Order of Vaccine Injection and Infant Pain Response

Objective  To determine if acute pain response after administration of the diphtheria, polio, and tetanus toxoids and acellular pertussis and Haemophilus influenzae type b (DPTaP-Hib) vaccine and the pneumococcal conjugate vaccine (PCV) is affected by the order in which they are given.

Design  Single-center, double-blind, randomized clinical trial.

Setting  Outpatient pediatric clinic in Toronto, Ontario, Canada.

Participants  Healthy infants 2 to 6 months of age undergoing routine immunization.

Interventions  Infants received either their primary DPTaP-Hib vaccine or the PCV first, followed by the other vaccine.

Main Outcome Measures  The primary outcome was infant pain during vaccine injection as assessed by a validated measure, the Modified Behavioral Pain Scale (MBPS), using videotaped recordings of the procedure. In addition, parents rated pain using a 10-cm visual analog scale (VAS). Crying (yes/no) was also measured.

Results  The study was conducted between July 21, 2006, and June 21, 2007. A total of 120 infants participated: 60 received the DPTaP-Hib vaccine first and 60 received the PCV first. Infant characteristics did not differ between groups. Overall mean (SD) pain scores per infant after receiving both vaccine injections were significantly lower when DPTaP-Hib was administered first compared with when PCV was administered first (MBPS score, 7.6 [1.5] vs 8.2 [1.5], P = .037; parent VAS score, 4.2 [2.3] vs 5.6 [2.6], P = .003). When given first, the DPTaP-Hib vaccine caused significantly less pain (P < .001) than the PCV, as assessed by the MBPS, VAS, and crying.

Conclusions  Pain was reduced when the DPTaP-Hib vaccine was administered before the PCV in infants undergoing routine vaccination. We recommend that the order of vaccine injections be the DPTaP-Hib vaccine followed by the PCV.

Trial Registration  clinicaltrials.gov Identifier: NCT00390130

Vaccine injections are the most common painful iatrogenic procedures performed in childhood. Multiple injections are routinely administered during a single visit to a physician. Because some vaccines cause more pain than others,¹ the order in which they are given may affect the overall pain experience. The objective of this study was to determine if acute pain response after administration of 2 separate vaccines was affected by the order in which they were administered.

We conducted a randomized, double-blind study of healthy infants 2 to 6 months of age who were attending a shared pediatric community practice in Toronto, Ontario, Canada, for their routine primary series of vaccinations. We excluded infants with acute febrile illness, chronic medical conditions, and allergy to any of the vaccine components or those concurrently receiving topical local anesthetics. Use of systemic analgesia (eg, ibuprofen, acetaminophen) before the vaccination was recorded and was not an exclusionary factor.

Infants received the diphtheria and tetanus toxoids, polio, acellular pertussis, and Haemophilus influenzae type b conjugate vaccine (DPTaP-Hib) (Pentacel; Sanofi Pasteur, Toronto) and the pneumococcal conjugate vaccine (PCV) (Prevnar; Wyeth, Montreal, Quebec, Canada) at the same physician's visit. Infants were randomized, using random computer-generated numbers, to receive either the DPTaP-Hib vaccine first or the PCV first immediately followed by the other vaccine.

Concealment of randomization allocation was achieved by performing the randomization off site by one of the investigators (P.C.P.) and placing the treatment assignment for each consecutive participating infant in a numbered and sealed opaque envelope that was opened by a clinic nurse immediately before vaccine injection. The clinic nurse preloaded the reconstituted vaccines into individual 3.5-mL syringes and labeled them according to the order in which they were to be administered. The clinic nurse was not involved in any other aspect of the study. Neither the pediatrician performing the injection nor the parent of the infant being vaccinated was aware of which vaccine was being administered. The composition of the different vaccines is given in Table 1. Both vaccines had the same pearly white appearance after reconstitution and were indistinguishable from one another in both color and volume injected.

Infants were immunized using a 25-gauge, 22-mm needle by 1 of 2 pediatricians (M.I. or M.G.). The immunization procedure was standardized. Infants were held during the entire procedure by a parent. During injection, the needle was inserted intramuscularly at 90° with steady pressure in the anterolateral aspect of the left or right thigh. The first and second vaccines were injected on alternate limbs within 1 to 2 minutes of each other. No aspiration was performed, and the vaccine material was rapidly injected for 1 to 2 seconds followed by rapid withdrawal of the needle.²

Infants were videotaped using a handheld camera (×40 magnification; Canon Optura Pi, Mississauga, Ontario, Canada) during administration of the vaccines. The primary outcome measure was infant pain, which was assessed from the videotapes by a research assistant blinded to the study hypothesis and treatment allocation, using the Modified Behavioral Pain Scale (MBPS). The MBPS is a behavioral measure that examines facial expression, crying, and body movement by assigning each behavior a score; scores for each observed behavior are summed, resulting in a total score per phase (before and after the painful event); the minimum score is 0, and the maximum score is 10. The MBPS was used to score baseline pain and postvaccination pain for each vaccination procedure. In all instances, the prevaccination pain scores were assessed 5 seconds before the commencement of vaccination; scores from 0 to 3 were assigned for each individual category of facial expression, crying, and body movement. Postvaccination pain scores were assessed within 15 seconds after the vaccination; facial expression and body movement scores ranged from 0 to 3, whereas crying scores ranged from 0 to 4. Scores were totaled for each phase; postvaccination scores were taken as the final MBPS score.³ In addition, parents rated pain using a 10-cm visual analog scale (VAS), where the left anchor denoted “no pain” and the right anchor denoted “worst possible pain.” Pain scores were obtained immediately after the first and second vaccine injections. Crying (yes/no) was assessed from the videotapes.

The study protocol was approved by the research ethics board at The Hospital for Sick Children, Toronto. Informed, signed consent was obtained from parents before enrolling participating infants.

A sample size of 57 infants in each group was calculated to be able to demonstrate a difference of 50% in pain scores between the 2 vaccines. The sample size calculation was made using data from a previous study¹ that used the MBPS. We recruited 60 infants in each group to account for missing data and dropouts.

The primary analysis compared the mean of the pain scores obtained per infant after the first and second vaccine injections between the 2 groups (ie, DPTaP-Hib vaccine injected first or PCV injected first), for the MBPS administered by an observer (hereafter, observer MBPS) and the VAS used by a parent (hereafter, parent VAS) using t tests. Pain scores were then compared between the groups (DPTaP-Hib vaccine injected first or PCV injected first) for each vaccine injection separately, using the t test (observer MBPS and parent VAS) or χ² (crying). We compared pain after the first vs second injection for all infants using the paired-samples t test. Baseline characteristics were compared between groups using the t test for continuous variables and the χ² test for categorical variables. The statistical significance level was P≤.05. All analyses were conducted using a commercially available software program (SPSS, version 15.0; SPSS Inc, Chicago, Illinois).

The study was conducted between July 21, 2006, and June 21, 2007. Of 126 parents of infants approached for participation, 120 infants were eligible and all of the parents agreed to let their children participate. Sixty infants were randomized to receive the DPTaP-Hib vaccine first and 60 received the PCV first (Figure). Demographic characteristics did not differ between groups (Table 2). Outcome data were available for all 120 infants using observer MBPS and crying scores and for 119 infants using parent VAS scores.

The primary analysis showed that the overall mean (SD) pain scores per infant following both vaccine injections were significantly lower when the DPTaP-Hib vaccine was administered first compared with when the PCV was administered first (MBPS score, 7.6 [1.5] vs 8.2 [1.5], P = .037; parent VAS score, 4.2 [2.3] vs 5.6 [2.6], P = .003) (Table 3).

Pain after the first injection was significantly lower when the DPTaP-Hib vaccine was administered first compared with when the PCV was administered first as assessed by observer MBPS (P < .001), parent VAS (P < .001), and crying (P < .001) (Table 4). Pain was lower after the second injection for observer MBPS (P = .004) but not for parent VAS (P = .94) or for crying in infants (P = .11) (Table 4). In all infants, pain increased from the first to the second injection (observer MBPS score, 7.3 [2.4] vs 8.6 [1.5], P < .001; parent VAS score, 3.9 [3.0] vs 5.9 [2.7], P < .001).

Infant pain response during routine intramuscular vaccine injection was affected by the order of administration of the vaccine. Infants given the less painful DPTaP-Hib vaccine first followed by the more painful PCV experienced less pain overall when compared with those given the vaccines in the reverse order. In addition, pain increased from the first to the second injection, regardless of the order of vaccine injection.

Our finding of variability in pain from different vaccine formulations is consistent with previous research.¹ The reason for these pain differences is presumed to be related to the physicochemical properties of the vaccine. The 2 vaccines used in this study have several differences (Table 1), including pH, which may account for the pain variability. In addition, our finding of an increase in pain with subsequent injections in infants exposed to repeated painful procedures is consistent with research in infants undergoing repeated heel lances⁴ and vaccine injections.⁵

To our knowledge, the effect of varying the order in which vaccines of different degrees of painfulness are given has not previously been examined. Our data suggest that the least painful vaccine should be administered first when 2 vaccines are given at 1 physician's visit to reduce overall pain. We hypothesize that, in the alternative, giving the more painful injection first focuses the infant's attention on the procedure and activates central and peripheral mechanisms of pain processing that together result in amplification of the pain signal during subsequent injections administered immediately thereafter.

Minimizing the pain of vaccine injection experienced by infants and children is currently receiving considerable attention by clinicians and pain researchers.⁶ Steps to minimize vaccine-related pain reduces the pain experienced by the child and improves the immunization experience of parents and health care workers. This is important because in a recent study⁷ of pediatricians in the United States, more than 90% reported at least 1 parental vaccine refusal in the past year, most commonly as a result of pain from multiple vaccines. Reductions in pain therefore have the potential to improve compliance with the vaccination schedule, thereby preventing a resurgence of vaccine-preventable infections. Varying the order of vaccine administration to reduce pain is a strategy that is simple and effective, cost free, and easily incorporated into clinical practice. In considering methods of reducing pain with vaccination, vaccine manufacturers must play a more integral role in attempting to produce vaccine formulations that are less painful.¹

In conclusion, pain was reduced when the DPTaP-Hib vaccine was administered before the PCV in infants undergoing routine vaccination. On the basis of these results, we recommend that the order of vaccines be the DPTaP-Hib vaccine followed by the PCV.

Correspondence: Moshe Ipp, MBBCh, Department of Paediatrics, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (mm.ipp@utoronto.ca).

Accepted for Publication: November 19, 2008.

Author Contributions:Study concept and design: Ipp, Parkin, Lear, and Taddio. Acquisition of data: Ipp, Lear, and Goldbach. Analysis and interpretation of data: Ipp, Parkin, and Taddio. Drafting of the manuscript: Ipp, Lear, and Taddio. Critical revision of the manuscript for important intellectual content: Ipp, Parkin, Goldbach, and Taddio. Statistical analysis: Parkin and Taddio. Obtained funding: Ipp. Administrative, technical, and material support: Ipp and Taddio. Study supervision: Ipp.

Financial Disclosure: None reported.

Funding/Support: This study was funded by an unrestricted grant from Sanofi Pasteur, Toronto, Ontario, Canada. Dr Taddio is supported by a New Investigator Award by the Canadian Institutes of Health Research. The Pediatric Outcomes Research Team is supported by a grant from The Hospital for Sick Children Foundation.