the prolonged duration of bupivacaine.

In response, certain practitioners promoted mixing short- and long-acting drugs as a pragmatic compromise to combine the rapid onset of short-acting agents with the prolonged duration of long-acting drugs. The conceptual appeal is clear, as in the adage about the tortoise and the hare. The hare quickly sets up the block to facilitate surgery, and the tortoise subsequently takes over to provide prolonged pain relief during the postoperative period. Such metaphors capture the clinical intuition: lidocaine or mepivacaine ensures rapid anesthesia, while bupivacaine or ropivacaine sustains the block. Despite its popularity, mixing has increasingly come under scrutiny. Early pharmacology studies questioned whether meaningful synergy existed between agents. Clinical trials produced mixed results, with high variability in block onset, duration, and quality.¹ More recently, three systematic reviews and meta-analyses have synthesized available evidence.^2-4 One review demonstrated a modest reduction in surgical block onset, but two others found no clinically meaningful benefit. Together, they suggest that mixing offers little benefit in modern practice and carries potential risks. This does not even take into account the safety concerns associated with mixing. Local anesthetic toxicity is additive, and toxicity is dose-dependent,^5-7 without package insert guidance on how to mix safely. Furthermore, clinicians often rely on tradition or local “recipes,” a strategy that is vulnerable to error.

This pro-con debate highlights the tension between clinical pragmatism and evidence-based caution. The pro-side highlights potential latency benefits, intermediate-duration tailoring, and niche clinical applications. The con-side emphasizes mechanistic implausibility, shortened block duration, and additive toxicity risks. Ultimately, the most significant concern may not be latency or duration, but the lack of guidance on safe dosing when agents are combined. This absence of consensus leaves patients vulnerable to preventable adverse outcomes, and specialty societies should prioritize developing dosing recommendations to reconcile common practice with safe standards.

The Pro Side

Advocates of mixing LAs argue that the practice is rooted in pharmacologic complementarity and pragmatic clinical needs. Short-acting agents, with lower pKa values and greater lipid solubility, can penetrate neuronal membranes quickly, resulting in an early onset. Long-acting agents bind more avidly to sodium channels and plasma proteins, prolonging nerve blockade. Administered together, they would appear to provide an ideal block, with rapid onset and sustained analgesia.

Clinical data support this reasoning. The most comprehensive meta-analysis to date, published in the Brazilian Journal of Anesthesiology in 2025, pooled results from 19 randomized trials including more than 1,000 participants.³The analysis found that mixtures reduced surgical block latency by an average of 8.4 minutes compared with long-acting agents alone. The effect was particularly notable in femoral and sciatic nerve blocks, where mixing LAs reduced latency by nearly 15 minutes. For high-throughput operating rooms, where efficiency is crucial, this reduction may have significant practical implications. These gains in latency may be most relevant in high-turnover environments or in clinical settings where ultrasound is not used (eg, surgeon-administered field blocks). In nerve stimulator-guided blocks, or when trainees with limited ultrasound technical skill perform procedures, pharmacologic acceleration may compensate for less precise needle placement. While small in absolute terms, these time savings may enhance workflow and improve patient experience in specific contexts.

The hare quickly sets up the block to facilitate surgery, and the tortoise subsequently takes over to provide prolonged pain relief during the postoperative period. Such metaphors capture the clinical intuition: lidocaine or mepivacaine ensures rapid anesthesia, while bupivacaine or ropivacaine sustains the block.

Another potential advantage of mixing is the ability to tailor block duration. Mepivacaine typically provides about4 to 6hours of analgesia, bupivacaine 12 to 18 hours, and their combination leads to approximately 8to 12 hours.¹ For outpatient surgeries, such as arthroscopy or mastectomy, intermediate-duration blocks may be desirable, long enough to cover the immediate postoperative window without producing late-night motor weakness or fall risk. What some view as a drawback—shorter overall duration—can, in the right patient, become a feature. It may even be possible to tailor the block duration to the mixture, as demonstrated by multiple authors.^1,8 Not all patients prefer an immobile and insensate arm for more than 15 hours, particularly after surgeries associated with low anticipated pain burden. In these scenarios, a medium-duration block may be optimal and could be achieved by mixing. There are also hints of a safety upside. Small pharmacokinetic studies have suggested that mixtures may reduce peak plasma concentrations of long-acting agents, thereby lowering systemic exposure.⁹ This could, in theory, decrease local anesthetic systemic toxicity (LAST) risk for drugs like bupivacaine, though the evidence is preliminary and far from conclusive.

Finally, anecdotally, many providers report using mixtures of LAs. Such persistence suggests that clinicians perceive meaningful utility, even in the absence of formal guidance. Advocates argue that guideline bodies should embrace this reality and provide recommendations for safe use rather than ignoring a practice already embedded in clinical workflows.

The Con Side

Several arguments support the contrarian view on mixing LAs. Skeptics of mixing emphasize that the theoretical rationale is weak, the clinical benefits marginal, and the safety risks considerable. From a mechanistic standpoint, there is little basis for expecting synergy. Bupivacaine, for example, exhibits concentration-dependent kinetics. At low concentrations, binding to sodium channels is slow, resulting in a delayed onset. At higher concentrations, binding accelerates, resulting in a rapid onset.¹⁰ Thus, latency can be improved simply by increasing the overall bupivacaine dose rather than adding a second drug.^11,12

The layering model—lidocaine initiating block, bupivacaine sustaining it—oversimplifies sodium channel pharmacology. LAs interact with channels in resting, open, and inactive states, each with different binding affinities.¹³ As lidocaine unbinds and is cleared, channels may return to functional states, creating the possibility of breakthrough pain. Sequential rather than synergistic action appears to underlie the observed effects. Clinical evidence supports this skepticism. A systematic review published in Regional Anesthesia & Pain Medicine in early 2025 analyzed 10 randomized trials involving more than 500 patients.² All blocks were performed under ultrasound guidance. The review found no clinically meaningful effect of mixing on onset, reporting a mean reduction of only 1.6 minutes, well below the 5-minute threshold typically considered relevant. A second meta-analysis published in the Journal of Clinical Anesthesia later that year included 11 randomized trials of brachial plexus blocks.⁴ This review likewise found no benefit in sensory or motor onset with mixtures. These findings align with modern practice, where ultrasound guidance already ensures precise perineural deposition, rendering any pharmacologic latency advantage redundant. The consistent finding across all three meta-analyses is shortened block duration. In the Regional Anesthesia & Pain Medicine review, mixtures reduced the sensory block by more than 2 hours.² Lin and colleagues reported reductions of nearly 4 hours for both sensory and motor blockade.³ Oweidat and coauthors reached similar conclusions for brachial plexus blocks.⁴

The mechanisms are likely multifactorial, including dilution of the long-acting agent, vasodilatory effects of lidocaine accelerating systemic absorption, and reduced concentration gradients limiting tissue penetration. Regardless of cause, the consequence is clear: mixing the duration, undermining the very rationale for using long-acting drugs. Safety concerns further complicate the picture. Toxicity from LAs is additive.^14-18 Maximum doses should be calculated as the sum of fractional contributions from each agent. Yet clinical practice often ignores this principle. Survey data show that anesthesiologists routinely administer combinations that exceed recommended cumulative doses. For example, recipes including 30 mL of 0.75% bupivacaine plus 20 mL of 2% mepivacaine can surpass safe thresholds for average-weight adults but are used based on anecdotal discussion. Case reports of LAST associated with mixtures highlight the danger of such complacency.^7,19

The absence of formal guidance exacerbates the risk. Package inserts provide clear maximums for single agents but are silent on mixtures. Professional societies have not issued consensus statements, leaving clinicians without benchmarks. In the event of toxicity, medico-legal vulnerability is significant. For skeptics, the value proposition is poor. Latency gains are negligible under ultrasound; duration is consistently shortened, and toxicity risks are amplified. Mixing may offer pragmatic benefits in rare scenarios, but as a routine practice, it appears more perilous than promising.

Conclusions

The debate over mixing LAs reflects the broader tension between clinical tradition and evidence-based practice. Advocates see value in modest latency reductions, intermediate-duration tailoring, and in settings where efficiency pressures dominate. Critics emphasize mechanistic implausibility, reduced block longevity, and the additive toxicity risks that accompany cumulative dosing. The weight of evidence favors caution. In contemporary practice, where ultrasound guidance is standard, mixtures do not meaningfully accelerate onset. The benefits that exist are marginal and limited to specific contexts. The consistent and clinically significant finding is that mixtures shorten block duration, often by several hours.^2-4 For most patients, this undermines the goal of sustained postoperative analgesia.

The most significant concern is not efficacy but safety. Toxicity from LAs is additive, and complications are dose-dependent;^5-7 yet clinicians lack clear dosing standards when combining drugs. National and international professional societies such as the ASRA Pain Medicine and the European Society of Regional Anesthesia are uniquely positioned to address this gap. Given these organizations’ history of providing high-impact practice advisories, such as anticoagulation management, LAST treatment, and infection-control practice guidelines, their deeper analysis of dosing for local anesthetic mixtures may yield evidence-based guidance that could inform clinical practice and enhance patient safety. Until such guidance is available, clinicians should exercise caution. Mixing may have a role in select scenarios, but its widespread use cannot be justified. The debate underscores that what appears to be the “best of both worlds” may in fact be “playing with fire.”

References

1. Gadsden J, Hadzic A, Gandhi K, et al. The effect of mixing 1.5% mepivacaine and 0.5% bupivacaine on duration of analgesia and latency of block onset in ultrasound-guided interscalene block. Anesth Analg2011;112:471-6. https://doi.org/10.1213/ANE.0b013e3182042f7f
2. Pietroski Dos Santos N, Silva VDP, Oliveira GSDS, et al. Efficacy of long-acting local anesthetics versus their mixture with shorter-acting local anesthetics for peripheral nerve blocks guided by ultrasound: a systematic review with meta-analysis of randomized controlled trials. Reg Anesth Pain Med 2025;rapm-2024-106104. https://doi.org/10.1136/rapm-2024-106104
3. Lin C, Guerrero AL, Jesin J, et al. Comparing block characteristics of mixtures of short/intermediate- and long-acting local anesthetics for peripheral nerve block: a systematic review and meta-analysis. Brazilian Journal of Anesthesiology (English Edition) 2025;75. https://doi.org/10.1016/j.bjane.2025.844617
4. Oweidat A, Hightower CR, Uppal V, et al. Combination of shorter and longer-acting LA vs. longer-acting LA for brachial plexus block: systematic review and meta-analysis of randomized clinical trials. J Clin Anesth 2025;107. https://doi.org/10.1016/j.jclinane.2025.112017
5. Bungart B, Joudeh L, Fettiplace M: Local anesthetic dosing and toxicity of adult truncal catheters: a narrative review of published practice. Reg Anesth Pain Med 2024;49:209-22. https://doi.org/10.1136/rapm-2023-104667
6. Fettiplace MR, Weinberg G, Nixon HC, et al. The impact of local anesthetic systemic toxicity advisories on reporting to the National Poison Data System. Reg Anesth Pain Med 2025; In press. https://doi.org/10.1136/rapm-2025-106464
7. Fettiplace MR, Weinberg G, Chiang C, et al. Contemporary local anaesthetic-associated adverse events and mortality: a pharmacovigilance analysis of a US reporting system. Br J Anaesth 2025;135:1015-25. https://doi.org/10.1016/j.bja.2025.06.044
8. Sripriya R, Sivashanmugam T, Rajadurai D, et al. Equal mixture of 2% lidocaine with adrenaline and 0.5% bupivacaine 20 mL provided faster onset of complete conduction blockade during ultrasound-guided supraclavicular brachial plexus block than 20 mL of 0.5% bupivacaine alone: a randomized double-blinded clinical trial. Reg Anesth Pain Med 2024;49:104-9. https://doi.org/10.1136/rapm-2023-104542
9. Cuvillon P, Nouvellon E, Ripart J, et al. A comparison of the pharmacodynamics and pharmacokinetics of bupivacaine, ropivacaine (with epinephrine) and their equal volume mixtures with lidocaine used for femoral and sciatic nerve blocks: A double-blind randomized study. Anesth Analg 2009;108:641-9. https://doi.org/10.1213/ane.0b013e31819237f8
10. Clarkson C, Hondeghem L. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985;62:396-405.
11. Duggan J, Bowler GMR, McClure JH, et al. Extradural block with bupivacaine: influence of dose, volume, concentration and patient characteristics. Br J Anaesth 1988;61:324-31. https://doi.org/10.1093/bja/61.3.324
12. Gupta PK, Hopkins PM. Effect of concentration of local anaesthetic solution on the ED 50 of bupivacaine for supraclavicular brachial plexus block. Br J Anaesth 2013;111:293-6. https://doi.org/10.1093/bja/aet033
13. Taylor A, McLeod G. Basic pharmacology of local anaesthetics. BJA Educ 2020;20:34-41. https://doi.org/10.1016/j.bjae.2019.10.002
14. Wan QX, Bo YL, Li HB, et al. Effects of mixture of lidocaine and ropivacaine at different concentrations on the central nervous system and cardiovascular toxicity in rats. Chin Med J (Engl) 2010;123:79-83.
15. Mets B, Janicki PK, James MF, et al. Lidocaine and bupivacaine cardiorespiratory toxicity is additive: a study in rats. Anesth Analg 1992;75:611-4. https://doi.org/10.1213/00000539-199210000-00026
16. Simon L, Kariya N, Pelle-Lancien E, et al. Bupivacaine-Induced QRS prolongation is enhanced by lidocaine and by phenytoin in rabbit hearts. Anesth Analg 2002;94:203-10. https://doi.org/10.1097/00000539-200201000-00039
17. Brecher MJ, Greenberg RA, Greene NM. Drug interactions (toxicity) associated with drug combinations. Acta Anaesthesiol Scand 1972;16:22-6. https://doi.org/10.1111/j.1399-6576.1972.tb00563.x
18. Jong RH de, Bonin JD. Mixtures of local anesthetics are no more toxic than the parent drugs. Anesthesiology 1981;54:177-81. https://doi.org/10.1097/00000542-198103000-00001
19. Vadi MG, Patel N, Stiegler MP. Local anesthetic systemic toxicity after combined psoas compartment-sciatic nerve block: analysis of decision factors and diagnostic delay. Anesthesiology 2014;120:987-96. https://doi.org/10.1097/ALN.0000000000000154