Response to Bradshaw et al “Suzetrigine for Acute Pain in the Emergency Department: A First-in-Class NaV1.8 Blocker.”

To the Editor:

The arrival of suzetrigine, the first selective Nav1.8 inhibitor to reach the market, has generated considerable excitement, and rightly so.¹ A "first-in-class" analgesic that sidesteps opioid receptors entirely is an understandably attractive narrative. Yet as clinicians, we have to remain critical even when novel agents can seem exciting, even compelling.

The opioid crisis still casts a long shadow. Oxycodone was introduced with assurances of low addiction potential, and these claims proved to be catastrophically wrong, fueling an epidemic whose legal and human costs continue to mount. The ink on those settlements is barely dry. Suzetrigine seems unlikely to follow the same path; it works differently, and by all accounts lacks classical abuse potential. However, the broader lesson that marketing narratives routinely outpace clinical reality still stands. Nonaddictive itself is a descriptor that should inspire skepticism rather than relief; the "first-in-class" label is of limited relevance to the bedside physician weighing efficacy, safety, and tolerability for an individual patient.

We should recall that Nav1.8 is not an untouched target. Lidocaine, mexiletine, and lamotrigine all modulate voltage-gated sodium channels, including Nav1.8. Their effects are broader and less selective, but they are not absent. Perhaps suzetrigine is to these other drugs as bisoprolol is to propranolol, selective but fundamentally from the same class of drug. Suzetrigine’s selectivity might be useful clinically, but robust trials, years of clinical experience, and incident reporting are required to determine its true indication and risk profile. It makes me think of my clinical pharmacology professor at Liverpool Medical School, Prof. Winstanley, an erudite man with a bone-dry sense of humor. He wryly observed that the asterisks next to new drugs in the British National Formulary were a reminder to allow other doctors to make the mistakes for one to learn from. That is to say, we have a lot to understand about new drugs long after they reach licensed use.

For the bedside clinician, there are grounds for caution. Sodium-channel blocking drugs have a well-documented capacity for cardiac and neurologic toxicity. In suzetrigine’s case, polymorphisms of the Nav1.8 channel (SCN10A) have already been linked to abnormalities of the PR and QT interval^2,3 as well as a significant proportion of cases of Brugada syndrome.⁴ This would seem to suggest that it could indeed have concerning electrophysiological effects in some patients, or conversely, it could be a therapeutic target in these conditions. Even if the latter is the case, we know from experience that most antiarrhythmic drugs are potentially dangerous in overdose or in unsuitable patients. Furthermore, although Nav 1.8 is not seen in healthy heart and muscle tissue, it is seen in these tissues in disease states like heart failure and multiple sclerosis.⁵ The safety of suzetrigine in certain clinical circumstances is simply not currently known. In addition, suzetrigine undergoes significant renal excretion and has numerous cytochrome P450 interactions. This is a pharmacokinetic profile that historically complicates dosing in the many of the populations who experience pain, such as the elderly or those with renal impairment. Drugs, such as these, demand careful titration, vigilant monitoring, and a healthy respect for the unexpected. I am not convinced that the role for these new drugs will be in facilitating early discharge of patients with significant analgesic requirements.

Time will tell whether these concerns are unfounded. New pharmacological options for pain are welcome, but they will have to fit into a holistic, functional pain assessment that does not solely prioritize the reduction of unidimensional pain scores. Let us allow time for the evidence and experience to accrue and prescribe with the memory of other “new” drugs in mind.

Funding and Support

By JACEP Open policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.