Antidepressants for chronic non‐cancer pain in children and adolescents Stable (no update expected for reasons given in 'What's new')
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 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.
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 arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.
Antidepressants have been used in adults for pain relief and pain management since the 1970s. The clinical impression from extended use over many years is that antidepressants are useful for some neuropathic pain symptoms, and that effects on pain relief are divorced and different from effects on depression; for example, the effects of tricyclic antidepressants on pain may occur at different, and often lower, doses than those on depression. Amitriptyline is one of the most commonly used drugs for treating neuropathic pain in the UK.Objectives
To assess the analgesic efficacy and adverse events of antidepressants 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, and searched online clinical trial registries.Selection criteria
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non‐cancer pain in children and adolescents, comparing any antidepressant 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. We assessed the evidence using GRADE and created three 'Summary of findings' tables.Main results
We included four studies with a total of 272 participants (6 to 18 years of age) who had either chronic neuropathic pain, complex regional pain syndrome type 1, irritable bowel syndrome, functional abdominal pain, or functional dyspepsia. All of the studies were small. One study investigated amitriptyline versus gabapentin (34 participants), two studies investigated amitriptyline versus placebo (123 participants), and one study investigated citalopram versus placebo (115 participants). Due to a lack of available data we were unable to complete any quantitative analysis.
Risk of bias for the four included studies varied, due to issues with randomisation and allocation concealment (low to unclear risk); blinding of participants, personnel, and outcome assessors (low to unclear risk); reporting of results (low to unclear risk); and size of the study populations (high risk). We judged the remaining domains, attrition and other potential sources of bias, as low risk of bias.
No studies reported our primary outcomes of participant‐reported pain relief of 30% or greater or 50% or greater, or Patient Global Impression of Change.
All studies measured adverse events, with very few reported (11 out of 272 participants). All but one adverse event occurred in the active treatment groups (amitriptyline, citalopram, and gabapentin). Adverse events in all studies, across active treatment and comparator groups, were considered to be a mild reaction, such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort (very low‐quality evidence).
There were also very few withdrawals due to adverse events, again all but one from the active treatment groups (very low‐quality evidence).
No serious adverse events were reported across any of the studies (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
We identified only a small number of studies with small numbers of participants and insufficient data for analysis.
As we could undertake no meta‐analysis, we are unable to comment about efficacy or harm from the use of antidepressants 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 antidepressants, such as amitriptyline, can provide some pain relief in certain chronic non‐cancer pain conditions.
Tess E Cooper, Lauren C Heathcote, Jacqui Clinch, Jeffrey I. Gold, Richard Howard, Susan M Lord, Neil Schechter, Chantal Wood, Philip J Wiffen
Plain language summary
Antidepressants for chronic non‐cancer pain in children and adolescents
We are uncertain as to whether antidepressants provide pain relief for chronic non‐cancer pain in children and adolescents. We do not have evidence to suggest that one type of antidepressant is more effective than another.
Children can experience chronic or recurrent pain related to genetic conditions, nerve damage, muscle or bone pain, stomach pain, as well as for unknown reasons. Chronic pain is pain that lasts three months or longer and is commonly accompanied by changes in lifestyle and functional abilities, as well as by signs and symptoms of depression and anxiety.
Antidepressants have been used for pain relief and pain management since the 1970s and are considered by clinicians to be useful for symptoms of nerve, menstrual, muscular, joint, and stomach pain. Examples of antidepressants that have been used to treat neuropathic pain include amitriptyline, milnacipran, and citalopram.
In September 2016 we searched for clinical trials in which antidepressants were used to treat chronic nerve, menstrual, muscular, joint, or stomach pain. We found four trials with a total of 272 participants (aged 6 to 18 years old) who had nerve pain, general painful inflammation, stomach pain, or irritable bowel syndrome, for more than 3 months.
No studies reported on pain relief of 30% or greater, or 50% or greater. Side effects were uncommon, and occurred only as mild reactions such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort (4 due to amitriptyline, 5 due to citalopram, 1 due to gabapentin, and 1 due to placebo). These 11 participants withdrew from the study due to these mild side effects. There were no serious side effects.
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, Lauren C Heathcote, Jacqui Clinch, Jeffrey I. Gold, Richard Howard, Susan M Lord, Neil Schechter, Chantal Wood, Philip J Wiffen
Implications for practice General
We identified four randomised controlled trials, however we were unable to analyse these to determine whether to support or refute the use of antidepressants to treat chronic non‐cancer pain in children and adolescents. There is evidence from adult randomised controlled trials that some antidepressants, such as amitriptyline, can provide some pain relief in certain chronic neuropathic pain conditions (Moore 2015).
This is disappointing as children and adolescents with chronic non‐cancer pain have specific needs for analgesia.
In current practice, despite the lack of evidence on effectiveness and safety, and despite lack of licensing for use in pain below 18 years of age, clinicians prescribe antidepressants to children and adolescents when medically necessary, based on extrapolation from adult guidelines. However, extrapolating from adult data may be unreliable, and risks compromising safety in children and adolescents.
The only current guidelines are from the World Health Organization on the pharmacological treatment of persisting pain in children with medical illnesses (WHO 2012).For children and adolescents with chronic non‐cancer pain
The amount and quality of evidence around the use of antidepressants 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 for the use of antidepressants 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 for the use of antidepressants 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
The amount and quality of evidence for the use of antidepressants 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.
Implications for research General
The lack of robust evidence of efficacy and safety found in this review highlighted the need to design and fund high quality and clinically relevant research on this topic.
Overall, there appears to be a gap between how antidepressant 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 tend to be 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 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 none of the 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 treatments have equal efficacy, a treatment 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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