Non‐steroidal anti‐inflammatory drugs (NSAIDs) for cancer‐related pain in children and adolescents Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

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 persisting pain in children acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.

We designed a suite of seven reviews in chronic non‐cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non‐steroidal anti‐inflammatory drugs, opioids, and paracetamol as priority areas) to review the evidence for children's pain using pharmacological interventions.

As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Specific mortality and morbidity data relating to children are not currently identified. All childhood cancer rates are on the rise; for example, in the USA approximately 10,380 children aged under 15 years were expected to be diagnosed with cancer by the end of 2016. However, with survival rates also increasing, over 80% of paediatric cancer patients are expected to survive for five years or more, thus identifying the need to address pain management in this population.

Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer‐related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer‐related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti‐inflammatory properties. They are commonly used within paediatric pain management. NSAIDs are currently licensed for use in western countries, however not approved for infants aged under three months. Primary adverse effects include gastrointestinal issues and possible renal impairment with long term use. Other adverse effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.

Objectives

To assess the analgesic efficacy, and adverse events, of non‐steroidal anti‐inflammatory drugs (NSAIDs) used to treat cancer‐related pain in children and adolescents aged from 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 21 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Selection criteria

Randomised, double‐blind trials of any dose, and any route, treating cancer‐related pain in children and adolescents, comparing NSAIDs 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 planned to assess GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.

Main results

No studies were eligible for inclusion in this review.

There is no evidence to support or refute the use of NSAIDs for treating cancer‐related pain in children and adolescents.

Authors' conclusions

There is no evidence from randomised controlled trials to support or refute the use of NSAIDs to treat chronic cancer‐related pain in children and adolescents. We are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic cancer‐related pain in children and adolescents.

Author(s)

Tess E Cooper, Lauren C Heathcote, Brian Anderson, Marie‐Claude Grégoire, Gustaf Ljungman, Christopher Eccleston

Abstract

Plain language summary

NSAIDs for cancer‐related pain in children and adolescents

Bottom line

We are uncertain whether NSAIDs will provide pain relief for cancer‐related pain in children or adolescents.

Background

Childhood cancer is one of the leading causes of disease and death for children and adolescents in the world today. Its associated pain is a major health concern and specific data for children are not currently well known.

Cancer pain in infants, children, and adolescents is primarily nerve pain with negative long term effects. Cancer‐related pain is generally caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.

NSAIDs are used to treat pain or reduce fever, and are commonly used in children. NSAIDs are currently licensed for use in western countries, but they are not approved for infants aged under three months. The key side effects of NSAIDs are stomach problems and possible damage to kidneys following long term use. Other side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, flatulence, stomach pain, and indigestion.

Key results

In February 2017 we searched for randomised controlled clinical trials where any NSAIDs were used to treat any cancer‐related pain in people aged from birth to 17 years. We found no studies that met the requirements for this review. Several studies tested NSAIDs on adults in chronic pain, but none in participants aged from birth to 17 years.

Quality of the evidence

We planned to rate 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.

We were unable to rate the quality of the evidence as there was no evidence from randomised controlled trials to support or refute the suggestion that NSAIDs in any dose will reduce chronic cancer‐related pain in children or adolescents.

Author(s)

Tess E Cooper, Lauren C Heathcote, Brian Anderson, Marie‐Claude Grégoire, Gustaf Ljungman, Christopher Eccleston

Reviewer's Conclusions

Authors' conclusions

Implications for practice General

We identified no randomised controlled trials (RCTs), to support or refute the use of NSAIDs to treat cancer‐related pain in children and adolescents.

This is disappointing as children and adolescents have specific needs for analgesia. Extrapolating from adult data may be possible but could compromise effectiveness and safety.

Despite the lack of evidence of long‐term effectiveness and safety, we know that clinicians prescribe NSAIDs to children and adolescents when medically necessary, based on extrapolation from adult guidelines (e.g. CDC Guidelines, Dowell 2016), when perceived benefits in conjunction with other multi‐modalities improve a child’s care. The evidence for the use of NSAIDs for cancer pain in adults is low quality (Derry 2017)

In current practice, despite the lack of high quality evidence, NSAIDs are given to young children and adolescents based on clinical knowledge and experience.

For children with cancer‐related pain

Children and adolescents experiencing cancer pain need to be adequately treated, despite there being little good evidence around the use of NSAIDs for treating cancer‐related pain. At present, treatment is based on clinical experience, extrapolation from evidence and experience in adults, and advice from respected authorities. No judgment can be made about adverse events or withdrawals.

For clinicians

Children and adolescents experiencing cancer pain need to be adequately treated, despite there being little good evidence around the use of NSAIDs for treating cancer‐related pain. At present, treatment is based on clinical experience, extrapolation from evidence and experience in adults, and advice from respected authorities. No judgment can be made about adverse events or withdrawals.

For policy makers

Children and adolescents experiencing cancer pain need to be adequately treated, despite there being little good evidence around the use of NSAIDs for treating cancer‐related pain. At present, treatment is based on clinical experience, extrapolation from evidence and experience in adults, and advice from respected authorities. No judgment can be made about adverse events or withdrawals.

For funders

Children and adolescents experiencing cancer pain need to be adequately treated, despite there being little good evidence around the use of NSAIDs for treating cancer‐related pain. At present, treatment is based on clinical experience, extrapolation from evidence and experience in adults, and advice from respected authorities. No judgment can be made about adverse events or withdrawals.

Implications for research General

The heterogenous nature of pain in children needs to be recognised and presents challenges in designing research studies. In addition, children experience fewer solid tumours and so generally do not experience pain from that source.

Overall, there appears to be a gap between what is done in practice and what is investigated in prospective clinical trials for treating children's and adolescents' pain with NSAIDs.

The lack of evidence highlighted in this review implies there is a need to fund and support suitable research for the treatment of cancer‐related pain in children and adolescents using NSAIDs.

Design

Several methodological issues stand out.

The first is the use of outcomes of value to children with cancer pain. Existing trials are designed more for purposes of registration and marketing than informing and improving clinical practice, often because the outcomes chosen are average pain scores, or statistical differences, and rarely how many children achieve satisfactory pain relief. In the situation where initial pain is mild or moderate, some consideration needs to be given to what constitutes a satisfactory outcome. The situation is somewhat different to that of strong opioids in cancer pain that are used for moderate to severe pain.

The second is the time taken to achieve good pain relief. We have no information about what constitutes a reasonable time to achieve a satisfactory result. Initially this may best be approached with a Delphi methodology involving children and their carers.

The third is design. Studies with cross‐over design often have significant attrition. Parallel group designs may be preferable.

The fourth 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. This may require a multicentre approach.

There are some other design issues that might be addressed. Most important might well be a clear decision concerning the gold‐standard treatment comparator. Placebo‐controlled studies in cancer pain are unlikely to be ethically feasible. It may be that low dose oral morphine is a suitable comparator, as a suggested alternative treatment for mild to moderate pain.

An alternative approach might be to design large registry studies. This could provide an opportunity to foster collaboration among paediatric clinicians and researchers to create an evidence base.

Measurement (endpoints)

Trials need to consider additional endpoints of no worse than mild pain as well as the standard approaches to pain assessment.

Other

Prospective randomised trials is the obvious design of choice, but other pragmatic designs may be worth considering. Studies could incorporate initial randomisation, but a pragmatic design to provide immediately‐relevant information on effectiveness and costs. Such designs in pain conditions have been published (Moore 2010e).

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