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Paucity of renal complications associated with nonsteroidal antiinfl ammatory drugs in children with chronic arthritis . J Pediatr , 119 , 815 \200\223817. Xie , R. , Hammarlund-Udenaes , M. , de Boer , A. G. , and de Lange , E. C. ( 1999 ). Th e role of P-glycoprotein in blood-brain barrier transportation of morphine: transcortical mic rodialysis studies in mdr1a (-/-) and mdr1a (+/+) mice . Br J Pharmacol , 128 , 563 \200 \223568. Taiwo , Y. O. , and Levine , J. D. ( 1988 ). Prostaglandins inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses . J Neurosci , 8 , 13 46 \200\2231349. Yaster , M , and Deshpande , J. K. ( 1988 ). Management of pediatric pain with Takahashi , H. , Ishikawa , S. , Nomoto , S. , Nishigaki , Y. , Ando , F. , Kashima , T. , et al . ( 2000 ). Developmental changes in pharmacokinetics and pharmacodynamics of warfari n enantiomers in Japanese children . Clin Pharmacol Th er , 68 , 541 \200\223555. opioid analgesics . J Pediatr , 113 , 421 \200\223429. Zwisler , S. T. , Enggaard , T. P. , Noehr-Jensen , L. , Mikkelsen , S. , Verstuyft , C. , Becquemont , L. , et al . ( 2010 ). Th e antinociceptive eff ect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes . Fundam Clin Pharmacol , 24 , 517 \200\223524. Tateishi , T. , Nakura , H. , Asoh , M. , Watanabe , M. , Tanaka , M. , Kumai , T. , et al . ( 1997 ). A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy . Life Sci , 61 , 2567 \200\2232574. CHAPTER 43 Th e non-steroidal anti-in \202 ammatory drugs and acetaminophen Brian J. Ander son Summary Th e non-steroidal anti-infl ammatory drugs (NSAIDs) and aceta- minophen (N-acetyl- p-aminophenol, APAP) are the common- est analgesic drugs used in childhood. Although both d rugs act through inhibition of prostaglandin H 2 synthetase (PGHS), aceta- minophen lacks t he anti-infl ammatory eff ects of the NSAIDs. Neonatal acetaminophen hepatic clearance is r educed in pre- mature neonates (5 \200\22310% adult rates) and increases to 30% adult rates in neonates born at term; adult rates (approximately 16 \200\22320 L/h/70 kg) are reached within the fi rst year of life. NSAID clearance maturation, mostly through cytochrome P450 mixed oxidases, is more rapid. Concentration \200\223response relationships suggest a maxi- mum pain reduction of 5 or 6 on a 10-point scale for both drugs. Combination therapy does not increase this maximum eff ect but does prolong duration of analgesia. While both drugs have good safety profi les, dosing of both drug groups is tempered by concerns about toxici ty. Acetaminophen hepatotoxicity is associated with single doses (>250 mg/kg in preschool c hildren, >150 mg/kg in adults) and therapy duration longer than 3 to 5 days (>90 mg/kg/ day ).Th e most common minor adverse events in NSAID recipients are nausea, dizziness, and head ache. More concerning is the poten- tial of NSAIDs to cause gastrointestinal irritation, bl ood clotting disorders, renal impairment, neutrophil dysfunction, and bron- choconstriction . Th ese adverse eff ects are uncommon provided care is taken with drug dose, duration of t herapy, and recognition of contraindications. the reported association between Reye \200\231s syndrome and aspirin in the 1980s (Committe e on Infectious Disease, 1982 ). Acetaminophen is widely used in the management of pain and fever, but is lacking anti-infl ammatory eff ects. Debate exists about the site of action. Prostaglandin H 2 synthetase (PGHS) is the enzyme r esponsible for metabolism of arachidonic acid to the unstable prostaglandin H 2 . Th e two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS is co mprised of two sites; a cyclo-oxygenase (COX) site and a peroxidise (POX) site ( Figure 43. 1 ). Th e conversion of arachi- donic acid to prostaglandin G 2 is dependent on a tyrosine- 385 radi- cal at the COX site. Acetaminophen acts as a reducing cosubstrate on the POX site and lessens the amount of tyrosine-385 radical at the COX site. Alternatively, acetaminoph en eff ects may be medi- ated by an active metabolite (p-aminophenol). P-aminophenol is con jugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts eff ect through cannabinoid receptors (Anderson, 2008 ). Pharmacodynamics Th e relation between drug concentration and response may be described by the Hill equation or E max model: ) ) ( ( Ce N NCe+ Ce E E= +E 0 Effect Equation 43.1 N EC where E0 is the baseline response, E max is the maximum eff ect change, Ce is the concentra tion in the eff ect compartment, EC 50 is the concentration producing 50% E max and N is th e Hill coef- fi cient defi ning the steepness of the concentration-response curve ( Figure 43.2 ). Effi cacy is the maximum response on a dose or con- centration-response curve. Acetaminophen Mechanism of action Acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) has been used in clinical practice for more than 100 years and is the most commonly prescr ibed pediatric medicine. Acetanilid, the parent compound of acetaminophen, was introduced i n 1886. Toxicity-related problems with acetanilid led to the introduction of acetaminophen in 1893. Th e popularity of acetaminophen over the non-steroidal anti-infl ammatory drugs ( NSAIDs) ascended aft er A delay oft en exists between plasma and eff ect site concentration. A single fi rst-order parameter (T 1/2 keo) describes the equilibration half-time between plasma and eff ect site . Th e concentration in the eff ect compartment is used to describe the concentration \200 \223eff ect relationship. CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 437 PGG2 (hydroperoxide substrate) PGH2 Fe3+ Figure 43.1 Prostaglandin H 2 synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable prostaglandin H 2 . Formation of tyrosine-385 radical (Ty e385*) at the COX site is dependent on the reduction of a ferrylprotoporphyrin IX radical c ation (Fe 4+ = OPP* + ) at the POX site. Acetaminophen is a reducing cosubstrate that parti ally reduces Fe 4+ = OPP* + , decreasing the amount available for regeneration of Tyr385*. Reproduced from Brian J. Anderson, Paracetamol (Acetaminophen): mechanisms of action, Pedia tric Anasthesia , Volume 18, Issue 10, pp. 915 \200\223921, Copyright 2008 Th e Author, by permission of John Wiley & Sons, Inc., http://onlinelibrary.wiley. com/journal/10.1111/% 28ISSN%291460-9592. Tyr385* radical Arachidonic acid O2 Reducing cosubstrate e.g. paracetamol Paracetamol Fe4+=OPP*+ Fe4+=O electron transfer Tyr385 PGG2* radical PGG2 Peroxidase Cyclooxygenase Analgesia Acetaminophen is an eff ective analgesic drug. Th irty seven per cent of patients (>13 years of age) given an intravenous (IV) acetami- nophen formulation for postoperative pain experienced at least 50% pain relief over 4 h compared with 16% receiving placebo (nu mber needed to treat (NNT) 4.0, 95% confi dence interval (CI) 3.5 \200\2234.8; Inomata et a l., 2003 ). Increased analgesia has been reported with increasing plasma concentration unti l a maximum eff ect (e.g. E max 5.17/10; visual analog pain score 0 \200\22310 aft er pedia tric ton- sillectomy). However, the analgesic eff ect of acetaminophen is not directly rela ted to plasma concentration. Further time is required for the drug to move from the plasma into the eff ect site. Th ere are time delays of approximately 1 h between peak concentrati on and peak eff ect ( Figure 43.3 ); the equilibration half-time (T 1/2 keo) was 53 min ( F igure 43.4 ). A target eff ect compartment concentration of 10 mg/L is associated with a pa in reduction of 2.6/10 (Anderson et al., 2001 ). Pain fl uctuations, pain type, and placebo eff ects com- plicate interpretation of clinical studies. 18 Maximum response 16 14 1/2 Emax 12 e s n o p s e R 10 N = 0.3 N = 1 (Emax) N = 3 N = 10 8 Emax=14 6 4 E0=2 2 EC50=8 0 0 5 10 15 20 25 30 Concentration Figure 43.2 Th e E max model is commonly used to describe the relationship between drug res ponse and concentration. Changing the Hill coe \203 cient dramatically alters the shape of the curve. Attempts to unravel these time relationships with studies using oral or rectal acetaminophe n are diffi cult because there are fur- ther time delays associated with absorption from th e gastrointes- tinal (GI) tract into the blood. Th e use of an IV acetaminophen formulation allows greater dosing accuracy, less pharmacokinetic variability attributable to absorptio n, and more rapid speed of eff ect onset (Gibb and Anderson, 2008 ). Infusions over 15 min of IV acetaminophen 15 mg/kg following inguinal hernia repair in children resulted in a ste ep reduction in pain between 15 and 30 min (Murat et al., 2005 ), consistent with a delay a chieving eff ect site concentrations in the brain. Two European Centers have published dosi ng guidelines in neonates (Allegaert et al., 2007 ; Bartocci and Lundeberg, 2007 ). Th ese regimens attempt to achieve a steady-state target concentration of 10 mg/L. 2 min 10 4 min 9 e r o c S n i a P 18 min 8 8 h 5 h 30 min 3 h 7 1 h 6 5 0 2 4 10 Plasma concentration (mg/L) 6 8 12 14 Figure 43.3 Th e relationship between the plasma concentration and analgesic e \200 ect de monstrates clockwise hysteresis. Th e equilibration half-time (T 1/2 keo) of the analgesic e \200 ect compartment was 53 min. Reproduced with permission from I. A. Gibb and B. J. An derson, Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration , Archives of Disease in Childhood , Volume 93, Issue 3, pp. 241 \200\223247, Copyright 2008 BMJ Publishing Group Ltd and Royal College of Pediatrics and Child Health, http://adc. bmj.com/. Acetaminophen is commonly used to supplement postop- erative analgesia from morphine infusi on, but this usually only reduces morphine consumption by 10% to 20% and is probably insuff i cient to decrease morphine-related adverse eff ects (Maund et al., 2011 ). SECTION 6 pharmacological interventions 438 40 10 Small concentration increases have maximal e \200ect on pain score 9 ) g k 0 7 / h / L ( e c n a r a e l C 30 8 e r o c s n i a P 7 20 6 10 Increasing concentration has minimal e \200ect on pain score 5 4 0 0 20 5 E \200ect compartment concentration (mg/L) 10 15 25 10 100 1000 Postmenstrual age (weeks) Figure 43.4 Th e e \200 ect compartment \200\223response relationship for acetaminophen an algesia after tonsillectomy. Reproduced with permission from I. A. Gibb and B. J. Anderson, Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration, Archi ves of Disease in Childhood , Volume 93, Issue 3, pp. 241 \200\223247, Copyright 2008 BM J Publishing Group Ltd and Royal College of Pediatrics and Child Health, http://adc.bmj.com /. Figure 43.5 Clearance changes with age. Individual predicted clearances, standardized to a 70 kg person, from the NONMEM program \200\231s post hoc step are plotted against age. Th e thin line demonstrates the predicted non-linear relationship between clearance and age. Re produced from Brian J. Anderson and Karel Allegaert, Intravenous neonatal acetaminophen dos ing; the magic of ten days, Pediatric Anesthesia , Volume 19, Issue 4, pp. 289 \200\223295, Copyright 2009 Th e Authors, by permission of John Wiley & Sons, Inc., http://onlinelib rary.wiley.com/journal/10.1111/%28ISSN%291460-9592. Pharmacokinetics Oral absorption Acetaminophen has low fi rst-pass metabolism, and the hepa tic extraction ratio is 0.11 to 0.37. Acetaminophen is rapidly absorbed from the duodenum t o the systemic circulation. Th ere is usually a short interval before the drug enters the d uodenum from the stomach (5 min) and then absorption is rapid; absorption half-life is 2 to 5 min (Anderson et al., 2000 ; Brown et al., 1992 ). Absorption in children under the age of 3 months is delayed because absorption depends on gastric emptying, and gastric emptying is slow and erratic in the neonate. Normal adult rates may not be reached until 6 to 8 mon ths. (20 g/m 2 ) when used to augment alkylating drugs for melanoma treatment (Wolchok et al., 2 003 ). Volume of distribution Th e volume of distribution in children is similar to those reported in adults (56 \200\22370 L; Prescott, 1996 ). Peripheral volume of distribu- tion decrease d from 27 weeks postmenstrual age (45.0 L/70 kg) to reach 110% of its mature value by 6 mon ths of age ( Figure 43.6 ) (Anderson et al., 2005 ), refl ecting neonatal body composition and the rapid changes in body water distribution in early life. Disease states Th e eff ects of altered physiology such as fever, anesthesia, or mildly imp aired hepatic dysfunction on pharmacokinetic parameters have received little attention, but appear to have minimal impact in children. Similarly, chronic conditions such as diabetes and renal failure have minimal impact on pharmacokinetics. Clearance is reduced in dis- eas e states where we might expect reduced hepatic function; hypothy- roidism, congestive heart failure, acute viral hepatitis. Th e impact of obesity is unknown. Bilirubin is also clear ed by a glucuronosyltrans- ferase (UGT1A1); increased unconjugated bilirubin concentration in neonates is an indicator of reduced hepatic function and consequently reduced clearance. However size (predicted by weight) is the major covariate of clearance variance in neonate s (Allegaert et al., 2011 ). Rectal absorption Rectal acetaminophen is widely used in children presenting for sur- gical procedures because of GI dysfunction or preoperative fasting guidelines that disallow food or fl uids up to 6 h before surgery. It is also preferable in children with nausea and vom iting. Th e rela- tive bioavailability of rectal compared with oral acetaminophen formulati ons ranges from 0.24 to 0.98. Absorption through the rec- tal route is slow and erratic (ab sorption half-life 0.65 \200\2231.34 h). Th e absorption half-life for rectal formulations is prolonged in infants younger than 3 months (1.51 times greater) compared to values in ol der children (Anderson et al., 2002 ). Clearance Acetaminophen is metabolized predominantly by uridine diphos- pho-glucuronosyltra nsferases (UGT1A6). Th is enzyme is immature in neonates, although some acetaminophen can b e metabolized by sulfate conjugation, which is mature in term neonates. Maturation of clear ance is completed in within the fi rst few years of life and refl ects the maturation of th e UGT1A6 isoenzyme (Miyagi and Collier, 2011 ). Clearance increases from 27 weeks postmenst rual age (1.87 L/h/70 kg) to reach 84% of the mature value ( c .16 \200\22320 L/h/70 kg) by 1 year of age ( Figure 43.5 ) (Anderson et al., 2002 , 2005 ). Clearance through sulfate c onjugation is saturable and dependent on substrate availability (Reith et al., 2009 ). It i s also possible that APAP may induce glucutonosyltransferase, leading to increased clearanc e aft er repeat therapeutic dosing (Gelotte et al., 2007 ). Total body clearance is fi rst order aft er very high doses Toxicity Chronic use of acetaminophen Hepatotoxicity is the principal adverse eff ect. Th e toxic metabolite of acetaminophen, N -acetyl- p -benzoquinone imine (NAPQI), is formed by the CYP2E1. Hepatotoxicity is dependent on the balance between the rate of NAPQI formation, capacity of the safe elimi- nation pathways of sulfate and glucuronide production, and the initial content and maximal rate of synthesis of hepatic glutathione that mops up NAPQI. N APQI binds to intracellular hepatic macro- molecules to produce cell necrosis and damage. D uring hepatocyte lysis APAP-protein adducts are released into plasma and these can be used as specifi c biomarkers of APAP toxicity in patients with acute liver injury (Bond, 2009 ; James et al., 2009 ). CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 439 induced hepatotoxicity seen in neonates, despite reports of high serum concentrations in ne wborn neonates. Neonatal hepatotoxicity has been reported in an ex-term (41-week) neonate w ho presented encephalopathic at 5 days following 3 days of oral acetaminophen dosing \200 \224initially 156 mg/kg/day and then 78 mg/kg/day. Th e neonate had an unconjugated hyperbi lirubinaemia (130 mol/L) on admission with marked liver derangement and aft er receiving N-acetyl cysteine recovered fully over 7 days (Walls et al., 2007 ). 80 Allegaert 2004 Flandin 1988 Pons 1992 Allegaert 2003 Ganry 1992 Cavellat 1984 Autret 1993 n o i t u b i r t s i d f o e m u l o v l a r e h p i r e P 70 60 50 ) g k 0 7 / l ( 40 30 20 10 Dosing with formulation Suggested acetaminophen dosing for diff erent age groups is shown i n Table 43.1 . Th ese dosing regimens achieve a target concentration of 10 mg/L, but may be considered too high as concerns about dose and hepatotoxicity increase. Children seek rapi d relief from symp- toms, be they pain or fever. In general, the smaller the child, the sho rter the T 1/2 keo, but absorption characteristics of enteral aceta- minophen in neonates d elays analgesia onset. Speed of onset may be shortened by giving a larger initial dose or i mproving absorption characteristics or changing the formulation (Gibb and Anderson, 2008 ). Target eff ect compartment concentrations (and eff ect) will be reached earlier as dose is increased. Th e administration of a large ini- tial oral or rectal \200\230loading \200 \231 dose will achieve the target concentration speedily, but such dosing may exceed the su bsequent daily dose rec- ommendation. Formulation has considerable impact. For example the slow absorption of rectal acetaminophen suppositories means peak concentrations are only re ached aft er several hours. In contrast an IV formulation has rapid onset of analgesia ( Fi gure 43.7 ). 0 10 100 Post conception age (weeks) 1000 Figure 43.6 Peripheral volume of distribution changes with age. Individual predicted volume s, standardized to a 70 kg person, against age. Th e solid line demonstrates the non-linear relationship between volume of distribution and age. Th ose children given multiple doses have volume of distribution estimates linked by a \201 ne line to demonstrate between occ asion variability. Reproduced from Brian J. Anderson et al., Pediatric intravenous acetamin ophen (propacetamol) pharmacokinetics; a population analysis. Pediatric Anesthesia , Volume 15, Issue 4, pp. 282 \200\223292, Copyright 2005 Th e Authors, by permission of John Wi ley & Sons, Inc., http://onlinelibrary.wiley.com/ journal/10.1111/%28ISSN%291460-9592 Signifi cant hepatic and renal disease, malnutrition, and dehy- dration may increase the pr opensity for toxicity. Medications that induce the NAPQI formation (e.g. phenobarbitone, ph eny- toin, and rifampicin) may also increase the risk of hepatotoxicity. Th e infl uence of disease on acetaminophen toxicity is unknown. Hepatotoxicity causing death or requiring li ver transplantation has been reported with doses above 75 mg/kg/day in children and 90 mg/k g/day in infants. It is possible that even these traditional regi- mens may cause hepatotox icity if used for longer than 2 to 3 days (Kearns et al., 1998 ). Non-steroidal anti-in \202 ammatory drugs Mechanism of action Th e NSAIDs are a heterogene ous group of compounds that share common antipyretic, analgesic, and anti-infl ammatory eff ects ( Table 43.2 ). Th eir major action is through inhibition of prostaglan- din synthesi s. NSAIDs act by reducing prostaglandin biosynthesis through inhibition at the COX site of PGHS ( Figure 43.8 ). Th e two major forms of this enzyme are the constitutive PGHS-1 and t he inducible PGHS-2 (COX-1 and COX-2). Th is enzyme converts ara- chidonic acid to cyclic e ndoperoxides. Th e prostinoids produced by COX-1 protect the gastric mucosa, regulate renal blood fl ow, and induce platelet aggregation. NSAID-induced GI toxicity, for example, is g enerally believed to occur through blockade of COX-1 activity, whereas the anti-infl ammato ry eff ects of NSAIDs are thought to occur primarily through inhibition of the inducible is o- form, COX-2. Relative COX-1/COX-2 specifi city ratios vary from greater than 1 (aspirin, indomethacin, ibuprofen), approximately 1 (diclofenac, naproxen), to less than 1 (celecoxi b, etoricoxib). Hepatic enzyme profi les have been used as a surrogate assess- ment in neonatal studies. Al though no hepatic changes occurred during the treatment periods that extended over a median of 4 days, the value of hepatic changes is debated (Anderson and Allegaert, 2009 ). It is currently impossible to predict which individuals have an enhanced susceptibility to cellul ar injury from acetaminophen. Single dose of acetaminophen Th e Rumack and Matthew (Rumack and Matthew, 1975 ) acetami- n ophen toxicity nomogram is widely used to guide management of acetaminophen overdose in adu lts and children. Acetaminophen concentrations of more than 300 mg/L at 4 h were always ass ociated with severe hepatic lesions, but none were observed in adults with concentrations l ess than 150 mg/L. Th e half-life was less than 4 h in all patients without liver damage. Pharmacodynamics Th e NSAIDs are commonly used in children for antipyresis and analgesia. T h e anti-infl ammatory properties of the NSAIDs have, in addition, been used in such divers e disorders as juvenile idiopathic arthritis, renal and biliary colic, dysmenorrhoea, Kawas aki disease, and cystic fi brosis. Th e NSAIDs indomethacin and ibuprofen are also used to treat delayed closure of patent ductus arteriosis in pre- mature neonates. Clearance, expressed as L/h/kg is greater in children than adults. Th e 4 h concentration i s determined by clearance in preschool chil- dren following accidental ingestion of elixir where absorption is rapid. As a consequence, younger children (1 \200\2235 years) require l arger doses than older children and adults to achieve similar concentra- tions at 4 h. Chil dren (1 \200\2235 years) with reported accidental ingestion of greater than 250 mg/kg (comp are to 150 mg/kg in adults) can have serum concentration measured at 2 h aft er ingestion r ather than the 4 h time point recommended in adults (Anderson et al., 1999 ). Pain relief attributable to NSAIDs has been compared to pain relief from other analgesics o r analgesic modalities (e.g. caudal blockade, acetaminophen, and morphine). Studies compari ng Neonates can produce NAPQI, but CYP2E1 in neonates is imma- ture at birth. Th is may explai n the low occurrence of acetaminophen- SECTION 6 pharmacological interventions 440 Table 43.1 Suggested acetaminophen dosing Age Typical body weight (kg) Acetaminophen clearance (L/h/kg) Acetaminophen dose (oral) Neonate 3.3 0.21 50 mg, 8 h 3 months 6 0.25 90 mg, 6 h 6 months 7.5 0.27 120 mg, 6 h 1 year 10 0.29 120 mg, 4 h 5 years 18 0.25 250 mg, 4 h 8 years 24 0.24 300 mg, 4 h 12 years 38 0.21 375 mg, 4 h 16 years 50 0.3 500 mg, 4 h Adult 70 0.3 1000 mg, 6 h Th e maintenance dose of acetaminophen for a patient is calculated as follows: acetaminophe n maintenance dose = acetaminophen clearance \227 target concentration. Individual clearan ce values can be predicted from weight and age (Anderson et al., 2002 ). Most of the age-re lated changes in clearance are complete by 1 year of age. Th ere are also size-related chan ges in clearance so that the value per kg continues to decrease as weight increases in chil dren (Anderson and Meakin, 2002 ; Anderson et al., 1997 ). Clearance in adults is reported as higher than in children. Th e doses have been calculated to maintain a target serum acet aminophen concentration of 10 mg/L and a lower target may be preferred because of hepatotox icity concerns For patients more than 20% overweight, use ideal body weight. Children prefer elixir to cap sules or tablets. It is important to note that elixir formulation is available in di \200 erent formulation strengths when prescribing the dose by volume. Proprietary cough and cold medications containing acetaminophen are also available. Concurrent use of such medication s can result in inadvertent acetaminophen toxicity. Th e relative bioavailability of rectal formulations is reduced out of the neonatal period and dose can be increased by 30%. Dose is reduced in premature neonates (e.g. 24 and 45 mg/kg/d at 30 and 34 weeks postmenstrual a ge, respectively. Serum concentration E \200ect compartment concentration Pain Score (A) ketorolac (0.75 \200\2231 g/kg) to morphine (0.1 mg/kg) for analgesia aft er pediatric tons illectomy, strabismus surgery, or general sur- gery have demonstrated similar degrees of an algesia with reduced emesis with some increased bleeding in children given ketorolac. Diclo fenac and ketorolac reduce morphine use by up to 40% in children aft er a surgical insult. 10 14 ) 0 1 \200\223 0 S A V ( e r o c s n i a P ) L / g m 12 8 10 ( n o i t a r t n e c n o C 6 8 6 4 Confl icting reports plague the literature as to whether NSAIDs or acetaminophen display gr eater analgesic eff ect when given alone. An early meta-analysis comparing single doses of acetaminophen 7 to 15 mg/kg with ibuprofen 4 to 10 mg/kg found similar analgesic eff ect in children (Perrott et al., 2004 ). A more recent meta-analy- sis identifi ed 54 studies dir ectly comparing the analgesic eff ect of acetaminophen with ibuprofen (Pierce and Voss, 201 0 ). Th e authors concluded that ibuprofen is at least as eff ective as, if not more so tha n, acetaminophen in both adults and children. Th ese compari- sons are diffi cult to interp ret because of diff erences in pain insult, timing of response, duration and nature of pain scores, patient ages, doses administered, and formulations used (Anderson, 2004 ). 4 2 2 0 0 0 2 4 6 8 10 Time (h) (B) 10 20 ) 0 1 \200\223 0 S A V ( e r o c s n i a P ) L / g m 8 15 ( n o i t a r t n e c n o C 6 10 4 Plasma concentration E \200ect compartment concentration Pain Score NSAIDs appear to be equally eff ective at commonly used doses (Davies and Skjodt, 2000 ). I t has been suggested (Maunuksela and Olkkola, 2003 ) that 1 mg/kg of rectal diclofenac = 10 mg/kg of oral ibuprofen = 40 mg/kg of rectal acetaminophen = 5 mg/kg of IV ketoprofen = 0. 5 mg/kg of IV ketorolac. A single dose of ibuprofen 400 mg had a NNT of 2.5 for at least 50 % pain relief compared with placebo (Collins et al., 2002 ; Kopacz and Bernards, 2001 ). Th is means that two of every fi ve adults with pain of moderate to severe intensity will exp erience at least 50% pain relief with ibupro- fen, which they would not have had with place bo. Th e equivalent NNTs for ibuprofen 200 and 600 mg were 3.3 and 2.4, respectively, and t hose for diclofenac 25, 50, and 100 mg were 2.6, 2.3, and 1.8, respectively ( Table 43.3 ). 5 2 0 0 0 2 4 6 8 10 12 Time (h) Figure 43.7 (A) Th e temporal relationships for plasma concentration, e \200 ect compartme nt concentration and analgesic e \200 ect after 12.5 mg/kg acetaminophen elixir in a child . Th e absorption half-time used was 4.5 min. (B) Th e temporal relationships for plasma co ncentration, e \200 ect compartment concentration and analgesic e \200 ect after 20 mg/kg acetaminophen suppository in an adult. Maximum e \200 ect lags an hour behind the 4 h pea k concentration. Reproduced with permission from I. A. Gibb and B. J. Anderson, Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration, Archives of Disea se in Childhood , Volume 93, Issue 3, pp. 241 \200\223247, Copyright 2008 BMJ Publishing Group Ltd and Royal College of Pediatrics and Child Health, http://adc.bmj.com/. NSAID concentration \200\223response relationships are rare in chil- dren, but have been de scribed for adults. Data from adults given CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 441 Table 43.2 Classi \201 cation of common NSAIDs Table 43.3 Number needed to treat (NNT) for ibuprofen and diclofenac in adults Sulphonanilides Fenamic acid derivatives Selective COX-2 inhibitors Ibuprofen (mg) NNT (95% CI) Diclofenac (mg) NNT (95% CI) Nimesulide Mefenamic acid Etoricoxib 50 4.7 (3.3 \200\2238) 25 2.6 (2.2 \200\2233.3) Meclofenamic acid Paracoxib 100 4.3 (3.2 \200\2236.4) 50 2.7 (2.4 \200\2233) Salicylic acid derivatives Tofenamic acid Celecoxib 200 2.7 (2.5 \200\2233) 100 2.3 (2 \200\2232.5) 400 2.5 (2.4 \200\2232.6) Aspirin Flufenamic acid 600 2.7 (2.0 \200\2234.2) Acetic acid derivatives Sodium salicylate 800 1.6 (1.3 \200\2232.2) Propionic acid derivatives Etodolac Di \202 unisal Source: data from Derry, P., Derry, S., Moore, R. A., and McQuay, H.J., Single dose oral di clofenac for acute postoperative pain in adults, Cochrane Database of Systematic Reviews 20 09, Issue 2, Copyright 2009 Th e Cochrane Collaboration and Derry, C. J., Derry, S., Moo re, R. A., and McQuay, H. J., Single dose oral ibuprofen for acute postoperative pain in ad ults, Cochrane Database of Systematic Reviews 2009, Issue 3, Copyright 2009 Th e Cochran e Collaboration. Fenoprofen Indomethacin Enolic acids Ibuprofen Sulindac Meloxicam Flurtiprofen Ketorolac Phenylbutazone Ketoprofen Diclofenac Piroxicam Naproxen Tenoxicam Dexketoprofen compound. Approximately 20% of the parent drug is processed to this metabolite. Despite the impact of this metabolite, there are rea- sonable data to support the contention that dicl ofenac 50 mg is as eff ective as diclofenac 100 mg in adults (McQuay and Moore, 1998 ; Wong and Baker, 1988 ). Little or no information on developmental diff erences in arachidonic a cid release, prostaglandin formation, or COX-2 expression is available for the pediatric po pulation. It has been assumed that attaining similar adult exposure to 50 mg in children sh ould give similar eff ectiveness. Th is argument has been used to support a single dose of diclofenac 0.3 mg/kg for IV, 0.5 mg/ kg for suppositories, and 1 mg/kg for oral diclofenac in children aged 1 to 12 years (Standing et al., 2011 ). Phospholipids Phospholipase A2 Inhibited by steroids Arachidonic acid +lysophospholipids Cyclooxygenase Inhibited by NSAIDs PGH2 Peroxidase Pharmacokinetics Pharmacokinetic age-related changes and covariate eff ects are poorly docu mented for many of the NSAIDs. Th ere are limited data in infants less than 6 months age (L italien and Jacqz-Aigrain, 2001 ). NSAID formulations may be administered orally, topically , intraoc- ularly, intra-articularly, intravenously, intramuscularly, and rectally. NSAIDs are rapidly absorbed in the GI tract aft er oral adminis- tration. Time to maximal concentr ation is generally 1 to 2 h, but depends on formulation and concomitant food intake. Absorp tion due to the dissolution time of diclofenac tablets is slower than that associated with eff ervescent or liquid formulations (Standing et al., 2011 ). An absorption lag time of 1 h has been reported in children given enteric-coated diclofenac tablets (Romsing et al., 20 01 ). Th e relative bioavailability of oral preparations approaches 1 compared to IV admini stration. Th e rate and extent of rectal absorption of NSAIDs such as ibuprofen, diclofenac , fl urbiprofen, indomethacin, and nimesulide is generally less than those by oral routes. PGG2 PGF2a reductase TXA2 synthetase PGI2 synthetase PGE2 synthetase TXA2 PGF2a PGI2 PGE2 Figure 43.8 Th e conversion of arachidonic acid to PGG 2 , the precursor of the prostagland ins is controlled by prostaglandin H 2 synthetase (PGHS). PGHS comprises of two sites; a cy clooxygenase (COX) site and a peroxidise (POX) site