Each year, according to the U.S. Department of Agriculture, roughly 820,800 guinea pigs, dogs, cats, and other animals covered by the Animal Welfare Act are used in research in the U.S.; of those, about 71,370 are subjected to unalleviated pain. These stats don’t track the millions of mice and rats that are used in lab experiments and excluded from the animal protection law (although the rodents are covered by other federal regulations). Scientists and their institutions say they’re committed to keeping pain or distress to a minimum in lab animals where they can. But how do you know how much pain a mouse or a zebrafish feels? And who decides how much pain is too much?

DILEMMAS:

Of science, ethics, and us.

The issue of animal suffering was in the headlines earlier this year, when landlocked Switzerland banned the culinary practice of boiling lobsters alive. No one knows for sure whether these big-clawed crustaceans, equipped with only a rudimentary nervous system, experience pain. Nonetheless, Swiss authorities now require stunning lobsters in a humane way before tossing them into the pot.

I read of this milestone in crustacean rights with bemused fascination and anthropomorphic cringing, as I imagined the lobster’s hypothetical plight. But the Swiss move also made me wonder how scientists measure and deal with animal pain in research studies. Experiments that use critters to simulate human illness or injury are stepping stones to the medical treatments we all use. Yet, the benefits we reap must outweigh the costs to animal welfare for those sacrifices to be justified, ethicists and animal advocates say.

To learn more, I called veterinarian Larry Carbone, director of the animal care and use program at the University of California, San Francisco (UCSF). Policies in most countries call for easing or preventing pain or distress in lab animals whenever possible. Since the animals can’t talk, knowing how much discomfort they’re in to begin with “is really difficult,” Carbone told me. But over the years, researchers have devised good standardized ways to measure reactions to painful stimuli in rodents and other animals. This might, for instance, include timing how fast a mouse yanks its paw away when you shine a hot light on it, and seeing how that reflex differs when a pain drug is administered.

More sophisticated tests track behavioral changes to gauge how much a painful situation bothers a rodent, Carbone said. For example, if mice in pain are given a choice between a chamber where their chow was laced with an analgesic, versus a chamber with regular food, they spend more time in the place that’s associated with pain relief. (Animals respond to many of the same analgesic drugs as we do.)

After rodents have undergone abdominal surgery in an experiment, researchers also can monitor for signs of pain (such as writhing or unsteady walking, or changes in burrowing or nest-building habits.) Mice are highly motivated to build nests, Carbone said, and “we know if they’re in really bad pain, as much as they want a nice nest, they’re not gonna put the work into doing that.”

Still, scientists don’t have ways to measure animal discomfort or distress in all experimental contexts, including those causing chronic pain or anxiety. And it’s been controversial whether certain kinds of creatures — not just lobsters but also fish, whose brains are so different from ours — suffer from pain at all.

While most animals reflexively react to harmful stimuli (think of that hot light), that’s not the same thing as feeling pain and suffering, which are subjective experiences. “We can never know for sure” whether lobsters and fish go through that, said biologist Hanno Würbel, who chairs the animal welfare division at the University of Bern in Switzerland.

Still, he believes that recent studies make “a plausible case” that they do.

By law, research labs in the U.S. are supposed to assume that things that are painful to people are painful to other animals — including fish. The task of then deciding how much pain may be inflicted in experiments falls to a committee that oversees the care and use of animals at each research institution in accordance with the Animal Welfare Act and U.S. Public Health Service regulations and guidelines. These local committees approve or reject proposed study protocols, reviewing whether the pain or suffering in animals would exceed acceptable limits, or could be allayed by anesthesia or analgesics.

Every case is different, said bioethicist Tom Beauchamp of Georgetown University. “There’s a huge range of territory for people to disagree over these matters, which is why there’s so much disagreement about the justifiability of laboratory animal research to begin with,” he told me. Compared to the U.S., regulations in the European Union are tougher, requiring a formal, detailed analysis of whether the expected harms to animals in an experiment are justified by the anticipated societal benefits of the research. Animal advocates such as Cathy Liss, president of the Animal Welfare Institute, point out that the U.S. has long been “out of step” with many other countries in failing to include lab rodents under the protective requirements of the Animal Welfare Act.

But on either side of the Atlantic, the bottom-line is that U.S. and European policies do allow for experiments that cause severe, unalleviated pain to animals when it’s the only way to gather valuable scientific data.

The dilemma, Carbone told me, is that some experiments — testing a new drug designed to treat the agony of bone cancer against a placebo, for example — are difficult to do without inflicting pain. In other cases, scientists have legitimate concerns that using painkillers to treat discomfort caused by experimental procedures could skew the results. A study using rodents to assess whether an infusion of stem cells could help patients after a heart attack could be one such instance, Carbone noted. Dosing the rodents with pain relievers after they’ve undergone a surgical procedure that simulates a heart attack might affect their response to the stem-cell therapy.

On the other hand, he pointed out, pain itself can trigger immune system responses, hinder sleep and eating patterns, and possibly impede postsurgical healing — so if you don’t treat the animals’ pain, it might also skew the experiment’s outcomes. So is the quality of a research study better when pain is relieved, or not?

It can be a real ethical and scientific conundrum, Carbone said, often with no clear answers. Maybe it turns out that to get usable data on a particular question, untreated pain is unavoidable. “But then, the ethical question is, Okay, is that worth it?” he said. “Do we really need this? Is every single scientific question important enough to subject animals to pain?”

From Liss’s perch at the Animal Welfare Institute, any study that looks to use animals warrants careful consideration, she said, but “there should be an incredibly high bar if any individual animal is caused unrelieved pain.”

In a report this March from the University of Bristol in the U.K., medical sociologist Pandora Pound and animal welfare researcher Christine Nicol provided a big-picture perspective on whether animal research is worth it. In the first study of its kind, they systematically assessed the harms versus benefits of 212 animal studies relating to six drug therapies, four of which are in clinical use today. Conducted from 1967 to 2005, those studies collectively used around 27,149 mice, rats, pigs, sheep, monkeys, and other animals.

Most of the protocols appeared to inflict severe harms on the animals, with 13 percent of the studies failing to report use of anesthesia and 97 percent making no mention of pain-relieving drugs. Overall, they found, the studies were poorly designed, which meant they couldn’t contribute conclusive findings toward clinical benefit. In such cases, “any suffering endured by animals loses its moral justification,” Pound and Nicol wrote in an email to me.

Using a cost-benefit analysis tool to assess the ethical acceptability of the studies, Pound and Nicol deemed that more than 93 percent failed to pass muster. “At present the situation is deeply unethical,” they concluded, adding that the general argument that harms of animal research are justified by benefits to people “does not hold up.”

These are sobering and contentious charges, and Pound has previously drawn criticism for her views. But there are important caveats to this latest work. For starters, it’s always hard to predict the ultimate benefits from any animal study, especially with basic research that investigates how biology works.

Further, while almost none of the studies in the analysis reported using analgesic drugs, we don’t know for sure how often animal pain actually went untreated. In a 2016 study, Carbone and a UCSF colleague found that 40 percent of animal studies involving major surgery failed to mention using anesthesia — even though such surgeries usually do employ it, Carbone told me, because otherwise a mouse or rat won’t stay still for it. Many researchers just don’t bother including the information in their write-ups.

At the same time, around 75 percent of studies didn’t mention giving pain relievers, also suggesting that post-surgical discomfort is probably undertreated in animals. But without detailed data, the UCSF researchers noted, it’s hard to draw firm conclusions. Carbone is hopeful that things are getting better: More and more, he told me, it’s becoming standard for lab veterinarians to give rodents long-lasting pain drugs after surgery.

The authors of the newer U.K. report acknowledged that some animal severity ratings in their analysis may have been lower if anesthesia and painkillers were indeed administered — although Pound noted that those ratings were only one of the factors weighing into the overall harm-benefit analysis results. For now, they’re sticking with their conclusions and recommending reforms, including adoption of technological alternatives to animal research.

Würbel, the Swiss biologist, called for a more measured reading of things, however. The U.K. study is innovative, he said, but it’s one “in a whole ocean” of meta-research parsing the reliability and value of animal studies. “I think if you look at everything, then you will get a more nuanced picture of the situation,” he said. “I think we have learned a great deal from animal research.”

Meanwhile, when I asked the NIH Office of Laboratory Animal Welfare for its take on the report, a spokesman (in the Office of Extramural Research) sent me a five-page email response that explained the laws and policies that govern NIH-funded experiments on lab animals. To cut to the chase: The agency takes the humane use and care of research animals “very seriously.” It pointed out that the U.K. analysis reviewed an older body of studies, which don’t reflect today’s U.S. standards for the use of lab animals. And it emphasized that animal research helped pave the way for treatments for many devastating conditions in people and “continues to revolutionize our understanding of health and disease.”

Okay. Yet it also seems clear that current practices involving animal experiments remain far from perfect. As Würbel put it, “there is huge scope for improvement” — including a pressing need to address the problem of sloppily conducted animal research whose results fail to hold up in studies of people.

If studies don’t produce valid, reproducible results, he said, “you’re simply wasting animals for no good reason.”

Ingfei Chen is a California-based writer whose stories have appeared in publications including Scientific American, The New York Times, and Spectrum. She is a former Knight Science Journalism fellow at MIT.

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