Between promise and peril: role of suzetrigine as a non-opioid analgesic

Despite recent approval from the US Food and Drug Administration, the clinical benefits of suzetrigine remain modest and contested

In the current landscape of the opioid crisis, which was responsible for over 100,000 overdose deaths in the United States in 2022 alone, interest in the development of non-opioid analgesics has been considerable.¹ Yet progress in developing novel analgesic drug treatments has been slow and as such, opioids continue to be used for many indications including the treatment of acute pain. This practice is problematic because use of opioids to treat acute pain, including for postoperative analgesia, is a known precursor for persistent opioid use.^{2 3} The most recent pain medication approved by the US Food and Drug Administration (FDA) was celecoxib in 1998.⁴ Although initially greeted with enthusiasm for its purported gastrointestinal safety relative to its non-steroidal anti-inflammatory drug (NSAID) counterparts, it received an FDA black box warning shortly thereafter as postmarketing data revealed evidence of serious and sometimes fatal cardiovascular and gastrointestinal risks. This denouement has long served as a cautionary tale for analgesic drug development.

In this backdrop enters suzetrigine, a novel analgesic that recently obtained FDA approval for treating moderate-to-severe acute pain.⁵ Suzetrigine is a non-opioid analgesic that inhibits the voltage-gated sodium channel Na_v1.8 in peripheral sensory neurons with high selectivity. At least four sodium channels have major roles in acute inflammatory and chronic (especially neuropathic) pain, so the main advantage of selective Na_v blockers is their lack of off-target side effects, particularly cardiac and central nervous system (CNS) effects.⁶ While marketed as a non-opioid analgesic lacking addictive properties, CNS effects, and related harms, its supporting data are fraught with ambiguity that warrant further scrutiny.⁷ Therefore, despite being the first analgesic drug to receive FDA approval in over 25 years, suzetrigine's arrival should be met with cautious optimism. In the midst of the opioid crisis for which directed interventions have yielded mixed results, how should regulators within the FDA balance the need for non-opioid analgesics against imperatives for substantiated scientific evidence?

Supportive evidence

The FDA approval for suzetrigine (initially labelled VX-548) was driven by two phase 2, placebo-controlled, double-blind randomised trials that demonstrated statistical significance within groups but clinically ambiguous superiority in treating pain after bunionectomy and abdominoplasty, based on the sum of differences in pain intensity that have no established effect sizes.^{5 7} Although these studies possess strengths that merit recognition, substantial methodological and interpretational flaws limit their impact and warrant cautious interpretation.

The active treatments studied in the trials included placebo, a combination of acetaminophen and hydrocodone (5-325 mg) every 6 hours, and multiple doses of suzetrigine (high: 100 mg loading dose followed by 50 mg every 12 hours; medium: 60 mg loading dose followed by 30 mg every 12 hours; low, only in the bunionectomy trial: 20 mg loading dose followed by 10 mg every 12 hours).⁷ Across both trials, only the high dose of suzetrigine showed superiority over placebo across a 48-hour, postoperative period. Although the investigators should be commended for incorporating an active control, the study compared two fundamentally different treatment arms. Doubts about the dose of acetaminophen-hydrocodone used as an active comparator have emerged because it not only failed to outperform placebo, but also represents a relatively low opioid dose for treating postoperative pain. The limited efficacy observed with the opioid comparator calls for consideration of more clinically relevant active comparators that are pragmatically more useful for clinical care.

The choice of bunionectomy and abdominoplasty as surgical contexts and restricting time points to the first 48 hours after surgery also warrant scrutiny, because they limit generalizability to more common and invasive surgeries such as large joint arthroplasty and spine surgeries where postoperative pain frequently persists for weeks, and management poses greater challenges.⁸ The short study duration is particularly problematic given that the study data were extrapolated by the FDA to justify and approve the use of suzetrigine for any acute pain scenario. Another principal concern includes the unreported use of NSAIDs for rescue analgesia, which may confound results and make it difficult to determine whether the observed effects stem from suzetrigine or adjunctive pain drug treatments. Additionally, industry-led trials carry an inherent risk of bias, particularly when sponsors have direct access to data and analysis (NCT04988336, NCT05034952), raising concerns about selective reporting and potential conflicts of interest.⁹

Research context for pain medicine

The trials exploring the effectiveness of suzetrigine underscore the challenges and complexities with pain medicine research. Unlike clinical spheres such as oncology where endpoints are objectively ascertained, significant placebo responses in pain medicine are commonplace and frequently account for over half of measured analgesic benefit.¹⁰ Such considerable placebo responses are also why sham-controlled trials evaluating surgical interventions for pain have mostly been negative, and why methodologically rigorous studies are necessary.¹¹ While placebo interventions are ethically debatable in studying cancer treatments whereby lifesaving treatment might be withheld, they are necessary for evaluating pain interventions, particularly in acute pain where even groups that receive placebo treatments are expected to normally recover. Consequently, appropriately interpreting suzetrigine's superiority over placebo response has many challenges.

Compounding this ambiguity is the reality that numerous pain medications currently used have not fared better in clinical studies. One study found that only 14-17% of patients had ≥50% pain reduction with gabapentin over placebo for neuropathic pain.¹² Despite unclear analgesic value, gabapentin's harms have clearly emerged, with recent data implicating it in up to 10% of overdose deaths in the US between 2019 and 20.¹³ As such, drug-related harms and known mortality risks with current analgesics (including opioids, gabapentinoids, and NSAIDs) erode the risk-benefit profiles and highlight the need to prioritize safety. For drugs such as suzetrigine that have ambiguous benefits, their purported safety profiles warrant further consideration.

Drug approval context

Given that the opioid crisis has exerted enormous pressure on regulators to approve non-opioid alternatives, the FDA granted suzetrigine ‘fast track’, ‘breakthrough therapy’, and ‘priority review’ designations to facilitate and expedite the review process.⁵ Although well intentioned, this same urgency has previously resulted in devastating outcomes, as evidenced by extended-release oxycodone receiving FDA approval despite incomplete safety data.¹⁴ In 2019, esketamine received similar ‘fast track’ and ‘breakthrough’ designations and FDA approval for treatment refractory depression despite unresolved safety concerns, which were partly the basis for its continued rejection by the National Institute of Health and Care Excellence in the UK.^{15 16} Reaching divergent regulatory recommendations despite the same body of evidence indicates a philosophical divide between public health considerations and strict scientific standards.

Future implications and conclusions

The FDA's emphasis on non-opioid safety is admirable, but comes at the steep cost of diluted scientific rigor. Suzetrigine's approval signifies a bright future for treating pain with sodium channel blockers, which have received a surge of research interest. However, establishing a precedent where a novel drug's potential and safety eclipse efficacy carries a downside. Recalibration of the ethos of the drug approval process may unfavorably incentivize the pharmaceutical industry to prioritize minimal viability over transformative therapy and temper innovation in drug development. Therefore, the FDA needs to use a nuanced approach to carefully balance public health pressures with regulatory vigilance. In the case of suzetrigine, rigorous postmarket surveillance focusing on drug safety and opioid-sparing benefits is essential for adoption into clinical practice. The role of suzetrigine in chronic pain remains unclear. For lumbosacral radiculopathy, suzetrigine showed statistically significant and meaningful clinical improvement but failed to separate itself from placebo (NCT06176196).¹⁷ Moving forward, the FDA could benefit from more balanced priority designations for streamlined drug approvals. The opioid crisis warrants innovation in drug development, but not at the cost of repeating history.