Pain Research and Management

Pain Research and Management / 2016 / Article

Review Article | Open Access

Volume 2016 |Article ID 5346819 | 15 pages | https://doi.org/10.1155/2016/5346819

How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review

Academic Editor: José W. Geurts
Received08 Feb 2016
Revised18 Oct 2016
Accepted27 Oct 2016
Published18 Dec 2016

Abstract

Background. Fear of adverse events and occurrence of side effects are commonly cited by families and physicians as obstructive to appropriate use of pain medication in children. We examined evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children (<18 years) treated in ambulatory settings. Methods. A comprehensive search was performed to July 2015, including review of national data registries. Two reviewers screened articles for inclusion, assessed methodological quality, and extracted data. Risks (incidence rates) were pooled using a random effects model. Results. Forty-four studies were included; 23 reported on adverse events. Based on limited current evidence, acetaminophen, ibuprofen, and opioids have similar nausea and vomiting profiles. Opioids have the greatest risk of central nervous system adverse events. Dual therapy with a nonopioid/opioid combination resulted in a lower risk of adverse events than opioids alone. Conclusions. Ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids. Dual therapy with a nonopioid/opioid combination confers a protective effect for adverse events over opioids alone. This research highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials.

1. Introduction

Pain is the most common reason for seeking healthcare in the Western world [13]. Key organizations have voiced concern with our medical services’ inability to provide appropriate analgesia for children’s pain [48]. Inadequate pain treatment can have significant detrimental effects [912]. Still, fear of adverse events (AEs) is commonly cited by both families and physicians as an obstruction to appropriate use of analgesic medication in childhood [13, 14].

AEs are a major health problem for affected children, their family, and society [1517]. Surprisingly, comprehensive drug safety in children remains understudied, despite emerging evidence that AEs are frequent and are commonly cited as a reason for terminating prescribed therapy [15, 16]. A systematic review of AEs in hospitalized pediatric patients reported an overall incidence rate of 9% [18]. Furthermore, up to 30–50% of pediatric analgesic users will experience at least one AE [13]. Milder AEs (i.e., vomiting, sleepiness, and constipation) contribute to limitations in activity and function for children and negatively impact their caregivers’ productivity and time off work [14]. Importantly, AEs may discourage future use of analgesics, thereby exposing children to unnecessary pain and its resultant negative consequences.

Children’s pain management varies greatly across North America [14, 19]. Recently, clinicians have been compelled to rapidly shift their prescribing practices due, in part, to concerns regarding the safety profile of oral opioids [14, 2024]. With the FDA boxed warning regarding codeine use in children post-ENT surgery [23] as well as the European Medicines Agency and Health Canada’s advisory to avoid all codeine use in children less than 12 years of age [24, 25], clinicians have reduced their use of codeine and now search for a suitable alternative oral opioid. A recent survey of North American physicians showed considerable variability in practice management by center, country, and specialty [26]. The American Academy of Pediatrics’ consensus statement on the assessment and management of pain in children recommends acetaminophen, ibuprofen, and opioids as the top three medication choices for the treatment of acute pain in children [4]. These are also the top three most commonly used treatments in the emergency department for children with fracture pain [14, 22, 2628]. It stands to reason that clinicians (and certainly patients and their families) would prefer the drug that has the best safety profile. However, as noted in the 2014 report by the Council of Canadian Academies, available published literature is not properly synthesized to provide the data needed to make such treatment decisions [29].

This systematic review compares the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), and opioids, to manage acute, nonsurgical pain in children treated in ambulatory settings. While much has been written about the efficacy of these medications, to date, there has been no comprehensive synthesis of safety and in particular their comparative safety. Moreover, since emerging studies are suggesting equivalence (or close to equivalence) and clinical equipoise for many of the current pain management options [13, 19, 30, 31], clinicians may make practical decisions driven by the perceived safety profile. In an effort to address known challenges in safety literature nomenclature [32], we attempted to capture a range of undesirable effects (e.g., side effects, adverse effects, adverse events, and adverse reactions). For the purposes of this manuscript, we use the term “adverse events” to represent all safety concerns captured by this variable nomenclature.

2. Methods

We followed a protocol established a priori (available from authors) based on standards for conducting and reporting systematic reviews [3335].

2.1. Search

A research librarian searched (from inception to July 2015) the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Appendix  A), EMBASE, International Pharmaceutical Abstracts, TOXNET, BIOSIS Previews, PubMed, and Web of Science. We searched relevant conference proceedings and abstracts from the American Pain Society (2011–2015), Canadian Pain Society (2011–2015), International Symposium of Pediatric Pain (2015), North American Congress of Clinical Toxicology (2011–2015), and the European Association of Poison Centers and Clinical Toxicologists (2011–2015). We also searched clinicaltrials.gov and the Australian New Zealand Clinical Trials Registry. We checked reference lists of relevant studies and searched websites of regulatory agencies. We contacted the U.S. Food and Drug Administration (FDA) and Health Canada for safety data related to the medications of interest. For all included studies we searched to see if they had been cited by new, relevant studies using Web of Knowledge and Google Scholar. Searches were not restricted by language or publication status.

2.2. Study Selection

Search results were screened independently by two reviewers. Two reviewers then assessed the full text of all potentially relevant citations using a standard form with predefined eligibility criteria. Disagreements were resolved by consensus.

2.3. Inclusion Criteria

We included primary studies of any design involving children (<18 years) with acute pain (pain related to injury or illness less than 3 months in duration) who were treated in an ambulatory setting (e.g., outpatient clinics, emergency). The ambulatory setting was chosen as it represents the most common location for presentation of children with acute injuries and illnesses requiring short-term analgesic use. Pain medications included acetaminophen, NSAIDS, and opioids. We included any study design and publication type. We excluded studies of surgically induced pain, as we felt these patients represented medically induced pain and included the possible influence of general or regional anesthesia.

2.4. Data Extraction

One reviewer extracted data using a structured form; a second reviewer verified data for accuracy and completeness. We extracted study and patient characteristics; interventions (type, dose, route of administration, timing, and duration); care setting (e.g., emergency department, outpatient clinic, primary care, and others); AEs; and funding source.

We extracted AEs as reported in the studies and grouped them into nine categories: nausea, vomiting, other gastrointestinal symptoms, headache, drowsiness (includes sleepiness and tiredness), dizziness, other CNS symptoms, dermatological symptoms, and pulmonary symptoms. For each AE, we counted each event as if it corresponded to a unique individual.

2.5. Assessment of Methodological Quality

We used the McMaster Quality Assessment Scale of Harms, a validated tool covering issues of how data on harms were defined, collected, and reported. Two reviewers independently assessed quality and resolved discrepancies through discussion.

2.6. Data Synthesis

A description of the studies is provided in tables. We present a summary of AEs by treatment arm (i.e., intervention) for an overall picture of which interventions had a high risk of specific AEs. This enabled us to include data from both comparative and noncomparative studies. For each AE, risks (incidence rates) were pooled using a random effects model to obtain a summary estimate and 95% confidence interval (CI). Analyses were conducted using Review Manager 5.2 (Cochrane Collaboration, 2012).

3. Results

Forty-four studies met our inclusion criteria; however, 21 did not report AEs (Figure 1) [3656]. Therefore, we included 23 studies involving 2,300 patients: 17 randomized controlled trials, 2 nonrandomized controlled trials, 1 case report, cross-sectional survey, 1 chart review, and 1 prospective cohort (Table 1) [13, 19, 27, 5776]. Studies were published between 1991 and 2014 (median year 2007) and were conducted in the United States (), Canada (5), France (3), Italy (3), and Germany (2) and one each in Finland, New Zealand, and the United Kingdom. Most studies did not report on sources of funding (), one specifically reported no funding [68], seven reported grant funding [13, 19, 62, 64, 66, 69, 75, 76], and two reported funding from industry [70, 75].


Author, year country,
funding source
Study designSetting
age, range (years)
Painful condition studiedComparisons ( = number of subjects/patients)AE defined a priori by authorsAuthor conclusions

Bertin et al., 1991, France,
NR
RCTED
mean 7.95 (SD 1.85)
Acute tonsillitis and pharyngitis (duration of sore throat ≤ 48 h)(i) Ibuprofen (10 mg/kg),
(ii) Acetaminophen (10 mg/kg),
(iii) Placebo (10 mg/kg),
Nausea, abdominal pain, cutaneous rashIbuprofen, combined with antibiotic therapy, is effective and well-tolerated short-term treatment for pain

Bertin et al., 1996, France,
NR
RCTOutpatient clinic
1–6.75 (mean 2.98 ± 1.33)
Otoscopically proven acute otitis media, either unilateral or bilateral(i) Ibuprofen (10 mg/kg),
(ii) Acetaminophen (10 mg/kg),
(iii) Placebo,
Nausea, vomiting, abdominal pain, cutaneous rash11 children experienced mild unexpected events; treatment was never interrupted because of unexpected events

Hämäläinen et al., 1997,
Finland,
NR
RCTED
NR
Migraine (≥2 migraine attacks/month lasting ≥2 h)(i) Acetaminophen (15 mg/kg),
(ii) Ibuprofen (10 mg/kg),
(iii) Placebo: cellulose (NR),
Nausea, vomiting, gastric painNo significant difference in number of AEs; acetaminophen and ibuprofen are effective and well-tolerated for acute migraine, with acetaminophen having faster onset but slightly less effect and ibuprofen giving best relief

Pothmann and Lobisch, 2000,
Germany,
NR
RCT, cross-overAmbulatory clinic + home
6–12
Tension-type headache (IHS criteria)(i) Flupirtine (6–8 years = 50 mg, 9–12 y = 100 mg)  
(ii) Acetaminophen (6–8 y = 250 mg, 9–12 y = 500 mg),
NRRelevant side effects could not be observed

Soriani et al., 2001, Italy,
NR
NRCTED
mean 12.8 (SD 3.1)
Migraine (≥6-month duration and ≥1 attacks/month)(i) Acetaminophen (15 mg/kg),
(ii) Nimesulide (2.5 mg/kg),
Mild abdominal discomfort, nauseaNo significant difference in side effects; nimesulide associated with low occurrence of ADRs especially in GI tract; effects in liver are within or below the general incidence with other NSAIDs

Lewis et al., 2002, USA,
NR
RCTHome
6–12
Migraine (IHS-R criteria)(i) Ibuprofen (7.5 mg/kg),
(ii) Placebo,
Nausea, vomiting, photophobia, phonophobiaChildren’s ibuprofen suspension (7.5 mg/kg) is effective and well-tolerated for pain relief in acute treatment of migraine, particularly in boys.

Tanabe et al., 2002,
USA,
grants from multiple nonindustry sources
NRCTED
5–17
Minor extremity trauma including and distal to elbow and knee(i) Standard care (ice, elevation, and immobilization),
(ii) Standard care + distraction (e.g., guided imagery, music therapy, reading, or being read to),
(iii) Standard care + ibuprofen (10 mg/kg),
NROne child experienced nausea after taking ibuprofen

Wille et al., 2005,
France,
NR
Prospective cohort (single arm)ED
0.5–6
Injuries to extremities with deformation; burns requiring hospitalizationMorphine (0.5 mg/kg), Nausea, vomiting, decrease in oxygen saturation, drowsinessNo serious AEs and few minor side effects; oral morphine monotherapy can be given within an analgesic protocol with few minor side effects

Drendel et al., 2006,
USA,
NR
Cross-sectional surveyHospital-based pediatric orthopedic clinic
1–18
Isolated extremity fracture receiving follow-up care at orthopedic clinic within 10 days of injuryPatients () received ibuprofen, acetaminophen + codeine, acetaminophen, other narcotics (hydrocodone, oxycodone, and rofecoxib), or a combination of ibuprofen, acetaminophen, and acetaminophen + codeine; 6 patients received no pain medication; 3 were unsure“Other” effects from the medicationAEs not reported by drug; those receiving acetaminophen + codeine appeared to experience more other effects. Physicians and caregivers may have concerns about these side effects when dosing the medication

Evers et al., 2006,
Germany,
NR
RCTOutpatient clinic
6–18
Migraine with and without aura(i) Zolmitriptan (2.5 mg),
(ii) Ibuprofen (200 mg for children <12 or 400 mg for adolescents),
(iii) Placebo,
Dizziness, somnolence, gastrointestinalNo serious AEs occurred; all AEs were mild and resolved completely; zolmitriptan but not ibuprofen produced significantly more AEs than placebo

Clark et al., 2007,
Canada,
Hospital Research Institute
RCTED
6–17
Musculoskeletal injury (to extremities, neck, or back) occurring within 48 h(i) Codeine (1 mg/kg, max 60 mg),
(ii) Acetaminophen (15 mg/kg, max 650 mg),
(iii) Ibuprofen (10 mg/kg, max 600 mg),
Minor AEs such as nausea, sleepiness, constipationAEs were minimal; no significant difference between groups for minor AEs (nausea, sleepiness, constipation)

Cukiernik et al., 2007,
Canada,
Health Research Institutes
RCTED
8–14
Isolated soft tissue injury of ankle (no history of gastric ulcers or allergy to acetaminophen or naproxen)(i) Naproxen (20 mg/kg),
(ii) Acetaminophen (15 mg/kg),
NRNo significant difference in efficacy or AEs. Given acetaminophen’s wider safety margin and a large experience in children, acetaminophen may be the preferred agent for therapy of soft tissue injury in children and adolescents

Ismail et al., 2007,
UK,
NR
Case reportGP clinic
8
2-day history of neck and back pain(i) Acetaminophen (500 mg) and ibuprofen (200 mg), NAIbuprofen is generally safe and effective as antipyretic and analgesic; risk of acute papillary necrosis, particularly in dehydrated children

Koller et al., 2007,
USA,
Academic
RCTEDSuspected orthopedic injury; patients with baseline score of ≥4 on faces pain scale(i) Oxycodone (0.1 mg/kg),
(ii) Ibuprofen (10 mg/kg),
(iii) Oxycodone + ibuprofen (0.1 mg/kg, 10 mg/kg),
NROxycodone or ibuprofen monotherapy avoids the increase in AEs more than when given together

Charney et al., 2008,
USA,
NR
RCTEDSuspected isolated forearm fractures(i) Oxycodone (0.2 mg/kg),
(ii) Codeine (2 mg/kg),
Vomiting, headache, dizziness, difficulty walking, difficulty breathing, tiredness, abdominal pain, itching, sweating, dry mouthMinor AEs in both groups; itching less in oxycodone group

Drendel et al., 2009,
USA,
hospital foundation
RCTED
4–18
Fracture of radius, ulna, or humerus (no open fracture)(i) Acetaminophen + codeine (120 mg/5 mg per 5 mL),
(ii) Ibuprofen (100 mg/5 mL),
Nausea, vomiting, drowsy, dizzy, constipation, otherChildren receiving ibuprofen had significantly fewer AEs; both children and parents were more satisfied with ibuprofen; significantly higher rates of nausea and vomiting for children receiving acetaminophen + codeine

Friday et al., 2009,
USA,
NR
RCTEDIsolated extremity injury with tenderness to palpation from clavicle or femoral neck to distal phalanges; pain score ≥ 5 (of 10) at triage(i) Acetaminophen + codeine (1 mg/kg, max 60 mg),
(ii) Ibuprofen (10 mg/kg, max 400 mg),
Vomiting, pruritus, nauseaAEs were minimal

Shepherd and Aickin, 2009,
New Zealand,
no funding
RCTED
5–14
Fracture management within 24 h of injury; acute, nonpathological fracture of distal humerus, any part of radius, ulna, tibia, or fibula; patient able to be managed as outpatient(i) Acetaminophen (15 mg/kg),
(ii) Ibuprofen (10 mg/kg),
Vomiting, tiredness, dizzinessParent-reported sleep quality did not differ between groups; no significant differences in side effects between groups

Richer et al., 2010,
Canada,
hospital foundation, national health funding agency
Chart reviewED
5–17
Migraine (headache at time of physician assessment and diagnosis of migraine by emergency physician)(i) Ibuprofen (various doses)  
(ii) Acetaminophen (various doses)
1694 patients in study
NANo serious AEs; dystonia, agitation, hypotension, and paresthesias were observed in association with a dopamine receptor antagonist

Ruperto et al., 2011,
Italy,
industry, research agency
RCTED
6–12
Pharyngotonsillitis(i) Acetaminophen (12 mg/kg corresponding to 1 mL/2 kg),
(ii) Ketoprofen lysine salt (40 mg),
(iii) Placebo,
Bronchitis, rash, diarrhoea, coughNo serious AE; no events were related to the drugs or placebo

Le May et al., 2013, 
Canada,
hospital research centre, national agency, industry
RCTED
7–18
Musculoskeletal injury to limb within 72 h; pain score > 3 on 0–10 VAS; bony tenderness, swelling, limited ROM, or angulation < 30°(i) Codeine (1 mg/kg, max 60 mg) + Ibuprofen (10 mg/kg, max 600 mg),
(ii) Ibuprofen + placebo (10 mg/kg, max 600 mg),
Drowsiness, nausea, vomiting, dizziness1 patient in experimental group with nausea; no other side effects or AEs reported in either group; side effects were minimal

Neri et al., 2013,
Italy,
NR
RCTED
4–17
Suspected fracture or dislocation(i) Ketorolac (0.5 mg/kg, to a max of 20 mg (= 0.025 mL/kg of the solution, maximum 1 mL),
(ii) Tramadol (2 mg/kg, to a max of 100 mg, 0.020 mL/kg mL of the solution, and maximum of 1 mL),
(iii) Placebo, = unclear
Vomiting, vomiting, dry mouthNo significant differences in AEs; fewer side effects reported in ketorolac group

Poonai et al., 2014,
Canada,
university research grant
RCTED
5–17
Nonoperative, radiographically evident extremity fracture(i) Morphine (0.5 mg/kg, to a max of 10 mg),
(ii) Ibuprofen (10 mg/kg, to a max of 600 mg),
NRNo severe adverse drug reactions (e.g., immune-mediated hypersensitivity) were reported by any of the participants, and there were no deaths. Significantly more participants in the morphine group had adverse effects, the most common of which was drowsiness

Only five studies described how AEs were measured: Bertin et al. 1991 (on basis of clinical criteria); Evers et al. 2006 (patients or parents recorded adverse events at baseline and at 0.5, 1, 2, 4, and 24 hours after drug intake); Wille et al. 2005 (evaluated by nurse); Drendel et al. 2006 (26-question survey from patient’s caregiver); Drendel et al. 2009 (caregivers and their children used diary to record tolerability of assigned medication daily).

The median quality score was 8/14 (interquartile range 6 to 8) (Appendix  B). Only 41% predefined harms while none defined serious or severe AEs. Sixty-nine percent included active data collection for AEs; 48% involved passive (six studies used both). Seventy-eight percent specified who collected AE data, and 57% provided information on their training and/or background. Forty-three percent specified the timing and frequency of AE collection; only 9% used a standard scale or checklist for harms collection. The majority (83%) specified that the reported harms encompassed all events (not a select sample). The majority specified the number of AEs in each study arm (90%), the number that withdrew or were lost to follow-up for each group (87%), and the number for each type of AE (78%). Few specified the type of analyses undertaken for harms data (35%).

Figures 24 present the risks of AEs for all pain medications and placebo (Appendix  C provides detailed risk data). The following summarizes the data by type of AE.

Gastrointestinal (GI) (Figure 2). Acetaminophen had a similar GI AE profile as NSAIDS. Opioids trended towards greater “other GI AEs,” including constipation. Codeine monotherapy showed cumulatively more GI AEs than all other analgesics. NSAIDS and acetaminophen reported less than 10% rate of GI AEs. Opioid/nonopioid combinations had varying degrees of GI AEs associated with them; of note, oral morphine demonstrated the highest reported risk of nausea, followed by acetaminophen with codeine combination medication. Placebo-related AEs of nausea and vomiting were equal to or greater than that of some pain medications.

Central Nervous System (CNS) (Figure 3). Opioid monotherapy showed the highest risk of CNS AEs, with drowsiness/tiredness being noted in close to one-third of children receiving oxycodone or oral morphine and half of children receiving codeine. CNS symptoms of drowsiness and dizziness were notably higher for all opioid medications, when compared to nonopioid choices. Oxycodone and oral morphine have comparable risks for both drowsiness and dizziness. Opioid/nonopioid combination medications had a lower risk of CNS AEs.

Dermatological and Pulmonary System (Figure 4). Opioid medications demonstrated a greater risk of dermatologic symptoms. Children receiving only codeine had almost double the risk of experiencing dermatologic manifestations compared to all other medications. Pulmonary AEs were rare. No children receiving a NSAID experienced bronchospasm.

4. Registry Data

We requested acetaminophen data from the U.S. Food and Drug Administration (FDA) through the U.S. FDA Adverse Event Reporting System. The report provided was a nonsearchable PDF comprising 7,523 pages with 17,806 reports of AEs for acetaminophen for all ages (i.e., adults and children). The team confirmed with the FDA that it was not possible to restrict the search results by age group or intention (i.e., nonintentional causes). Consequently, it was not feasible to include FDA data in this manuscript.

Through Health Canada, we received reports of AEs among children and youth from the Canada Vigilance Adverse Reaction Online Database. We received a total of 625 reports for all the three classes of drugs. For acetaminophen, we identified 232 reports; 39 were relevant based on our inclusion criteria. The median age was 5 years (range 7 weeks to 18 years). The most common AEs were vomiting (), dermatological symptoms (), other GI symptoms (), and psychiatric effects (). The remaining AEs were reported for either one or two patients. For NSAIDS, we identified 209 reports; 69 were relevant. The median age was 7 years (range 3 months to 18 years). The most common AEs were allergic-type reactions (), headache (), vomiting (), nausea (), other GI symptoms (), dermatological (), and psychiatric effects (). For opioids, we identified 184 reports; 21 were relevant. The median age was 13 years (range 18 months to 18 years). The most common AEs were other GI symptoms (), vomiting (), nausea (), and dermatological ().

Four deaths were reported in the Health Canada data (Table 2). Case  1 was a 2-year-old who took morphine (route of administration unclear) and suffered respiratory failure. Case  2 was an 18- year-old who took acetaminophen, alone, as well as an acetaminophen/codeine combination. The route of administration for both was oral; no dosing information was provided. Case  3 was a 4-year-old who took an acetaminophen/codeine combination (oral; no dosing information). The patient was described as having a “medically important condition” but no further description was provided. Respiratory distress was plausible with codeine use. Case  4 was a 3-month-old, 4 kg child who was given acetaminophen. Reaction information included apnea, cyanosis, and respiratory depression, which are not typical AEs of acetaminophen. Drug levels were noted to be supratherapeutic but no further details were provided; a 4 kg weight likely suggests prematurity or chronic illness.


AgeSource of reportMedicationOther relevant information

2 yearsNonhealth professionalMorphine (no route or dosing information)Respiratory failure was reported
18 yearsPhysicianTylenol and acetaminophen plus codeine (both oral; no dosing information)None reported
4 yearsNonphysician health professionalAcetaminophen plus codeine (oral; no dosing information)Patient described as having a medically important condition. Respiratory distress was reported
3 months (4 kg)Nonphysician health professionalAcetaminophenApnea, cyanosis, respiratory depression, and supratherapeutic drug levels were reported

5. Discussion

Each year, more than 50% of children use at least one medication [77], with acetaminophen and ibuprofen being the most common. There is an alarming paucity of research regarding the drug safety of common analgesics in children. Children’s response to medications is often different from that of adults due to metabolism, ontogeny, and other age-related differences; as such, examination of safety data must be specific to children. Our study is one of the first to synthesize the currently available evidence and provides urgently needed safety information for clinicians treating children with acute pain in ambulatory settings.

Our study of the safety profiles of commonly used pain medications for children in the outpatient setting has demonstrated that (1) acetaminophen and ibuprofen have similar risk of nausea and vomiting, (2) opioids have the greatest risk of CNS AEs, and (3) dual therapy with a nonopioid/opioid medications results in a lower risk of AEs than opioids alone.

Our findings, specific to its use for acute, painful conditions, are consistent with previous work that has examined acetaminophen and ibuprofen in the context of its antipyretic use. A large randomized controlled trial (RCT) of ibuprofen and acetaminophen in outpatient practice showed the risk of hospitalization for gastrointestinal bleeding, renal failure, or anaphylaxis was not increased following short-term use of ibuprofen [78]. A notable limitation of their study was the lack of information on less severe outcomes. A second large RCT of febrile infants (<2 years of age) receiving acetaminophen or ibuprofen demonstrated a 1.4% risk of serious AEs (defined as rate of admission for acute gastrointestinal bleeding, acute renal failure, anaphylaxis, Reye’s syndrome, asthma, bronchiolitis, and vomiting/gastritis) [79]. A 2004 systematic review of acetaminophen and ibuprofen, consisting of 3 pain studies and 14 fever studies in children, concluded that single doses of ibuprofen and acetaminophen had similar safety profiles, when assessing “major” (e.g., abdominal pain, vomiting, and hypothermia) and “minor” (e.g., nausea, sweating, and cutaneous rash) AEs [80]. Our study adds important and comprehensive information regarding AEs for healthy children with injury or illness-related pain. This group is medically different from febrile and infected children and, as such, merits separate consideration.

Determining the appropriate analgesic agent for a child with acute pain can be a complex decision, influenced by multiple factors including patient age and genomics, anticipated degree and duration of pain, ability to swallow pills, and preexisting medical problems. An understanding of the AE profile can aid in making an evidence-based, personalized choice that takes into account a child’s individual circumstances.

We have determined that acetaminophen, traditionally considered one of the most widely studied, gastrointestinally “benign” pain medications (as compared to NSAIDs or opioids), has a similar GI side effect profile as ibuprofen, for children. As such, it would make clinical sense to use the pain medication that conferred the most clinical analgesic effect, even when GI side effects were of concern for a specific child. Limiting short-term ibuprofen use due to concern for GI AEs is not supported by current evidence. It is noteworthy that the placebo-related side effects of nausea and vomiting were equal to or greater than that of the various pain medications. This phenomenon has been previously well-described [81] and underscores the importance of measuring and comparing relative differences in side effect profiles, rather than only absolute values. Further, in the context of treating pain, one must be cautious to attribute all AEs to the pain medications used, as pain, itself, may plausibly have a causative role in some of the symptoms (e.g., nausea, agitation).

Oxycodone, oral morphine, and codeine monotherapy had the greatest risk of CNS side effects, with drowsiness/tiredness being noted in close to one-third of children receiving oxycodone or oral morphine and half of children receiving codeine. CNS symptoms of drowsiness and dizziness were notably higher for all opioid medications, when compared to nonopioid choices. This makes physiologic sense, as opioids have CNS depressant effects which NSAIDS and acetaminophen lack. A child who needs to avoid CNS symptoms (e.g., a school-aged child, during daytime hours) should likely be treated with ibuprofen or acetaminophen for mild-moderate pain, as they have a lower AE profile, as compared to low-mid dose opioids, a comparably potent analgesic agent [19, 27, 66]. Current evidence suggests that ibuprofen likely has superior analgesic potency for many clinical conditions including fractures, sprains, and postoperative pain [13, 19, 76, 8184]. Further, knowing that its GI AE profile is comparable to acetaminophen, one would likely choose ibuprofen as first line therapy for most such pediatric acute pain conditions with mild to moderate pain. When escalating pain necessitates the use of oral opioids, dual therapy (with a nonopioid medication, such as ibuprofen or acetaminophen) appears to “protect” the child against many of the negative AEs associated with opioids, particularly CNS effects. This is likely due to decreased opioid dosage required to achieve analgesia. Opioid medications should be added to, rather than replace, these nonopioids when needed for moderate-severe pain, a strategy endorsed by the World Health Organization [85].

Opioid medications were associated with a greater risk of dermatologic symptoms, which is plausible given the histamine release phenomenon that can occur with their use [86]. Children receiving only codeine had almost double the risk of experiencing dermatologic manifestations compared to all other medications. Of note, however, the confidence intervals for all opioid mono- and combination therapies overlapped significantly, with the notable exception of codeine monotherapy; children receiving only codeine had almost double the risk of experiencing dermatologic manifestations. Pulmonary side effects were rare. No children in the included studies receiving an NSAID experienced bronchospasm, a suggested risk for ibuprofen in some medical literature pertaining to fever management [87, 88].

Codeine monotherapy has cumulatively more gastrointestinal side effects than all other analgesics that were a part of this review, including other opioids. GI AEs associated with codeine monotherapy are poorly tolerated by children and may result in premature termination of therapy [13, 89] and significant short- and long-term effects [9092] due to untreated pain. This information, coupled with the recent FDA warning [93] and other recommendations [24, 25, 94] to avoid codeine use in children under 12 years of age, supports the general avoidance of codeine use in opioid-naïve children, except in the exceptional circumstance of an older child who has previously received codeine and tolerated it well.

This study has also led to some noteworthy observations regarding the use of national databases for medication-related research. We contacted the FDA through the Adverse Event Reporting System and received a report that was not usable for study purposes. We contacted Health Canada for data collected through the Canada Vigilance Adverse Reaction Online Database, and reports were readily available to us. While we were able to review them for relevance, it was impossible to draw conclusions regarding causality. As such, the results should be interpreted cautiously as there are several limitations: there is no denominator information to calculate incidence rates; reports are voluntarily submitted by consumers and nonphysician health professionals and lack details. We recommend that federal agencies consider modifying the manner in which medication-related AEs are reported and recorded. This would allow researchers and policy-makers to understand and use this information in a more meaningful way. Specifically, we suggest recording the treating clinicians’ postulated interpretation of the cause of the AEs, creation of a searchable database, and clearer recording of the dose and frequency of the drugs used.

Given the inconsistent and often passive information collection of AEs in past studies, it is imperative that future trials of pain medications include a standardized and universal approach to the collection of AEs, in order to create a growing repository of such information, which can be resynthesized at a future date, and lead to even more robust conclusions regarding safety.

6. Strengths and Limitations

To our knowledge, this is the first clinician-friendly, comprehensive synthesis of AEs for the most commonly used pain medications for children. This is an important first step in addressing the lack of postmarket safety data for medications for children. Our unique style of presenting the data, based on AE rather than medication type, provides a more clinically meaningful way to interpret the results, as clinicians generally approach decision-making for patients from the perspective of “Which medication will provide the most pain relief with the least symptoms of concern for my patient?”

This study has some limitations. The synthesis of information was dependent on accurate and explicit recording of AEs within the original studies. Many of the included studies were not designed to systematically collect data on adverse events. As such, our results are a reflection of what is available but may not exactly reflect the true postmarket safety of the included medications. Further, the number of studies and patients is small given the prevalent use of these agents in practice. In some cases, the rates were variable across studies with wide confidence intervals. This could be due to a number of factors (e.g., dosing); however, few studies and sparse data did not allow for subgroup analyses to delineate risks according to other factors. Data was particularly sparse for NSAIDs other than ibuprofen. Results and conclusions regarding ibuprofen should not be extrapolated to other NSAIDs that may have more potent adverse event profiles. Finally, we were not able to interpret the FDA and Health Canada data in a meaningful fashion.

7. Conclusion

Based on the available evidence, ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids, for the initial treatment of acute pain in children in ambulatory settings. Dual therapy with a nonopioid/opioid combination confers a protective effect for AEs over opioids alone, suggesting that opioid medications should be added to, rather than replace, nonopioids when needed for moderate-severe pain. In order to allow for meaningful synthesis and evidence-informed care, it is imperative that future trials of pain medications include a standardized and universal approach to the collection of AEs and that ongoing national data registry monitoring be more detailed surrounding AEs (particularly causation).

Abbreviations

AE:Adverse event
CNS:Central nervous system
FDA:Food and Drug Administration
GI:Gastrointestinal
NSAID:Nonsteroidal anti-inflammatory drug
RCT:Randomized controlled trial.

Disclosure

The funder played no role in formulating the question, collecting and interpreting data, or reporting results. Dr. Lisa Hartling holds a New Investigator Salary Award from CIHR. Dr. Patrick J. McGrath holds a Canada Research Chair.

Competing Interests

Dr. Amy L. Drendel, Dr. Amy C. Plint, and Dr. Samina Ali are authors on some of the studies included in the review. The other authors have indicated they have no potential conflicts of interest to disclose.

Acknowledgments

The authors thank Elizabeth Sumamo-Schellenberg for project coordination, Andrea Milne for searching the literature, Ben Vandermeer for statistical analysis, and Kassi Shave for assisting with screening and data verification. This work was supported by a Knowledge Synthesis Grant from the Canadian Institutes of Health Research (CIHR).

Supplementary Materials

Appendix A: Search strategy for Medline. Appendix B: Detailed risk data by study and adverse event. Appendix C: This file contains study level details for each of the AEs described, including the dosage, the number of events, the sample size, and the risk.

  1. Supplementary Material

References

  1. P. Tanabe and M. Buschmann, “A prospective study of ED pain management practices and the patient's perspective,” Journal of emergency nursing: JEN: official publication of the Emergency Department Nurses Association, vol. 25, no. 3, pp. 171–177, 1999. View at: Publisher Site | Google Scholar
  2. W. H. Cordell, K. K. Keene, B. K. Giles, J. B. Jones, J. H. Jones, and E. J. Brizendine, “The high prevalence of pain in emergency medical care,” The American Journal of Emergency Medicine, vol. 20, no. 3, pp. 165–169, 2002. View at: Publisher Site | Google Scholar
  3. C. C. Johnston, A. J. Gagnon, C. J. Pepler, and P. Bourgault, “Pain in the emergency department with one-week follow-up of pain resolution,” Pain Research and Management, vol. 10, no. 2, pp. 67–70, 2005. View at: Publisher Site | Google Scholar
  4. Pediatrics AAo, “Committee on Psychosocial Aspects of Child and Family Health TFoPiI, Children, and Adolescents: the assessment and management of acute pain in infants, children, and adolescents,” Pediatrics, vol. 108, no. 3, pp. 793–797, 2001. View at: Publisher Site | Google Scholar
  5. C. M. McMurtry, “Needle and dread: is it just a little poke? A call for implementation of evidence-based policies for the management of needle pain in clinical settings,” Paediatrics and Child Health, vol. 12, no. 2, pp. 101–102, 2007. View at: Google Scholar
  6. W. Zempsky and J. Cravero, “Medicine AAoPCoPEMaSoAaP: relief of pain and anxiety in pediatric patients in emergency medical systems,” Pediatrics, vol. 114, no. 5, pp. 1348–1356, 2004. View at: Publisher Site | Google Scholar
  7. D. B. Gordon, J. L. Dahl, C. Miaskowski et al., “American pain society recommendations for improving the quality of acute and cancer pain management,” Archives of Internal Medicine, vol. 165, no. 14, pp. 1574–1580, 2005. View at: Publisher Site | Google Scholar
  8. S. E. Mace, I. A. Barata, J. P. Cravero et al., “Clinical policy: evidence-based approach to pharmacologic agents used in pediatric sedation and analgesia in the emergency department,” Annals of Emergency Medicine, vol. 44, no. 4, pp. 342–377, 2004. View at: Publisher Site | Google Scholar
  9. K. J. S. Anand, “Pain, plasticity, and premature birth: a prescription for permanent suffering?” Nature Medicine, vol. 6, no. 9, pp. 971–973, 2000. View at: Publisher Site | Google Scholar
  10. R. F. Howard, “Current status of pain management in children,” Journal of the American Medical Association, vol. 290, no. 18, pp. 2464–2469, 2003. View at: Publisher Site | Google Scholar
  11. S. J. Weisman, B. Bernstein, and N. L. Schechter, “Consequences of inadequate analgesia during painful procedures in children,” Archives of Pediatrics and Adolescent Medicine, vol. 152, no. 2, pp. 147–149, 1998. View at: Google Scholar
  12. K. Haraldstad, R. Sørum, H. Eide, G. K. Natvig, and S. Helseth, “Pain in children and adolescents: prevalence, impact on daily life, and parents' perception, a school survey,” Scandinavian Journal of Caring Sciences, vol. 25, no. 1, pp. 27–36, 2011. View at: Publisher Site | Google Scholar
  13. A. L. Drendel, M. H. Gorelick, S. J. Weisman, R. Lyon, D. C. Brousseau, and M. K. Kim, “A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain,” Annals of Emergency Medicine, vol. 54, no. 4, pp. 553–560, 2009. View at: Publisher Site | Google Scholar
  14. A. Drendel, R. Lyon, J. Bergholte, and M. Kim, “Outpatient pediatric pain management practices for fractures,” Pediatric Emergency Care, vol. 22, no. 2, pp. 94–99, 2006. View at: Google Scholar
  15. K. Wester, A. K. Jönsson, O. Spigset, H. Druid, and S. Hägg, “Incidence of fatal adverse drug reactions: a population based study,” British Journal of Clinical Pharmacology, vol. 65, no. 4, pp. 573–579, 2008. View at: Publisher Site | Google Scholar
  16. R. Voelker, “Children's deaths linked with postsurgical codeine,” JAMA—Journal of the American Medical Association, vol. 308, no. 10, p. 963, 2012. View at: Publisher Site | Google Scholar
  17. F. T. Bourgeois, K. D. Mandl, C. Valim, and M. W. Shannon, “Pediatric adverse drug events in the outpatient setting: an 11-year national analysis,” Pediatrics, vol. 124, no. 4, pp. e744–e750, 2009. View at: Publisher Site | Google Scholar
  18. E. N. De Vries, M. A. Ramrattan, S. M. Smorenburg, D. J. Gouma, and M. A. Boermeester, “The incidence and nature of in-hospital adverse events: a systematic review,” Quality & Safety in Health Care, vol. 17, no. 3, pp. 216–223, 2008. View at: Publisher Site | Google Scholar
  19. E. Clark, A. C. Plint, R. Correll, I. Gaboury, and B. Passi, “A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma,” Pediatrics, vol. 119, no. 3, pp. 460–467, 2007. View at: Publisher Site | Google Scholar
  20. P. Madadi, G. Koren, J. Cairns et al., “Safety of codeine during breastfeeding: fetal morphine poisoning in the breastfed neonate of a mother presecribed codeine,” Canadian Family Physician, vol. 53, no. 1, pp. 33–35, 2007. View at: Google Scholar
  21. M. Hermanns-Clausen, W. Weinmann, V. Auwärter et al., “Drug dosing error with drops—severe clinical course of codeine intoxication in twins,” European Journal of Pediatrics, vol. 168, no. 7, pp. 819–824, 2009. View at: Publisher Site | Google Scholar
  22. S. Ali, S. Curtis, D. Johnson, E. Logue, B. Vandermeer, and A. Newton, “Pediatric pain practice variation amongst emergency doctors: a canadian survey,” CJEM, vol. 13, no. 3, pp. 229–278, 2010. View at: Google Scholar
  23. Administration USFaD: FDA Drug Safety Communication: Codeine Use in Certain Children after Tonsillectomy and/or Adenoidectomy May Lead to Rare, but Life-Threatening Adverse Events or Death, FDA, Silver Spring, Md, USA, 2013.
  24. Health Canada's review recommends codeine only be used in patients aged 12 and over, http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/33915a-eng.php.
  25. E. M. Agency, Restrictions on Use of Codeine for Pain Relief in Children—CMDh Endorses PRAC Recommendation, European Medicines Agency, London, UK, 2013.
  26. J. Kircher, S. Ali, A. Drendel, S. Dulai, A. Plint, and A. Newton, “Acute musculoskeletal pain treatment: a North American survey of practice variation,” CJEM, vol. 14, no. 1S, p. S32, 2012. View at: Google Scholar
  27. J. H. Friday, J. T. Kanegaye, I. McCaslin, A. Zheng, and J. R. Harley, “Ibuprofen provides analgesia equivalent to acetaminophen-codeine in the treatment of acute pain in children with extremity injuries: a randomized clinical trial,” Academic Emergency Medicine, vol. 16, no. 8, pp. 711–716, 2009. View at: Publisher Site | Google Scholar
  28. J. Kircher, S. Ali, A. Drendel, S. Dulai, and A. Newton, “Pediatric musculoskeletal pain management in the ED: a medical record review,” Canadian Journal of Emergency Medicine, vol. 14, no. 1, p. S32, 2012. View at: Google Scholar
  29. “Academies CoC: Improving Medicines for Children in Canada,” Ottawa, Ontario, 2014. View at: Google Scholar
  30. M. S. Moir, E. Bair, P. Shinnick, and A. Messner, “Acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy,” Laryngoscope, vol. 110, no. 11, pp. 1824–1827, 2000. View at: Publisher Site | Google Scholar
  31. S. Manzano, E. Doyon-Trottier, and B. Bailey, “Myth: ibuprofen is superior to acetaminophen for the treatment of benign headaches in children and adults,” Canadian Journal of Emergency Medicine, vol. 12, no. 3, pp. 220–222, 2010. View at: Google Scholar
  32. P. J. McGrath, G. A. Walco, D. C. Turk et al., “Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations,” The Journal of Pain, vol. 9, no. 9, pp. 771–783, 2008. View at: Publisher Site | Google Scholar
  33. J. P. T. Higgins and S. Green, Cochrane Handbook for Systematic Reviews of Interventions, John Wiley & Sons, Chichester, UK, 2011.
  34. IOM, IoM: Finding What Works in Health Care. Standards for Systematic Review, The National Academies Press, Washington, DC, USA, 2011.
  35. D. Moher, A. Liberati, J. Tetzlaff, D. G. Altman, and The PRISMA Group, “Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement,” Annals of Internal Medicine, vol. 151, no. 4, pp. 264–269, 2009. View at: Publisher Site | Google Scholar
  36. S. Thikkurissy, P. H. Allen, M. K. Smiley, and P. S. Casamassimo, “Waiting for the pain to get worse: characteristics of a pediatric population with acute dental pain,” Pediatric Dentistry, vol. 34, no. 4, pp. 289–294, 2012. View at: Google Scholar
  37. H. A. Obu, J. M. Chinawa, A. C. Ubesie, C. B. Eke, and I. K. Ndu, “Paracetamol use (and/or misuse) in children in Enugu, South-East, Nigeria,” BMC Pediatrics, vol. 12, article 103, 2012. View at: Publisher Site | Google Scholar
  38. R. E. Bushman and L. K. Patterson, “Muscle pain in the emergency department: a case of myositis,” Journal of Pediatric Health Care, vol. 26, no. 3, pp. 204–208, 2012. View at: Publisher Site | Google Scholar
  39. M. Galinski, N. Picco, B. Hennequin et al., “Out-of-hospital emergency medicine in pediatric patients: prevalence and management of pain,” American Journal of Emergency Medicine, vol. 29, no. 9, pp. 1062–1066, 2011. View at: Publisher Site | Google Scholar
  40. G. Rosenbluth, S. D. Wilson, J. H. Maselli, and A. D. Auerbach, “Analgesic prescribing practices can be improved by low-cost point-of-care decision support,” Journal of Pain & Symptom Management, vol. 42, no. 4, pp. 623–631, 2011. View at: Publisher Site | Google Scholar
  41. M. Dixson, “Pediatric rash and joint pain: a case review,” Journal of Emergency Nursing, vol. 36, no. 6, pp. 591–593, 2010. View at: Publisher Site | Google Scholar
  42. O. M. S. Fredheim, T. Log, W. Olsen, S. Skurtveit, Ø. Sagen, and P. C. Borchgrevink, “Prescriptions of opioids to children and adolescents; a study from a national prescription database in Norway,” Paediatric Anaesthesia, vol. 20, no. 6, pp. 537–544, 2010. View at: Publisher Site | Google Scholar
  43. Y.-M. Weng, Y.-C. Chang, and Y.-J. Lin, “Triage pain scales cannot predict analgesia provision to pediatric patients with long-bone fracture,” The American Journal of Emergency Medicine, vol. 28, no. 4, pp. 412–417, 2010. View at: Publisher Site | Google Scholar
  44. J. Furyk and M. Sumner, “Pain score documentation and analgesia: a comparison of children and adults with appendicitis,” EMA - Emergency Medicine Australasia, vol. 20, no. 6, pp. 482–487, 2008. View at: Publisher Site | Google Scholar
  45. R. Y. Zisk, M. Grey, B. Medoff-Cooper, J. E. MacLaren, and Z. N. Kain, “The squeaky wheel gets the grease: parental pain management of children treated for bone fractures,” Pediatric Emergency Care, vol. 24, no. 2, pp. 89–96, 2008. View at: Publisher Site | Google Scholar
  46. A. L. Rogovik and R. D. Goldman, “Prehospital use of analgesics at home or en route to the hospital in children with extremity injuries,” American Journal of Emergency Medicine, vol. 25, no. 4, pp. 400–405, 2007. View at: Publisher Site | Google Scholar
  47. M. S. Maimon, L. Marques, and R. D. Goldman, “Parental administration of analgesic medication in children after a limb injury,” Pediatric Emergency Care, vol. 23, no. 4, pp. 223–226, 2007. View at: Publisher Site | Google Scholar
  48. A. L. Rogovik, M. Rostami, S. Hussain, and R. D. Goldman, “Physician pain reminder as an intervention to enhance analgesia for extremity and clavicle injuries in pediatric emergency,” Journal of Pain, vol. 8, no. 1, pp. 26–32, 2007. View at: Publisher Site | Google Scholar
  49. J. Pulkki, S. Huikko, U.-M. Rautakorpi et al., “Management of pain in acute otitis media in Finnish primary care,” Scandinavian Journal of Infectious Diseases, vol. 38, no. 4, pp. 265–267, 2006. View at: Publisher Site | Google Scholar
  50. J. D. Losek, “Acetaminophen dose accuracy and pediatric emergency care,” Pediatric Emergency Care, vol. 20, no. 5, pp. 285–288, 2004. View at: Google Scholar
  51. J. P. Beale, A. J. Oglesby, A. Jones, J. Clancy, and T. F. Beattie, “Comparison of oral and intravenous morphine following acute injury in children,” European Journal of Emergency Medicine, vol. 8, no. 4, pp. 271–274, 2001. View at: Publisher Site | Google Scholar
  52. D. W. Herd and B. Salehi, “Palatability of two forms of paracetamol (acetaminophen) suspension: a randomised trial,” Paediatric and Perinatal Drug Therapy, vol. 7, no. 4, pp. 189–193, 2006. View at: Publisher Site | Google Scholar
  53. M. B. Caurín, G. Armero, V. Arias, Y. Fernández, V. Trenchs, and C. Luaces Cubells, “Prevalence and management of pain in an emergency department,” Pediatria Catalana, vol. 72, no. 4, pp. 147–152, 2012. View at: Google Scholar
  54. L. Dong, A. Donaldson, R. Metzger, and H. Keenan, “Analgesic administration in the emergency department for children requiring hospitalization for long-bone fracture,” Pediatric Emergency Care, vol. 28, no. 2, pp. 109–114, 2012. View at: Publisher Site | Google Scholar
  55. P. Scagni and R. Pagliero, “Headache in an Italian pediatric emergency department,” Journal of Headache and Pain, vol. 9, no. 2, pp. 83–87, 2008. View at: Publisher Site | Google Scholar
  56. C. Donald, R. Duncan, L. Blair, S. Thakore, and M. Clark, “Paediatric analgesia in the emergency department, are we getting it right?” European Journal of Emergency Medicine, vol. 14, no. 3, pp. 157–159, 2007. View at: Publisher Site | Google Scholar
  57. L. Bertin, G. Pons, P. d'Athis et al., “Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children,” The Journal of Pediatrics, vol. 119, no. 5, pp. 811–814, 1991. View at: Publisher Site | Google Scholar
  58. L. Bertin, G. Pons, P. D'Athis et al., “A randomized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children,” Fundamental and Clinical Pharmacology, vol. 10, no. 4, pp. 387–392, 1996. View at: Publisher Site | Google Scholar
  59. R. Pothmann and M. Lobisch, “Acute treatment of episodic childhood tension-type headache with flupirtine and paracetamol—a double-blind crossover-study,” Schmerz, vol. 14, no. 1, pp. 1–4, 2000. View at: Google Scholar
  60. S. Soriani, P. A. Battistella, C. Naccarella, E. Tozzi, E. Fiumana, and S. Fanaro, “Nimesulide and acetaminophen for the treatment of juvenile migraine: a study for comparison of efficacy, safety, and tolerability,” Headache Quarterly, vol. 12, no. 4, pp. 233–236, 2001. View at: Google Scholar
  61. D. W. Lewis, D. Kellstein, G. Dahl et al., “Children's ibuprofen suspension for the acute treatment of pediatric migraine,” Headache, vol. 42, no. 8, pp. 780–786, 2002. View at: Publisher Site | Google Scholar
  62. P. Tanabe, K. Ferket, R. Thomas, J. Paice, and R. Marcantonio, “The effect of standard care, ibuprofen, and distraction on pain relief and patient satisfaction in children with musculoskeletal trauma,” Journal of Emergency Nursing, vol. 28, no. 2, pp. 118–125, 2002. View at: Publisher Site | Google Scholar
  63. C. Wille, N. Bocquet, B. Cojocaru, A. Leis, and G. Chéron, “Oral morphine administration for children's traumatic pain,” Archives de Pediatrie, vol. 12, no. 3, pp. 248–253, 2005. View at: Publisher Site | Google Scholar
  64. V. A. Cukiernik, R. Lim, D. Warren, J. A. Seabrook, D. Matsui, and M. J. Rieder, “Naproxen versus acetaminophen for therapy of soft tissue injuries to the ankle in children,” Annals of Pharmacotherapy, vol. 41, no. 9, pp. 1368–1374, 2007. View at: Publisher Site | Google Scholar
  65. M. Ismail, P. K. Hegarty, A. Taghizadah, N. Kumar, and I. Mushtaq, “Ibuprofen-induced papillary necrosis causing bilateral ureteric obstruction,” Journal of Pediatric Urology, vol. 3, no. 1, pp. 60–62, 2007. View at: Publisher Site | Google Scholar
  66. D. M. Koller, A. B. Myers, D. Lorenz, and S. A. Godambe, “Effectiveness of oxycodone, ibuprofen, or the combination in the initial management of orthopedic injury-related pain in children,” Pediatric Emergency Care, vol. 23, no. 9, pp. 627–633, 2007. View at: Publisher Site | Google Scholar
  67. R. L. Charney, Y. Yan, M. Schootman, R. M. Kennedy, and J. D. Luhmann, “Oxycodone versus codeine for triage pain in children with suspected forearm fracture: a randomized controlled trial,” Pediatric Emergency Care, vol. 24, no. 9, pp. 595–600, 2008. View at: Publisher Site | Google Scholar
  68. M. Shepherd and R. Aickin, “Paracetamol versus ibuprofen: a randomized controlled trial of outpatient analgesia efficacy for paediatric acute limb fractures,” Emergency Medicine Australasia, vol. 21, no. 6, pp. 484–490, 2009. View at: Publisher Site | Google Scholar
  69. L. P. Richer, K. Laycock, K. Millar et al., “Treatment of children with migraine in emergency departments: national practice variation study,” Pediatrics, vol. 126, no. 1, pp. e150–e155, 2010. View at: Publisher Site | Google Scholar
  70. N. Ruperto, L. Carozzino, R. Jamone et al., “A randomized, double-blind, placebo-controlled trial of paracetamol and ketoprofren lysine salt for pain control in children with pharyngotonsillitis cared by family pediatricians,” Italian Journal of Pediatrics, vol. 37, no. 1, article 48, 2011. View at: Publisher Site | Google Scholar
  71. S. Evers, A. Rahmann, C. Kraemer et al., “Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen,” Neurology, vol. 67, no. 3, pp. 497–499, 2006. View at: Publisher Site | Google Scholar
  72. M. L. Hämäläinen, K. Hoppu, E. Valkeila, and P. Santavuori, “Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study,” Neurology, vol. 48, no. 1, pp. 103–107, 1997. View at: Publisher Site | Google Scholar
  73. A. L. Drendel, R. Lyon, J. Bergholte, and M. K. Kim, “Outpatient pediatric pain management practices for fractures,” Pediatric Emergency Care, vol. 22, no. 2, pp. 94–99, 2006. View at: Publisher Site | Google Scholar
  74. E. Neri, A. Maestro, F. Minen et al., “Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial,” Archives of Disease in Childhood, vol. 98, no. 9, pp. 721–724, 2013. View at: Publisher Site | Google Scholar
  75. S. Le May, S. Gouin, C. Fortin, A. Messier, M.-A. Robert, and M. Julien, “Efficacy of an ibuprofen/codeine combination for pain management in children presenting to the emergency department with a limb injury: a pilot study,” Journal of Emergency Medicine, vol. 44, no. 2, pp. 536–542, 2013. View at: Publisher Site | Google Scholar
  76. N. Poonai, G. Bhullar, K. Lin et al., “Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial,” CMAJ, vol. 186, no. 18, pp. 1358–1363, 2014. View at: Publisher Site | Google Scholar
  77. L. Vernacchio, J. P. Kelly, D. W. Kaufman, and A. A. Mitchell, “Medication use among children <12 years of age in the United States: results from the slone survey,” Pediatrics, vol. 124, no. 2, pp. 446–454, 2009. View at: Publisher Site | Google Scholar
  78. S. M. Lesko and A. A. Mitchell, “An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial,” Journal of the American Medical Association, vol. 273, no. 12, pp. 929–933, 1995. View at: Publisher Site | Google Scholar
  79. S. M. Lesko and A. A. Mitchell, “The safety of acetaminophen and ibuprofen among children younger than two years old,” Pediatrics, vol. 104, no. 4, article e39, 1999. View at: Publisher Site | Google Scholar
  80. D. A. Perrott, T. Piira, B. Goodenough, and G. D. Champion, “Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis,” Archives of Pediatrics and Adolescent Medicine, vol. 158, no. 6, pp. 521–526, 2004. View at: Publisher Site | Google Scholar
  81. G. L. Petersen, N. B. Finnerup, L. Colloca et al., “The magnitude of nocebo effects in pain: a meta-analysis,” Pain, vol. 155, no. 8, pp. 1426–1434, 2014. View at: Publisher Site | Google Scholar
  82. L. E. Kelly, D. D. Sommer, J. Ramakrishna et al., “Morphine or ibuprofen for post-tonsillectomy analgesia: a randomized trial,” Pediatrics, vol. 135, no. 2, pp. 307–313, 2015. View at: Publisher Site | Google Scholar
  83. G. Gazal and I. C. Mackie, “A comparison of paracetamol, ibuprofen or their combination for pain relief following extractions in children under general anaesthesia: a randomized controlled trial,” International Journal of Paediatric Dentistry, vol. 17, no. 3, pp. 169–177, 2007. View at: Publisher Site | Google Scholar
  84. L. Morris, D. Stulberg, and J. J. Stevermer, “Fracture pain relief for kids? Ibuprofen does it better,” Journal of Family Practice, vol. 59, no. 5, pp. 273–275, 2010. View at: Google Scholar
  85. WHO, Cancer Pain Relief, WHO, Geneva, Switzerland, 1986.
  86. B. A. Baldo and N. H. Pham, “Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two,” Anaesthesia and Intensive Care, vol. 40, no. 2, pp. 216–235, 2012. View at: Google Scholar
  87. J. S. Debley, E. R. Carter, R. L. Gibson, M. Rosenfeld, and G. J. Redding, “The prevalence of ibuprofen-sensitive asthma in children: a randomized controlled bronchoprovocation challenge study,” Journal of Pediatrics, vol. 147, no. 2, pp. 233–238, 2005. View at: Publisher Site | Google Scholar
  88. R. E. Kauffman and M. Lieh-Lai, “Ibuprofen and increased morbidity in children with asthma: fact or fiction?” Pediatric Drugs, vol. 6, no. 5, pp. 267–272, 2004. View at: Publisher Site | Google Scholar
  89. S. Ali, A. L. Drendel, J. Kircher, and S. Beno, “Pain management of musculoskeletal injuries in children: current state and future directions,” Pediatric Emergency Care, vol. 26, no. 7, pp. 518–524, 2010. View at: Publisher Site | Google Scholar
  90. J. A. Fein, W. T. Zempsky, J. P. Cravero et al., “Relief of pain and anxiety in pediatric patients in emergency medical systems,” Pediatrics, vol. 130, no. 5, pp. E1391–E1405, 2012. View at: Publisher Site | Google Scholar
  91. K. J. S. Anand, “Consensus statement for the prevention and management of pain in the newborn,” Archives of Pediatrics & Adolescent Medicine, vol. 155, no. 2, pp. 173–180, 2001. View at: Publisher Site | Google Scholar
  92. R. M. Kennedy, J. Luhmann, and W. T. Zempsky, “Clinical implications of unmanaged needle-insertion pain and distress in children,” Pediatrics, vol. 122, no. 3, pp. S130–S133, 2008. View at: Publisher Site | Google Scholar
  93. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy, http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm.
  94. Agency MaHpR: Codeine for analgesia: restricted use in children because of reports of morphine toxicity, 2013.

Copyright © 2016 Lisa Hartling et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

2891 Views | 1218 Downloads | 16 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.