Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.
We designed a suite of seven reviews on chronic non‐cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non‐steroidal anti‐inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.
As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.
Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment.Objectives
To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non‐cancer pain in children and adolescents aged between birth and 17 years, in any setting.Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries.Selection criteria
Randomised controlled trials, with or without blinding, by any route, treating chronic non‐cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator.Data collection and analysis
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables.Main results
We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS‐I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS‐I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis.
Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias.
One study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes.
The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low‐quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low‐quality evidence).
In one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6‐week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15‐week trial) (very low‐quality evidence).
Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low‐quality evidence).
Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low‐quality evidence).
There were few or no data for our remaining secondary outcomes.
Quality of evidence
For the outcomes with available data, we downgraded the quality of the evidence by three levels to very low‐quality due to too few data and the fact that the number of events was too small to be meaningful.Authors' conclusions
This review identified only two small studies, with insufficient data for analysis.
As we could undertake no meta‐analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non‐cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.
We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.
Tess E Cooper, Philip J Wiffen, Lauren C Heathcote, Jacqui Clinch, Richard Howard, Elliot Krane, Susan M Lord, Navil Sethna, Neil Schechter, Chantal Wood
Plain language summary
Antiepileptic drugs for chronic non‐cancer pain in children and adolescents
We are uncertain as to whether antiepileptic drugs provide pain relief for chronic non‐cancer pain in children and adolescents. We do not have evidence to suggest that one type of antiepileptic drug is more effective than another.
Children can experience chronic or recurrent pain related to genetic conditions, nerve damage, muscle or joint pain, stomach pain, or for other unknown reasons. Chronic pain is pain that lasts three months or more and is commonly accompanied by changes in lifestyle and functional abilities, as well as by signs and symptoms of depression and anxiety.
Antiepileptic (anticonvulsant) drugs were originally developed to treat epilepsy, but some of these drugs have been shown to provide pain relief in some chronic painful conditions in adults.
In September 2016 we searched for clinical trials in which antiepileptic drugs were used to treat chronic pain. We found two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1, or fibromyalgia, which they had for more than 3 months.
One study looked at pregabalin versus placebo for people with fibromyalgia, and found no significant change in pain scores. The other study evaluated gabapentin compared to amitriptyline, but did not report our specified pain outcomes.
Side effects were uncommon, and only mild reactions (such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort): pregabalin 38 participants, gabapentin 2 participants, amitriptyline 1 participant, and placebo 34 participants. Only 11 participants withdrew due to these mild side effects (4 pregabalin, 2 gabapentin, 1 amitriptyline, 4 placebo).
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results.
The available evidence in this review was of very low‐quality due to a lack of data and small study sizes.
Tess E Cooper, Philip J Wiffen, Lauren C Heathcote, Jacqui Clinch, Richard Howard, Elliot Krane, Susan M Lord, Navil Sethna, Neil Schechter, Chantal Wood
Implications for practice General
We identified two randomised controlled trials, however we were unable to analyse these to determine whether to support or refute the use of antiepileptic drugs to treat chronic non‐cancer pain in children and adolescents.
This is disappointing as children and adolescents with chronic non‐cancer pain have specific needs for analgesia. While extrapolating from adult data may be possible, it could also compromise effectiveness and safety.
Despite the lack of evidence of long‐term effectiveness and safety, clinicians prescribe antiepileptic drugs to children and adolescents when medically necessary, based on extrapolation from adult guidelines, when perceived benefits in conjunction with other multimodalities improve a child’s care. However, extrapolating from adult data may be unreliable, and risks compromising safety in children and adolescents. It is important to consider recent suggestions and government warnings about the risks of antiepileptic drugs towards mental health and suicide when used in children (FDA 2008). Until new evidence emerges, individual clinician judgement, and informed consent regarding off‐licence use of antiepileptic drugs for children and adolescents with chronic non‐cancer pain, will continue to be necessary.
Appropriate medical management is necessary in disease‐specific conditions such as incurable progressive degenerative conditions of Duchenne muscular dystrophy, osteogenesis imperfecta, congenital degenerative spine, and neurodegenerative conditions such as spasticity/dystonia in mitochondrial Leigh’s disease, leukoencephalopathy, and severe cerebral palsy.
In current practice, antiepileptic drugs are given to young children and adolescents, despite the lack of evidence and although no antiepileptic is licensed for use in pain in those below 18 years of age. Our only current source is the World Health Organization guideline on the pharmacological treatment of persisting pain in children with medical illnesses (WHO 2012).
The rationale for the use of antiepileptic agents for management of chronic neuropathic pain is based on their effectiveness on damaged nervous system (e.g. postherpetic neuralgia). Their use in chronic pain disorders is based on the assumption that there is dysfunction of nervous system (e.g. CRPS, juvenile fibromyalgia, etc.). A common mechanism evoked among the various symptomatically overlapping chronic pain disorders is central sensitisation. In general, chronic pain disorders are poorly defined, particularly in the paediatric population, because of unclear pathoaetiology, poor response to commonly used analgesics, and medical models of care. Chronic pain disorders are associated with multiple somatic symptoms that are usually influenced by the psychosocial stressors that shape the overall pain experience, and are therefore optimally managed by a multidisciplinary approach.
The case definitions, and especially diagnostic criteria of various disorders, have not been fully validated in the paediatric population and are extrapolated from adult experience, for example the CRPS Budapest criteria have yet to be validated in children and adolescents, and central sensitisation in juvenile fibromyalgia is not reliably confirmed and the diagnosis relies on clinical criteria.For children and adolescents with chronic non‐cancer pain
The amount and quality of evidence around the use of antiepileptic drugs for treating chronic non‐cancer pain is very low. This means that at present, treatment is based on clinical experience and advice from respected authorities. We could make no judgement about adverse events or withdrawals.For clinicians
The amount and quality of evidence around the use of antiepileptic drugs for treating chronic non‐cancer pain is very low. This means that at present, treatment is based on clinical experience and advice from respected authorities. We could make no judgement about adverse events or withdrawals.For policymakers
The amount and quality of evidence around the use of antiepileptic drugs for treating chronic non‐cancer pain is very low. This means that at present, treatment is based on clinical experience and advice from respected authorities. We could make no judgement about adverse events or withdrawals.For funders
Implications for research General
The lack of robust evidence of efficacy and safety found in this review highlights the need to design and fund high quality and clinically relevant research on this topic. The heterogenous nature of pain in children needs to be recognised and presents challenges in designing research studies.
Overall, there appears to be a gap between how antiepileptic drugs are used in clinical practice to treat chronic non‐cancer pain in children and adolescents, and how this drug class has been investigated in prospective clinical trials.
The challenge is to develop clinician‐ and patient‐informed trial protocols examining clinically‐meaningful, patient‐centred outcomes.Design
Several methodological issues stand out.
The first is the use of outcomes of value to children with chronic non‐cancer pain. Existing trials are designed more for purposes of registration and marketing than informing and improving clinical practice, that is the outcomes are often average pain scores or statistical differences, and rarely how many individuals achieve satisfactory pain relief. In the case where pain is initially mild or moderate, consideration needs to be given to what constitutes a satisfactory outcome.
The second issue is the time taken to achieve good pain relief. We have no information about what constitutes a reasonable time to achieve a satisfactory result. This may best be approached initially with a Delphi methodology.
The third issue is design. Studies with a cross‐over design often have significant attrition, therefore parallel‐group designs may be preferable. The use of suitable validated scales is important.
The fourth issue is size. The studies need to be suitably powered to ensure adequate data after the effect of attrition due to various causes. Much larger studies of several hundred participants or more are needed.
There are some other design issues that might be addressed. Most important might well be a clear decision concerning the gold‐standard treatment comparator.
An alternative approach may be to design large registry studies. This could provide an opportunity to foster collaboration among paediatric clinicians and researchers, in order to create an evidence base.Measurement (endpoints)
Trials need to consider the additional endpoint of 'no worse than mild pain' as well as the standard approaches to pain assessment.
Primary outcomes need to be outcomes of value to children with chronic non‐cancer pain and their families. To help them make decisions about drug treatment, families seek to know what chance their child has of achieving relief that is meaningful to them. There is as yet no patient‐defined level of pain relief, or improvement in function, that is considered meaningful. This could be addressed in future using Delphi methodology.
As a surrogate, expert consensus recommends reporting the proportion of participants achieving at least 30% or 50% pain relief, but only one of the two included studies did so. Consideration could also be given to reporting the proportion of participants achieving the endpoint of ‘no worse than mild pain’ and ‘no pain’. The endpoint might depend on whether participants are selected for having severe pain at baseline, or whether children whose pain is mild‐moderate are included. For fluctuating conditions, endpoints might be proportion of pain‐free days, or days in which pain does not reach a specific level (PedIMMPACT 2008).
Time to achieve benefit was not reported, yet this is of great interest to children and families. Where drugs have equal efficacy, a drug with earlier onset might still be considered ‘superior’ by consumers. Future research should measure and report the time to achieve outcome and the longevity of benefits.Other
The obvious study design of choice is the prospective randomised trial, but other pragmatic designs may be worth considering. Studies could incorporate initial randomisation but a pragmatic design in order to provide immediately relevant information on effectiveness and costs. Such designs in pain conditions have been published (Moore 2010e).Get full text at The Cochrane Library
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