Pediatric Annals

Taking the Sting Out of Shots: Control of Vaccination-Associated Pain and Adverse Reactions

Evelyn Cohen Reis, MD; Robert M Jacobson, MD; Sally Tarbell, PhD; Bruce G Weniger, MD, MPH

Abstract

In recent years, physician enthusiasm for the protection provided by newly licensed vaccines has been tempered by concerns about the pain and adverse reactions associated with additional injections. Physician and parent anxiety about multiple simultaneous injections is widespread and often leads to the withholding of scheduled vaccines.1'5 Specifically, concern about multiple injections has limited universal acceptance of hepatitis B and varicella vaccines.6,7 In addition, these injection-related worries are a significant obstacle to adding new vaccines to the immunization schedule as they are developed and licensed. Soon, new parenteral vaccines will be available to protect infants from pneumococcal and meningococcal diseases. Resistance to the addition of injections denies children the protection afforded by these advances in immunization biotechnology.

Interestingly, recent studies indicate that parents will agree to multiple injections if their child's pediatrician strongly recommends it.8,9 This suggests that promoting physician willingness to recommend simultaneous administration of all scheduled vaccines (as directed by Pediatric Immunization Practice Standard #8)10 is the key to overcoming missed opportunities to immunize during well care visits. The purpose of our article is to enhance physician knowledge about methods to reduce the pain and adverse reactions associated with vaccination. We hope that, by incorporating these techniques into routine practice, pediatricians will have less cause to withhold valuable vaccines, and children and parents will experience less distress with immunization.

REDUCTION OF ADVERSE REACTIONS

The more common adverse reactions to parenteral vaccines include fever and local injection-site pain and inflammation. Less frequent reactions of note include allergic reactions and a variety of neurologic and non-neurologic complications associated with a variety of vaccines.

Fever

Parents do consider fever and other common adverse effects in their acceptance of vaccines.11 Although fever itself should not be construed as necessarily harmful, it certainly can be discomforting to the child and distressing to the parent. Furthermore, fever from a vaccine may lead to a febrile convulsion and insinuate the vaccine as a cause of more sinister neurologic sequelae. 12,13

The main approaches to fever control with vaccination have been prevention and treatment. The mainstay of both prevention and treatment have been in the use of acetaminophen. A landmark randomized, placebo-controlled trial compared a multipledose regimen of acetaminophen given at the time of DTP vaccination and repeated every 4 hours for two additional doses. That study demonstrated a statistically significant decrease in local and systemic reactions and a halving of the rate of fever.14 The Advisory Committee on Immunization Practices recommends acetaminophen to prevent post-vaccination fever in children at risk for febrile convulsions.15 A second randomized clinical trial found similar results. In that study, acetaminophen or placebo was given at the time of vaccination and at 3, 7, 12, and 18 hours afterward.16 The investigators found that acetaminophen in a multiple-dose regimen was effective in reducing fever, pain, and fussiness. In this study, no statistically significant difference was noted on local redness and swelling. In a third trial, however, a single dose of acetaminophen did not appear to prevent fever after DTP vaccination.1'

The acellular form of the pertussis vaccine produces significantly less fever18 and thus the need for prevention may be less compelling. No studies to date have examined the impact of acetaminophen prophylaxis in those receiving acellular pertussis. Certainly studies have shown far less use of acetaminophen to treat fever following the administration of acellular pertussis-containing vaccines as contrasted with whole cell pertussis-containing vaccines.19'22 One study measured fever occurring in 31% of those having received acellular pertussis vaccine. This contrasts with an occurrence rate of 63% in those who received the whole-cell pertussis vaccine.20 Rates of fever following the administration of other vaccines…

In recent years, physician enthusiasm for the protection provided by newly licensed vaccines has been tempered by concerns about the pain and adverse reactions associated with additional injections. Physician and parent anxiety about multiple simultaneous injections is widespread and often leads to the withholding of scheduled vaccines.1'5 Specifically, concern about multiple injections has limited universal acceptance of hepatitis B and varicella vaccines.6,7 In addition, these injection-related worries are a significant obstacle to adding new vaccines to the immunization schedule as they are developed and licensed. Soon, new parenteral vaccines will be available to protect infants from pneumococcal and meningococcal diseases. Resistance to the addition of injections denies children the protection afforded by these advances in immunization biotechnology.

Interestingly, recent studies indicate that parents will agree to multiple injections if their child's pediatrician strongly recommends it.8,9 This suggests that promoting physician willingness to recommend simultaneous administration of all scheduled vaccines (as directed by Pediatric Immunization Practice Standard #8)10 is the key to overcoming missed opportunities to immunize during well care visits. The purpose of our article is to enhance physician knowledge about methods to reduce the pain and adverse reactions associated with vaccination. We hope that, by incorporating these techniques into routine practice, pediatricians will have less cause to withhold valuable vaccines, and children and parents will experience less distress with immunization.

REDUCTION OF ADVERSE REACTIONS

The more common adverse reactions to parenteral vaccines include fever and local injection-site pain and inflammation. Less frequent reactions of note include allergic reactions and a variety of neurologic and non-neurologic complications associated with a variety of vaccines.

Fever

Parents do consider fever and other common adverse effects in their acceptance of vaccines.11 Although fever itself should not be construed as necessarily harmful, it certainly can be discomforting to the child and distressing to the parent. Furthermore, fever from a vaccine may lead to a febrile convulsion and insinuate the vaccine as a cause of more sinister neurologic sequelae. 12,13

The main approaches to fever control with vaccination have been prevention and treatment. The mainstay of both prevention and treatment have been in the use of acetaminophen. A landmark randomized, placebo-controlled trial compared a multipledose regimen of acetaminophen given at the time of DTP vaccination and repeated every 4 hours for two additional doses. That study demonstrated a statistically significant decrease in local and systemic reactions and a halving of the rate of fever.14 The Advisory Committee on Immunization Practices recommends acetaminophen to prevent post-vaccination fever in children at risk for febrile convulsions.15 A second randomized clinical trial found similar results. In that study, acetaminophen or placebo was given at the time of vaccination and at 3, 7, 12, and 18 hours afterward.16 The investigators found that acetaminophen in a multiple-dose regimen was effective in reducing fever, pain, and fussiness. In this study, no statistically significant difference was noted on local redness and swelling. In a third trial, however, a single dose of acetaminophen did not appear to prevent fever after DTP vaccination.1'

The acellular form of the pertussis vaccine produces significantly less fever18 and thus the need for prevention may be less compelling. No studies to date have examined the impact of acetaminophen prophylaxis in those receiving acellular pertussis. Certainly studies have shown far less use of acetaminophen to treat fever following the administration of acellular pertussis-containing vaccines as contrasted with whole cell pertussis-containing vaccines.19'22 One study measured fever occurring in 31% of those having received acellular pertussis vaccine. This contrasts with an occurrence rate of 63% in those who received the whole-cell pertussis vaccine.20 Rates of fever following the administration of other vaccines are usually less than that seen with acellular and whole cell pertussis vaccines.

Experts have also proposed the use of Ibuprofen, an otherwise commonly used over-the-counter antipyretic. The Vaccine Information Statement produced by the Centers for Disease Control and Prevention (CDC) for DTP specifically suggests Ibuprofen as an equivalent alternative to acetaminophen to prevent or reduce the fever and soreness commonly associated with the vaccine. Currently, however, no published research demonstrates ibuptofen's safety or efficacy in the prevention or treatment of DTP-induced fevers. Ibuprofen has powerful vasoactive effects at the kidney, heart, and brain in neonates. The US has not licensed the use of Ibuprofen for children under 6 months. Furthermore, Ibuprofen has a relatively high rate of gastrointestinal adverse effects. Thus, in older but preverbal infants and toddlers, Ibuprofen may produce gastrointestinal discomfort that may mimic irritability from vaccination and lead to a vicious cycle of dosing.

Other Adverse Reactions

Acetaminophen has appeared to be effective in preventing local inflammation and systemic reactions other than fever with the DTP vaccine.14·16 Otherwise, the main approaches to the prevention of local injection site inflammation (pain, redness, swelling, and warmth) have focused on needle technique and site of vaccination. Using longer needles (1 inch or 25mm) rather than shorter needles (5/8 inch or 16mm) for the intramuscular injection of DTP decreased redness and swelling.23 In a study of 18-month-old children, parents viewed the reactions associated with thigh injections as more often moderate or severe than with deltoid injections.23 A study using ultrasound to examine injection depth found similarly less pain with a longer needle, which correlated with true intramuscular injection as compared with subcutaneous injection.

Along these lines, studies of granulomas formed after injection found that almost all formed in the subcutaneous tissues. These studies suggest that granuloma formation after intramuscular injection resulted from inadvertent injection of the subcutaneous tissues with an aluminum salt containing vaccine such as DTP.24'28 One should take care then to use a long enough needle to administer vaccines in a truly intramuscular fashion.29,30

Multiple vaccine-administration does increase the rate of local and systematic reactions31 but allows the child to be fully immunized at each opportunity. A significant proportion of clinicians withhold administration of multiple vaccines apparently to prevent pain, reactions, and psychological distress - more so in private practice than in public health clinics.32 Nevertheless, because the reactions are generally minor,31 these fail to provide a reason to withhold multiple vaccinations when indicated.33

The prevention of other adverse effects has depended primarily on avoiding giving vaccines to those patients who have contraindications such as previously recognized allergies to specific vaccines or vaccine constituents. Clinicians providing vaccines should remain prepared to handle anaphylaxis as well as other allergic reactions, panic, and syncope.

REDUCTION OF PAIN AND DISTRESS

Injections are among the most aversive medical procedures for children.34,35 If efforts are not made to help them cope, children may become more distressed with each procedure rather than get used to them.36 Such needle-related distress often adversely affects children's relationships with their healthcare providers. Pediatricians and parents commonly hear children ask fearfully at the outset of the pediatric visit, "Am I going to get a shot?" Consequently, we must aim to reduce pain and distress, combining nonpharmacologic and pharmacologic techniques at each child's immunization procedure.

NONPHARMACOLOGIC METHODS

Nonpharmacologic methods, which include cognitive-behavioral techniques, are the least expensive, safest, and easiest to incorporate into pediatric practice. Although they appear to be quite simple, use of these methods alone can effectively reduce the pain and distress of many pediatric procedures, including vaccination. Their effect is even further enhanced when they are combined with a pharmacologic paincontrol component.

The success of cognitive-behavioral techniques can best be explained through a brief review of the physiology of pain perception, including the gatecontrol theory of pain.37 AU pediatricians have noted that the same noxious stimulus (eg, DTP vaccination) produces markedly different pain and distress responses among children, even of the same age. Parents will recall that even for the same child, the same stimulus can prompt different reactions. The reason that the same amount of tissue injury does not produce the identical response in different individuals, or in the same individual at different times, is that the ascending pain impulses generated by the tissue injury are modulated ("gated") by other influences, including impulses descending from the brain (Figure 1). Cognitive and emotional techniques appear to work through activation of the endogenous pain inhibitory system, which dampens the effect of the noxious stimulus and lessens the degree of pain perceived. An excellent example, which parents and pediatricians will appreciate, is the immediate pain reduction provided to a toddler by a parent's kiss on a skinned knee. The toddler's belief in the power of the parent's kiss to "make it all better" actually lessens his perceived pain as it blocks ascending pain impulses from the injured knee.

Figure 1 . According to the gate control theory, pain perception is not a simple function of the amount of tissue damage, but rather is the result of active modulation of the incoming sensory input by the central nervous system. This modulation includes: 1) the "gating" of incoming nociceptive (noxious sensation) input as a function of the firing of afferent fibers in the dorsal horn of the spinal cord, and 2) modification through descending pathways from higher levels of the central nervous system, including the limbic system and the cerebral cortex, to the dorsal horn. These descending pathways are influenced by a range of cognitive (eg, attention, understanding, expectation) and affective (eg, anxiety, fear, confidence, trust) factors. Methods to reduce perceived pain from injection-related tissue injury utilize both the gating and descending inhibitory mechanisms.

Figure 1 . According to the gate control theory, pain perception is not a simple function of the amount of tissue damage, but rather is the result of active modulation of the incoming sensory input by the central nervous system. This modulation includes: 1) the "gating" of incoming nociceptive (noxious sensation) input as a function of the firing of afferent fibers in the dorsal horn of the spinal cord, and 2) modification through descending pathways from higher levels of the central nervous system, including the limbic system and the cerebral cortex, to the dorsal horn. These descending pathways are influenced by a range of cognitive (eg, attention, understanding, expectation) and affective (eg, anxiety, fear, confidence, trust) factors. Methods to reduce perceived pain from injection-related tissue injury utilize both the gating and descending inhibitory mechanisms.

Nonpharmacologic interventions include behavioral, cognitive, interactional, and physical strategies to decrease pain and distress associated with immunization. For all age groups, physical interventions should be utilized to reduce tissue damage and optimize gating of pain impulses. To limit tissue injury, injections should be performed with a rapid puncture of the skin at a 90° angle, a slow instillation of the vaccine over several seconds, and a quick, smooth withdrawal.38 Rubbing or applying firm pressure to the injection site before and after the immunization can directly reduce the sensation of pain by stimulating nerve fibers that activate a pain gating mechanism in the dorsal horn of the spinal cord.39,40 The choice of additional nonpharmacologic methods of pain control is directed by the child's developmental level.

Figure 2. A 4-year-old child, supported by his mother, practices blowing on a pinwheel while a vapocoolant-saturated cotton ball is applied to the injection site 15 seconds prior to immunization.

Figure 2. A 4-year-old child, supported by his mother, practices blowing on a pinwheel while a vapocoolant-saturated cotton ball is applied to the injection site 15 seconds prior to immunization.

Infants

For infants, nonpharmacologic pain control strategies include external comfort measures such as swaddling and providing a pacifier,41 having the parent hold and soothe the infant, and offering a distracting activity. There also is evidence that newborns' procedure-related distress can be reduced by allowing them to suck pacifier dipped in a sucrose solution42 (one standard packet of table sugar dissolved in 10 cc water);43 however, use of this "sucrose analgesia" alone is less effective in children beyond the newborn period.44 In addition, attempts should be made to reduce baseline distress (hunger, fatigue) before the procedure. Infants who are already aroused will react with greater intensity to the painful stimulus than those who are calm and relaxed.43

Toddlers

Once children become toddlers, new possibilities exist for the nonpharmacologic management of pain. Children as young as 2 years can benefit from more formal preparation, including the provision of simple procedural and sensory information about the upcoming procedure.46·4' The information provided needs to be geared to the child's developmental level and the word "shot" avoided, lest the child think they are in fact going to be shot. Sensory words like "sting" or "prick" should be substituted for words like hurt and pain, so as not to provide the child with a self-fulfilling prophesy. Speaking to the child with hopeful language, such as "you may be surprised by how quick we get this done" may also help reduce fear and anxiety. As with infants, distraction techniques can also be helpful. Some distracting activities include having children blow bubbles, party blowers, or pinwheels, taking deep breaths while imagining they are blowing out birthday candles, having them look at pop-up or similarly involving picture books, and engaging the child in a conversation about something that is special to them like a favorite toy, pet, or story.48,49 Noting that the needle makes a hole in their skin, toddlers can become very concerned about body integrity, fearing they will bleed uncontrollably or that the vaccine will leak out. The application of an adhesive bandage can usually quell these fears, and allowing the child to choose a particular bandage design may also prove useful for reducing injectionrelated distress.

Preschool and Early School-aged Children

Several techniques have been identified as helpful in reducing vaccination-related fear and pain. In addition to the distraction techniques described above, listening to music with headphones50 or watching a cartoon videotape51 reduces distress in this age group. Parent behaviors that aim to distract the child, such as non-procedural talk and humor, as well as prompts to the child to engage in coping behaviors (eg, deep breathing), also reduce child distress.32'" In contrast, excessive parental reassurance, criticism, and apologies to the child are ineffective at reducing children's distress'6 and in some cases increase the child's distress.53'55 Because nearly all children prefer to have a parent present,57 pediatricians should give parents specific instructions in assisting their children.

Figure 3. Two available forms of vapocoolant spray, Ethyl Chloride and Fluori-Methane®, are shown. The spray is applied to the skin either directly or with a saturated cotton ball immediately prior to the injection (Photograph reproduced with permission of Gebauer Company, Cleveland, OH).

Figure 3. Two available forms of vapocoolant spray, Ethyl Chloride and Fluori-Methane®, are shown. The spray is applied to the skin either directly or with a saturated cotton ball immediately prior to the injection (Photograph reproduced with permission of Gebauer Company, Cleveland, OH).

Figure 4. EMLA® Cream, shown in the 2-dose (5-gram tube) form, is applied to the skin 60 minutes prior to injection and covered with the occlusive dressing provided (Photograph reproduced with permission of Astra, USA, Inc., Westborough, MA. EMLA® is Astra's registered trademark.

Figure 4. EMLA® Cream, shown in the 2-dose (5-gram tube) form, is applied to the skin 60 minutes prior to injection and covered with the occlusive dressing provided (Photograph reproduced with permission of Astra, USA, Inc., Westborough, MA. EMLA® is Astra's registered trademark.

School-aged and Adolescent Children

School-aged and adolescent children benefit from many of the distraction techniques mentioned above. They also can make use of additional techniques that take advantage of their cognitive maturity. For example, it is helpful to get the child's perspective on the upcoming immunization to identify and to help dispel any "catastrophizing" thoughts the child may have. Children can be encouraged to consider adaptive selfstatements whereby they silently repeat coping statements to themselves (eg, "I can do it")- This technique may be especially helpful if practiced well ahead of the planned immunization. Asking children what has helped in the past may also uncover coping strategies they already have available to them. Talking with other children who have learned to cope with immunizations can provide the child with a peer model to assist in their coping efforts.46,58

Children aged 7 and older can learn to independently engage in other pain modifying techniques such as relaxation and self-hypnosis.36 With older children, the primary nonpharmacologic intervention is helping them identify their native abilities for coping with pain, offering them new skills or strategies as indicated, and prompting them to use them.

PHARMACOLOGIC METHODS

As described earlier, nonpharmacologic techniques are effective when used alone, but their effect will be further enhanced when combined with one of the pharmacologic components discussed below.

Vapocoolant Spray

Local cooling has been used extensively for relief of acute and chronic pain, especially pain that is musculoskeletal in origin. It is inexpensive, has few side effects, and may be applied with ice, gel packs, or volatile liquid spray.59 Volatile refrigerant liquids, known as "vapocoolant sprays", provide cutaneous anesthesia by lowering the skin temperature through their rapid evaporation. Possible mechanisms of action include desensitized pain receptors60 or lowtemperature specific gating of the pain message.61

Vapocoolant spray was first described as a pain reduction method for injections in 1955 by Travell.62 Subsequently, vapocoolants have been shown to effectively reduce injection pain in infants and early school-aged children undergoing vaccination.63,64 We recently demonstrated in a study of 4- to 6-year-old children that, when combined with distraction (a pinwheel), vapocoolant spray is equally effective as EMLA cream in reducing vaccination pain, and both are superior to distraction alone.65

We have found that the advantages of vapocoolant spray include the low cost (less than $0.50 per child), rapid onset, and ease of application. Although the volatile liquid may be sprayed directly on the injection site, its fine, forceful spray may be perceived as noxious. Instead, we apply a liquid-saturated cotton ball to the skin, using forceps to avoid cooling the nurse's fingers. After holding the cotton ball firmly on the site for 15 seconds, the liquid is allowed to evaporate (1-2 seconds). The skin will be maximally cooled for only 1 to 2 minutes, so care is taken to quickly clean the site with alcohol and administer the injection. Vapocoolant also is easily complemented by a nonpharmacologic cognitive approach. For optimal effect as well as improved acceptance of the cold liquid, children may be asked to think of their favorite cold things (eg, ice cream, snow balls) while the vapocoolant is applied. Older children respond favorably when they learn that vapocoolant is often used for professional athletes who are injured to help them "get back in the game." Such positive associations enhance the pain reduction effect and help the child achieve a sense of mastery with the immunization procedure.

Figure 5. The Numby Stuff® system, including the drug delivery and ground electrodes and the battery-powered electronic unit, provides effective local anesthesia in approximately 10 minutes (Photograph reproduced with permission of IOMED, Inc., Salt Lake City, Utah).

Figure 5. The Numby Stuff® system, including the drug delivery and ground electrodes and the battery-powered electronic unit, provides effective local anesthesia in approximately 10 minutes (Photograph reproduced with permission of IOMED, Inc., Salt Lake City, Utah).

Adverse reactions to vapocoolant spray are reported to include skin sensitivity if the vapocoolant spray is applied repeatedly. In addition, the time of exposure should be limited to approximately 15 seconds because freezing of the skin may occur if the liquid is applied to the skin for an excessive amount of time. Environmental concerns also should be considered. Ethyl chloride, the liquid used in the original study by Travell, is flammable. Currently, the common alternative nonflammable liquid, Fluori-Methane® (Gebauer Company, Cleveland, Ohio), contains fluorocarbons. A new nonflammable, fluorocarbon-free compound is currently under development by the manufacturer.

EMLA Cream

The introduction of EMLA cream (Eutectic Mixture of Local Anesthetics, Astra Pharmaceutical Products, Inc., Westborough, MA) in the late 1980s represented a breakthrough in delivery of local anesthetics . Prior to its conception, topical anesthetics were applied by injection, as transdermal absorption (ie, via intact skin) was limited. EMLA's name indicates the process by which its components, 2.5% lidocaine and 2.5% prilocaine, achieve enhanced transdermal absorption. In this eutectic mixture, the lidocaine -prilocaine combination has a lower melting point than either component has independently, allowing it to be a liquid at room temperature. Created as an oil- in- water emulsion, EMLA achieves higher effective concentration of the anesthetics, stimulating improved absorption at lower total drug concentrations. EMLA cream has been shown to penetrate to a depth of 5mm, effectively reducing pain in numerous pediatric procedures, including injections.66-69

Despite its proven efficacy, EMLA has not been widely accepted for pain reduction for routine vaccination. The most likely reasons are inconvenience and expense. To provide adequate anesthesia, EMLA cream must be applied to each injection site at least 60 minutes prior to the procedure, which may prolong the office visit. Parents may be trained to apply EMLA cream at home prior to the visit, but explicit instructions are necessary to ensure that the correct sites are treated and that the cream is not left in contact with the skin for a longer time than prescribed. The cost of EMLA is also a consideration. The pharmacy charge is approximately $15.00 for a 2 -dose tube ($7.50/dose). Although this cost may be covered by insurance for some families, EMLA may be prohibitively expensive to adopt as part of the standard immunization routine.

Table

TABLEPain Reduction Methods for Immunization Injections

TABLE

Pain Reduction Methods for Immunization Injections

Common side effects of EMLA cream include transient blanching and erythema of the treated skin, which resolves in 1 to 2 hours. In addition, children may complain about the sensation of the occlusive adhesive dressing (6 cm x 7 cm) that covers the cream, especially at the time of its removal. It is important that parents ensure that children do not inadvertently traumatize the anesthetized area by scratching or rubbing, until sensation returns (1 to 2 hours after removal of the cream). Finally, there are patients for whom the use of EMLA is contraindicated: infants younger than 1 month, children taking class I antiarrhythmic drugs, and children at increased risk of prilocaine-induced methemaglobinemia (children with rare congenital or idiopathic methemoglobinemia, and infants younger than 12 months or children with G6PD taking methemoglobinemia- inducing agents, eg, sulfonamides).

Figure 6. The Biojector 2000*. a handheld, C02-powered device used for immunization. The sterile, disposable cartridge shown in the foreground is filled manually with vaccine prior to insertion into the device (Photograph reproduced with permission of Bioject, Inc., Portland, OR, USA).

Figure 6. The Biojector 2000*. a handheld, C02-powered device used for immunization. The sterile, disposable cartridge shown in the foreground is filled manually with vaccine prior to insertion into the device (Photograph reproduced with permission of Bioject, Inc., Portland, OR, USA).

Iontophoresis

Iontophoresis is a mode of transdermal drug delivery in which a mild electric current drives ionized substances across the epidermis. During the passage of the painless electric current, positively or negatively charged drug particles (ions) are repelled into the skin by an identical charge on the electrode surface placed over it.70

The total amount of drug delivered is related to the amount of drug available for transport, the surface area of the drug delivery electrode, and the total delivery current (expressed in mA-min).71 This method can be used to deliver many medications into and across the skin, including topical anesthetics.

For pre-injection iontophoresis (commercially available as Numby Stuff [lomed, Salt Lake City, UT]), a drug delivery electrode hydrated with lcc of lidocaine is placed on the site to be anesthetized, and a second ground electrode is placed more than 4 inches from the first. Both electrodes are attached to the small battery powered electronic unit. A low level direct current (approximately 3 mA) is applied for 7 to 10 minutes to achieve a dose approximately 30 mA/min. Iontophoretic delivery of lidocaine has been shown to effectively reduce the pain of injections,72,73 but it has not specifically been studied for immunization injections.

The cost of Numby Stuff is equivalent to EMLA cream ($7.50/dose), if large quantities are purchased ( 1 power unit provided without charge for each 150 dosekits purchased). Adverse reactions of lidocaine iontophoresis are similar to EMLA cream, including transient erythema and blanching, as well as paresthesias during the application of the electric current. Although lidocaine iontophoresis offers the advantages of more rapid onset (10 minutes) and greater penetration (up to 10 mm) than EMLA cream, it may be more cumbersome to set up multiple power units for simultaneous injections. However, its rapid absorption makes iontophoresis attractive for other painful procedures, such as intravenous cannulation.71

For all three pharmacologic methods discussed above, vapocoolant spray, EMLA cream, and iontophoresis, no data have been published regarding the impact, if any, on the immunogenicity of vaccines administered through treated skin.

NEEDLE-FREE JET INJECTION

Another means of avoiding needle phobia is to eliminate the needle drugs can be administered parenterally by shooting through the skin a fine stream of liquid under high pressure through a small orifice. The technique originated as aquapuncture in France in the 1860s and was revived in the late 1940s with the introduction of the first commercial, needle-free jet injector device designed to reduce the discomfort and needle phobia of insulin injections for diabetic children.74'78 Over the years, numerous other needle-free devices for self-administration of insulin were developed,79,80 and current models now occupy an established niche in this market. Among needle-free insulin jet injectors on the US market in 1998 were the Advantajet® and Gentlejet® (Health-Mor Personal Care Corporation, Bradley, IL), the Medi-Jector Choice™ (Medi-Ject Corporation, Minneapolis, MN), and the Vitajet® (Laguna Hills, CA).

High-Workload Jet "Guns" for Mass Immunization

Beginning in the 1950s, needle-free injectors achieved wide-scale application on the development of "high-workload" devices to vaccinate large numbers of persons in short periods of time. These jet "guns" are capable of administering several hundred vaccine doses per hour, often using fjigger-operated, hydraulically powered pistons to fill a chamber from stock vaccine vials as large as 50 doses.78,81,82 Recycling time between spring- or gas-powered injections can be as fast as every 5 to 15 seconds. Originally designed under military specifications, these high-workload devices are solidly built, relatively heavy (the hand-held components can weigh up to 1.2 kg [2.6 pounds]), and have a high capital cost (currently US $2,000-3,000). They require specialized training for routine maintenance and repair, but they are capable of delivering tens of thousands of injections before major overhaul of parts. Thus, they can reduce amortized costs to less than $0.01 per injection over their useful lifetime. Since the 1950s, they have been used to administer hundreds of millions of vaccine doses in military induction centers, epidemic situations, and mass immunization campaigns around the world.78 High-workload jet injectors available in recent years include the Am-O-Jet™ (American Jet Injector, Inc., Lansdale, PA), Med-E-Jet™ (Med-E-Jet Corporation, Cleveland, Ohio), and Ped-O-Jet™ (Keystone Industries, Cherry Hill, NJ).

Concern Over Multiple-Use Nozzle Devices

In the mid-1980s, an outbreak of hepatitis B was caused by noncompliant use of one high-workload model (Med-E-Jet™) in a weight loss clinic.83,84 Laboratory study of the device suggested blood on the nozzle surface and crevices could contaminate subsequent injections, even with the routinely recommended alcohol swabbing of the nozzle between injections. This raised concern that perhaps other jet injectors in which the same nozzle is used for multiple vaccine recipients may pose a risk of bloodbome pathogen transmission.85,86 Despite the extensive use of jet injectors, no other case of bloodborne disease transmitted between vaccinées has ever been documented. However, Mycobacterium chelonae contaminating a jet injector disinfectant solution infected eight patients in a pediatric clinic.87

Low- Workload Injectors for Routine Immunization

In contrast to high-workload jet injectors, smaller, lighter, less-costly devices have been developed that are more practical for routine clinical use. These "low-workload" devices generally use hand-wound springs or small CO2 gas cylinders for power and usually require more time to prepare between doses, because many do not reload automatically from multidose vials. They are commonly used to inject lidocaine for dental anaesthesia88 and have been used to administer antibiotics,77 corticosteroids,89 erythropoietin,90 growth hormone,91 heparin,92 local anesthetic and nerve blocks,93,94 morphine,92 preoperative pediatric sedation,95 tuberculin,96 and vitamins,97 as well as vaccines.

As with current high-workload models, some lowworkload jet injectors use the same permanent nozzle and distal fluid pathway for sequential injections, raising doubt as to their suitability for immunization clinics, where sterilizing nozzles between patients would be impractical.

New Generation Devices with Disposable Cartridges

A new generation of jet injector devices with a disposable fluid path to satisfy concerns about the safety of injectors with multiple-use nozzles are now coming on the market. The nozzle, with orifice, medicine chamber, and fluid piston, is disposed after each injection, and some are automatically damaged to prevent reuse. The Biojector™ 2000 (Bioject Inc., Portland, OR 97224, www.bioject.com/) is now used for immunization by a number of public and private clinics in the United States. Its disposable vaccine cartridges are filled manually just before vaccination. At a street price of about $550, plus the cost of disposables and maintenance, its overall amortized cost for each injection was estimated to be about $0.62.98

Another new-generation device (Mini-Imojet®, Pasteur-Mérieux Serums et Vaccins, Lyon, France)not yet marketed - uses a novel factory-prefilled vaccine vial (Imule®, Pasteur-Mérieux Serums et Vaccins, Lyon, France), which becomes the injector cartridge with its own disposable orifice and piston.99 Another inventive prototype (MEDi VAX™, Vitajet Corporation (Program for Appropriate Technology in Health, Seattle, WA), still in development, combines the advantages of disposable cartridges with the ability to fill them automatically from multidose vials, yielding a capacity of up to 1000 injections per day that rivals traditional highworkload devices.

Deposition and Immunogenicity

Drug or vaccine administered by jet injection spreads along paths of least resistance in a conical distribution - with apex at the injection site - and is generally more widespread than that achieved with needle injection.75100 Although fascia is harder to penetrate, deposition into muscle can be achieved depending on the thickness of the skin and the amount it is stretched taut, the angle of injection, and the force and width of the jet stream.74'76 However, these latter factors are not easily adjusted in most devices. Thus, jet injectors cannot, unlike needles, target precisely the deposition of the dose, some of which will remain in subcutaneous tissues and dermis. Nevertheless, studies with a variety of both live vaccines (eg, BCG,101 measles,102 smallpox,102,103 and yellow fever102,104) and inactivated ones (eg, cholera, diphtheria-tetanus-pertussis,99·105 hepatitis A,99,106 hepatitis B,107 influenza,81,99,108 plague, polio,109 tetanus,99 and typhoid99,110) have demonstrated that jet injectors produce immunogenic responses that are equivalent to and often higher than those produced by needle and syringe.

Needle-Phobia and Pain

Obviously, jet injectors eliminate the object of fear and avoidance among patients, and are thus reassuring.81'92 Various controlled and uncontrolled studies in adults and children generally report that a few patients describe no pain at all, a substantial proportion of subjects rate the pain of these devices to be less than with needles, and other subjects find no difference.74,76·81,97,109 Pain from jet injectors may correlate directly with increasing pressure of the jet, greater size of the orifice, larger volume of the dose, and higher chemical irritability of the vaccine.76,95,110

Jet injector orifice diameters usually vary from 0.08 mm - about the size of a mosquito proboscis75 - to 0.2 mm. This is several times smaller than a 2 5 -gauge needle (about 1.0 mm) and may account for the decreased pain compared with needles. Inactivated vaccines often contain somewhat irritating alum adjuvants, which is why they are recommended for intramuscular administration. Clinical trials and experience with jet injection of inactivated vaccines, however, indicate satisfactory tolerance and safety for this indication.

Adverse Events and Complications

Jet injection of inactivated adjuvanted vaccines do tend to produce somewhat higher rates of delayed local soreness or edema compared with control needle injections.99110 Jet injectors also result in slightly higher frequencies of blood appearing at the injection site, and subsequent ecchymosis74,76,78,81,91,92,95,99,109 or redness.106 If the limb moves in relation to the device during injection, laceration can result from the cutting effect of the jet stream.74,78,81 Other injuries have been reported,89,111 but probably at no greater frequency than trauma caused by needle and syringe.

Additional advantages of needle-free injection

Needles and syringes have other drawbacks besides inducing fear and pain in children (and some adults) and the effect on compliance with recommended immunizations: In many developing countries they are often improperly disposed of and are sometimes reused unsterile. Everywhere, they cause needlestick injuries. Needles and syringes are also not practical for vaccinating large populations quickly, a feature needed for epidemic control or global disease eradication programs. New-generation jet injector devices with disposable nozzles and cartridges to satisfy concerns over the safety of previous jet injectors are now coming on the market. Further improvements to increase the speed and convenience of loading these new devices, and studies to determine if reduced dose volumes would work, might increase their advantages over needle and syringe.

CONCLUSIONS

Anxiety about the excessive pain and adverse reactions associated with multiple immunization injections causes children to miss scheduled vaccines, and limits the acceptance of newly developed vaccines. Fortunately, many methods exist to reduce the injection-related pain and reactions that worry physicians and parents. These include administration techniques (such as proper needle length), nonpharmacologic and pharmacologic pain control interventions, and improved injection devices (such as needle-free jet injectors). Optimally, a combination of these methods will be chosen, based on the individual child, family, and staff needs, and applied at each vaccination. By adopting these techniques, pediatricians can enhance immunization protection of their patients, while reducing much of the unnecessary distress of children and parents.

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TABLE

Pain Reduction Methods for Immunization Injections

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