Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents: Cochrane systematic review

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.

Paracetamol (acetaminophen) is one of the most widely used analgesics in both adults and children. The recommended dosage in the UK, Europe, Australia, and the USA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended analgesic for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential adverse effects of paracetamol if overdosed or overused in children include liver and kidney failure.

Objectives

To assess the analgesic efficacy and adverse events of paracetamol (acetaminophen) 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 paracetamol 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 numbers needed to treat, using standard methods where data were available. We planned to assess GRADE (Grading of Recommendations Assessment, Development and Evaluation) and create a 'Summary of findings' table.

Main results

No studies were eligible for inclusion in this review. Due to the lack of evidence in this field, we are unable to judge the quality of evidence and therefore there is no evidence to support or refute the use of paracetamol for children with chronic non-cancer pain.

Authors' conclusions

There was no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non-cancer pain in children and adolescents.

We know from adult randomised controlled trials that paracetamol can be effective, in certain doses, and in certain pain conditions (not always chronic).

This means that no conclusions could be made about efficacy or harm in the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents.

Author(s)

Cooper Tess E, Fisher Emma, Anderson Brian, Wilkinson Nick MR, Williams David G, Eccleston Christopher

Summary

Paracetamol 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 paracetamol (acetaminophen) in any dose will provide pain relief for chronic non-cancer pain in children or adolescents.

Background

Children can experience chronic or recurrent pain related to genetic conditions, nerve damage pain, 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, functional abilities, as well as by signs and symptoms of depression and anxiety.

Paracetamol (acetaminophen) is one of the most widely used painkillers in both adults and children. The recommended dosage in the UK, Europe, Australia, and theUSA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended painkiller for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential side effects of paracetamol if overdosed or overused in children include liver and kidney failure.

Key results

In September 2016 we searched for clinical trials where paracetamol was 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 paracetamol on adults with chronic pain, but none included participants from birth to 17 years old.

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.

No studies were available, and so we were unable to rate the quality of the body of evidence. There is no evidence to support or refute the use of paracetamol for chronic non-cancer pain in children or adolescents.

Reviewer's Conclusions

Implications for practice

General:

We identified no randomised controlled trials to support or refute the use of paracetamol 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 paracetamol to children and adolescents when medically necessary, based on extrapolation from adult guidelines, or when perceived benefits in conjunction with other multimodalities improve a child’s care. Appropriate medical management is necessary in disease-specific conditions such as for 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.

For children with chronic non-cancer pain:

The amount and quality of evidence around the use of paracetamol 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 and quality of evidence around the use of paracetamol 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 and quality of evidence around the use of paracetamol 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 and quality of evidence around the use of paracetamol 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 heterogeneous 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 paracetamol.

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 is somewhat different 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. Alternative concentration-response or dose-response relationships in individual children could be explored using population analysis techniques (Anderson 2015). These have been used to explore acute pain in both adults and children as well as chronic pain in adults (Shinoda 2007).

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.

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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