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April 2004

Effect of Choice of Measles-Mumps-Rubella Vaccine on Immediate Vaccination Pain in Infants

Author Affiliations

From the Division of Paediatric Medicine, Hospital for Sick Children, and Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario. Dr Ipp was invited to present the results of this study at the 21st Annual Meeting of the European Society for Paediatric Infectious Diseases, April 9-11, 2003, as one of several speakers at a GlaxoSmithKline Vaccine Satellite Symposium. GlaxoSmithKline covered the cost of Dr Ipp's transportation and accommodation at the meeting and provided an honorarium of €1600.

Arch Pediatr Adolesc Med. 2004;158(4):323-326. doi:10.1001/archpedi.158.4.323

Objective  To compare acute pain response to 2 measles-mumps-rubella vaccines.

Design  Double-blind clinical trial.

Setting  Hospital for Sick Children, Toronto, Ontario.

Patients  Forty-nine infants 12 months of age receiving their first measles-mumps-rubella vaccination.

Interventions  Random allocation to receive Priorix or M-M-R II.

Main Outcome Measures  Pain responses before (baseline) and after (within 15 seconds) vaccination were quantified by visual analog scale (VAS; range, 0-100), completed by the parent and independently by the pediatrician, and the Modified Behavioral Pain Scale (range, 0-10), scored by a coder blinded to the vaccine allocation. Crying (yes or no) and latency to the first cry after injection were also measured.

Results  Twenty-six infants received Priorix and 23 received M-M-R II. There were no differences between the 2 groups in baseline characteristics or prevaccination baseline pain scores. Median pain scores after vaccination (Priorix vs M-M-R II) were as follows: pediatrician VAS, 15 vs 58 (P = .001); parent VAS, 22 vs 53 (P = .007); and Modified Behavioral Pain Scale, 6 vs 8 (P = .02). Median difference in pain scores (after minus before) for Priorix vs M-M-R II were as follows: pediatrician VAS, 15 vs 53 (P = .003); parent VAS, 22 vs 47 (P = .008); and Modified Behavioral Pain Scale, 3 vs 5 (P = .03). The median latency to first cry was 1.5 seconds in the Priorix group compared with 1 second in the M-M-R II group (P = .26).

Conclusions  Priorix vaccine causes significantly less pain than M-M-R II at the time of injection for 12-month-old infants receiving their first measles-mumps-rubella vaccination.

Vaccination is often a stressful medical procedure for healthy infants and is a common cause of childhood iatrogenic pain.1,2 Concern about the adverse effects of immunization (including pain) may negatively influence vaccination uptake.3 A painful response to the measles-mumps-rubella (MMR) vaccination has previously been described,4 and several industry studies have reported less vaccination pain with Priorix (SmithKline Beecham Pharma, Oakville, Ontario) than M-M-R II (Merck Frosst Canada & Co, Montreal, Quebec).58 These studies, however, did not distinguish between immediate pain (at the time of injection) and delayed pain (at 30 minutes). The studies were also limited by the use of a single crude measure of pain (crying or not crying),4 lack of blinding,5 and the use of subjective, nonstandardized parent diaries.7

The objective of this study was to compare the immediate pain response to 2 licensed MMR vaccine products in infants receiving their first immunization at 12 months of age.


A randomized, double-blind, clinical trial was conducted. Pain responses to the subcutaneous administration of 2 commercially available MMR vaccines were measured. The Research Ethics Board of the Hospital for Sick Children, Toronto, Ontario, approved the study, and informed consent was obtained from all parents.

Study population

The sampling frame for the study was healthy children presenting to their community pediatrician (M.I. or M.G.) for their first MMR vaccination according to national guidelines.9 Children were excluded if they had chronic illness, immune deficiency, immunosuppression, history of anaphylaxis to egg protein, fever, or any acute illness that prevented the administration of the vaccine.


Two licensed vaccines were compared: Priorix and M-M-R II, both of which were supplied by the Ontario provincial government. Priorix is also available in Australia and Europe but not in the United States, and it does not have US Food and Drug Administration approval. Characteristics of the 2 MMR vaccines are shown in Table 1. Priorix contains the mumps strain RIT4385, which is a pure isolate of the dominant of 2 virus populations derived from the Jeryl Lynn mumps vaccine.10 Both vaccines were supplied in single-dose vials, each containing a freeze-dried pellet, and were stored at 2°C to 8°C. The vaccines were supplied with preservative-free diluent; the entire volume of the diluent (approximately 0.5 mL) was used to reconstitute the vaccine, and the entire volume was administered subcutaneously with a 25-gauge, 15-mm (⅝-in) needle into the lateral deltoid area.

Table 1. 
Characteristics of M-M-R II and Priorix Vaccines
Characteristics of M-M-R II and Priorix Vaccines
Randomization and study procedures

A random-numbers table was used to create a randomization schedule for the study. Numbered and sealed opaque envelopes contained information on vaccine allocation (Priorix or M-M-R II). Subjects were consecutively assigned a study number on recruitment that was linked to the same number on the randomization envelopes. To maintain blinding, a clinic nurse, who was not involved in the administration of the vaccine and who was unaware of the study hypothesis, reconstituted the vaccines. The nurse preloaded the reconstituted MMR vaccine in a 3.5-mL syringe and then wrapped the barrel with an opaque adhesive label. (Priorix, when reconstituted, has a pale pink color, while M-M-R II has a pale straw color.) Neither the pediatrician performing the injection (M.I. or M.G.) nor the parent of the infant being vaccinated was aware of which vaccine was being administered. No child was given topical (eg, lidocaine-prilocaine) or systemic (eg, ibuprofen, acetaminophen) analgesia before the vaccination. Immediately before the injection, the deltoid area was wiped with an alcohol swab and then dried with a cotton swab. The vaccine material was injected subcutaneously according to standard recommendations.11 The needle was inserted by a rapid plunge into a pinched-up fold of skin and subcutaneous tissue. "Aspiration," ie, pulling back on the syringe before injection, was not performed, as there are no data to document the necessity for this technique.11 The procedure was videotaped with a color digital camera, beginning 5 seconds before the vaccine was administered and continuing for 15 seconds after the vaccination. A mirror was mounted on the wall behind the examining table so that the videographer could film the infant's pain reaction both face on and from the mirror image. The videographer stood 1 m from the subject so as not to interfere with the procedure.

Outcome measures

Several outcome measures were used to assess the immediate pain response. Videotape recordings were used to calculate the Modified Behavior Pain Scale (MBPS) for infants (Table 2). Baseline and postvaccination pain scores (within 15 seconds) were based on a review of the videotapes by experienced coders who were blind to the vaccine allocation. The coders were specifically trained, by coding methods previously described, with good interrater agreement.12 The videotape was run in slow mode at 30 frames per second, allowing for precise measurement, in fractions of a second. The MBPS scale, previously validated in children, ranged from 0 to 10.12 Videotape recordings were also used to estimate cry duration and latency to first cry. Delayed pain response was not measured.

Table 2. 
Modified Behavioral Pain Scale*
Modified Behavioral Pain Scale*

At the time of vaccination, infants were held by a parent. No specific comfort measures were provided. A parent completed a 100-mm visual analog scale (VAS) before and after vaccination. For the VAS, 0 mm denoted no pain and 100 mm denoted maximum possible pain. The VAS has been used previously in the context of scoring infant pain.13 Parents were trained to use the VAS before the study. The first VAS was scored 5 seconds before injection and described the infant's prevaccination status. The second VAS was performed within 15 seconds of the vaccination and described the infant's pain response to the injection. The pediatrician similarly rated the infant's pain response before and after vaccination by means of the VAS. Agreement between parent and pediatrician VAS scores were estimated with the Pearson coefficient.

Sample size and analysis

The primary outcome was pain response to vaccination. On the basis of an α level of 5%, a "clinically important difference" in mean MBPS score between groups of 2 units, and a standard deviation of 2, a sample size of 42 subjects (21 per group) was required to provide 90% power to detect such a difference.12 Baseline characteristics of the 2 groups, ie, age, sex, previous hospital admission, previous circumcision, and distribution of subjects across pediatricians, were compared by means of the χ2 test or Mann-Whitney test. Prevaccination and postvaccination pain scores and the differences (after minus before vaccination) for the MBPS, pediatrician VAS, and parent VAS for the 2 groups (Priorix and M-M-R II), were compared with the Mann-Whitney test. P<.05 was considered significant.


Of the 49 subjects enrolled, 26 were randomized to Priorix and 23 to M-M-R II. As shown in Table 3, there were no significant differences between the 2 groups in age, sex, previous hospital admission, previous circumcision, or distribution of subjects across pediatricians. Because the outcomes measures were nonnormally distributed, medians (rather than means) were used as summary estimates. There were no differences between the 2 groups in prevaccination pain scores (Table 4). Median pain scores after vaccination, however, were significantly lower for Priorix than M-M-R II for all 3 outcome measures (pediatrician VAS, parent VAS, and MBPS). The median difference in pain scores (after minus before) showed similar results: Priorix vs M-M-R II for pediatrician VAS, 15 vs 53, respectively (P = .003); parent VAS, 22 vs 47, respectively (P = .008); and MBPS, 3 vs 5, respectively (P = .03). Physician and parent VAS scores were strongly correlated (Pearson coefficients ranging from 0.8 to 0.9). The median latency to first cry was 1.5 seconds in the Priorix group, compared with 1 second in the M-M-R II group (P = .26).

Table 3. 
Baseline Characteristics of the 2 Groups*
Baseline Characteristics of the 2 Groups*
Table 4. 
Outcome Pain Measurements for M-M-R II vs Priorix*
Outcome Pain Measurements for M-M-R II vs Priorix*

This study of 12-month-old infants showed that Priorix injection was associated with less pain at the time of vaccination than M-M-R II. All pain outcomes, completed by several different blinded assessors, favored Priorix. From a clinical significance perspective, the magnitude of the difference in MBPS pain scores between the 2 vaccines was similar to the difference in postvaccination MBPS pain scores between a local anesthetic (lidocaine-prilocaine cream) and placebo.13

One possible explanation for the variation in pain response between the 2 products is the difference in pH of the injected material. M-M-R II is slightly acidic (pH 6.2-6.6) compared with Priorix, which has a more neutral pH (pH 7.2-7.6).6 The excipients, stabilizers, preservatives, and adjuvants for each product are also likely different and may be contributing factors to the pain response.

Other studies68 have demonstrated better local tolerability of Priorix than M-M-R II. However, these studies had major methodologic limitations, such as poorly described pain tools, no blinding, and failure to distinguish immediate pain (within 15 seconds) from delayed pain (up to 30 minutes) after vaccination. A difference in pain response on injection was also shown, in a previous study, between M-M-R II and Pluserix (SmithKline French, Welwyn Garden City, England), a product similar to Priorix.4 Those given M-M-R II (Wellcome, Manchester, England) were 2.3 times more likely to cry than those given Pluserix. The children in that study, however, were significantly older (mean age, 44 months) than those in our study. In addition, the investigators used only a single crude measure of pain (crying or not crying). This may limit interpretation of the results, given that validated instruments have become available that more accurately measure pain in children. The use of videotape recording and the importance of facial expression for the evaluation of infant pain have contributed significantly to the accuracy of pain measurement in this age group.12,13

The study had several limitations. No attempt was made to assess vaccine reactogenicity beyond the immediate postvaccination period. Vaccine immunogenicity was not studied, but it has been shown to be equivalent for both vaccines.6 Infant temperament and the time of the last feeding were not assessed; however, one advantage of randomization is that both known and unknown confounders are likely distributed equally across the 2 groups.

With the plethora of vaccines that are now recommended for infants, the burden of pain, distress, and other common adverse vaccine reactions may interfere with parental compliance and aggravate antivaccine sentiment.14 Therefore, action to minimize vaccination pain would be a valuable strategy to improve vaccine tolerability. Strategies to diminish pain associated with vaccination should address vaccine components, which may play an important role in the pain of vaccination.

What This Study Adds

Pain may influence vaccination uptake. Previous studies have noted differences in pain response to MMR vaccine products; however, interpretation of these results has been limited because of methodologic and study design issues.

This randomized controlled trial showed that one MMR vaccine was less painful than another as determined by 3 outcome measures. Strategies to diminish pain associated with vaccination should consider the role of vaccine components.

Corresponding author: Moshe Ipp, MBBCh, Division of Paediatric Medicine, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8 (e-mail: mm.ipp@utoronto.ca).

Accepted for publication September 23, 2003.

We thank Suzanne Stewart for videotaping, Anne Jack for videotape coding, and Maha Chaltaf for administrative support.

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