Mixing Local Anesthetics - Evidence or Anecdote?

Voices in Pain Medicine: Mixing Local Anesthetics: Is this Evidence-based or Anecdote-driven?

Local anesthetics are a cornerstone of peripheral nerve blocks, but they come with familiar trade-offs. A faster onset often means a shorter duration, while longer-acting agents may take more time to work. To get around this, many clinicians routinely mix agents like lidocaine and bupivacaine, aiming to combine rapid onset with prolonged analgesia. It’s an appealing idea and widely taught in practice… but does it actually work?

Despite its popularity, mixing local anesthetics has persisted more out of habit than strong evidence, especially as regional anesthesia has evolved with ultrasound guidance and a more refined understanding of pharmacology. As the field continues to prioritize precision and evidence-based practice, it’s worth asking whether mixing local anesthetics truly improves block quality or simply adds unnecessary complexity and risk. In this post, we’ll explore the theory behind local anesthetic mixtures, review the available evidence, and discuss the practical implications for everyday clinical practice.

Local anesthetics differ in key properties such as onset, duration, lipid solubility, protein binding, and pKa. For example, lidocaine has a lower pKa, which results in a higher fraction of non-ionized drug at physiologic pH, allowing for more rapid nerve penetration and faster onset. In contrast, longer-acting agents like bupivacaine and ropivacaine are more lipid-soluble and highly protein-bound, contributing to a longer duration of action. Based on these differences, combining agents is often thought to produce additive, or even synergistic effects. However, this assumption oversimplifies the underlying pharmacology. Mixing local anesthetics also dilutes the concentration of each agent, introducing competition at the sodium channel, and results in additive systemic toxicity. These factors raise an important question: do the theoretical advantages of mixing actually translate into meaningful clinical benefits?

What does the literature show?

1. Faster onset, but just by a little. A double-blind randomized study by Cuvillon et al. compared bupivacaine and ropivacaine with epinephrine to equal-volume mixtures with lidocaine for femoral and sciatic nerve blocks. They assessed onset time, duration of blockade, and morphine consumption, and found that adding lidocaine shortened onset time by only a few minutes (16 vs 28 minutes for bupivacaine; 16 vs 23 minutes for ropivacaine). Despite statistical significance, this modest reduction in onset time did not improve surgical readiness, block quality, or reliability.
2. Shorter block duration is a consistent finding. Bobik et al. conducted a randomized prospective study to assess onset time and duration of sensory and motor blockade using 0.375% bupivacaine with epinephrine, 0.5% ropivacaine, and a 0.5% bupivacaine–2% lidocaine (1:1) mixture for axillary brachial plexus block. They found no significant differences in sensory onset time between groups but did observe a faster onset of motor block with a shorter duration in the bupivacaine–lidocaine group.
3. Reviews remain consistent in concluding: No reliable advantage, additive risk. Nestor and colleagues provided a comprehensive narrative review examining the pharmacologic and clinical implications of local anesthetic mixtures. They found that mixing agents reduces the concentration of each component, potentially diminishing the concentration gradient required for effective nerve penetration. Importantly, the review found no consistent evidence that mixtures decrease onset time or prolong block duration compared with appropriately dosed single agents. It also emphasized that systemic toxicity is additive when local anesthetics are combined.
4. Recent study on infraclavicular blocks: duration can be shortened significantly. A randomized, blinded, controlled trial evaluated the effects of combining ropivacaine with lidocaine and epinephrine for lateral infraclavicular nerve blocks. Patients who received 30 mL of 0.5% ropivacaine had a duration of analgesia of 847 minutes. In contrast, those who received mixtures, 20 mL of 0.5% ropivacaine + 10 mL of 2% lidocaine with epinephrine, or 10 mL of 0.75% ropivacaine + 10 mL of 2% lidocaine with epinephrine, had shorter durations of 536 minutes and 671 minutes, respectively. Sensory onset times were similar across groups, ranging from 17 to 18 minutes.

Why does the practice persist?

Despite limited high-quality evidence, the anecdote-driven nature of mixing local anesthetics likely explains why it remains common practice. Some clinicians report real-world benefits and improved reliability, driven by the perceived faster onset and greater procedural flexibility, reinforcing the habit through repeated personal success. These experiences are often passed down through mentorship and embedded in departmental protocols, allowing the practice to persist in the absence of strong supporting data. In private practice or high-efficiency clinical settings, where patient comfort and workflow are prioritized, this approach can feel justified, particularly when adverse outcomes appear rare.

As a result, mixing local anesthetics is often viewed less as an evidence-based intervention and more as a practice shaped by tradition, experience, and situational demands.

Anesthesia consideration and implications for practice

Evidence supporting the use of combined local anesthetics to improve block success, onset, or density is inconsistent. In contrast, mixing short and long-acting agents has consistently been shown to shorten the duration of both sensory and motor blockade. From a pharmacologic perspective, the additive nature of sodium channel blockade may increase the risk of systemic toxicity. In addition, mixing local anesthetics can increase the risk of dosing errors and may obscure optimization strategies with proven efficacy, such as appropriate concentration selection and volume management. Finally, evidence-based alternatives, including the use of well-studied adjuvants or optimized single-agent dosing, offer a clearer safety profile and more predictable clinical outcomes.

Conclusion

Mixing local anesthetics continues to occupy a grey zone where clinical experience and scientific evidence intersect but do not always align. While faster onset and improved block quality are often cited and reinforced by anecdotal success, consistent evidence supporting the combination of local anesthetics remains limited. The routine use of these mixtures warrants reconsideration, with a need for high-quality studies that better define pharmacologic interactions, safety profiles, and true clinical benefit. Until then, the use of a single, appropriately selected local anesthetic offers greater safety, predictability, and reliability in clinical practice.

Brenda Iriele, MD
Kara Segna, MD
Johns Hopkins Hospital
Acute Pain Medicine SIG

References

1. 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 PDF
2. Comparison of the pharmacological properties of 0.375% bupivacaine with epinephrine, 0.5% ropivacaine and a mixture of bupivacaine with epinephrine and lignocaine–a randomized prospective study.
3. Pharmacological and clinical implications of local anaesthetic mixtures: a narrative review
4. The effect of combining lidocaine and ropivacaine on the duration and onset time of an ultrasound-guided infraclavicular brachial plexus nerve block

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