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We thank Milam et al., Siddiqui et al., and Xiang et al. for their commentary.1–3 The phase 3 randomized controlled trials of suzetrigine for moderate-to-severe acute pain after abdominoplasty and bunionectomy had significant representation of Black/African American (abdominoplasty, 299 of 1,118; bunionectomy, 260 of 1,073) and Hispanic/Latino participants (abdominoplasty, 380 of 1,118; bunionectomy, 364 of 1,073).4 While our studies were not designed to detect differences within subgroups, ad hoc analyses demonstrated that the efficacy of suzetrigine compared to placebo (measured by sum of the pain intensity difference in numeric pain rating scale from 0 to 48 h [SPID48], primary endpoint) was generally consistent across racial and ethnic subgroups. In a study by McCoun et al., involving diverse surgical and nonsurgical pain conditions, participants’ perception of suzetrigine’s effectiveness in managing pain at the end of treatment (assessed by the proportion of participants reporting good, very good, or excellent pain relief) was similar among White (84%, 180 of 214), Black/African American (79%, 27 of 34), and Hispanic/Latino (83%, 90 of 108) participants.5 With regard to sex, our bunionectomy study, which enrolled a sufficient number of males, showed that SPID48 was similar in male and female participants.4 Further, suzetrigine’s effectiveness was similar in male (80%, 66 of 83) and female (85%, 147 of 173) participants in the McCoun et al. study.5 Literature also indicates that sex does not significantly impact analgesic efficacy.6–10 Collectively, these studies demonstrate that suzetrigine provides effective pain relief regardless of race, ethnicity, or sex with a consistent safety profile.4,5 Although equitable access and systemic bias are important healthcare topics,11,12 phase 3 trials are not designed to address these objectives; further research on socioeconomic influences is warranted.

suzetrigine provides effective pain relief regardless of race, ethnicity, or sex with a consistent safety profile.4,5 Although equitable access and systemic bias are important healthcare topics,11,12 phase 3 trials are not designed to address these objectives; further research on socioeconomic influences is warranted. The methodologies used to assess clinical meaningfulness of investigational analgesic drugs in clinical trials evaluating moderate-to-severe pain and the extent of analgesia and its relationship to the analgesic drug’s mechanism of action are important topics for consideration. The phase 3 clinical trials with suzetrigine were the largest randomized controlled trials ever conducted for moderate-to-severe acute pain; these trials demonstrate the clinical meaningfulness of suzetrigine based on several considerations.4 Clinically meaningful pain relief is defined as a 2-point or greater within-group reduction in numeric pain rating scale score from baseline and should not be applied to between-group comparisons.13,14 Suzetrigine achieved a mean pain intensity difference of −3.4 from baseline at 48 h, representing an approximately 50% reduction (mean numeric pain rating scale) in pain and greater pain relief than placebo.4 The time to clinically meaningful reduction in pain (time to a 2-point or greater within-group reduction in numeric pain rating scale from baseline, a key secondary endpoint), was more rapid for suzetrigine than for placebo.4 Additional factors supporting the clinical meaningfulness were (1) the responder analyses (the proportion of participants achieving at least 30%, 50%, and 70% reduction in pain), which were greater for suzetrigine than placebo; (2) rapid onset of pain relief (within 1 h); (3) a treatment effect that was similar to hydrocodone bitartrate/acetaminophen; and (4) high patient adherence.

) the responder analyses (the proportion of participants achieving at least 30%, 50%, and 70% reduction in pain), which were greater for suzetrigine than placebo; (2) rapid onset of pain relief (within 1 h); (3) a treatment effect that was similar to hydrocodone bitartrate/acetaminophen; and (4) high patient adherence. Across five clinical trials with more than 3,000 participants, suzetrigine demonstrated consistent efficacy with a well-tolerated safety profile.4,5,15,16 The pain relief observed with suzetrigine is similar to that of hydrocodone bitartrate/acetaminophen administered at 5 mg/325 mg every 6 h,4 which is a moderate-strength opioid and acetaminophen combination and the most frequently prescribed opioid at the most commonly prescribed dose for acute pain in the United States. The ranges of placebo-adjusted mean SPID48 from historical opioid trials in abdominoplasty and bunionectomy (with tramadol, morphine, and oliceridine) and with hydrocodone bitartrate/acetaminophen in the phase 2 and phase 3 trials of suzetrigine in these same models show highly variable results for the placebo-adjusted mean SPID48, which may be due to the known large interindividual response to opioids.17,18 Suzetrigine, as a monotherapy, has demonstrated consistent efficacy within this range. The range of placebo-adjusted mean SPID48 for these opioids in abdominoplasty clinical trials is 4.0 to 59.7, while for suzetrigine it is 48.4 in phase 3 and 37.8 in phase 2. In bunionectomy clinical trials, the placebo-adjusted mean SPID48 range for these opioids is 13.1 to 107.6, while for suzetrigine it is 29.3 in phase 3 and 36.8 in phase 2. Overall, based on the clinical development program, suzetrigine is approved for the treatment of moderate-to-severe acute pain.19 In contrast, oral acetaminophen is approved only for mild pain, and intravenous lidocaine is approved only for local or regional anesthesia.20,21

e it is 29.3 in phase 3 and 36.8 in phase 2. Overall, based on the clinical development program, suzetrigine is approved for the treatment of moderate-to-severe acute pain.19 In contrast, oral acetaminophen is approved only for mild pain, and intravenous lidocaine is approved only for local or regional anesthesia.20,21 Suzetrigine, a highly selective nonopioid analgesic, achieves its analgesic effect only through inhibition of NaV1.8. There are no off-target effects, as evidenced by extensive preclinical data; suzetrigine is greater than or equal to 31,000-fold selective for NaV1.8 over all other NaV channels and has no off-target activity based on an assessment of more than 180 targets, including opioid, γ-aminobutyric acid, and serotonin receptors.16 The high selectivity of suzetrigine is further demonstrated by its highly favorable safety profile. Finally, based on its selective mechanism of action on NaV1.8 inhibition and because NaV1.8 is selectively expressed in peripheral sensory nociceptors and there is no NaV1.8 expression in the brain, suzetrigine does not have addictive potential.16 The phase 2 dose-ranging trials of suzetrigine were designed to find the appropriate dose for evaluation in phase 3. Therefore, the phase 2 trials intentionally included doses with a broad range of predicted efficacy.15 It is expected that the lower doses may not be as effective as the high dose because these lower doses/exposures have less NaV1.8 inhibition than the high dose.

to find the appropriate dose for evaluation in phase 3. Therefore, the phase 2 trials intentionally included doses with a broad range of predicted efficacy.15 It is expected that the lower doses may not be as effective as the high dose because these lower doses/exposures have less NaV1.8 inhibition than the high dose. In conclusion, suzetrigine’s analgesic effect is similar to that of hydrocodone bitartrate/acetaminophen—the most prescribed opioid for acute pain in the United States—at standard dosing. Notably, suzetrigine delivers significant and consistent pain relief across demographic groups without the safety, tolerability, or addiction concerns associated with opioids, making it a safe and effective nonopioid option for moderate-to-severe acute pain.4,5,15,16

Dr. Bertoch and Dr. Weiner have reported personal fees from Vertex Pharmaceuticals (Boston, Massachusetts) as members of the Acute Pain Steering Committee. Dr. Weiner has reported fees/honoraria from Cessation Therapeutics, Inc. (Chapel Hill, North Carolina). Dr. Bozic is an employee of Vertex Pharmaceuticals and owns stock and/or options in the company.