Opioids have been the mainstay of postoperative analgesia for decades. However, their side effects and potential complications, such as respiratory depression, postoperative nausea, vomiting, and ileus, have fueled the search for alternative ways to control pain. Thus, the concept of multimodal analgesia was born—a technique using a combination of different analgesic modalities, including acetaminophen, nonsteroidal anti-inflammatories, N-methyl-D-aspartate receptor antagonists, intravenous lidocaine infusion, local anesthetic infiltration, regional anesthesia, and peripheral nerve blocks, that can result in maximal pain relief with the minimum necessary dose of opioids to lessen their side effects. This strategy has coincided with the adoption of enhanced recovery after surgery protocols that have helped promote multimodal analgesia to minimize opioid use while permitting a more expedient recovery.1
Recently, suzetrigine, a voltage-gated sodium channel 1.8 (NaV1.8) blocker, was approved by the US Food and Drug Administration (FDA), leading to interest in possibly adding this nonopioid analgesic to the multimodal analgesic regimen.
THE FIRST SYSTEMIC SODIUM CHANNEL BLOCKER ORAL ANALGESIC
Sodium channels have long been a known target for analgesia. Local anesthetics, in particular, inhibit nerve conduction via the intracellular blockade of sodium channels. However, systemic administration of local anesthetic agents has remained limited and considered off-label use. Systemic lidocaine administration has been studied for acute postsurgical pain, but side effects stemming from nonselective inhibition of sodium channels in the heart and central nervous system, as well as a lack of evidence that it is effective beyond 24 hours postoperatively, have limited its use.2,3
Suzetrigine is the first systemic sodium channel blocker that has been approved by the FDA for the indication of treating moderate to severe postoperative pain. If suzetrigine proves over time to be effective enough to reduce or even supplant opioids, the current workhorse, it would be a significant advancement in pain management.
PHARMACODYNAMICS AND PHARMACOKINETICS
Suzetrigine is a highly selective sodium channel blocker that primarily targets the NaV1.8 voltage-gated sodium channel.4 Its chemical name is 4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-4-(trifluoromethyl)oxolane-2-amido]pyridine-2-carboxamide, and in clinical trials it was referred to as VX-548.4 The NaV1.8 voltage-gated sodium channel appears to be highly expressed in the dorsal root ganglia of peripheral sensory neurons but not significantly expressed in the central nervous system or the heart.5–7 Because NaV1.8 channels are only found in peripheral sensory neurons, there is optimism that a peripherally mediated therapeutic effect can be achieved without a significant risk of central nervous system–mediated side effects, arrhythmogenesis, or high potential for abuse and addiction.8,9
Suzetrigine has a peak plasma time to maximum concentration of 3 hours in fasting conditions and a half-life of 23.6 hours; 49.9% is eliminated in feces and 44% in urine.10 There seems to be no clinically significant pharmacokinetic differences based on age, sex, body weight, race, or renal impairment.
Suzetrigine is primarily metabolized by the liver into the active metabolite M6-SUZ, which is a weaker NaV1.8 inhibitor.11 Because this process is mediated through the cytochrome P450 3A (CYP3A) enzyme, suzetrigine should be used cautiously in those taking moderate to strong CYP3A inhibitors, as well as in patients with hepatic impairment as increased levels of the drug and its active metabolite have been seen. In those with moderate hepatic impairment (Child-Pugh class B), the area under the plasma concentration-time curve from time 0 to 12 hours for suzetrigine increased by 1.5-fold and the maximum concentration increased by 1.3-fold.10 Therefore, lower doses should be used in patients with hepatic impairment classified as Child-Pugh class B and should be avoided in patients with Child-Pugh class C cirrhosis.11
FDA APPROVAL PROCESS FOR NEW PAIN MEDICATIONS
For a new medication to earn FDA approval as a non-opioid analgesic indicated for acute pain, supporting clinical trials must meet rigorous design and evidentiary standards. Investigational drugs may pursue either a general indication for acute pain by demonstrating efficacy across varied pain models or a specific indication for acute pain, eg, postoperative pain. A general indication requires at least 2 well-controlled trials in different pain populations, while novel mechanisms of action may necessitate broader testing.12
Trials must be randomized, double-blind superiority studies, with the treatment duration reflecting the pain model and lasting at least 24 hours for multi-dose regimens.13 The primary end point should be a patient-reported measure of pain intensity, using a numerical rating scale assessed at regular intervals. The sum of pain-intensity difference is often used to evaluate cumulative pain relief over time.
The trial design must also account for rescue medication use, ensuring it does not mask the investigational drug’s effect. Additional secondary end points, such as time to onset of pain relief and need for rescue medication use, also help characterize the drug’s efficacy profile.
PAIN MANAGEMENT EFFECTIVENESS
Acute postsurgical pain
The FDA approved suzetrigine based on 2 phase 3 randomized controlled trials that evaluated pain-control response in adults age 18 to 80 years undergoing abdominoplasty or bunionectomy who were expected to experience moderate to severe postoperative pain (verbal numerical pain score ≥ 4 of 10).14 Patients with any sensory abnormalities and those with painful physical conditions that might interfere with their ability to assess postoperative pain were not eligible. The trials also excluded patients with a history of long-term opioid or nonsteroidal anti-inflammatory use.
Patients in the abdominoplasty trial were given fentanyl for postoperative analgesia until they were lucid enough for oral medication, at which point they were randomized in a 2:2:1 fashion 15 minutes after last analgesic administration to either suzetrigine, hydrocodone bitrate and acetaminophen, or placebo.14 Patients in the bunionectomy trial had their pain initially controlled with a popliteal nerve block, so randomization occurred once the block had worn off completely. Ibuprofen 400 mg every 6 hours was allowed as rescue medication for breakthrough pain, but all other pain medications, including opioids, were restricted. The total amount of rescue medication use was recorded, and prerescue pain scores were carried over for 6 hours to ensure the integrity of the pain assessment. The primary end point was a time-weighted sum of pain-intensity difference from baseline over 48 hours. The secondary end point was the time needed to achieve a 2-point or greater reduction in pain compared with hydrocodone bitrate 5 mg and acetaminophen 325 mg.
Suzetrigine showed statistically significant superiority over placebo in reducing pain intensity over 48 hours in both the abdominoplasty (least squares mean difference 48.4, P < .0001) and bunionectomy (least squares mean difference 29.3, P = .0002) trials.14 However, suzetrigine did not meet the secondary end point of superiority over hydrocodone bitrate and acetaminophen, as no significant difference in pain scores after abdominoplasty and inferior results after bunionectomy were seen. Suzetrigine provided faster onset of clinically meaningful pain relief (≥ 2-point numeric pain rating scale reduction), with median times of 119 minutes after abdominoplasty and 240 minutes after bunionectomy, compared with placebo.
Post hoc analyses confirmed more rapid relief, especially in patients in the bunionectomy trial who had higher baseline pain. Suzetrigine also showed faster time to perceptible pain relief (≥ 1-point reduction); greater responder rates at 12, 24, and 48 hours; and higher patient global assessment scores vs placebo. Additionally, suzetrigine was associated with significantly lower rates of nausea and vomiting than hydrocodone bitrate and acetaminophen, and patients required less rescue medication after abdominoplasty, though rescue medication use was the same after bunionectomy (ibuprofen 800 mg in both groups). The results of the sum of the pain-intensity difference over 24 hours supported the primary findings, confirming suzetrigine’s efficacy in acute postsurgical pain management.14
Acute nonsurgical pain
Suzetrigine is currently only available in an oral formulation, which severely limits its perioperative use to postsurgical pain after patients resume oral intake but creates an opportunity to potentially use it for acute nonsurgical pain.
A single-arm, open-label, phase 3 study evaluated suzetrigine’s efficacy for both surgical and nonsurgical acute pain.15 Investigators included patients who presented with new acute pain (onset < 48 hours) in addition to the acute postsurgical pain populations seen in prior studies. A wider variety of surgical populations were enrolled, including otorhinolaryngology and general surgery. The modestly sized nonsurgical group (n = 34) included patients with back, extremity, and facial pain. The dosing regimen was consistent with the previous phase 3 trials: 100 mg for the first dose and subsequent doses of 50 mg every 12 hours for 14 days or until pain resolved.
Good to excellent pain relief, the secondary outcome in this study, was experienced by 91.2% of the nonsurgical population compared with 82% of the surgical population.15 This is a strong signal that suzetrigine might have a role in managing acute nonsurgical pain, but more robust, placebo-controlled studies are required for FDA approval in this population.
SIDE EFFECTS
In the study that evaluated suzetrigine’s efficacy for nonsurgical pain, the primary end point was adverse events, which were seen in 36.7% of participants, but were mostly mild (27.7%) and included side effects like headache (7%), nausea (3.1%), and constipation (3.5%).15 Five patients had significant adverse events that required discontinuation, and these included accidental overdose, exacerbation of preexisting arrhythmia, nausea, rash, and somnolence. These incidents were not covered in detail, but it was noted that the patients did not experience poor outcomes.
Although long-term carcinogenic potential has not been studied, animal studies of suzetrigine have shown no effect on mutagenesis or fertility.11 Dependence and addiction are not expected due to the lack of central nervous system receptors, but further studies will be needed. Tolerance development and effects on bowel motility are also highly relevant primary end points for future safety studies.
All trials thus far have also been limited to short follow-up periods of only a few weeks, so phase 4 studies will show what side effects may occur with chronic use.
FDA LABELING REQUIREMENTS
The FDA does not support vague labeling claims like “opioid sparing” because such wording lacks clarity. However, it does provide labeling guidance for more specific benefits like reducing or eliminating opioid use.12,13 A nonopioid drug must meet 3 qualifications to merit label inclusion of these claims:
Eliminates the need for opioids in a pain setting where they are typically required
Allows patients to be discharged without opioid prescriptions when opioids are usually needed after discharge
Reduces opioid use in conjunction with a direct clinical benefit, such as faster functional recovery or fewer opioid-related side effects (eg, less nausea or sedation).
A drug may qualify for these labels if they are supported by data from at least 2 adequate, well-controlled trials and if the nonopioid medication provides analgesia comparable to that of opioids.13 Simply reducing opioid dose or duration is not sufficient without demonstrating a clear, meaningful benefit to the patient.
In clinical trials, suzetrigine was unable to establish superiority when compared with the comparator opioid medication, suggesting that it may be unable to eliminate opioid use in most patients.14 Additionally, over 80% of participants still required rescue ibuprofen, and opioid rescue was not assessed. Furthermore, no data were reported on discharge without opioids or long-term functional outcomes. While suzetrigine was associated with reductions in nausea and vomiting compared with the comparator opioid hydrocodone bitrate and acetaminophen, these findings were not clearly linked to reduced opioid exposure.
OPPORTUNITIES AND LIMITATIONS
As previously mentioned, suzetrigine is only available as an oral formulation, which imposes challenges but offers opportunities at the same time. The oral formulation limits its use to the postoperative period after oral intake is resumed. An intravenous formulation might be more useful during the perioperative period, expanding its use to the intraoperative and immediate postoperative periods, and may prove to be more effective than the current formulation. On the other hand, the oral formulation makes it useful for postoperative pain management after discharge by potentially reducing or replacing opioid therapy, as well as enabling it to treat different acute and perhaps chronic nonsurgical pain indications, such as back pain, renal colic, biliary pain, and so on.
As suzetrigine becomes more widely available, off-label use by physicians seems likely to increase. Current off-label use includes treatment of acute and chronic pain as well as combining it with analgesic treatment modalities to decrease the side effects of opioids by lowering their dose. Although efforts to limit perioperative opioid use are clinically valuable, current evidence indicates that inadequate postoperative pain control and preoperative opioid exposure are among the most significant predictors of both prolonged opioid use and the development of opioid use disorder.16,17
Finally, while suzetrigine is not extremely expensive (wholesale cost is $15.50 per pill or approximately $434.00 for a 2-week supply), cost-effectiveness is yet to be established.18 In addition, coverage by Medicare, Medicaid, and private insurance is highly variable and depends on the formularies they use.
Suzetrigine prescribing and cost information is listed in Table 1.11,18
Suzetrigine prescribing and cost information
CONCLUSION
Although suzetrigine is a promising novel agent in the analgesic landscape, current clinical trials have not yet demonstrated its superiority over opioids in managing acute postoperative pain. Furthermore, suzetrigine’s efficacy in patients with chronic opioid use—particularly in reducing the daily dose of opioids required or improving pain outcomes—as well as the possibility of dependence remain unstudied. Suzetrigine has certainly shown it is an effective analgesic for acute pain and may have an important role as another option for multimodal postoperative analgesia regimens and for managing acute nonsurgical pain.
DISCLOSURES
Dr. Abdelmalak has disclosed teaching and speaking for Medtronic and Mindray North America. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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