Authors: Bertoch T et al.
Journal: Anesthesiology, December 11, 2025. DOI: 10.1097/ALN.0000000000005825
Summary
This reply addresses multiple commentaries regarding the clinical meaningfulness, demographic consistency, and comparative efficacy of suzetrigine for moderate-to-severe acute pain. The authors clarify points raised about subgroup effects, outcome interpretation, and comparison with established opioid analgesics.
The authors emphasize that phase 3 randomized controlled trials of suzetrigine included substantial racial and ethnic diversity and that exploratory analyses demonstrated consistent analgesic efficacy across race, ethnicity, and sex. Although the trials were not powered for subgroup analyses, pain reduction and patient-reported effectiveness were similar among Black/African American, Hispanic/Latino, and White participants, as well as between men and women. These findings support generalizability across demographic groups.
Regarding clinical meaningfulness, the authors clarify that a within-group reduction of 2 or more points on the numeric pain rating scale defines meaningful pain relief and should not be misapplied to between-group comparisons. Suzetrigine achieved approximately a 50% reduction in pain by 48 hours with a faster onset of meaningful analgesia than placebo. Additional evidence supporting meaningful benefit included higher responder rates, rapid onset within 1 hour, strong adherence, and an overall magnitude of effect comparable to hydrocodone bitartrate/acetaminophen.
Comparisons with historical opioid trials demonstrated that suzetrigine’s efficacy falls squarely within the wide range of placebo-adjusted effects observed with commonly used opioids, while offering more consistent responses. The authors highlight that variability in opioid analgesic trials is well recognized due to interindividual response differences.
Mechanistically, suzetrigine is described as a highly selective NaV1.8 inhibitor with no meaningful off-target activity and no central nervous system expression of its target. This peripheral selectivity underpins its favorable safety profile and lack of addictive potential. The authors conclude that suzetrigine represents an effective nonopioid alternative for moderate-to-severe acute pain, offering opioid-level analgesia without opioid-related risks.
Key Points
-
Suzetrigine demonstrates consistent analgesic efficacy across race, ethnicity, and sex.
-
Clinically meaningful pain relief is supported by magnitude, speed of onset, responder analyses, and adherence.
-
Analgesic effect is comparable to hydrocodone/acetaminophen at standard dosing.
-
Variability seen with opioids underscores the value of consistent nonopioid efficacy.
-
Suzetrigine selectively inhibits NaV1.8 with no central nervous system activity or addiction potential.
-
The drug offers a safe and effective nonopioid option for moderate-to-severe acute pain.
Thank you for allowing us to use this article from Anesthesiology.