Family caregiver observations of pain behaviors in infants and young children less than 3 years of age.

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Published in final edited form as: J Pain. 2025 Jun 1;33:105454. doi: 10.1016/j.jpain.2025.105454 Family Caregiver Observations of Pain Behaviors in Infants and Young Children Less Than 3 Years of Age Kathryn E Gustafson 1, 2 , Kanecia O Zimmerman 1, 3 , Alexy Hernandez 4 , Katelyn E Plyler 1 , Christy K Zigler 5 , Aline B Maddux 6 , Amira Al-Uzri 7 , Chi Dang Hornik 1, 3 , Marisa Meyer 8, 9 , Bonnie Stevens 10, 11 , Ernest A Kopecky 12 , Gary A Walco 13, 14 , Frank W Rockhold 3, 15 , Bryce B Reeve 1, 3, 4, 16 Author information Article notes Copyright and License information 1 Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA 2 Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC, USA 3 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA 4 Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA 5 Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 6 Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA 7 Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA 8 Division of Critical Care, Department of Pediatrics, Nemours Children’s Hospital, Wilmington, DE, USA 9 Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA 10 Lawrence Bloomberg Faculty of Nursing University of Toronto, Toronto, ON, Canada 11 Research Institute, The Hospital for SickKids Children, Toronto, ON, Canada 12 Teva Branded Pharmaceutical Products, West Chester, PA, USA 13 Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA 14 Seattle Children’s Hospital, Seattle, WA, USA 15 Biostatistic and Bioinformatics, Duke University School of Medicine, Durham, NC, USA. 16 Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. Author contributions KEG: Conceptualization, Investigation, Supervision, Writing – original draft, Writing – review & editing KOZ: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – review & editing AH: Investigation, Methodology, Writing – review & editing KEP: Investigation, Methodology, Writing – review & editing CKZ: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing ABM: Investigation, Resources, Writing – review & editing AAU: Investigation, Resources, Writing – review & editing CDH: Investigation, Resources, Writing – review & editing MM: Investigation, Resources, Writing – review & editing BS: Conceptualization, Methodology, Writing – review & editing EAK: Conceptualization, Writing – review & editing GAW: Conceptualization, Methodology, Writing – review & editing FWR: Conceptualization, Writing – review & editing BBR: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing ✉ Corresponding author: Kathryn E. Gustafson, PhD, 2608 Erwin Rd; Suite 300; Durham, NC 27705; katie.gustafson@duke.edu Issue date 2025 Aug. PMC Copyright notice PMCID: PMC12239472  NIHMSID: NIHMS2090817  PMID: 40460900 The publisher's version of this article is available at J Pain Abstract Pain in very young, preverbal children is often inadequately assessed and thus poorly treated, leading to short- and long-term negative consequences. Family caregivers are often the primary observers of young children’s pain, but their perspectives are often overlooked. There are no well-designed or validated caregiver-reported pain measures for children under 3 years of age. This study used qualitative concept elicitation interviews with 44 caregivers of young children aged birth to <3 years who had experienced acute pain associated with injury, chronic illness, or medical procedure to identify key indicators caregivers use when assessing pain in their children. Caregivers described pain indicators that were categorized as sounds, movements, facial color change and expressions, emotional expression/behavioral changes, and related elements, such as vital sign changes. Caregivers also identified key indicators for mild, moderate, and severe pain. Most caregivers noted that it became easier to identify pain over time as they learned their child’s cues and as their child’s communication developed. Caregivers of young children provide a unique perspective on their child’s pain experience and severity. Caregiver-identified pain indicators from this study will inform the design of a caregiver-reported acute pain measure that, once validated, could be used in clinical research studies and trials or practice. Keywords: Family caregivers, Clinical outcome assessment, Acute pain, Pediatric population, Observer-reported outcomes, Qualitative study PERSPECTIVE Validated family caregiver-reported pain measures for children <3 years are lacking. Using concept elicitation interviews, caregivers of children <3 who recently experienced acute pain described pain indicators in the categories of sounds, movements, facial color/expressions, emotional/behavioral changes, and physiological changes. Caregivers offer a unique perspective on young children’s pain experiences. INTRODUCTION Young children frequently experience pain, 1 yet their pain is often inadequately assessed and undertreated. 2 – 4 Children aged 6–24 months were significantly less likely to receive analgesics than those aged 6–10 years when presenting to an emergency department with acute injuries, such as fractures and burns. 5 In another study, only 2% of children under age 2 years with bone fractures received adequate pain treatment; children aged 10–15 years were 2.5 times more likely to receive adequate pain treatment than children under age 2 years. 6 Acute pain is also underassessed and undertreated in hospitalized children. In a study of 234 neonatal intensive care units (NICUs), fewer than 32% of neonates received one assessment of continuous pain and only 10% received daily assessments. 7 Of 241 hospitalized children (a majority under age 4 years), 77% experienced acute pain and 64% reported moderate to severe pain; yet 42% received no analgesics and only 25% received ongoing analgesia. 4 Frequent and repeated exposure to painful experiences and inadequate treatment of pain can lead to significant short- and long-term negative consequences. 8 Neonates, including those born preterm, and young children who experience pain from procedures, surgery, or injuries may have altered pain sensitivity and pain processing later in childhood, 9 , 10 poorer developmental outcomes with long-lasting modifications in brain structure and connectivity, 11 – 19 increased maladaptive behavior, 14 , 20 – 23 and increased risk for chronic pain or altered pain sensitivity in adulthood. 24 – 27 Such outcomes violate the basic ethical principal of “do no harm,” as they likely can be mitigated with appropriate assessment and treatment of pain. A crucial step in addressing pain is access to validated pain measures. 2 For young preverbal children, self-report, the current gold standard, is not feasible, 28 , 29 making systematic observation of pain indicators critical. In clinical trials, clinical outcome assessments (COAs) of pain may include clinician-reported outcome (ClinRO) measures and observer-reported outcome (ObsRO) measures, completed by a parent or other primary caregiver. While there are recommendations for a core set of ClinRO measures to assess pain in research and clinical settings across all child ages, 30 – 34 there are no validated family caregiver ObsRO measures designed specifically for children under age 3 years. Adaptions of ClinRO measures, such as the Faces, Legs, Activity, Cry and Consolability scale (FLACC), 35 have been used with family caregivers, 22 , 36 – 38 but these were not developed following COA design guidance and require training to complete. 39 , 40 Numeric rating scales have been used but do not include observable descriptors of pain behaviors. To date, the only ObsRO measure developed specifically for family caregivers is the Parents’ Postoperative Pain Measure, which is not validated with children younger than 2 years. 41 Parents and other family caregivers of children (hereafter “caregivers”) provide an important perspective, as they are often the primary interpreters of pain expression and severity for young children who do not have the developmental capability to self-report. 37 , 42 , 43 Caregivers are confident in evaluating their infant’s pain 44 and better recognize facial expressions of pain in their infants than do pediatric clinicians. 45 Caregivers report that facial expressions, body movements, and sounds are important factors in judging pain. 46 Yet, these critical perspectives are inconsistently considered in the design of COAs and infrequently included in pain assessment within clinical research studies and trials of acute pain therapeutics in young children. 47 The International Association for the Study of Pain (IASP) 48 emphasizes that pain is a personal experience influenced by biological, psychological, and social factors; therefore, caregivers who are familiar with the child need to be included. 48 Our study conducted qualitative interviews with caregivers of children birth to <3 years who have experienced an acute pain event to gain understanding of how caregivers determine the presence and severity of pain in their children. METHODS All phases of this research study were guided by FDA representatives as part of a pilot program to develop COAs 65 through regular meetings to discuss progress and next steps, including feedback on the proposed study and interpretation of findings. In addition, this study was also supported by an advisory committee composed of experts in pediatric pain research and four parents of children with chronic illnesses associated with acute pain experiences. Their insights informed the design and relevance of the study. Additionally, the Pediatric Trials Network Steering Committee contributed scientific oversight of the study protocol and supported recruitment efforts by facilitating engagement with caregivers at Pediatric Trials Network sites. Participants Family caregivers were recruited through the Pediatric Trials Network (PTN), a group of clinical research sites in the United States and Canada that cooperate in designing and conducting pediatric clinical trials. PTN sites participating in recruitment for this study included Oregon Health & Science University Hospital, Nemours/Alfred I. duPont Hospital for Children, Children’s Hospital Colorado, and Duke University Medical Center. Site investigators identified all consecutive potential participants and completed a consent-to-contact form with those who agreed to be contacted by the research team. The study protocol was approved by the Duke University Health System’s Institutional Review Board. Caregivers who met the following criteria were enrolled: Older than 18 years of age, spoke and understood English, capable of providing informed consent, and caring for a child between birth and <3 years of age who has experienced pain within the context of a chronic illness, injury or surgery. Acute pain was defined as a painful experience or episode lasting <6 months, in one of the following categories: malignant or nonmalignant visceral or hematologic disease, surgery, trauma or injury, or congenital condition. For children <2 years of age who were born prematurely, chronological age was corrected for number of weeks of prematurity. All participants at each site who met eligibility criteria were approached for potential participation. Caregivers were excluded if they lacked access to a telephone or computer for the interview or if their child was born very prematurely at <32 weeks gestation given that children who were very preterm may experience or express pain differently 23 . Given the rapid developmental change that occurs in the first several years of life, 49 information was collected across distinct age groups. A sample size of 44 participants was selected based on a minimum of six caregivers with children enrolled in each of the following seven age groups: 0 to <2 months, 2 to <6 months, 6 to <12 months, 12 to <18 months, 18 to <24 months, 24 to <30 months, and 30 to <36 months. Some age groups (e.g., 6 to <12 months, 12 to <18 months) had more than six caregivers to make sure that content saturation was achieved and recruitment in each age group was discontinued once this was achieved. In each age group, the research team attempted to achieve a balance in the children’s demographics in terms of sex and racial or ethnic representation, and to have a diversity of medical conditions that were related to their pain experience. Procedures Following informed consent procedures when the purpose and goals of the study were reviewed, caregivers completed a single semi-structured phone or video interview with one of two clinical research coordinators (AH or KEP). Both interviewers were experienced in conducting qualitive interviews, were part of the research team and familiar with the study goals, and participated in training on the interview procedures and guide. Each interview lasted approximately one hour. The interviews, which were digitally recorded, collected demographic information and then used open-ended questions about their child’s medical and pain history, pain expression, differentiation of pain and non-pain distress, interventions for pain and non-pain distress, past use of pain scales, and other concepts essential to caregivers, such as pain medication side effects, sedative effects, and medication cost. The interview began with the trained interviewer asking the caregiver to describe their child’s pain behaviors in an open-ended way in order to allow caregivers to describe those pain behaviors and pain indicators that they believe to be cues for their child’s pain experience and how their child expresses pain (e.g., Please tell me how you know when your child is in pain. How could you tell from the way your child was behaving that he/she was in pain?). The interviewer then used conditional probes, if the caregivers did not mention them, on different types of pain expressions such as movements, sounds, and facial expressions. These different types of pain expressions were informed from a review of the literature of pain expression in young children and existing measures of pain (e.g., FLACC). To preclude limitation only to these typical pain indicators, interviewers asked, “Are there other things your child did to let you know he/she was in pain?” See the full interview script in Supplement 1 . The analysis then consisted of categorizing the individual indicators collected in the caregiver interviews with labels that were consistent with information obtained from the literature review. Following all interviews, interviewers completed a debriefing form capturing key themes and concepts, and digital recordings were transcribed. Participants did not subsequently review their own transcripts nor review the study findings. The research team was attentive to reaching content saturation, meaning that no new insights (pain indicators) emerged from consecutive caregiver interviews. 50 Content saturation was closely monitored using tracking tables that included the terms and ways caregivers described their child’s pain expressions and the number of caregivers, by their child’s age group, who mentioned the pain indicators. Data analysis Thematic analysis of the data was completed by coding transcripts and debriefing forms using NVivo software (version 12, [formerly QSR International] Lumivero, Denver, CO 51 ). Based on the literature and review of the interview debriefing forms by the investigators, a codebook was developed by the study team, and analysts applied structural codes to the data, such as sounds, movements, facial color and expressions, and emotional expressions/behavioral changes. The first transcript was coded independently by three trained analysts, inter-coder reliability (ICR) was calculated, and coding results were compared. Discrepancies were discussed and clarified. Once coders achieved at least 80% reliability, which occurred within the first 2–3 transcripts, transcripts were coded individually. To ensure continued consistency in coding, every tenth transcript was coded by all three analysts and ICR was calculated to ensure at least 80% reliability, before they continued. After all transcripts and debriefing forms were coded, reports were generated by specific codes and age groups. Coding reports were analyzed by the research team and were used to develop the final tables of caregiver responses. RESULTS Demographic characteristics of the 44 participants and their children are shown in Table 1 . Table 2 shows that the children’s sex, race, and ethnicity were distributed fairly evenly across the six age groups. The large variety of specific medical conditions, procedures, and injuries of the children of the caregivers are listed in Supplement 2 . Once consented, no participants withdrew from the study. Table 1. Demographics of caregivers and their children (N=44) Caregiver Demographics N (%) Sex Female 38 (86%) Male 6 (14%) Marital Status Married (or living like married) 37 (84%) Single 6 (16%) Race Asian 4 (9%) Black 1 (2%) White 33 (75%) Multiracial 3 (7%) Other 3 (7%) Ethnicity Hispanic 7 (16%) Education High School Diploma 7 (16%) Partial College 10 (23%) College Degree 16 (36%) Postgraduate Degree 11 (25%) Caregiver Employment Status Full-time Paid Work 22 (50%) Part-time Paid Work 5 (11%) Stay-At-Home Caregiver/ Unemployed/Full-time Student (Unpaid Work) 17 (39%) # Children of Caregiver One child 15 (34%) Two children 14 (32%) Three or more children 15 (34%) Child Demographics N (%) Sex Female 22 (50%) Male 22 (50%) Race Asian 3 (7%) Black 1 (2%) White 30 (68%) Multiracial 5 (11%) Other 5 (11%) Ethnicity Hispanic 11 (25%) Open in a new tab Table 2. Interviews completed by child age, child race/ethnicity, and child sex Child Age Number of completed interviews White non-Hispanic child Non-white or Hispanic child Male Female 0 to <2 months 6 3 3 4 2 2 to <6 months 6 3 3 3 3 6 to <12 months 7 5 2 2 5 12 to <18 months 7 4 3 4 3 18 to <24 months 6 4 2 4 2 24 to <30 months 6 2 4 2 4 30 to <36 months 6 4 2 3 3 Total 44 25 19 22 22 Open in a new tab Pain Indicators Pain indicators reported by caregivers as useful when identifying and assessing pain in their children were coded by the study team into the following categories: sounds, movements, facial color and expressions, emotional expressions/behavioral changes, and related elements, such as vital sign changes and the use of context clues. See Table 3 for pain indicators identified by children’s age group. Illustrative caregiver quotes for each type of key pain indicator are provided in Table 4 . Table 3. Key pain indicators described by 44 caregivers Children’s Age Ranges (Months) Total 0 to < 2 2 to < 6 6 to < 12 12 to < 18 18 to < 24 24 to < 30 30 to < 36 Number of Caregivers Per Age Group Endorsing Each Pain Indicator Sounds (5 of 6) (6 of 6) (7 of 7) (7 of 7) (6 of 6) (6 of 6) (6 of 6) (42 of 44) Crying, changes in crying 5 5 7 6 6 5 6 40 Whining, whimpering 1 3 5 6 3 3 4 25 Screams, shrieks, yells, yelps 4 2 3 4 4 1 3 21 Verbalizes pain (ow, ouch) 0 0 1 1 4 5 6 17 Grunting, groaning, moaning 1 2 3 0 1 0 3 10 Gasping, wheezing, panting 1 1 0 0 2 0 0 4 Facial Color and Expressions (5 of 6) (5 of 6) (7 of 7) (7 of 7) (6 of 6) (4 of 6) (5 of 6) (39 of 44) Face color change (red, purple) 5 4 4 1 1 1 0 16 Scrunching face 1 3 3 3 1 1 2 14 Eye changes (close, wide) 2 2 5 2 0 1 2 14 Sad or crying face 1 3 4 2 1 1 0 12 Specific face (angry, tense) 2 1 0 2 2 0 1 8 Open mouth 1 2 2 0 0 0 0 5 Frown 0 0 1 1 1 1 1 5 Furrowed brow 0 0 1 2 1 0 1 5 Winces 0 0 2 2 1 0 0 5 Grimace 0 1 0 1 0 1 1 4 Painful facial expression 0 0 2 0 0 0 1 3 Other (not smiling, bottom lip out, lip quiver) 1 0 2 3 0 2 1 9 Movements (5 of 6) (6 of 6) (6 of 7) (7 of 7) (5 of 6) (6 of 6) (6 of 6) (41 of 44) Indicating pain location 0 1 3 2 3 4 6 19 Arching, posture change 4 4 4 1 0 2 2 17 Rocking, shaking, writhing 2 4 5 2 3 0 1 17 Flailing extremities (kicking, arms) 2 4 3 0 1 0 1 11 Active resistance movements (push away, protect area) 1 0 3 3 0 2 1 10 Freezing, reduced movements 0 1 0 2 1 0 0 4 Increased activity (fidgety, bouncing) 0 1 0 3 0 0 0 4 Turns away from pain 0 1 0 1 0 0 1 3 Physically self-soothing 0 0 0 0 0 0 2 2 Hand or Foot movements 0 0 0 0 1 0 1 2 Other (tug at ears, hand in mouth, pulls hair) 0 0 3 2 1 1 0 7 Emotional Expressions/Behavior Changes (4 of 6) (6 of 6) (7 of 7) (6 of 7) (6 of 6) (6 of 6) (4 of 6) (39 of 44) Irritable, emotion dysregulation (fussy, irritable, grumpy, upset) 2 4 2 6 4 2 2 22 Clinginess, seeking comfort, inconsolability 2 2 4 3 1 3 3 18 Sleep, eat, play pattern changes 2 1 3 3 1 2 2 14 Breathing pattern changes 1 3 2 0 3 0 0 9 Restlessness 1 1 0 1 1 1 0 5 Withdrawal, Avoidance behaviors 0 0 2 0 0 1 1 4 Other (4 of 6) (5 of 6) (5 of 7) (1 of 7) (4 of 6) (0 of 6) (2 of 6) (21 of 44) Vital sign, physiological changes, symptoms (heart rate, body temp) 1 5 1 1 3 0 2 13 Context clues (after surgery) 2 0 4 0 1 0 0 7 Other (looks uncomfortable) 2 1 3 0 1 0 1 8 Open in a new tab Table 4. Key pain indicators: illustrative quotes from caregivers Illustrative Quotes from Caregivers Related to Sounds: So, well, crying, but usually a type of cry that doesn’t really stop and you know he’ll kind of get tired and subside, and then he’ll start again. Nothing really soothes him. Sometimes being held or things will temporarily soothe him, but it doesn’t really get to the base of it, and as soon you stop, he starts fussing again. And like with infants, they kind of have different types of cries, so it’s a different type of cry, like a fussy cry, or a hungry cry. It’s a very specific type of crying. It’s kind of a more intense cry that I’ve noticed and it doesn’t stop when you address other possible factors, but a lot of times it can be mistaken for an infant being fussy, but it’s a different cry than his fussy cry. I can tell the difference, but it’s not as clear to others. – Caregiver of an infant 0–<2 months Yeah, first and foremost the crying. But it’s really the type of crying that he does. In that particular scenario he was also very out of it at that time, so he was kinda sleeping a lot in between him expressing that he was in pain. So, he would sort of whimper at first and then it would sort of grow as the pain didn’t subside. – Caregiver of an infant 6–<12 months Illustrative Quotes from Caregivers Related to Facial Expressions: So, it’s the most sad face, lot of bottom lip lowering. His face turns red. He looks like he’s crying. It’s a very sad looking cry. – Caregiver of an infant 0–<2 months She kind of does this little like, wince thing. Like, she’ll partially close her eyes and then just kinda whimper. She like, scrunches up her face. Caregiver of an infant 12–<18 months So, he’s not smiling. He’s scrunching his face when he’s crying. His little eyebrows drop almost like I’m thinking of an emoji where if the eyebrows were straight, they’re more pointed. The center part of the eyebrows are pointed upwards. They’re angled almost like worried kind of eyebrows. – Caregiver of an infant 30–<36 months Illustrative Quotes from Caregivers Related to Movements Movement-wise, she would tend to arch her back, or if I was holding her chest to chest she would stand up and straighten her legs on my stomach because she was in pain in her stomach region, and that would be it. – Caregiver of an infant 2–<6 months But yeah, she was very tense and scrunched up, and I do think also had really pretty rigid posture. Almost like she was in a lot of pain, so she just didn’t want to move her body a whole lot. I think similar to maybe what you or I would do if we were in a lot of pain and stuff. – Caregiver of an infant 6–<12 months He would point to his bump, he calls it the bump, which is the hand wrapped in the splint. Yeah, he would point to it and say “Bump.” or he’d say, “It hurts.” - Caregiver of a child 18–<24 months Illustrative Quotes from Caregivers Related to Behavior Changes She pretty much just wants to be held unless she’s in extreme amounts of pain. And, she will reach for me, but then, when I pick her up, she pushes me away. So, I don’t know if I’m touching something that hurts or she just can’t get comfortable. So, she’s just super mad and wants to be loved. Like I said, she’ll reach for me or try to grab my hand, but it doesn’t calm her. – Caregiver of an infant 6–<12 months I think the fussiness a lot, there was one specific day because it was a few days after the surgery, he was just cranky and I guess he was also looking for a lot of comfort, he’d want to snuggle or cuddle, or have us sing to him and perhaps that was just for comfort because he was in pain. – Caregiver of an infant 18–<24 months Open in a new tab Sounds. The majority of caregivers (n=40) across all age groups identified crying, or changes in crying, as key sound indicators of pain in their children. A few caregivers, particularly those of children 12 months or older, noted that their children used a high-pitched, shrieking, or wailing cry when in pain or that they were inconsolable. Other common sounds were whining and whimpering (n=25), and screaming, shrieking, yelling, or yelping (n=21). Caregivers of children in the oldest categories, those 18 months or older (n=15), identified use of verbal expressions of pain using pain-related words such as “ow” or “ouch.” Movements. Movements were commonly mentioned as key indicators of pain, with 41 of 44 caregivers describing the physical motions their child makes when they are in pain. A majority of the caregivers of older children (18–36 months) noted that their child can indicate the pain location. Caregivers of younger children were more likely to note posture changes including arching, becoming rigid or stiff, or twisting/turning or pulling knees to the chest (n=17), rocking, shaking, squirming, or writhing (n=17), and flailing extremities, such as kicking their legs or waving their arms (n=11). Some caregivers described active resistance movements, such as pushing people away, pulling away from others, fighting/hitting, or covering/protecting the painful spot (n=10). Facial Color and Expressions. Facial color changes and facial expressions were also identified as key indicators of pain in infants and young children among most caregivers (39 of 44). Changes in face color, such as turning red, purple, or becoming paler, was noted by 16 caregivers, particularly for the younger groups of children <12 months. Thirteen caregivers reported that their child’s face turns red when they are in pain. Of these, one caregiver reported that their child is Black, five reported that their child is Hispanic White, two reported that their child is multiracial, and five reported that their child is non-Hispanic White. Three caregivers reported that their child’s face turns purple when they experience pain. Of these, two caregivers reported that their child was Hispanic (one reported White race and the other multiracial), and one reported that their child was non-Hispanic White. Facial expressions involving the whole face were also frequently identified, with descriptions such as scrunching their face (n=14), a crying or sad face (n=12), and wincing (n=5). Facial expressions involving a portion of the face were also identified including the eyes (n=14), such as closed eyes, widened eyes, tears in the eyes, raised eyebrows, droopy eyes, squinty eyes, and “puppy dog eyes.” Furrowed eyebrows were mentioned by five caregivers, but by no caregivers in the youngest or oldest group. Fewer caregivers mentioned facial expression related to the mouth, such as opening the mouth before crying (n=5), frowning (n=5), not smiling (n=4), sticking out the lower lip (n=2), and quivering lips (n=1). Emotional Expression/Behavioral Changes. Emotional and behavioral indicators of pain were described by 39 caregivers. Most commonly, caregivers across the age grouping noted increased emotional behaviors (n=22), including fussiness, irritability, and anger. Caregivers also reported increased clinginess and comfort seeking behaviors, and decreased ability to console or calm the child down (n=18). In addition, caregivers noted changes in the child’s sleeping, eating, or playing patterns (n=14), and changes in breathing, such as holding their breath or taking deep gasping breaths (n=9). Other Pain Indicators. Some caregivers noted other key indicators of pain in their children that were not categorized under sounds, facial color and expressions, movements, or emotional expression/behavioral changes. Several caregivers noted vital sign changes or physiological changes (n=13), including changes in heart rate, respiration, blood pressure, oxygen saturation level, or temperature. Parents of children with chronic conditions or acute illness may be more attentive to these types of physiological changes when measured within a medical setting. A few caregivers (n=7) also noted that they know when their child is in pain based on context, such as when receiving an injection, or heel prick or after surgery, or due to parental instinct or previous experience with pain cues in the child or their siblings. Pain Severity Indicators Caregivers were also asked to identify key indicators of mild, moderate, and severe pain observed in their children. All 44 caregivers identified key indicators of mild pain, and most caregivers identified key indicators of both moderate pain (n=39) and severe pain (n=42). A few caregivers did not provide indicators of moderate pain and may have felt most comfortable differentiating no, mild, and severe pain behaviors in their children. Mild Pain. Crying or changes in crying was the most commonly identified indicator of mild pain severity (n=16). This was identified by caregivers in most age groups but particularly in the youngest age groups from birth to 18 months. These caregivers described crying associated with mild pain as a “softer cry” or that the child “cries a little bit” or “doesn’t cry as long.” No caregivers of children in the oldest age group (30 to <36 months) reported crying changes as an indicator of mild pain. Whining or whimpering (n=13) and irritability or fussiness (n=10) were also identified as indicators of mild pain. Some caregivers identified degrees of consolability (n=9), stating that their children were more easily calmed or soothed when in mild pain. Half the caregivers in the oldest age groups (24 to <36 months) indicated that their child was able to verbalize mild pain, such as saying “booboo,” “ow,” “ouch,” or “it hurts” (n=6). Several caregivers identified facial expressions (n=6; e.g., “scrunching face,” “pouty face”), resilience (n=6; e.g., “recovers quickly,” “self-soothes”), or comfort seeking (n=5; e.g. “cuddling,” “wanting to be held”) as indicators of mild pain. Moderate Pain. A majority of caregivers (n=28) reported crying or changes in crying as a key indicator of moderate pain. Caregivers noted that children will cry more intensely or for a longer period of time. Other indicators of moderate pain were less commonly reported, such as clinginess and seeking comfort (n=9), arching or other posture changes (n=7), increased whining or whimpering (n=6), responsiveness to consoling or distraction strategies such as caregiver comforting or watching television (n=6), and active resistance behaviors such as pushing a caregiver away (n=5). Severe Pain. A majority of caregivers (n=36) described cries that were associated with severe pain as “louder,” “more intense,” “harder,” “more dramatic,” and “panicked,” with the pitch “higher,” “piercing,” or “shrill,” and lasting “longer” or being “nonstop.” Other indicators of severe pain were increased inconsolability (n=13), and screaming, shrieking, or yelling (n=11). Among younger age groups, caregivers noted changes in the color of the child’s face (n=9; <24 months), and flailing extremities (n=7; <12 months) as indicators of severe pain. Family Caregivers’ Ability to Assess Pain Based on Children’s Age. Most caregivers (n=39) reported that it was easier to identify pain in their children as their child has gotten older, because they better know their child’s behaviors and their cues (n=16), or that their child is better able to communicate nonverbally (n=10), verbally (n=8), or both verbally and nonverbally (n=3). Only one caregiver (of a child 18 to <24 months) reported that assessing their child’s pain has gotten harder with age, because the child previously only cried for pain but now cries for many reasons. Two caregivers reported no difference with age, although one of those caregivers was of a child <2 months who said that the child had not changed enough yet to make a difference, whereas the other caregiver of a child 18 to <24 months said their child’s cries have not changed. And finally, two caregivers reported that assessing their child’s pain has become both easier and harder with age due to variability in the child’s mood and pain expression on different days or because there are more variables to consider. Although, again, one of these children was in the <2 months age group and the caregiver reported their child has not yet changed enough to see a difference. Table 5 provides illustrative caregiver quotes about changes in the ability to assess pain in their children with age. Table 5. Easier or harder to determine pain with age: illustrative quotes from caregivers Easier to Determine If Child in Pain I think because I know him better now. You know, because he is so young, so the longer he’s with us, the longer he’s alive, the more I’m sure of his signals, because they’re kind of confirmed to me. You know when I see him get treated for pain, he calms back down, then it kind of reaffirms that that was the problem. – Caregiver of an infant 0–<2 months I think experience of — with these multiple surgeries, every time kind of learning new behaviors on her pain and also her expressions when she’s in pain have become more I guess — they’re easier to see than when she was a newborn from her first surgery when all she could do was cry for anything. So, now, I think a lot of it is experience and knowing what to look for. – Caregiver of an infant 6–<12 months So, it has become easier to tell, now that he’s older, that he’s in pain. He’s able to verbalize it, at least to some degree. When he was a baby, obviously, he really could only cry or moan, basically, but now he is able to verbalize it more. He’s able to use his hands to indicate where he might have some pain... he’s starting to be able to figure out how to communicate. “Oh. I have an owie on my knee,” or, “on my arm,” or whatever.” – Caregiver of a child 30–<36 months Harder to Determine If Child in Pain I think it’s actually become harder. And I think he was diagnosed in June, and he started that yell around July while he was in the hospital. ... And the – and for a few months, it was really only attributed to irritability and pain and wanting attention. But now, he’ll also do it when he wants something. So, I think he’s starting to – like, he gets more attention if he does that, too, so it’s hard to tell if that’s pain or if it’s he just wants attention. – Caregiver of an infant 18–<24 months No Change in Ability to Determine Child in Pain I wouldn’t say too much. It’s still, pretty much, his main communication of pain is through crying. Honestly, I think it’s stayed about the same. As his mom – he’s kind of had the different cries like the cry for just “Pay attention and look at me” or is a cry for “I’m hungry”. It’s kind of been about the same. Because when it’s a cry for pain, if it’s just a quick little bump, it’s usually something that I know happened and it’s like, “Okay, you’re okay,” and then it’s over with, or it will be like sort of the big inhale then big scream let out of pain that happens shortly after he’s hurt himself in some way. Yeah, just from being his mom and him being basically in the same stage of not communicating with words, but just sort of paying attention to his crying pattern has stayed about the same. Both Easier and Harder to Determine If Child is in Pain Harder, because there’s more variables, but easier to distinguish, because she’s more expressive and she knows what she wants. So, even though it’s easier to hear it because it’s louder, or you can gauge it because she’s expressing more frustration, but it’s harder because you’re like, there’s so much more variables on, just basic discomfort, or things that displease her. So, we have more troubleshooting. – Caregiver of an infant 0–<2 months Open in a new tab DISCUSSION In semi-structured qualitative interviews with 44 family caregivers of young children aged birth to <3 years who had experienced acute pain from injury, chronic illness, or medical procedure, caregivers described several key indicators they observed to assess their children’s pain. The purpose of this work was to identify key indicators caregivers use when assessing pain in their children. These pain indicators were categorized as sounds, movements, facial color changes and expressions, emotional expressions/behavioral changes, and related elements, such as vital sign changes. Caregivers also described key indicators that they use to distinguish mild, moderate, and severe pain; the majority of caregivers noted that it became easier to identify pain in their children over time as they learned their child’s cues and as the child’s communication developed. These pain indicators are consistent with other published research that has shown that facial expression, body movements, and vocalizations are the most important pain indicators for judging young children’s pain intensity. 46 The majority of caregivers in the present study reported using crying or changes in crying to judge pain. Similarly, an observational study of 20 NICU infants aged 29 to 40 weeks gestation reported increased crying and vocalizations when experiencing pain. 52 In a study of four male newborns experiencing circumcision pain, investigators noted crying among all children for 76% of the observation time and noted increased variation in the pitch, tempo, and urgency of the cry compared to non-pain distress events. 53 In a study of 32 children aged birth to 36 months who experienced tissue trauma, crying and other verbalizations of pain were important in all age groups, and as found in the present study, by 18 months of age, children started to use pain words such as “ow.” 54 Most caregivers in the present study reported that their child’s movements were important in judging their child’s pain, including movements such as posture changes, rocking or writhing, flailing extremities, or resistance movements such as pushing away. Similarly, in the published study of NICU infants, investigators observed motor responses of flinching, muscle rigidity, clinched hands, and withdrawal. 52 The published study of newborns experiencing circumcision-related pain reported that the neonate’s upper limbs were tense with extension of their hands approximately 63% of the time, the neonates shifted their shoulders in a downward motion approximately 25% of the time, and their limbs were jerky approximately 10% of the time. 53 In the published study of young children with tissue trauma, children across all age groups exhibited pain-related movements, such as kicking, wriggling, thrashing, flailing, and jerking. 54 Older infants exhibited more refined and purposeful movements. Facial color or expression changes were noted by most caregivers in this study, which has also been reported in previous studies. In NICU infants, investigators observed facial responses, including an open mouth, brow bulge, grimace, chin quiver, nasolabial furrow, eye squeeze, taut tongue, and changes in color. 52 Facial expressions were also important in the observational study of young children who experienced tissue trauma. 54 The newborns exhibited frown, grimace, or clenched jaw, infants 3 to 6 months also made expressions that were serious, surprised, or made an “O” mouth, and infants 6 to 9 months also showed expressions of fear, sadness, or flinching. Similar facial expressions to young children were observed in older children, although pouting was also noted in one toddler. Caregivers of young children provide a unique and valuable perspective on their children’s pain expressions. Parents report confidence in their ability to evaluate pain in their children 44 and want input and involvement in treating their child’s pain. 55 , 56 Moreover, recent research reflects the importance of parental involvement in shared decision-making about pediatric pain treatment. 57 Indeed, caregivers share responsibility with clinicians for the postoperative care of their children. 58 Caregivers are often the primary interpreters of pain expression and pain severity for infants and young children who do not yet have the cognitive and language developmental capability to self-report their pain. 59 Participation by caregivers in pain assessment may influence the attention clinicians give to the evaluation and care of postoperative pain. 27 , 56 , 60 However, there are no ObsRO measures that have been developed specifically for caregivers of infants and young children younger than 2 years. Although the Parents’ Postoperative Pain Measure, 41 which has only been validated for children aged 2 years and older, includes some similar indicators as found in our study, including crying, whining, changes in eating and play, and increased comfort seeking, other important indicators identified in our study, including facial color and expression changes and changes in movements are not included. This measure may not include key pain indicators relevant to infants and young toddlers. The commonly used FLACC, 35 which was developed as a ClinRO rather than an ObsRO, does have similarities with the key indicators identified in this study, including changes in facial expression, leg movements, body movements, crying, and consolability, but the descriptions of pain states in the FLACC include few details, potentially making this measure more difficult for parents. Validity data for parent use of this measure is lacking despite its frequent use. Given the lack of ObsRO pain measures and the importance of caregiver interpretation of child pain, there is a need to design a caregiver-reported measure of acute pain built directly from caregiver input. The information obtained in this study directly from caregivers about how they naturally assess acute pain severity while caring for their young children will be used to design a caregiver-reported measure that will subsequently be evaluated to make sure it is understandable, appropriate, and useful for caregivers. This measure could then be used in clinical research studies and trials or healthcare delivery settings. This study has some limitations. First, findings may not generalize to caregivers who are demographically different from our sample. Although some caregivers identified as from a racial group that is traditionally underrepresented in clinical research, the majority of the caregivers in this study self-identified as White and non-Hispanic. In addition, as is often the case in pediatric research, the majority of caregivers who participated were mothers. The sample was also relatively educated, with 84% of caregiver participants having at least some college, a college diploma, or postgraduate education. In addition, caregivers were all from the United States, and findings may not generalize to caregivers from other countries. Further studies with a diverse international sample are recommended. Another limitation is that we did not ask caregivers about their own previous pain experiences or pain cognitions, which previous research has found could potentially affect how caregivers evaluate pain in their children. 61 , 62 A further limitation of this study was the difficulty in recruiting caregivers of neonates. All the children in our 0 to <2 months age group were at least 5 weeks old at the time of the interview with their caregiver, although the acute pain experiences described by caregivers occurred during the first few weeks of life. Caregivers of neonates who have experienced acute pain may be overwhelmed or stressed and less willing to participate in a one-hour interview. The first few weeks of an infant’s life can be hectic and overwhelming, even for caregivers of healthy children. Moreover, this study was not pre-registered as recommended to enhance reproducibility. 63 However, the design of this concept elicitation study is consistent with recommendations by the U.S. Food and Drug Administration Patient-Focused Drug Development (PFDD) Guidance 39 and organizations like the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). 64 Specifically, FDA PFDD Guidance 1 focuses on the necessity of including the caregiver’s voices in describing their children’s experiences as they are the primary caregivers and spend the most time with the child, and FDA PFDD Guidance 2 describes the strength of using qualitative methods to elicit the caregivers’ perceptions and experiences. All phases of this research study were guided by FDA representatives as part of a pilot program to develop COAs 65 and an advisory committee composed of experts in pediatric pain research and four parents of children with experiences with acute pain oversaw the study design and data analyses. In addition, although this study focused on a relatively narrow age group, the age span from birth to <36 months reflects the most rapid developmental trajectory across the entire lifespan. 49 While this study included six age categories, more narrow age ranges (birth to <1 month, 1 to <2 months) may have elicited more distinct pain behaviors by age but at the expense of additional resources to identify available caregivers. Despite these limitations, this study both confirms and expands the understanding of key pain indicators in infants and young children. This was a necessary step in creating a caregiver-reported acute pain measure focusing on key indicators of sounds, movements, facial color changes and expressions, and emotional expression/behavioral changes using terms provided by the caregivers. This tool will address a gap in available pain assessment tools for infants and young children. Subsequent studies will evaluate how the caregivers’ reports are associated with clinicians’ ratings using established measures to assess acute pain in children and how the tool can be used to evaluate the effectiveness of pain treatment. Supplementary Material 1 NIHMS2090817-supplement-1.docx (28.7KB, docx) Highlights. No validated parent-reported pain measures exist for children <3 years of age Parents provide a unique perspective on their young child’s pain experience Parent-identified key indicators are sounds, movements, facial, behavioral, physiological changes Parents described key pain indicators for mild, moderate, and severe levels of pain Parents noted it is easier to identify pain in their young child over time Acknowledgments We would like to acknowledge the important contributions from our advisory committee members including Sharon Brown (Parent of a Child with a Chronic Illness), Meghan (Pogue) Pascal (Parent of a Child with Congenital Heart Disease; Tricuspid Atresia), David O. Warner, MD (Mayo Clinic College of Medicine and Science), and Leanne L. West (International Children’s Advisory Network), and Liz Wing, who provided writing and formatting support for this manuscript. In addition, we acknowledge the contributions of the Pediatric Trials Network Steering Committee, who provided scientific oversight of the protocol to recruit caregivers from Pediatric Trials Network sites. Disclosures This work was supported by the U.S. Food and Drug Administration CDER Pilot Grant Award (1UG3-FD006797–01). In addition, this work was funded under National Institute of Child Health and Human Development (NICHD) contract [HHSN275201000003I] for the Pediatric Trials Network (PI Danny Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. BS has research funding from the Canadian Institute of Health Research and receives royalties from Oxford University Press. FWR has received research funding from NIH, Astra Zeneca, PCORI, American Regent, Gates, BMS, Pfizer, Eidos; received consulting fees from Intercept, Clover, Amgen, Inventprise; has equity interest in GlaxoSmthKline, Clover, Adaptic Health, Spencer Health, Doctor Evidence; and participated in data safety monitoring boards or advisory boards at Lilly, AstraZeneca, Novartis, Biogen, UCB, Gilead, Dirunal, Mural, BridgeBio, Amgen, BMS, Merck. CD has been on the scientific advisory board for Fresenius Kabi, Amarin, Melinta, and Tellus Therapeutics. All other authors have no disclosures. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Data availability statement: Summary reports are available upon request to the corresponding author. REFERENCES 1. American Academy of Pediatrics. The assessment and management of acute pain in infants, children, and adolescents. Pediatrics. 2001;108(3):793–7. 10.1542/peds.108.3.793 [ DOI ] [ PubMed ] [ Google Scholar ] 2. Craig KD, Shriver A. Ethics of pain management in infants and older children. In: Stevens BJ, Hathway G, Zempsky WT, eds. Oxford Textbook of Pediatric Pain (2nd Ed): Oxford University Press; 2021. [ Google Scholar ] 3. Eccleston C, Fisher E, Howard RF, et al. Delivering transformative action in paediatric pain: a Lancet Child & Adolescent Health Commission. Lancet Child Adolesc Health. 2021;5(1):47–87. 10.1016/s2352-4642(20)30277-7 [ DOI ] [ PubMed ] [ Google Scholar ] 4. Taylor EM, Boyer K, Campbell FA. Pain in hospitalized children: a prospective cross-sectional survey of pain prevalence, intensity, assessment and management in a Canadian pediatric teaching hospital. Pain Res Manag 2008;13(1):25–32. 10.1155/2008/478102 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Alexander J, Manno M. Underuse of analgesia in very young pediatric patients with isolated painful injuries. Ann Emerg Med. 2003;41(5):617–22. 10.1067/mem.2003.138 [ DOI ] [ PubMed ] [ Google Scholar ] 6. Dong L, Donaldson A, Metzger R, Keenan H. Analgesic administration in the emergency department for children requiring hospitalization for long-bone fracture. Pediatr Emerg Care. 2012;28(2):109–14. 10.1097/PEC.0b013e3182442c25 [ DOI ] [ PubMed ] [ Google Scholar ] 7. Anand KJS, Eriksson M, Boyle EM, et al. Assessment of continuous pain in newborns admitted to NICUs in 18 European countries. Acta Paediatr. 2017;106(8):1248–59. 10.1111/apa.13810 [ DOI ] [ PubMed ] [ Google Scholar ] 8. Melchior M, Kuhn P, Poisbeau P. The burden of early life stress on the nociceptive system development and pain responses. Eur J Neurosci. 2022;55(9–10):2216–41. 10.1111/ejn.15153 [ DOI ] [ PubMed ] [ Google Scholar ] 9. Hermann C, Hohmeister J, Demirakca S, Katrin Z, Herta F. Long-term alternation of pain sensitivity in school-aged children with early pain experiences. Pain. 2006;125(5):278–85. [ DOI ] [ PubMed ] [ Google Scholar ] 10. Wollgarten-Hadamek I, Hohmeister J, Demirakça S, Zohsel K, Flor H, Hermann C. Do burn injuries during infancy affect pain and sensory sensitivity in later childhood? Pain. 2009;141(1–2):165–72. 10.1016/j.pain.2008.11.008 [ DOI ] [ PubMed ] [ Google Scholar ] 11. Grunau RE. Neonatal pain in very preterm infants: long-term effects on brain, neurodevelopment and pain reactivity. Rambam Maimonides Med J 2013;4(4):e0025. 10.5041/rmmj.10132 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 12. Walker SM, Franck LS, Fitzgerald M, Myles J, Stocks J, Marlow N. Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm. Pain. 2009;141(1–2):79–87. 10.1016/j.pain.2008.10.012 [ DOI ] [ PubMed ] [ Google Scholar ] 13. Ranger M, Grunau RE. Early repetitive pain in preterm infants in relation to the developing brain. Pain Manag. 2014;4(1):57–67. 10.2217/pmt.13.61 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 14. Cook KM, De Asis-Cruz J, Kim J-H, et al. Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits. BMC Medicine. 2023;21(1):435. 10.1186/s12916-023-03141-w [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 15. Doesburg SM, Chau CM, Cheung TPL, et al. Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age. Pain. 2013;154(10):1946–52. 10.1016/j.pain.2013.04.009 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 16. Duerden EG, Grunau RE, Guo T, et al. Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates. J Neurosci. 2018;38(4):878–86. 10.1523/jneurosci.0867-17.2017 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 17. Giordano V, Deindl P, Gal E, et al. Pain and neurodevelopmental outcomes of infants born very preterm. Dev Med Child Neurol. 2023;65(8):1043–52. 10.1111/dmcn.15505 [ DOI ] [ PubMed ] [ Google Scholar ] 18. Ranger M, Zwicker JG, Chau CM, et al. Neonatal Pain and Infection Relate to Smaller Cerebellum in Very Preterm Children at School Age. J Pediatr. 2015;167(2):292–8.e1. 10.1016/j.jpeds.2015.04.055 [ DOI ] [ PubMed ] [ Google Scholar ] 19. Vinall J, Miller SP, Bjornson BH, et al. Invasive procedures in preterm children: brain and cognitive development at school age. Pediatrics. 2014;133(3):412–21. 10.1542/peds.2013-1863 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 20. Hohmeister J, Demirakça S, Zohsel K, Flor H, Hermann C. Responses to pain in school-aged children with experience in a neonatal intensive care unit: cognitive aspects and maternal influences. Eur J Pain. 2009;13(1):94–101. 10.1016/j.ejpain.2008.03.004 [ DOI ] [ PubMed ] [ Google Scholar ] 21. McLean MA, Scoten OC, Chau CMY, Synnes A, Miller SP, Grunau RE. Association of Neonatal Pain-Related Stress and Parent Interaction With Internalizing Behaviors Across 1.5, 3.0, 4.5, and 8.0 Years in Children Born Very Preterm. JAMA Network Open. 2022;5(10):e2238088-e. 10.1001/jamanetworkopen.2022.38088 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 22. Ranger M, Synnes AR, Vinall J, Grunau RE. Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure. Eur J Pain. 2014;18(6):844–52. 10.1002/j.1532-2149.2013.00431.x [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 23. Valeri BO, Holsti L, Linhares MB. Neonatal pain and developmental outcomes in children born preterm: a systematic review. Clin J Pain. 2015;31(4):355–62. 10.1097/ajp.0000000000000114 [ DOI ] [ PubMed ] [ Google Scholar ] 24. Jones GT, Power C, Macfarlane GJ. Adverse events in childhood and chronic widespreadpain in adult life: Results from the 1958 British Birth Cohort Study. Pain. 2009;143(1–2):92–6. [ DOI ] [ PubMed ] [ Google Scholar ] 25. Schwaller F, Fitzgerald M. The consequences of pain in early life: injury-induced plasticity in developing pain pathways. Eur J Neurosci. 2014;39(3):344–52. 10.1111/ejn.12414 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 26. Walco GA, Cassidy RC, Schechter NL. Pain, hurt, and harm. The ethics of pain control in infants and children. N Engl J Med. 1994;331(8):541–4. 10.1056/nejm199408253310812 [ DOI ] [ PubMed ] [ Google Scholar ] 27. Bapat R, Duran M, Piazza A, et al. A Multicenter Collaborative to Improve Postoperative Pain Management in the NICU. Pediatrics. 2023;152(2). 10.1542/peds.2022-059860 [ DOI ] [ PubMed ] [ Google Scholar ] 28. Chan JY, von Baeyer CL. Cognitive developmental influences on the ability of preschool-aged children to self-report their pain intensity. Pain. 2016;157(5):997–1001. 10.1097/j.pain.0000000000000476 [ DOI ] [ PubMed ] [ Google Scholar ] 29. von Baeyer CL, Jaaniste T, Vo HLT, Brunsdon G, Lao HC, Champion GD. Systematic Review of Self-Report Measures of Pain Intensity in 3- and 4-Year-Old Children: Bridging a Period of Rapid Cognitive Development. J Pain 2017;18(9):1017–26. 10.1016/j.jpain.2017.03.005 [ DOI ] [ PubMed ] [ Google Scholar ] 30. Beltramini A, Milojevic K, Pateron D. Pain Assessment in Newborns, Infants, and Children. Pediatr Ann 2017;46(10):e387–e95. 10.3928/19382359-20170921-03 [ DOI ] [ PubMed ] [ Google Scholar ] 31. Berde CB, Walco GA, Krane EJ, et al. Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop. Pediatrics. 2012;129(2):354–64. 10.1542/peds.2010-3591 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 32. Cohen LL, Lemanek K, Blount RL, et al. Evidence-based assessment of pediatric pain. J Pediatr Psychol. 2008;33(9):939–55; discussion 56-7. 10.1093/jpepsy/jsm103 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 33. Giordano V, Edobor J, Deindl P, et al. Pain and Sedation Scales for Neonatal and Pediatric Patients in a Preverbal Stage of Development: A Systematic Review. JAMA Pediatr. 2019;173(12):1186–97. 10.1001/jamapediatrics.2019.3351 [ DOI ] [ PubMed ] [ Google Scholar ] 34. McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain. 2008;9(9):771–83. 10.1016/j.jpain.2008.04.007 [ DOI ] [ PubMed ] [ Google Scholar ] 35. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997;23(3):293–7. [ PubMed ] [ Google Scholar ] 36. de Jong AE, Bremer M, Schouten M, Tuinebreijer WE, Faber AW. Reliability and validity of the pain observation scale for young children and the visual analogue scale in children with burns. Burns. 2005;31(2):198–204. 10.1016/j.burns.2004.09.013 [ DOI ] [ PubMed ] [ Google Scholar ] 37. Uitti JM, Salantera S, Laine MK, Tahtinen PA, Ruohola A. Adaptation of pain scales for parent observation: are pain scales and symptoms useful in detecting pain of young children with the suspicion of acute otitis media? BMC Pediatr. 2018;18(1):392. 10.1186/s12887-018-1361-y [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 38. Wilson GA, Doyle E. Validation of three paediatric pain scores for use by parents. Anaesthesia. 1996;51(11):1005–7. 10.1111/j.1365-2044.1996.tb14991.x [ DOI ] [ PubMed ] [ Google Scholar ] 39. Food and Drug Administration. FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making. Published June 16, 2020. Accessed April 2, 2025. https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical . [ Google Scholar ] 40. Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L. Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report. Value Health 2017;20(7):838–55. 10.1016/j.jval.2017.05.015 [ DOI ] [ PubMed ] [ Google Scholar ] 41. Chambers CT, Finley AG, McGrath PJ, Walsh TM. The parents’ postoperative pain measure: replication and extension to 2–6-year-old children. Pain. 2003;105(3):437–43. 10.1016/s0304-3959(03)00256-2 [ DOI ] [ PubMed ] [ Google Scholar ] 42. Kappesser J, de Laffolie J, Faas D, Ehrhardt H, Hermann C. Comparison of two neonatal pain assessment tools (Children and Infant’s Postoperative Pain Scale and the Neonatal Facial Coding System-Revised) and their relations to clinicians’ intuitive pain estimates. Eur J Pain 2019;23(4):708–18. 10.1002/ejp.1338 [ DOI ] [ PubMed ] [ Google Scholar ] 43. Pillai Riddell RR, Horton RE, Hillgrove J, Craig KD. Understanding caregiver judgments of infant pain: contrasts of parents, nurses and pediatricians. Pain Res Manag 2008;13(6):489–96. 10.1155/2008/694745 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 44. Boyle EM, Bradshaw J, Blake KI. Persistent pain in neonates: challenges in assessment without the aid of a clinical tool. Acta Paediatr. 2018;107(1):63–7. 10.1111/apa.14081 [ DOI ] [ PubMed ] [ Google Scholar ] 45. Xavier Balda R, Guinsburg R, de Almeida MF, Peres C, Miyoshi MH, Kopelman BI. The recognition of facial expression of pain in full-term newborns by parents and health professionals. Arch Pediatr Adolesc Med. 2000;154(10):1009–16. 10.1001/archpedi.154.10.1009 [ DOI ] [ PubMed ] [ Google Scholar ] 46. Pillai Riddell RR, Badali MA, Craig KD. Parental judgements of infant pain: importance of perceived cognitive abilities, behavioural cues and contextual cues. Pain Res Manag 2004;9(2):73–80. 10.1155/2004/150463 [ DOI ] [ PubMed ] [ Google Scholar ] 47. Bueno M, Eriksson M, Stevens BJ. Neonatal and infant pain assessment. In: Stevens BJ, Hathway G, Zempsky WT, eds. Oxford Textbook of Pediatric Pain (2nd Ed): Oxford University Press: 2021. [ Google Scholar ] 48. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–82. 10.1097/j.pain.0000000000001939 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 49. Pillai Riddell RR, Jasim S, Hamwi L. Out of the mouth of babes: a lot about pain has nothing to do with pain. Pain. 2022;163(Suppl 1):S117–s25. 10.1097/j.pain.0000000000002761 [ DOI ] [ PubMed ] [ Google Scholar ] 50. Saunders B, Sim J, Kingstone T, et al. Saturation in qualitative research: exploring its conceptualization and operationalization. Qual Quant. 2018;52(4):1893–907. 10.1007/s11135-017-0574-8 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 51. Dhakal K NVivo. J Med Libr Assoc. 2022;110(2):270–2. 10.5195/jmla.2022.1271 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 52. Bozzette M Observation of pain behavior in the NICU: an exploratory study. J Perinat Neonatal Nurs. 1993;7(1):76–87. 10.1097/00005237-199306000-00010 [ DOI ] [ PubMed ] [ Google Scholar ] 53. Warnock F, Sandrin D. Comprehensive description of newborn distress behavior in response to acute pain (newborn male circumcision). Pain. 2004;107(3):242–55. 10.1016/j.pain.2003.11.006 [ DOI ] [ PubMed ] [ Google Scholar ] 54. Mills NM. Pain behaviors in infants and toddlers. J Pain Symptom Manage. 1989;4(4):184–90. 10.1016/0885-3924(89)90041-9 [ DOI ] [ PubMed ] [ Google Scholar ] 55. Tait AR, Voepel-Lewis T, Munro HM, Malviya S. Parents’ preferences for participation in decisions made regarding their child’s anaesthetic care. Paediatr Anaesth. 2001;11(3):283–90. 10.1046/j.1460-9592.2001.00651.x [ DOI ] [ PubMed ] [ Google Scholar ] 56. Franck LS, Oulton K, Nderitu S, Lim M, Fang S, Kaiser A. Parent involvement in pain management for NICU infants: a randomized controlled trial. Pediatrics. 2011;128(3):510–8. 10.1542/peds.2011-0272 [ DOI ] [ PubMed ] [ Google Scholar ] 57. MacKenzie NE, Tutelman PR, Chambers CT, et al. Can sharing improve caring? A call to prioritize shared decision making in pediatric pain management. Clinical Practice in Pediatric Psychology. 2023;11(3):253–61. 10.1037/cpp0000488 [ DOI ] [ Google Scholar ] 58. Chambers CT, Reid GJ, McGrath PJ, Finley GA. Development and preliminary validation of a postoperative pain measure for parents. Pain. 1996;68(2–3):307–13. 10.1016/s0304-3959(96)03209-5 [ DOI ] [ PubMed ] [ Google Scholar ] 59. Merkel S, Voepel-Lewis T, Malviya S. Pain assessment in infants and young children: the FLACC scale. Am J Nurs. 2002;102(10):55–8. 10.1097/00000446-200210000-00024 [ DOI ] [ PubMed ] [ Google Scholar ] 60. Ottosson C, Lantz B. Parental participation in neonatal care. Journal of Neonatal Nursing. 2017;23:112–8. [ Google Scholar ] 61. Wolff N, Darlington AS, Hunfeld J, et al. Determinants of somatic complaints in 18-month-old children: the generation R study. J Pediatr Psychol. 2010;35(3):306–16. 10.1093/jpepsy/jsp058 [ DOI ] [ PubMed ] [ Google Scholar ] 62. Palermo TM, Valrie CR, Karlson CW. Family and parent influences on pediatric chronic pain: a developmental perspective. Am Psychol. 2014;69(2):142–52. 10.1037/a0035216 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 63. Lee H, Lamb SE, Bagg MK, Toomey E, Cashin AG, Moseley GL. Reproducible and replicable pain research: a critical review. Pain. 2018;159(9):1683–9. 10.1097/j.pain.0000000000001254 [ DOI ] [ PubMed ] [ Google Scholar ] 64. Patrick DL, Burke LB, Gwaltney CJ, et al. Content validity—establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: part 1—eliciting concepts for a new PRO instrument. Value Health 2011;14(8):967–77. 10.1016/j.jval.2011.06.014 [ DOI ] [ PubMed ] [ Google Scholar ] 65. Food and Drug Administration. CDER Pilot Grant Program: Standard Core Clinical Outcome Assessments (COAs) and their Related Endpoints Published April 29, 2021. Accessed March 27, 2025. https://www.fda.gov/drugs/development-approval-process-drugs/cder-pilot-grant-program-standard-core-clinical-outcome-assessments-coas-and-their-related-endpoints . [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials 1 NIHMS2090817-supplement-1.docx (28.7KB, docx) Data Availability Statement Summary reports are available upon request to the corresponding author. 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