Stop me if you’ve heard this one before: A miracle new painkiller promises to save us all from the scourge of addiction while effectively treating acute and perhaps even chronic pain. The media goes wild.
This time around, the media is making a fuss about Vertex Pharmaceuticals Incorporated’s suzetrigine, a newly FDA-approved painkiller that also goes by the equally unpronounceable brand name Journavx. Suzetrigine has a highly specific mechanism totally different from the way opioids dull pain.
Opioids bind to receptors in the brain and spinal cord, providing system-wide pain relief and system-wide side effects. By contrast, suzetrigine inhibits pain by taking advantage of voltage-gated sodium channels found on the membranes of neurons, muscle cells and glial cells, particularly at the junction between neurons and muscle cells. These sodium channels open and close as needed to allow sodium ions to cross the cell membranes, activating neurons to do their job
As a result, they play a downstream role in several different aspects of pain. This means that the effect of gaining control of them is likely to be short acting, disassociating and reassociating with each painful signal, limited to the peripheral system, not working on the brain at all — and so highly unlikely to cause addiction or some of the other body-wide effects of opioids.
Researchers have been trying out different drugs for years to find one that could inhibit, or turn off, different sodium channels. Finally, they’ve encountered one that works, and last month the Food and Drug Administration approved its use in the treatment of acute pain, which affects some 80.2 million U.S. patients every year. A new painkiller could be great news — if the drug is as effective as what already exists. Dr. Stefan Kertesz, a clinician-scientist at the University of Alabama who provides primary and addiction care to veterans in the Birmingham, Alabama VA Health Care System, said we still don’t know enough about this medication to be sure.
“There are some obvious gaps in the data,” Kertesz said in a phone interview with Salon. While suzetrigine seems to be a relatively low-risk intervention, it’s not clear that it is good enough for the purposes for which it’s been approved, or for likely future or off-label uses. “To my view this is not convincing that this is better than opioids.”
"There are some obvious gaps in the data."
Kertesz is not the only one skeptical based on the evidence presented to date. The authors of a report released last week from the Institute for Clinical and Economic Review (ICER) noted several caveats: we don’t know how many patients in the phase 3 trial resorted to rescue medications (probably opioids); we don’t yet have data on how suzetrigine stacks up against non-steroidal inflammatory drugs (NSAIDs), the other main alternative to opioids but one that often comes with serious side effects or intolerability; and we don’t have data comparing suzetrigine with real-world opioid doses, which are often much higher than those used in the trial.
It’s also important to note that suzetrigine is approved only for short-term or acute pain following surgery. However, trials are underway for its potential use in certain kinds of chronic pain, although phase 2 results to date are not impressive. This shouldn’t be surprising, given its highly specific, peripheral mechanism.
“It shouldn’t work for centralized pain. It really shouldn’t,” Kertesz told Salon, referring to the centralization that can occur in some types of chronic pain where pain persists despite there being no evidence of inflammation or tissue damage: processes in the brain are causing the feeling of pain nevertheless. Poorly treated acute pain can sometimes turn into centralized, chronic pain, and a peripherally-functioning medication like suzetrigine should have no relevance to that. But what if your chronic pain involves both a centralized component and some ongoing tissue damage? Some questions are still unanswered.
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Kertesz noted that in a 12-week, phase 2 trial of suzetrigine for the treatment of a type of pain in the lower back and sacrum, Vertex found no difference between suzetrigine and placebo, though the study wasn’t “designed nor powered for statistical comparison” between the two.
“I still think we don’t have all the data we were supposed to have, but it looks like it’s low risk,” Kertesz said. Side effects that have been noted for suzetrigine are relatively mild, although as the authors of the ICER report noted, “We have concerns about as-yet-unknown harms of suzetrigine as we would for any drug with a new mechanism of action; we are particularly concerned about whether there could be an increased risk for cardiac arrhythmias given inhibition of NaV1.8 [the sodium ion channel the drug targets] and possible acute renal injury given a study in people with diabetes.”
"I expect [suzetrigine] to be an order of magnitude more expensive."
Vertex says its plan is to keep suzetrigine affordable, or at least competitive with opioid costs, although Peter Friedmann, a physician specializing in addiction, and professor of Population & Quantitative Health Sciences at UMass Chan Medical School, noted that generic opioids and NSAIDs are already incredibly cheap.
“Opioids are effective, inexpensive and safe when properly prescribed. Surgery and post-op care are usually bundled … so the price will really have to be competitive to convince hospitals/surgicenters,” Friedmann told Salon by email. “I expect it [suzetrigine] to be an order of magnitude more expensive.”
ICER, using using a placeholder price for suzetrigine of $420 for a one-week course, suggests that, taking into account the wide range of estimates that exist of opioid use disorder risk of a one-week course of a typical hydrocodone/acetaminophen combination, there may be a slight long-term cost saving in using suzetrigine due to avoidance of that risk.
Do we really need a new type of painkiller?
Many painkiller options already exist, with opioids remaining the most effective drugs in most cases where severe acute, nociceptive pain is concerned — that aching, throbbing pain encompassing everything from bruises to arthritis to broken bones. For neuropathic pain, which concerns the nerves, medications like gabapentin are more appropriate. Opioids prescribed at the lowest effective dose also make sense for some other patients who do not tolerate or benefit adequately from alternatives.
“The early trials show superiority of the high dose regimen to placebo for acute pain with a reasonable side effect profile, which is necessary for FDA approval,” Friedmann said “Noninferiority would be if it were compared to a known efficacious med like hydrocodone/acetaminophen.”
Indeed, this has been done, as part of the phase 3 trials. Suzetrigine was found to be about equally effective to the opioid/acetaminophen combo for abdominoplasty (tummy tuck) pain but provided a slower onset of pain relief, which might or might not be a problem, in the case of pain from removing bunions. Notably, these are both relatively minor surgeries. Suzetrigine is nowhere near being able to replace prescription fentanyl, a vital medication for severe pain during and after surgery.
Friedmann believes we do need opioid alternatives, particularly for chronic pain (for which suzetrigine has not shown efficacy to date.) But like Kertesz, he sees suzetrigine as modestly useful for certain very specific indications, such as after minor surgery in patients, but is doubtful as to whether it represents that magic alternative to opioids.
“Analgesic efficacy is only one part of the equation — we also need randomized trials in chronic pain that look at function and long-term tolerability in comparison to NSAIDs,” Friedmann said.
Beyond wanting to create more effective drugs, the motivations for constant attempts to produce new, non-opioid painkillers are largely either commercial — because opioid availability is limited by prior authorization and DEA production limits — or legal or at least administrative, because the requirements for prescribing opioids have become increasingly mummified in red tape and legal jeopardy for prescribers. But culture plays a role as well.
You wouldn’t know it, given the casual media conflation of prescription fentanyl with the unregulated, often contaminated, unknown-dose illicit version, but opioid prescription rates in the U.S. have plummeted to levels not seen since Kurt Cobain was alive. It has been about a decade since prescription of opioids showed a causal link with the overdose crisis. Both prescribing rates and associated overdose deaths have been in decline since 2011.
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Nevertheless, the idea that prescription opioids are deeply harmful to society seems to have a deathgrip on the cultural conversation — as Friedmann puts it, a non-addictive analgesic is “a holy grail in medicine.” It’s one we seem unable to let go, which results in non-opioids being prescribed to patients even when they are not indicated for the condition or when an opioid medication would be more appropriate for the particular patient. As Drs. Christopher Goodman and Allan Brett wrote in American Family Physician in 2019, for example:
“Gabapentinoid drugs [like Neurontin or Lyrica] ... are increasingly being prescribed for pain because physicians and patients seek alternatives to opioids in the midst of the opioid crisis. However, such widespread and often indiscriminate prescribing of gabapentinoids is not supported by robust evidence, and it carries known and unknown risks.”
Risks of such indiscriminate anything-but-opioid prescribing might include undertreated pain and the patient resorting to illicit opioids, addiction to the alternatives, and death from side effects, dose escalation or polypharmacy due to unresolved pain, or overdose. For this reason, it’s important not to oversell the potential role suzetrigine may play in future pain care.
“What bothers me in the coverage,” Kertesz said, “is that even though the medication is interesting and probably good … there really is this idea that this is the gigantic solution to addiction, and somehow this is the beginning of the end of opioid addiction. And I think that’s a nutty idea.”
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