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 6 \200\22312 years of age 40 \200\223150 mg >12 years of age 50 \200\223400 mg Senna, by mouth 10 \200\22320 mg/kg/dose 1 \200\2232 times a day Bisacodyl tablets, by mouth 5 \200\22310 mg (must be able to swallow a tablet whole) Suppository, rectally 5 mg (<2 years of age), 10 mg (>2 years of age) Magnesium citrate, by mouth: <6 years of age 2 \200\2234 ml/kg a day (in single or divided doses) 6 \200\22312 years of age 100 \200\223150 ml once a day 12 years of age or older 150 \200\223300 ml by mouth once a day Magnesium hydroxide, by mouth: <2 years of age 0.5 ml once a day 2 \200\2235 years of age 5 \200\22315 ml once a day 6 \200\22312 years of age 5 \200\22330 ml once a day 12 years of age or older 30 \200\22360 ml once a day Mineral oil: 5 \200\22311 years of age, by mouth 5 \200\22315 ml once a day 12 years of age or older, by mouth 15 \200\22345 ml once a day 2 \200\22311 years of age, rectally 30 \200\22360 ml 12 years of age or older, rectally 60 \200\223150 ml retention enema Glycerin: under 6 years of age, rectal or enema 1 infant suppository, one or two times, or 2 \200\2235 ml as an enema 6 years of age or older, rectal or enema 1 adult suppository, one or two times, or 5 \200\22315 ml as an enema Lactulose, by mouth 7.5 ml once a day after breakfast Polyethylene glycol, by mouth (in 4 \200\2238 ounces of \202 uid) 8.5 \200\22317 grams (0.5 \200\2231 capful or packet) one to three times a day (Continued) CHAPTER 45 opioids in clinical practice 467 Table 45.6 (Continued) Side e \200 ect and drugs Neonates Infants Children Adolescents Polyethylene glycol \200\223electrolyte solution, by mouth 25 \200\22340 ml/kg/h until constipation is relieved Methylnaltrexone, b subcutaneously or enterally 0.15 mg/kg once every other day to every day Naloxone, by mouth a 2 \200\22312 mg three times a day Prevention of constipation should be with a stool softener/laxative combination, such as se nna with docusate. a Naloxone and nalbuphine must be titrated carefully to avoid reversing opioid analgesia and precipitating withdrawal symptoms. b Methylnaltrexone dosing is based on a case report of one 4-year-old patient with epidemolysis bullosa (Lee and Mooney, 2012 ; Facts & Comparisons). Safety and e \203 cacy have not been evaluated for labeling purpos es in children. Th e dose of 0.15 mg/kg is the usual adult dose for persons weighing less t han 38 kg. For adults who weigh 38 \200\223less than 62 kg, the dose is 8 mg, and for perso ns who weigh 62 \200\223114 kg, the dose is 12 mg. Source: data from Lexicomp and Facts & Comparisons , Copyright Wolters Kluwer Heal th, Inc.; Johns Hopkins Hospital, Kristin Arcara and Megan T Schudy, Th e Harriet Lane Hand book , 19th Edition, Mosby, Inc., an a \203 liate of Elsevier Inc., Copyright 2012; Bru ce P. Himelstein et al., Pediatric Palliative Care, New England Journal of Medicine , Volum e 350, Number 17, pp. 1752 \200\2231763, Copyright 2004 Massachusetts Medical Society an d NCCN 2007 Pediatric Cancer Pain (pp. 23, PEDP-E 2 of 3, 3 of 3). who have limited respiratory function, or conditions like asthma. Tolerance to this eff ect generally happens reasonably quickly. time supported neither a class eff ect of the opioid antagonists, nor was there evidence of superiority of one drug over another (McNicol et al., 2008 ). Similarly, they found that n either safety nor effi cacy of naloxone or nalbuphine was supported for use in patients wit h postoperative ileus or opioid-induced constipation. Sedation is a more useful measure of the risk of respiratory depression than respiratory ra te alone, since sedation occurs before the person \200\231s breathing is depressed. A varie ty of sedation scales are used in clinical practice; these typically include a measure of h ow sedated the person is, as well as how easily the person is aroused. Th e level of sedati on may be useful, along with the trend. Treatment for respiratory depression focuses on use of naloxone and, if needed, oxygen. If naloxone is used, however, it should be given slowl y to avoid antagonizing analgesia. Additionally, since the half-life of naloxone is short, the dose will likely need to be repeated (Yaksh and Wallace, 2011 ). Hyperalgesia Hyperalgesia refers to an increased response to a painful stimulus at either a normal or increased threshold (IASP 2011 ). In contrast, the term opioid-induced hyperalge sia (OIH) is broadly defi ned as patients becoming more sensitive to pain due specifi cally to the use of opioids (Compton et al., 2001 ; Mao, 2008 ; McNicol, 2007 ; Werner, 2012 ). Th ere are signifi cant gaps in understanding the mechanisms underlying OIH, as well as the clinical relevance of this phenomenon (Chapman et al., 2010 ; Werner, 2012 ). Constipation Although constipation is common in persons who are treated with opioids, toler ance to this eff ect develops only slowly, if at all. As a result, prophylactic use of laxa tives \200\224typically a stimulant such as senna with a stool soft ener \200\224is conside red fi rst-line therapy. In practice, however, as well as in persons at the end of life, ei ther no treatment or prevention, or use of only a stool soft ener remains relatively common . In one study of pediatric and adult hospice patients, for example, approximately 26% of p ersons were not pre- scribed any laxatives, and 4% were prescribed only a stool soft ener ( Strassels et al., 2010 ). Th e problem with using just a stool soft ener is that it doesn \200\231t address the decreased gastrointestinal motion that occurs with opioid use. Additi onally, as gastrointestinal transit time is increased, there is more time for water to be a bsorbed, in addi- tion to drying eff ects of the opioids. Other options include drugs such as methylnaltrexone, alvimopan, nalbuphine, and naloxone. Alvimopan and methylnaltrexone ar e peripheral mu-opioid recep- tor antagonists. Th e concept underlying these drugs is that antago- nism of peripheral opioid receptors is useful to treat opioid-induced side eff ects , like constipation, without aff ecting centrally-mediated analgesia. Although no English-l anguage reports of the use of alvi- mopan in children with opioid-induced constipation have been published in PubMed-indexed journals as of this writing (January 2013), two case repo rts of the use of methylnaltrexone in children with opioid-induced constipation have been p ublished (Kissling et al., 2012 ; Lee and Mooney, 2012 ) In each of these reports, 0.15 mg/ kg was used. It is worth noting that, in a 2008 Cochrane review conducted on the use of mu- opioid antagonists for opioid-induced bowel dysfunction, the authors concluded that the evi dence at the Th e pathophysiology of OIH is incompletely understood, and it remains important to emphasi ze that decreased analgesia from opioids may refl ect hyperalgesia, tolerance, worsening di sease, or a combination of these phenomena which remains a puzzle that has not yet been sol ved (Ballantyne and Shin, 2008 ). Having said that, the science underlying increases in pain sen- sitivity is growing rapidly . Specifi cally, hyperalgesia appears to occur in a wide variety of clinical settings and p atient populations, including persons on maintenance opioid use and in withdrawal of opioid , as well as persons receiving methadone for opioid main- tenance and surgical patients (An gst and Clark, 2006 ). Th ere also appears to be variation in the type of increased painful response to diff erent stimulation. For example, in persons being maintained on methadone, hyperalgesia was found to occur to cold, but to a lesser degree for electrical stimuli and not to mechanical pain. In persons who underwent surgery, the development of hyperalgesia appeared to be associated with receiving higher opioid doses, although this fi nding has no t been consistent, nor is it necessarily easy to separate hyperalgesia from tolerance. Remifentanil, a potent opioid that is used primarily in surgi- cal settings, is known to pr oduce a post-infusion hyperalgesia. In a recent study of ten patients, persons who received remifentanil and propranolol did not experience mechanical hyperalgesia, while individuals who received remifentanil and placebo did have hyper- algesia (Chu et al., 2012a ). Althou gh the sample size for this study was very small, these authors concluded that propranolol may be useful to prevent hyperalgesia in persons treated with opioids. SECTION 6 pharmacological interventions 468 In a separate publication, in a study of adults with chronic non- radicular low back pain w ho used sustained-release morphine, these authors have also demonstrated that tolerance can occur independently from OIH (Chu et al., 2012b ). the number of these events was greater than that of motor vehi- cle deaths and larger than deaths attributed to cocaine and heroin overdoses. (Alexander et al., 2012 ; Centers for Di sease Control and Prevention, 2011 ). While these data do not tell us important infor- mati on such as where the drugs were obtained, whether the over- dose was intentional or acciden tal, and if the event was due to use of one drug or multiple medications, it is clear that there is a serious problem. As a result, there are a variety of eff orts underway to bet- t er educate healthcare providers, and to monitor use of controlled medications. Another recent study provides some insight into the molecu- lar link between increased pain and opioids. In the OPRM1 gene (which codes for the mu opioid receptor) higher levels of D NA methylation was associated with chronic opioid use in former opioid addicts being treate d with methadone as replacement com- pared with matched healthy controls, (Doehring et al., 2013 ; Stone and Szyf, 2013 ). Although this change was not associated with cod- ing for t he mu opioid receptor, it was associated with increased chronic pain. Prescription monitoring programs (PMP) As of October, 2012, 41 US states have an operationa l PMP in place and an additional ten (including the District of Columbia and Guam) have ena cted legislation, but the program has not yet begun operating (Alliance of States with Pres cription Monitoring Programs, 2012 ). Th ese programs generally collect informa- tion about the patient, the drug and amount being prescribed, the date the prescription was written a nd the date it was fi lled, and the drugstore that fi lled the prescription. States diff er in terms of what data are collected, what time lag between fi lling the prescription and s ubmitting the information is allowed, and who is respon- sible for maintaining the dataset (In Texas, it is the Department of Public Safety, in other states, the Board of Drugstore o r other groups are responsible.) Yet, despite the prevalence of PMPs, it remains unclear ho w to best use this information to achieve opti- mally safe and eff ective pain management. Here are a few chal- lenges and opportunities that remain for healthcare providers and heal th policy decision-makers before the promise of these data can be fully realized. Risk factors for development of OIH are not yet well understood. In the 2010 research guide line on future research pertaining to the use of opioids for chronic non-cancer pain, the a uthors note that several critical topics have yet to be addressed, including the epide- mio logy of OIH, the likelihood of developing OIH as a function of clinical and demographic cha racteristics, the interaction between hyperalgesia and acute pain, and, notably, dose and d uration of therapy. While facets of a patient \200\231s clinical presentation such as dose, duration of therapy, and quantitative sensory testing may be helpful to identify patients at increased risk for altered pain sensi- tivity, these factors are neither sensitive nor s pecifi c. Treatment regimens for suspected OIH generally include options such as dose increase (to ru le out tolerance), dose decrease, add- ing (or changing to) drugs that are antagonists at t he N-methyl D-aspartate receptor (ketamine and methadone, respectively), clonidine, and dex medetomidine. Buprenorphine may be useful, and multimodal analgesia also has potential, as a function of the opioid-sparing eff ect of these regimens. Th ere are not many studies of treatment for hyperalgesia in children, thus dosing information is similarly limited. Much of the PMP-related literature and discussions focus on drug abuse, oft en using prescr iber- or drugstore-shopping as markers of inappropriate use of controlled substances. Yet, we don \200\231t know the right number of prescribers or pharmacies, the right time period to consider, or whether there is even a right number. For example, in a literature search o f \200\230prescription monitoring program \200\231 AND \200\230opioid \200\231, time inte rvals used to defi ne either doctor- or drugstore shopping included zero (concurrent use of opioids or controlled substances from diff erent prescribers; Ives et al., 2006 ), 6 month s (Pradel et al., 2009 ), 30 days (prescription for the same medica- tion from at least two practitioners fi lled by at least two pharmacies; Gilson et al., 2012 ; Wilsey et al., 201 0 ), and 1 year (Baehren et al., 2010 ; Hall et al., 2008 ; Wilsey et al., 2011 ), although one consensus statement published in 2004 defi ned use of multiple prescribers as at least six prescribers over a 1-year period (Parente et al., 2004 ). In a recent analysis, Wilsey and colleagues used California PMP data to assess diff erences between people who used onl y one prescriber compared to individuals who used two to fi ve prescribers over a 1-year pe riod (Wilsey et al., 2010 ). Th ese investigators found that people who used two to fi ve p rescribers were not diff erent in terms of male sex, younger age, or location in larger geo graphic areas \200\224 factors thought to be associated with drug abuse. In one case report of suspected OIH in a medically complex infant with gastroschisis, morph ine and fentanyl were used for postoperative pain initially. In the face of increasing pain and irrita- bility, a variety of pharmacological approaches were tried with suc- cess aft er 46 days, including addition of IV clonidine at 0.33 \200\2230.45 mcg/kg/h, switching the opioid to hydromorphone, introduction of IV ketamine at 0.1 mg/kg/h, and IV dexmedetomidin e at 0.7 mcg/ kg/h in place of clonidine (Hallett and Chalkiadis, 2012 ). Use of dexmedetom idine (dose range 0.2 \200\2230.7 mcg/kg/h) in a case series of 11 patients, including a 9- year-old male and two adolescents, has also been reported (Belgrade and Hall, 2010 ). More than half of the individuals reported in this series experienced substantial decreases in t heir opioid requirements aft er use of dexmedetomidine, none had clinically signifi cant wi thdrawal symptoms, and pain intensity was stable or decreased for most patients. E \200 orts to improve safe access to opioids Th ere is ample evidence in the biomedical l iterature document- ing the need for improved care for people with pain. At the same time, there is signifi cant concern about the potential for opioids to be misused, abused, or div erted, resulting in adverse events and deaths. In 2011, the US Centers for Disease Control and Prevention estimated that the rate of deaths related to prescription analgesic overdose had increased by more than threefold since 1990, that To make things more complex, the allure of considering data in isolation is powerful, even though looking at a broader picture oft en provides insight that a simple view cannot. As H . L. Mencken ( 1917 ) said, \200\230Th ere is always an easy solution to every human prob- lem \200\224neat, plausible, and wrong \200\231. One example of this idea is that the peri od of time in which the prescriptions were fi lled may help CHAPTER 45 opioids in clinical practice 469 explain the observed numbers of prescribers and pharmacies. Th e longer that period, the mo re likely it is that multiple explanations for a patient \200\231s behavior are important i n understanding their med- ication use. and prevalence trajectories, and use of geospatial tools to better understand access issues . PMP data are also useful to better under- stand and improve the safety of opioid use, whe ther these drugs are used alone or in combination with other analgesics. Last, it may be po ssible to link these data to other population-level resources to better understand the resu lts and consequences of using pain man- agement resources, including unintended consequence s of public policy. Along these lines, it is worth looking beyond the absolute number of prescribers and pharma cies from multiple prescribers or pharmacies to ask why people might get prescriptions, asi de from potential abuse, misuse, or diversion. A single medical prac- tice may include seve ral people writing prescriptions, individuals may see other prescribers when their usual ca regiver is not avail- able, and people who are medically complex may have good rea- sons fo r obtaining controlled substances from multiple prescribers. Similarly, there may be import ant diff erences between groups of people who use prescription opioids non-medically, but f or pain only as opposed to persons who obtain these drugs for nonmedi- cal and non-pain use (Zacny and Lichtor, 2008 ). Th e count of pharmacies is also suspect. People may choose to go to diff erent pharmacies for any number of reasons, and this is not necessarily a probl em. It is common for pharmacies to off er fi nancial incen- tives to people who transfer pr escriptions, convenience of loca- tion is oft en important, and pharmacies don \200\231t al ways carry (or can \200\231t get) the specifi c medication the patient is looking for in th e needed timeframe. Despite the potential to limit legitimate access to pain management ser vices, in November 2011, the drugstore chain CVS/Caremark ( 2011 ) announced a new policy t o refuse to fi ll prescriptions for Schedule II controlled medications from some prescriber s in Florida. Pharmacies \200\231 decisions to not carry certain medications or blanket ref usals to fi ll prescriptions are likely to result in unnecessary suff ering among the vast majority of pain patients who use their medications appropriately and to increase the barri ers to needed health care these people must face. PMPs and other data collection eff orts are used elsewhere as well. While systems that are used to collect information about prescribed drugs are common in many countries, allowing s urveillance of opioid prescribing and dispensing, the literature on this topic pub- lished in the last 5 years pertains primarily to Australia, Canada, and France. In one examples of PMP use in New South Wales, Australia, with other large datasets to esta blish drug source and reason for use, the mortality associated with overdoses of methadone or buprenor- phine was estimated (Bell et al., 2009 ). In this analysis, investigators foun d that approximately fi ve times as many people were treated with methadone than with bupre norphine for opioid dependence. Of the individuals who died, 60 were on methadone and seven were using buprenorphine. Half of the methadone patients and none of the buprenorphine pat ients who died were in treatment. Th e authors concluded that the risk of overdose death wa s lower in buprenorphine patients than in methadone patients, although the confi dence inte rval for the relative rate was wide (relative risk 4.25, 95% confi dence interval 1.03 \200 \22317.54). Th e authors also noted that use of more than one drug was common among the per sons treated with methadone, particularly of heroin, benzodiazepine, and antidepressants. Among the analyzes exploring opioid use in Canada, one study found that interprovincial dis parities in the numbers and types of opioids prescribed were common during 2005 to 2010 (Fi scher et al., 2011 ). Th e authors also found that increases in the use of strong opioids w as an important driver of this result, although this paper focused on the drug dispensing a nd not specifi c outcomes as a result of dispensing. Data quality is another issue that needs close attention (Strassels, 2012 ). Th e informati on that comes out of PMPs is only as good as the data that are put in. Th ese data are gene rally input at busy pharmacies, patient names and birthdates may be the same, and prescribe rs oft en have multiple offi ces. Data may also be miss- ing, misspelled, or otherwise inco rrect. Furthermore, as a result, interpretation of these data may be challenging, and presc ribers and pharmacists must not jump to conclusions and inadvertently contribute to diffi c ulties in access to appropriate pain management services. Building on these results, an analysis was carried out to estimate the relation between use of prescription opioids and mortality in British Columbia and Ontario from 2005 to 2009 (F ischer et al., 2013 ). Th ese authors found strong correlations between the use of fentanyl , hydromorphone, morphine, and oxycodone and drug-re- lated mortality, although they also n oted that non-retail dispensing was not included here, nor were they able to assess concomi tant use of drugs that may have contributed to death, such as non-opioid medications or alc ohol. Assessment and identifi cation of prescription drug abuse or mis- use in pediatric populati ons presents challenges in addition to those that apply to adults. For example, while many discussions of PMPs and prescription drug abuse, misuse, and diversion focus on opioids, we must recognize that these drugs and prescribing rates do not tell the whole story. Individ uals being treated for chronic pain are oft en on multiple psychoactive medications, such a s mus- cle relaxants, benzodiazepines, and antidepressants, and that these combinations may have their own problems. For example, in a 2006 editorial on whether being on chronic opio id therapy should be a contraindication to driving, Zacny ( 2006 ) counsels caution, since we don \200\231t know to what extent diff erent combinations of drugs result in what outcom es. In France, analyzes were conducted to estimate the diversion of opioids relative to benzodi azepines and to quantify the eff ect of a PMP on doctor-shopping for high-dose buprenorphin e ther- apy from 2000 to 2004. In the fi rst paper, the authors found that, although benzod iazepines were dispensed more frequently than opioids, abuse, and diversion were observed m ainly in association with opioid maintenance therapy, morphine, and benzodiazepines, and le ss so to non-morphine opioids (Pauly et al., 2012 ). In the second analyzes, the authors es timated that, from 2004 to 2005, the prescription drug database contributed to a decrease i n doc- tor-shopping, without adversely aff ecting the number of patients treated or the tot al prescribed doses (Pradel et al., 2009 ). Although much of the discussion surrounding PMPs emphasizes their use as tools for drug enf orcement, they can also be used to bet- ter understand patient outcomes, including estimati ng the present and future needs for pain management services based on incidence SECTION 6 pharmacological interventions 470 Baehren , D. F. , Marco , C. A. , Droz , D. E. , Sinha , S. , Callan , E. M. , and Akpunonu , P ( 2010 ). A statewide prescription monitoring program aff ects emergency department pr escribing behaviors . Ann Emerg Med , 56 , 19 \200\22323. Case example Jackson is a 13-year-old, 50 kg boy with sickle cell disease. He usually manages his pain a t home with oxycodone 5 mg as needed. He has not been hospitalized in 2 years. Over the las t 2 days Jackson has had persistent pain in his abdomen and legs which has not improved des pite taking oxycodone every 3 to 4 h. His mother brings him to the emergency department. Ballantyne , J. C. , and Shin , N. S. ( 2008 ). Effi cacy of opioids for chronic pain: a review of the evidence . Clin J Pain , 24 (6), 469 \200\223478. Benet , L. Z. ( 1984 ). Pharmacokinetics: basic principles and its use as a tool in drug me tabolism . In J. R. Mitchell , and M. G. Horning (eds) Drug metabolism and drug toxicity , pp. 199 \200\223211. New York : Raven Press . Belgrade , M. and Hall , S. ( 2010 ). Dexmed etomidine infusion for the management of opioid-induced hyperalgesia . Pain Med , 11 , 1819 \200\2231826. Bell , J. R. , Butler , B. , Lawrance , A. , Batey , R. , and Salmelainen , P. ( 2009 ). Comparing overdose mortality associated with methadone and buprenorphine trea tment . Drug Alcohol Depend , 104 (1 \200\2232), 73 \200\22377. Berde , C. B. , Walco , G. A. , Krane , E. J. , Anand , K. J. , Aranda , J. V. , Craig , K. D. , et al . ( 2012 ). Pe diatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA sci entifi c workshop . Pediatrics , 129 (2), 354 \200\223364. At triage in the emergency department Jackson reports his pain score as 10 out of 10 on a v isual analog scale. He is given fentanyl 50 mcg intranasally and brought immediately back t o a patient care room. He is then evaluated by the physician and 30 min aft er the fen- tanyl his pain score is a 9. An IV line is started and he is given 5 mg of morphine IV as well as 30 mg of ketorolac and IV fl uids. His pain score remains a 9 and 40 min later he is given another 5 mg dose o f morphine. Th is does not result in improvement and he is transferred to the inpatient uni t. Borland , M. , Milson , S. , and Esson , A. ( 2011 ). Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a pediatri c emergency department: a randomized controlled trial . Emerg Med Australas , 23 (2), 202 \200\223208. Birmingham , P. K. , Tobin , M. J. , Henthorn , T. K. , Fisher , D. M. , Berke lhammer , M. C. , Smith , F. A. , et al . ( 1997 ). Twenty-four-hour pharmacokinetics of re ctal acetaminophen in children. An old drug with new recommendations . Anesthesiology , 87 , 244 \200\223252. On the inpatient fl oor he reports a pain score of 9. He also complains of itching and requ ests that he be switched to hydro- morphone as that did not cause him as much itching durin g his last hospitalization. He is placed on a hydromorphone via patient-controlled anal- gesia with a 0.2 mg per hour c ontinuous infusion and a 0.1 mg bolus every 6 min as needed. He is also placed on IV fl uid s and senna. He is encouraged to use an incentive spirometer. Briggs , G. C. , Freeman , R. K. , and Yaff e , S. J ( 2008 ). Drugs in pregnancy and lacta tion: a reference guide to fetal and neonatal risk (8th edn). Philadelphia, PA : Lippincott Williams & Wilkins . Centers for Disease Control and Prevention . ( 2011 ). Policy impact: prescription painkill er overdoses . Available at: < http://www.cdc.gov/ homeandrecreationalsafety/rxbrief/ > (ac cessed 16 January 2013). Over the next 24 h Jackson continues to have severe pain. His continuous infusion is increased to 0.3 mg per hour. By day 3 of hospitalization he reports his pain is now a 5. On this day his continuous infu sion is stopped and he is placed on extended release oxycodone (10 mg every 12 h). He remai ns on a bolus only PCA for 24 more hours and then this is discontinued. He is sent home on the extended release oxycodone as well as 5 mg of immediate-release oxycodone to be used as needed. He is told to remain on the senna as long as he is taking the oxycodone. A follow- up appointment is made for 5 days aft er discharge. Chapman , C. R. , Lipschitz , D. L. , Angst , M. S. , Chou , R. , Denisco , R. C. , Donalds on , G. W. , et al . ( 2010 ). Opioid pharmacotherapy for chronic non-cancer pain in the Un ited States: a research guideline for developing an evidence-base . J Pain , 11 (9), 807 \200\223829. Chorney , J. M. , McGrath , P. , and Finley , G. A. ( 2010 ). Pain as the neglected adverse event . CMAJ , 182 (7), 732 . Chou , R. , Fanciullo , G. J. , Fine , P. G. , Adler , J. A. , Ballantyne , J. C. , Davies , P. , et al . ( 2009 a). Clinical guidelines for the use of chronic opioid therapy in chro nic noncancer pain . J Pain , 10 (2), 113 \200\223130. Chou , R. , Ballantyne , J. C. , Fanciullo , G. J. , Fine , P. G. , and Miaskowski , C. ( 2 009 b). 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