Comments on “Substitution of liposomal bupivacaine for lidocaine reduces incidence of injection-emergent adverse events after intraarticular therapies for knee osteoarthritis: a prospective cohort study”

Dear Editor,

We read with interest the cohort study by Lin et al, which compares injection-emergent adverse events (IEAEs) in knee osteoarthritis patients receiving liposomal bupivacaine (LB) versus lidocaine as local anesthesia during intraarticular therapies (IATs) [glucocorticoids, platelet-rich plasma (PRP), and hyaluronic acid]^[1]. While the study provides valuable mechanistic insights, several critical methodological and interpretive issues warrant further discussion. Notably, this commentary has been prepared in accordance with the TITAN Guidelines 2025, ensuring transparent and responsible integration of AI tools to support content generation, critical appraisal, and linguistic refinement^[2].

1. Non-randomized enrollment and temporal allocation bias

Participants were allocated to LB or lidocaine based solely on enrollment timing rather than randomization or clinical indication. This design introduces potential temporal confounding, for instance, secular trends in injection technique, operator experience, or patient selection over time that could bias outcomes independent of the anesthetic agent^[3].

• 2. Cohort size and statistical power limitations

The study enrolled 103 patients in the LB group and 123 in the lidocaine group, relatively modest sample sizes for capturing less frequent but clinically relevant IEAEs. Although adjusted logistic regression reduced confounding by sex, BMI, age, baseline WOMAC score, and K–L grade, smaller events and subgroup-level nuances may remain underpowered and unexamined^[4].

• 3. Heterogeneity in intra-articular therapies

Patients received various IAT types, e.g., steroids, PRP, and hyaluronic acid, based on patient preference and clinician discussion. Without stratified analysis by treatment type, it is difficult to disentangle whether the observed safety benefit stems from the anesthetic choice or variation in procedural therapies, each of which may confer different risk profiles^[5].

• 4. Short-term follow-up and limited outcome scope

The focus on IEAEs within the first 2 weeks (particularly week 1) provides early insights, yet leaves longer-term consequences (e.g., chondrotoxicity, joint deterioration, and functional recovery) unaddressed. Secondary outcomes like VAS and WOMAC showed only early benefit; the lack of longer follow-up beyond day 14 limits understanding of sustained safety or clinical efficacy^[6].

• 5. Unexamined chondrotoxicity and systemic safety profiles

LB is known from prior in vitro studies to be less chondrotoxic than standard bupivacaine and lidocaine, but not entirely safe, especially with time-dependent dose exposure^[7]. Moreover, real‑world pharmacovigilance flags delayed systemic adverse events, including gastrointestinal, cardiac, and neurological signals that were not assessed in Lin et al’s study with follow-up too short to capture these outcomes^[8].

• 6. Need for randomized controlled trials and broader comparative data

Although Lin et al appropriately conclude that future randomized controlled trials (RCTs) are warranted, robust randomized trials with stratification by IAT type, standardized dosing, blinding, and longitudinal follow-up are essential. Prior RCTs in arthroplasty populations showed no significant advantage of LB over standard bupivacaine for pain control or adverse events, and no cost-effectiveness benefit either^[9].

Lin et al offer a promising early signal that substituting LB for lidocaine may reduce short-term injection-related adverse events in knee IAT. However, the non-randomized design, limited follow-up, unstructured therapy comparisons, and lack of chondrotoxic/systemic safety evaluation temper confidence. Careful large-scale RCTs and mechanistic studies are needed before endorsing routine LB substitution.

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Not applicable for this study.

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Author contributions

S.F.: Study design, data collection, writing, and editing of the draft. The author accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.

Conflicts of interest disclosure

The authors have no conflict of interest.

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All the authors of this paper accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

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