A Gentle Test of a Nose-Spray Painkiller for Premature Babies

How a small Toronto study of intranasal fentanyl during IV-line placement (Tabbara et al., 2025) ran into an unexpected obstacle — and what it means for families

Doctors in Toronto wanted to find a kinder way to ease the pain premature babies feel when a long IV line is placed into a vein, so they tested a painkiller sprayed into the nose instead of given by needle. Their small study set out to enrol 24 babies but reached only 8, mostly because these procedures happen at all hours while the study could only run on weekday daytimes. The spray caused no harmful side effects and was welcomed by the nurses who used it, and the researchers concluded that a larger, definitive study is worth doing — but only if it can operate around the clock.

Why pain in tiny babies is such an important problem

Newborns in intensive care, especially those born many weeks early, go through a surprising number of uncomfortable procedures every day — heel pricks, blood draws, and the placement of tubes and lines. One large study found that these babies undergo more than a dozen painful procedures a day, and for years most were done without any specific pain relief [1]. It was once wrongly assumed that very young babies did not really feel or remember pain. That view has been firmly overturned. Researchers began pulling together the evidence two decades ago, showing that untreated pain and stress in newborns have real short- and long-term consequences [2]. We now know that repeated pain in babies born very early is linked to changes in how their bodies handle stress and to differences in later development [3], and a wider review of the science connects a heavy load of early pain to effects on the growing brain [4]. In other words, easing a premature baby's pain is not only about comfort in the moment; it may help protect the brain during a critical window of growth.

What families and clinicians could offer before this study

Caring for babies in pain has come a long way, though there is still distance to travel. Today, most units use a small amount of sweet sugar water placed on the tongue, which has been shown to calm babies during quick needle procedures [5], together with gentle, drug-free comfort measures such as swaddling, skin-to-skin holding, and letting the baby suck on a pacifier, all of which are supported by careful reviews of the evidence [6]. These approaches work well for brief pokes. The harder challenge is a longer, more involved procedure called a PICC — a peripherally inserted central catheter, which is a thin, soft tube threaded through a vein so that nutrition and medicines can be given safely over days or weeks [7]. Placing one can take time and several attempts, and it is one of the more uncomfortable things a baby in intensive care goes through. Because these lines are used in nearly every unit [8], finding a good way to ease the pain of putting them in would help a great many babies. Yet a proven medicine to add to the sugar water and comfort measures has been missing — which is exactly the gap this study aimed to explore.

What the researchers actually did

The study, nicknamed INFENT PICC (short for Intranasal Fentanyl in Preterm Infants Undergoing PICC Placement), took place in one newborn intensive care unit at Mount Sinai Hospital in Toronto, Canada [9]. Importantly, the researchers were not yet trying to prove that the spray works. They were asking a more basic question first: could a full, proper study even be carried out the way they planned? This kind of "dress rehearsal" is called a feasibility study, and doing it first is a sign of careful science — it catches practical problems before a large, expensive trial is launched.

Babies born before 32 weeks (or weighing under 1.5 kg) who needed their first PICC were placed, by chance and in secret, into one of two groups. One group received a spray of the painkiller fentanyl into a single nostril; the other received a look-alike spray of harmless salt water. Neither the family nor the bedside team knew which baby got which — a design that keeps the results fair and unbiased. Every baby, in both groups, still received the usual sugar water and comfort care. The spray was given about ten minutes before the procedure using a small device that turns the liquid into a fine mist. To measure comfort, the team video-recorded each procedure and had two trained reviewers — who also did not know which spray the baby received — score the baby's pain using a standard newborn pain scale.

What they found

The study's results came in two parts. The disappointing part was that they could not enrol enough babies: they hoped for 24 but got 8, and only 6 completed the procedure. The reason was not that families said no. In fact, half of the families who were asked agreed to take part, which met the researchers' goal. The real problem was timing. Most PICCs were placed in the evenings, overnight, on weekends, or in a hurry — and the study could only give the spray during weekday daytime hours, because that was when the pharmacy could prepare it. As a result, most eligible babies were never even able to be offered a spot in the study.

The encouraging part was everything else. When procedures did go ahead, the video recordings worked every single time, so the researchers confirmed that their method of measuring pain is reliable and ready for a bigger study. Just as importantly, the spray appeared safe: there were no harmful side effects such as pauses in breathing, slow heart rate, or drops in oxygen during the six hours the babies were watched afterward. And the nurses and doctors who used the spray generally liked it — most did not find it stressful to give, and the great majority said they would support making it a regular option, though some wanted more training and more experience with this less familiar way of giving medicine.

One detail from the study is worth understanding, because it may reassure families who feel uneasy at the word "fentanyl." Fentanyl has been in the news as a dangerous street drug, and a few parents in the study said that reputation was part of why they hesitated to take part. In a hospital, though, the same medicine is a long-established, tightly controlled painkiller used every day in children's care. In this study the amount was calculated precisely for each baby's weight, given as a single tiny misted dose, and followed by hours of close monitoring. The researchers deliberately did not include the most fragile babies — those who were already on other strong pain or sedative medicines, or who were unstable — because adding an opioid would carry more risk for them. That careful, conservative approach is typical of how new treatments are tested in newborns: safety first, in the babies most likely to tolerate it, before anything is considered more broadly.

It also helps to know why a "dress rehearsal" study like this one is genuinely useful even when it does not enrol enough babies. By discovering the timing problem now — before spending years and a great deal of money on a large trial — the researchers can redesign the next study so it actually works. Learning that families are willing, that the spray is well tolerated, and that the pain-measurement method is reliable are all real gains. In science, a small study that clearly identifies the obstacle is often what makes the eventual breakthrough possible.

What this means for your baby's care

If your baby is in the NICU, the most important thing to understand is what this study does and does not tell us. Because so few babies took part, it cannot yet tell us whether the nose spray actually reduces the pain of a PICC — that answer will have to wait for a larger study. It does tell us that the idea is safe enough and practical enough to keep testing, and that the tools to measure whether it helps are working well. For now, your care team will continue to rely on the approaches we know help, such as sugar water and comfort measures, and past experience has taught them to be cautious about adopting a new medicine before strong evidence is in — earlier efforts to ease line-placement pain, including numbing gels and other medicines, have often not lived up to their early promise [10][11]. You can always ask your baby's nurse or doctor what is being done to keep your baby comfortable during procedures; comfort is a legitimate and important part of care, and teams welcome the conversation.

What researchers are working on next

The study's authors are clear about how to make a future trial succeed. The biggest fix is to make the spray available at all hours, so that babies who need a line at 2 a.m. or on a Sunday are not left out. They also want to involve parents as partners in designing the study, which can make families more comfortable taking part, and to simplify how the spray is prepared so it is easier and quicker for busy staff to use. Perhaps the deepest lesson reaches beyond this one spray: even after decades of progress, one of the main reasons good pain treatments for babies are slow to arrive is not the medicine itself but the practical difficulty of studying it well [12]. By naming that obstacle so plainly, this small study helps clear the path for the larger one that could finally answer whether a gentle nose spray can make a hard procedure a little easier for the smallest patients.

References

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  2. Hall RW, Anand KJS. Short- and long-term impact of neonatal pain and stress. NeoReviews. 2005;6(2):e69–e75. doi:10.1542/neo.6-2-e69 ↩
  3. Vinall J, Grunau RE. Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res. 2014;75(5):584–587. doi:10.1038/pr.2014.16 ↩
  4. Boggini T, Pozzoli S, Schiavolin P, et al. Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies. Neurosci Biobehav Rev. 2021;123:320–336. doi:10.1016/j.neubiorev.2020.12.016 ↩
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  9. Tabbara N, McLeod SL, Taddio A, Shah V. Intranasal Fentanyl in Preterm Infants Undergoing Peripherally Inserted Central Catheter Placement (INFENT PICC): A Feasibility Randomized Controlled Trial. Children (Basel). 2025;12(9):1156. doi:10.3390/children12091156 ↩
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