Authors: Siddiqui A et al.
Journal: Anesthesiology, February 2026 (accepted October 17, 2025). DOI: 10.1097/ALN.0000000000005828
Summary
This letter to the editor provides a critical appraisal of recently published phase 3 trials evaluating suzetrigine for the treatment of moderate-to-severe acute pain. The authors focus on the interpretation of efficacy metrics and whether the reported outcomes meet accepted thresholds for clinical meaningfulness when compared with established opioid analgesics.
The letter highlights concerns regarding the reliance on SPID48 as the primary endpoint, noting that while suzetrigine demonstrated statistical superiority over placebo, the magnitude of pain score differences may not consistently exceed thresholds for clinical significance as defined by the original investigators. The authors argue that SPID48 may preferentially reflect prolonged duration of modest analgesia rather than a strong peak analgesic effect, raising questions about real-world effectiveness for patients experiencing severe postoperative pain.
They further note the absence of head-to-head comparisons with opioids in contemporary phase 3 designs and emphasize that historical opioid trials demonstrate more robust peak analgesic effects. The authors caution that comparing suzetrigine favorably to opioids using indirect or heterogeneous datasets may overstate its relative efficacy. Additionally, they suggest that outcomes such as quality of recovery, functional status, and patient-centered endpoints should be prioritized alongside numeric pain scores when assessing new analgesic agents.
Overall, the commentary acknowledges suzetrigine as a promising nonopioid therapy while urging caution in how efficacy claims are framed. The authors call for clearer benchmarking against existing standards of care and emphasize the importance of distinguishing statistical significance from clinically meaningful pain relief.
Key Points
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SPID48 may overemphasize duration of analgesia rather than peak pain relief.
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Reported pain score differences may not consistently meet predefined thresholds for clinical meaningfulness.
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Lack of direct comparisons with opioids limits conclusions about relative efficacy.
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Peak analgesic effect and functional recovery are critical patient-centered outcomes.
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Caution is warranted when interpreting nonopioid analgesic trial results against opioid standards.
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