Rebound Pain as a Treatment-Dependent Endpoint in the ITMB Non-Inferiority Trial [Letter]

We read with considerable interest the randomized non-inferiority trial by Yin et al comparing ultrasound-guided infraspinatus-teres minor interfascial block (ITMB) with interscalene brachial plexus block (ISB) after arthroscopic shoulder surgery. 1 The study provides clinically important evidence that ITMB can achieve non-inferior 24-hour opioid consumption while substantially reducing early hemidiaphragmatic paralysis.Recent correspondence has appropriately discussed the opposing early and late analgesic profiles of the two techniques and the influence of the relatively highvolume ISB comparator. 2 Our concern is distinct: these temporal analgesic differences may interact with the operational definition of rebound pain itself, thereby influencing which patients become eligible to be classified as experiencing the event.The reported rebound-pain incidence-26.8%after ISB versus 2.6% after ITMB-is striking.However, rebound pain was defined as a transition from NRS ≤3 while the block was effective to NRS ≥7 within 24 hours.This definition conditions event classification on first achieving sufficiently profound analgesia, yet the probability of satisfying that prerequisite was itself affected by treatment assignment.ISB produced significantly lower resting pain scores at 1 and 6 hours and reduced oxycodone consumption by 3.9 mg during 0-12 hours, whereas ITMB became more favorable during 12-24 hours.Consequently, an ISB recipient whose pain rises from NRS 1 to 7 fulfills the rebound-pain definition, whereas an ITMB recipient whose early pain is NRS 4 and subsequently reaches the same severe level of NRS 7 does not, because the prerequisite NRS ≤3 was never documented.Thus, superior early analgesia may paradoxically increase the opportunity to qualify for the rebound-pain endpoint.This is more than a semantic concern.Rebound pain remains an incompletely standardized construct, and recent discussion has questioned whether it necessarily represents a distinct hyperalgesic phenomenon or, in some patients, simply reflects surgical pain becoming apparent as regional anesthesia resolves.3 In the present trial, the large binary difference in rebound-pain incidence may therefore combine at least two components: a genuine difference in the experience of block resolution and definition-dependent ascertainment arising from different analgesic trajectories.Importantly, this does not imply that the observed 2.6% versus 26.8% difference is spurious.Rather, it limits how confidently the difference can be interpreted as evidence that ITMB biologically prevents rebound hyperalgesia.The authors appropriately describe such mechanistic explanations as speculative, and the outcome definition itself provides an additional reason for that caution.A related clinical consideration is whether the reported physiological respiratory advantage translates into a patientimportant benefit.Ultrasound-defined hemidiaphragmatic paralysis occurred in 90.2% of ISB recipients but only 2.6% of ITMB recipients, whereas patient-reported dyspnea occurred in 19.5% and 2.6%, respectively.This discrepancy illustrates that sonographic phrenic involvement, although physiologically meaningful, is not synonymous with Therapy 2026:20 658504 1 Drug Design, Development and