INTRODUCTION: SCOPE OF THIS DOCUMENT

The intention of this review is to provide a comprehensive synopsis of information to improve the use of ibuprofen and acetaminophen (APAP) in the management of uncomplicated fever and mild to moderate pain in children. The emphasis has been placed on more recent efficacy and safety data. Severe pain, such as associated with major trauma, cancer, or meningitis, are not within the scope of this document; neither are chronic pain, as in juvenile rheumatoid arthritis, or intractable fever. While the review is comprehensive, this is not an official guideline, and has not been produced using standard procedures for the creation of guidelines.

The management of fever and pain in children has changed in several important ways over the last 15 years. Until the early 1980s, acetylsalicylic acid (ASA) was the most commonly used analgesic/antipyretic; however, evidence associating ASA exposure with Reye’s syndrome made it advisable to use caution when treating young children with fever of unknown origin.⁽¹⁾ As a result, APAP, which had been available without prescription since 1960, became the non-narcotic analgesic/antipyretic of choice in children. Most recently, ibuprofen has achieved over-the-counter status, but unlike APAP, because of insufficient clinical experience, it is not labelled for use in children under the age of two.⁽²⁾ The extensive use of ibuprofen in children is thus relatively new, but it will become increasingly widespread, bringing into play the issues associated with increased occurrence of rare side effects and unintentional overdosing.

Fortunately, the efficacy and tolerability of both APAP and ibuprofen have been studied in many well-designed clinical trials in recent years, so that choices can be informed by good evidence. In addition, there has been close scrutiny of the adverse effects of these drugs, with the result that epidemiologic evidence is also available to allow better understanding of both dose-related and idiosyncratic reactions.

FEVER IN CHILDREN: BACKGROUND

Fever is one of the most common symptoms of disease in children. Although it usually indicates minor infection, it can also be a sign of serious, life-threatening disease. In certain individuals, as in infants and the immunocompromised, appropriate management often depends on early diagnosis of the cause.

It is important to distinguish between fever and hyperthermia. In fever, the hypothalamic thermoregulatory set-point has been adjusted upward with the result that, by using mechanisms such as vasoconstriction and shivering, body temperature is raised. Antipyretics act by lowering the raised set-point. In hyperthermia, set point is not altered, and body temperature can be reduced without discomfort using external cooling techniques, including sponging and removal of clothing. Such measures are inappropriate for fever because, unless the set-point is first lowered, the physiological response mechanisms cause discomfort.

There is abundant evidence that uncomplicated fever is a relatively harmless but important immunologic defence mechanism. Some beneficial components of the immune reaction are enhanced by a moderate increase in temperature⁽³⁾ and this knowledge has been used to support arguments against treating fever. It has also been suggested that lowering temperature may obliterate valuable diagnostic signs that may allow better patient evaluation. However, no correlation between etiology and either fever severity or pattern of temperature increase has been demonstrated,⁽⁴⁾ and it is generally agreed that use of antipyretics does not prolong illness or adversely affect outcome.⁽⁵⁾ The fact that fever responds to antipyretics cannot be used to distinguish between serious and uncomplicated disease. Although a slightly greater response to APAP was reported in children with bacterial disease or pneumonia than in those without, the difference was less than half a degree, not clinically useful to distinguish among causes of illness.⁽⁶⁾

Although consideration of the physiological role of fever raises the question of the appropriateness of any treatment, many clinicians favour the use of antipyretics when needed to alleviate distressful symptoms. The child who feels better is likely to eat better, avoiding the debilitating effect of increased metabolic rate in the absence of adequate intake of protein, fluid and electrolytes.

There is more agreement about the management of children prone to febrile seizures, which occur in 2-5% of those under the age of five.⁽⁷⁾ Because seizures recur in about 30% of cases, it is common practice to treat febrile young children who have a history of febrile seizures after exclusion of serious causes, such as CNS disorders or hypoglycemia. Although accepted management of fever for this population, there are no supporting clinical studies and, in fact, prophylaxis in high risk children has been shown to be ineffective.⁽⁸⁾ However, the Committee on Infectious Diseases of the American Academy of Paediatrics suggests that children with a family history of a convulsive disorder might benefit from prophylactic APAP 15 mg/kg at the time of DPT vaccination, repeated every four hours for three doses.⁽⁹⁾

TREATMENT OF FEVER IN CHILDREN

Once the decision to treat fever has been made, a number of measures are available. There is a place for physical treatments such as tepid sponging and fanning. Although these can reduce temperature rapidly, the effect often adds to the child’s discomfort without achieving adequate temperature control. In addition or alternatively, pharmacotherapy can be initiated with either APAP or ibuprofen.

CLINICAL STUDIES

The safety and efficacy of APAP and ibuprofen have been studied in at least 30 clinical trials since 1976 (Table 1 and Table 2). About half of these were conducted after 1990, and the majority included both APAP and ibuprofen treatment groups. The overall aim of these studies has been to determine doses of the two drugs that reliably reduce fever, and to compare degree of temperature reduction, time of onset and duration of effect, as well as type, number and severity of adverse events. One reason such a large number of studies were undertaken to sort out pharmacodynamic details in children appears to be failure to establish early the optimal dosages by conducting dose-ranging and pharmacokinetic studies.

The recent studies were more likely than those conducted before about 1990 to be placebo-controlled and double-blind, to have larger sample size and to use higher drug doses. In these studies, patients tended to range in age from about 0.5 to 10 years, and to have initial body temperatures from 38 to 40.5^oC. Single doses were compared over a period of three to 12 hours. There was less consistency in both number and nature of outcome measures. Depending on the study, temperature response has been assessed as change in absolute value, overall mean, percentage decrease or maximum decrease; these could be at one fixed time, or over one or more specified periods of time post-dose. Other measures have included maximum temperature decrease achieved, rate of decrease, decrease in area under the curve (AUC) or percent decrease in AUC, as well as time to onset of effect, duration of decrease below a predetermined value, proportion of patients achieving a specified absolute temperature decrease and number of patients achieving euthermia. Less frequently reported are number of patients requiring rescue, time to rescue, palatability and a measure of overall comfort. The number of measures per study varies from one to more than ten, and it comes as no surprise that statistically significant differences often emerge from this maze of variables. The challenge is to determine whether there are clinically detectable and important differences among treatments.

In the pursuit of equieffective doses of ibuprofen and APAP in these studies, one or more among six doses of each drug have been compared in a total of 17 different combinations. However, summarizing overall outcomes is made less involved by the tendency to compare smaller doses of both drugs in earlier studies, and, as continuing research increased confidence, to compare larger doses of both drugs in more recent work. The result over time has been a gradual focusing on equieffective doses.

In six studies, drugs were given in multiple doses; however, because primary efficacy outcomes were measured within the first dosing interval, these studies can be included with studies that investigated only single doses.

DRUG EFFICACY

In this summary of the efficacy data for the two drugs, APAP is considered standard therapy and various doses of ibuprofen are compared to increasing doses of APAP.

Four of the earlier studies used what would now be considered low doses of both drugs (5 to 8 mg/kg) and tended to match APAP and ibuprofen doses quite closely.^(10-13) Overall, there was no difference in temperature reduction, except in one study showing that APAP was more effective than ibuprofen, but only at the earliest time point studied.

Starting in 1988, studies were published in which APAP 10 mg/kg and ibuprofen 5-10 mg/kg were compared.^(14-19) There are six of these altogether, including two quite recently published. The antipyretic effect of 5 or 6 mg/kg ibuprofen was not different from APAP 10 mg/kg, however, higher ibuprofen doses (7.5 to 10 mg/kg) tended to have significantly greater efficacy than this dose of APAP, at least at some time points. Doses of 10 mg/kg of both drugs were compared in two large studies: one found no difference,⁽¹⁴⁾ and in the other ibuprofen was more effective than APAP.⁽¹⁶⁾

APAP 12.5 mg/kg has been compared to ibuprofen 5-10 mg/kg in five studies (including one using an average APAP dose of 11.6 mg/kg).^(20-24) Three showed that 6 to 10 mg/kg ibuprofen caused greater temperature reduction,^(20-22) and two that ibuprofen 5 mg/kg was not different from APAP 12.5 mg/kg ^(20,24) A 1976 study showed that ibuprofen 6 mg/kg was as effective as APAP 12.5 mg/kg.⁽²³⁾

Finally, 15 mg/kg APAP has been compared to ibuprofen 2.5-10 mg/kg in four studies.^(25-28) At this dose, APAP was superior to low doses of ibuprofen (2.5-5 mg/kg) but equivalent to higher doses (7.5-10 mg/kg). Two studies showed that a dose of 7.5 and 8 mg/kg ibuprofen was superior to APAP 15 mg/kg, but at only one time point.^(27,28)

Either APAP or ibuprofen, but not both drugs, were studied in another ten clinical trials (Table 2) and, although direct comparisons of their effectiveness in fever are not possible, several interesting findings were reported.^(5,8,29-36) Schnaiderman et al showed that the number of recurrences of febrile convulsions did not differ in children given APAP every four hours compared to APAP on an as-needed basis.⁽⁸⁾ Two studies showed that ibuprofen in doses of 6 or 7 mg/kg was as effective as ASA 10 or 15 mg/kg,^(32,35) and other studies reported dose-response effects with ibuprofen^(30,34) and APAP.⁽³⁶⁾ Lastly, Kauffman and Nelson demonstrated that the effect of ibuprofen was greater in infants one year old or less than in older children.⁽²⁹⁾

MULTIPLE DOSE STUDIES

The effects of multiple doses of APAP and ibuprofen in children are probably more important than temperature decreases due to single doses, particularly from the point of view of possible drug accumulation and side effects. However, there are few studies of multiple doses on which to base a consideration of effective pharmacotherapy. Well controlled studies are difficult to perform: use of ideal dosing intervals makes blinding practically impossible and short-lived fevers may react differently from more persistent fevers. The problems are illustrated in a recent study by McIntyre and Hull.⁽²⁴⁾ These investigators compared APAP 12.5 mg/kg and ibuprofen 5 mg/kg, both at six-hour intervals. Neither dosage is ideal, and no differences in effects on temperature were found. Interestingly, whereas the first dose returned temperature to normal, all subsequent doses were only half as effective. This was probably the effect of removal from the study of children who had become afebrile, and provides indirect evidence that euthermia is not required to give adequate comfort to children with fever. This observation also calls into question the failure to demonstrate the same effect in other studies in which patients who became euthermic were removed.

Van Esch compared APAP 10 mg/kg and ibuprofen 5 mg/kg in children with a history of febrile seizures, and found a significantly greater decrease in temperature with ibuprofen after four hours, a difference of 0.5^oC, but not at any other time point over 24 hours.⁽¹⁹⁾ Autret reported similar results with APAP 10 mg/kg and ibuprofen 7.5 mg/kg; subgroup analysis showed a difference of about 0.5^oC for patients with high but not low initial temperatures.⁽¹⁷⁾ Finally, a small study that included a dose-ranging component for ibuprofen, showed that the effect of ibuprofen 10 mg/kg was the same as APAP 15 mg/kg over a period of 48 hours.⁽²⁶⁾ In all of these studies, dosing interval was six hours, longer than recommended for APAP, and shorter than usual for ibuprofen. Except for the high initial temperature subgroup analysis, none of these four studies showed a significant difference between the two antipyretics after the first dose.

ALTERNATING THERAPY

At one time it was not uncommon to treat resistant fevers with alternating doses of ASA and APAP, although there were and are no clinical studies supporting this practice, either using these two drugs or with the combination of APAP and ibuprofen. The goal of selecting doses and dosing intervals is to maintain adequate antipyretic blood levels. For drugs with different half lives achieving this would require extraordinary care, as illustrated by the pharmacokinetic modelling of Wilson and colleagues,⁽³⁷⁾ and alternating therapy should only be used under professional supervision after consideration of possible risks and benefits of exposing a child to two drugs.

SUMMARY

The objectives of temperature reduction in the febrile child are to alleviate discomfort as well as to avoid possible debilitating effects of prolonged fever. At the same time, it is recognized that children tolerate some degree of fever without undue discomfort or risk. Based on numerous clinical studies that have investigated the effect of single doses of APAP and ibuprofen in febrile children, it has been determined that approximately equieffective doses are APAP 15 mg/kg and ibuprofen 10 mg/kg. Many combinations of doses of the two drugs have been tested, with the result that sometimes one produces an effect that is statistically greater than the other; this depends on the particular combination. However, for a difference to be significant it must make a difference to the patient. In the end it is the clinical effectiveness that is important and this is more difficult to measure. A potentially useful qualitative variable that gives a measure of clinical effectiveness is the simple patient global well-being score, rarely used in these studies because the conveniently objective outcome measure, body temperature, is so easily obtained.

There is a dearth of multiple dose efficacy studies. This is problematic since antipyretics are probably seldom used in single doses. The four studies that are available show that the pattern of temperature response to antipyretics can be quite different for the first dose compared to subsequent doses. Direct comparisons are not possible because the dose combinations of APAP and ibuprofen differ, but an overall assessment of results illustrates an important point: in two studies the first doses have a pronounced effect on temperature following which temperature increases in spite of additional doses, whereas in the other two, temperature continues to decline after the first dose. An explanation for the clearly different responses to multiple dosing in these studies is not apparent, although it may be related to dose, since the further decrease in temperature tends to occur with higher doses. Taken together, this is weak evidence on which to base recommendations for optimal dosing intervals. With increasing concern about drug accumulation and overdosing with therapeutic intent, much could be learned from additional rigorously designed studies.

MILD TO MODERATE PAIN IN CHILDREN: BACKGROUND

Causes of pain

The causes of mild to moderate pain in children can be classified broadly, with some crossover, as those involving infection, those related to minor surgery and those that fall into neither of these categories. Pain is associated with infection in otitis media, tonsillitis, pharyngitis and other upper respiratory tract problems. Minor surgery causing significant pain includes tonsillectomy, bilateral myringotomy with tympanostomy tube placement (BM&T) and dental procedures. Headache and pain of minor trauma fall into the last category. Not all of these situations are suitable for controlled clinical studies, for example there are few studies in children of the alleviation of headache and of pain associated with minor trauma.

Measurement of pain

Assessing the efficacy of drug intervention in pain is difficult even in adults, but in children the objective measurement of pain is more challenging because verbal communication is impossible or unreliable. ‘Smiley-faces’ and ‘hurt thermometers’ take the place of visual analogue scales and rating instruments based on verbal statements. There have been numerous attempts to develop a suitable scoring system, some of which have been successful, however, few of the scales developed for children have been formally validated. This is unfortunate, because it complicates another dilemma in pain assessment, the high placebo response rate. In conducting clinical studies there are several ways of contending with this problem. One is to include a battery of scales with the goal of finding one that demonstrates a difference, but this strategy increases the chance of a false positive conclusion. Another is to enroll large numbers of patients to increase the power to detect a difference, however, this calls into question the clinical importance of any difference so identified. Finally, the inclusion of a placebo control in paediatric studies is sometimes not possible for ethical reasons. Certainly such a design is not appropriate when there is a significant risk of pain.

TREATMENT OF MILD TO MODERATE PAIN IN CHILDREN (Table 3)

BILATERAL MYRINGOTOMY AND TUBE PLACEMENT

Two well designed placebo-controlled studies have shown that neither ibuprofen nor APAP provide significant pain relief in children undergoing BM&T. The analgesic effect of APAP 15 mg/kg and ibuprofen 10 mg/kg (doses shown to reliably reduce fever) could not be distinguished from that of placebo when administered 30 minutes preoperatively.⁽³⁸⁾ Likewise, Derkay et al found no differences among placebo, APAP 10 mg/kg, ibuprofen 10 mg/kg or APAP 10 mg/kg + codeine 1 mg/kg.⁽³⁹⁾ In this last study, sufficient analgesia may have been attained with 4% lidocaine eardrops administered to all patients before the procedure. It is recognized that BM&T is associated with significant pain, and failure to show an effect with these analgesics may reflect either inadequate assessment tools or lack of efficacy in the type and severity of pain associated with this procedure. However, in three other studies that included neither an ibuprofen nor a placebo group, a difference between the two positive treatments being tested was detectable.^(40-42) It can be surmised that there would also have been differences from placebo treatment.

TONSILLITIS/PHARYNGITIS (SORE THROAT)

The efficacy of ibuprofen and APAP have been compared in the management of pain associated with tonsillitis/pharyngitis in several studies. Schachtel assessed measures of pain in children using a newly developed sore throat model that involved independent measures for the child, parent and paediatrician.⁽²⁵⁾ Analgesia obtained with ibuprofen 10 mg/kg was the same as that with APAP 15 mg/kg, and with both drugs analgesia was significantly better than with placebo. Bertin, in one of the few studies to assess analgesia in children in a multiple dose study, found that ibuprofen 10 mg/kg was equivalent to APAP 10 mg/kg, both given eight-hourly, and that both drugs were significantly better than placebo.⁽⁴³⁾ This finding, that a dose less than 15 mg/kg of APAP, given at a longer than recommended interval, is as efficacious as ibuprofen 10 mg/kg is unusual, and again suggests that more studies of multiple doses would be helpful.

A study conducted in 1990-92 by McNeil Consumer Products Company showed that there was little difference in sore throat relief among patients treated with APAP 12.5 mg/kg or ibuprofen 5 or 10 mg/kg, and that these drugs produced effects superior to placebo only for some measures at a few timepoints.⁽⁴⁴⁾ The duration of ibuprofen effect was longer than placebo for more of the measurement scales than was that of APAP. The fact that neither drug was uniformly active in all outcome variables, in spite of an uncommonly large sample size, suggests that the differences between the two drugs might not be clinically detectable.

HEADACHE

Although there is ample evidence that headache occurs in significant numbers of children, its treatment with non-prescription analgesics has rarely been studied. Hamalainen et al compared APAP 15 mg/kg to ibuprofen 10 mg/kg in children with migraine in a placebo controlled crossover study of and showed that, whereas these drugs were equally effective after one hour, the primary endpoint, reduction in pain at two hours, was reached twice as often with ibuprofen as with acetaminophen.⁽⁴⁵⁾ The conclusion was that ibuprofen gave better overall relief, however statistical analysis did not support this claim, and the difference between these two drugs may not have been clinically meaningful. Additional studies are needed in children, since these drugs have both been shown effective in adults with headache, in spite of often prominent placebo effects.⁽⁴⁶⁾

OTITIS MEDIA

Schachtel and Thoden found a significant improvement in two of seven efficacy measures with ibuprofen 10 mg/kg compared to placebo, but not with APAP 15 mg/kg, and only at the 30-minute time point.⁽²⁵⁾ The fact that this was the only effect, and in a study with adequate power suggests that over-the-counter analgesics may not be very potent against this kind of pain.

A study conducted in 1990-92 by McNeil Consumer Products Company found that ibuprofen 10 mg/kg provided superior relief of ear pain compared to placebo in three of four efficacy measures, and ibuprofen 5 mg/kg in two of four measures, whereas APAP 12.5 mg/kg did not differ from placebo in any measures.⁽⁴⁷⁾ In an overall global assessment performed by the patient, parent or nurse, only the higher dose of ibuprofen was better than placebo. As measured by two of the four paediatric scales, the duration of effect of ibuprofen 10 mg/kg was significantly longer than that of acetaminophen. However, all three treatments rated significantly better than previous medication judged retrospectively. Assessment of study results is complicated by the large number of outcome measures and a considerable placebo effect as well as the occurrence of a statistically significant centre effect, but this is the only evidence that either one of these two drugs may alleviate pain associated with otitis media.

POST PROCEDURE PAIN

St. Charles et al compared recommended doses of APAP + codeine (15 + 1 mg/kg) and ibuprofen (5 or 10 mg/kg, depending on temperature) in an open label study of post-tonsillectomy pain and found equivalent efficacy.⁽⁴⁸⁾ However, 22% of ibuprofen patients required additional treatment with codeine with or without acetaminophen, whereas only 4% of APAP patients required additional treatment with ibuprofen. Significantly more nausea occurred in the APAP + codeine group. Holloway and Logan reported that three combinations of analgesic therapy before and/or after tonsillectomy had the same efficacy: morphine + APAP 12 mg/kg given before and after the procedure, morphine before and ibuprofen 10 mg/kg after, and ibuprofen 10 mg/kg given before and after the procedure.⁽⁴⁹⁾

Pretreatment with APAP at about 10 mg/kg with and without codeine 1 mg/kg were compared to aluminum ibuprofen at about 6 mg/kg in the pain of tooth extraction in children.⁽⁵⁰⁾ Ibuprofen and APAP + codeine but not APAP alone provided more relief than placebo up to two hours after the procedure, and after two hours all three active treatments were more effective than placebo. The scale capable of distinguishing between placebo and active treatment was a simple four-point scoring system. Similar success has not been achieved with the pain of otitis media or sore throat, suggesting that etiology is an important variable determining outcomes in the management of mild to moderate pain in children.

SUMMARY

Results of clinical studies of APAP and ibuprofen for mild to moderate pain in children are not easily translated into straightforward conclusions. Few studies have been done, and these have struggled to find objective measures of pain capable of reliably distinguishing between active treatment and placebo. For perceived ethical reasons, no placebo comparator was included in about half the studies. Of five studies of pain associated with BM&T, three showed that neither drug, used in doses shown to be effective in fever, differed from placebo; two studies without placebo groups concluded that there was no difference between drugs tested. In otitis media, two studies showed that ibuprofen 10 mg/kg was better than placebo, whereas in one study APAP 12.5 mg/kg did not differ from placebo. When the pain of tonsillopharyngitis was the target, the two drugs were shown to have equal activity and to be better than placebo in two studies; a third study showed that ibuprofen 10 mg/kg was superior to APAP 12.5 mg/kg for some, but not all, outcome measures. In two studies tonsillectomy pain was not improved by APAP or ibuprofen. Finally, one study of headache in children revealed no clear difference between the two drugs, although both gave more relief than placebo. A measure of overall patient status was included in five of the 14 studies reviewed: three showed that ibuprofen 10 mg/kg was somewhat better than APAP at doses of 10 or 12.5 mg/kg, whereas in the other two the observers did not distinguish between the two drugs given at full doses.

Pending the availability of more evidence, it can be concluded only that the non-narcotic analgesics, APAP and ibuprofen, in doses shown to be effective in reducing fever, may provide some relief of mild to moderate pain in children.

SAFETY OF ACETAMINOPHEN AND IBUPROFEN

ACETAMINOPHEN AND IBUPROFEN SAFETY DATA FROM CLINICAL TRIALS

The safety of APAP and ibuprofen in therapeutic dosages has recently been reviewed in depth by Rainsford et al.⁽⁵¹⁾ These authors searched appropriate databases for prospective studies in which either of the two drugs were of primary interest, and in which adverse events were monitored. Selection criteria were met by 111 publications, including 10 in children. They concluded that both drugs are remarkably safe as used in clinical trials, that there are no statistically significant differences between APAP and ibuprofen in reports of adverse events in any organ system, irrespective of the type or frequency of event. In particular, there are no reports of hepatotoxicity with APAP or gastrointestinal bleeding or renal impairment with ibuprofen. The overall incidence of minor adverse events was 10% for APAP and 8% for ibuprofen, rates that are not unexpected given that events were monitored prospectively. However, in contrast with outcomes under the ideal circumstances in clinical trials, when drugs are used as ubiquitously as APAP and ibuprofen, therapeutic misadventure resulting from incorrect dose calculation is certain to happen.

ACETAMINOPHEN SAFETY

Recently, the hazard of overdosing with therapeutic intent has been demonstrated with respect to APAP-induced hepatotoxicity in children in two studies.^(52,53) Heubi et al collected 47 such cases through a search of the published literature and FDA files, and reported a mortality rate of 55%, with half the deaths in children less than two years old. In about half of the 47 cases, adult APAP preparations had been substituted for paediatric use with incorrect quantity adjustment. It was determined that doses ranged from 60-420 mg/kg per day and were given for between 1 and 42 days and, although data collected retrospectively can be imprecise, six patients in this series may have received as little as 50-75 mg/kg/day. The conclusion based on this and other investigations is that APAP can cause serious hepatotoxicity in children in dosages as low as 125-150 mg/kg/day when taken for two to four days.^(53,54) It had also been shown in a prospective study published in 1984 that repeated therapy at recommended doses can result in accumulation.⁽⁵⁶⁾

The experience with APAP-induced hepatotoxicity in Ontario since 1990 has been quite different (B. Bailey, personal communication). Of 110 admissions with APAP overdose to The Hospital for Sick Children, four were children and the rest adolescents. Among the children, three were acute overdoses and one a therapeutic error in whom a transient moderate increase in liver enzymes occurred. In the province of Quebec there has been one death associated with APAP in the paediatric age group in the last 10 years. A total of 249 liver transplantations were performed in children during the years 1986-1996 in the two provinces, none due to APAP-induced liver damage. The reason for these differences from the experience in the United States is not evident, but may be found in an investigation of patient demographics.

Information on hepatotoxicity must be viewed within the context of the millions of children treated with APAP every day. Although the chances of misadventure are very remote, it is important to recognize the patient at risk. Kearns et al ⁽⁵⁷⁾ have suggested that the susceptible patient is likely the child who is less than two years of age, has been taking 90 mg/kg/day or more APAP for more than one day, and who is acutely malnourished and dehydrated due to vomiting, diarrhea or decreased liquid and nutrient intake. With this combination of factors, the mechanisms for detoxification of the hepatotoxic metabolite of APAP are more likely to be deficient. In addition to a greater appreciation of the characteristics of the patient at risk for APAP hepatotoxicity, a better understanding of multiple dose pharmacokinetics is clearly called for. Certainly, the practice of decreasing the dosing interval from four to two hours for resistant fevers is ill-advised.

It has been estimated that 96 APAP-containing preparations are available in the US without prescription, of which 22 are in liquid form and presumably intended for paediatric use.⁽⁵⁷⁾ Physican awareness, direct caregiver education and improved product labelling are all required in order to facilitate appropriate use of APAP.

IBUPROFEN SAFETY

Like APAP, ibuprofen is remarkably free of side effects when taken in therapeutic doses. Possible adverse events are, as for other nonsteroidal antiinflammatory drugs (NSAIDs), related to inhibition of cyclooxygenase and prostaglandin production, and include gastrointestinal bleeding, renal impairment, asthma and hepatic toxicity. Of these, minor gastrointestinal side effects are the most commonly reported in clinical trials, but it is notable that there are no reports in any controlled study, in adults or children, of any sign or symptom of gastrointestinal bleeding.⁽⁵¹⁾ In a review of 126 cases of ibuprofen overdose, including 88 children, Hall et al reported that 81% were asymptomatic, and that in these children ibuprofen blood levels indicated an average ingestion of 114 mg/kg,⁽⁵⁸⁾ equivalent to the intake of at least 10 times the recommended dose.

In adults, the most common severe adverse effect of intentional overdosing is renal dysfunction, but even after very high ibuprofen doses this is rarely fatal.⁽⁵⁹⁾ There have been a few case reports of renal complications in children at therapeutic doses of ibuprofen, but these are inconclusive because of confounding by indication. However, in a prospective study of more than 83,000 children treated prospectively for fever with APAP or ibuprofen, there were no hospitalizations for renal failure, and milder renal impairment was unlikely since BUN and creatinine were within normal range.⁽⁶⁰⁾ This study also showed that the risk of gastrointestinal bleeding was not different from APAP. There are limited data on the risk of renal toxicity in children associated with long term use of ibuprofen, although a prospective study in adults showed no renal impairment.⁽⁶¹⁾

Several reports have suggested an association between severe soft tissue superinfections and the use of NSAIDs. In particular, ibuprofen was implicated when its use in children with varicella was linked with the subsequent development of invasive Group A streptococcal infections.^(62,63) This concern prompted a retrospective cohort study in which data from over 7000 children with varicella were examined.⁽⁶⁴⁾ An association was not established by this study because, although children given ibuprofen were about three times more likely to develop a superinfection, the 95% confidence interval was such that the association was not statistically significant. Nevertheless, NSAIDs have been shown to alter some immunologic processes, including inhibition of neutrophil function and enhancement of cytokine production,⁽⁶⁵⁾ and it has been suggested that NSAIDs should be used judiciously in cases of local complications of varicella to avoid masking clinical features that might be useful in early recognition.⁽⁶⁶⁾

Because ASA may be associated with Reye’s syndrome, and ibuprofen is also an NSAID, there is at least the theoretical risk of a similar relationship for ibuprofen. The occurrence of this syndrome was monitored prospectively in more than 56,000 children in the study by Lesko and Mitchell.⁽⁶⁰⁾ There were no children hospitalized with evidence of this syndrome in the four weeks following drug use.

CONCLUSIONS

(1) Clinical studies show that, in febrile children with temperatures less than 41^oC, significant antipyresis can be achieved with single doses of APAP of 10 to 15 mg/kg and with ibuprofen doses of 5 to 10 mg/kg. The few clinical studies using multiple doses of these drugs provide some support for these doses. Information on dosing intervals rely on pharmacokinetic rather than multiple-dose efficacy studies: 4 to 6 hours for APAP, and 6 to 8 hours for ibuprofen.^(37,67)

(2) Recommended doses of APAP and ibuprofen may provide relief of mild to moderate pain in children. Clinical studies show that these drugs are more effective than placebo in about half the children tested. Consideration should be given to using these drugs before resorting to more potent agents.

(3) Evaluation of the safety of APAP and ibuprofen must bear in mind the millions of children receiving these drugs every day worldwide and the fact that use of APAP has been far more extensive than ibuprofen. At this point it appears unlikely that a serious risk such as the association between ASA and Reye’s syndrome will surface for APAP. However, the same cannot yet be said for ibuprofen with the same degree of certitude, and until adverse event data collected over a period of years prove conclusively that rare serious events are not associated with ibuprofen, APAP must remain the drug of choice. Ibuprofen should be reserved for second line therapy, and then used on an episode by episode basis.

Supported by a grant from McNeil Consumer Products Company.

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