When a baby is born early, their first months of life can be hectic and painful. Doctors can implant breathing tubes, and perform multiple surgeries as the baby's young organs continue developing. Up until the '80s though, one major element of that hospital experience was missing: pain medication and anesthesia. Preemies undergoing open heart surgery might receive a paralytic, but no more, because doctors believed that newborns either couldn’t feel pain or didn’t remember it.

Clinicians' practice flipped in the late '80s after a key review paper compiled the overwhelming evidence of physiological traces of pain, and today preemies get anesthesia and opioids just like any other patient. But that practice just got more complicated. In December, the FDA mandated new warnings for using anesthetics in young children. Now, parents will be warned that “repeated or lengthy use of general anesthetics and sedation drugs during surgeries or procedures in children younger than 3 years […] may affect the development of children’s brains.”

The announcement took some clinicians by surprise. While researchers and doctors are indeed concerned that drugs like ketamine and pentobarbital could cause brain cell death after multiple uses or long-term use, many studies on humans aren’t conclusive. And two recent clinical trials showed that young children exposed just once to anesthetics turn out just fine.

At the same time, evidence from animal and human studies suggests that not treating pain in newborns could also cause disabilities later on. According to large studies of hospitals in Canada, France, and the Netherlands, a premature baby in the neonatal ICU experiences an average of 14 painful procedures a day during the first two weeks of life. “Now we know that untreated pain causes changes in brain development," says Lynne Maxwell, an anesthesiologist at The Children's Hospital of Philadelphia. "So after fighting that battle, to think that the drugs that we have developed to prevent those bad outcomes from pain are actually causing damage themselves is really scary."

Clinicians agree that using anesthetics will continue to be a major part of pain management for infants. So now there's an even bigger challenge for doctors trying to balance the risks: Figuring out exactly when infants are feeling pain, and how much they're feeling.

A Painful History

At some point while a baby develops, pain starts. When that happens is mostly a philosophical question. “It depends on what you mean by pain,” says Rebecca Pillai Riddell, a psychologist at York University in Toronto who studies infant pain. For adults and older children, pain is mostly self-reported. If a baby can’t express that they feel pain, do they really feel it?

Identifying pain is even more complicated in premature infants because everything about them is underdeveloped, including their cries and facial expressions. (This may be one of the reasons that researchers got it in their heads that babies didn’t feel pain—preemies can sleep through a painful procedure.) In the last 15 years, though, researchers have amassed evidence from the brain that preemies feel something during painful procedures: Prick the heel of a preemie to draw blood for a procedure, and most of the time, the cortex sends off electrical zingers.

But brain scans are cumbersome in a round-the-clock intensive care unit. So nurses pick up on an infant's pain level by assessing behaviors like crying and facial expressions along with physiological measures like heart rate and blood pressure. Those measurements can be subjective, though: Two people might think a baby is experiencing a different amount of pain, and make a different decision about treatment.

That lack of information is especially problematic now, with the FDA currently working with drug companies to roll out updated labels warning of the long-term impacts of anesthesia in young children. Parents will be forced to decide, based on limited information, whether they should potentially risk their child's brain development to protect them from an unknown amount of pain—and the long-term effects of that pain, which are equally unknown.

Studies have confirmed that untreated pain in infancy can impact cognition and behavior in children. But those disabilities are the same kind that anesthetics may cause, notes Dean Andropoulos, an anesthesiologist at Texas Children's Hospital who wrote a recent op-ed on the FDA warning. With so many confounding factors—preemies are likely to have preexisting medical conditions that impact development, and experience untreated painful procedures like heel sticks and eye exams in addition to surgeries that involve anesthetics—the research on the impact of pain vs. pain prevention is “very difficult to interpret,” says Andropoulos.

The Pain Challenge

So researchers continue to search for more objective measures of pain in infants. They'll measure whether features of babies’ cries are correlated with brain signals for pain, and look for outward signs of the intensity of pain like sweating, heart rate, or facial cues. But so far, nothing is consistent enough for the clinic on its own.

Nathalie Maitre, a neonatologist at Nationwide Children's Hospital in Nashville, is taking a different approach: She's just trying to find interventions that counteract painful events. “I don’t pretend to be a baby whisperer," she says. "I actually think I'm pretty ignorant." In a paper published last week, she recorded responses to light air puffs applied to babies’ hands—both preemies and full-term infants—and compared their brain activity as measured by EEG. She found a correlation between the number of painful interventions a child experiences and how abnormal their brain’s response to touch was. But she also found that when babies experience lots of positive touch—like breastfeeding, massage, or kangaroo care—their touch responses looked more like full-term babies’.

Maitre hopes to design interventions, and then use measurements of brain responses with EEG like the one in her study to test whether those interventions make a difference. She’s developed a tool for playing recordings of parents singing to premature infants to help with the development of their hearing, and thinks interventions from parents and therapists could go a long way toward mitigating the trauma of daily pain.

Others, like Andropolous, are hopeful that the information gleaned from better-controlled, larger clinical trials might help clinicians perform the cost-benefit of anesthetics. “The FDA warning has really kind of brought this to the forefront," he says, "and hopefully one of the things that it might foster is more research." Several clinical trials in the UK and US to study the effects of multiple exposures to anesthetics and opioids are currently underway.

In the meantime, it's reassuring that doctors have moved far beyond the days of performing surgery without anesthesia. "Anesthesiologists do their best to provide good pain relief," says Maxwell—even though their measures are imprecise.