Pain is a common experience during childhood and adolescence.41,49 Pain lasting for longer than 3 months is defined as “chronic,” and is reported by approximately 25% of children and adolescents.68 Around 5% of children report disabling chronic pain needing more intensive complex intervention.41 Chronic pain can be disease- or treatment-related (eg, cancer, arthritis, and sickle cell disease), of idiopathic origin (eg, functional abdominal pain), or can persist after surgical intervention.71 Chronic pain in childhood and adolescence, whatever its origin, is a major burden on individuals, families, and wider society.33,44,73 Pain is also the most frequent symptom of patients with cancer, including in childhood,21,63,98 and patients with cancer pain report lower quality of life.1
Multidisciplinary and biopsychosocial approaches to chronic pain management are generally advocated,53 and psychological27,28 and multidisciplinary rehabilitative36 approaches to pain management have been described. The latter review included one randomised controlled trial (RCT) and 9 nonrandomised trials. The authors found large improvements for disability, and small-to-moderate improvements for pain and depression across these trials.36 Mixed findings have been identified for psychological interventions delivered to this population; small-to-moderate effects were identified for reducing pain intensity and for improving disability outcomes when delivered face-to-face. However, the quality of evidence across these reviews is low or very low, indicating that further evidence is likely to substantially change the estimate of effect.27,28
The first approach to manage pain is often pharmacological. There is, however, relatively little literature examining the efficacy and harm of pharmacological interventions in young people with chronic pain. This embarrassing lack of evidence for the pharmacological treatment of chronic pain in children was reported in 2003.23,40 In part, the historical absence of research is due to the lack of testing of pharmacological interventions in children with chronic pain, and ethical difficulties concerning withholding medications from young people in pain. The U.S. Food and Drug Administration required all new drugs to be tested in children and adolescents under the Pediatric Research Equity Act in 2003. However, few new chemical entities have been submitted for authorisation; so, this regulation, and the equivalent in Europe, has had limited impact. Despite the lack of evidence, analgesics are regularly prescribed to children and adolescents with chronic pain and cancer pain.87 There is a wealth of evidence in adults that is extrapolated to children, despite various warnings of the dangers of using such evidence to guide paediatric practice.78
In this overview, we were interested in pharmacological interventions for the management of chronic pain in children and adolescents, in which the primary outcome was pain relief. Our aim was to provide a comprehensive summary of the evidence, appraise its quality, and set a path for the development of the field.
A protocol for this review was registered on PROSPERO (Prospero ID: CRD42018086900), in accordance with the Pain, Palliative, and Supportive Care (PaPaS) Cochrane group's standard approach to conducting an overview review. This review was based on an approach taken by PaPaS for an overview in adult neuropathic pain.92
We searched the Cochrane Database of Systematic Reviews, Medline and Medline in process, EMBASE to March 2018, and DARE to issue 2 of 4, 2015, without date or language restrictions. Search strategies (eTable 1, available at http://links.lww.com/PAIN/A798) were based on the strategies previously developed for the individual systematic reviews on this topic.11–15,22,91 We required full peer-reviewed publication of reviews to be eligible for inclusion.
We included systematic reviews investigating pharmacological treatments for children and adolescents (from birth to 18 years of age) with chronic pain. Chronic pain (lasting for 3 months or longer) was defined within 2 categories:
- (1) Chronic noncancer pain (CNCP): pain not related to cancer and not relieved by disease-specific treatments. Chronic noncancer pain includes but is not limited to neuropathic pain, chronic musculoskeletal pain, and chronic abdominal pain; or
- (2) Chronic cancer-related pain (CCRP): pain directly related to cancer or its treatment.
We only included systematic reviews that included RCTs, with or without blinding, and participant- or observer-reported outcomes. We excluded children and adolescents taking pharmacological treatments for acute pain, headache, migraine, postsurgical pain, and pain associated with primary disease (with the exception of cancer). Disease-related pain conditions (eg, rheumatoid arthritis, diabetes, and inflammatory bowel disease) often have pain as a symptom, but may have different underlying mechanisms of their pain and disease-modifying treatments. These conditions were beyond the scope of our review.
Two review authors independently selected systematic reviews for inclusion, and disagreements were resolved by discussion or advice from a third author. We included any systematic review that met our inclusion criteria, regardless of whether they found studies. We checked if the average age was ≤ 18 years of age or if children were reported separately to adults in studies that were ambiguous about the age range of participants. We included studies that reported average age as ≤ 18 years of age or reported children separately to adults.
Our primary outcomes included:
- (1) Participant-reported pain relief of 30% or greater;
- (2) Participant-reported pain relief of 50% or greater;
- (3) Patient global impression of change much or very much improved.
In the absence of self-reported pain, we considered the use of “other-reported” pain, typically by an observer such as a parent, carer, or health care professional.
Our secondary outcomes followed PedIMMPACT guidance.57 These guidelines suggest core outcomes in paediatric chronic pain including:
- (1) Carer global impression of change;
- (2) Requirement for rescue analgesia;
- (3) Sleep duration and quality;
- (4) Acceptability of treatment;
- (5) Physical functioning as defined by validated scales;
- (6) Quality of life as defined by validated scales;
- (7) Any adverse events;
- (8) Withdrawals due to adverse events;
- (9) Any serious adverse event.
Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is an important medical event that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics or consequences.
Two review authors independently extracted characteristics and the GRADE assessments in individual reviews. We also extracted primary and secondary outcomes as specified in our protocol from each review, regardless of whether they were reported as primary or secondary outcomes in the included reviews. We evaluated the reviews using the quality rating scale AMSTAR-2 criteria.81 Two authors independently rated each of the systematic reviews, and any disagreement was resolved by consulting a third author.
In line with our protocol, we used the amount and quality of evidence to report results in a hierarchical way, and followed a similar scheme used in other reviews.60,96 We split the available information into 5 groups, essentially according to the GRADE descriptors developed by the Evaluation of the Practice and Organisation of Care Cochrane Review Group (EPOC),25 but also took into account the increasing evidence of the importance of small trial size, both because of random chance7,59,85 and as an important source of bias.16,17,26,42,66 In the first 3 groups, the amount and quality of evidence was insufficient to have confidence in the results. In the other 2 groups, there was sufficient evidence to have confidence in the results (Table 1).
We planned to extract data for groups 4 and 5 for each drug and pain condition. We planned to complete the following tasks for reviews that met the criteria of groups 4 or 5: (1) report or calculate results from available data and report them in 4 ways: the risk ratio, the risk difference (percentage benefitting with intervention minus the percentage benefitting with placebo), the number needed to treat (risk difference divided into 100), and the success rate.58 (2) To calculate the maximum possible success as 100% minus placebo response, and drug-specific success as active response minus placebo response; the success rate was expressed as a percentage of maximum possible response. (3) To collect available information on the number of patients experiencing any adverse event, the number with a serious adverse event, and the number withdrawing because of adverse events.
We planned to conduct our own GRADE assessment of the main efficacy outcome in all reviews using EPOC criteria25 (Table 1), irrespective of whether or not GRADE had been assessed in the included reviews, and the judgments made by authors. We planned to consider 4 sources of bias as being critically important because each of them alone could possibly change a positive result (“this intervention works”) to a negative (“this intervention does not work”). The 4 criteria needed for evidence to be high quality included (1) randomisation, (2) double-blind assessment of pain by patients, (3) avoidance of completer analyses or last observation carried forward data imputation if there were high adverse event withdrawals, and (4) having sufficient information in large studies to avoid random chance and small study bias effects. The absence of any one of these criteria could, in certain circumstances, reduce the quality assessment from high to very low quality. If there were no, or very little, evidence, we judged it to be of very low quality.34
We narratively summarised the findings using the above judgements of confidence in the overall estimates of effect and harm for CNCP and CCRP separately. We summarised EPOC and GRADE judgements, included studies within the reviews, and AMSTAR judgements of the reviews. We were not able to synthesise data across reviews. We were unable to conduct planned subgroup analyses on the types of drugs and for children and adolescents with CCRP and CNCP due to lack of data.
This review was part funded by the United Kingdom National Institute for Health Research (NIHR), United Kingdom: NIHR Cochrane Programme Grant: 13/89/29—Addressing the unmet need of chronic pain: providing the evidence for treatments of pain. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
We searched databases for systematic reviews investigating pharmacological interventions for children with CNCP or CCRP. We found 866 abstracts, and 8 additional reviews through searching reference lists and conducting citation searches (Fig. 1). Therefore, we screened 704 abstracts after duplicates had been removed and read 47 reviews in full to assess eligibility for inclusion. Twenty-four of these reviews were excluded (eTable 2, available at http://links.lww.com/PAIN/A798). Consequently, we included 23 systematic reviews in this overview.5,6,11–15,22,35,37,45,51,56,65,70,76,79,83,90,91,93,95,97
We found that 11 of these 23 included reviews investigated children with CNCP, 10 investigated children with CCRP, one investigated children with either CNCP or CCRP, and one investigated children with life-limiting conditions. The reviews investigated a range of pharmacological treatments (Table 2).
There were 16 of the 23 reviews that searched for children with CNCP or CCRP that fitted with EPOC evidence class 1: reviews that did not find any studies of children with CNCP or CCRP (Table 2). Those reviews attempted to find trials on opioids, nonsteroidal anti-inflammatory drugs, or paracetamol in children with CCRP or opioids, paracetamol, or nonsteroidal anti-inflammatory drugs for children with CNCP, but failed to find any.
The remaining 7 reviews were classified as evidence class 2 (inadequate information: fewer than 200 participants in comparisons, in at least 2 studies). These reviews included 18 trials,2–4,8,10,38,46–48,50,64,69,72,75,77,80,84,99 of which 6 trials delivered analgesic drugs (Table 3). We have not grouped these trials by our predetermined outcomes, and most did not report the a priori primary or secondary outcomes defined in our methods. Therefore, we have reported the closest corresponding outcomes to summarise the evidence in the most transparent way. We did not find any reviews that could be placed into EPOC classes 3, 4, or 5.
We found 2 reviews that exclusively included trials that investigated the efficacy of antidepressants,14,45 and a further 3 reviews that included other pharmacological interventions including antidepressants.51,56,76 Cooper et al.14 included all antidepressant studies identified in the other 4 reviews, as well as newer trials and therefore, we will only discuss this review.
Cooper et al.14 included 4 trials (272 participants) of antidepressants; 3 trials delivered amitriptyline and one study delivered citalopram to children. Cooper et al.14 judged the evidence for antidepressants for children with CNCP as very low across all our outcomes, agreeing with other reviews of the use of antidepressants as adjuvants to pain treatment.45,51
3.1. Antidepressants vs active control
One trial (n = 34) compared amitriptyline with an antiepileptic (gabapentin) control.8 No data relating to pain reduction were available from this trial. The decrease in pain intensity in each group exceeded the minimally important difference of 1/10 on the coloured analogue scale (decrease of 1.16 ± 2.26 for amitriptyline and 1.56 ± 2.27 for gabapentin). Three adverse events were reported, but the authors reported that they were not linked to the study drugs and there were no serious adverse events. Regarding secondary outcomes, children in both conditions reported better sleep quality. No other outcomes of interest to this overview were reported.
3.2. Antidepressants vs placebo control
Three trials (n = 238) compared amitriptyline or citalopram with placebo but none reported on our primary outcomes of 30 or 50% pain reduction.4,72,77 However, each study reported no difference between groups on reduction of pain intensity and therefore there is no evidence of a beneficial effect of taking an antidepressant over a placebo for reducing pain symptoms. There was a low number of adverse events, and all studies reported that there were no serious adverse events. However, a small number of children withdrew from 272,77 of the 3 studies due to adverse events. With regards to the other secondary outcomes, there was insufficient evidence to combine one or more studies and no data could be combined into a meta-analysis. One study reported that the treatment group reported at least a 15% improvement in quality of life after treatment compared with the control group.4 The authors14 concluded that there was no evidence that antidepressants are effective or ineffective at treating CNCP.
One review15 including 2 studies2,8 of 141 children and adolescents with fibromyalgia or CRPS investigated antiepileptic drugs. The trials delivered either oral pregabalin vs placebo2 or gabapentin vs amitriptyline (described earlier).8 Cooper et al.15 judged all evidence to be very low quality, meaning that the true effect is likely to be substantially different, and the estimates could alter with the addition of new data.
3.3. Antiepileptic drugs vs active control
No data for our primary outcomes could be extracted when antiepileptic drugs were compared with an antidepressant comparator (see antidepressant vs active control for description of study outcomes).8
3.4. Antiepileptic drugs vs placebo control
A study involving 107 participants did not find differences between groups for 30 or 50% reduction in pain when pregabalin was compared with placebo.2 However, patient global impression of change was significantly higher in the pregabalin group compared with the placebo group. For secondary outcomes, similarly, carer global impression of change was much higher in the treatment compared with the placebo group. There was no significant difference over the course of the treatment period of 15 weeks for sleep quality and physical functioning. There were more adverse events and withdrawals due to adverse events in the treatment group compared with the placebo group. One serious adverse event was reported in the treatment group.2 No other outcomes can be reported due to lack of data.
3.5. Serotonin (5HT2) antagonist vs placebo control
A crossover trial (n = 14) administering pizotifen to a placebo control84 was included in 3 reviews.56,76,90 This drug aims to prevent functional abdominal pain. The method of randomisation was not clear in this study. Nevertheless, in the absence of data from other trials, we report those findings here but advocate caution when interpreting the findings.
None of our primary or secondary outcomes was reported in the trial.84 However, children taking the serotonin antagonist reported 8 fewer days of pain compared with control (but this was unclear from the study what duration this was over). No other validated measures were assessed, although pain severity was significantly reduced and the Index of Misery (a nonvalidated scale) was marginally reduced in the intervention group.84 Two patients reported side effects including increased appetite and drowsiness during the trial. The trial was stopped early because the trial drugs expired and there was evidence that patients preferred the intervention drug.
Two review authors independently rated the quality of included reviews with the AMSTAR2 quality rating system (eTable 3, available at http://links.lww.com/PAIN/A798). Overall, the quality of included reviews was high, most likely a reflection of 19 out of 23 of the reviews being published as Cochrane reviews. We judged systematic reviews published outside of the Cochrane Library as being of lower quality, due to missing aspects such as the absence of a registered protocol before review production. Overall, we also found that some reviews did not report funding sources of individual trials. We could not judge a number of items because reviews were empty (ie, did not include any studies eligible for inclusion in this review) and therefore we allocated these items as “not applicable.”
Overall, there is no high-quality evidence for delivering any pharmacological intervention to a child or adolescent with chronic pain, and although the quality of the systematic reviews themselves is good, the quality of the evidence is very low, primarily due to the lack of data. Unusually, there are more reviews than trials. We found 23 reviews overall, of which 16 had no included studies with respect to children, and 7 reviews included data from 6 RCTs that delivered analgesic drugs in children with CNCP. There were no RCTs of any pharmacological treatments for the management of cancer-related pain in children.
Despite calls for more evidence,23,40 few attempts have been made to improve the number or quality of trials. Of the 6 trials in CNCP, the first was published in 1995 and the most recent in 2016. The average number of patients recruited to each trial was 66 (range 14-115). At this rate of one trial of 19 patients entering into evidence every 3.5 years, it will take a conservative 1000 years to establish the evidence to substantially reduce the uncertainty around the estimates of effect for any pharmacological intervention for paediatric chronic pain management; 1000 years will not be enough to establish evidence in cancer pain.
The paucity of results for pharmacological interventions for pain in children contrasts sharply with the very different situation in adults, where almost 300,000 patients have been identified in overviews or their equivalent. A network meta-analyses involved 146,524 adults with arthritis,86 and 39,753 with acute postoperative pain.61 Overview reviews also involve large numbers: 13,524 for opioids in cancer pain,96 37,143 in an overview of exercise therapy,31 2895 in an overview of TENS,32 and 13,800 in an overview of antiepileptic drugs for neuropathic pain,94 with an estimate of over 50,000 for all drugs for treating neuropathic pain. Furthermore, the RCT evidence base for psychological interventions for children with chronic pain is also larger, including over 3500 participants.27,28
We need to better understand the barriers to producing evidence in paediatric chronic pain pharmacotherapy. There are practical and ethical considerations to conducting RCTs, but these are no different to other areas of paediatric pharmacological research where there is a need for more research.54 There is a view that primary research is less important when one can extend evidence partially or completely (as supported by safety data) from adult medicine.20,82 However, the type and spectrum of chronic pain in young people differ from those in adults, and the influence of developmental considerations is likely to be substantial.9 There is good evidence for efficacy and safety of pharmacological management in adult chronic pain, but these treatments are not as effective as commonly believed.30 Without primary evidence, we are ignorant as to whether the same pattern of findings is replicated or differs in children and adolescents.
Currently, there are no regulatory barriers to the off-licence prescription and use of most paediatric medicines, and there is common use of medicines licenced for adults in paediatric cases.29,89 Given the lack of market incentives for manufacturers, manufacturing and testing older drugs for young people do not attract the required resources.43 In discussing the related problem of the lack of licensed analgesics for acute pain, researchers have reviewed attempts from the U.S. Food and Drug Administration and the European Medicines Agency to incentivise manufacturers to undertake trials in children.88 Better classification and assessment of chronic paediatric pain, with a focus on genetic and behavioural markers for pain that becomes chronic, may provide methods of identifying subgroups of patients for whom novel analgesics could be developed.
To establish new comparative effectiveness research, there is an urgent need to explore alternatives to the RCT, but alternatives that are able to manage biases reliably and convincingly, and which are ethically acceptable. For example, the use of microrandomised trials is promising in which all members of a sample are exposed to the same treatment (avoiding ethical problems of an untreated group), but randomised to different features of that treatment (eg, dose or length of administration). Target concentration strategies involving dose escalation39 and the use of modelling and simulation55 may reduce patient recruitment obligations. Similarly, advances in enriched enrolment randomised withdrawal trials may be relevant. Such designs are particularly useful when placebo effects are likely to inflate the number needed to complete a trial.77 Advances in single case designs, pioneered in psychology and rehabilitation, are especially relevant to the study of chronic cancer pain.62 The benefits of single case designs are that they can capture an individual's dynamic course of illness (and treatment response), individuals act as their own control, and findings can have greater ecological validity.67 Furthermore, mandatory reporting of adverse events and publishing of trial data in a repository should be required in every trial investigating pharmacological interventions.
Finally, given the widespread use of off-licence prescribing in paediatric pain medicine and the absence of data concerning pain and its management, we need to focus on benefits of drugs as well as harms and harm reduction. We know that millions of people are exposed to medicines that may not provide the desirable effect, but may also cause more harm than benefit.19,74 Furthermore, the modern history of adult pain medicine is one of excessive exposure to ineffective medicines,52 which in some countries have caused major population harm18 and in others excessive restriction.24 The same dangers may be apparent in paediatric chronic pain. The better use of existing registers or the creation of new registers of analgesic use is needed. Where there is established infrastructure, it may be possible to build research alliances and share treatment plans. We know of no national or transnational prescription register that would enable outcome and/or adverse event monitoring specifically for medicines prescribed for paediatric chronic pain.
In conclusion, there is no high-quality evidence and we are uncertain of the efficacy or safety of any pharmacological treatments for paediatric CNCP. There is no evidence from RCTs for paediatric cancer pain. We have relatively high-quality systematic reviews of the few primary studies. More than ever before, we need to better understand the barriers to evidence production in childhood chronic pain, improve the classification and assessment of chronic pain, integrate clinical trials as part of routine clinical care, explore alternative RCT methods, and urgently establish the case for national or transnational registries of patients treated for chronic pain, with a primary focus on analgesic medicines, benefits, harms, and harm reduction.
Conflict of interest statement
S.M. Lord is a specialist pain medicine physician in a public service that treats children and adolescents with complex pain. R.A. Moore reports personal fees from Futura Pharma, Advertising Standards Authority, Novartis, RB, and Menarini, outside the submitted work. M.A.L. van Tilburg is a Consultant to Mahana Therapeutics. P.J. Wiffen manages a business named Oxford Systematic Review Services. This business provides consultancy to a small number of pharmaceutical companies from time to time. B. Zernikow reports personal fees from Grünenthal and PHARM, during the conduct of the study. The remaining authors have no conflicts of interest to declare.
The authors thank information specialist Joanne Abbott for her contribution to the database search strategies.
This overview was partly funded by the National Institute for Health Research (NIHR), United Kingdom: NIHR Cochrane Programme Grant: 13/89/29—Addressing the unmet need of chronic pain: providing the evidence for treatments of pain.
Cochrane Review Group funding acknowledgement: this project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health.
Author's contributions: C. Eccleston conceptualised the manuscript, wrote the protocol, interpreted the results, and drafted the manuscript. E. Fisher sifted reviews for inclusion, extracted data from included studies, conducted quality assessments, and drafted the manuscript. T.E. Cooper sifted reviews for inclusion, interpreted the data, and edited the protocol and manuscript. M.-C. Grégoire, L.C. Heathcote, E. Krane, S.M. Lord, and N.F. Sethna extracted data from included reviews, conducted quality assessments, interpreted the data, and edited the protocol and manuscript. A.-K. Anderson, B. Anderson, J. Clinch, A.L. Gray, J.I. Gold, R.F. Howard, G. Ljungman, R.A. Moore, N. Schechter, P.J. Wiffen, N.M.R. Wilkinson, D.G. Williams, C. Wood, M.A.L. van Tilburg, and B. Zernikow interpreted the data and edited the protocol and manuscript.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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