https://orcid.org/0000-0003-1863-5584
Figures
Abstract
Background
Access to adequate pain treatment is a fundamental right, yet international data suggest that a considerable number of children experience acute and persistent pain. Little is known about the occurrence of both acute and persistent pain in children. The incidence of persistent postoperative pain in children is an unexplored area but international studies suggest that many children experience long-term pain after surgery, with a major impact on daily life. In 4P, Persistent Postoperative Pediatric Pain, we want to estimate the incidence of acute and persistent postoperative pediatric pain. The European Society for Paediatric Anaesthesiology has developed guidelines for perioperative pain management. We aim to examine how well these guidelines are followed and whether adherence to guidelines influences the pain experienced after surgery.
Method
4P is a prospective observational study of children aged 1–17, planned for surgery in southern Sweden 2023–2024. After agreement from all caregivers, data concerning preoperative pain, pre-emptive analgesia, perioperative management and postoperative pain will be collected. Via an electronic management software, pain will be evaluated at home (or in hospital) at 24h, 3, 6 and 12 months after surgery. We will include 1000 patients.
Discussion
4P will prospectively follow a large number of children after general pediatric surgeries and evaluate the occurrence of postoperative pain, both acute (APOP) and persistent (PPOP). The study will assess pain treatment regimens and identify risk factors associated with the development of acute and persistent pediatric postoperative pain.
Citation: Broman J, Nielsen N, Persson AKM (2025) A prospective observational study on persistent postoperative pediatric pain, 4P: The study protocol. PLoS ONE 20(1): e0316533. https://doi.org/10.1371/journal.pone.0316533
Editor: Frances Chung, University of Toronto, CANADA
Received: September 13, 2024; Accepted: December 12, 2024; Published: January 14, 2025
Copyright: © 2025 Broman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.
Funding: JB has recieved grants from Stig and Ragna Gorthon Foundation Helsingborg AP has recieved grants from The Scientific council of Southern Sweden, Lund University, the Research and Educational fund in Halland County and Region Halland. https://www.gorthonstiftelsen.se https://www.vr.se/english.html https://www.lunduniversity.lu.se https://www.hh.se https://www.regionhalland.se The funders did not play any role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Despite the fact that the Montreal Declaration from 2010 as well as the Swedish Convention on the Rights of the Child (Swedish law since January 1, 2020) establish that "access to adequate pain treatment is a fundamental right", it is estimated that 80% of the world’s population is affected by inadequate pain management, and children are a particularly vulnerable group [1]. According to international data a considerable number of children (approximately 15 to 25%) experience persistent pain and this can, in addition to causing great personal suffering with non-attendance in school and social isolation, also entail a significant public health problem [2, 3]. 24–27% of children admitted to hospital suffer from moderate to severe pain, with the majority related to surgery [4, 5].
In adults, the prevalence of persistent postoperative pain (PPOP) ranges from 5 to 50% [3, 6] and in children it has been suggested to be around 20%, [6] but reliable data is missing [7]. There are a few studies suggesting the incidence of PPOP in children to be around 10–20%. In a retrospective study looking at children after cardiac surgery, with a median follow up of 3.8 years, 21% experienced persistent pain and in 10% the pain was moderate to severe (>4.0 NRS (Numeric Rating Scale, used to assess pain severity using a 0–10 scale, with zero meaning “no pain” and 10 meaning “the worst pain imaginable”)) [8]. In a cross-sectional study, a structured telephone interview was carried out including children between the ages of two and 17 years who had undergone general, urologic or orthopedic surgery in the preceding ten months. Fifteen (13%) of 113 children reported current pain related to the surgery. The average intensity of pain was 4.2 on an NRS (0–10), and in most children the pain had some interference with daily activities [9]. Two studies on children at three and six months after orthopedic and general surgery showed, in 10.9% and 23% respectively, that the children experienced pain greater than 3 on the NRS [10, 11]. A meta-analysis from 2017 by Rabbitts et al. found only four studies reporting the prevalence of PPOP and with pain assessed at different time-points. They concluded the prevalence to be around 20% in mixed surgery [6] and summarized that further studies on this topic were urgently needed. Since 2017, we have found no prospective studies on the incidence of acute or persistent postoperative pain in children. Thus, the prevalence is uncertain.
It is known that children who develop long-term pain are at greater risk of suffering from pain-related problems than adults [6]. Surgery is a potential trigger for pain and is an important aspect to address [3]. A majority of adult patients undergoing surgery experience postoperative pain and inevitably surgery is sometimes necessary also in childhood. In addition, pain treatment after pediatric surgery is particularly challenging since each child is unique concerning age, development, and size and the optimal dose of analgesics can differ greatly from child to child. Results from studies in different countries show that pain treatment of children often is inadequate [12–14].
In adults the most important risk factors for postoperative pain, both acute and persistent, are age, female gender, pain before surgery [15], and psychosocial factors [16]. Concerning childhood pain, gender differences have been reported when it comes to headache and stomach pain, where girls tend to have more pain than boys [2]. Clinical studies on postoperative pain are consistent with this, suggesting that acute and persistent postoperative pain tend to be more prevalent in girls than boys [17]. Concerning age, some studies suggest that low age is associated with lower risk of PPOP [3, 12], yet other studies find that younger ages do not protect against PPOP after adjusting for confounding variables [11]. Larger studies are lacking. There are also implications of the influence of psychological factors. Children are highly dependent and influenced by the behavior of their caregivers. One potential risk factor is an increased level of parental anxiety related to their child’s surgery [18]. Parental catastrophizing scores have also been shown to influence, like parental mental health and chronic pain [7, 19]. Studies suggest that the parental influence on the pain response of the child increases as time from surgery passes [7].
The European Society for Paediatric Anaesthesiology (ESPA) has published guidelines for perioperative pain management in various common surgical procedures and interventions in children. These guidelines are in accordance with the WHO Pain Relief Ladder and created with the aim to improve perioperative analgesia for children in Europe [1]. Pain treatment guidelines are not always followed in clinical practice for various reasons. One example is that many pediatric clinics do not use regional anesthesia techniques to the same extent as in the adult population, even though it has been proven safe and effective [5].
The aim of the 4P study is to estimate the incidence of acute and persistent postoperative pain in children, identify risk factors for developing acute and persistent postoperative pediatric pain, and to investigate adherence to the European perioperative guidelines for pain management in children.
Materials and methods
General design
4P is a prospective observational study, designed in accordance with STROBE guidelines. Recruitment period of the study is Sept 1st, 2023, to December 31st, 2024 (Fig 1).
Abbreviations: APOP = Acute postoperative pain: PPOP = Persistent postoperative pain.
Research ethics approval
This study was ethically approved by the the Swedish Ethics Review Authority on 1st of Dec 2022 with identification number: Dnr 2022–04821. The research protocol has also been preregistered at clinicaltrials.gov under the record NCT06035042.
Study setting
Children aged 1–17 years planned for surgery in southern Sweden (hospitals of Kristianstad, Trelleborg, Ystad, Malmö, Lund, Helsingborg, Ängelholm, Växjö, Halmstad, Gothenburg) will be included. This is a representation of hospitals of different sizes and settings, including university hospitals (Gothenburg, Lund and Malmö) with pediatric anesthesia units.
Eligibility criteria
Inclusion criteria: age 1–17 years, planned for surgery in one of ESPA defined pediatric surgical procedures; inguinal hernia, circumcision/hypospadias/cryptorchidism, adenoidectomy/tonsillectomy/tonsillotomy, appendectomy, orthopedic acute fracture surgery.
Exclusion criteria: repeated surgery, inability of child or caregiver to speak/read Swedish, inability of child/caregiver to understand the implication of participation.
Patient information and consent
Patients (15 years or older) or caregivers (if <15 years old) will be informed in writing a few days before surgery, and in person upon arrival to the hospital. Written and oral consent will be mandatory. In patients <15 years old we will seek acceptance from both caregivers in order to continue inclusion as demanded by the Swedish Ethical Review Authority.
Study timeline
The timeline for the 4P-study protocol is depicted in Fig 2.
Abbreviations: eCRF = electronic case report form; APOP = acute postoperative pain; PPOP = persistent postoperative pain; PACU = post anesthesia care unit.
Measurement and definition of pain
Throughout this study, we will evaluate pain with different scales depending on age:
Age 1–3: FLACC (Face/Legs/Activity/Cry/Consolability Pain scale) Score range 0–10 [20]
Age 4–14: FPS-Revised (The Faces Pain Scale–Revised) Score range 0–10 [21]
Age 15–18: NRS (Numeric rating scale) Score range 0–10 [22]
Higher values indicate more pain, with zero meaning “no pain”.
In statistical analyses we will compare levels (0–10) independent of scale.
We will evaluate preoperative pain via a questionnaire sent to the patient prior to surgery and ask if the child has experienced recurrent pain before surgery (yes/no) and level of pain (using FLACC, FPS or NRS (0–10)), and if yes, for how long and whether or not this has influenced normal activities. We will also ask if the child has experienced pain 24 hours prior to surgery (yes/no) and note whether analgesics were offered.
We will evaluate acute postoperative pain in the postoperative care unit (PACU), where pain will be measured repeatedly by nursing staff using FLACC, FPS and NRS (0–10). The worst pain measured during the visit will be registered and used for analysis. For secondary outcomes a cut-off for moderate- to severe acute postoperative pain, APOP, is set to 4.0 (FLACC, FPS or NRS).
Twenty-four hours after surgery, we will evaluate pain with a questionnaire where the patient/caregiver is asked to note the worst pain experienced since they left the PACU (FLACC, FPS, NRS (0–10)).
We will evaluate persistent postoperative pain at three months, six months and one year post surgery with a questionnaire where patients/caregivers are asked to note present pain (FLACC, FPS, NRS (0–10)). PPOP is set to 1 (FLACC, FPS or NRS) or higher and moderate to severe PPOP is defined as pain ≥ 4 [6, 8] but the existence will be accompanied with a description of level.
Evaluation of potential risk factors
We will register gender and age, allowing for a comparison of groups.
We will evaluate sleep quality and anxiety via a questionnaire sent to the patient prior to surgery, asking if the child experienced problems before surgery, and if yes, for how long and whether or not it influenced normal activities.
We will register the level of parental stress (1–10) at 24 hours, three and six months and one year after surgery.
Study outcomes
The primary outcome is the incidence of acute postoperative pain in children.
Secondary outcomes are adherence to guidelines from ESPA regarding perioperative analgesia, incidence of persistent postoperative pain, the influence of regional blocks on APOP and PPOP, the influence of parental stress, age and gender on APOP and PPOP, and the association of the choice of pain treatment (premedication/long vs short acting opioid/paracetamol/NSAID/ketamine/local anesthetics/betamethasone) on APOP and PPOP (Fig 1).
Sample size
We will screen all patients meeting the inclusion criteria at the participating hospitals between September 2023 –December 2024 for study eligibility.
The primary outcome in 4P is descriptive and hypothesis generating, therefore we have elected not to perform a power calculation. Previous studies [6] give us reason to believe that 20% of the patients will experience PPOP and possibly APOP and thus 1000 children included will allow for analysis of risk factors.
Data management
We will use the data management software Entermedic (Entergate ®, Halmstad Sweden) where patient data and contact information are stored. We will keep an electronic chart for each patient included in the platform Entermedic. The primary investigator will register information regarding drugs used during anesthesia in Entermedic, as well as APOP in the PACU. The patient/caregiver will register acute postoperative pain between 1.5 and 24 hours after surgery, and PPOP after three and six months and one year in the eCRF (Entermedic). We have programmed the software to send out reminder text messages with a narrow interval, avoiding inaccurate data. When all data points are complete, the system stops sending out text reminders. As a back-up, investigators check for potential incomplete data regularly.
Entermedic is specifically designed for simplicity and security regarding data management. Ethical approval from the Swedish Ethical Review Authority is mandatory when using the service. Entergate® has their servers in Sweden and do not outsource data for any reason. Entermedic is also certified with the international standard regarding security standard (ISO 27000:1) and completely adapted to the European Union’s demands on General Data Protection Regulation (GDPR). The service is also adapted to fit Swedish law for patient data reporting, holding and management (Department of social affairs number 2008:335, 2010:659 and 1985:562). Furthermore, Entermedic is also approved by the Swedish Medical Products Agency.
Status of study
We included the first patient Sept 1st, 2023. By Aug. 1st 2024 we have 959 registered eligible and 380 included patients.
Statistical methods
We will present the incidence of APOP and PPOP at different timepoints as percent with confidence intervals in tables. We will present the distribution of age, gender and type of surgery in tables. We will also present mean APOP and PPOP in different age-groups. The time frame is acute—within 24 hours (APOP) and at three and six months and one year after surgery (PPOP).
Adherence to ESPA guidelines: We will present how well the guidelines are followed in a qualitative description using percentages and confidence intervals. We will compare the groups (Yes: guidelines followed/No: guidelines not followed) concerning APOP and PPOP with Mann Whitney, U-test and description of the deviation. The time frame is perioperative, within 24 hours (APOP) and at three and six months and one year after surgery (PPOP).
Influence of regional blocks on APOP and PPOP: we will compare groups with Mann Whitney, U-test. The time frame is acute–within 24 hours (APOP) and at three months after surgery (PPOP).
We will evaluate risk factor analysis regarding parental stress, age and gender with logistic regression. The time frame is acute—within 24 hours (APOP) and at three and six months and one year after surgery (PPOP). To investigate whether children who experience APOP (≥4.0) have increased risk of PPOP (3 months) we will use logistic regression.
We will investigate the effect of preemptive analgesia, choice of perioperative opioid given during TIVA (Alfentanil, Remifentanil), and method of anesthesia (volatile compared to total intravenous) on APOP. Group comparison of APOP in PACU and at 24 h with Mann Whitney.
Monitoring
This study is strictly observational and hence has no appointed Data Monitoring Committee (DMC) and no interim analysis are planned.
Protocol amendments
New approval will be sought out for any amendments (eligibility criteria, allocation, intervention protocol).
Discussion
There are a variety of strengths in our study. 4P is a multicenter study, with different characteristics of the participating hospitals, providing a broad picture of the pediatric anesthesia being conducted in southern Sweden. All registration forms are filled out electronically directly following patient contact or by the patient or caregiver directly, hence allowing an accurate and current observation. We use pain scales adjusted for age, all on a numerical scale 1–10 which allows for comparison of groups.
At the same time, it should be noted that several limitations may exist. Persistent postoperative pain (PPOP) is defined as pain lasting more than three months after surgery. The actual value used for defining existing PPOP differs in different studies, making comparison of results difficult [3, 8, 9, 11, 23] and no international consensus has yet been met [24]. We have chosen to use any pain after 3 months, in other words pain level ≥ 1 with the respective scale depending on age of the child but also to describe the level at the respective timepoint.
The centers involved are diverse, which may lead to a bias when it comes to inclusion and type of surgery. All hospitals anesthetize children from the age of one. At the more rural sites the primary surgery type will be ear nose throat surgery, and we suspect that they will represent a large bulk of the patients. This is also a type of surgery where we have widespread national guidelines on perioperative treatment [25, 26]. The University hospitals (Gothenburg, Lund and Malmö) handle the younger children, as well as the most critically ill. Some types of surgery will primarily be performed at these centers, namely inguinal hernia, circumcision/hypospadias/cryptorchidism. Appendectomies and fracture surgery will be performed at all sites.
According to the Swedish Ethics Review Authority it is mandatory for both caregivers, if there are more than one, to leave written consent in advance. This makes the process of inclusion time-consuming, and we suspect we might fail to include a proportion of patients due to this, thus risking confounding due to many missed to include.
In summary, with this prospective observational study we aim to estimate the incidence of acute and persistent postoperative pain in a pediatric population in Sweden, illustrate what pain treatment is commonly used and hopefully identify factors possible to improve. This important topic is poorly covered and there is a significant knowledge gap.
Acknowledgments
To everyone involved in 4P at the hospitals of Kristianstad, Trelleborg, Ystad, Malmö, Lund, Helsingborg, Ängelholm, Växjö, Halmstad, Göteborg. Thank you for your enthusiasm, time and engagement. Thank you, Stefan Lundeberg, for your support and inspiration.
References
- 1. Vittinghoff M, Lonnqvist PA, Mossetti V, Heschl S, Simic D, Colovic V, et al. Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative). Paediatr Anaesth. 2018;28(6):493–506. Epub 2018/04/11. pmid:29635764.
- 2. King S, Chambers CT, Huguet A, MacNevin RC, McGrath PJ, Parker L, et al. The epidemiology of chronic pain in children and adolescents revisited: a systematic review. Pain. 2011;152(12):2729–38. Epub 2011/11/15. pmid:22078064.
- 3. Sieberg CB, Simons LE, Edelstein MR, DeAngelis MR, Pielech M, Sethna N, et al. Pain prevalence and trajectories following pediatric spinal fusion surgery. J Pain. 2013;14(12):1694–702. Epub 2013/12/03. pmid:24290449; PubMed Central PMCID: PMC3873090.
- 4. Walther-Larsen S, Pedersen MT, Friis SM, Aagaard GB, Romsing J, Jeppesen EM, et al. Pain prevalence in hospitalized children: a prospective cross-sectional survey in four Danish university hospitals. Acta Anaesthesiol Scand. 2017;61(3):328–37. Epub 2016/12/30. pmid:28032329.
- 5. Groenewald CB, Rabbitts JA, Schroeder DR, Harrison TE. Prevalence of moderate-severe pain in hospitalized children. Paediatr Anaesth. 2012;22(7):661–8. Epub 2012/02/16. pmid:22332912.
- 6. Rabbitts JA, Fisher E, Rosenbloom BN, Palermo TM. Prevalence and Predictors of Chronic Postsurgical Pain in Children: A Systematic Review and Meta-Analysis. J Pain. 2017;18(6):605–14. Epub 2017/04/02. pmid:28363861; PubMed Central PMCID: PMC5457338.
- 7. Page MG, Campbell F, Isaac L, Stinson J, Katz J. Parental risk factors for the development of pediatric acute and chronic postsurgical pain: a longitudinal study. Journal of pain research. 2013;6:727–41. Epub 2013/10/11. pmid:24109194; PubMed Central PMCID: PMC3792832.
- 8. Lauridsen MH, Kristensen AD, Hjortdal VE, Jensen TS, Nikolajsen L. Chronic pain in children after cardiac surgery via sternotomy. Cardiol Young. 2014;24(5):893–9. Epub 2013/09/21. pmid:24044632.
- 9. Fortier MA, Chou J, Maurer EL, Kain ZN. Acute to chronic postoperative pain in children: preliminary findings. Journal of pediatric surgery. 2011;46(9):1700–5. Epub 2011/09/21. pmid:21929977.
- 10. Page MG, Stinson J, Campbell F, Isaac L, Katz J. Identification of pain-related psychological risk factors for the development and maintenance of pediatric chronic postsurgical pain. Journal of pain research. 2013;6:167–80. Epub 2013/03/19. pmid:23503375; PubMed Central PMCID: PMC3594915.
- 11. Batoz H, Semjen F, Bordes-Demolis M, Benard A, Nouette-Gaulain K. Chronic postsurgical pain in children: prevalence and risk factors. A prospective observational study. Br J Anaesth. 2016;117(4):489–96. Epub 2017/01/13. pmid:28077537.
- 12. Alm F, Stalfors J, Nerfeldt P, Ericsson E. Patient reported pain-related outcome measures after tonsil surgery: an analysis of 32,225 children from the National Tonsil Surgery Register in Sweden 2009–2016. Eur Arch Otorhinolaryngol. 2017;274(10):3711–22. Epub 2017/08/18. pmid:28815308; PubMed Central PMCID: PMC5591799.
- 13. Ferland CE, Vega E, Ingelmo PM. Acute pain management in children: challenges and recent improvements. Curr Opin Anaesthesiol. 2018;31(3):327–32. Epub 2018/02/13. pmid:29432292.
- 14. Smeland AH, Rustoen T, Naess T, Nybro L, Lundeberg S, Reinertsen H, et al. Children’s views on postsurgical pain in recovery units in Norway: A qualitative study. J Clin Nurs. 2019;28(11–12):2157–70. Epub 2019/01/23. pmid:30667569.
- 15. Gerbershagen HJ, Pogatzki-Zahn E, Aduckathil S, Peelen LM, Kappen TH, van Wijck AJ, et al. Procedure-specific risk factor analysis for the development of severe postoperative pain. Anesthesiology. 2014;120(5):1237–45. pmid:24356102.
- 16. Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: a systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain. 2012;28(9):819–41. pmid:22760489.
- 17. Page MG, Stinson J, Campbell F, Isaac L, Katz J. Pain-related psychological correlates of pediatric acute post-surgical pain. Journal of pain research. 2012;5:547–58. Epub 2012/12/04. pmid:23204864; PubMed Central PMCID: PMC3508661.
- 18. Chow CHT, Schmidt LA, Buckley DN. The role of anxiety and related states in pediatric postsurgical pain. Can J Pain. 2020;4(4):26–36. Epub 2021/05/15. pmid:33987517; PubMed Central PMCID: PMC7942768.
- 19. Beveridge JK, Noel M, Soltani S, Neville A, Orr SL, Madigan S, et al. The association between parent mental health and pediatric chronic pain: a systematic review and meta-analysis. Pain. 2023. Epub 2023/12/19. pmid:38112571.
- 20. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs. 2003;29(2):140–6. Epub 2003/05/02. pmid:12723828.
- 21. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain. 2001;93(2):173–83. Epub 2001/06/28. pmid:11427329.
- 22. von Baeyer CL, Spagrud LJ, McCormick JC, Choo E, Neville K, Connelly MA. Three new datasets supporting use of the Numerical Rating Scale (NRS-11) for children’s self-reports of pain intensity. Pain. 2009;143(3):223–7. Epub 2009/04/11. pmid:19359097.
- 23. Nikolajsen L, Brix LD. Chronic pain after surgery in children. Curr Opin Anaesthesiol. 2014;27(5):507–12. Epub 2014/07/23. pmid:25051264.
- 24. VanDenKerkhof EG, Peters ML, Bruce J. Chronic pain after surgery: time for standardization? A framework to establish core risk factor and outcome domains for epidemiological studies. Clin J Pain. 2013;29(1):2–8. Epub 2012/12/06. pmid:23211602.
- 25. Alm F, Jaensson M, Lundeberg S, Ericsson E. Adherence to Swedish guidelines for pain treatment in relation to pediatric tonsil surgery: A survey of the multidisciplinary team. Int J Pediatr Otorhinolaryngol. 2017;101:123–31. Epub 2017/10/02. pmid:28964282.
- 26. Ericsson E, Brattwall M, Lundeberg S. Swedish guidelines for the treatment of pain in tonsil surgery in pediatric patients up to 18 years. Int J Pediatr Otorhinolaryngol. 2015;79(4):443–50. Epub 2015/02/14. pmid:25677565.