Paracetamol (acetaminophen) for chronic non‐cancer pain in children and adolescents
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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.
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 Organisation (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 (WHO 2012). 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. Since the 1970s, studies comparing child and adult pain management revealed a variety of responses to pain, fuelling the need to focus on paediatric pain in more depth (Caes 2016).
Infants (zero to 12 months), children (1 to 9 years), and adolescents (10 to 18 years) (WHO 2012) account for 27% (1.9 billion) of the world's population (United Nations 2015), and the proportion of those aged 14 years and under varies from 12% (in Hong Kong) to 50% (in Niger) (World Bank 2014). However, we know little about the pain management needs of this population. For example, in the Cochrane Library, approximately 12 reviews produced by the Cochrane Pain, Palliative and Supportive Care (PaPaS) Review Group in the past 18 years have been specifically concerned with children and adolescents, compared to over 100 reviews specific to adults. Additional motivating factors for investigating children's pain include the vast amount of unmanaged pain in the paediatric population and new technologies and treatments being developed. We convened an international group of leaders in paediatric pain to design a suite of seven reviews in chronic 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 under a programme grant for children's pain utilising pharmacological interventions in children and adolescents (Appendix 1).
This protocol is based on a template for reviews of pharmacotherapies used to relieve pain in infants, children and adolescents. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence (Moore 2010a; Moore 2012; Appendix 2). This review will focus on paracetamol (acetaminophen) to treat chronic non‐cancer pain.
Description of the condition
This review will focus on chronic non‐cancer pain experienced by children and adolescents as a result of any type of chronic disease that occurs throughout the global paediatric population. Children's level of pain can be mild, moderate or severe, and pain management is an essential element of patient management during all care stages of chronic disease.
As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, or psychogenic. Chronic pain is pain that lasts three months or longer and can be accompanied by changes in lifestyle, personality and functional abilities, as well as by signs and symptoms of depression (Ripamonti 2008).
Whilst diagnostic and perioperative procedures performed to treat chronic diseases are a known common cause of pain in these patients, this review will not cover perioperative pain or adverse effects of treatments such as mucositis.
Description of the intervention
Paracetamol (also known as acetaminophen) is one of the most widely‐used analgesics around the world in both the adult and paediatric populations.
First marketed in the US and United Kingdom in the 1950s, paracetamol is now recommended in all healthcare setting guidelines as the first‐line analgesic for both adults and children who are experiencing mild to moderate pain (NICE 2016). Paracetamol is currently available across most countries worldwide in healthcare settings and can be accessed without prescription (WHO 2012).
The recommended dosage for adolescents (12 years and older) is generally a 500 mg to 1000 mg oral tablet or liquid formula (via rectum if necessary), at a frequency of every four to six hours, with a maximum of 4 grams over 24 hours (NICE 2016). For children below 12 years, oral and rectal doses are recommended as follows at the same frequency: 500 mg (10 to 12 years), 375 mg (8 to 10 years), 250 mg (6 to 8 years), 240 mg (4 to 6 years), 180 mg (2 to 4 years), 120 mg (6 to 24 months), 60 mg (3 to 6 months) (NICE 2016). For children under 3 months of age, the only recommended analgesic option is paracetamol (WHO 2012).
Paracetamol has proven to be safe in appropriate and controlled dosages (Forrest 1982). However, adverse effects of paracetamol in the paediatric population can include hepatic or renal failure with overuse or overdose (Zyoud 2015). Other, less common, side effects include: malaise; toxic epidermal necrolysis skin reactions (including Stevens‐Johnson syndrome), acute generalised exanthematous pustulosis; blood disorders including neutropenia, leucopenia, thrombocytopenia; and upon infusion, hypotension, flushing, and tachycardia (Forrest 1982; BNF 2016).
How the intervention might work
Although paracetamol has been widely used in medical practice, its mechanism of action remains uncertain (Graham 2013). The main proposed mechanism is the inhibition of cyclooxygenase (COX) enzymes through metabolism by the peroxidase function of these isoenzymes. This process results in inhibition of phenoxylradical formation from a critical tyrosine residue important for the cyclooxygenase activity of COX‐1 and COX‐2 and prostaglandin synthesis (Graham 2013; Jozwiak‐Bebenista 2014). Paracetamolis a preferential inhibitor of COX‐2 due to its gastrointestinal tolerance and poor inhibition of platelet activity (Graham 2013; Hinz 2008; Hinz 2012). In addition, recent evidence suggests that the analgesic action of paracetamol is mediated by inhibition of COX‐3 (Botting 2005).
Paracetamol is widely considered to be a safe drug when administered in appropriate doses (Jozwiak‐Bebenista 2014); however, there is clear evidence that higher doses or prolonged use of paracetamol can lead to liver failure (where the paracetamol compounds are metabolised), cardiovascular events and even death (Chan 2006; Daly 2008; Forman 2005; Graham 2013; Roberts 2015; Sheen 2002). Overall, paracetamol is considered a safe and effective analgesic option, which is tolerable with the majority of paediatric patients around the world. Using the recommended doses, severe side effects can be avoided and adequate relief of chronic pain can be achieved for the infant, child or adolescent.
Why it is important to do this review
The paediatric population is at risk of inadequate management of pain (AMA 2013). Some conditions that would be aggressively treated in adult patients are being managed with insufficient analgesia in the younger populations (AMA 2013). Although there have been repeated calls for best evidence to treat children's pain, such as Eccleston 2003, there are no easily available summaries of the most effective paediatric pain relief.
This review will form part of a Programme Grant to address the unmet needs of people with chronic pain, commissioned by the National Institute for Health Research (NIHR) in the UK. This topic was identified in June 2015 during consultation with experts in paediatric pain. Please see Appendix 1 for full details of the meeting. The standards used to assess evidence in chronic pain trials have changed substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is to encourage a move from using average pain scores, or average change in pain scores, to the number of people who have a large decrease in pain (by at least 50%). Pain intensity reduction of 50% or more has been shown to correlate with improvements in comorbid symptoms, function, and quality of life (Moore 2011a). These standards are set out in the reference guide for pain studies (AUREF 2012).
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.
Methods
Criteria for considering studies for this review
Types of studies
We will only include randomised controlled trials (RCTs), with or without blinding, and participant or observer reported outcomes.
Full journal publication is required, with the exception of online clinical trial results, summaries of otherwise unpublished clinical trials and abstracts with sufficient data for analysis. We will include studies published in any language. We will exclude abstracts (usually meeting reports) or unpublished data, non‐randomised studies, studies of experimental pain, case reports, and clinical observations.
Types of participants
We will include studies of infants, children, and adolescents, aged from birth to 17 years old, who have chronic or recurrent pain (lasting for three months or longer, or for more than half one's life), arising from genetic conditions, neuropathy, or other conditions.
We will exclude studies of perioperative pain, acute pain, cancer pain, headache, migraine, and pain associated with primary disease or its treatment.
We will include studies of participants with more than one type of chronic pain, and then we will analyse results according to the primary condition.
Types of interventions
We will include studies reporting interventions prescribing paracetamol for the relief of chronic pain; by any route, in any dose, with comparison to a placebo or any active comparator. We will not consider interventions prescribing paracetamol in combination with another drug (such as opioids), as this comparison is covered in the two opioid reviews as part of this suite (Cooper 2017a; Wiffen 2017a).
Types of outcome measures
Studies must report pain assessment to be eligible for inclusion in this review, as well as meeting the other selection criteria.
We will include trials measuring pain intensity and pain relief assessed using validated tools such as numerical rating scale (NRS), visual analogue scale (VAS), Faces Pain Scale ‐ Revised (FPS‐R), Colour Analogue Scale (CAS), or any other validated numerical rating scale.
We are particularly interested in Paediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT) definitions for moderate and substantial benefit in chronic pain studies (PedIMMPACT 2008). These are defined as: at least 30% pain relief over baseline (moderate); at least 50% pain relief over baseline (substantial); much or very much improved on Patient Global Impression of Change scale (PGIC; moderate); very much improved on PGIC (substantial).
These outcomes are different from those used in most earlier reviews, concentrating as they do on dichotomous outcomes where pain responses do not follow a normal (Gaussian) distribution. People with chronic pain desire high levels of pain relief, ideally more than 50% pain intensity reduction, and ideally having no worse than mild pain (Moore 2013a; O'Brien 2010).
We will also record any reported adverse events. We will report the timing of outcome assessments.
Primary outcomes
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Participant‐reported pain relief of 30% or greater.
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Participant‐reported pain relief of 50% or greater.
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PGIC much or very much improved.
In the absence of self‐reported pain, we will consider the use of 'other‐reported' pain, typically by an observer such as a parent, carer, or healthcare professional (Stinson 2006; von Baeyer 2007).
Secondary outcomes
We identified the following with reference to the PedIMMPACT recommendations, which suggest core outcome domains and measures for consideration in paediatric acute and chronic/recurrent pain clinical trials (PedIMMPACT 2008):
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carer global impression;
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requirement for rescue analgesia;
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sleep duration and quality;
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acceptability of treatment;
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physical functioning as defined by validated scales;
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quality of life as defined by validated scales;
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any adverse events;
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withdrawals due to adverse events; and
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any serious adverse event. Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an 'important medical event' that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics or consequences.
Search methods for identification of studies
The authors will develop the search strategy, based on previous strategies used within the PaPaS Review Group, and we will carry out the searches.
Electronic searches
We will search the following databases:
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Cochrane Central Register of Controlled Trials (CENTRAL) (via the Cochrane Library);
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MEDLINE (via Ovid); and
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Embase (via Ovid).
We will use medical subject headings (MeSH) or equivalent and text word terms. We will restrict our search for randomised controlled trials and clinical trials. There will be no language restrictions. There will be no date restrictions. The focus of the key words in our search terms will be on chronic pain and paracetamol. Searches will be tailored to individual databases. The search strategy for MEDLINE is in Appendix 3.
Searching other resources
We will search clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials. In addition, we will check reference lists of reviews and retrieved articles for additional studies, and perform citation searches on key articles. We will contact experts in the field for unpublished and ongoing trials. We will contact study authors where necessary for additional information.
Data collection and analysis
We will perform separate analyses according to particular chronic pain conditions. We will combine different chronic pain conditions in analyses for exploratory purposes only.
Selection of studies
Two review authors will independently determine eligibility by reading the abstract of each study identified by the search. Independent review authors will eliminate studies that clearly do not satisfy inclusion criteria, and obtain full copies of the remaining studies. Two review authors will read these studies independently to select relevant studies, and in the event of disagreement, a third author will adjudicate. We will not anonymise the studies in any way before assessment. We will include a PRISMA flow chart in the full review which will show the status of identified studies (Moher 2009) as recommended in part 2, section 11.2.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will include studies in the review irrespective of whether measured outcome data are reported in a ‘usable’ way.
Data extraction and management
We will obtain full copies of the studies and two authors will independently carry out data extraction. Where available, data extraction will include information about the pain condition, number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration and follow‐up, analgesic outcome measures and results, withdrawals, and adverse events (participants experiencing any adverse event, or serious adverse event). We will collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review. We will collect characteristics of the included studies in sufficient detail to populate a table of ‘Characteristics of included studies’ in the full review.
We will use a template data extraction form and check for agreement before entry into Cochrane's statistical software Review Manager 5.3 (RevMan 2014).
If a study has more than two intervention arms, we will only include in the review intervention groups and control groups that meet the eligibility criteria. If multi‐arm studies are included, we will analyse multiple intervention groups in an appropriate way that avoids arbitrary omission of relevant groups and double‐counting of participants.
Assessment of risk of bias in included studies
Two authors will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will complete a 'Risk of bias' table for each included study using the 'Risk of bias' tool in RevMan (RevMan 2014).
We will assess the following for each study. Any disagreements will be resolved by discussion between review authors and where necessary, a third review author.
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Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (i.e. any truly random process, for example random number table; computer random number generator); or unclear risk of bias (when the method used to generate the sequence is not clearly stated). We will exclude studies at high risk of bias that use a non‐random process (for example, odd or even date of birth; hospital or clinic record number).
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Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We will assess the methods as: low risk of bias (for example, telephone or central randomisation; consecutively numbered, sealed, opaque envelopes); or unclear risk of bias (when the method is not clearly stated). We will exclude studies that do not conceal allocation and are therefore at a high risk of bias (for example, open list).
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Blinding of participants and personnel (checking for possible performance bias). We will assess any methods used to blind the participants and personnel from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that the participants and personnel involved were blinded to treatment groups); unclear risk of bias (study does not state either way as to whether participants and personnel were blinded to treatment groups); or high risk of bias (participants or personnel were not blinded) (as stated in Types of studies, we will still include trials, with or without blinding, and participant or observer reported outcomes).
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Blinding of outcome assessment (checking for possible detection bias). We will assess any methods used to blind the outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (e.g. study states that it was single‐blinded and describes the method used to achieve blinding of the outcome assessor); unclear risk of bias (study states that outcome assessors were blinded but does not provide an adequate description of how it was achieved); or high risk of bias (outcome assessors were not blinded) (as stated in Types of studies, we will still include trials, with or without blinding, and participant or observer reported outcomes).
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Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk of bias (i.e. less than 10% of participants did not complete the study or used 'baseline observation carried forward' (BOCF) analysis, or both); unclear risk of bias (used 'last observation carried forward' (LOCF) analysis); or high risk of bias (used 'completer' analysis).
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Selective reporting (checking for possible reporting bias). We will assess the methods used to report the outcomes of the study as: low risk of bias (if all planned outcomes in the protocol or methods were also reported in the results); unclear risk of bias (if there is not a clear distinction between planned outcomes and reported outcomes); high risk of bias (if some planned outcomes from the protocol or methods are clearly left out of the results).
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Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (fewer than 50 participants per treatment arm).
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Other bias. We will assess studies for any additional sources of bias as low, unclear or high, and provide rationale.
Measures of treatment effect
Where dichotomous data are available, we will calculate a risk ratio (RR) with 95% confidence intervals (CIs) and meta‐analyse the data as appropriate. We will calculate numbers needed to treat for an additional beneficial outcome (NNTBs) where appropriate (McQuay 1998); for unwanted effects the NNTB becomes the number needed to treat for an additional harmful outcome (NNTH) and is calculated in the same manner. Where continuous data are reported, we will use appropriate methods to combine these data in the meta‐analysis.
Unit of analysis issues
We will accept randomisation to the individual patient only. We will split the control treatment arm between active treatment arms in a single study if the active treatment arms are not combined for analysis.
Dealing with missing data
We will use intention‐to‐treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post‐baseline assessment. Missing participants will be assigned zero improvement wherever possible.
Assessment of heterogeneity
We will identify and measure heterogeneity as recommended in chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will deal with clinical heterogeneity by combining studies that examine similar conditions. We will undertake and present a meta‐analysis only if participants, interventions, comparisons, and outcomes are judged to be sufficiently similar to ensure an answer that is clinically meaningful. We will assess statistical heterogeneity visually (L'Abbé 1987), and with the use of the I² statistic. When I² is greater than 50%, we will consider the possible reasons.
Assessment of reporting biases
We will use the Cochrane tool for assessing the risk of reporting bias, as recommended in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
The aim of this review is to use dichotomous outcomes of known utility and of value to patients (Hoffman 2010; Moore 2010b; Moore 2010c; Moore 2010d; Moore 2013a). The review will not depend on what the authors of the original studies chose to report or not, though clearly difficulties will arise in studies failing to report any dichotomous results. We will extract and use continuous data, which probably will reflect efficacy and utility poorly, and may be useful for illustrative purposes only.
We will assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean a number needed to treat (NNT) of 10 or higher; Moore 2008).
Data synthesis
We plan to use a fixed‐effect model for meta‐analysis. We will use a random‐effects model for meta‐analysis if there is significant clinical heterogeneity and it is considered appropriate to combine studies. We will conduct our analysis using the primary outcomes of pain and adverse events, and we plan to calculate the NNTHs for adverse events. We will use the Cochrane software program Review Manager 5.3 (RevMan 2014).
Quality of evidence
To analyse data, two review authors will independently rate the quality of each outcome. We will use the GRADE approach to assess the quality of the body of the evidence related to each of the key outcomes, and report our judgement in the 'Summary of findings' table (chapter 12, Higgins 2011; Appendix 4).
In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, if there are so few data that the results are highly susceptible to the random play of chance, or if studies use LOCF imputation in circumstances where there are substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where there were no data reported for an outcome, we would report the level of evidence as no evidence to support or refute (Guyatt 2013b).
'Summary of findings' table
We plan to include a 'Summary of findings' table as set out in the Cochrane Pain, Palliative and Supportive Care Review Group’s author guide (AUREF 2012), and recommended in the Cochrane Handbook for Systematic Reviews of Interventions, chapter 4.6.6 (Higgins 2011). We will justify and document all assessments of the quality of the body of evidence.
In an attempt to interpret reliability of the findings for this systematic review, we will assess the summarised data using the GRADE guidelines (Appendix 4) to rate the quality of the body of evidence (Guyatt 2011) of each of the key outcomes listed in Types of outcome measures (chapter 12, Higgins 2011), as appropriate. Utilising the explicit criteria against: study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect, we will summarise the evidence in an informative, transparent and succinct 'Summary of findings' table or 'Evidence profile' table (Guyatt 2011).
Subgroup analysis and investigation of heterogeneity
We plan to perform subgroup analyses where a minimum number of data are available (at least 200 participants per treatment arm). We will analyse according to age group; type of drug; geographical location or country; type of control group; baseline measures; frequency, dose and duration of drugs; nature of drug.
We will investigate whether the results of subgroups are significantly different by inspecting the overlap of confidence intervals and performing the test for subgroup differences available in RevMan.
Sensitivity analysis
We do not plan to carry out any sensitivity analysis because the evidence base is known to be too small to allow reliable analysis; we will not pool results from chronic pain of different origins in the primary analyses. We will examine details of dose escalation schedules in the unlikely situation that this could provide some basis for a sensitivity analysis.
