Quality of Studies and Risk of Bias
Table 3 shows the results for the risk of bias assessment for critical outcomes. All trials had a high overall risk of bias primarily due to lack of blinding of important personnel.
Overall Quality of Evidence and Treatment Effects
A quantitative summary of the treatment effects for available critical outcomes is provided below, according to the clinical question; a qualitative summary is displayed in Table 4. Supporting GRADE Evidence Profiles and Summary of Findings tables (see Tables, Supplemental Digital Content 1 to 14, http://links.lww.com/CJP/A282, http://links.lww.com/CJP/A283, http://links.lww.com/CJP/A284, http://links.lww.com/CJP/A285, http://links.lww.com/CJP/A286, http://links.lww.com/CJP/A287, http://links.lww.com/CJP/A288, http://links.lww.com/CJP/A289, http://links.lww.com/CJP/A290, http://links.lww.com/CJP/A291, http://links.lww.com/CJP/A292, http://links.lww.com/CJP/A293, http://links.lww.com/CJP/A294, http://links.lww.com/CJP/A295) and accompanying Forest plots (see Figures, Supplemental Digital Content 1-14, http://links.lww.com/CJP/A296, http://links.lww.com/CJP/A297, http://links.lww.com/CJP/A298, http://links.lww.com/CJP/A299, http://links.lww.com/CJP/A300, http://links.lww.com/CJP/A301, http://links.lww.com/CJP/A302, http://links.lww.com/CJP/A303, http://links.lww.com/CJP/A304, http://links.lww.com/CJP/A305, http://links.lww.com/CJP/A306, http://links.lww.com/CJP/A307, http://links.lww.com/CJP/A308, http://links.lww.com/CJP/A309) for critically important and important outcomes are included as Supplemental Digital Content.
Should No Aspiration be Used (Rather Than Aspiration) During IM Injections in Individuals of All Ages?
Three trials including infants, children, and adults investigated the effects of not aspirating before IM vaccine injections.10–12 There was very low quality of evidence and the results were mixed (see Table, http://links.lww.com/CJP/A282 and Figure, http://links.lww.com/CJP/A296 SDC 1). In one of the studies including 114 children and adults, there was no evidence of a benefit for individuals vaccinated in the absence of aspiration versus those vaccinated with aspiration: SMD 0.28 (95% CI: −0.12, 0.68). In the other 2 studies including 313 infants, however, levels of acute distress were lower in those who received fast injections without aspiration compared with those who received slow injections with aspiration: SMD −0.82 (95% CI: −1.18, −0.46). Either a benefit or no difference was observed for other indicators of distress. It was not clear whether differences between groups were obscured in the former analysis by an insufficient duration of time allocated for aspiration, variability in the anatomic injection site, or the specific vaccine being administered to the participants. Injection speed was a potential confounder in the latter analysis.
Should Injecting the Most Painful Vaccine Last be Used (Rather Than First) During Vaccine Injections in Individuals of All Ages?
Two trials including infants in the first 6 months of life investigated the effect of injecting the most painful vaccine last.13,14 Included studies compared either: (1) pneumococcus conjugate vaccine, PCV (Prevnar) to diphtheria and tetanus toxoids, polio, acellular pertussis, and Haemophilus influenzae type b conjugate vaccine, DPTaP-Hib (Pentacel), or (2) Bacille Calmette-Guérin vaccine, BCG (Tubervac) to hepatitis B vaccine (GeneVac-B). There was moderate quality evidence for distress, the critical outcome (see Table, http://links.lww.com/CJP/A283 SDC 2). When given first, PCV and hepatitis B caused more pain than DPTaP-Hib and BCG, respectively. Administering the most painful vaccine last (ie, PCV after DPTaP-Hib and hepatitis B after BCG, respectively) caused lower overall infant acute distress for both injections (n=196): SMD −0.69 (95% CI: −0.98, −0.40) (see Table http://links.lww.com/CJP/A283 and Figure http://links.lww.com/CJP/A297, SDC 2).
Should Simultaneous Injections be Used (Rather Than Sequential Injections) During Vaccine Injection in Infants 0 to 1 Year?
Two studies including infants aged 2 to 6 months were included.15,16 The quality of evidence for the critical outcome of distress was low and the results were mixed for different indicators of distress (see Table http://links.lww.com/CJP/A284 and Figure, http://links.lww.com/CJP/A298 SDC 3). In the only analysis that included data from both studies (n=172), there was evidence for a reduction in acute distress in the simultaneous injection group: SMD −0.56 (95% CI: −0.87, −0.25). Either a benefit or no difference was observed for other indicators of distress.
Should Simultaneous Injections be Used (Rather Than Sequential Injections) During Vaccine Injection in Children Above 1 to 10 Years?
In 1 study including children aged 4 to 6 years,17 there was no evidence of a benefit for pain from simultaneous injections (n=44): SMD 0.31 (95% CI: −0.29, 0.90) (see Table http://links.lww.com/CJP/A285 and Figure, http://links.lww.com/CJP/A299 SDC 4). There was very low quality of evidence for this outcome (see Table, http://links.lww.com/CJP/A285 SDC 4).
Should the Vastus Lateralis be Used (Rather Than the Deltoid) as the Site of Injection During Vaccine Injections in Infants 0 to 11 Months?
One trial including 185 infants aged 4 months compared vaccine injections in the vastus lateralis versus the deltoid muscle.18 The quality of the evidence was low and the results were mixed (see Table http://links.lww.com/CJP/A286 and Figure, http://links.lww.com/CJP/A300 SDC 5). Less distress was observed for the vastus lateralis site during the acute and recovery procedure phases combined: SMD −0.70 (95% CI: −1.00, −0.41); however, there was no difference between groups during the acute procedure phase: SMD 0.11 (95% CI: −0.18, 0.40).
Should Skin-to-Skin Contact be Used During Vaccine Injections in Neonates 0 to 1 Month?
Three randomized trials in 736 neonates investigated skin-to-skin contact (whereby diaper-clad infants are positioned between their mother’s breasts) versus lying supine.19–21 Skin-to-skin contact was initiated at least 2 minutes before vaccine injection(s). The quality of evidence was moderate and there was evidence of benefit of this intervention across different phases of the procedure (see Table http://links.lww.com/CJP/A287 and Figure, http://links.lww.com/CJP/A301 SDC 6). For acute procedural distress specifically, the SMD was −0.65 (95% CI: −1.05, −0.25). For the recovery procedure phase, the SMD was −0.89 (95% CI: −1.26, −0.52).
Should Holding be Used (Rather Than Lying Supine) During Vaccine Injections in Children 0 to 3 Years?
Three trials examined holding versus lying supine during injections in infants aged 6 weeks to 6 months.22,23,44 Holding was carried out by a parent and was initiated before vaccine injection(s) and continued during and after injection(s). There was low to very low quality evidence across the different outcomes of distress (see Table, http://links.lww.com/CJP/A288 SDC 7). No significant benefit of holding was observed (n=213): SMD −0.72 (95% CI: −1.95, 0.51); however, in 1 included study, there was contamination of the control (lying supine) group whereby parents picked up infants immediately after vaccinations.23 Removal of the data from this study altered the results for acute distress; infants in the holding group had lower levels of distress compared with infants in the supine group: SMD −1.25 (95% CI: −2.05, −0.46). The results were not significant for other distress outcomes; although data were obtained by the same methodologically diverse study (see Table http://links.lww.com/CJP/A288 and Figure, http://links.lww.com/CJP/A302 SDC 7).
If Holding is Not Used During Vaccine Injections, Should a Combined Holding Intervention (Including Patting and/or Rocking) be Used After Vaccine Injections in Children 0 to 3 Years?
Two studies in infants aged 1 day to 4 months examined holding interventions after injections in infants lying supine during vaccination.24,25 The holding interventions included cuddling and back-patting24 or swaddling, side-lying, swinging, shushing, and sucking25 by a clinician. The way parents usually comfort their infants after vaccination was the comparison condition. There was low quality evidence and a benefit of the holding intervention was observed for both measures of distress evaluated: acute procedure distress and acute and recovery procedure distress combined (see Table http://links.lww.com/CJP/A289 and Figure, http://links.lww.com/CJP/A303 SDC 8). In the analysis including data from both studies (ie, distress during the acute and recovery phases) (n=417 infants), the SMD was −0.65 (95% CI: −1.08, −0.22).
Should Sitting Upright be Used (Rather Than Lying Supine) During Vaccine Injections in Children Above 3 Years and Adults?
In 1 trial including children aged 4 to 6 years, sitting upright was compared with lying supine.26 Pain and fear were critically important outcomes, and for both, the quality of evidence was low (see Table, http://links.lww.com/CJP/A290 SDC 9). The results were mixed: children in the sitting upright group reported lower levels of fear than those lying supine group postintervention (ie, after positioning but before the procedure) (n=107): SMD −0.39 (95% CI: −0.77, −0.01); pain from vaccination, however, did not differ significantly between groups: SMD 0.07 (95% CI: −0.31, 0.45). Given the young age range of the children that participated and the possibility of difficulty with self-report in this age group, we also examined distress. There was a significant reduction in acute and recovery period distress combined in the intervention group: SMD −10.3 (95% CI: −20.18, −0.42) (see Table http://links.lww.com/CJP/A290 and Figure, http://links.lww.com/CJP/A304 SDC 9).
Should Non-nutritive Sucking (eg, Finger/Thumb, Pacifier) be Used During Vaccine Injections in Children 0 to 2 Years?
Two studies including infants from 0 to 4 months of age were included in the systematic review.27,28 There was low quality evidence across the different outcomes of distress that were evaluated and evidence of benefit for all of them (see Table http://links.lww.com/CJP/A291 and Figure, http://links.lww.com/CJP/A305 SDC 10). In the only analysis including both studies (n=186 infants), the SMD was −1.88 (95% CI: −2.57, −1.18) for the outcome of acute distress. The rate of sucking may be important for effectiveness; included studies did not determine sucking rate.
Should Manual Tactile Stimulation be Used During Vaccine Injections in Individuals of All Ages?
Altogether, 6 studies investigated the effects of manual tactile stimulation versus no treatment on vaccine injection pain in infants, children, and adults.29–34 The intervention was delivered in various ways, including; manual pressure, rubbing/stroking, and tapping. The clinician delivered the intervention in all but 1 study, which used a parent instead.30 There was moderate to very low quality evidence for critical outcomes (pain and distress) (see Table, http://links.lww.com/CJP/A292 SDC 11). For 3 studies including an evaluation of self-reported pain (n=893),29,32,33 there was insufficient evidence of a benefit of manual tactile stimulation: SMD −0.38 (95% CI: −0.96, 0.21). In the remaining 3 studies in infants,30,31,34 there was no evidence of a benefit across indicators of distress, even when the study including parents as the deliverers of the intervention30 was excluded. In the only analysis that included all studies (n=301 infants), the SMD was −0.69 (95% CI: −1.77, 0.39) for acute distress (see Table http://links.lww.com/CJP/A292 and Figure, http://links.lww.com/CJP/A306 SDC 11). The evidence base included heterogeneity in the delivery of the intervention, type of injection, and cointerventions.
Should Tactile Stimulation Using an External Vibrating Device and Cold be Used During Vaccine Injection in Children Above 3 to 17 Years?
Two studies including children aged 4 to 7 years investigated the effect of externally applied vibrating devices with cold.35,36 In 1 study, a multifaceted tactile intervention was used whereby a vibrating device was applied to the contralateral arm in the form of a game, and an external tactile device was pressed on the skin on the ipsilateral side. In addition, a vapocoolant was sprayed on the vaccination site immediately before injection with a verbal suggestion of diminished sensation.35 In the other study, a vibrating device decorated as a bee with an ice pack attached to the underside (Buzzy) was applied by a researcher on the arm being vaccinated just above the injection site and kept there until the end of the injection.36 The quality of evidence for the critical outcomes (pain, fear) was low (see Table 12, http://links.lww.com/CJP/A293 SDC 12). There was a benefit of the vibrating device plus cold on pain (n=145): SMD −1.23 (95% CI: −1.58, −0.87). There was no evidence of a benefit for fear (n=104): SMD 0.28 (95% CI: −0.11, 0.66) (see Table http://links.lww.com/CJP/A293 and Figure, http://links.lww.com/CJP/A307 SDC 12). The contribution of cold and distraction to the effectiveness of both of these tactile interventions is not known.
Should Warming the Vaccine Before Vaccine Injections be Used in Individuals of All Ages?
One study evaluated the effect of warming the vaccine on vaccine injection pain in 150 adults.37 Vaccines warmed by rubbing with hands or by inserting into an incubator immediately before injection were compared with no warming. Because of similarities in the temperature of the vaccine achieved with both warming techniques (27 and 29°C, respectively), the data were combined and compared with the no warming group (19°C). There was low quality evidence for the critical outcome of pain and pain did not differ between those that received the warmed vaccine versus those that received unwarmed vaccine: SMD 0.02 (95% CI: −0.32, 0.36) (see Table http://links.lww.com/CJP/A294 and Figure, http://links.lww.com/CJP/A308 SDC 13).
Should Muscle Tension be Used for Vaccine Injections in Children 7 Years and Above and Adults With a History of Fainting?
Three studies including individuals in mid to late adolescence through adulthood were included; none of the studies evaluated the vaccination context.38,39,40 Muscle tension was achieved using a variety of physical maneuvers and both cyclical (muscle tension then release and repeat) and holding (continuous tension) methods were used. Some training was provided (eg, demonstration, instruction, practice with biofeedback, photos of maneuvers, supervision, and feedback). The critical outcome was fainting. Two of the studies were included in the meta-analysis38,39 and fainting was assessed in these studies using a tilt-table test or year-long follow-up of everyday life. The results were mixed for different indicators of fainting and the quality of evidence was very low (see Table http://links.lww.com/CJP/A295 and Figure, http://links.lww.com/CJP/A309 SDC 14). Muscle tension resulted in benefits in the number of individuals fainting acutely during a procedure (n=38; RR: 0.11 [0.02, 0.79]), number of individuals fainting over a 1-year period (n=208; RR: 0.62 [0.44, 0.88]), and number of fainting episodes/individual/year (n=208; SMD: −3.32 [95% CI: −3.74, −2.90]). It did not demonstrate a benefit on postprocedural fainting (although the tension had ceased at that time), or time to recurrence at follow-up.
This systematic review was undertaken to determine the effectiveness of different procedural and physical interventions that can be used by immunizers to reduce pain, fear, distress, fainting related to vaccine injections, or more than one. There was some evidence to support the following interventions in select populations: no aspiration during IM injections, injecting the most painful vaccine last when multiple vaccines are injected, simultaneous injections rather than sequential injections, IM injection into the vastus lateralis rather than the deltoid, positioning interventions (skin-to-skin contact, holding, or upright positioning rather than lying supine), non-nutritive sucking, tactile stimulation using an external vibrating device and cold, and muscle tension. There was insufficient evidence to support warming the vaccine before injection and manual tactile stimulation.
The results were mixed regarding the impact of no aspiration for IM vaccine injections. In 1 study including adolescents and adults,12 there was no evidence of a benefit of avoiding aspiration on self-reported pain, whereas in the other studies including infants,10,11 there was a benefit on measures of infant distress. The discrepant results in the former study may be explained by differences in study design and execution, including: use of a particularly painful vaccine,54 insufficient time for aspiration, and variability in anatomic site of injection. As aspiration is not a necessary step of IM vaccine injections55 and incurs additional needle dwelling time to ensure it is undertaken appropriately with the potential for wiggling of the needle within the tissue, additional tissue damage and pain, there is no rationale for performing it. It is unclear whether the results in the latter studies were confounded by differences in injection speed as the no aspiration technique was coupled with a fast injection (vs. aspiration with slow injection). The specific impact of injection speed requires further study.
This review found that injecting the most painful vaccine last when 2 vaccines are administered sequentially results in less pain. The findings are consistent with animal and human studies demonstrating a relationship between future pain and previous pain, and increasing pain after repeated noxious sensory stimulation.56–60 These results, however, are limited to the combinations of vaccines that were evaluated in included studies. Additional studies are needed to determine the relative “painfulness” of other vaccines that are routinely given in combination to provide more complete guidance to immunizers with respect to the order of their administration to minimize pain.
Another intervention with some evidence of a benefit in the context of multiple separate vaccine injections is simultaneous injections. Simultaneous injections were demonstrated to reduce infant distress. However, there was no observable benefit in children. It is possible that children become fearful when approached by 2 immunizers and that this counteracts any benefit of the intervention in this age group. It is important to note that infants begin to develop “stranger anxiety” in the presence of unknown adults that may be exacerbated in the presence of a greater number of unknown adults needed to deliver this intervention, which could increase distress; in such cases, alternatives to this intervention should be considered. Stranger anxiety is developmentally normal and tends to be present in infants above 6 months.61 Additional resources (ie, multiple immunizers) are also required to deliver this intervention making feasibility an issue.
The vastus lateralis is a muscle situated on the outer aspect of the upper thigh and is currently recommended as the primary site of vaccination for infants.55 One study compared infant distress from vaccine injection in the vastus lateralis versus the deltoid,18 a muscle in the upper arm—the preferred vaccination site in older children and adults.55 There was some evidence of benefit on infant distress, providing support for the vastus lateralis as the primary site for vaccination of infants. There were no other studies that compared the effects of alternative anatomic sites of injection on pain. There are, however, observational studies reporting on preferences or actual uptake of vaccines according to the route of administration. In these studies, the intranasal route was preferred over the IM route.62–64
There was clear evidence of a benefit of skin-to-skin contact for reducing vaccine injection pain in neonates. These results are consistent with a recent meta-analysis of skin-to-skin contact for procedural pain in neonates.65 The effectiveness of this intervention when applied by individuals other than the mother (eg, father) in the context of vaccination, however, is not known. In limited data in hospitalized neonates undergoing other needle procedures, there was no evidence of a difference when this intervention was delivered by a different individual, including the father or an alternate female.65
There was some evidence of a benefit of holding during vaccine injections in infants after removal of the data from 1 study from the meta-analysis that included contamination of the control group.23 The optimal holding position, however, is not known and may depend on infant preferences; holding in a parent’s lap in a gentle hug with the child’s legs on either side of the parent may be one way to deliver this intervention that results in child comfort and keeps limbs still without leading to undue restraint (that can further increase distress).66 A combined holding intervention administered after injection was also demonstrated to reduce infant distress. The intervention consisted of cuddling and back-patting24 or swaddling, side-lying, swinging, sucking, and shushing.25 In included studies, however, the holding intervention was delivered by a clinician and parents would have to be trained to deliver the intervention to make it a feasible intervention across clinical settings. Of note, close proximity soothing is regarded as a developmental need for infants in distress.67
There was a benefit of sitting upright on children’s self-reported fear in 1 study included in the systematic review.26 It has been hypothesized that individuals are less afraid when sitting up than lying down and sitting up has been recommended for children as soon as they can maintain head and trunk control.66,68 As with infants, methods of positioning that effectively comfort and secure limbs without undue force are recommended for children. This may include sitting on a parent’s lap. Of note, in included studies, parents also preferred to have their children sitting up for injections and there was no evidence of an increase in the duration of the procedure.26
Non-nutritive sucking was demonstrated to reduce infant distress during vaccination. This is consistent with the findings of a separate systematic review of procedural pain management in neonates including non-nutritive sucking.69 The mechanism underlying the effectiveness of non-nutritive sucking is not known, but may involve blocking the perception of pain, distraction, or both.70 The rate of sucking may be important for effectiveness; included studies, however, did not determine the sucking rate. This intervention is suitable for infants that regularly use pacifiers. An adult may also be required to gently hold the device in place to stimulate sucking and to prevent it from falling out of the child’s mouth. It is important to note that some infants may refuse to suck and should not be forced to do so as it may increase distress.
There was no evidence of a benefit of manual tactile stimulation. The proposed mechanism of tactile stimulation as a pain treatment involves the gate control theory of pain and the notion that the touch sensation competes with the pain sensation to reduce the pain signal to the brain.71 There are several possible reasons for the lack of observed effect of manual tactile stimulation, including: (1) discomfort induced by the intervention due to excessive pressure, other aversive aspects of intervention delivery, or both; (2) fear induced by proximity of the immunizer and increased attention to the vaccination procedure by the individual; and (3) cointervention due to tactile stimulation being applied when holding infants and children or when securing limbs before vaccine administration, concurrent tactile stimulation applied during actual vaccine delivery (eg, pinching or pressing on the skin), or both. Together, these factors may have obscured or reduced any observable benefit of this intervention.
There was, however, a benefit observed for tactile stimulation when delivered to children undergoing vaccine injections using an external vibrating device coupled with cold. It is likely that the effectiveness of this intervention involves more than 1 mechanism. Distraction, cold, and suggestion may all have played a role in the effectiveness of this intervention. Separately, significant benefit of the intervention has been observed in children up to 18 years undergoing venipuncture.72,73 Limitations for the use of this intervention includes the need for additional resources to deliver them, including supplies (vibrating devices) and personnel (to administer it). One recent study trained parents to administer the intervention to avoid the need for additional personnel.74 Finally, consideration should be given to the cold sensation produced with this intervention (ie, vapocoolant spray or Buzzy) as it may lead to discomfort in some individuals.2,75,76 It is possible to deliver the tactile component of both interventions without the cold component although the effectiveness of this is not known.
Warming the vaccine was not demonstrated to impact pain. The proposed mechanism for this intervention is that cold solutions stimulate nociceptors.77 It is possible that the temperature achieved in the warming group, which was <30°C, was not sufficiently close to the body temperature to prevent pain. In a previous meta-analysis of warming local anesthetic solutions before injection, a significant reduction was demonstrated when body temperature (≥37°C) was attained during warming of the solution.77 In contrast, it is possible that the temperature achieved in the control group, which was approximately room temperature, may have been sufficiently high compared with usual refrigerated vaccine temperatures that it approximated an active treatment and was not sufficiently cooler than the warmed vaccine for warming to have demonstrated a benefit. Because of the lack of observed benefit of warming from the included trial, warming of vaccines is not recommended. It is important to additionally note that correct storage and handling temperatures are of paramount importance in maintaining biological activity of vaccines and that warming may impact vaccine effectiveness.
Pain and seeing blood, needle procedures, or both are included in the top 5 triggers for fainting.78 Muscle tension combats the vasovagal response that otherwise leads to fainting by increasing blood pressure and cerebral blood flow. In this intervention, individuals learn to tense muscles of the body and can also learn the signs of a drop in blood pressure (ie, prodromal vasovagal signs) so that the tension technique can be utilized to prevent the onset of symptoms, or both arrest them once they appear. There was evidence for the effectiveness of muscle tension with respect to fainting both acutely during a procedure and number of fainting episodes per patient per year. Although the evidence base did not include vaccine injections specifically, there is no reason to believe that results would be different in this context; muscle tension has also reduced fainting responses in volunteer blood donors.79 The use of muscle tension in vaccination contexts should be addressed in future research, including training of individuals on the spot. Caution is recommended with respect to positioning during vaccine injections to avoid falls; supported or a reclined sitting position are possible options.
A major limitation of the findings from this knowledge synthesis is the scant evidence base that exists for most of the evaluated interventions. Considering the vast number of vaccine injections that are performed worldwide and the fact that they occur in individuals of all ages, it is surprising that such little empiric evaluation of physical and procedural interventions has been undertaken. There is the possibility that some trials may have been missed, however, this risk was reduced by having a broad search strategy including gray literature (theses), articles published in other languages, and involving 2 reviewers in screening citation lists.3 The risk of bias was high for all included trials, leading to uncertainty in the internal validity of the findings. In most cases it was difficult to blind personnel, such as immunizers, to the intervention. In addition, included studies often evaluated individuals of limited age ranges, and it is unclear that the results can be extrapolated to other ages. Strengths of the analysis, however, include the rigorous approach that included both GRADE and Cochrane methodologies, and a comprehensive approach to data synthesis that utilized the results of multiple outcome measures assessing the same construct within studies and combined data across studies. A priori, the effectiveness of specific interventions was analyzed separately to account for differences in intervention characteristics (eg, delivery) and developmental stage. This allowed for more fine-grained examination of intervention effectiveness. Other aspects of the methodological approach used in this systematic review are reviewed separately in another manuscript in this series.80
In conclusion, there are a variety of procedural and physical interventions that clinicians can use to improve the quality of pain care in individuals undergoing vaccine injections. Implementation of these interventions is contingent on the ability and willingness of vaccinators to use them. To this end, government agencies and educational institutions are encouraged to develop policies and resources that facilitate uptake of these interventions across practice settings. In addition, additional research is recommended to expand and strengthen the evidence base. New technologies are also warranted, including: adjustment of physicochemical characteristics of new vaccines to be less painful, combination vaccines, microneedles, and needle-free vaccine approaches (such as oral, transdermal, mucosal, and inhalational).
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pain management; randomized controlled trial; systematic review; vaccination; injection techniques
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