Managing pain without opioids is on the horizon – if we decide it’s worth it

By Peter Kolchinsky

SCIENCE | POLICY | BIOTECH

November 13, 2024

Thanks to the relentless efforts of scientists at Vertex Pharmaceuticals, there will likely soon be a novel type of pain medicine, a non-opioid drug called suzetrigine. Suzetrigine inhibits a protein called NaV1.8 found on neurons and is important to making them sense and signal pain. 

This new medicine is not a panacea, but it is exciting progress. Phase 3 data suggest we’re a big step closer to pain drugs that work as well as opioids but without opioids’ side effects and devastating addiction risks. 

Pain is a symptom of many diseases and disorders. It’s helpful in the very short term to teach us to avoid things that can cause us harm, but it can wreck our lives and crush our joy when it persists. Opioids are important because they are the most powerful weapon in our arsenal against pain. But we know their harms and it would be better for society not to rely on them.

So imagine a future where any intolerable pain can be managed with a medicine – one you don’t have to worry will entice you into addiction and doesn’t come with the risk of life-threatening overdose. Imagine a safe way to manage pain.

That future won’t come all at once. It will come step by step, as with most medical progress. Ibuprofen (and other NSAIDs), acetaminophen, and pregabalin are examples of non-opioid pain medicines we already have that help millions of people manage pain. When pain isn’t too severe, those medicines may be enough. But for many people, the pain is severe enough to require opioids. If approved, suzetrigine will be yet another, quite novel step in that journey towards a world in which we can manage all serious pain without opioids. Back in July, Vertex said the FDA accepted their submission for suzetrigine and granted it priority review, with a decision on approval coming in late January 2025. 

Incentivizing incremental innovation

It’s going to take a lot more ingenuity to complete the journey to total non-opioid pain management. And whether suzetrigine sells well will influence whether investors remain interested in funding that R&D. The private sector pays attention to what society values, as you can see from the tremendous investment in better weight loss drugs once it started to become clear that Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound were on their way to being commercial blockbusters. 

The reason that investors have funded research into new pain medicines is that the quest for non-opioid pain treatment has been upheld as being of high value to society, which implies that whoever cracks this problem should expect significant profits. We hear a lot about the high cost of the opioid epidemic. We spend a lot to help people break free from opioid addiction. And some non-opioid drugs have sold very well. For example, gabapentin, a non-opioid medicine approved in the 1990s that treats certain types of pain, was a blockbuster many times over. Its success spurred drugmakers to improve on it – a successor, pregabalin, also was a commercial success and is now also generic. You may know it as Lyrica. 

But the successes in pain are few and far between. Solving pain is incredibly hard. Pain is wired into our nervous system. It’s hard to know when testing on cells in petri dishes and even in mice whether a drug is addressing pain effectively without causing other problems. So preclinical research is very risky, telling us little about how well a drug will work in people, and we can only answer the big questions in large human trials. Is it really safe? Is it addictive? Is it effective? Making progress in the treatment of cancer might actually be easier than developing medicines to treat pain.

And so it’s important that we encourage humanity’s progress towards managing pain. It’s a daunting climb but one well worth incentivizing. If Vertex succeeds we will soon have another test of whether society rewards reaching this rung of the ladder. Will we reward this breakthrough richly enough to spur investors and companies to continue to work on pain? There are many more rungs to climb. If Vertex’s drug doesn’t sell well, okay – message received. Investors will always shift their capital to where society signals a willingness to pay for what it values. No one wants to squander their savings on inventing things that won’t generate a good return.

The question of access

Assuming all goes well for Vertex’s FDA review, next year it will start negotiating with insurance plans for coverage. It’s common for insurance to demand that patients have tried generic options before being allowed to get an expensive branded drug. 

Trying a generic first is almost always reasonable. For example, if someone has high cholesterol and could benefit from a generic statin, it’s reasonable to require that the person try a statin before a plan authorizes coverage of a more expensive and powerful drug such as a PCSK9 inhibitor. Maybe the statin will lower their LDL to a healthy range and that will be that. If not, then insurance would pay for a PCSK9 inhibitor. 

Same in theory goes for pain. If generic pain medicines might work well enough for someone, it’s not unreasonable for insurance to nudge patients to try them first. But should that include generic opioids? That’s the key question. 

If generic pain medicines might work well enough for someone, it’s not unreasonable for insurance to nudge patients to try them first. But should that include generic opioids? That’s the key question.

What if an insurance plan required a physician to provide evidence that a person is at risk of becoming addicted to opioids before authorizing coverage of a more expensive non-opioid pain drug? That’s difficult and awkward. How do you measure someone not becoming addicted to opioids?

However hard it might be to appreciate the benefit of a non-opioid alternative at the level of an individual patient who might not seem to be at risk of opioid addiction, insurance plans, Medicare, Medicaid, and large US employers are each going to determine whether suzetrigine’s unmeasurable benefits matter enough to cover it. 

Let’s say some plans will cover the new drug. The devil is in the conditions these plans impose before granting patients access. Even if they don’t require a patient first ​“step through” a generic opioid, there are other ways plans could nudge people away from suzetrigine. For example, with out-of-pocket costs.

A plan could say ​“Oh, sure, we’ll cover Vertex’s drug, but of course, since it’s branded, we have to charge a $50 copay. By the way, have you noticed, this generic opioid copay is only $10?” Every year, in Medicare Part D alone, more than 12 million seniors receive opioid prescriptions, and more than 1 million seniors are treated for opioid use disorder. A third of those opioid scripts have no copay at all and nearly 90% have copays less than $10. When there’s a safe and effective alternative, will Medicare patients be forced to choose between a free generic opioid and a branded non-opioid with a copay?

Either requiring someone try a generic opioid first or charging high out-of-pockets for a non-opioid will result in a lot of people using generic opioids; some of those people might have had sufficient pain relief with the non-opioid Vertex drug. The latter tactic will come across as more benign since the plan will say that it’s covering all pain medicines without restriction and just offering people a choice.

Most people who take the generic opioids won’t become addicted, but some will. Will that be the insurance plan’s problem? Hardly. After all, they were just covering all the options and the physician wrote the script. Meanwhile, the physician will say that they would have liked to prescribe the non-opioid but the patient told them they couldn’t afford the copay. Seeing the patient suffer from intolerable pain and having a heart, the doctor did what they could, writing for the opioid and counseling the patient to take it only as prescribed and for no longer than needed. 

A doctor might not find out about the few times a patient does become addicted until it’s too late. Insurance plans that nudge people toward the opioids likely won’t get a bad rep. Formulary design won’t hit the front pages as a reason for America’s continuing reliance on opioids and its consequences. They don’t make award-winning miniseries about bureaucratic coverage decisions. And yet, the banal truth is that this is all about insurance design.

For society to avoid opioids, it has to get insurance to cover non-opioid medicines by setting their out-of-pocket costs to be as low as those for generic opioids, ideally at zero.

Why charge a copay at all? Vertex’s drug isn’t ​“likable.” It’s not something anyone would seek to take unless they were in pain. That’s what makes it so different from opioids. So what would an insurance plan be trying to achieve by setting a high out-of-pocket cost for suzetrigine but a low one for an opioid? 

The market finds a price 

No doubt some will feel like Vertex has an unfair advantage. They created a medicine that feels unconscionable to deny to people in pain, because it may keep many of them from needing an opioid. 

You might think the company will be able to charge whatever it wants, right? When they launch the drug, someone will no doubt take its list price and multiply it by 50M Americans suffering from pain and claim that Vertex wants to make hundreds of billions of dollars per year from its invention. They might even trace some element of Vertex’s R&D back to NIH research and claim Vertex didn’t actually invent anything, so this drug should be price-controlled or its patents waived. Don’t fall for that.

It’s safe to say the list price Vertex sets for suzetrigine won’t be anywhere close to the actual price that anyone pays. What the insurance plans pay will be a lower net price that gets negotiated over time in a careful dance where Vertex tries to get plans to offer broader, more liberal coverage to patients in exchange for discounts (rebates). Vertex will try to help patients with their copays using coupons and insurance plans will let them because those plans won’t want to deny access… they’re just trying to pay as little as possible. And if someone doesn’t have insurance, I would expect Vertex to offer free or nearly free access to its drug. It’s what they and other companies have done before with their other drugs, because ultimately they don’t want to see anyone go without. (This is ​“the system”; it’s not perfect, it’s not even necessary, but it’s ours.)

Plans might decide that Vertex’s price is too high and refuse to cover the drug. Some employers might get bad press because of this. Of those, some might change their minds and decide that society puts a high enough value on non-opioid pain treatment that it’s better to cover this new medicine than to deal with the fallout of not covering it. That such things even play out in the press might seem like a bug in the system, a kind of unfair coercion to pay for a drug that isn’t worth its high price. And yet, this debate, in the media and on social media, is exactly how society makes its values known.Market-based pricing is all about competing plans deciding for themselves what coverage to offer and adjusting in response to market feedback.

There are lots of drugs and treatments that plans don’t cover without sparking much outrage. Plans don’t cover Botox for wrinkles. Many refuse to cover GLP‑1 drugs for weight loss, even if they’ll cover them for diabetes. Plans are capable of saying no. But they avoid saying no when they know that people will care enough to switch plans. They certainly want to avoid bad press or to earn a reputation for being heartless, if that will cost them market share. 

But sometimes it’s hard to tell if a plan is being heartless or if it’s being cost-savvy by not paying for something that isn’t really worth it. ICER’s economists will insist that they can calculate what price is appropriate for the value that Vertex’s drug offers (ICER’s suzetrigine review will come out in February). So they will do some math called a ​“cost-effectiveness analysis,” or CEA. And here’s the thing… they will either do earnest math that truly tries to capture all the value that a non-opioid medicine offers to society for the rest of time, or they will slant the math in ways most people won’t notice to try to make it seem that the drug isn’t worth it.

Consider that suzetrigine, a simple pill, will eventually go the way of gabapentin and pregabalin, becoming an inexpensive generic after its patents expire. It will help manage pain and avert opioid addiction for the rest of time, long after any insurance plan has to worry about its cost to their budgets. In fact, most novel medicines only stay branded for about 14 years after they launch and then go generic. But some economists simplistically only judge a drug by its price at launch, pretending in their math that the drug will never go generic, to help justify not covering it in the first place. They might ignore that avoiding addiction means helping not only patients but their families, and even their communities. These extra benefits of a medicine are called ​“spillovers.” There’s math that shows how valuable spillovers are. We don’t have to ignore them. But some health economists will bend and cut the math to yield the preordained outcome that a drug is overpriced.

Not their first rodeo

Vertex has experience with such skimpy math and its consequences, though. The company is best known for its remarkable treatments for cystic fibrosis (CF), particularly a triple combination pill called Trikafta. People with CF are constantly experiencing infections that land them in ERs and hospitals. Trikafta costs about $270k/​year and is covered by just about every insurance plan in the US. Other countries have not been as generous but are starting to catch up. Part of the reason other countries didn’t cover Trikafta is because their health economists declared that Trikafta cost too much. That it isn’t cost-effective.

But if you take some of the missing factors into account, notably that Trikafta will go generic, it turns out that its price is a raging bargain. In fact the drug is so cost-effective that it will ultimately result in cost savings for society, despite Vertex’s enviable revenues. How could that be? Because Trikafta will forever save society the high cost of hospitals and ER visits and early death due to CF, and those savings are enormous. However much Vertex is making, it’s destined to save us far far more. 

Consider that Vice President Harris, during her presidential campaign, proposed aggressive price controls on medicines to help pay for more spending on long-term care. On the surface, that might sound compelling. Pharma seems like an infinitely large piggy bank, and providing long-term care for people we love is undoubtedly a good thing. But consider that the best solution to providing long-term care is to invent a way to allow each of us to be our own caregiver. And that’s exactly what Trikafta does. Patients that previously were dependent on their families and hospitals are now healthy and able to care for themselves and others. 

And this new pain drug will almost certainly set us down a path to do the same. Opioids have been with us for millennia and been destroying lives over all that time. We haven’t been able to quit them because maybe the only thing worse than opioids is unmitigated pain. Pain is highly debilitating. When one member of the family is suffering intolerable pain, they may not be able to care for themselves. Resolving that pain liberates them and their caregivers. The best way to afford long-term care is to ensure we continue to invent ways to let everyone take care of themselves for as long as possible, not by defunding that innovation just to build more nursing homes and hire more nurses. And that means that worthwhile novel drugs need to be very profitable. 

So Vertex could come out with some list price that seems high and insurance plans will negotiate and quite likely total healthcare spending will climb for some time. A drug that generates $3 billion per year in the US, when spread across the premiums of hundreds of millions of Americans, impacts premiums by less than a dollar per month. In fact, all branded medicines only add up to about 8% of what we spend each month on insurance in taxes and premiums. But even if Vertex made $20B/​year in revenue in the US, that would be around a tenth of what Americans spend on their cell phones each year and less than 0.07% of US GDP, so any claims that it’s unaffordable to the US are nonsense. Rather, those costs would be borne by everyone through insurance premiums and taxes (for Medicare, Medicaid, and ACA insurance subsidies). Considering all that the US affords, we have the funds to reward innovation like this as long as it comes out of all our premiums and not out of the pockets of the comparatively few patients who need treatment at any one time. 

If the idea of rising insurance premiums feels unacceptable to you, consider that keeping them flat isn’t really on the table. As long as there is unaddressed suffering, we end up paying the price one way or another. Without novel medicines, premiums would skyrocket as we build more hospitals and hire more doctors and nurses and pay them more each year (since neither hospitals nor healthcare providers go generic). That’s like paying rent to live in a terrible apartment. A drug that keeps us out of hospitals and healthy is only temporarily high priced, like a new home that we have to pay the mortgage on, but then it goes generic, which is like paying off the mortgage. 

So paying a slightly higher premium to pay off the mortgage on a novel medicine that will restore people to health so they don’t need more hospitals and more caregivers is the better and more productive use of our healthcare dollars than refusing to pay more in premiums for medicines and then being stuck with rising hospital and physician costs.

Sometimes medicines even pay for themselves before going generic, but only if you look beyond healthcare costs.

For example, consider that HIV drugs generate about $12B in sales annually in the US but keep over 1M HIV+ Americans healthy and productive, generating over $60B of annual wages (in addition to avoiding tens of billions of hospital costs). Clearly these drugs are paying for themselves. And eventually, those drugs will go generic and offer an even greater bargain. 

That’s what Vertex’s pain drug represents. An opportunity to put our premium dollars to work incentivizing more such innovation to decouple ourselves from opioids. And after about 14 years, that cost will dwindle to nearly nothing as the drug goes generic. Over that time, we will likely see a perceptible and permanent decrease in our reliance on opioids. And the reward Vertex earns will inspire continued research into pain treatments that will hopefully lead to even better non-opioid drugs. That’s our path to liberating ourselves as a society from the ravages and costs of the difficult choice between intolerable pain and opioids.

Ensuring access to non-opioid alternatives before opioids

Up to this point, I’ve made a case for why the US healthcare marketplace, made up of many competing healthcare plans, should be willing to cover Vertex’s drug without stepping patients through generic opioids and with a low or no copay. This article might serve as a tool of persuasion. Maybe Vertex would try to charge too much and plans would say no and some patients wouldn’t get access. After all, there’s an upper limit to what anything is worth to society. 

But what if we could enter into a kind of forward contract with Vertex and all non-opioid pain drug developers. What if we told them that we’ll mandate by law that non-opioid drugs be accessible ahead of opioids with similar copays as generic opioids in exchange for them charging prices that don’t climb too far above historic market-based prices for such non-opioid medicines?

It’s a worthy experiment, and one that some policymakers are embarking on. Most prominently, the Alternatives to PAIN Act would exempt qualifying non-opioid medicines from deductibles, establish patient copay limits no greater than the copay for a generic opioid (typically $15 or less), prevent plans from requiring patients risk addiction by ​“failing” opioids first, and prevent plans from requiring prior authorization to access a non-opioid pain treatment. Note the term ​“qualifying,” which in this bill requires that a medicine be priced below the Part D Specialty Tier Threshold, which is $31 a day, unless it’s gone generic (in which case competition would likely cause the price to plummet far lower anyways). 

It’s fair to impose a price limit since the bill basically makes it mandatory for any plan to cover the drug, and if plans are mandated to cover a drug then they can hardly negotiate its price. Is this a price control? Consider that $31 per day reflects a price limit that is above the market-based prices of chronically used pain drugs in the past, including Lyrica and OxyContin. So it’s more of a guard rail that keeps new medicines’ prices within range of what the market has paid for other pain medicines.

There could be some types of pain due to orphan conditions that would require prices above the Part D Specialty Tier Threshold, in which case the worst that would happen is that plans would be free to decide for themselves whether they dare not cover effective drugs ahead of opioids. So assuming that a company that priced above $31/​day would simply no longer enjoy the mandatory coverage contemplated by the Alternatives to PAIN Act, I wouldn’t even consider this law to be a price control but rather an optional forward contract that innovators may enter into if they choose.

Whether this bill passes is anyone’s guess.

CMS has rulemaking power that wouldn’t even require such legislation (though it doesn’t have jurisdiction over the employer-sponsored insurance plans that cover most working Americans). It could boost awareness of non-opioid options to combat the opioid crisis, encourage rapid formulary access as non-opioid drugs get approved (instead of waiting for a new plan year), or require Medicare, Medicaid, and ACA Exchange plans to cover a non-opioid alternative with limited or no prior-authorization or generic step-through requirements.

However plans manage access, I hope that Vertex generates high enough sales that many other companies and their investors will be motivated to try to invent yet better non-opioid treatments for pain. If we could spur the tsunami of innovation in pain management that we’re seeing now in the fields of obesity and autoimmune disorders and cancer, we would have pain solved within a few decades. 

Universal access in the long run? Yes. 

In the short run? Up to us.

However flawed America’s health insurance system, in the long run everyone will have access to these novel medicines because they will go generic and payors will drop barriers to access. These medicines may even someday be over the counter, like Tylenol is today. 

What matters most to our long-run aspiration to vanquish pain with non-opioid drugs is preserving the incentives for continued investment in innovation. You don’t get more generic drugs unless investors fund their development. To put it bluntly, we need these kinds of medicines to be very profitable so investors want to fund development of even better ones. Then we’ll be able to look forward to better medicines, at first as branded drugs and eventually as generics.

Whether all patients who need non-opioid drugs like suzetrigine will have access to them before they go generic is a choice we make through the insurance policies we design as a society.

What you can do

If you are won over to the idea that we should be incentivizing the development of more non-opioid pain medicines by making sure they are covered ahead of generic opioids with low copays for all patients, then there’s something you can do.

To encourage the incoming US Secretary of Health and Human Services to require health plans provide affordable access to safe and effective non-opioid pain treatments add your name here to endorse this article. Share this article with your friends, your family, your colleagues. Opioids have devastated lives across America regardless of geography, race and income – let’s tear down the barriers to less risky alternatives.