Experiencing pain at any point in our lives causes significant distress to not just the patient but also to their families and caregivers. Effective management of pain is the focus of considerable clinical effort be that for the alleviation of acute procedural pain (eg, postsurgical pain), pain as a consequence of disease (eg, cancer-related pain), or from chronic pain conditions (such as chronic musculoskeletal pain). The age of a patient, however, presents particular challenges to diagnosing and managing pain. Historically, children and young adults have at times been treated as small adults; yet, considerable laboratory and clinical evidence demonstrates that pain processing in peripheral and central nervous systems is significantly different before adulthood and that responses to analgesic drugs are also different.4 The year 2019 is IASP's Global Year Against Pain in the Most Vulnerable, and it is therefore prescient that Eccleston et al.,2 in this edition of PAIN, have conducted a thorough and startling investigation of pharmacological interventions that are purported to reduce pain in children.
The overview by Eccleston et al.2 aimed to provide a comprehensive review of the current evidence on pharmacological interventions for pain management in children and adolescents (birth to 18 years old) in chronic noncancer pain (CNCP) and chronic cancer-related pain, evaluate its quality, and make relevant recommendations for the future of the field. Their aim was to perform a review of current systematic reviews in the area. However, the primary take-away from this overview review was the paucity of information available. Only 6 trials involving the delivery of analgesic drugs in children and adolescents were found to have taken place, all were determined to be of low quality, and no randomised controlled trials (RCTs) for pharmacological treatments of CRCP in children and adolescents were found.
Eccleston et al.2 conducted their searches for relevant peer-reviewed reviews on the Cochrane Database of Systematic Reviews, MEDLINE and MEDLINE in process, EMBASE, and Database of Reviews of Effects. Through the extraction of primary and secondary outcomes set out in their protocol, using AMSTAR-2 criteria (quality rating scale),5 and GRADE assessments developed by the EPOC review group,3 the available information was assessed and split into 5 groups. Groups 1 to 3 were deemed to have evidence that was of an insufficient amount and quality to have confidence in the results, whereas studies in groups 4 and 5 provided sufficient evidence to have this confidence.
The authors then described a well-designed protocol to analyse and summarise data that met the quality requirements to be in groups 4 and 5. However, of 704 abstracts initially found in their searches, only 23 systematic reviews met the inclusion requirements. Of these 23 reviews, 16 were classed as being in group 1 (reviews that did not find any studies of children with CNCP or chronic cancer-related pain) and the other 7 were classified as group 2 (inadequate information). This is a startling discovery highlighting the low quality of patient-based assessments of efficacy and safety of pharmacological treatment of pain in children. Within these reviews, only 6 actual trials that included delivery of analgesic drugs were identified and commented upon, and all these were in patients with CNCP. Thus, the planned analysis could not be conducted. Instead, Eccleston et al. review those 6 trials which delivered analgesic drugs, summarise their findings, and discuss them.
This overview highlights not only the lack of RCTs of pharmacological interventions for pain management in young people but also links this to the subsequent wide-spread use of off-licence prescribing in paediatric pain. Adult data are extrapolated for the use in children and adolescents despite differences in the chronic pain types between children and adults and without taking into account developmental considerations.1 Leading on from this, Eccleston et al.2 discuss the ethical difficulties surrounding testing pharmacological treatments in children and adolescents, such as concern for withholding medications, as well as alternatives to classic RCTs such as microrandomised trials, and recommend the implementation of registers of patients treated for chronic pain nationally or internationally.
Pain in early life, although difficult to diagnose and treat, is known to impact on pain processing and more widely mental and physical health and well-being into maturity and maybe for the rest of that individual's life.6 This review highlights the need for a directed and concerted effort to understand how pain processing in early life and adolescence differs mechanistically to that in maturity. It identifies a need to better classify and measure pain in these patients. Crucially, it argues for an increase in the quality of clinical studies of pain and pain management in paediatric patients, integrating clinical trials into routine clinical care, and exploring alternate RCT approaches, so that the benefits and harms of pain management approaches can be better assessed and shared between practitioners.
Conflict of interest statement
The authors have no conflict of interest to declare.
. Choonara I, Sammons H. Paediatric clinical pharmacology in the UK. Arch Dis Child 2014;99:1143–6.
. Eccleston C, Fisher E, Cooper T, Grégoire M-C, Heathcote L, Krane E, Lord S, Sethna N, Anderson AK, Anderson A, Clinch J, Gray A, Gold J, Howard R, Ljungman G, Moore RA, Schechter N, Wiffen P, Wilkinson N, Williams D, Wood C, van Tilburg M, Zernikow B. Pharmacological interventions for chronic pain in children: an overview of systematic reviews. PAIN 2019;160:1698–1707.
. Schwaller F, Fitzgerald M, The consequences of pain in early life: injury-induced plasticity in developing pain pathways 2014;39:344–52.
. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358:j4008.
. Walker SM, Melbourne A, O'Reilly H, Beckmann J, Eaton-Rosen Z, Ourselin S, Marlow N Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery Br J Anaesth 2018;121:623–35.