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Pain Management of Musculoskeletal Injuries in ChildrenCurrent State and Future Directions

Samina Ali, MD, FRCPC, FAAP,* Amy L. Drendel, DO, MS,! Janeva Kircher, BEng,"and Suzanne Beno, MD, FRCPC§

Background: Pain is the most common reason for seeking healthcare in the Western world and is a contributing factor in up to 80% of allemergency department (ED) visits. In the pediatric emergency setting,musculoskeletal injuries are one of the most common painful presen-tations. Inadequate pain management during medical care, especiallyamong very young children, can have numerous detrimental effects.No standard of care exists for the management of acute musculoskeletalinjuryYrelated pain in children. Within the ED setting, pain from suchinjuries has been repeatedly shown to be undertreated.Objectives: Upon completion of this CME article, the reader should bebetter able to (1) distinguish multiple nonpharmacological techniquesfor minimizing and treating pain and anxiety in children with musculo-skeletal injuries, (2) apply recent medical literature in deciding pharma-cological strategies for the treatment of children with musculoskeletalinjuries, and (3) interpret the basic principles of pharmacogenomics andhow they relate to analgesic efficacy.Results: Pediatric musculoskeletal injuries are both common andpainful. There is growing evidence that, in addition to pharmacologicaltherapy, nonpharmacological methods can be introduced to improveanalgesia in the ED and after discharge. Traditionally, acetaminophenwith codeine has been used to treat moderate orthopedic injuryYrelatedpain in children. Other oral opioids (hydrocodone, oxycodone) aregaining popularity, as well. Current data suggest that ibuprofen is at leastas effective as acetaminophen-codeine and codeine alone. Medicationcompliance might be improved if adverse effects were minimized, andibuprofen has been shown to have a similar or better adverse effect profilethan the oral opioids to which it has been compared. Pharmacogenomicdata show that nearly 50% of individuals have at least 1 reduced func-tioning allele resulting in suboptimal conversion of codeine to activeanalgesic, so it is not surprising that codeine analgesic efficacy is notoptimal. At the same time, nonpharmacological therapies are emergingas commonly used treatment options by parents and adjuncts to analgesicmedication. The efficacy and role of techniques (massage, music therapy,transcutaneous electrical nerve stimulation), although promising, requirefurther clarification in the treatment of orthopedic injury pain.

Conclusions: There is a need to optimize the measurement, docu-mentation, and treatment of pain in children. There is growing evidencethat nonpharmacological methods can be introduced to improve anal-gesia in the ED, and efforts to help parents implement these methodsat home might be advantageous to optimize outpatient treatment plans.In pharmacotherapy, ibuprofen has emerged as an appropriate first-linechoice for mild-moderate orthopedic pain. Other oral opioids (hydro-codone, oxycodone) are gaining popularity over codeine, because of thecurrent understanding of the pharmacogenomics of such medications.

Key Words: orthopedic injury, pain management, fractures, analgesia,nonpharmacological pain treatment, pharmacogenomics

(Pediatr Emer Care 2010;26: 518Y528)

TARGET AUDIENCEThis CME activity is intended for physicians, nurses, nurse

practitioners, and physician assistants who care for children whoare ill or injured. Specialists including pediatricians, emergencyphysicians, pediatric emergency physicians, orthopedic surgeons,and family practitioners will find this information particularlyuseful.

LEARNING OBJECTIVESUpon completion of this CME article, the reader should be

better able to:1. Distinguish multiple nonpharmacological techniques for

minimizing and treating pain and anxiety in children withmusculoskeletal injuries.

2. Apply recent medical literature in deciding pharmacolo-gical strategies for the treatment of children with muscu-loskeletal injuries.

3. Interpret the basic principles of pharmacogenomics and howthey relate to analgesic efficacy.

OVERVIEWPain is the most common reason for seeking health care

in the Western world and is a contributing factor in up to 80% ofall emergency department (ED) visits.1Y3 In the pediatric emer-gency setting, musculoskeletal injuries are one of the most com-mon painful presentations.4 Diagnoses of dislocations, sprains,strains, and fractures are made in 16.5% of children after acuteinjury.5 Furthermore, between one fourth and one half of chil-dren will sustain a fracture before the age of 16 years.6Y8 Boththe injury itself and its required treatments (such as examiningthe limb or casting it) can cause pain to the child.9

The World Health Organization supports optimal paintreatment as a fundamental human right.10,11 Inadequate painmanagement during medical care, especially among very youngchildren, can have numerous detrimental effects. In the shortterm, it can result in extended length of stay and slower healingas well as emotional trauma and suffering. Negative effects canalso extend to adulthood and include fear of medical events

CME REVIEWARTICLE

518 www.pec-online.com Pediatric Emergency Care & Volume 26, Number 7, July 2010

*Associate Professor, Division of Pediatric Emergency Medicine, Depart-ment of Pediatrics, University of Alberta, Edmonton, Alberta, Canada (Ali);†Assistant Professor (Drendel), Department of Pediatrics, Children’s Hospi-tal of Wisconsin, Milwaukee, WI; ‡Medical Student (Kircher), School ofMedicine, Queen’s University, Kingston, Ontario; and §Assistant Professor(Beno), Division of Pediatric EmergencyMedicine, Department of Pediatrics,University of Alberta, Edmonton, Alberta, Canada.Reprints: Samina Ali, MD, FRCPC, FAAP, 2nd Floor, Rm. 7217A 11402,

Aberhart Centre 1, University Avenue, Edmonton AB, Canada T6G 2J3(e-mail: sali@)ualberta.ca).

The authors have disclosed that they have no significant relationship withor financial interests in any commercial companies that pertain to thiseducational activity.

All staff in a position to control the content of this CME activity havedisclosed that they have no financial relationships with, or financialinterests in, any commercial companies pertaining to this educationalactivity.

Lippincott CME Institute has identified and resolved all faculty conflicts ofinterest regarding this educational activity.

Copyright * 2010 by Lippincott Williams & WilkinsISSN: 0749-5161

Copyright @ 20 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.10

or health care consultations and avoidance of or heightenedsensitivity to subsequent medical care.12Y14 Furthermore, inad-equate analgesia in young children can reduce the effect of an-algesia when undergoing the same procedure at a future pointin time, whereas pain in infants may actually change pain pro-cessing for the future.15

CURRENT PRACTICENo standard of care exists for the management of acute

musculoskeletal injury in children. Within the ED setting, painfrom such injuries has been repeatedly shown to be under-treated.16Y24 A recently conducted North American study by Toddet al25 assessed the current state of ED pain management andfound that patients present with high levels of pain, analgesia isunderutilized, and, when used, there are significant delays in an-algesia delivery.

Orthopedic injury pain does not subside at discharge fromthe ED. Drendel et al26 surveyed 98 caregivers of children pre-senting to an orthopedic injury follow-up clinic. They found thatchildren received on average 3.2 days of analgesia, with 45.3%receiving ibuprofen and 26.1% receiving acetaminophen-codeine.The worst pain experienced following the injury was in the first48 hours, and 82.7% of children had at least one area of functionaloutcome (including sleep, play, eating, and going to school) thatwas negatively affected.

In addition, oligoanalgesia, or the undertreatment of pain,does not end at discharge from the ED. A recent study askedcaregivers of children diagnosed with a fracture to complete a2-day pain record.27 All families were discharged from the EDwith written instructions for pharmacological analgesia adminis-tration. On day 1 postinjury, 20% of children received no anal-gesia, and 44% received only one dose, whereas on day 2, 30%received no analgesia. This low administration of analgesia iscontradictory to what one might expect given the previouslymentioned findings that the first 48 hours postinjury representsthe period of maximal pain.26

Analgesic medications are suboptimally used for childrenwith orthopedic injuries in both the ED and postdischarge. Thereis no standard of care for the treatment of such pain. As such,several recent studies have set out to determine the most appro-priate techniques and medications to address this gap in knowl-edge. At the end of this CME activity, the reader will gain anunderstanding of both nonpharmacological and pharmacologi-cal interventions for the treatment of orthopedic injuryYrelatedpain and explore the emerging area of pharmacogenomics inpain management.

NONPHARMACOLOGICAL STRATEGIESPediatric pain is best managed via a multimodel, multi-

system approach. Psychological and behavioral factors areknown to influence pain, and nonpharmacological interventionsplay an important role in altering pain perception and behav-ior.28,29 This has particular significance in the setting of the EDwhere anticipatory anxiety can greatly increase pain percep-tion.30 The same phenomenon can occur at home. By intro-ducing nonpharmacological pain management strategies in theED, children might experience improved pain relief, and theircaregivers may then use some of the same strategies to managetheir future pain or distress at home. There are specific techni-ques in orthopedic injury management that may optimize paintreatment. These include the so-called PRICE method, or pro-tection, rest, ice, compression, and elevation.31

Appropriate immobilization with good discharge instruc-tions regarding splint/cast care is part of standard care for

orthopedic injuries. Plint et al32 studied children with buckle(torus fractures) of the distal arm and concluded that removablesplints resulted in similar pain scores but improved function andactivity scores, when compared with circumferential short-armcasts. A recent trial of pediatric supracondylar fracture immo-bilization for 1 to 4 weeks in a backslab versus a collar and cufffocused on the reports of pain and return to activity.33 This studyconcluded that use of an above-elbow posterior slab producedshorter duration of pain (median duration of pain was 4.0 vs 6.0days for the collar-and-cuff group; P = 0.07) and reduced thetime taken to become active again (median of 2.0 vs 7.0 days;P = 0.01). Both of these studies highlight that immobilizationtechniques affect the pain experience and should be chosen tominimize duration and intensity of pain and maximize normalfunction.

The mechanism by which ice reduces pain after injury is notclear. It may reduce nerve conduction or muscle spasm or simplyreduce the metabolism of the tissues to reduce the degree ofcell injury. Ice also causes vasoconstriction and decreased per-meability of the local blood vessels, therefore decreasing theinflammation and release of cell mediators that might be asso-ciated with increased pain.34 Despite its frequent use, there isnot strong evidence to support the use of ice for the treatmentof acute pain. One study showed a significant reduction in thepain experienced 1 week after an ankle injury if ice is appliedfor 10 minutes, then removed for 10 minutes and then reappliedfor another 10 minutes. This intermittent icing was superior toice application for 20 minutes every 2 hours during the sameperiod.34 The recommendation to use ice should be advised withthe potential risk for cold-induced tissue damage with prolongedexposure and very cold temperatures reported in case reports.35

More studies are needed to define the best icing method, in-cluding the mode, duration, and frequency of application tooptimize outcomes.36

Other nonpharmacological methods that give children asense of control with or without the addition of pharmacologicaltherapy are more broadly applicable. These techniques are welldescribed in a recent Cochrane review of psychological therapiesfor pediatric pain, as well as a review of complementary andalternative medicine for the treatment of acute procedural pain,but no studies have assessed their impact on acute musculo-skeletal pain in children.29,37 The most widely used methods inED include preparatory information, imagery, distraction, re-laxation, breathing techniques, and positive reinforcement toalleviate pain (Table 1). These techniques are particularly usefulin young children and can be applied easily in the home settingby parents.27,38,39 A randomized controlled trial used a family-centered behavioral preparation program in the perioperativesetting that reduced the use of in-hospital analgesics with a

TABLE 1. Nonpharmacological Strategies to ManageMusculoskeletal Injury

Physical Methods Cognitive-Behavioral Methods

Immobilization Adequate preparationThermal regulation(ice/heating packs)

Imagery

RestDistraction (books, TV, music, etc)

ElevationRelaxation

MassageCreate a comfortable environment

PositioningBreathing techniques

TENS/acupuncturePositive reinforcementEmotional support

Help with daily activities

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parallel trend in the home setting.28 A similar strategy could beused in the ED for fracture pain with training from child lifespecialists or ED staff to help prompt parents to use planneddistraction strategies or coping tools at home.

Music likely exerts an analgesic effect through distraction,although the mechanism of action is not clear. It has beenevaluated in a number of pediatric studies including injectionand surgical pain.40Y42 The therapeutic effects of music for painreduction have been mixed, although many studies are not rig-orous or high quality.43 A meta-analysis showed that listeningto music modestly reduced pain intensity and opioid require-ments; however, the magnitude of opioid-sparing effect of musicis lower than the effect produced by the use of acetaminophenor over-the-counter nonsteroidal medication. Although musicshould not be considered the primary method for pain treatment,it shows promise as a useful adjunct for acute musculoskeletalpain. Furthermore, emotional support with a comforting andreassuring presence, in addition to having the caregiver help indaily activities, and the creation of a comfortable environmentare also considered useful nonpharmacological techniques forpain management.44Y46

Another category of nonpharmacological strategies usesphysical methods. These include thermal regulation, massage,positioning, and TENS (transcutaneous electrical nerve stimula-tion). Although it may be intuitive to think many of these methodswould likely reduce pain, evidence for their use in children foracute pain is lacking. The role of massage in pain control has beenprimarily focused on its effect on chronic pain. A single pediat-ric study showed it reduced distress during burn treatments;whether these same effects would be found for musculoskeletalpain is unclear.47 The TENS delivers electric current from a smallbattery-operated device to the skin via surface electrodes and ispostulated to modulate the perception of pain through the gate-control theory. A single double-blind controlled analgesic studyof adultswith acute traumatic pain in the outpatient setting showeda statistically significant difference in pain relief compared withplacebo. The effect on pain was comparable to pain relief afteracetaminophen (300Y600 mg) with codeine (30Y60 mg).48 Astudy of treatment for rib fractures also showed efficacy.49 Thereare no pediatric studies using the TENS, but these adult studiesshow promise.

There is building evidence that nonpharmacological in-terventions are commonly used for children. Maimon et al38

evaluated the parents’ approach to their child’s pain from a limbinjury before arriving at an ED and demonstrated that about onethird of parents used nonpharmacological measures, with almosthalf using them exclusively. The PAMPER (Pain ManagementPractices in a Pediatric Emergency Room) study looked at nursinginterventions to ease children’s pain in the ED and revealed thattechniques such as ice packs and heat are used in many settings.39

Zisk et al27 examined parental pain management practices athome after an extremity fracture and found, similar to a studyevaluating pediatric pain management after tonsillectomy, manynonpharmacological techniques were used.45 A notable findingwas the trend toward parents using more nonpharmacologicalmethods for younger children.

PHARMACOLOGICAL TREATMENT OPTIONSAcetaminophen, codeine, and ibuprofen are the most com-

monly used oral medications to treat mild-moderate pain inchildren. However, the most efficacious analgesic to alleviatemusculoskeletal pain in children has long been debated. A smallnumber of well-designed, recently published studies providesome evidence to help answer this question.

Clark et al50 designed a superiority trial comparing pain re-duction after a single dose of ibuprofen (10 mg/kg), acetamino-phen (15 mg/kg), or codeine (1 mg/kg). They recruited more than300 children with fractures and soft-tissue injuries in the ED,with a primary outcome of reduction in pain score at 60 minutesafter analgesia administration. Ibuprofen was found to have a sig-nificantly greater decrease in the pain visual analog scale (VAS)score (j24 mm; 95% confidence interval [CI],j29 toj20) thaneither acetaminophen (j12 mm; 95% CI,j16 toj8) or codeine(j11 mm; 95% CI, j16 to j5). Interestingly, no more thanhalf of the 3 medication groups met the investigators’ definitionfor adequate analgesia (defined as a VAS score G30 mm at60 minutes), highlighting that oligoanalgesia remains a signifi-cant problem in pediatric ED care. Fifty-two percent of childrenin the ibuprofen arm achieved adequate analgesia, and this wassignificantly more than for codeine (40%) or acetaminophen(36%). There was no significant difference in rates of adverseoutcomes reported in the 3 groups (7.7%Y16.2%).

Friday et al51 completed an equivalency trial comparingibuprofen (10 mg/kg) and acetaminophen-codeine (codeine1 mg/kg) in 68 pediatric ED patients with a diagnosis of eitherfracture or dislocation. They demonstrated that both analgesicswere associated with measurable decreases in pain scores40 minutes after administration. Children who used ibuprofenimproved their pain score by 4.8 T 3.0 cm, whereas children whoused acetaminophen-codeine improved their pain by 4.4 T 2.8 cmon a 10-cm VAS. The authors concluded these 2 medicationshad equivalent analgesic effectiveness. There were no statisticalor clinically important differences in reported adverse effectsor use of rescue medications.

Oxycodone has also been investigated for the managementof musculoskeletal injuries. Koller et al52 compared the efficacyof ibuprofen (10 mg/kg), oxycodone (0.1 mg/kg), and ibuprofen-oxycodone combination for 66 children with orthopedic inju-ries. All 3 treatment arms of this trial had decreased pain scores at120 minutes, with no statistical difference between the groups.Of note, however, nonpharmacological analgesics (ie, ice) wereinconsistently used among the study arms, and the combinationgroup described more adverse effects. Charney et al53 randomized107 children in triagewith a suspected orthopedic injury to receiveeither codeine (2 mg/kg) or oxycodone (0.2 mg/kg). Althoughboth groups had significant reductions in pain scores measuredevery 30 minutes for 3 hours, children receiving oxycodone had astatistically significant greater reduction in pain scores comparedwith codeine at all time intervals. Increased pruritus was associ-ated with codeine use.

These investigations of analgesic efficacy within the pedi-atric ED show that ibuprofen has at least similar efficacy toacetaminophen and codeine, with a better adverse effect profile.Oxycodone is also emerging as an effective choice for moderatemusculoskeletal pain, if an oral narcotic is required. (See Table 2for summary).

The only study to look at analgesic efficacy after dischargehome was done by Drendel et al.54 Three hundred thirty-six chil-dren with unreduced upper limb fractures were randomly assignedto receive 3 days of ibuprofen (10 mg/kg) or acetaminophen-codeine (codeine 1 mg/kg) for use at home. The primary outcomewas the failure of analgesia, defined as the use of a rescue medi-cation within 1 hour after study drug administration. This studyfound that ibuprofen was at least as good as acetaminophen-codeine. The difference in failure rates between ibuprofen(20.3%) and acetaminophen-codeine (31.0%) nearly reached sta-tistical significance (10.7%; 95%CI,j0.2% to 21.6%). Ibuprofendemonstrated a more favorable adverse effect profile, with lessnausea and vomiting and more normal eating and play patterns. At

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completion of the study, participants were asked if they wouldwant the same medication again; 27.5% of the acetaminophen-codeine group did not, compared with 10.0% in the ibuprofengroup (a difference of 17.5%; 95% CI, 7.3%Y28.3%).

Currently, ibuprofen is emerging as a favorable choice forthe treatment of acute musculoskeletal injury pain. Theoreticalconcerns regarding ibuprofen’s effects upon fracture healing doexist. Currently, there is no conclusive evidence from humanstudies that ibuprofen (or other nonsteroidal anti-inflammatorydrugs) can adversely affect fracture healing,55,56 This would bean important area for future research that would help definitivelyanswer the question of optimal analgesic choices for childrenwith orthopedic injuries. Furthermore, the significant interindi-vidual variation seen in analgesic response to all forms ofinterventions needs to be addressed.

FUTURE DIRECTIONS: PHARMACOGENOMICSOF PAIN TREATMENT

It is clear from both medical literature and clinical experi-ence that there is variation in interindividual response to painmedication. There are many variables that may play a role in thisvariance, but increasingly, genetic variation is being recognizedas an important factor. Pharmacogenomics is the study of howvariations in the human genome affect an individual’s responseto medications. New discoveries in this field are being madeevery day, and translating this new knowledge into clinically rel-evant and applicable information is a challenge for emergencymedicine physicians.

In the ED of the future, the patient’s entire genotype will beat the clinician’s fingertips and will be integral in guiding thephysician to choose Bthe right[ medication at Bthe best[ dosingschedule for that child’s optimal treatment plan. This personal-ized approach is not currently feasible. In fact, the application ofpharmacogenomics in the ED is in its infancy; we are challengedby the breadth of available knowledge and the limitations ofa fast-paced environment with primarily new patient encoun-ters. Nonetheless, there is a variety of opportunities that a phy-sician might use the current knowledge of pharmacogenomicsto personalize the analgesic prescription for children. There isa growing body of pharmacogenetic literature that is clinicallyrelevant for opioids. An understanding of the effect of geneticvariation on efficacy for nonsteroidal anti-inflammatory medi-cations is also in its early stages. The following is a review ofthe current knowledge of pharmacogenomics that might affectanalgesics prescription practices for musculoskeletal injuries.

Codeine is the only analgesic for which a genetic predispo-sition to analgesic responsiveness has been absolutely identified.57

Codeine is converted by the cytochrome P450Ymetabolizing en-zyme 2D6 (CYP2D6) to an active morphine metabolite. The genethat encodes this enzyme is highly polymorphic (or variable),with 136 single-nucleotide polymorphisms identified.58 There arenonfunctional, reduced function, and duplicated alleles, and eachresults in an inherited ability to metabolize codeine to its activeform. Therefore, with knowledge of a patient’s genotype, childrencan be classified for their potential analgesic response to codeine.Patients can be categorized into 1 of 4 phenotypes; 2 nonfunc-tioning alleles determine a poor metabolizer; at least 1 reducedfunctioning allele is an intermediate metabolizer; at least 1 func-tional allele is an extensive metabolizer; and multiple copies ofa functional allele are an ultrarapid metabolizer. The most com-mon phenotype is an extensive metabolizer. These children wouldhave the expected pain-relieving response to codeine comparedwith a poor metabolizer who would likely have less analgesic ef-fect. Although this is an oversimplification, because of significantvariability even within the defined phenotypes, understandingthese broad categorizations aids in the understanding of rela-tionship between genotype, metabolism, and analgesic efficacy.Because codeine requires conversion to an active metabolite tobe effective, patients with a genotype that is classified as poormetabolizers are unlikely to attain adequate drug concentrationsto achieve optimal analgesia.

The prevalence of a genetic variant in the population is im-portant to discern its clinical impact. For CYP2D6, certain allelesare more common in distinct ethnic groups. Polymorphisms forpoor metabolizers for CYP2D6, which would be associated withpoor clinical effect for codeine, are estimated to occur in 6% to10% of non-Hispanic whites, 0% to 4.8% of Asians, 2.2% to 6.6%of Hispanics, and 1.9% to 7.3% of African American popula-tions.59 It is reported that almost 50% of individuals will have atleast 1 reduced functioning allele.59Y62 Depending on the ethnicdiversity of the population in your ED, the allelic frequencies willdiffer, as will the potential for poor metabolism and inadequateresponse to codeine.

Codeine has a relatively narrow therapeutic window, so ge-netic variability in metabolism is more likely to have a relevantclinical effect. Pharmacokinetic studies investigating serum con-centrations of the active metabolite in adults have found a 5- to17-fold difference between individuals known to be poor meta-bolizers and those who are extensive metabolizers.63Y65 Studies ofexperimentally induced pain have found that those who are poormetabolizers had lower metabolite concentrations and an expecteddecreased tolerance to pain.66 Studies of clinical pain have mixedresults highlighting the complexity of clinical pain experi-ence.67,68 Overall, the association between genotype and clinical

TABLE 2. Oral Analgesic Efficacy Within the ED

Study Study Medications Primary Outcome

Clark et al50 Acetaminophen 15 mg/kg Ibuprofen improved pain score significantly more than acetaminophen andcodeine 60 min after administrationCodeine 1 mg/kg

Ibuprofen 10 mg/kg

Charney et al53 Codeine 2 mg/kg Patients receiving oxycodone reported significantly greater reductions in painscore throughout the 180-min study periodOxycodone 0.2 mg/kg

Friday et al51 Codeine 1 mg/kg There was no statistically significant difference between pain score reductionin the 2 groups at 40 minIbuprofen 10 mg/kg

Koller et al52 Oxycodone 0.1 mg/kg There were no statistically significant differences in pain score reductionbetween the 3 groups at 120 minIbuprofen 10 mg/kg

Ibuprofen-oxycodone




effect is strong and should affect the prescription practices ofmedical providers.

Genetic polymorphisms in metabolizing enzymes are notthe only genetic variations that might affect analgesic outcomes.There are complex interactions between genetic variations in drugabsorption, distribution, metabolism, and elimination that mightaffect analgesic efficacy. But the clinical relevance of these var-iants has not been extensively researched, making it difficult toapply to bedside decisions at this time.

Overall, the body of evidence is strongly supporting thecorrelation between CYP2D6 genotype and serum concentrationof active codeine metabolites. The variability in analgesic effectthat can be attributed to CYP2D6 genotype has not been com-pletely defined in the clinical setting, but studies suggest thatknowledge of genotype could optimize the treatment of pain.Alternatively, instead of determining the genotype before pre-scribing codeine, the use of analgesics that do not requireCYP2D6 metabolism might improve clinical efficacy. Both hy-drocodone and oxycodone are semisynthetic oral opioids thatare used for children with moderate to severe pain. Both medi-cations undergo metabolism via CYP2D6, but the parent com-pounds are also active opioids. Therefore, the parent compound/metabolite mismatch that was illustrated for codeine does notoccur. The pain relief provided by hydrocodone and oxycodone isnot dependent on metabolism by CYP2D6. This might, in part,explain the difference in efficacy for codeine and oxycodone inthe study of Charney et al.53 This suggests that hydrocodone andoxycodone are viable options for children who are known to havea poor metabolizing phenotype or children for whom genotypeis not known. It is interesting to note that hydrocodone and oxy-codone are prescribed more often than codeine in some NorthAmerican EDs.25

Although the evidence is growing, determining genotype orconsideration of alternative medication prescription to reduceadverse effects for patients taking opioids analgesics is not sup-ported by the current literature.69Y72 This will likely be an areaof future focus, given the increased reports of opioid-related fa-talities and misuse of oral prescription opioids.73Y75

Significant intersubject variation in analgesic response toibuprofen is alsowell recognized; 1 possible explanation is geneticvariation. Ibuprofen is the active compound that provides painrelief, and it is metabolized to the inactive form. Therefore, re-duced functioning genetic variants would be associated with in-creased serum concentrations of active ibuprofen that might beassociated with improved clinical efficacy or increased adverseeffects. CYP2C9 is the predominant enzyme responsible foribuprofen metabolism, and it is known to be highly variable with389 single-nucleotide polymorphisms identified.58 Six of thecommon genetic variants are associated with reduced metabolicactivity.76 One of these genetic variants has been shown to beassociated with a significant reduction in the clearance of ibu-profen, but the clinical impact is not clear.77Y79 The effect ofgenetic variation on ibuprofen clinical efficacy and adverse effectshas not been clearly delineated. This is an area that requires furtherresearch before meaningful clinical conclusions can be made.

SUMMARYPediatric musculoskeletal injuries are both common and

painful. We need to optimize the measurement, documentation,and treatment of pain in children. There is growing evidence thatnonpharmacological methods can be introduced to improve an-algesia in the ED, and efforts to help parents implement thesemethods at home might be advantageous to optimize outpatienttreatment plans. Traditionally, acetaminophen with codeine hasbeen used to treat moderate orthopedic injuryYrelated pain in

children. More recently, ibuprofen has emerged as a commonlyused therapy. Other oral opioids (hydrocodone, oxycodone) aregaining popularity, as well. Current pediatric clinical trial dataindicate that ibuprofen is at least as effective as acetaminophen-codeine and codeine alone. Medication compliance might beimproved if adverse effects were minimized, and ibuprofen hasbeen shown to have a similar or better adverse effect profile thanthe oral opioids to which it has been compared. One must alsoconsider the socially responsible treatment of pain, given the in-creasing misuse of oral prescription opioids and accidental over-doses with resulting fatalities occurring in North America.

Pharmacogenomic data show that nearly 50% of individualshave at least 1 reduced functioning allele resulting in suboptimalconversion of codeine to active analgesic, so it is not surprisingthat codeine analgesic efficacy is not optimal. Further researchshould focus on alternative pharmaceutical options that are notdependent on CYP2D6 enzyme metabolism, to provide clinicianswith more choices for outpatient treatment of moderate pain.Although codeine is looking to be less desirable than we mighthave first thought, and oxycodone is beginning to emerge as abetter choice than codeine, further research is required to confirmoxycodone effectiveness in children with musculoskeletal inju-ries. At the same time, nonpharmacological therapies are emerg-ing as commonly used treatment options by parents and adjunctsto analgesic medication. The efficacy and role of techniques(massage, music therapy, TENS), although promising, requirefurther clarification in the treatment of orthopedic injury pain.The reader should now be more comfortable in decision-makingregarding the pharmacologic and non-pharmacologic treatmentof orthopedic-related pain, while being aware that certain ques-tions remained to be answered.

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30. Krauss B. Managing acute pain and anxiety in children undergoingprocedures in the emergency department. Emerg Med (Fremantle).2001;13(3):293Y304.

31. Bleakley CM, O’Connor S, Tully MA, et al. The PRICE study(protection rest ice compression elevation): design of a randomisedcontrolled trial comparing standard versus cryokinetic ice applicationsin the management of acute ankle sprain [ISRCTN13903946]. BMCMusculoskelet Disord. 2007;8:125.

32. Plint AC, Perry JJ, Correll R, et al. A randomized, controlled trial of

removable splinting versus casting for wrist buckle fractures inchildren. Pediatrics. 2006;117(3):691Y697.

33. Oakley E, Barnett P, Babl FE. Backslab versus nonbackslab forimmobilization of undisplaced supracondylar fractures: a randomizedtrial. Pediatr Emerg Care. 2009;25(7):452Y456.

34. Bleakley CM, McDonough SM, MacAuley DC, et al. Cryotherapyfor acute ankle sprains: a randomised controlled study of two differenticing protocols. Br J Sports Med. 2006;40(8):700Y705; discussion 705.

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36. Bleakley C, McDonough S, MacAuley D. The use of ice in thetreatment of acute soft-tissue injury: a systematic review of randomizedcontrolled trials. Am J Sports Med. 2004;32(1):251Y261.

37. Evans S, Tsao JC, Zeltzer LK. Complementary and alternativemedicine for acute procedural pain in children. Altern Ther Health Med.2008;14(5):52Y56.

38. Maimon MS, Marques L, Goldman RD. Parental administration ofanalgesic medication in children after a limb injury. PediatrEmerg Care. 2007;23(4):223Y226.

39. Le May S, Johnston CC, Choiniere M, et al. Pain managementpractices in a pediatric emergency room (PAMPER) study: interventionswith nurses. Pediatr Emerg Care. 2009;25(8):498Y503.

40. Hatem TP, Lira PI, Mattos SS. The therapeutic effects of music inchildren following cardiac surgery. J Pediatr (Rio J ). 2006;82(3):186Y192.

41. Caprilli S, Anastasi F, Grotto RP, et al. Interactive music as a treatmentfor pain and stress in children during venipuncture: a randomizedprospective study. J Dev Behav Pediatr. 2007;28(5):399Y403.

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44. Polkki T, Vehvilainen-Julkunen K, Pietila AM. Parents’ roles inusing non-pharmacological methods in their child’s postoperative painalleviation. J Clin Nurs. 2002;11(4):526Y536.

45. Idvall E, Holm C, Runeson I. Pain experiences andnon-pharmacological strategies for pain management aftertonsillectomy: a qualitative interview study of children and parents.J Child Health Care. 2005;9(3):196Y207.

46. O’Donnell JJ, Maurice SC, Beattie TF. Emergency analgesia in thepaediatric population. Part III non-pharmacological measures of painrelief and anxiolysis. Emerg Med J. 2002;19(3):195Y197.

47. Hernandez-Reif M, Field T, Largie S, et al. Children’s distress duringburn treatment is reduced by massage therapy. J Burn Care Rehabil.2001;22(2):191Y195; discussion 190.

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53. Charney RL, Yan Y, Schootman M, et al. Oxycodone versus codeinefor triage pain in children with suspected forearm fracture: arandomized controlled trial. Pediatr Emerg Care.2008;24(9):595Y600.

54. Drendel AL, Gorelick MH, Weisman SJ, et al. A randomized clinicaltrial of ibuprofen versus acetaminophen with codeine for acutepediatric arm fracture pain. Ann Emerg Med. 2009;54(4):553Y560.

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CME EXAMINSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSi

Pediatric Emergency Care includes CME-certified content that is designed to meet the educational needs of its readers.An annual total of 12 AMA PRA Category 1 Creditsi is available through the twelve 2010 issues of the Pediatric EmergencyCare. This activity is available for credit through December 15, 2010.

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Education to provide continuing medical education for physicians.To earn CME credit, you must read the article in Pediatric Emergency Care and complete the quiz, answering at least 80

percent of the questions correctly. Mail the completed quiz to the Lippincott CME Institute, Inc., Wolters Kluwer Health, TwoCommerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103; fax: 215-827-5614. Only the first entry will beconsidered for credit, and must be postmarked by the expiration date. There is no cost for CME credit or quiz processing. Answersheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation.

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PRA Category 1 Crediti. Physicians should only claim credit commensurate with the extent of their participation in the activity.

CME EXAMINATIONJULY 2010

Please mark your answers on the ANSWER SHEET.

Pain Management of Musculoskeletal Injuries in Children, Ali et al.

1. Oligoanalgesia is defined as:a. The undertreatment of painb. The use of the wrong medications for the treatment of

painc. Not enough paind. Extreme paine. No pain

2. Which of the following would be appropriate interventionsfor a child discharged from the ED with a buckle fracture?a. Volar splintb. Distraction strategiesc. Ice packsd. Storytellinge. All of the above

3. Name the analgesic for which a genetic predisposition toanalgesic responsiveness has been absolutely identified.a. Oxycodoneb. Hydrocodone

c. Codeined. Ibuprofene. Ketorolac

4. Pharmacogenomics is the study of:a. drug interactionsb. how genetics influence a person’s risk for injuryc. how variations in the human genome affect an indivi-

dual’s response to medicationsd. the unique chemical fingerprints that specific cellular

processes leave behinde. large-scale protein structure and function

5. Examples of nonpharmacological interventions that couldbe easily used in the ED include:a. Distraction (ie, music)b. Preparatory informationc. Guided imageryd. Breathing techniquese. All of the above




ANSWER SHEET FOR THE PEDIATRIC EMERGENCY CARECME PROGRAM EXAM

July 2010

Please answer the questions on page 525 by filling in the appropriate circles on the answer sheet below. Please mark the one bestanswer and fill in the circle until the letter is no longer visible. To process your exam, you must also provide the followinginformation:Name (please print):Street AddressCity/State/ZipDaytime PhoneSpecialty

1. !A!B!C!D!E2. !A!B!C!D!E3. !A!B!C!D!E4. !A!B!C!D!E5. !A!B!C!D!E

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° G20% ° 20%Y40% ° 40Y60% ° 60Y80% ° 980%

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within the next 6 months? (1 Y definitely will not change, 5 Y definitely will change) ° ° ° ° °

How will you apply what you learned from these activiies (mark all that apply):In diagnosing patients ° In making treatment decisions °In monitoring patients ° As a foundation to learn more °In educating students and colleagues ° In educating patients and their caregivers °As part of a quality or peformance improvement project ° To confirm current practice °For maintenance of board certification ° For maintenance of licensure °

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CME EXAM ANSWERS

Answers for the Pediatric Emergency Care CME Program Exam

Below you will find the answers to the examination covering the review article in the April 2010 issue. All participantswhose examinations were received by June 15, 2010 and who achieved a score of 80% or greater will receive a certificatefrom Lippincott CME Institute, Inc.

EXAM ANSWERS

April 2010

1. E2. D3. B4. E5. D


