Vaccine Reports

Pain in Adolescent Girls Receiving Human Papillomavirus Vaccine With Concomitantly Administered Vaccines Emmanuel B. Walter, MD, MPH,* Alex R. Kemper, MD, MPH, MS,* Rowena J. Dolor MD, MHS,* and Eileen F. Dunne MD, MPH† Abstract: Using the Faces Pain Scale - Revised, we assessed injection site pain 10 minutes after vaccination in young females randomized to receive either quadrivalent human papillomavirus vaccine (HPV4) before or after concomitantly administered vaccines. Although pain was modestly more after HPV4 injection than after other vaccines, the pain intensity after HPV4 injection was significantly less in those who received HPV4 before receiving other concomitant vaccines. Key Words: human papillomavirus, vaccine, pain (Pediatr Infect Dis J 2015;34:200–202)

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he Advisory Committee on Immunization Practices recommends routine administration of human papillomavirus vaccine (HPV) at age 11 or 12 years.1,2 The tolerability of HPV has been described when administered either alone or concomitantly with other vaccines; quadrivalent HPV (HPV4) was noted to be less painful when compared with tetanus, diphtheria and acellular pertussis vaccine.3 Nonetheless, anecdotal reports suggest that HPV hurts more than other vaccines.4 In clinical investigations, injection site pain following HPV is generally assessed by the use of daily diary cards completed by either the participant or their parent up to 7 days after vaccination. In this report, we describe the use of the Faces Pain Scale - Revised (FPS-R) to describe injection site pain after the administration of HPV4 and concomitantly administered vaccines.

METHODS This was a nested un-blinded randomized clinical trial to assess pain associated with administration of HPV4 and other concomitantly administered vaccines. Between June 2009 and March 2012, adolescent females aged 9–18 years were recruited from 3 pediatric practices in Durham and Chapel Hill, North Carolina. All participants were simultaneously enrolled in a larger observational cohort study of HPV4 immunity assessed prior to and following a Accepted for publication August 04, 2014. From the *Clinical Vaccine Unit and Primary Care Research Consortium, Duke University School of Medicine, Durham, NC and †Division of STD Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia. This work was supported by a cooperative agreement between Duke University School of Medicine and AAMC-CDC: #5U36CD319276. Dr. Walter has been a speaker, consultant, clinical investigator and served on an advisory board for Merck & Co., Inc. Disclaimer: The views in this article are those of the authors and do not necessarily represent the views of the Association of American Medical Colleges or the Centers for Disease Control and Prevention, US Department of Health and Human Services. Prior Presentation of Data: Data were previously presented in part at the Pediatric Academic Societies Annual Meeting, May 4–7, 2013, Washington, DC. Address for correspondence: Emmanuel B. Walter, MD, MPH, Duke Children’s Primary Care, 4020 North Roxboro Street, Durham, NC 27704. E-mail: [email protected] Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3402-0200 DOI: 10.1097/INF.0000000000000537

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3rd dose of HPV4. Using a blocked randomization scheme, participants received either a 3rd dose of HPV4 followed by concomitant vaccines or concomitant vaccines followed by a 3rd dose of HPV4. Clinic staff were instructed to administer HPV4 in the nondominant arm and concomitant injections in the dominant arm. Participants were not blinded to which vaccine was being administered. The FPS-R (scale: 0–10) was used to assess pain in each arm proximate to the site of the injection or injections 10 minutes following vaccination.5,6 The study protocol was approved by the Duke University Health System Institutional Review Board and was also registered with ClinicalTrials.gov (NCT00862810). Descriptive and exploratory analyses examined demographic characteristics and pain following HPV4 and concomitantly administered vaccinations. An intention-to-treat (ITT) analysis included all randomized subjects receiving HPV4 and at least 1 concomitantly administered vaccine. A per-protocol (PP) analysis included those randomized subjects who received HPV4 and their concomitantly administered vaccines in alternate arms as specified in the protocol. The χ2 test or Fisher exact test was used for categorical data analysis. In a matched pair analysis, the Wilcoxon signedrank test was used to compare pain scores between arms and the Wilcoxon rank-sum test was used to compare pain scores between randomized groups (JMP Pro 10.0.0; SAS Institute Inc., Cary, NC).

RESULTS Of 331 adolescent females enrolled in the larger study of HPV4 immunogenicity, 72 participants received 1 or more injectable vaccines in addition to their 3rd dose of HPV4 and comprise the ITT population. Forty percent of the ITT population was 9–13 years of age with the remaining 60% being older (Table 1). Thirtythree (46%) participants were randomized to the group receiving the HPV first and 39 (54%) participants to the group receiving concomitant vaccines first. No significant differences in age or race were observed between the study groups. In the ITT group, 60 (83.3%) participants received 1 vaccine in addition to HPV4, 11 (15.3%) received 2 vaccines and a single (1.4%) participant received 3 vaccines. The types of vaccines administered are described in Table 1. The number of concomitant vaccines received did not vary significantly according to the order in which HPV4 was administered. Hepatitis A vaccine was received more often in those receiving concomitant immunizations first while the distribution of the other vaccines received did not differ between groups. Sixty-four (89%) participants received HPV4 and concomitantly administered vaccines in opposite arms, as specified, and comprise the PP population. In both ITT and PP analyses, girls reported higher pain scores in the arm where HPV4 vaccine was administered (median = 2 and range: 0–8 for both) when compared with the arm where concomitant vaccines were administered (median = 0 for both and range: 0–8 for ITT and 0–6 for PP), (P < 0.001 for both analyses). This finding was consistent for both randomized groups regardless of whether they received HPV4 or concomitant vaccines first. In the PP analysis, the median pain score in the arm where HPV was administered was 4 in the group receiving concomitant vaccines first and 2 in the

The Pediatric Infectious Disease Journal  •  Volume 34, Number 2, February 2015

The Pediatric Infectious Disease Journal  •  Volume 34, Number 2, February 2015

Pain Following HPV Vaccine

TABLE 1  Participant Demographics, Concomitant Vaccines and Reported Pain in Each Arm Using the Faces Pain Scale - Revised According to Whether They Received Human Papillomavirus Vaccine or Concomitant Vaccines First

Demographic information   Age (years)    9–13    14–18  Ethnicity    Hispanic    Non-Hispanic  Race    Black   White   Asian    Other Concomitant vaccines   Number received    One   Two   Three  Type    Inactivated influenza    Hepatitis A    Meningococcal conjugate   Tetanus, diphtheria, acellular pertussis   Varicella   Measles, mumps, rubella  Pain   FPS-R score higher in arm where HPV   received c­ ompared with arm where   concomitant vaccines received

HPV4 First n = 33

Concomitant Vaccines First n = 39

Total Group N = 72

n (%)

n (%)

n (%)

P

14 (42.4) 19 (57.6)

15 (38.5) 24 (61.5)

29 (40.3) 43 (59.7)

0.73*

0 (0.0) 33 (100.0)

1 (2.6) 38 (97.4)

1 (1.4) 71 (98.6)

0.35*

15 (45.5) 16 (48.5) 1 (3.0) 1 (3.0)

15 (38.5) 23 (59.0) 1 (2.5) 0 (0.0)

30 (41.7) 39 (54.1) 2 (2.8) 1 (1.4)

0.62*

28 (84.8) 5 (15.2) 0 (0.0)

32 (82.0) 6 (15.4) 1 (2.6)

60 (83.3) 11 (15.3) 1 (1.4)

0.65*

18 (54.5) 4 (12.1) 10 (30.3) 3 (9.1) 2 (6.1) 1 (3.0)

20 (51.3) 14 (35.9) 8 (20.5) 3 (7.7) 2 (5.1) 0 (0.0)

38 (52.8) 18 (25.0) 18 (25.0) 6 (8.3) 4 (5.6) 1 (1.4)

0.82† 0.03† 0.42† 1.00† 1.00† 0.46†

17 (51.5)

32 (82.0)

49 (68.0)

0.005*

FPS-R indicates Faces Pain Scale - Revised; HPV, human papillomavirus. *χ2 test. †Fisher exact test.

group receiving HPV4 first (P = 0.022). Similarly, when compared to participants randomized to receive their concomitant vaccine first, a smaller proportion of participants randomized to receive HPV4 first reported more pain in the arm where HPV4 was administered when compared with the other arm (Table 1). These findings were consistent in the PP population with 30 of 35 receiving concomitant vaccines first reporting more pain and 15 of 29 receiving HPV first reporting more pain (P = 0.003). These findings were true even after excluding those who received hepatitis A vaccine. In the ITT, population demographic variables, including age and race, were unrelated to pain scores in the HPV4 arm (P = 0.26 and P = 0.61, respectively) or to the occurrence of more pain in the HPV4 arm rather than the alternate arm (P = 0.51 and P = 0.27, respectively).

DISCUSSION In our study, young girls reported a modestly higher pain score in the arm where HPV4 was administered in the period immediately following receipt of HPV4 when contrasted to the pain score in the arm where other vaccines were concomitantly administered. These findings differ from a report in which parents reported that their daughters experienced less pain following HPV4 compared with either meningococcal conjugate or tetanus, diphtheria and acellular pertussis vaccines.7 We also noted that administering HPV4 prior to other vaccine mitigates the report of pain severity as 30% fewer girls report more pain in the arm where HPV4 was received if they received HPV4 first rather than last. These findings conflict with those in infants suggesting that administering © 2014 Wolters Kluwer Health

the most painful vaccine last reduces the pain when 2 vaccines are given together.8,9 However, pain measurement methods varied significantly in these 2 different aged populations. Our investigation was small in size and exploratory. Participants were not blinded to treatment which could have introduced bias in pain reports. Furthermore, our participants were all female adolescents receiving their 3rd dose of HPV4 and findings may not be generalizable to males, older females, or to those receiving 1st or 2nd doses. Nonetheless, our findings are relevant for physicians administering HPV4 along with other immunizations as it may be preferable for clinicians to administer HPV4 vaccine first. Increasing HPV4 vaccine tolerability by administering HPV4 first could potentially increase vaccine acceptability and thereby help improve lagging HPV vaccination coverage.

ACKNOWLEDGMENTS The authors wish to acknowledge the contributions of the following study team members: Beth Patterson RN, Lynn Harrington RN, Lori Hendrickson RN, Liz Fisher, Luis Ballon and Kathlene Chmielewski. In addition, we wish to acknowledge the assistance and support of the following pediatric practices: Durham Pediatrics, Duke Children’s Primary Care and Chapel Hill Pediatrics. References 1. Centers for Disease Control and Prevention. Quadrivalent Human Papillomavirus Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007;56(No. RR-2):1–24.

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The Pediatric Infectious Disease Journal  •  Volume 34, Number 2, February 2015

2. Centers for Disease Control and Prevention. Recommendations on the Use of Quadrivalent Human Papillomavirus Vaccine in Males — Advisory Committee on Immunization Practices (ACIP), 2011. MMWR. 2011;60:1705–1708. 3. Arguedas A, Soley C, Loaiza C, et al. Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines. Vaccine. 2010;28:3171–3179. 4. Associated Press. Cervical cancer vaccine called most painful shot. FoxNews [Internet]. Available at: http://www.foxnews.com/ story/2008/01/04/cervical-cancer-vaccine-called-most-painful-shot/. Accessed January 4, 2008. 5. Bieri D, Reeve R, Champion GD, et al. The Faces Pain Scale for the selfassessment of the severity of pain experienced by children: Development,

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initial validation and preliminary investigation for ratio scale properties. Pain. 1990;41:139–150. 6. Hicks CL, von Baeyer CL, Spafford P, et al. The Faces Pain Scale Revised: Toward a common metric in pediatric pain measurement. Pain. 2001;93:173–183. 7. Reiter PL, Brewer NT, Gottlieb SL, et al. “How much will it hurt?” HPV vaccine side effects and influence on completion of the three-dose regimen. Vaccine. 2009;27(49):6840–6844. 8. Taddio A, Ilersich AL, Ipp M, et al.; HELPinKIDS Team. Physical i­ nterventions and injection techniques for reducing injection pain during routine childhood immunizations: Systematic review of randomized controlled trials and quasirandomized controlled trials. Clin Ther. 2009;31(Suppl 2):S48–S76. 9. Ipp M, Parkin PC, Lear N, et al. Order of vaccine injection and infant pain response. Arch Pediatr Adolesc Med. 2009;163(5):469–472.

© 2014 Wolters Kluwer Health

Pain in adolescent girls receiving human papillomavirus vaccine with concomitantly administered vaccines.

Using the Faces Pain Scale - Revised, we assessed injection site pain 10 minutes after vaccination in young females randomized to receive either quadr...
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