MethodsWe conducted a multicentre, longitudinal, double-blind, doubledummy, add-on, randomized controlled trial. Healthy infants receiving vaccinations in 3 pediatric outpatient clinics, including 7 physician practices in Toronto were eligible. We excluded infants born before 36 weeks' gestation, infants who had stayed in hospital outside of postnatal care, and infants who were allergic to amide ABSTRACT BACKGROUND: Vaccine injections can cause acute pain and distress in infants, which can contribute to dissatisfaction with the vaccination experience and vaccine hesitancy. We sought to compare the effectiveness of additive pain interventions administered consistently during vaccine injections in the first year of life. RESEARCH Relative effectiveness of additive pain interventions during vaccination in infantsAnna METHODS:We conducted a multicentre, longitudinal, double-blind, add-on, randomized controlled trial. Healthy infants were randomly assigned to 1 of 4 levels of pain management for all vaccine injections at 2, 4, 6 and 12 months: (i) placebo control; (ii) parent-directed video education about infant soothing; (iii) the video plus sucrose administered orally or (iv) the video plus sucrose plus liposomal lidocaine applied topically. All infants benefit from injection techniques that minimize pain. We used a doubledummy design; hence all parents watched a video (active psychological intervention or placebo) and all infants received oral solution (sucrose or placebo) and topical cream (lidocaine or placebo). We assessed infant distress during 3 phases -preinjection (baseline), vaccine injection (needle), and 1 minute postinjection (recovery) -using the Modified Behavioural Pain Scale (range 0-10). We compared scores between groups and across infant ages using a mixed-model repeated-measures analysis. RESULTS:A total of 352 infants participated in the study, from Jan. 17, 2012, to Feb. 2, 2016. Demographics did not differ among intervention groups (p > 0.05). Baseline pain scores did not differ among intervention groups (p = 0.4), but did differ across ages (p < 0.001). Needle pain scores differed among groups (p = 0.003) and across ages (p < 0.001). The mean (± standard deviation) needle score was 6.3 (± 0.8) in the video-sucrose-lidocaine group compared with 6.7 (± 0.8) in each of the other groups. There were no other between-group differences. Recovery scores did not differ among groups (p = 0.98), but did differ across ages (p < 0.001). INTERPRETATION:Only liposomal lidocaine provided consistent analgesia within an additive pain intervention regimen during vaccinations in infants. Trial registration: ClinicalTrials.gov, no. NCT01503060 RESEARCH E228CMAJ | FEBRUARY 13, 2017 | VOLUME 189 | ISSUE 6anesthetics or vaccines and for whom mothers planned to use topical anesthetics, sucrose or breast feeding during vaccinations. Infants were randomly assigned to 1 of 4 pain-relieving regimens for all vaccine injections in their first year of life: (i) placebo control; (ii) parent-directed video education about i...