Th e second contribution made by the 2012 WHO guidelines is explicit discussion of codeine and tramadol \200\224drugs that were excluded from these recommendations. Codeine, a prodru g with analgesic activity due to its conversion to morphine via cytochrome P450 (CYP) 2D6, was excluded because of problems with safety and effi cacy due to the variability caused by genetic polymorphism in that metabolic pathway. Further, fetal CYP2D6 activity is extremel y CHAPTER 45 opioids in clinical practice 459 Pharmacokinetics Pharmacokinetics refers to how physiological processes aff ect the absorpt ion, distribution, metabolism, and excretion of drugs \200\224in short, these processes are oft en referred to as what the body does to the drug, as opposed to pharmacology or pharma codynamics, which are what the drug does to the body (Benet, 1984 ). Th e aspects of pharma cokinetics are absorption, distribution, metabolism, and elimination. Each of these phases includes issues that may aff ect use of the opioids in pediatrics. action for infants compared to older children and adults, as well as in adolescent girls co mpared to adolescent boys. In general, once absorbed into the bloodstream, a given drug must be free (unbound) in orde r to be pharmacologically active. As a result, the degree to which drugs are bound to plasm a proteins has the potential to infl uence medications; this fraction can be aff ected by t he concentration of the protein, the affi nity of the drug for the protein, and the ability of the protein to interact with the drug (Maples et al., 2006 , p. 217). As a result, in p ersons with hypoalbu- minaemia or in persons with conditions in which the binding sites on albumin for a drug are altered and binding is decreased, phar- macological activity of a dr ug is likely to be increased. Acidic drugs are generally bound to albumin, while basic drug s are bound to alpha-1 acid glycoprotein. For example, albumin levels are lower in prematur e than in term babies, and there are fewer binding sites. In neonates, alpha-1-acid glycopr otein is present, but at about one- third of adult levels, which occur at approximately 1 y ear of age. Absorption Th e stratum corneum is structurally complete by 34 weeks of gestation, and in a term infant, continues to thicken until about 4 months of age (Maples et al., 2006 ). Sinc e younger infants have greater water loss than older infants as a function of body surface area: body weight, preterm infants and term infants early in life have greater absorption o f drugs through the skin than older children and adults, potentially making the transdermal route more effi cient in younger infants, although the changing nature of the skin also pr esents important challenges (Maples et al., 2006 , p. 214). Th e opioids thought to be most likely to be aff ected by changes in plasma proteins are th ose that are at least 80% protein bound (Maples et al., 2006 , p. 217). Among the opioids, these include alfentanil (92%), buprenorphine (96%), fentanyl (84%), methadone (90%), and s ufentanil (79% in neonates, 91 \200\22393% otherwise). Morphine is approximately 30% bound. Th e extent to which hydrocodone is bound to plasma proteins is not completely understood, although it is thought to be in the same range as other semisynthetic opioids, such as hyd romorphone and oxycodone, approximately 19% to 45% (Vintage Pharmaceuticals, 2012 ). Th e c linical implications of these phenomena are not well understood, however, preterm infants a nd neonates may require lower doses of these drugs. Prodrugs are inactive, and require transformation to become active. As a result, activity o f these medications may be decreased if enzymatic activity is insuffi cient to produce the active drug (as in preterm infants); lipophilic drugs may be absorbed erratically secondary to evolving lipolytic capacity; bile acids may be dimin- ished, resulting in changes in en terohepatic recirculation of glu- curonidated metabolites (morphine, hydromorphone), absorp tion may be increased, as a function of delayed gastric emptying and gastrointestinal trans it time, which can be aff ected by diet. Metabolism Generally speaking, fetal drug metabolism is lower than in infants, and then inc reases in early childhood. Th e hepatic enzymes most commonly discussed in the context of o pioid metabolism are CYP2D6 and CYP3A4, and the drugs most commonly aff ected are codeine, fentanyl, and hydrocodone. CYP2D6 is particularly important because it is known to show gen etic polymorphism, with poor and extensive metabolizer groups (Leeder and Kearns 1997 ; May 1994 ). Th e drug most aff ected by variations in 2D6 activ- ity is codeine, although abou t 4% of hydrocodone is metabolized to hydromorphone via this route. About 10% of a codeine dose is metabolized to morphine, however since poor metabolizers are not expected to genera te any morphine and codeine is a prodrug, these individuals will not receive any analgesia from codeine (Yaksh and Wallace 2011 ). Extensive metabolizers, on the other hand, will pro duce more morphine from the same amount of codeine, which may result in signifi cant toxici ty. Codeine use by a nursing exten- sive-metabolizer mother has also resulted in death of t he infant, and several children aft er tonsillectomy. A similar case in which a child who w as a CYP2D6 poor metabolizer and was also receiving other drugs that interfered with metabo lism of hydrocodone and its metabolites died has also been published. Rectal administration may be useful when administration of meds orally or by other routes i s not available, but absorption may be unpredictable (Birmingham et al., 1997 ; Nolke 1956 ). One study of 48 persons aft er minor surgery found that the amount of oxy- codone was ab sorbed from a rectal suppository was similar to that from the oral route, but was about 42% of the IV dose (Leow et al., 1992 ). In healthy, young men, approximately bioavailability of rec- tal hydromorphone was approximately 33% (Parab et al., 1988 ). Th e nasal and transmucosal routes of administration have also become popular. For example, in the US, fentanyl is available as a buccal tablet, a transmucosal lozenge, which is rubb ed on inside of the cheek, a nasal solution, and a sublingual spray. It is critically impor tant to note that these products are not bioequivalent and cannot be used interchangeably w ithout careful titration. Distribution Total body water accounts for approximately 75% of total body weight in a newb orn infant and about 92% in premature infants, gradually decreasing to 60% at 6 months of l ife (Friis-Hansen 1971 , 1983 ). Similarly, extracellular fl uid accounts for a greater per cent- age of total body weight than in adults (45% at birth (50% in pre- mature infants), 2 8% at year 1, 20% for adults). Th e result is that water-soluble drugs, such as morphine, h ave a larger volume of distribution. In contrast, the amount of body fat increases over the fi rst year of life before decreasing over time to adult levels. Fat levels as a percentag e of body weight are higher in girls than boys during adolescence. Th e implication here is that fat-soluble drugs (among the opioids, diamorphine, fentanyl, alfentanil, and sufentan il are more lipophilic than morphine) may have a longer duration of Th e CYP3A4 isozyme is important in this context mainly in the biotransformation of alfenta nil, fentanyl, sufentanil, and metha- done (Yaksh and Wallace 2011 ). Persons with diminish ed enzyme activity or who are taking drugs that are themselves metabolized by this route or that inhibit this enzyme (e.g. macrolide antibiotics (erythromycin, clarithromycin, telith romycin)), azole antifungals (ketoconazole, itraconazole), or protease inhibitors, among ot hers, SECTION 6 pharmacological interventions 460 are at risk for toxicity due to increased levels of these opioids (see Table 45.1 ). One clinical scenario involving use of codeine by a nursing mother bears mention here. Alth ough use by nursing mothers for short periods has been considered safe, use over a 2-week p eriod by an ultrarapid metabolizer of has resulted in the death of a nursing infant (Koren et al., 2006 ). Elimination With the exception of methadone, the kidney is the primary route of elimination for the opioids. Methadone is eliminated via the gas- trointestinal tract in bile, as well as in urine (Yaksh and Wallace, 2011 ). For children with decreased renal function, the do ses of renally eliminated drugs are decreased (Nahata and Taketomo, 2011 ). In general, how ever, conditions and diseases that reduce blood fl ow to the liver (e.g. cirrhosis, congest ive heart failure) reduce the clearance and increase oral bioavailability of drugs with hig h hepatic extraction. Among the opioids, the drugs that are highly hepatically extracted in adults include morphine, meperi- dine, fentanyl, sufentanil, but not alfentanil or remifen tanil (Davis 2007 ; Tegeder et al., 1999 ). Language Among the many challenges to providing high-quality pain man- agement is making su re that patients, clinicians, and other car- egivers, families, and regulatory offi cials a re all speaking the same language. Th is is particularly important because the words and co ncepts involved are not only emotionally powerful, they have implications for clinicians \200\231 willingness to prescribe, and pharma- cies \200\231 ability and willingness to fi ll prescriptions. One of the challenges that complicates the treatment of pain and, particularly, the use of opioids is that the defi nitions (and conse- quently, understanding) of commonly used terms diff er between medicine and psychology. For example, in the 2003 consensus defi - nitions published by the American Society of Addiction Medicine, the American Pain Society, and th e American Academy of Pain Medicine, addiction is defi ned as a primary, chronic, multifact orial, Nursing and lactation As shown in Table 45.2 , data on opioid use by nursing mothers is lim ited. In general, clinical decision-making rests on a founda- tion of assessing risk-to ben efi t ratio, and the expected duration of therapy. Table 45.1 Opioid metabolism Opioid Metabolic pathway Major metabolites Comments Alfentanil CYP3A4 NA NA Codeine CYP2D6 Morphine Approximately 10% of codeine dose is converted to morphine, however pharmacogenetic variati on may result in varying clinical e \200 ects, from no production of morphine to higher co nversion to morphine (resulting in toxicity or death) Fentanyl CYP3A4 NA Fentanyl is available in various dosage forms (transdermal, transmucosal, buccal, sublingua l, nasal), which are NOT bioequivalent. Hydrocodone CYP2D6 Hydromorphone About 4% of dose is converted to hydromorphone Hydromorphone Glucuronidation Hydromorphone-3-glucuronide NA Levorphanol Glucuronidation NA NA Meperidine Hepatic Normeperidine Normeperidine is toxic, and may cause seizures. Accumulation may occur in persons with decr eased renal function Methadone CYP3A4, CYP2D6 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine (EDDP) EDDP is inactive; Higher doses of methadone are associated with QT prolongation and potenti al for torsades de pointes Morphine Conjugation Morphine-3-glucuronide, morphine- 6-glucuronide Metabolites accumulate with decreased renal function. M6G is analgesic, M3G may be proalges ic Oxycodone CYP2D6 Oxymorphone Present only in small amounts Glucuronidation Noroxycodone Weaker than parent drug Oxymorphone Glucuronidation Oxymorphone-6-glucuronide, 6-OH- oxymorphone Remifentanil Ester hydrolysis NA NA Sufentanil N-dealkylation, O-demethylation via CYP3A4 NA NA Tapentadol Conjugation, CYP2C9, CYP2C19, CYP2D6 Tapentadol-O-glucuronide No active metabolites Tramadol CYP2D6, CYP3A4, conjugation O-desmethyltramadol (M1) M1 contributes to analgesic activity Source: data from Yaksh and Wallace, 2011 ; Tegeder et al., 1999 ; Lundeberg and Roelofse, 2011 ; Tateishi et al., 1996 ; Sullivan and Due, 1973 and Eap et al., 2002 . NA = not appli cable. CHAPTER 45 opioids in clinical practice 461 Table 45.2 Opioids in breast milk Drug Excreted into breast milk? Clinically important? Alfentanil Yes Limited human data \200\224probably compatible Codeine Yes Limited human data \200\224potential toxicity Fentanyl Yes Compatible Hydrocodone Not known No human data \200\224probably compatible Hydromorphone Yes Limited human data - probably compatible Levorphanol Not known No human data \200\223 probably compatible Meperidine Yes Compatible Methadone Yes Limited human data \200\223 probably compatible Morphine Yes Limited human data \200\224probably compatible Oxycodone Yes Limited human data \200\224probably compatible Oxymorphone Not known No human data \200\224probably compatible Remifentanil Not known No human data \200\224probably compatible Sufentanil Not known No human data \200\224probably compatible Tapentadol Not known Manufacturer does not recommend use during breastfeeding Tramadol Yes Limited human data \200\224probably compatible Compatible: either the drug is not excreted in clinically signi \201 cant amounts into hum an breast milk or its use during lactation does not, or is not expected to, cause toxicity in a nursing infant. No (limited) human data \200\224probably compatible: there may or may not be human pregnanc y experience, but the characteristics of the drug suggest that it does not represent a sign i \201 cant risk to the embryo/fetus. For example, other drugs in the same class or with s imilar mechanisms are compatible or the drug does not obtain signi \201 cant systemic conc entrations. Any animal reproduction data are not relevant. Reproduced with permission from Briggs et al. (ed.) Drugs in Pregnancy and Lactation: A Ref erence Guide to Fetal and Neonatal Risk (8th edn), Lippincott Williams & Wilkins, Philadelp hia, USA, Copyright 2008. neurobiological disease, characterized by impaired control over drug use, compulsive use, c ontinued use despite harm, and craving. In the Diagnostic and Statistical Manual of Mental Disorders , fourth edition , text revision the term \200\230dependence \200\231 is used (A merican Psychiatric Association, 2000 ; Savage et al., 2003 ). currently understood to be a state of physiological adaptation, and can be a measure of saf ety. Th e heart of this defi nition is centered on the diminution of a specifi c eff ect. T h us, in referring to tolerance to an opioid, the assumption may be that the drug \200\231s analgesic eff ect has decreased, even if it is another eff ect of that drug. For example, in the opioids, tolerance to respiratory depression typically occurs fairly quickly, while tolerance to the constipating eff ects generally occurs slowly, if at all. Drugs are oft en referred to as being addictive. Yet, while it is generally true that the r eward experienced from a given drug is an important component of the decision to repeat use , there are also patient-specifi c factors that are important patient contributors to the d evelopment of addiction (Savage et al., 2003 ). In general, then, rather than blaming a dru g or class of drugs for addiction, it is the combination of a physiologically and psycholog ically vulnerable person (and the degree of vulnerability is not constant), with a sub- sta nce that produces reward that requires our attention. Th is idea also seems to help explain why some people prefer a class of drugs over others (alcohol versus nicotine versus opioid s, and so on), as well as drugs within a class (codeine versus fentanyl, and so on). Opioid analgesics In general, opioids can be organized by the main type of opioid receptor the drug interacts with ( Table 45.3 ), and by the drugs \200\231 gen- eral chemical struct ure ( Table 45.4 ). Th e three main types of opioid receptor are mu, kappa, and delta (Yaks h and Wallace, 2011 ). While agonism at each of these receptors produces analgesia, most op ioids currently available are mu agonists, and none of the opioids used in the US are delta agonists. Although the partial agonists and kappa agonists/mu antagonists were originally developed to be safer alternatives to the mu agonist drugs, the diff erence between these g roups when given in equianalgesic doses is small and not thought to be clinically meaningfu l. Physical dependence is defi ned as a state of physiological adapta- tion in which a class-s pecifi c withdrawal syndrome occurs upon suddenly stopping use of a drug, quickly reducing the dose, use of an antagonist, or otherwise decreasing the blood level of drug (Savage et al., 2003 ). In other words, when sudden discontinua- tion of a drug is not recommended (fo r whatever reason), it can be viewed as dependence. Many drug classes fall into this catego ry, not just opioids, including corticosteroids, anticonvulsants, and antihy- pertensives, among others. Opioids are categorized chemically as phenanthrenes, phenyl- piperidines, or diphenylpropyl amines (Yaksh and Wallace, 2011 ). Th e clinical implication of these diff erences is that, generally speak- ing, if a person cannot take a drug in one chemical group, such as morphi ne, it may be possible to cautiously use a drug from one of the other groups, such as metha done or fentanyl. Tolerance occurs when a specifi c eff ect of a drug decreases over time (Savage et al., 200 3 ). Like physical dependence, tolerance is SECTION 6 pharmacological interventions 462 Table 45.3 Opioids by receptor activity Mu agonists Kappa agonist/Mu antagonists Mu antagonists Alfentanil Opium Buprenorphine (partial agonist) Nalmefene Codeine Oxycodone Butorphanol Naloxone Diamorphine (Heroin; not used clinically in the US) Oxymorphone Nalbuphine Naltrexone Fentanyl Propoxyphene (withdrawn from the US market in 2010) Pentazocine Hydrocodone Remifentanil Hydromorphone Sufentanil Levorphanol Tapentadol Meperidine (Pethidine) Tramadol Methadone Morphine Table 45.4 Opioid analgesics by chemical structure Phenanthrenes Phenylpiperidines Diphenylpropylamines Codeine Alfentanil Methadone Hydrocodone Fentanyl Propoxyphene (withdrawn from the US market in 2010) Levorphanol (a morphinan) Meperidine Morphine Remifentanil Oxycodone Sufentanil Oxymorphone Since the focus of this chapter is to provide general clinical insight into opioid use for the treatment of pain, the discussion in this sec- tion will emphasize those opioids that a re most commonly used in that setting (see Table 45.5 ). Alfentanil, remifentanil, and sufe ntanil are primarily used in surgical settings, and while nalmefene and naltrexone are opio id antagonists, they are used mainly in the treat- ment of alcohol dependence. As a result, the use of these drugs is beyond the scope of this eff ort. been studied in a small group of children with cancer-related pain (Ruggiero et al., 2013 ) . Codeine Codeine is not recommended for use in children with persistent pain, due to well-do cumented problems with effi cacy and safety (World Health Organization, 2012 ). Th is recom mendation makes sense for children with other types of pain, as well. Specifi cally, codein e is a prodrug, and its analgesic activity is dependent on its conversion to morphine via C YP2D6. Persons with an absolute or functional lack of this will not experience analgesia fr om codeine or they may experience diminished analgesia relative to a given dose. Conversely , persons who are considered rapid or extensive metabolizers will experience more analgesia than would otherwise be expected. Toxicity and deaths have occurred in rapid metabo- lizer s, as well as in children of nursing mothers who were taking codeine. Approximately 10% of a codeine dose is converted to mor- phine, and bioavailability is estimated as 30% to 60%. Th us, a 10 mg oral dose of codeine would be expected to provide approximately 0.3 to 0.6 m g of morphine. Given that genetic polymorphism with codeine has been well documented, there have been serious adverse events due to the use of therapeutic codeine doses, and morphine is readily available, the continued need to use codeine for analgesia is questionable at b est (Ciszkowski et al., 2009 ; Kelly et al., 2012 ; Koren et al., 2006 ). Buprenorphine Buprenorphine is a partial agonist at the mu opioid receptor, as well as an a ntagonist at the kappa and delta opioid receptors (Yaksh and Wallace, 2011 ). Its half-life in premature neonates aft er IV use is approximately 20 h (standard deviation 8), and it i s metabolized to norbuprenorphine and other compounds. Th e role of buprenorphine in caring for children with pain is unclear, in part because of limited research on this topic, and in part because use of the agonist-antagonist drugs (buprenorphine, butorphanol, nalbuphine , and pentazocine) may precipitate with- drawal in persons who have been receiving mu agoni st opioids. In two studies of children with postoperative pain aft er orthopae- dic surgery , morphine and buprenorphine were each considered good or very good analgesics, with simila r side eff ect profi les, despite the studies being considered to be low quality (World Hea lth Organization, 2012 ). Transdermal buprenorphine has also CHAPTER 45 opioids in clinical practice 463 Table 45.5 Dosing for commonly used opioids Drug Neonates Infants Children Adolescents Buprenorphine: slow IV 2 \200\2236 mcg/kg every 4 \200\2238 h (2 \200\22312 years of age) 3 mcg/kg every 6 \200\2238 h ( \211 13 years of age) Fentanyl a Oral transmucosal 0.01 mg/kg/dose or 10 \200\22315 mcg/kg (oralet) Intranasal 1 \200\2232 mcg/kg IV bolus 0.001 mg/kg/dose or 0.5 \200\2231 mcg/kg every 1 \200\2232 h IV infusion 0.5 mcg/kg/h Hydrocodone 0.1 \200\2230.2 mg/kg every 4 h Hydromorphone Oral 40 \200\22380 mcg/kg every 4 h IV bolus 10 \200\22320 mcg/kg every 3 \200\2234 h IV infusion 3 \200\2235 mcg/kg/h Methadone Initial intravenous 0.05 \200\2230.1 mg/kg (up to 10 mg) every 3 \200\2234 h for 2 \200\2233 doses, then every 6 \200\22312 h Oral and subcutaneous 0.1 mg/kg (up to 10 mg) every 4 h for 2 \200\2233 doses, then every 6 \200\22312 h. Alterna tely, 0.7 mg/kg/day (up to 10 mg/dose) divided every 4 \200\2236 h Morphine Oral, immediate release 0.2 \200\2230.5 mg/kg every 3 \200\2234 h Oral, sustained release (older children & adolescents) 0.25 \200\2230.5 mg/kg every 8 \200\22312 h IV bolus Preterm: 10 \200\22325 mcg/kg every 2 \200\2234 h 50 \200\223100 mcg/kg every 3 h Full-term: 25 \200\22350 mcg/kg every 3 \200\2234 h IV infusion Preterm: 0.01 \200\2230.03 mg/kg/h or 2 \200\22310 mcg/kg/h 15 \200\22330 mcg/kg/h Full-term: 5 \200\22320 mcg/kg/h Oxycodone 0.05 \200\2230.2 mg/kg every 4 \200\2236 h a Fentanyl: transdermal, transmucosal, intranasal use is not for use in outpatient or unobs erved settings, or in opioid-na ve patients. Source: dosing data from Johns Hopkins Hospital, Kristin Arcara and Megan Tschudy, Th e Har riet Lane Handbook , 19th Edition, Mosby, Inc., an a \203 liate of Elsevier Inc., Copyrigh t 2012; Lexicomp and Facts & Comparisons , Copyright Wolters Kluwer Health, Inc . and John Barnes Rose, Analgesic Medications for Acute Pain Management in Children, in Gar y A. Walco and Kenneth R. Goldschneider (eds), Pain in Children: A Practical Guide for Prim ary Care , Humana Press, Totowa, New Jersey, USA, pp. 73 \200\22385, Copyright 2008. Diamorphine (diacetylmorphine, heroin) Although not available for clinical use in the US, d iamorphine is used in the UK in children for a variety of painful conditions and for pain a t the end of life (Hewitt et al., 2008 ), intranasal use in emergency settings (Finn and Ha rris, 2010 ; Hadley et al., 2010 ), and sickle cell pain (Telfer et al., 2009 ). its ability to produce analgesia over drugs that are even more lipid- soluble, such as meth adone or fentanyl, when given by the same route. Fentanyl Fentanyl is approximately 100 times more potent than mor- phine on a milligram-to- milligram basis (Yaksh and Wallace, 2011 ). It is also lipophilic, which results in relativ ely rapid onset of action (except when used transdermally). Although fenta- nyl is metaboli zed to inactive products via CYP3A4, this process is decreased by a wide variety of drugs. Th ese drugs include, but are not limited to amiodarone, aprepritant, the azole antifungals Metabolism to 3- and 6-monoacetylmorphine and then to mor- phine occurs quickly when diamor phine is given by mouth. In contrast, administration by injection or other routes that avoi d the fi rst-pass eff ect allows the drug to cross the blood \200\223brain barrier more rap idly than morphine or other, less fat-soluble opioids. It is not known if diamorphine off e rs any clinical advantage in terms of SECTION 6 pharmacological interventions 464 (i.e. fl uconazole, itraconazole, ketoconazole), calcium channel blockers (e.g. diltiazem, verapamil), macrolide antibiotics (clari- thromycin, erythromycin, telithromycin), nefazodo ne, and pro- tease inhibitors (e.g. fosamprenavir, ritonavir, indinavir, nelfi navir, saqui navir). Th e result of this interaction has included fatalities due to respiratory depressi on. As a result, close monitoring (including dose reduction of fentanyl as indicated) is ab solutely required, par- ticularly when using fentanyl with drugs that inhibit the CYP3A4 pa thway. 2009 ). In older children and adolescents who weigh less than 50 kg, oral doses of 0.03 to 0.08 mg/kg every 3 to 4 h, 0.015 mg/kg intrave- nously every 3 to 6 h, or 0.003 to 0.005 mg /kg/h up to a maximum of 0.2 mg/h by continuous IV infusion. Meperidine (British approved name: pethidine) Meperidine is not recommended for use as an a nalgesic, due to its active and toxic metabolite, normeperidine, which can accumu- late (el imination half-life in neonates is 30 \200\22385 h) and cause sei- zures. Because of its po or risk:benefi t profi le, meperidine has been removed from many formularies in the US. Mep eridine is about one-tenth as potent as morphine and it is about 30% bioavailable when give n by mouth (Lexicomp, 2013c ). If alternatives to mepe- ridine are not available or are con traindicated, usual meperidine dosing in children is 1 to 1.5 mg/kg every 3 to 4 h by mouth or parenterally. By continuous IV infusion, a loading dose of 0.5 to 1 mg/kg can be given, followed by 0.3 mg/kg/h initially, with titration to eff ect up to 0.5 to 0.7 mg/kg/h. Fentanyl is also of interest because it is one of the only opioids that is available for tr ansdermal use, along with buprenorphine, or intranasal use (diamorphine is used intranasall y in the UK) and fentanyl is the only opioid available for transmucosal use. Transdermal fe ntanyl should not be used in people who are opioid- na ve. Additionally, although there are several transmucosal and one intranasal fentanyl products available, they are not bioeq uiva- lent to each other, and cannot be interchanged without titrating. Further, using thes e products in children is a challenge because the doses are chosen based on adult opioid do sing, although Borland et al. ( 2011 ) assessed the use of intranasal fentanyl in 50 mcg/ml or 300 mcg/ml concentrations using a calibrated delivery device to provide 1.5 mcg/kg (up to 0.2 ml per nostril) in 189 children aged 3 to 15 years who presented to an Australian em ergency department with clinically deformed closed long bone fractures. Th ese authors conc luded that these concentrations were clinically equivalent in their provision of analgesia, and that the lower concentration was reasonable for children weighing less than 50 kg. Methadone Methadone is a potent opioid that is challenging to use, due to its long eliminat ion half-life of approximately 19 h (range 4 \200\22362), and because the elimination half- life is substantially longer than the duration of analgesia, which is 6 to 8 h initially (L exicomp, 2013d ). Methadone is approximately 80% bioavailable and is metabolized to an inac tive product via CYP3A4 and CYP2D6, and eliminated in the urine (approximately 10% of uncha nged drug) and feces. It also has the potential to cause cardiac arrhythmias. Choice of a d ose must be done carefully, and is best viewed as a process, rather than a single event, si nce the dose and dosing interval will likely change over the fi rst few days of therapy due to accumulation (Weschules and Bain, 2008 ). It is also critically important to rec- ogniz e that equianalgesic conversion involving methadone is not a linear calculation. For exampl e, in contrast to the idea that hydro- morphone is about fi ve times as potent as morphine or that fentanyl is about 100 times as potent as morphine, the ratio of methadone to morphi ne varies based in part on how much morphine the per- son was receiving. Th ere are several methods available to estimate methadone doses, and while each diff ers slightly from each other, the hallmark is that the expected dose of methadone decreases as the dose of morphin e increases. Hydrocodone Most hydrocodone is used in the US, although it is also available (to a much sm aller degree) in other countries, including Argentina, Belgium, Canada, Columbia, Germany, Guatemala, and Switzerland (International Narcotics Control Board, 2013 ). Bioavailability infor- mation is not available, and limited data suggest that hydrocodone is roughly equipo tent to morphine on a milligram to milligram basis. Approximately 4% of a hydrocodone dose is transformed to hydromorphone via CYP2D6. Since CYP2D6 is the same pathway that biotransf orms codeine, similar safety and effi cacy problems are possible. In the US, hydrocodone is not available for parenteral use, and it is always used in combin ation with other drugs, most typically acetaminophen (paracetamol). While the usual initial dose in opi- oid-na ve children who weigh less than 50 kg is 0.1 to 0.2 mg/kg every 3 t o 4 h, and 5 to 10 mg every 3 to 4 h in children who weight at least 50 kg, maximum dosing is a function of other drugs (i.e. acetaminophen) present (Lexicomp, 2013a ). Morphine Morphine is the prototypical opioid and is generally the opioid of fi rst choice, due to its eff ectiveness, extensive clinical experience using it, and low cost. When given by mouth, it is approximately 30% bioavailable, and is metabolized to morphine-3- and mor- phine-6-glucuronides (Lexicomp, 2013e ; Yaksh and Wallace, 2011 ). While morphine-3-glucur onide is not an analgesic, some evidence suggests that it may be proalgesic. In contrast, m orphine-6-glu- curonide has analgesic activity. Both compounds can accumulate in people wit h decreased renal function. Th e elimination half-life of morphine generally decreases from 10 to 20 h in preterm infants to 1 to 2 h in preschool-aged children. Hydromorphone Hydromorphone is approximately fi ve times as potent than mor- phine on a mil ligram to milligram basis (Yaksh and Wallace, 2011 ). Its oral bioavailability is approxima tely 20% to 60% (Lexicomp, 2013b ) by mouth and approximately 51% intranasally, although, i n one study, the interindividual variability was 59%. Metabolism is via glucuronidation to inactive products, which are eliminated in the urine. Usual initial doses for infants older than 6 months of age who weigh more than 10 kg are 0.03 to 0.06 mg/kg given by mouth every 3 to 4 h as needed, 0.01 mg/kg intravenously, given every 3 to 6 h, or 0.003 to 0.005 mg/k g/h by continuous IV infusion (Friedrichsdorf and Kang 2007 ; Lexicomp 2013b ; Zernikow et al., Opium Although used primarily as an antidiarrheal, opium can also be used as an analgesic. It contains several alkaloids, including mor- phine (10% of opium) and codeine (0.5% of opi um) (Yaksh and CHAPTER 45 opioids in clinical practice 465 Wallace, 2011 ). It is important to note that opium is available as a tincture (10 mg morph ine/ml), as well as in paregoric (2 mg morphine/5 ml). Th e diff erence between these produ cts is criti- cal, since opium tincture contains 25 times more morphine than paregoric. Ped iatric dosing of paregoric is 0.25 \200\2230.50 ml/kg one to four times a day (Lexicomp, 20 13f ). diff erent routes of administration, and use of drugs with diff erent mechanisms of action to help decrease the patient \200\231s opioid require- ment. Although we are moving into a time in which comparative eff ectiveness studies are considered increasingly important, muc h of the published biomedical literature relies heavily on placebo- controlled trials. As a result, although randomized, controlled tri- als comparing opioids are not very common, cl inical practice oft en includes trying another drug in a class if the patient doesn \200 \231t tolerate the fi rst drug chosen. Oxycodone Th e main diff erences between oxycodone and morphine have to do with metabolism and bioavailability. Oxycodone is metabolized via CYP2D6 to oxymorphone (which is present o nly in small amounts) and is glucuronidated to noroxycodone (Yaksh and Wallace, 2011 ). Th e relative lack of clinically important active metabolites makes oxycodone a reasonable cho ice for patients with diminished renal function. Oxycodone is approximately 80% bioavailabl e. Nausea and vomiting Nausea and vomiting are among the most undesirable adverse eff ects of clinical anesthesia, from the points of view of patients as well as clinicians (Macario et al., 1999a , 1999b ). Despite the impor- tance of avoiding these adverse eff ects, preventi on and treatment have remained challenging, in part due to varying mechanisms of action. Wh ile opioids are oft en implicated as causes due to their eff ects on the central nervous sy stem, gastrointestinal tract, and other physiological systems, other drugs and pain also ca use nau- sea. Depending on the underlying cause, treatment typically con- sists of a variet y of drugs, including phenothiazines, haloperidol, and the 5-HT 3 receptor antagonists, of which dolasetron, ondanset- ron, and palonosetron have been approved by the US Food & Drug Administration for prevention of postoperative nausea and vomit- ing (Hardy et al., 2002 ; Schug et al., 1992 ; Sussman et al., 1999 ). Antihistamines, transdermal scopolamine, and m etoclopramide have also been used. Tapentadol Metabolism of tapentadol is via conjugation, as well as CYP2C9, CYP2C19, and CYP 2D6 to inactive products. In terms of effi cacy, tapentadol is broadly considered to be sim ilar to tramadol, although tapentadol has less eff ect on serotonin reuptake inhibition tha n tra- madol (Yaksh and Wallace, 2011 ). No articles on tapentadol and children were identi fi ed in a literature search of PubMed-indexed journals. According to the professional pres cribing information, the safety and eff ectiveness of tapentadol has not been established i n patients less than 18 years of age (Janssen Pharmaceuticals, 2012 ). Tramadol Tramadol is not recommended for treatment of persistent pain in medically ill chil dren, due to lack of evidence and lack of regulatory approval in this population (World Hea lth Organization, 2012 ). Th is recommendation likely applies to children with other kinds of pain as well. Although tramadol is considered a codeine analog, it is structurally dissi milar from the other phenanthrene opioids, thus, it may be a reasonable choice in people wh o cannot take other opioids (Yaksh and Wallace, 2011 ). Itching Although commonly attributed to histamine release (and treated that way), the patho physiological mechanisms underlying opioid- related itching are hypothesized multiple pathw ays to involve spinal opioid receptors, disinhibition of specifi c neurons, or central sero t- onin (5-HT-3) receptors (McNicol, 2007 ; Schmelz, 2002; Schug et al., 1992 ). It is also important to recognize that itching may be caused or aggravated by other diseases and cond itions, including choles- tatic liver disease, as well as skin conditions, like dry skin or eczema, although the latter are typically localized versus generalized. Side e \200 ects and adverse events While respiratory depression is commonly considered th e most concerning potential side eff ect of the opioids, other side eff ects closely associ ated with the opioids include nausea and vomiting, itching, urinary retention, dizziness, a nd sedation (see Table 45.6 ). Since adverse events considered broadly are simply things th at are undesirable at the time and from the perspective being considered, it also makes sen se to think about these occurrences more broadly. One example of this is a commentary by Ch orney et al. ( 2010 ), in which the authors consider the implications of viewing pain as an adverse event itself. Treatment of itching is oft en focused on H 1 -receptor antagonists, although itching also occurs with fentanyl and sufentanil, which do not cause histamine release (Schug et al., 19 92 ). If antihistamines are used, there is potential for drug interactions to enhance sedat ion. In these individuals, more frequent monitoring for respiratory func- tion will be impo rtant. Nalbuphine has also been used, but this drug is an antagonist at the mu opioid recep tor, so there is the potential for analgesia to be reversed or withdrawal to be induced (Ya ksh and Wallace, 2011 ). In one recent review, Miller and Hagemann ( 2011 ) evaluated the p ublished biomedical literature on the use of naloxone, naltrexone, or methylnaltrexone for management of opioid-induced itching. Th ese authors concluded that IV doses of 0.25 to 1 m cg/kg/h of naloxone is optimal for reversal of itching without also aff ecting analgesia. Y et, since most people in an ambulatory setting don \200\231t have percutaneous access, opti mal treatment of itching in community- based patients will likely center on opioid rotation . Pain management aside for a moment, the general approach to addressing adverse events and s ide eff ects consists of prevention when possible, followed by decreasing the dose (or admi nistration frequency), using a diff erent drug in place of the implicated medi- cation, or as a last resort, continuing with the medication associ- ated with the adverse event and ad ding another drug to treat the unwanted event or symptom. An example of the latter situatio n is to use low doses of a central nervous system stimulant in a person whose pain is well controlled, but who is sedated. A variety of treat- ment methods have been used, including opioid rotation, use of Respiratory depression/sedation Opioids produce a dose-related decrease on all phases of re spiration (Yaksh and Wallace, 2011 ). It is a more common occurrence in indi- viduals who a re opioid-na ve or -inexperienced, as well as persons SECTION 6 pharmacological interventions 466 Table 45.6 Selected drugs and dosing for opioid-related side e \200 ects Side e \200 ect and drugs Neonates Infants Children Adolescents Nausea Diphenhydramine, by mouth or intravenously 0.5 \200\2231 mg/kg every 4 \200\2236 h as needed Lorazepam, by mouth or intravenously 0.02 \200\2230.04 mg/kg (up to 2 mg) every 6 h Ondansetron, by mouth or intravenously 0.15 mg/kg (up to 8 mg) 1 \200\2234 times a day Prochlorperazine, by mouth or rectally 0.1 \200\2230.15 mg/kg every 6 \200\2238 h Promethazine, by mouth or intravenously 0.25 \200\2230.5 mg/kg every 4 \200\2236 h as needed Respiratory depression/sedation Naloxone 0.02 mg every 30 \200\22360 secs until improvement (may need to repeat) Itching: diphenhydramine, by mouth or intravenously 0.5 \200\2231 mg/kg every 6 \200\2238 h Nalbuphine, intravenously a 0.01 \200\2230.02 mg/kg every 6 \200\2238 h as needed Naloxone, by infusion 0.25 \200\2231 mcg/kg/h Constipation: docusate (1 \200\2234 divided doses by mouth per day) <3 years of age 10 \200\22340 mg 3 \200\2236 years of age 20 \200\22360 mg