Why it's so hard to treat pain in infants

Doctors once believed that infants—especially premature babies—did not feel pain, and if they did, they would not remember it.

This might sound like Medieval medicine. But as recently as the 1980s, babies undergoing surgery were given a muscle relaxant to paralyse them while in the operating room but were not given any pain medication, says Fiona Moultrie, a paediatrician and researcher at the University of Oxford who focuses on neonatal pain. “At the time, it was assumed that most of the behaviours that infants were exhibiting were just reflexes.”

Over the next decades, studies documented changes in infant behaviour, stress hormones, and brain activity, proving that even the tiniest babies did indeed suffer pain. Research also revealed that continued pain could derail a child’s short- and long-term neurological, social, and motor development, especially in fragile, preterm babies born earlier than 37 weeks, says Björn Westrup, a neonatologist and researcher at the Karolinska Institute near Stockholm, Sweden.

Rapid advances in medicine now allow very fragile, tiny, preterm babies to survive. But ‘preemies’ may spend weeks or months in the hospital undergoing the constant, often painful procedures needed to save their lives. Strategies to make such procedures less traumatic are vital, as premature births are rising globally. In the United States alone, about 380,000 babies are born prematurely each year, or about one in 10 births. Worldwide, it’s about 15 million.

The medical profession tries to manage or prevent infant suffering with drugs such as ibuprofen (for mild to moderate pain) and fentanyl (used to alleviate extreme pain). For most analgesic drugs, though, the proper dosage, effectiveness, or effects on the brain remain unknown, so increasingly, hospitals are incorporating non-pharmaceutical interventions that centre on techniques known as developmental care, which keep babies and their families together rather than isolating infants in incubators.

That’s critical, says Manuela Filippa, a researcher at the University of Geneva who studies prematurity, because separating sick babies from their parents compounds pain with toxic stress that creates serious developmental problems. Inside a neonatal intensive care unit, or NICU, lights are bright and monitors blink. It’s loud, with machines beeping, alarms going off, people talking, and ventilators thumping and hissing.

“Brain maturation is based on sensory experience,” Filippa explains, “and the [traditional] neonatal intensive care unit is very stressful.”

How do babies express pain?

Babies born extremely early are whisked from the delivery room to the NICU. The youngest, those under 36 weeks, have underdeveloped lungs and may be intubated and hooked up to a ventilator. They are too weak to suckle and must be fed through tubes in the nose or mouth. Nurses need to lance their tiny heels for blood tests up to 10 times a day, and they are engulfed in IV lines, tubes, and wires.

In the early 1980s, Canadian newborn medicine researcher Celeste Johnston, an emeritus professor at McGill University in Montreal, was approached by nurses working in the NICU who wanted a way to measure pain in infants. In 1986, she was among the first to publish evidence that infants’ heart rates and oxygen levels changed when they were subjected to painful procedures. Their cries and facial expressions revealed what she calls “honest signalling,” behaviours that babies are born with that communicate distress.

“There is a particular grimace that was described by Darwin in the 1800s that is recognised universally as pain,” she says. That’s ironic, Moultrie notes, “as Darwin’s celebrated work on evolutionary theory and the expression of emotions in man promoted the concept of infants as primitive beings with under-developed senses and merely reflexive behaviours.”

Johnston was later horrified to learn that in intensive care, babies averaged about 14 painful procedures each day.

But understanding how these small, nonverbal beings experience pain is extremely difficult. “One of the biggest challenges in caring for preterm and sick infants is that they can’t tell us,” says Erin Keels, a nurse practitioner and director of advanced neonatal providers at Nationwide Children's Hospital in Columbus, Ohio. “We can only infer by their behaviours and their vital signs.”

Forty different pain scores have been compiled over the last three decades, which can be used to evaluate pain levels. They each include various combinations of heart rate, oxygen saturation, facial expressions, or body movements. But since physiology can change for many reasons, and a baby may be too sick or too medicated to grimace, these are not always objective markers. There is an ongoing quest to better understand how infants perceive and experience painful stimuli.

“Although there has been great progress, we still don't fully understand pain in neonates,” says the University of Oxford’s Moultrie. She and others have been trying to measure pain by observing bursts of electrical activity in the brain using electroencephalogram (EEG) testing. They identified a pain-related pattern of brain activity in infants, which is now being used in clinical trials to test the efficacy of medications. It could revolutionise pain treatment.

In a later studies, researchers at the University of Oxford used MRI scans to pinpoint brain activity. They found that 20 out of 22 brain regions activated in an adult’s brain in response to pain are also activated in a newborn baby’s brain. One area that did not register was the amygdala, which is associated with fear and anxiety, likely because days-old babies may not yet make these associations, Moultrie says.

But there’s still a lot researchers still don’t know about exactly what's going on in the infant brain. “When you're tiny and underdeveloped, differentiation between pain and stress is not clear,” says Johnston.

At the same time, researchers are uncovering the potential long-lasting physiological consequences of preemie pain, Filippa notes. The amount of pain-related stress predicts the thickness of the brain’s cortex, for instance. One study found that at school age, children who were born very preterm—at 24 to 32 weeks gestational age—had a thinner cortex in 21 of 66 cerebral regions, predominately in the frontal and parietal lobes. This has been linked to motor and cognitive impairments.

Preterm babies also face significant risk for lowered IQ, attention deficit disorder, memory issues, and difficulty with social interactions and emotional control. Heidelise Als, a pioneer in understanding physical and behavioural risks for both preterm and sick infants, attributes this at least partly to the vastly altered sensory experiences that can influence preterm babies’ immature nervous systems.

Alternatives to alleviate pain

Without an accurate way to measure pain, though, it’s tough to test how effective any given drug is. By the 1990s, doctors understood that using anesthesia during major surgeries improved outcomes. Babies that were intubated and on ventilators were—and still are—given morphine, though there’s ongoing controversy over whether it reduces their pain, says Moultrie. Meanwhile, the risks of pharmacological interventions include opioid addiction, withdrawal, difficulty breathing, and possible impacts on neurodevelopment.

The downside of painkillers has spurred the search for alternate treatments. One method gives babies sucrose before procedures because it can release endorphins and potentially ease pain. While it seems to soothe them and lower physical response to painful stimuli, the baby’s stress hormones and reactive brain signals remain high, says Nils Bergman, a researcher and paediatric specialist also at Karolinska Institute. Other work has found that breastfeeding during needle-related procedures provides more pain relief than interventions such as swaddling, being held, topical anaesthetics, music therapy, or a dummy.

The physical environment also matters in reducing a baby’s stress during painful procedures. In 2000, a trial in Sweden compared the progress of babies cared for in a traditional intensive care ward versus a darkened, quiet, more womb-like room with parents present. The latter group was discharged quicker and had grown slightly more by the end of their stay.

Today, many neonatal experts think this kind of family-centred care is the wave of the future. One of the most effective methods is Kangaroo Mother Care, which involves wrapping an infant skin-to-skin on its mother’s or father’s chest.

The method was developed in Colombia by paediatrician Edgar Rey, who began using it at Bogotá’s Maternal and Child Institute in 1978. At the time, some 70 percent of preemies died in their overcrowded neonatal ward. Rey had stumbled upon a report describing how a kangaroo raised its peanut-size underdeveloped joey to about a quarter of her own weight, raising it inside her pouch and keeping it warm through skin-to-skin contact.

Rey discovered that human babies also thrived in this way, and after implementing the technique, preemie death rates plummeted. The World Health Organization recently estimated that annually, kangaroo care could save 450,000 lives.

Years later in Canada, Johnston found that skin-to-skin contact provided a calming situation for conducting routine procedures in the NICU and babies both showed a milder pain response and recovered more quickly .

Filippa has studied the effects of other family-based interventions, including how the sound of a mother’s voice might mitigate her child’s pain. Her team monitored 20 premature babies at the Parini Hospital in Italy during their daily heel-prick blood tests, with mothers talking to them or singing to them. Hearing their mother’s voice during a medical procedure significantly improved the infant’s pain score. Singing also helped, but less so.

When the team examined hormonal changes triggered when a baby hears its mother speaking to them, they found that oxytocin levels rose substantially. Oxytocin, sometimes called the attachment hormone, is produced in the hippocampus and plays a crucial role in modulating pain, stress, and social behaviours. It also protects against inflammation in a preterm infant’s brain, Filippa explains.

With lower oxytocin levels, the emotional brain – the hypothalamus – is less developed. The result is that “you're less able to face stressful events and have higher reactions to pain,” says Filippa. “Oxytocin is strong neuroprotection against the short- and long-term effects of pain.”

Toward zero separation

In 2010 Westrup revealed that even the smallest, sickest babies benefitted from having parents with them 24/7. Notably, there were fewer lung issues and much shorter hospital stays. Sweden has since incorporated this knowledge by redesigning many NICUs so parents can live with their baby, even in high intensive care situations. Pre-COVID-19, siblings could also visit.

This type of “zero separation” approach requires a holistic mindset that also cares for mothers: At least 50 percent of those who birth early have other health conditions and need obstetric care. In a number of countries, new NICUs are being built with individual rooms to house families. But government support is needed for most people to devote months to caring for their sick child.

In Sweden, nationalised medicine covers costs, and the government pays parental benefits up to 35 weeks; extended benefits can stretch to 61 weeks. In Canada, which also provides medical coverage, both mother and father are entitled to 240 days of paid leave.

The situation is far different in the U.S., for instance, where mothers are entitled to 12 weeks of unpaid leave if they work for a company with 50 or more employees. The U.S. is one of just six countries that has no national paid leave. Currently, Congress is considering four weeks of paid family leave as part of a $1.85 trillion (£1.3 trillion) domestic policy bill, which faces opposition. The U.S. also lacks nationalised health coverage – and has the world’s most expensive health care system.

Westrup and Bergman emphasise that we should not just wait until neonatal units are rebuilt or all the economic conditions are in place to act. Ultimately, there is substantial evidence that we need to change the system to embrace zero separation, they say. Teaching nurses and doctors how to provide this kind of developmental care will give children a healthier future.

Keels of Nationwide Children's Hospital is optimistic about the evolution in preemie care and the research that will continue to inform best practices. “I'm hopeful that in the near future, we'll have greater knowledge and better ways of evaluating pain so we can do really individualised medicine right at the bedside.”