Opioids for chronic non‐cancer 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 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 as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.

As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.

Opioids are used worldwide for the treatment of pain. They bind to opioid receptors in the central nervous system (mu, kappa, delta, and sigma) and can be agonists, antagonists, mixed agonist‐antagonists, or partial agonists. Opioids are generally available in healthcare settings across most high‐income countries, but access may be restricted in low‐ and middle‐income countries. For example, opioids currently available in the UK include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses (generally based on body weight for paediatric patients) by means of parenteral, transmucosal, transdermal, or oral administration (immediate release or modified release). To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is a lower dose gradually titrated to effect in the child.

Objectives

To assess the analgesic efficacy and adverse events of opioids 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 Library, 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 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, 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 opioids for treating chronic non‐cancer pain in children and adolescents.

Authors' conclusions

We are unable to comment about efficacy or harm from the use of opioids to treat chronic non‐cancer pain in children and adolescents.

We know from adult randomised controlled trials that some opioids, such as morphine and codeine, can be effective in certain chronic pain conditions.

Author(s)

Tess E Cooper, Emma Fisher, Andrew L Gray, Elliot Krane, Navil Sethna, Miranda AL van Tilburg, Boris Zernikow, Philip J Wiffen

Abstract

Plain language summary

Opioids for chronic non‐cancer pain in children and adolescents 

Bottom line 

There is no evidence from randomised controlled trials to support or refute the suggestion that opioids in any dose will provide pain relief for children or adolescents with chronic non‐cancer pain.

Background 

Children can experience chronic or recurrent pain related to genetic conditions, damaged nerves, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other 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.

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

Key results 

In September 2016 we searched for clinical trials where any opioids were used to treat chronic pain (potentially from either nerve pain, musculoskeletal problems, menstrual cramps, or abdominal discomfort).

We found no studies that met the requirements for this review. Several studies tested opioids in adults with chronic pain, but none in participants from birth to 17 years old.

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 opioids in any dose will reduce chronic non‐cancer pain in children or adolescents.

Author(s)

Tess E Cooper, Emma Fisher, Andrew L Gray, Elliot Krane, Navil Sethna, Miranda AL van Tilburg, Boris Zernikow, Philip J Wiffen

Reviewer's Conclusions

Authors' conclusions

Implications for practice General

We identified no randomised controlled trials to support or refute the use of opioids to treat chronic non‐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 historical and clinical experience, and on extrapolation from adult guidelines (e.g. Centers for Disease Control and Prevention guidelines, Dowell 2016), when perceived benefits in conjunction with other multimodalities improve a child’s care. Appropriate medical management is necessary in disease‐specific conditions such as incurable progressive degenerative conditions of Duchenne muscular dystrophy, osteogenesis imperfecta, congenital degenerative spine conditions, erythromelalgia, and neurodegenerative conditions such as spasticity/dystonia in mitochondrial Leigh’s disease, leukoencephalopathy, and severe cerebral palsy.

In current practice, despite the lack of evidence, opioids are sometimes given to young children and adolescents with chronic non‐cancer pain. Concerns about the use of opioids for chronic non‐cancer pain in adults need to be taken into consideration (Stannard 2016). We identified no guidelines for the use of opioids in chronic non‐cancer pain in the paediatric population.

For children with chronic non‐cancer pain

The amount of evidence around the use of opioids for treating chronic non‐cancer pain is 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 of evidence around the use of opioids for treating chronic non‐cancer pain is 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 of evidence around the use of opioids for treating chronic non‐cancer pain is 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 of evidence around the use of opioids for treating chronic non‐cancer pain is 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 heterogenous nature of pain in children at various developmental ages 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. Some potential reasons for the lack of randomised controlled trials in children include: low prevalence of chronic pain disorders; parental reluctance of their child being randomised to ineffective treatment (e.g. placebo); small market share for analgesic agents; and lack of industry funding incentives, as most opioids are generic and prescribed in children in clinical practice.

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

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 situation differs somewhat to that of strong opioids that are used for moderate to severe cancer pain.

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.

The fifth issue 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.

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.

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).

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