SECTION 6 pharmacological interventions 454 Activation of opiate receptors Excitatory Mode Inhibitory Mode Gs Go Gi AC/cAMP \206\223 AC/cAMP \206\221 PKA \206\221 gK \206\223 gK \206\223 gCa \206\221 gCa \206\221 APD \206\223 APD \206\221 Transmitter Release \206\223 Transmitter Release \206\221 Inhibitory e \200ects Excitatory e \200ects counteracts Figure 44.2 Bi-modal actions of opioid receptors. Classical opioid receptors act in an inhi bitory mode mediating their actions via Gi and Go pathways, decreasing production of cAMP, reducing calcium currents and increasing potassium currents which ultimately leads to decre ased neurotransmitter release. Alternatively opioid receptors can operate in an excitatory mode (at certain times in postnatal development or in states of opiate tolerance). In this mode receptors operate Gs (stimulatory) pathways increasing calcium currents and cAMP level s with increase neurotransmitter release. Adapted with permission from Trends in Pharmacolo gical Sciences , Volume 19, Issue 9, Stanley M. Crain and Ke-Fei Shen, Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid recept or functions, pp. 358 \200\223365, Copyright 1998, with permission from Elsevier, http:/ /www sciencedirect.com/science/journal/01656147. Another age-related alteration in opioid receptor pharmacology is the propensity of neonata l opioid receptors to weakly couple to their eff ector mechanisms. Th is is thought to be d ue to modifi cations in the way that the receptor interacts with G-proteins ( Figure 44.2 ) . All opioid receptors couple to Gi G-proteins and therefore have inhibi- tory eff ects on cellular excitability. Th e classic view of the intracel- lular events that take place foll owing activation of the receptor is that K + currents are increased and Ca 2+ currents are decreased, leading to a decrease in neurotransmitter release from the neuron (Crain and She n, 1998 ). However, what if this is too simple an explana- tion? Evidence for altered -o pioid receptor G-protein coupling was fi rst observed in 2003 (Nitsche and Pintar, 2003 ), when this group demonstrated radioligand binding to the receptor prior to agonist stimulate d [ 35 S]GTP S production in embryonic brain. Within the striatum of the postnatal rat, there is an age-dependent increase in Gi -opioid receptor coupling with postnatal age (T albot et al., 2005 ); with levels of Gi coupling at P15 approximately 50% of those in the a dult, and maximum levels of Gi coupling not being achieved until greater than P40 (approxim ately 250 g body weight). Further work is required to establish the functional consequences of this, but it implies that if the -opioid receptor is not coupled to Gi then it must either be coupled to some other G-protein, or is functionally inert and has no physiologica l role. However, this previous study concen- trated on opioid signaling within the basal ga nglia, and this may not be the case in areas more pertinent to pain. We, and others, have c learly shown functional responses to opioid in the RVM (Hathway et al., 2012 ), but further work in diff erent brain regions is required. dated literature that has not applied modern post-genomic method- ologies, and without a fu ll appreciation that neonatal and young ani- mals are not just smaller versions of adults. Behavioral studies clearly demonstrate analgesic responses to opioids from early developmen t, but changes in opioid receptor expression and signaling mature at dif- ferent rates in d iff erent parts of the nervous system, and this contrib- utes to age-related diff erences i n the degree and nature of response. In the coming years it is hoped that fresh approaches to evaluating post- natal alterations in opioid systems may shed new light on the role that endogenous and exogenous opioids may play in neurodevelopment, and potentially allow for t he development of new therapies that take into account the ontogeny of the opioidergic syst em. References Abbadie , C. , Pan , Y. , Drake , C. T. , and Pasternak , G. W. ( 2000 a). Compa rative immunohistochemical distributions of carboxy terminus epitopes from the mu-opioid re ceptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat CNS . Neuroscience , 1 00 , 141 \200\223153. Abbadie , C. , Pan , Y. X. , and Pasternak , G. W. 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Stereospecifi c binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate . Proc Natl Acad Sci U S A , 70 , 1947 \200\2231949. CHAPTER 45 Opioids in clinical practice Scott A. Strassels Introduction Opioid analgesics occupy a unique position in modern medicine. Th ey are indis pensable tools for the treatment of many types of moderate to severe pain, but are also the focus of intense atten- tion and criticism in the biomedical literature, lay press, and me dia (Meldrum, 2003 ; Whelan et al., 2011 ). Clinical outcomes associated with use of opioids Evidence-based medicine plays an important part of clinical prac- tice in many countries, from reimbursement decisions through pay fo r performance incentives. Yet, the evidence base for the use of opioids in children with pa inful conditions is uneven. Th e result of this situation is that there are few clinical pr actice guidelines (CPGs) focused on specifi c treatments for pain in children and adolescen ts. In the absence of high-quality evidence, clinicians are oft en left to practice accordi ng to habit, which may or may not result in optimal outcomes. Furthermore, there is a lack of consensus on the out- comes that are best to assess. For example, it is generally easy t o assess a patient \200\231s pain (and, indirectly, the quality of care) using a numeric an alog 0 to 10 or verbal rating scale, but pain intensity is just one of many facets of a com plex multidimensional experience (Gordon et al., 2005 ). Other dimensions of the pain exper ience, such as the ability to function in ways that are important to the patient, family, a nd caregivers, are also likely to be important. Th e epidemiology of painful conditions and diseases, as well as other common sources of pa in, including invasive procedures to diagnose and monitor diseases, help provide insight in to the need at the population level for opioids to provide safe and eff ective pre- vention and management of moderate to severe pain. At the patient level, the importance of these m edications is illustrated by tools such as the World Health Organization (WHO) pain ladder (Ventafridda et al., 1985 ), in which opioids are central to steps two and three, and by th e inclusion of morphine in the WHO essential medicines list of priority medicines for mothe rs and children (World Health Organization, 2011a ), the WHO Model List of Essential Medici nes for Children , 3rd list , published in March 2011 (WHO, 2011b ), and the WHO guidelines on the pharmacological treatment of persist- ing pain in children with medical illnesses ( WHO, 2012 ). To illustrate the current state of the biomedical literature on this topic, a literature se arch using the strategy [(pediatric OR paediat- ric) AND pain AND clinical practice guideli ne AND opioid] iden- tifi ed ten English-language, Pubmed-indexed papers published between 2007 and 2012. Of these, two were guidelines based on a systematic review of the literature . In one, the authors reviewed papers and abstracts published between 1996 and 2006 to prov ide recommendations for treatment of chronic and procedural pain in pediatric patients with rheumatic disease (Kimura and Walco, 2007 ). Th e other guideline provides recommendations from the Canadian Pain Society for drug treatment of neuropathic pain, and while none of t he contents are specifi c to pediatric patients, it makes sense that the insights may be us ed in caring for children as well as adults (Moulin et al., 2007 ). Other topics identifi e d in this search included the use of intravenous (IV) bolus morphine in a pediatric setting (Ellis et al., 2011 ), regulatory aspects of paediat- ric pain management in Europe (Forti nguerra et al., 2010 ), use of the WHO analgesic ladder to provide pain management to 39 ch il- dren with leukemia in a teaching hospital in India (Geeta et al., 2010 ), the results o f a survey on the eff ect of guidelines on pain management in Austrian, German, and Swiss n eonatal intensive care units (Gharavi et al., 2007 ), and the results of a survey of pae- d iatric anaesthesiologists in the US, published in 2010, which was undertaken to describe pa tient demographics, as well as whether Nonetheless, there is mixed consensus about the roles opioids play in society and medical p ractice, particularly as part of the care of persons with chronic, non-cancer pain. In part , this state of aff airs is due to our evolving understanding of opioids and their eff ects at the individual and population levels, to limited time spent educating clinicians on the appropriate use of these and other anal- gesics, and to substantial gaps in the evidence b ase, overall and particularly within children (Chou et al., 2009a , 2009b ; Chapman et al., 2010 ). Despite this uncertainty, the view of morphine, and by extension, other opioids, a s not just important, but absolutely essential contributors to clinical practice underscore s the belief that these are among the most useful medications of any sort. Yet, while the m edications in this class have numerous advantages, includ- ing a high degree of eff ectiven ess and safety when they are used appropriately, there are important patient and population issues and concerns regarding the use of these medications. As a result, it is critically important that all medical practitioners, as well as other clinical decision-makers be fami liar with the pharmacological and pharmacodynamic characteristics and eff ects of these age nts, as well as related issues that are of interest, such as opioid-induced hyperalgesia (O IH) and eff orts to address inappropriate opioid use at the population level. SECTION 6 pharmacological interventions 458 IV patient-controlled (or proxy-controlled) analgesia was available and used, and the degre e to which serious and life-threatening opi- oid-related adverse events occurred (Nelson et al., 2010 ). Among other fi ndings, these authors reported that facilities with more pedia tric beds were more likely to have a pediatric pain service, that IV patient-controlled ana lgesia was available at nearly all of the 252 institutions surveyed, and that only 38% of t hese institutions off ered IV proxy-controlled analgesia. low compared to adult levels, and rises to no more than 25% of the adult level in children under 5 years of age. Th e result has been no analgesia from codeine (in poor or low metabo lizers) and potential toxicity due to increased morphine production at the other end of the spectrum of activity. Tramadol was excluded due to a lack of evidence for its use in this patient population, and lack of regula- tory approval for pediatric use in some countries. Th e third major contribution in the new WHO guidelines is a two-step approach to the choic e of medications, as opposed to the three-step ladder used in previous WHO publications. In this new method, the fi rst step consists of treatment for mild pain using acetaminophen ( paracetamol) and ibuprofen. In contrast to the three-step WHO ladder, the second step now c onsists of adding a strong opioid to non-opioid therapy for moderate to severe pain. Other CPGs have also been published. In 2012, an updated practice guideline was published b y the American Society of Anesthesiologists for acute pain management in the perioperative setting (American Society of Anesthesiologists, 2012 ). While not specifi c to children, th is document includes general recommen- dations for assessing, preventing, and treating pain in pediatric patients. Th e National Comprehensive Cancer Network (NCCN) has also publishe d guidelines for the treatment of pediatric cancer pain in the past, most recently in 2007 (National Comprehensive Cancer Network, 2007 ). While the recommendations in this CPG are p rimarily based on lower-level evidence, including consensus, the authors recommend that tre atment be titrated to pain intensity and the patient \200\231s clinical condition, refl ect ing the understanding that pain aff ects and is aff ected by many other dimensions of the p ain experience besides just intensity. Th e Association of Pediatric Anesthetists of Great Britain and Ireland published the second edition of Good Practice in Postoperative and Proc edural Pain Management in 2012. Th is document is useful not only because it provides recom mendations by age (i.e. procedural pain in the neonate versus older children), it also addr esses assessment system- atically, using explicit criteria for the evaluation of evidence. Th us, while pain intensity is clearly important, other issues, such as dis- tress, consola bility, and parental report are also discussed. Underlying these CPGs, there is also a small group of clinical trials that assess opioid us e perioperatively or in specifi c painful conditions. Using the strategy [(child* OR pediat ric OR paedi- atric) AND outcome AND opioid AND pain], 207 articles pub- lished between 200 7 to 2012 were identifi ed. Of these, 30 papers remained aft er a review of the titles and abstracts. One paper assessed the use of all opioids in US emergency departments for any di agnosis (Pletcher et al., 2008 ). Several papers were reviews: one of opioid pharmacogenomi cs in the perioperative setting, one of analgesia in neonates (Allegaert et al., 2009 ), an d one of the pharmacotherapy for acute pain in children (Mak et al., 2011 ). Additionally, one paper was a systematic review of the eff ect of a continuous infusion with IV patient-c ontrolled analgesia on res- piratory depression, and one was a report from a Food and Drug Administration workshop on the design of pediatric analgesic clinical trials (Berde et al., 2012 ). Th e 2012 WHO guidelines on the pharmacological treatment of persisting pain in children wi th medical illnesses is important for three main contributions (World Health Organization, 2012 ). When considered as a group, the outcomes assessed in these papers typically emphasized pain relief, whether a drug or route of administration was used, or an adverse event occurred, rather than the result of care for the patient. For example, outcomes reported included the occurrence of adverse events (Ou et al., 2008 ), whether opioids were used in children wit h abdominal pain who presented to an emergency department (Goldman et al., 2008 ), the use of patient-controlled analgesia in children at the end of life (Schiessl et al., 2008 ), an d the use of ketamine as a way to decrease morphine use in children who underwent tonsillec tomy (Abu-Shahwan, 2008 ). In one trial, changes in pain intensity were compared between ch ildren who received ibuprofen and those who received acetaminophen with codeine for extremi ty injuries (Friday et al., 2009 ). Other outcomes studied included quality of sleep, play and level of activity, eating, speech, and cry (Ruggiero et al., 2013 ), assessment of pain compared to hospital standards (Vijenthira et al., 2012 ), and emergence delirium, emesis, hypox- aemia, and the need for airway intervention in a group of chil- dren who underwent bilateral myringotomy and placement of ventilating tubes (Hippard et al., 2012 ). Notably, in this last paper, although administering drugs by intramuscular injection is not recommen ded due to pain and unpredictable absorption from tissue, the authors of this study conclud ed that the intramuscu- lar route would be preferred due to the lack of a diff erence in th e effi cacy of intranasal fentanyl, intramuscular, or intravenous mor- phine, and the utili ty from the clinician \200\231s perspective of avoiding having to establish vascular access and the potential for laryngos- pasm from intranasal medications. First, this guideline focuses on chronic pain and excludes pain due to trauma, surgery, or invasive procedures, although the rec- ommendations are likely to apply to other patient po pulations, in other settings, and with other types and sources of pain. It also includes st rength of recommendation and quality of evidence rat- ings. For example, one such guideline is that \200\230the use of strong opio- ids is recommended for the relief of moderate to severe persisting pain in children with medical illnesses \200\231 (recommendation 4, World Health Organization, 2012 ). Although this statement is rated as a strong recommendation, the quality of evidence supporting this suggestion is low. Notably, it is unlikely that the strength of evi- dence for this and similar statements will be addressed. In order to stre ngthen the quality of evidence, it would be necessary to conduct well-designed clinical and epidemiological research to compare the ability of strong opioids to other drugs and non-p harmacological approaches to treat moderate to severe pain in medically ill chil- dren with persisting pain \200\224an eff ort that would bring up questions of appropriate and ethica l resource use. 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 ).