Postrandomization analgesic escalation and interpretability of spinal cord injury–related neuropathic pain trials

Letter to the Editor: Morse et al.3 present a thoughtfully designed pilot randomized, double-blind, placebo-controlled trial evaluating brivaracetam for neuropathic pain after spinal cord injury (SCI), addressing a persistent therapeutic challenge in contemporary spine and SCI practice. The study demonstrates the feasibility of remote recruitment, daily pain diary collection, and protocol adherence in a complex patient population. Nevertheless, we believe that one issue substantially limits the clinical interpretability of the reported efficacy signal: postrandomization changes in background analgesic therapy. Participants entered the trial receiving extensive concomitant treatment, including gabapentinoids, opioids, and cannabinoids, reflecting real-world management of SCI-related neuropathic pain.3 While this enhances external validity, it places particular importance on how changes in nonstudy analgesics during follow-up are addressed analytically. In this trial, the authors document several clinically meaningful postrandomization interventions (Table 8), including initiation or escalation of ketamine therapy and increases in opioid dosing, with escalation of narcotics or addition of ketamine occurring more frequently in the placebo group.3 From a spine surgeon's perspective, these interventions are not neutral background events. Ketamine infusions and opioid dose escalation are well-established strategies for severe, refractory neuropathic pain and are capable of independently altering pain intensity, temporal variability, and patient-reported outcomes. In a small pilot study, even a limited number of such events can materially influence between-group pain trajectories, particularly when outcomes rely on repeated self-reported pain ratings collected over time. Under these circumstances, it becomes difficult to determine whether observed differences in pain outcomes reflect the pharmacologic effect of brivaracetam or differential escalation of background therapy in response to uncontrolled pain. This challenge is well-recognized in chronic pain trial methodology. Postrandomization initiation or escalation of analgesics constitutes an intercurrent event that can fundamentally alter the clinical question being addressed, shifting interpretation from the isolated effect of the investigational drug to the effect of a broader treatment strategy.2 International guidance on estimands and sensitivity analyses emphasizes that such events should be prespecified and explicitly handled to avoid misinterpretation of treatment effects.2 Similarly, chronic pain consensus groups have highlighted the importance of monitoring and accounting for rescue and concomitant analgesic use when interpreting trial outcomes.1 In the context of SCI neuropathic pain, where polypharmacy is common and treatment escalation is frequent, failure to address these events can substantially limit translational relevance.4 This study appropriately reports analgesic changes descriptively; however, it does not clarify how these intercurrent events were handled in the primary or secondary analyses, nor whether sensitivity analyses were performed excluding participants who initiated or escalated potent analgesics during the diary period. As such, the observed efficacy signal should be interpreted as exploratory. Future confirmatory trials of brivaracetam in SCI-related neuropathic pain could substantially strengthen interpretability through pragmatic design strategies, including a prerandomization stabilization period for background analgesics, clearly defined rescue medication rules, systematic reporting of time-varying analgesic changes, and prespecified analytic approaches aligned with estimand principles.2,5 These steps would help clinicians better understand the incremental contribution of brivaracetam within established SCI pain management paradigms. Disclosures The authors have no conflicts of interest to declare.