Opioids 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 children's persisting pain 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) 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. 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.

Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child.

Objectives

To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer‐related 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 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Selection criteria

Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer‐related pain in children and adolescents, comparing opioids 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 identified that were eligible for inclusion in this review. Several studies tested opioids on adults with cancer‐related pain, but none in participants aged from birth to 17 years.

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

Author(s)

Philip J Wiffen, Tess E Cooper, Anna‐Karenia Anderson, Andrew L Gray, Marie‐Claude Grégoire, Gustaf Ljungman, Boris Zernikow

Abstract

Plain language summary

Opioids for cancer‐related pain in children and adolescents

Bottom line

There is no evidence from randomised controlled trials to support or contradict the suggestion that opioids in any dose will reduce 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‐related pain is generally caused directly by a tumour compressing on nerves or by organ inflammation, and can very distressing.

Opioids are used worldwide for the treatment of pain. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. For example, currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses and commonly administered via injection or oral tablets.

Key results

In February 2017 we searched for clinical trials where any opioids were used to treat 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 opioids on adults with cancer‐related 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 evidence as there was no evidence from randomised controlled trials to support or refute the suggestion that opioids in any dose will reduce cancer‐related pain in children or adolescents.

Author(s)

Philip J Wiffen, Tess E Cooper, Anna‐Karenia Anderson, Andrew L Gray, Marie‐Claude Grégoire, Gustaf Ljungman, Boris Zernikow

Reviewer's Conclusions

Authors' conclusions

Implications for practice General

We identified no randomised controlled trials (RCTs), to support or refute the use of opioids to treat cancer 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, clinicians prescribe opioids 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.

In current practice, despite the lack of high quality evidence, opioids are given to young children and adolescents based on clinical knowledge and experience. A recent Cochrane overview of opioids for cancer pain in adults (Wiffen 2017c) shows that opioids are capable of providing good pain relief for up to 90% of people who have severe cancer related pain. Morphine and transdermal fentanyl were supported by the best evidence but these and other opioids need to be used judiciously. Attention needs to be paid to managing common adverse effects.

For children with cancer‐related pain

Clearly children and adolescents experiencing cancer pain need to be adequately treated however the amount of evidence around the use of opioids for treating cancer pain is low. This means that at present, treatment is based on clinical experience and advice from respected authorities. No judgement can be made about adverse events or withdrawals.

For clinicians

Clearly children and adolescents experiencing cancer pain need to be adequately treated, however, the amount of evidence around the use of opioids for treating cancer pain is low. This means that at present, treatment is based on clinical experience and advice from respected authorities. No judgement can be made about adverse events or withdrawals.

For policy makers

Clearly children and adolescents experiencing cancer pain need to be adequately treated however the amount of evidence around the use of opioids for treating cancer pain is low. This means that at present, treatment is based on clinical experience and advice from respected authorities. No judgement can be made about adverse events or withdrawals.

For funders

Clearly children and adolescents experiencing cancer pain need to be adequately treated however the amount of evidence around the use of opioids for treating cancer pain is low. This means that at present, treatment is based on clinical experience and advice from respected authorities. No judgement 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.

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 opioids.

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.

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.

The fifth is ethics. Studies that randomise an opioid arm against a placebo arm will not likely meet ethical standards that protect vulnerable populations. Future studies must randomise against an active control, such as a non‐steroidal anti‐inflammatory drug with adequate provision for opioid rescue.

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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