Is it time to reassess local anesthetic and adjuvant mixtures, using the lowest effective concentrations and limiting adjuvants to those with proven safety in adults, especially the elderly or patients with cardiovascular, renal, hepatic disease, or a history of seizures?

Reassessment of Local Anesthetic and Adjuvant Mixtures

Yes, it is time to critically reassess and limit the routine use of local anesthetic mixtures and adjuvants, particularly for neuraxial techniques, given recent evidence of extensive crystallization in previously "safe" combinations and the lack of clear clinical benefit that outweighs these safety concerns. 1

The Crystallization Problem

Recent laboratory evidence fundamentally challenges current practice. Mixing local anesthetics with or without adjuvants produces extensive crystallization—even in combinations previously considered safe, such as lidocaine plus sodium bicarbonate. Of 50 tested mixtures, 26 showed high-grade crystallization (≥4 on a 0-5 scale) immediately upon mixing, and 41 reached this level within 60 minutes. This crystallization occurs regardless of pH adjustment and increases over time, raising serious concerns about particle embolization and tissue damage. 2

The crystallization appears independent of solution pH and worsens with time, meaning that even buffered solutions are not safe from this phenomenon. This represents a critical safety issue that was previously unrecognized in clinical practice.

Current Guideline Positions vs. New Evidence

There is a stark disconnect between existing guidelines and emerging safety data:

Existing guideline recommendations:

• The 2016 dermatology guidelines recommend sodium bicarbonate addition to reduce injection pain (Level A recommendation) 3
• The 2021 compartment syndrome guidelines suggest using low concentrations of local anesthetics without adjuncts for high-risk trauma cases 4
• Guidelines recommend lowest effective epinephrine concentrations when vasoconstrictors are used 3

However, the 2026 narrative review in Anesthesiology explicitly cautions against routine use of certain mixtures, especially for neuraxial techniques, due to unclear safety profiles and equivocal clinical benefit. 1

Clinical Efficacy: The Evidence is Weak

The pharmacologic rationale for mixing local anesthetics is fundamentally flawed. The common practice of combining long- and short-acting local anesthetics to hasten onset while extending duration contradicts basic pharmacokinetic principles. 5

For adjuvants, the evidence shows:

Dexamethasone demonstrates the strongest evidence for prolonging analgesia (3.33-fold increase in duration), with moderate-quality evidence supporting its use in local infiltration analgesia 6. However, this data applies primarily to infiltration, not neuraxial or major nerve blocks.

Alpha-2 agonists (clonidine, dexmedetomidine) show moderate evidence but are less effective than dexamethasone, with effects below clinical relevance for pain scores despite some impact on opioid consumption 6.

Opioids show homogenous but modest effects across different agents 6.

Specific Safety Concerns by Adjuvant Type

Steroids and NSAIDs: Risk of precipitation and subsequent embolization, though rare, can lead to serious adverse events. NSAIDs also carry chondrotoxic properties 5.

Epinephrine: Contains preservatives with potential neurotoxic properties. While safe for digits, hands, feet, ears, and nose (contrary to historical dogma) 3, its addition to mixtures may compound crystallization risks 2.

Midazolam: Neurotoxic properties documented 5.

Magnesium and Ketamine: May prolong block at the expense of motor block quality or delayed onset 5.

Critical Limitations in Current Practice

1. Most adjuvants lack licensing for perineural or neuraxial use 5
2. Pharmaceutical compatibility is not established for most combinations—drugs from the same class cannot be assumed compatible 5
3. Optimal dosing recommendations are lacking for most adjuvants, with dose-dependent adverse effects 5
4. Many studies fail to use systemic controls, making it unclear if perineural administration provides additional benefit over systemic administration 5

Practical Recommendations

For neuraxial techniques: Avoid routine mixing of local anesthetics or addition of adjuvants given crystallization risks and proximity to critical neural structures 1, 2.

For peripheral nerve blocks:

• Use single local anesthetic agents at appropriate concentrations
• If adjuvants are considered, limit to dexamethasone for infiltration analgesia where moderate evidence supports benefit 6
• Avoid mixing multiple local anesthetics—the pharmacologic rationale is unsound 5

For high-risk patients (elderly, cardiovascular/renal/hepatic disease, seizure history):

• Use lowest effective concentrations of single agents 4, 7
• Reduce doses for repeated or continuous administration in patients with reduced clearance (hepatic, renal, cardiac disease) 7
• Reduce initial doses when conditions increase uptake rate (pregnancy, advanced age, uremia) 7
• Have lipid emulsion immediately available and monitor for LAST, which can present with biphasic toxicity requiring extended observation (24 hours post-stabilization) 8

For trauma cases with compartment syndrome risk:

• Use low-concentration local anesthetics without adjuncts to preserve some sensation and allow breakthrough pain detection 4
• Note that severe pain is not always present in compartment syndrome, so clinical vigilance remains essential 4

When epinephrine is indicated:

• Safe for digits, hands, feet, ears, nose despite historical concerns 3
• Use lowest effective concentration (2.5-5 μg/mL) 3, 7
• Avoid in first trimester pregnancy when possible; delay elective procedures until after delivery 3

Common Pitfalls to Avoid

• Do not assume that buffering with sodium bicarbonate prevents crystallization—it does not 2
• Do not mix local anesthetics based on theoretical benefits—pharmacokinetics do not support this practice 5
• Do not use adjuvants simply because "we've always done it this way"—most lack proper safety validation 1, 5
• Do not forget that maximum dose recommendations are not evidence-based but rather extrapolated from animal studies and case reports; they must be adjusted for injection site and patient factors 7