One of the most widely used drugs in the world isn’t really a drug, at least not in the usual sense.

It’s more like a dye.

Physicians call this drug “contrast,” shorthand for contrast agent.

Contrast agents are chemical compounds that doctors use to improve the quality of an imaging test. In the emergency room, where I work, contrast is most commonly given intravenously during a CT scan.

About 80 million CT scans are performed annually in the U.S., and the majority are done with contrast.

Most contrast agents I use contain iodine, which can block X-rays. This effect causes parts of an image to light up, which significantly enhances doctors’ ability to detect things like tumors, certain kinds of infections and blood clots.

One thing about contrast agents that makes them different from typical drugs is that they have no direct therapeutic effect. They don’t make you feel better or treat what’s ailing you. But they might be crucial in helping your doctor make the right diagnosis.

Because these drugs are used in some people who might not turn out to have anything wrong with them, and in others who may be seriously ill, contrast agents need to be quite safe.

And by and large they are. Some patients may develop serious allergic reactions or cardiovascular complications, but these are rare. Others may experience nausea or headache.

But there is one widely feared adverse effect of contrast — kidney damage. As a result, contrast is often withheld from patients deemed by their doctors to be at risk for kidney problems. The downside is that these patients may not receive the diagnostic information that would be most useful for them.

In recent years, though, new research has led some physicians to question whether this effect has been overstated.

Is it time to rethink the risk?

The first report of kidney damage after intravenous contrast, which became known as contrast-induced nephropathy, or CIN, appeared in a Scandinavian medical journal in 1954. An early form of contrast had been given to a patient for a diagnostic test. The patient quickly developed renal failure and died. The authors proposed that the contrast may have been responsible, because they could find no other clear cause during an autopsy.

With other physicians now primed to the possibility, similar reports began appearing. By the 1970s, renal injury had become a “well-known complication” of contrast in patients with risk factors for kidney disease, like diabetes. By 1987, intravenous contrast was proclaimed to be the third-leading cause of hospital-acquired kidney failure.

The belief that contrast agents were risky had a significant effect on how often doctors used them. In a 1999 survey of European radiologists, 100 percent of respondents believed that CIN occurred in at least 10-20 percent of at-risk patients, and nearly 20 percent believed it occurred in over 30 percent of such patients. A 2006 survey found that 94 percent of radiologists considered contrast to be contraindicated beyond a certain threshold of renal function — a threshold that nearly 1 in 10 middle-aged American men could exceed.

But Dr. Jeffrey Newhouse, a professor of radiology at Columbia University, had a hunch that something wasn’t quite right with the conventional wisdom. He has administered contrast thousands of times, and rarely did it seem to him that contrast could be said to have been directly toxic. There were often far too many variables at play.

Newhouse decided to go back to the primary literature. In 2006, he and a colleague reviewed more than 3,000 studies on contrast-induced nephropathy and came to an astounding conclusion — only two had used control groups, and neither of those had found that contrast was dangerous.

“Everyone assumed that any kidney injury after contrast was a result of the contrast,” Newhouse said, “but these studies had no control groups!”

In other words, there was no group of patients who hadn’t received contrast to use for comparison.

Newhouse discovered that nearly every study supporting CIN had fallen prey to this shortcoming. The importance of controls in any experiment is elementary-level science; without them, you can’t say anything about causation.

What came next was brilliant. “Having criticized those that did the experiment without the control, we decided to do the control without the experiment,” Newhouse said. He reviewed 10 years of data from 32,000 hospitalized patients, none of whom received contrast. He found that more than half of the patients had fluctuations in their renal function that would have met criteria for CIN had they received contrast.

This raised the possibility that other causes of kidney injury — and not the contrast — could have explained the association found in earlier studies.

Other researchers stepped up after Newhouse published his findings in 2008. Physicians in Wisconsin conducted the first large study of CIN with a control group in 2009. In more than 11,500 patients, overall rates of kidney injury were similar between people who received contrast and those who hadn’t.

There was one major weakness with the study, though — it was retrospective, meaning it relied on medical records and previously collected data. When a study is performed this way, randomization to different treatments can’t be used to guard against biases that could distort results.

So, for instance, if the physicians treating patients in the Wisconsin study were worried about giving contrast to high-risk patients, they may have steered them into the group receiving CT scans without it. These sicker patients might have been more likely to have kidney injury from other causes, which could mask a true difference between the groups.

The next generation of retrospective studies tried to use a special statistical technique to control for these biases.

The first two appeared in 2013. Researchers in Michigan found that contrast was associated with kidney injury in only the highest-risk patients, while counterparts at the Mayo Clinic, using slightly more sophisticated methods, found no association between contrast and kidney injury.

A third study, from Johns Hopkins, appeared in 2017. It, too, found no relationship between contrast and kidney injury in nearly 18,000 patients. And in 2018, a meta-analysis of more than 100,000 patients also found no association.

What did Newhouse make of these results?

“Nearly harmless and totally harmless — we’re somewhere between those two,” he says. “But how much harm is done in withholding the stuff? We just don’t know.”

Still, Dr. Michael Rudnick, a kidney specialist at the University of Pennsylvania, isn’t so sure it’s time to clear contrast agents completely. He thinks there still could be some danger to the highest-risk patients, as the Michigan researchers found. And he pointed out that even sophisticated statistical analyses can’t control for all possible biases. Only a randomized trial can do that.

Here’s the rub, though. Rudnick says we’re unlikely to get a randomized, controlled trial because there’s still a possibility that contrast could be harmful, and ethics committees are unlikely to approve such a trial.

It’s a conundrum that existing belief about contrast agents could actually limit our ability to conduct the appropriate trials to investigate that belief.

Matthew Davenport, lead author of the 2013 Michigan study, and chair of the American College of Radiology’s Committee on Drugs and Contrast Media, says “the vast majority of things we used to think were CIN probably weren’t.”

But he does agree with Rudnick that there could still be real danger for the highest-risk patients. He echoed the current American College of Radiology recommendations that the decision to use contrast in patients with pre-existing renal disease should remain an individualized clinical decision.

For now, if you are in need of a scan that could require contrast, talk about the risks and benefits of the medicine for you and make the decision together with your doctor.

Clayton Dalton is a resident physician at Massachusetts General Hospital in Boston.

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Dr. Mitchell Creinin never expected to be in the position of investigating a treatment he doesn’t think works.

And yet, Creinin will be spending the next year or so using a research grant from the Society of Family Planning to put to the test a treatment he sees as dubious — one that recently has gained traction, mostly via the Internet, among groups that oppose abortion. They call it “abortion pill reversal.”

The technique — a series of oral or injected doses of the hormone progesterone given over the course of several days — arose outside the usual avenues of scientific testing, says Creinin, a medical researcher and professor at the University of California, Davis.

Creinin, an OB-GYN, has spent the bulk of his career in family planning research. He has studied topics ranging from different treatments for miscarriage to how women choose birth control methods.

Performing abortions, he says, has always been a part of his practice and philosophy. “I need to provide these services to help women,” Creinin says.

Proponents of “abortion pill reversal” say it can stop a medication-based abortion in the first trimester, if the progesterone is administered in time.

But Creinin says the progesterone treatments are ineffective at best in halting an abortion that has already begun. And, Creinin says, promotion of the treatment can be potentially harmful by giving pregnant women misleading information that an abortion can be undone.

Though critics of abortion pill reversal say the term is an unproven misnomer, it has been such a compelling phrase that it’s already been written into the laws of a number of states.

Legislators in Arkansas, Idaho, South Dakota and Utah have made it a legal requirement in recent years that doctors who provide medical abortions must tell their patients that “reversal” is an option, although they are not prevented from also telling patients if they think the treatment doesn’t work.

Medical researchers such as Creinin and the American College of Obstetrics and Gynecology are concerned by that trend.

“You create a law based on no science — absolutely zero science,” Creinin says.

Proponents of the technique say they do have evidence. But it’s anecdotal, Creinin says, or comes from studies that lack rigorous controls. It’s time, Creinin says, for a formal study that can be definitive.

“I want to own that,” he says.

Abortion choices

In the first 10 weeks of a pregnancy, women who are seeking abortions generally have two options: a surgical procedure or a medication-based abortion (after that, only surgical abortions are performed).

The medication-based regimen uses a combination of two medicines — mifepristone and misoprostol — which women usually take 24 hours apart.

Mifepristone pills work by blocking progesterone, a hormone that helps maintain a pregnancy. The second medicine, misoprostol, makes the uterus contract, to complete the abortion. Studies suggest that 95 percent to 98 percent of women who take both drugs in the prescribed regimen will end the pregnancy without harm to the woman. Surgical evacuation can complete the abortion, if necessary.

So what happens if a woman takes mifepristone, then changes her mind and wants to continue with the pregnancy?

If the change of heart comes in the first hour after she’s swallowed that initial medicine, her doctor might help her induce vomiting. If she hasn’t yet absorbed the first drug, the process may be stopped before it starts.

The bigger question, and one for which the data are murkier, is: What happens if a woman takes the first medicine but never goes on to take misoprostol, the second drug in the regimen?

According to the American College of Obstetrics and Gynecology, “as many as half of women who take only mifepristone continue their pregnancies.” (If the pregnancy does continue, mifepristone isn’t known to cause birth defects, ACOG notes.)

In 2012, a San Diego physician named George Delgado said he had hit upon a chemical way of stopping the abortion process with more certainty — a way to give more control to a woman who changed her mind. He called his protocol “abortion pill reversal.”

A family medicine physician, Delgado calls himself “pro-life,” not anti-abortion. He says about a decade ago he got interested in the 24-hour window after a woman takes mifepristone but before she takes misoprostol.

He’d received a call from a local activist who said a woman needed Delgado’s help. She had swallowed the first pill in the abortion regimen but had reconsidered and no longer wanted to end her pregnancy.

“People do change their minds all the time,” Delgado says.

Hoping to help the woman, Delgado gave her progesterone — a medication that has many uses, including as a treatment for irregular vaginal bleeding and as part of hormone replacement therapy during menopause. If progesterone is useful in these other ways, Delgado figured, it might stop the action of the progesterone-blocker mifepristone, and halt an abortion.

Delgado says the pregnancy of that first patient continued uneventfully, which he credits to the progesterone.

He then started giving the progesterone treatment to more patients who came to him. He went on to develop a network of clinicians around the country willing to give progesterone to patients who no longer want to go through with their abortions, although he wouldn’t say how many of those clinicians took part in his research.

These days, Delgado says, most women who come to him for the progesterone treatment are self-referrals. While searching online, many find the website for the Abortion Pill Rescue Network, a nationwide group of clinicians who provide the treatment.

The network is backed by Heartbeat International, an anti-abortion rights group, and, according to spokesperson Andrea Trudden, includes more than 500 clinicians willing to prescribe progesterone to patients who have initiated the medication abortion process.

In support of their claims about abortion pill reversal, Delgado and colleagues have published their research in medical journals.

In 2012, Delgado co-authored a report in the Annals of Pharmacotherapy on the experiences of six pregnant women who received mifepristone and then injections of progesterone. Four of the women, the paper said, were able to carry their pregnancies to term.

In a statement released in August 2017, ACOG said the results of the study, a type known as a case series that didn’t include a comparison group, “is not scientific evidence that progesterone resulted in the continuation of those pregnancies.” ACOG’s statement also said: “Case series with no control group are among the weakest forms of medical evidence.”

In 2018, Delgado and colleagues in his network of health providers published a larger case series, this one involving 754 patients, in the journal Issues in Law and Medicine. The paper concluded that the reversal of mifepristone’s effects with progesterone “is safe and effective.”

The researchers acknowledged that the study didn’t randomly assign women to receive a placebo or mifepristone. A study like that, called a randomized placebo-controlled trial, would provide strong evidence. But Delgado and his colleagues wrote that doing this kind of trial “in women who regret their abortion and want to save the pregnancy would be unethical.”

“There’s no alternative treatment,” he says. “You can’t always wait for the [randomized, controlled trials]. If it’s lifesaving, there’s no alternative.”

State legislatures consider “abortion reversal” bills

One of Delgado’s most outspoken critics, Dr. Daniel Grossman, an OB-GYN at the University of California, San Francisco, says all of the published studies supporting this use of progesterone have been marred by methodological flaws that inflate the “success rate” of the reversal treatment.

Last October, Grossman and Kari White, a sociologist at the University of Alabama, Birmingham who studies family planning issues, wrote an editorial in the New England Journal of Medicine criticizing Delgado’s research methodology, saying he used flawed statistics and didn’t set rigorous criteria for the characteristics patients had to fulfill to be included in the study.

“A systematic review we coauthored in 2015 found no evidence that pregnancy continuation was more likely after treatment with progesterone as compared with expectant management among women who had taken mifepristone,” they wrote.

“I think there’s a big bias against abortion pill reversal,” Delgado says in response. “ACOG typifies that bias by coming out with strong statements. … This is a new science, but we have a substantial amount of data, and it’s been proven to be safe.”

The critics haven’t slowed Delgado’s supporters.

Already in 2019, legislators in several states — Kansas, Kentucky, North Dakota and Nebraska — have been considering bills that would require abortion providers to tell their patients about abortion reversal. Back in 2017, Delgado testified in support of similar legislation in Colorado, although the proposal never made it into law.

Grossman says he’s furious that states are forcing abortion providers to give their patients inaccurate information related to abortion care.

What’s more, Grossman says, “these laws take an extra step … and essentially are encouraging patients to be a part of clinical research that isn’t really being appropriately monitored. … This is really an experimental treatment.”

Progesterone hasn’t been evaluated by the Food and Drug Administration for reversing a medication abortion. Doctors are permitted to prescribe drugs for uses not approved by the FDA as part of the practice of medicine. It’s known as off-label use.

Until Delgado published his 2018 paper, Delgado told his patients they were receiving a “novel treatment.” He says he believes there is now enough research to support the routine off-label prescription of progesterone for women who don’t want to complete a medication-based abortion.

“Now we have a substantial amount of data. There is no alternative. And it’s been proven to be safe,” Delgado says. “Why not give it a chance?”

Although Creinin disagrees that the evidence supports this use of progesterone, he is sympathetic to the idea that women who seek an abortion may not be certain about the decision at their first appointment. Creinin says he supports policies that allow women as much control as possible over the decision about whether or not to terminate a pregnancy.

“There are people who change their minds,” Creinin says. “That’s a normal part of human nature.”

UCSF’s Grossman agrees.

He encourages abortion providers, when possible, to send the mifepristone and misoprostol home with the patient, if she requests it. That way, she can start the protocol only if and when she’s ready, rather than make the decision in a clinic where she might feel rushed. (FDA rules about mifepristone say the pill can only be dispensed in certain types of clinics — usually clinics that provide abortions. And some states have additional restrictions on how and where the drugs can be prescribed and taken.)

Putting abortion reversal to the test

Creinin’s study, approved by the UC Davis institutional review board in December, has been registered with ClinicalTrials.gov, which tracks medical research.

The study is slated to involve 40 women who are between 44 and 63 days of pregnancy and are seeking to have a surgical abortion. As a condition of the research, the women would have to be willing to take mifepristone, the initial pill that would normally trigger a medical abortion, and then a placebo or progesterone.

Two weeks later, researchers will see if there’s any difference in the rates of continued pregnancy. If progesterone can prevent the effects of mifepristone, Creinin says, he’ll find that more women in the group that got progesterone are still pregnant, with a pregnancy that’s progressing.

The key ethical point, the researchers say, is that all the women in this study want to have an abortion and will get one by the study’s end. The study isn’t enrolling women who are seeking a “reversal.” They will be told upfront that if the mifepristone doesn’t prompt an abortion, they will be offered a surgical abortion.

Creinin says the study participants will be compensated for their time in the study, but won’t be paid for having an abortion. And patients will still be responsible for the cost of the surgical procedure — either through their insurance or out-of-pocket.

Creinin is skeptical that progesterone will have any effect, since it is thought that mifepristone irreversibly blocks progesterone in the body.

But if it does have a clinically significant effect, he says, “I want to know that.”

Creinin hopes that his work will help medical researchers better understand if this kind of treatment can actually help women who change their minds after taking mifepristone for a medication abortion.

If the results show the progesterone doesn’t work, Creinin hopes that it will discourage state legislators from mandating that doctors tell their patients about an ineffective treatment.

Creinin started enrolling patients in the study in February. He isn’t sure how long the study will take, but says he probably won’t have preliminary results for at least a year.

Dr. Mara Gordon is the NPR Health and Media Fellow from the Department of Family Medicine at Georgetown University School of Medicine.

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A new drug to treat postpartum depression is likely to reach the U.S. market in June, with a $34,000 price tag. The approval of the drug by the Food and Drug Administration comes on the heels of another approval, just two weeks ago, of a different antidepressant, whose retail price will be as much as $6,700 a month.

Those giant list prices send shivers through the insurance industry and across the federal government and state governments, which pay for about 40 percent of prescription drugs sold in the United States.

The Trump administration is working to bring those prices down. The Department of Health and Human Services in recent months has proposed a series of regulations aimed at reshaping the prescription drug market. The goal, administration officials say, is to create more competition and lower costs.

But economists and analysts, who applaud the efforts to bring clarity to what is now a murky pricing system, doubt the effort will actually cut total spending on prescription drugs.

“They’re trying to … improve the function of the market,” says Sara Fisher Ellison, a health economist at the Massachusetts Institute of Technology. “But, to be honest, they probably missed the mark.”

The biggest change proposed by HHS Secretary Alex Azar would upend the entire system that sets the prices for medications that people buy at their local pharmacies.

Today those prices are negotiated in secret, as rebates between drug companies and middlemen known as pharmacy benefit managers. The PBMs often keep a share of the rebates for themselves, and when consumers have to pay for their medications, to meet a deductible for example, they have to pay that full pre-rebate price.

Azar says his plan would “replace today’s opaque system of rebates, which drives prices higher and higher, with a system of transparent and upfront discounts delivered directly to patients that will finally drive prices down.”

Those discounts would no longer be secret, and consumers who have to pay for some drugs would pay that discounted price.

The plan would not only help consumers at the pharmacy counter, Azar says, but also motivate drugmakers to lower their inflated list prices. HHS is accepting public comments on this proposed rule until April 8.

The change is revolutionary, says Dr. Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.

“The competition between companies has been on how big a rebate they can give,” Gellad says, “and the way that you give a big rebate is by increasing the list price. So the idea is to get rid of that so that companies can compete based on getting the list price lower.”

But Len Nichols, an economist and the director of the Center for Health Policy Research and Ethics at George Mason University, doubts that the changes will end with overall prices being lower than the deals that pharmacy benefit managers get today.

“The truth is [the PBMs] still, on balance, lower prices from what they would be if they didn’t exist,” Nichols says. “Which is exactly why we need them.”

The drug market is not like a normal retail market, Nichols says, because it’s dominated by a few powerful companies — the PBMs — that are practically required to buy almost all the products offered by the drug companies.

In that type of system, price transparency can lead to higher prices, Nichols and other economists say.

“One way to think about it is … imagine if what you wanted was for a cartel to work perfectly,” he says. “One way a cartel works perfectly is if all members of the cartel know everybody else’s price.”

In October, Azar also proposed requiring drug companies to include the list prices of their medications in television and magazine ads — that proposal is still pending. Drugmakers oppose that requirement because, they say, those list prices are irrelevant precisely because of the rebate system. Nobody pays the actual list price, they argue.

But there is some evidence that drug companies don’t want the huge price tags they put on their products to be widely publicized. That “naming and shaming” of companies can have an impact on their behavior, says MIT’s Fisher Ellison.

Still, she says, while the focus on publicizing prices for consumers seems like it should work, it may not have much effect on overall spending.

That’s because consumers not only don’t pay list prices but also don’t really choose which medication they’re buying. That decision is in the hands of their doctor. And, unlike with toothpaste or soda, it’s not easy for a consumer to switch brands of medicine.

“You can imagine a patient walking into a pharmacy, and he has a prescription for Lipitor and then finds out that Zocor, which is a similar drug, is a lot cheaper. Well, there’s nothing he can do at that point,” Ellison says.

When it comes to driving down prices, analysts say HHS’s third proposal is likely to work. That plan would tie the price that Medicare pays for drugs that are administered in a hospital or clinic — such as IV drugs for cancer or arthritis — to the prices paid in other countries.

That proposed rule — which has received more than 2,700 public comments — is facing steep opposition from the U.S. Chamber of Commerce, which has been running an aggressive campaign against the proposal. It’s unclear when the proposal might be finalized.

And doctors who administer the drugs are also opposed, saying it may hurt patients’ access to medications.

“I’ve basically traveled the world … looking at cancer care,” says Ted Okun, the executive director of the Community Oncology Alliance, “and other countries do not have the access to the drugs that we have here.”

But Azar dismisses that argument. He says the U.S. price for a drug will still be higher than prices paid elsewhere and says he doubts any companies will stop selling their products in the huge U.S. market just because prices are lower than they are today.

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