|Effectiveness and tolerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyses
|Shah V, Taddio A, Rieder MJ, HELPinKIDS Team
The authors concluded that topical local anaesthetics, sweet-tasting solutions, and combined interventions, including breastfeeding, appeared to reduce pain in children receiving vaccine injections and should be recommended for routine used in clinical practice. The authors’ conclusions were generally based on limited evidence and their reliability is unclear.
To assess the effectiveness and tolerability of pharmacologic and combined interventions on pain reduction during routine childhood immunisations.
MEDLINE (from 1950), EMBASE (from 1980), CINAHL (from 1982), and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to 2008 for published articles and academic theses in any language. Search terms were reported. In addition, reference lists of retrieved articles were manually searched and experts in the field were contacted. Abstracts were excluded.
Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of one or more clearly defined pharmacologic interventions on pain or distress in children (aged 0 to 18 years) undergoing vaccination by injection (in any hospital or community setting) were eligible for inclusion. Eligible trials could assess pharmacologic interventions, compare two different analgesic interventions, or evaluate combinations of two or more analgesic interventions, including breastfeeding. Eligible trials were required to use a validated technique (self-report by the child or by others) to measure pain or distress within five minutes of the vaccination, or after the last injection if multiple injections were administered. Secondary outcomes included measures of tolerability as determined by the adverse events reported for each type of intervention.
Included trials were conducted in the USA, Canada, Denmark, Finland, Turkey, Australia, Spain, UK, Jordan, Iran, and Sweden. Interventions were compared with a placebo (specific for the intervention), no intervention, or other pharmacological interventions. The types of vaccines administered to children and outcome measures used varied between trials.
Two reviewers screened studies for inclusion.
Assessment of study quality
Two reviewers assessed the quality of the included trials according to the Cochrane Collaboration’s ‘Risk of Bias’ tool, including criteria on: sequence generation, allocation concealment, blinding, completeness of outcome data, selective outcome reporting, and other potential bias. Each trial was given an overall rating of low, high or unclear risk of bias. Discrepancies were resolved by consensus or referral to a third reviewer if necessary.
Two reviewers independently extracted means and standard deviations (SDs) to calculate mean differences and 95% confidence intervals (CIs) for continuous outcomes. Categorical data were extracted to calculate relative risks (RRs) and risk differences (RDs). Where possible, data were extracted on an intention-to-treat basis; otherwise a per-protocol basis was used.
Disagreements were resolved through discussion or by referral to a third reviewer if necessary.
Methods of synthesis
Mean differences and 95% confidence intervals were combined to calculate weighted mean differences (WMDs) or standardised mean differences (SMDs), and relative risks and risk differences were combined using a fixed-effects model. The number needed to treat was also calculated. Data for child and parent assessments were reported separately from other assessors.
Statistical heterogeneity was assessed using the I2 statistic and X2 test. Where statistical heterogeneity was evident, a priori subgroup analysis was planned based on children’s age; where this was not possible, data were presented as a narrative synthesis. Where appropriate, sensitivity analysis was performed by excluding trials at high risk of bias.
Where there were 10 or more studies, publication bias was assessed through visual inspection of funnel plots.
Results of the review
Thirty-two trials (n=3,856; range) were included in the review, of which 23 were included in the meta-analysis. Some trials were included in more than one comparison. Six trials were at low risk of bias, eight trials were at high risk of bias, and the quality of the remaining 18 trials was unclear.
Topical local anaesthetics (nine trials): The two trials that compared a topical local anaesthetic versus a placebo showed conflicting findings in child self-reported pain. Trials using a visual analogue scale (two trials) and trials using the Modified Behavioural Pain Scale (MBPS; two trials) found a reduction in pain in children receiving a topical local anaesthetic (SMD -0.75, 95% CI -1.00 to -0.49; SMD -0.43, 95% CI -0.60 to -0.26) compared with placebo. There was no evidence of statistical heterogeneity
Sweet-tasting solutions (11 trials): There was evidence of statistical heterogeneity. Four of six trials found that sucrose, with or without non-nutritive sucking (i.e. pacifier), significantly reduced pain compared to no intervention or sterile water with or without non-nutritive sucking. Three of four trials reported significant reductions in crying duration in children receiving sucrose compared to children in the control groups.
Vapocoolants (four trials): There was evidence of statistical heterogeneity. The findings were inconsistent for differences in pain using vapocoolant versus placebo (two trials), and vapocoolant versus typical care (no treatment; two trials).
Comparison of two analgesic interventions (four trials): No statistically significant differences in pain or distress were found between topical local anaesthetics versus sucrose or distraction, 50% sucrose versus 25% sucrose, or sucrose versus hydrogenated glucose.
Combinations of two or more analgesic interventions (six trials): Child self-reported pain ratings (SMD -0.52, 95% CI -0.73 to -0.30; four trials) and parent-rated child pain (SMD -0.76, 95% CI -0.98 to -0.55; three trials) was reduced in children receiving combined analgesic interventions versus control.
Breastfeeding (four trials): Children who were breastfed before, during and after the intervention had less pain and shorter cry duration than those who were not breastfed (three trials; p<0.001).
Qualitative analyses for trials not included in the meta-analysis plus three effectiveness of interventions (based on route of injection, local skin reactions and antibody responses) were also reported in the review.
Topical local anaesthetics, sweet-tasting solutions, and combined interventions including breastfeeding, appeared to reduce pain in children receiving vaccine injections and should be recommended for routine used in clinical practice.
The review question and inclusion criteria were clearly defined. The literature search was adequate and was not restricted by language. However, attempts were not made to locate unpublished data, which meant that potentially relevant papers may have been missed. The authors did not report the findings from the assessment of publication bias. The authors undertook each stage of the process in duplicate, minimising the risk of reviewer error and bias.
The authors performed an appropriate validity assessment, but the quality of the included trials was generally poor or unclear; this was not investigated as part of the data synthesis. A fixed-effect model may not have been appropriate given the potential for statistical heterogeneity, but where statistical heterogeneity was significant, data were appropriately presented as a narrative synthesis. The authors acknowledged certain limitations with the included trials, such as the small number of trials for some interventions, small sample sizes, limited number of vaccines evaluated, low quality ratings, variability in pain assessment, heterogeneity between trial control groups, and missing summary statistics for a few trials.
The authors’ conclusions were generally based on a small number of trials and outcomes were often measured using indirect observations, so the reliability of the authors’ conclusions is unclear.
Implications of the review for practice and research
Practice: The authors stated that topical local anaesthetics, sweet-tasting solutions, and combined interventions, including breastfeeding, should be recommended for routine used in clinical practice.
Research: The authors stated that further research is needed to evaluate the following interventions for injection vaccination pain: the effect of topical local anaesthetics on vaccination success rates as part of Phase III trials evaluating new vaccines and hypersensitivity; sucrose; vapocoolants; oral analgesics; and methods of bridging the gap between research findings and clinical practice.
Canadian Institutes of Health Research (CIHR) Knowledge Synthesis, grant number KRS-91783. One author received support from a CIHR New Investigator Award.
Shah V, Taddio A, Rieder MJ, HELPinKIDS Team. Effectiveness and tolerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyses. Clinical Therapeutics 2009; 31(Supplement 2): S104-S151
Other publications of related interest
Shah V, Taddio A, Rieder MJ. Effectiveness and tolerability of pharmacological and combined interventions for reducing injection pain during routine childhood immunizations: Systematic review and meta-analyses. Clinical Therapeutics; 2009; 31 (supplement B): S104-S151.
Subject indexing assigned by NLM
Acetaminophen /therapeutic use; Anesthetics, Local /therapeutic use; Anti-Inflammatory Agents, Non-Steroidal /therapeutic use; Breast Feeding /psychology; Child; Child, Preschool; Data Interpretation, Statistical; Databases, Bibliographic; Female; Humans; Ibuprofen /therapeutic use; Immunization /adverse effects; Infant; Injections /adverse effects; Male; Pain /etiology /prevention & control /psychology; Pain Measurement; Parents; Randomized Controlled Trials as Topic; Reproducibility of Results; Stress, Psychological /psychology; Sweetening Agents /therapeutic use; Taste /drug effects; Treatment Outcome
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.