Interpreting heterogeneity and effect size in meta-analysis of Suzetrigine for acute pain

Dear Editor, We read with interest the systematic review and meta-analysis by Bansal et al.[1] evaluating Suzetrigine, a selective NaV1.8 inhibitor, for acute postoperative pain. The authors should be commended for synthesizing emerging phase 2 and phase 3 data on this promising non-opioid analgesic. However, certain methodological considerations warrant further discussion to aid clinical interpretation. First, the primary efficacy outcomes demonstrated extremely high statistical heterogeneity [I² ≈ 99–100% for both sum of pain intensity difference over 48 h (SPID48) and over 24 h (SPID24)].[1] While the use of a random-effects model is appropriate, such levels of inconsistency substantially limit the interpretability of pooled estimates. Contemporary methodological guidance emphasizes that when heterogeneity approaches this magnitude, exploration through subgroup or sensitivity analyses becomes essential rather than relying solely on summary effects.[2] Given that the included trials represent two distinct surgical pain models, bunionectomy and abdominoplasty, procedure-specific subgroup analyses could have clarified whether treatment effects differ across nociceptive contexts. Second, in phase 2 trials evaluating multiple dosing regimens, only the highest-dose Suzetrigine arms were selectively incorporated into pooled analyses.[1] This approach risks dose-selection bias and potential inflation of effect size estimates. Current recommendations for evidence synthesis support inclusion of all clinically relevant dose arms or formal dose–response exploration to avoid selective aggregation.[2,3] Third, the reported standardized mean differences (SMD) for SPID outcomes exceeded 5, values rarely observed in analgesic research. Extreme SMD values may arise when pooled standard deviations are small, when least-squares means are used instead of raw means, or when heterogeneous trial populations are combined.[4] Methodological literature cautions that such magnitudes warrant careful scrutiny and should ideally be contextualized using absolute differences or responder thresholds anchored to minimal clinically important differences in pain trials.[5] Finally, the interpretation that Suzetrigine demonstrates efficacy comparable to hydrocodone/acetaminophen should be framed cautiously.[1] Absence of statistical difference in the setting of marked heterogeneity and wide confidence intervals does not establish therapeutic equivalence. CONSORT guidance for equivalence and noninferiority trials underscores that equivalence must be prospectively defined and statistically demonstrated rather than inferred from nonsignificant superiority testing.[6] To conclude, Suzetrigine represents a promising advance in peripherally targeted analgesic pharmacology. Future evidence syntheses incorporating heterogeneity exploration, dose–response evaluation, and clinically interpretable outcome measures will help clarify the therapeutic role of Suzetrigine within multimodal acute pain management strategies. Author contribution TM: Conceptualisation, Literature search, Writing - Original Draft, Review and Editing; ASN: Validation, Writing - Original Draft, Review and Editing, Supervision. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest to declare.