Introduction
Vaccination is the most common procedure performed in infancy, although parents might have significant concerns regarding the pain associated with routine vaccinations. Moreover, painful experiences very early in life can promote somatization later in life. Oral sucrose has been demonstrated to reduce pain reactions among neonates, and the current study examines this simple intervention prior to administration of routine vaccination at 2 and 4 months of age.
Best Evidence Reference
Hatfield LA, Gusic ME, Dyer A, Polomano RC
Analgesic Properties of Oral Sucrose During Routine Immunizations at 2 and 4 Months of Age
Pediatrics. 2008;121:e327-e334
Abstract
The study that this review is based on was selected from Medscape Best Evidence Medscape Best Evidence which uses the McMaster Online Rating of Evidence System. Out of a possible top score of 7, this study was ranked as 6 for relevance and 5 for newsworthiness by clinicians who used this system.
Commentary
Routine vaccinations are the most common procedures performed during infancy, and as recommendations for them have expanded to include varicella and influenza, children may now receive up to 24 injections by age 2. These vaccinations are critical to the prevention of morbidity and mortality in children, and parental involvement and consent is critical to achieve the goal of complete vaccination.
Parents generally agree with the need for vaccinations. In a study of 1600 parents completed in 1999, 87% of them believed that vaccination is extremely important to keep children well, and 84% preferred not to omit any required vaccines for their children.[1] However, 23% of these parents felt that their children received more vaccinations than was good for them, and one quarter of respondents feared that too many vaccinations would weaken their child’s immune system.
In another survey of parents, pain was their main concern regarding childhood vaccination.[2] Increasing the number of vaccinations in a single visit increased pain concerns among both parents and physicians. However, the majority of parents continued to prefer one visit for multiple vaccinations compared with several visits with fewer injections per visit, even when 4 injections were required at one visit.
The pain incurred during vaccination may do more than promote transient discomfort and parental anxiety. Some research has found that pain during the neonatal period is associated with increased sensitivity to pain during childhood, and animal studies suggest that pain early in life may produce permanent alterations in neuroanatomy and behavior.[3] In particular, neonates with a history of prematurity may be prone to the dual deleterious effects of prematurity and an increased number of painful procedures. In one comparison of 36 children with premature delivery and extremely low birth weight vs matched full-term controls, scores for somatization were higher in the premature cohort at age 4-1/2 years.[4] Rates of chronic illness were similar among the premature children with and without somatization, suggesting a causative role for trauma during the neonatal period.
Premature infants have been demonstrated to have increased pain sensitivity that can extend even beyond childhood. In a comparison of 60 adolescents with a history of preterm delivery and 60 adolescents delivered at full term, subjects with a history of preterm delivery had a higher number of tender points (6.0 vs 3.3) and also a lower pain threshold compared with subjects delivered at term.[5]
Despite data suggesting a long-term potential for complications related to pain experienced during the neonatal period, the practice of analgesia for this highly vulnerable population lags behind recommendations.[3] In a 2003 study of 151 neonates in the intensive care unit, the average number of procedures per day was 14, and 83.9% of procedures were judged to be painful.[6] However, fewer than 35% of neonates per study day received prophylactic analgesia, and 39.7% of the neonates did not receive any analgesic therapy at all during their stay in the intensive care unit. A 2006 review of whether oral sucrose administration alleviated pain from minor procedures in premature infants concluded that evidence was insufficient to draw any conclusions. However, sucrose was effective in reducing the pain response to single procedures among term infants.[7]
In the current study, the authors examined the effects analgesia on term infants, a group that has received less scrutiny in terms of trials of analgesia prior to painful procedures. Specifically, they performed a randomized, controlled trial of sucrose administration on healthy infants delivered between 37 and 42 weeks’ gestation. All infants were being seen for their routine vaccinations at ages 2 and 4 months. Infants who had been fed within 30 minutes of vaccination were excluded from study participation.
Participants received either a 24% disaccharide solution at a dose of 0.6 mL/kg, or matching placebo. Infants were not swaddled, cuddled, or restrained during vaccination or the ensuing data collection period.
Infants were assessed with the University of Wisconsin Children’s Pain Scale at baseline and 2, 5, 7, and 9 minutes after administration of the study treatment. This 5-point scale measures children’s pain using multiple variables, including cry, facial expression, behavior, and body movement, and is considered a valid means of assessing pain because of the use of multiple domains of measurement.
Infants received the combined diphtheria-tetanus-acellular pertussis, inactivated polio, and hepatitis B vaccine 2 minutes after receiving the study solution. They then received the Haemophilus influenzae type B vaccine 3 minutes later, and finally they received the pneumococcal conjugate vaccine 2 minutes after the H influenzae vaccine.
There were 100 infants were enrolled in the study, and 83 provided study data. Baseline data were similar between the sucrose and control groups. The mean gestational age and birth weight were 39 weeks and 3.5 kg, respectively.
The infants’ pain score peaked at 7 minutes, with mean scores of 3.80 and 4.81 in the sucrose and control groups, respectively. Sucrose was more effective than control therapy at 2 minutes (mean difference in pain score between sucrose and control treatment: -1.83), 5 minutes (-1.34), 7 minutes (-1.01), and 9 minutes (-2.16). At 9 minutes, the pain score had returned to near baseline in the sucrose group but remained elevated at 2.91 in the control group.
The study authors calculate that the number of additional infants needed to treat with sucrose vs placebo to achieve one more pain score of 0 or 1 at 2 minutes was 4. The number needed to treat to achieve a similar score at 9 minutes was only 2.
The most significant limitation of this study is that the vaccination procedure did not reflect that of most clinical practices. Whereas the separation of injections was important to standardize the current study protocol and monitor reactions to individual vaccines, most practices will perform all necessary vaccinations more rapidly in succession. Sucrose might have been even more effective in such a practice, assuming that sucrose produces a short, transient state of analgesia.
Sucrose has previously been demonstrated to improve outcomes among neonates undergoing painful procedures. In an analysis of 21 randomized controlled trials involving 1616 infants, sucrose at a wide range of doses (0.012 mg to 0.12 mg) improved the rate of crying at 30 and 60 seconds after heel lance.[8] However, sucrose was not effective in reducing heart rate at 1 and 3 minutes after heel lance.
Some practices employ other analgesic measures to reduce the pain of pediatric vaccinations. The application of the lidocaine-prilocaine patch prior to the first measles-mumps-rubella vaccine among children at least 12 months of age resulted in a significant reduction in Behavior Pain Scale scores vs placebo treatment.[9] Moreover, rates of irritability after vaccination were 16% in the lidocaine-prilocaine group vs 31% in the placebo group, and the antibody responses in the 2 groups to the vaccine components were similar.
Parents may also pretreat their children with oral analgesic medications prior to appointments for vaccination, and a study of acetaminophen delivered prior to administration of the diphtheria-pertussis-tetanus toxoids-polio vaccine largely supports this practice.[10] Compared with placebo, acetaminophen reduced the risk for fever greater than 38 degrees Celsius from 44% to 27%. Rates of behavioral changes after vaccination were 0.9% among the acetaminophen group vs 13% with placebo. However, acetaminophen was superior to placebo for primary vaccinations at 2 to 6 months of age but not for booster vaccination at 18 months of age. At the 18-month vaccination, the overall rate of systemic and local reactions was higher in both the acetaminophen and placebo groups. Another study has demonstrated that neither acetaminophen nor ibuprofen was effective in reducing the risk for local reactions such as erythema and swelling following the fifth diphtheria-tetanus toxoids-acellular pertussis vaccination.[11]
Two key questions remain regarding the implementation of sucrose for the prevention of pain in pediatric vaccinations. First, the weight-based dosing algorithm for sucrose in the current study certainly appeared effective, but the dosage range used in different studies has generally been quite wide. Further research should address the issue of the optimal dose of sucrose. In addition, it would be very easy to conceive that using other analgesics such as acetaminophen in addition to sucrose could be synergistic in improving pain and behavior after vaccination. Moreover, the use of antipyretic medications could also reduce the risk for postvaccination fever.
Regarding the practical utility of different methods of analgesia for routine infant vaccinations, lidocaine-prilocaine can be difficult to apply and maintain in place for the 30 minutes required for effective analgesia prior to procedures. Oral analgesics must also be delivered well before the vaccine is administered to be effective, and they expose infants and children to the remote possibility of significant adverse events. In contrast, sucrose appears to be a readily available and applicable means to reduce infants’ pain with vaccination. It is inexpensive and safe. Sucrose can also help parents to feel actively involved in protecting their infant from pain, and this should help increase acceptance of routine vaccinations. And that outcome should taste just like sugar for clinicians.
References
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American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee, Batton DG, Barrington KJ, Wallman C. Prevention and management of pain in the neonate: an update. Pediatrics. 2006;118:2231-2241. Abstract
Grunau RV, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors, as precursors of somatization: a prospective study of extremely premature and full term children. Pain. 1994;56:353-359. Abstract
Buskila D, Neumann L, Zmora E, Feldman M, Bolotin A, Press J. Pain sensitivity in prematurely born adolescents. Arch Pediatr Adolesc Med. 2003;157:1079-1082. Abstract
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Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev. 2004;3:CD001069.
Halperin SA, McGrath P, Smith B, Houston T. Lidocaine-prilocaine patch decreases the pain associated with the subcutaneous administration of the measles-mumps-rubella vaccine but does not adversely affect the antibody response. J Pediatr. 2000;136:789-794. Abstract
Ipp MM, Gold R, Greenberg S, et al. Acetaminophen prophylaxis of adverse reactions following vaccination of infants with diphtheria-pertussis-tetanus toxoids-polio vaccine. Pediatr Infect Dis J. 1987;6:721-725. Abstract
Jackson LA, Dunstan M, Starkovich P, et al. Prophylaxis with acetaminophen or ibuprofen for prevention of local reactions to the fifth diphtheria-tetanus toxoids-acellular pertussis vaccination: a randomized, controlled trial. Pediatrics. 2006;117:620-625.
Reviewed by Ramaz Mitaishvili, MD
