Multisocietal guidelines recommend multimodal analgesia and techniques, both non-pharmacological and pharmacological, in the management of postoperative pain in children and adults (strong recommendation, high-quality evidence). Systemic pharmacological therapy typically consists of varying combinations of opioids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, gabapentin or pregabalin, and ketamine or lidocaine, depending on patient characteristics, surgical procedure, and agent preference. Due to the novel mechanism and recent U.S. Food and Drug Administration (FDA) approval of suzetrigine, its role in multimodal analgesia has not yet been delineated. [1]
Suzetrigine (Journavx™) is a selective inhibitor of voltage-gated sodium channel NaV1.8, recently approved for pain management. The NaV1.8 receptor holds a role in transmitting nociceptive signals with selective expression in peripheral nociceptive neurons of the dorsal-root ganglia. Because the NaV1.8 receptor and the gene encoding it (SCN10A) are not found in the human brain, it is hypothesized that suzetrigine will not have central nervous system effects (including abuse and dependence potential). [2], [3], [4], [5]
On January 30, 2025, the U.S. Food and Drug Administration (FDA) approved suzetrigine to treat moderate-to-severe pain. This approval follows the FDA's acceptance of a new drug application (NDA) in July 2022, which was based on results from two phase 3 studies (Table 1) comparing suzetrigine to hydrocodone/acetaminophen and placebo following abdominoplasty and bunionectomy procedures. [4], [5], [6], [7]
Additional preliminary results were revealed in December 2024 (Table 2) of a phase 2 study comparing suzetrigine and placebo for treatment of painful lumbosacral radiculopathy. This 12-week study found a statistically significant and clinically meaningful within-group reduction from baseline pain in both groups. While this study did not statistically compare suzetrigine versus placebo, a similar change was observed in pain score change after 12 weeks (-2.02 vs -1.98). Suzetrigine also demonstrated positive results and a well-tolerated profile in a phase 2 study in patients with pain associated with diabetic peripheral neuropathy; however, preliminary results are not yet available. An additional phase 3 trial is similarly evaluating the long-term safety and effectiveness of suzetrigine in subjects with pain associated with diabetic neuropathy, but preliminary data are also not available at this time. [4], [5], [6], [7], [8]
Two phase 2, randomized, double-blind, double-dummy, placebo-controlled trials evaluated the efficacy and safety of suzetrigine for acute postoperative pain management. Participants were adults aged 18-75 years with moderate-to-severe pain following abdominoplasty or bunionectomy. Patients with a history of long-term opioid or non-steroidal anti-inflammatory use were excluded. In the abdominoplasty trial, 303 participants were assigned in a 1:1:1:1 ratio to high-dose suzetrigine (loading 100 mg, then 50 mg q12h), middle-dose suzetrigine (loading 60 mg, then 30 mg q12h), hydrocodone-acetaminophen (5/325 mg q6h), or placebo for 48 hours, while the bunionectomy trial involved 274 participants randomly assigned in a 2:2:1:2:2 ratio to receive high-, middle-, or low-dose suzetrigine (loading 20 mg, then 10 mg q12h), hydrocodone-acetaminophen, or placebo. Pain intensity was measured using the Numeric Pain Rating Scale (NPRS), with the time-weighted sum of the pain-intensity difference (SPID) over 48 hours (SPID48) serving as the primary outcome measure. Results showed that high-dose suzetrigine significantly reduced pain compared to placebo, with least-squares mean differences in SPID48 of 37.8 (95% confidence interval [CI] 9.2 to 66.4) for abdominoplasty and 36.8 (95% CI 4.6 to 69.0) for bunionectomy. Lower doses of suzetrigine produced outcomes similar to placebo. The high-dose suzetrigine arm also yielded higher percentages of participants achieving ≥30%, ≥50%, and ≥70% reductions in NPRS scores at 48 hours compared to placebo. Adverse events, including headache and constipation, were mild to moderate and occurred more frequently with high-dose suzetrigine than placebo, though no serious safety concerns were attributed to the intervention. The study is limited as it was not designed to detect a difference between suzetrigine and hydrocodone-acetaminophen. [9]
A 2025 original research article assessed the pharmacology, mechanism of action, and safety profiles of suzetrigine, a highly selective NaV1.8 inhibitor, for the treatment of moderate to severe pain. Through a combination of preclinical and clinical evaluations, the investigation characterized the compound’s ability to reduce nociceptive signaling without central nervous system (CNS) side effects or addictive potential. Preclinical studies utilized in vitro electrophysiological methods with human NaV-expressing cells and primary human dorsal root ganglion (DRG) sensory neurons to confirm that suzetrigine selectively inhibits NaV1.8 by binding to a unique site on its voltage-sensing domain 2 (VSD2) and stabilizing the channel’s closed state. The compound was found to be ≥31,000-fold selective for NaV1.8 compared to other NaV subtypes and 180 other molecular targets, including receptors associated with addictive potential, ensuring its specificity at clinically relevant concentrations. A systematic evaluation of safety and addictive potential was conducted in vitro, in animal models, and in over 2400 participants enrolled in phase 3 clinical trials. [10]
Nonclinical repeated-dose toxicity studies in rats and monkeys demonstrated no adverse behavioral, cardiovascular, or CNS effects at exposures exceeding therapeutic levels, with no evidence of physical dependence in animal withdrawal models. Clinical trials assessing suzetrigine in acute pain conditions revealed a favorable tolerability profile with no signs of abuse or dependence, as determined by an expansive analysis of adverse event reporting. These findings underscore suzetrigine’s promise as a novel, non-opioid analgesic that effectively targets peripheral pain pathways and offers an alternative to opioid-based therapies without associated risks of addiction or CNS-related side effects. [10]