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Antipyretics and analgesics: Explaining their role in immunization
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Discomfort and pain associated with the administration of vaccine products is likely a common reason why children and caregivers alike do not look forward to pediatric office visits.
Indeed, “Will I get a shot?” may be the most common fear of children when they visit their health care providers. Parents and caregivers as well may dread observing their infants display discomfort during and after the immunization process. As such, it is not uncommon for caregivers to request prophylactic and post-treatment oral analgesic regimens. Although these treatment regimens may seem logical and reasonable, it is important to consider the evidence for their effectiveness and safety.
Edward A.
Bell
The use of acetaminophen or ibuprofen for prophylaxis and treatment during the immunization process may be common. Taddio reported in Pediatrics on the results of 140 Toronto-based pediatricians who responded to a survey about their use of analgesics (oral and topical) for the immunization process (vaccine administration and post-injection, hours-days). Of these pediatricians, 32% and 64% reported they commonly recommend oral analgesics (acetaminophen or ibuprofen) in their practices for vaccine administration and post-injection, respectively. By contrast, topical anesthetic products (eg, lidocaine-prilocaine) were recommended for vaccine administration by only 6% of the surveyed pediatricians.
A change in practice
How commonly pediatric caregivers recommend the use of oral analgesics for vaccine administration adverse effects, including fever, may have changed in 2009. Prymula and colleagues published the results of two large (n=459), controlled trials that evaluated the effects of acetaminophen on infant febrile reaction rates and vaccine immunologic response. The medication was given in the first 24 hours after immunization (two studies — primary and booster) with several combination vaccine products.
This study was designed open-label — acetaminophen use was compared with no prophylactic acetaminophen use. Although high fever (>39.5°C) was uncommonly reported and did not differ between the two groups, fever of higher than 38°C more commonly occurred, although significantly less in infants receiving acetaminophen after administration of both primary and booster vaccines. More importantly, however, this study documented that antibody geometric mean concentrations were significantly decreased for several vaccine antigens in infants who received acetaminophen.
Although a negative effect of acetaminophen on immune response was demonstrated, most infants in this study (≥96%) produced protective antibody concentrations for the vaccine antigens. It is interesting to note that acetaminophen similarly affected immune responses in infants with and without febrile reactions to immunization, and this effect occurred mainly with the primary dose of conjugate and toxoid vaccines. These researchers concluded that prophylactic use of acetaminophen for vaccine administration should not be routinely recommended. Results of this study contrast with two previous studies of diphtheria-tetanus-whole-cell pertussis vaccine administration, conducted by Uhari and Long, respectively. These studies found no adverse effect of acetaminophen upon immune response from DTP vaccine administration.
Authors of editorials in the medical literature have discussed that future research is needed to address the many unknowns that Prymala’s study revealed (eg, effects of patient age, specific vaccine products, individual and population immunologic protection, etc).
The AAP describes in the 2012 Red Book that “routine preemptive administration of acetaminophen is not recommended” for managing injection pain.
Sleep may be affected
A recently published study evaluated a different aspect of the immunization process, and potential effects of acetaminophen upon it. Franck and colleagues sought to determine the effects of acetaminophen and temperature responses on infant sleep duration after immunization. Some evidence with adults indicates that reduced sleep may adversely affect immune response to immunization. The small controlled trial published in Pediatrics in 2011 by Franck enrolled 70 infants and assessed infant sleep before and after immunization at aged 2 months.
Infants in the control group received standard care (which included acetaminophen given as needed), whereas infants in the treatment group received acetaminophen before and after immunization for a total of five doses. Sleep duration in the first 24 hours after immunization was increased, especially in infants with elevated temperatures after immunization and when immunizations were administered after 1:30 p.m.
Acetaminophen use resulted in smaller increases in sleep duration, but its use was not a significant contributor to sleep duration when other factors were controlled. The authors speculate that the mechanism of sleep duration may involve increased temperatures, and they relate their findings to Prymula’s study, which suggested antipyretics should not be given prophylactically when administering immunizations to infants. Infants enrolled in the study by Prymula, however, displayed similar immune responses regardless of exhibiting febrile reactions to immunization, which suggests that the mechanism of acetaminophen’s potential for immune modulation is not fever suppression. The study by Franck is limited by its low enrollment and lack of direct assessment of immunologic response to immunization.
Prophylactic administration of analgesics
As to whether acetaminophen or ibuprofen given prophylactically diminishes any adverse effects (local and systemic) associated with pediatric immunizations, there are no supportive published data. Manley and Taddio evaluated the published literature through 2007 to investigate this practice, and they located five studies. Four of these studies evaluated acetaminophen or ibuprofen use with DTP vaccine administration, and some benefit was demonstrated to reduce local erythema, fever and fussiness. One placebo-controlled study evaluated acetaminophen or ibuprofen in children aged 4 to 6 years (n=372) who were given diphtheria-tetanus-acellular pertussis vaccine and found no difference in rates of fever, local reactions or pain.
Other than acetaminophen and ibuprofen, the most common oral analgesic and antipyretic agents given by pediatric health care providers and caregivers, other analgesic agents and behavioral techniques can be offered to caregivers expressing concern over pain and discomfort that may occur with vaccine administration.
The most commonly used local analgesic product, eutectic mixture of local anesthetics, lidocaine-prilocaine (EMLA, AstraZeneca), is labeled for use in infants (including neonates) and children as a local anesthetic. Several controlled trials support its efficacy for decreasing pain from intramuscular and subcutaneous vaccine administration. Evidence from several controlled trials additionally supports the safety and lack of adverse immune-modulating effects of lidocaine-prilocaine upon several vaccine products (MMR, DTaP-IPV-Hib, hepatitis B).
A significant disadvantage of lidocaine-prilocaine use is its onset of action, approximately 60 minutes. With adequate planning, however (ie, administration before office visit), this local anesthetic agent can be beneficial for some families. The 2012 Red Book states that additional studies are needed to ensure that immune response is not altered with lidocaine-prilocaine use. Other safe and effective techniques (eg, distraction, sucrose, etc) for reducing pain in infants and children associated with immunization have been evaluated, and are well described by Schechter in a 2007 study in Pediatrics.
Further study needed
In conclusion, evidence from a large, well-controlled trial indicates that acetaminophen can have an adverse immune-modulating effect upon immunization with some vaccine antigens. Although the overwhelming majority of infants enrolled in this study did not display such an adverse effect, the frequency of vaccine administration and the clinical and public health implications of vaccine efficacy diminution also must be considered. Some experts are in agreement with the study authors that routine acetaminophen prophylaxis for vaccine administration should be abandoned.
Certainly, much information related to vaccine administration, analgesic administration and adverse effects is not known — does prophylaxis similarly affect immune response to other vaccines; importance of age; does ibuprofen result in similar effects (or even more significant effects, related to its anti-inflammatory actions); Is acetaminophen dose/route of administration/dosing schedule important? These questions deserve attention and scientific evaluation.
Similarly, the role of fever and its association with immunization and the immune response require further study. This may warrant increased explanation to caregivers that fever is not necessarily an adverse effect of immunization, but may in fact be beneficial. Caregivers can also be assured that other pharmacotherapeutic agents and other techniques can be effectively used to reduce pain and discomfort after immunization.
References:
Chen R. Lancet. 2009;374:1305-1306.
Franck L. Pediatrics. 2011;128:1100-1108.
Homme JH. Evid Based Med. 2010;15:50-51.
Manley J. Ann Pharmacother. 2007;41:1227-1232.
Prymula R. Lancet. 2009;374:1339-1350.
Schechter NL. Pediatrics. 2007;119:e1184-e1198.
Taddio A. Pediatrics. 2007;120:e637-e643.
For more information:
Edward A. Bell, PharmD, BCPS, is a professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. He can be reached at: Drake University College of Pharmacy, 2507 University Ave., Des Moines, IA 50311; email: ed.bell@drake.edu.
Disclosure: Bell reports no relevant financial disclosures.