Pediatric Acute Pain Management

Anesthesiology Clin N Am 23 (2005) 789 – 814

Pediatric Acute Pain Management Robert P. Brislin, DOa,b,T, John B. Rose, MDa,b a

Department of Anesthesiology and Critical Care Medicine, and Pain Management Service, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA 19104-4399, USA b University of Pennsylvania School of Medicine, 295 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6055, USA

Children who undergo surgical procedures today may benefit from the many discoveries and improvements in pediatric pain management that have occurred over the past few decades. Changes in the attitudes of physicians, nurses, patients, families, and hospital administrators, along with increased political pressure from external regulatory agencies, also have spurred advancements in treating children’s pain. There is no longer any debate approximately whether infants and children have the capacity to feel pain or that the experience of pain by a child can have negative short- and long-term consequences. In fact, there is increasing evidence of biologic and behavioral consequences of improperly treated pain. Advances in developmental neurobiology and pharmacology are continuing to improve the available methods of both assessing and managing pediatric pain. Across the United States and around the world, formalized pediatric pain services have been established in larger centers. The Joint Commission on Accreditation of Health Care Organizations (JCAHO) mandate to assess and treat pain in all patients has added further impetus to this evolution in pain management for children. In addition, the pressure and incentives from the federal government have been put in place to encourage the inclusion of children in drug development studies. This review discusses selected topics in pediatric acute pain management, more specifically, acute postoperative pain management.

T Corresponding author. Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA 19104-4399. E-mail address: [email protected] (R.P. Brislin). 0889-8537/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.atc.2005.07.002 anesthesiology.theclinics.com

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Developmental neurobiology Neonates clearly perceive pain, as demonstrated by their integrated behavioral and physiologic responses to nociceptive stimulation [1,2]. In fact, pain in neonates may be accentuated because descending inhibitory pathways to the dorsal horn of the spinal cord (the relay destination of afferent nociceptive input from the periphery to higher centers in the central nervous system) are not developed at birth. Furthermore, dorsal horn neurons in neonates have wider receptive fields and lower excitatory thresholds than those in older children [1–3]. Repeated painful stimuli, such as heel lancing and intravenous (IV) placement, further lower the excitatory thresholds of dorsal horn neurons [3]. Although the neural transmission in peripheral nerves is slower in neonates because myelination is incomplete at birth, the major nociceptive neurons in neonates as well as in adults are either unmyelinated C fibers or thinly myelinated A delta fibers [4]. Repeated stimuli of these nociceptive fibers cause decreased excitatory thresholds resulting in peripheral sensitization. Hyperalgesia is the increased response to a noxious stimulus because of peripheral sensitization. Allodynia is another consequence of peripheral sensitization in which nonnociceptive fibers transmit noxious stimuli that result in the sensation of pain from non-noxious stimuli. In addition, repeated nociceptive input to the dorsal horn of the spinal cord causes the amplification of pain intensity and duration, which is termed ‘‘wind-up’’ or ‘‘central sensitization.’’ [3]. Although pain transmission may be somewhat slower in neonates, nociceptive input to the central nervous system (CNS) does indeed occur. Untreated pain in neonates can lead to amplified physiologic or behavioral responses to future noxious events [2,5,6]. Investigators continue work in developmental neurobiology, with much emphasis on pain transmission and neural plasticity in the developing dorsal horn of the spinal cord and the implications of painful events in infancy on nociceptive pathways [2,7].

Developmental pharmacology Despite the lack of formal drug studies in children compared with adults, there is a growing body of experience with the use of analgesic medications in children, based on pediatric pharmacologic and physiologic principles [8,9]. Most analgesics are lipophilic substances and require transformation into water-soluble substances to enable the body to excrete the substances in the form of urine or bile. Pharmacokinetic differences in children are significant and have implications for the dosage and intervals of analgesic medications. For example, body composition affects the volume of distribution of drugs. The higher body water content in neonates and infants results in a larger volume of distribution of water-soluble drugs and the potential for the longer duration of action of the drug. Smaller fat and muscle stores in neonates result in higher plasma concentrations of drugs because there is less drug uptake by these phar-

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macodynamically inactive sites. With a higher percentage of cardiac output going to the brain in neonates, the brain concentration of drugs may be higher in neonates than in older children and adults. Some authorities believe that an immature blood-brain barrier in neonates may further facilitate drug delivery to this pharmacologically active site. Protein binding of drugs is reduced in neonates compared with older children and adults because of lower plasma levels of albumin and a1-acid glycoprotein. Drugs that are highly protein bound, such as opioids and local anesthetics, will be present in a higher unbound concentration in plasma, leading to an increased drug effect or toxicity [8,10]. Hepatic metabolism of drugs involves either phase 1 reactions (oxidation, reduction, hydroxylation, and hydrolysis) or phase 2 reactions (conjugation processes). The cytochrome P-450 system is the most important phase 1 enzyme family and is responsible for the metabolism of many analgesics, including NSAIDs and opioids. At birth, the hepatic enzymes responsible for drug metabolism are immature, resulting in a reduced clearance of drugs. The levels of these hepatic enzymes quickly increase to adult levels in the first few months of life. Drug clearance in the 2- to 6-year-old age group is actually higher than adult levels because of the larger hepatic mass relative to body weight [11]. During these years, higher doses and shorter intervals of analgesics may be required. Pathophysiologic conditions that affect hepatic blood flow or function will obviously affect drug metabolism and require adjustment of analgesic dosing. The renal excretion of drugs depends on renal blood flow, glomerular filtration rate, and tubular secretory function, all of which are decreased in neonates, especially premature neonates. Renal function reaches adult levels by 1 year of age. With decreased renal function, parent compounds or active drug metabolites can accumulate to toxic levels. The morphine-6-glucuronide metabolite of morphine is an example. As with altered drug metabolism, in the presence of decreased renal function, drug dosages and intervals must be adjusted accordingly [8,10].

Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are used for the management of mild to moderate pain. They are used alone or in combination with opioids. Their advantage is that they do not cause respiratory depression or sedation. Their mechanism of action is through the inhibition of cyclooxygenase (COX), the enzyme responsible for metabolizing arachidonic acid [10,12]. When arachidonic acid is released from traumatized cell membranes, it is metabolized by COX to form prostaglandins and thromboxanes, which in turn sensitize peripheral nerve endings and vasodilate vessels, causing pain, erythema, and inflammation. There are two COX isoenzymes. The constitutive form of COX (COX-1) is present throughout the body, and the prostaglandins and thromboxanes that are produced are essential for functions such as gastric mucosa protection, renal blood flow regulation, and platelet aggregation. Potential

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complications of COX-1 inhibition include gastric ulceration, bleeding, altered renal function, and bronchoconstriction. COX-2 is called an ‘‘inducible COX’’ and is present only in traumatized cells or inflamed tissue. Most NSAIDs are nonselective COX inhibitors, but the potential attraction of selective COX-2 inhibition in the reduction of side effects is apparent. Selective COX-2 inhibitors have been used extensively in adults, and the COX-2 inhibitor rofecoxib has been studied in children [13]. Unfortunately, as of this writing, COX-2 inhibitors are under intense scrutiny because of increased cardiovascular morbidity in adults when the drugs are used for prolonged periods of time. Presently, the future of COX-2 inhibitors in children is uncertain. This is unfortunate because short-term therapy for acute postoperative pain in children may not be associated with an increased risk for cardiovascular complications. Acetylsalicylic acid (aspirin) is the oldest NSAID. Because of its association with Reye’s syndrome, aspirin is now used only rarely in pediatric patients suffering from rheumatologic conditions [14]. Ibuprofen and naproxen are the most common peripheral COX inhibitors used in pediatrics [12]. Ketorolac is the only parenteral NSAID available in the United States. Because it decreases platelet aggregation, ketorolac should not be used in children who are at risk for bleeding complications, nor should it be used for more than 5 days [10,15]. A concern in orthopedic surgery is that NSAIDs may interfere with osteoclast activity and prevent bone healing after osteotomies or spinal fusion [16]. Acetaminophen is the NSAID most widely used, both as an antipyretic as well as an analgesic. It is different from the other NSAIDs in that it does not inhibit peripheral COX. It lacks the troublesome side effects of other NSAIDs. Its effects are mediated by central COX inhibition. Acetaminophen can be given orally or rectally, although the initial rectal dose needs to be higher to achieve appropriate blood levels [17,18]. Careful attention to dosing is essential. Acetaminophen is metabolized in the liver primarily by glucuronidation and sulfation. In acetaminophen overdose, cytochrome P-450 oxidation is enhanced, producing the hepatotoxic metabolite N-acetyl-p-benzocinon-imine that can potentially cause hepatic necrosis, leading to fulminant hepatic failure (Table 1) [10,12].

Opioids Opioids are used for moderate to severe nociceptive pain, although they are sometimes used for neuropathic pain [10,19]. Opioids bind to pre- and postsynaptic cell membranes in the central nervous system through the specific opioid receptors, resulting in neuronal inhibition by decreasing excitatory neurotransmitter release from presynaptic terminals or by hyperpolarizing the postsynaptic neuron. Opioid receptors are classified as m, k, d, and s. The m receptor is further subdivided into subclasses m1, which mediates supraspinal analgesia and dependence, and m2, which mediates respiratory depression, intestinal dysmotility, sedation, and bradycardia. Most commonly used opioids work through m1-mediated analgesia. Opioids are classified as agonists, partial agonists, agonist-antagonists,

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pediatric acute pain management Table 1 NSAIDs Drug Aspirin

Preparation

Tabs: 81 mg, 325 mg Chewable tabs: 81 mg Acetaminophen Tabs: 325 mg, 500 mg Chewable tabs: 80 mg, 160 mg Elixir: 160 mg/5mL Drops: 80 mg/0.8 mL Suppositories: 80mg, 120 mg, 325mg, 650 mg Ibuprofen Tabs: 200mg, 400mg, 600 mg, 800 mg Chewable tabs: 50 mg, 100 mg Elixir: 100 mg/5mL Drops: 50 mg/1.25 mL Naproxen Tabs: 220 mg, 250 mg, 375 mg, 500 mg Elixir: 25 mg/mL Ketorolac Injectable: 15 mg/mL, 30 mg/mL

Dose

Interval

Maximum daily dose

PO: 10–15 mg/kg

4–6 h

90 mg/kg/d

PO: 10–15 mg/kg Rectal (single dose): 35–45 mg/kg Rectal (repeated dose): 20 mg/kg

PO: 4 h Rectal: 6 h Rectal (premature newborns): 12 h

PO: 6–10 mg/kg

4–6 h

Children: lesser of 100mg/kg/d or 4 g Infants: 75 mg/kg/d Newborns: (N 32 wks PCA): 60 mg/kg/d (28–32 PCA: 40 mg/kg/d Lesser of 40 mg/kg/d or 2.4 g

PO: 5–10 mg/kg

12 h

20 mg/kg/d

IV: 0.5 mg/kg

6h

Lesser of 2 mg/kg/d or 120 mg. Note: maximum 20 doses or 5 d

and antagonists [19,20]. Examples of the m1 agonists include morphine, hydromorphone, meperidine, methadone, fentanyl, sufentanil, remifentanil, codeine, oxycodone, and hydrocodone. Agonist-antagonist opioids, which are agonists at one receptor type and antagonists at another receptor, include nalbuphine and pentazocine. Analgesia by agonist-antagonists is mainly k- and s-mediated, with antagonism or partial agonism at the m receptor. A partial agonist such as buprenorphone exerts less than full response at a receptor site. Opioid antagonists include naloxone, naltrexone, and nalmefene. Side-effects common to opioid agonists include respiratory depression, sedation, nausea, vomiting, pruritus, urinary retention, ileus, and constipation. Less common effects are dysphoria, hallucinations, seizures, and myoclonic movements. There is significant individual variability in the side-effect profiles of the different opioid analgesics. In the presence of unacceptable side effects, switching to a different opioid may result in lessened side effects [21].

Morphine Morphine is the standard opioid with which all other opioids are compared [19]. It can be given through multiple routes (intravenous, oral, subcutaneous, intrathecal, epidural, and intra-articular). Morphine is metabolized in the liver to

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morphine-3- glucuronide (inactive) and morphine-6-glucuronide (active), which are both excreted by the kidneys. Generally, the elimination half-life is longer and the clearance is decreased in newborns compared with older children and adults. This difference is especially pronounced in preterm neonates. In addition, less morphine is protein bound in neonates, allowing a greater proportion of unbound morphine to penetrate the brain, thus increasing the risk for respiratory depression. The elimination half-life and clearance reach adult values within 2 months of age. The optimal plasma concentration of morphine needed to achieve analgesia in children is variable based on the existing data. Therefore, careful titration of morphine is required to obtain the desired level of analgesia while monitoring side effects [22–26].

Hydromorphone Hydromorphone is a synthetic derivative of morphine with a longer duration of action (4–6 hours) and elimination half-life (3–4 hours). It is approximately 10 times more lipophilic than morphine and five times more potent. It is often used as a second-line opioid to morphine and is being used more increasingly as a first-line choice. It is described as often having less associated nausea and pruritus than morphine [27,28].

Methadone Methadone is a synthetic opioid that is noted for its long elimination half-life and duration of action (12–36 hours). Traditionally used with opioid-dependent patients, methadone is being increasingly used in cases of acute pain to provide stable levels of opioid analgesia [10,19]. It has high bioavailability (80%), making it an attractive oral analgesic. The principle metabolite is morphine, which may explain its long duration of action. In addition to being a m agonist, methadone also is an N-methyl-d-aspartate (NMDA) receptor antagonist, resulting in incomplete cross-tolerance between methadone and morphine. As a result of this discovery, the recommended conversion ratio for morphine to methadone is now 1:0.1 rather than the 1:1 ratio used formerly. This must be considered when switching to methadone, or significant sedation and respiratory depression may result [29,30].

Fentanyl Fentanyl is a synthetic opioid that is 100 times more potent than morphine. It is highly lipophilic, resulting in significant brain penetration. Fentanyl has a

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short duration of action because of redistribution out of the plasma into body tissues. Once these sites are saturated, the elimination half-life is actually quite long (233 F 137 minutes in infants 3–12 months old; 244 F 79 minutes in children; and 129 F 42 minutes in adults) [10,31]. Fentanyl is highly protein bound to a1 acid glycoprotein in the plasma. Neonates have reduced levels of a1 acid glycoprotein, resulting in higher levels of free unbound fentanyl. Metabolism is through glucuronidation in the liver to inactive metabolites that are excreted by the kidney. Because of its potency, hemodynamic stability, and brief duration of action in small doses, fentanyl is an attractive analgesic for short painful procedures in children, especially in the intensive care unit setting [19]. Fentanyl can be given in multiple routes: intravenous, epidural, nasal, transmucosal, and transdermal. Given nasally in a dose of 2 mg/kg, fentanyl provides good analgesia in children who are undergoing myringotomy tube insertion [32]. Fentanyl is available in a candy matrix preparation for transmucosal administration. Transmucosal fentanyl has been used as a premedication for painful procedures, with an onset time of 20 minutes and a duration of 2 hours [33,34]. Transmucosal is more efficient than oral administration because it bypasses the hepatic first pass metabolism of the oral route, which reduces the availability of fentanyl by 25% to 33%. Transmucosal fentanyl provides good analgesia, but the incidence of nausea with this modality is troublesome. Transdermal fentanyl administration is available in patches of 12.5, 25, 50, 75, and 100 mg/h for use lasting 2 to 3 days. It has a long onset time but also a long duration that persists after the patch is removed. The fentanyl patch is not indicated for opioid-naRve patients because of the difficulty in quickly and safely titrating an effective dose [10,19].

Meperidine Meperidine is a synthetic opioid derived from phenylpiperidine. It has 0.10 the potency of morphine and is metabolized in the liver by hydrolysis and N-demethylation. It has an elimination half-life of approximately 3 hours. The metabolite normeperidine has the potential to cause seizures when meperidine is used for an extended period. Meperidine is being used less frequently as a first-line opioid analgesic in pediatric patients [10,19]. However, it is still used in single doses for postoperative shivering [35]. Meperidine should also not be used in conjunction with monoamine oxidase inhibitors or in patients with hyperthyroidism.

Codeine Codeine is a m agonist and a derivative of morphine. It is a commonly used oral opioid most often combined with acetaminophen in liquid or tablet form.

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Codeine is 0.10 as potent as morphine. Its bioavailability is 60% after oral administration, with an onset time of 20 minutes and an elimination half-life of 2.5 to 3 hours. Codeine is metabolized in the liver and then excreted in the urine [19,36]. Five to ten percent of codeine is metabolized by O-demethylation in the liver by a P-450 oxidase pathway (CYP2D6) to produce morphine. This conversion is necessary for analgesia to occur after codeine administration. Four to ten percent of the population lack the CYP2D6 enzyme responsible for this conversion and therefore derive no analgesic effect from codeine [37]. Because of the unpredictability of the analgesic effect and the significant incidence of nausea and vomiting associated with it, codeine is being used less as a first-line oral analgesic [10]. When the codeine and acetaminophen combination is used, care must be taken to stay within safe dosage ranges of acetaminophen.

Oxycodone and hydrocodone Oxycodone and hydrocodone are oral analgesics commonly combined with acetaminophen in tablet or liquid form. A new formulation of oxycodone combined with ibuprofen is now available. Oxycodone also is available alone in tablet or liquid form, although the liquid form may be difficult to obtain at pharmacies. Caution is advised when prescribing oxycodone liquid because it comes in 1 mg/mL and 20 mg/mL strengths. These analgesics are 10 times more potent than oral codeine. Their bioavailability is 60% after oral administration, with an onset time of 20 to 30 minutes and duration of 4 to 5 hours. They are metabolized in the liver. Oxycodone produces an active metabolite, oxymorphone, that can accumulate in renal failure [38]. Sustained release oxycodone is available for more prolonged analgesic needs, but negative publicity over its abuse has made it less desirable to parents [39]. Formulations of sustained release oral opioids that are more resistant to tampering are under development.

Nalbuphine Nalbuphine is a k agonist and a m antagonist. It has an analgesia equivalent to morphine up to a dose of approximately 200 mg/kg, at which point it has a ceiling effect of analgesia. k-mediated side effects of sedation, dysphoria, or euphoria are likely at higher doses. Nalbuphine is metabolized mainly in the liver and has a half-life of approximately 5 hours. It is usually given intravenously. When given orally, it has a bioavailability of only 20% to 25%. Nalbuphine is often used to antagonize m-mediated side effects from m agonist opioids, especially pruritus and respiratory depression [40]. Care is needed when using nalbuphine in opioid-dependent children in order not to induce opioid withdrawal.

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Naloxone Naloxone is an antagonist at all opioid receptors. It is used emergently for respiratory depression at a dosage of up to 10 mg/kg IV. It also is used in smaller doses for pruritus (1–2 mg/kg IV). Naloxone is metabolized in the liver and has an elimination half-life of 60 minutes [19]. Because this is a shorter half-life than the m agonists it is meant to counteract, continued monitoring of the patient is mandatory. Severe withdrawal can occur when naloxone is given to opioiddependent patients.

Tramadol Tramadol is an atypical opioid that is structurally related to codeine. Its dual mechanism of action involves both central inhibition of norepinephrine and serotonin reuptake and weak m receptor agonism by an active metabolite. Tramadol is 10 to 15 times less potent than morphine. It is known to have fewer side effects than other opioids. Seizures are a known but rare complication of tramadol. The use of tramadol should be avoided in patients known to have seizures or head trauma or who are taking medications that lower the seizure threshold. In general, tramadol is a safe and effective analgesic for mild to moderate pain in children [41]. The recommended dose of tramadol is 1 to 2 mg/kg (maximum 100 mg) every 6 hours, with a maximum daily dose of 8 mg/kg/d or 400 mg/d. Tramadol also is available in combination with acetaminophen.

Other analgesics: ketamine Ketamine is a phencyclidine derivative and a dissociative anesthetic. It is a potent analgesic in subanesthetic doses and is often used for short painful procedures in children in the emergency room and ICU settings [42,43]. It can be administered intravenously, orally, rectally, and intramuscularly. Because of increased secretions and possible dysphoric effects, ketamine is often combined with an anticholinergic agent and a benzodiazepine. Because of elevations of cerebral blood flow and oxygen consumption, ketamine is not recommended in children who have decreased intracranial compliance. The analgesic effects of ketamine are mediated by NMDA receptor antagonism and possibly m receptor agonism. Oral bioavailability is 20% to 25%. Ketamine is highly lipid soluble, with rapid redistribution. Ketamine is N-demethylated in the liver by the cytochrome P- 450 system [44]. Intravenous doses of 0.25 to 0.5 mg/kg can produce intense analgesia for 10 to 15 minutes, although the elimination half-life is 2 to 3 hours. A dose of 1 to 2 mg/kg IV may be needed for more painful procedures such as fracture reduction. There is increasing literature in adults on the intraoperative and postoperative use of ketamine as an adjunct to opioid analgesia [45].

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A2-Adrenergic agonists Clonidine Clonidine is an a2-adrenergic agonist used initially as an antihypertensive but increasingly being used as an anxiolytic and analgesic [46]. Clonidine also is used to control opioid and benzodiazepine withdrawal symptoms. Given orally preoperatively (4 mg/kg), clonidine decreases intraoperative anesthetic requirements and postoperative opioid consumption [47]. The mechanism of action involves sympatholysis by preventing norepinephrine from presynaptic nerve terminals. In addition, clonidine may increase the acetylcholine release from neurons in the dorsal horn of the spinal cord, thereby activating spinal acetylcholine receptors and augmenting analgesia. Clonidine is almost completely bioavailable when given orally. Clonidine also is available as transdermal patches (0.1, 0.2, and 0.3 mg) and that are changed every 7 days. Clonidine is very lipid soluble, so it can easily penetrate the brain and spinal cord [48]. The epidural or caudal dose is 1 to 2 mg/kg, which may be followed by an infusion of 0.05 to 0.33 mg/kg/h. Epidural clonidine may cause sedation and hypotension. When used as an adjunct to regional anesthesia, peripheral as well as epidural, clonidine augments the quality of analgesia and significantly prolongs the duration of analgesia [49,50]. Dexmedetomedine Dexmedetomedine is a centrally acting a2 receptor agonist with an affinity for the receptor that is eight times that of clonidine. Initially studied as a sedative for adults receiving mechanical ventilation, there is now literature on the use of dexmedetomedine in children. Although dexmedetomedine is being studied primarily as a sedative, it appears to have analgesic effects in that opioid requirements are decreased with dexmedetomedine therapy [51,52].

Local anesthetics Local anesthetics reversibly block impulse conduction along nerve fibers by interfering with sodium channels. The two classes of local anesthetics are amides and esters. The metabolism of amides occurs through the liver, whereas the metabolism of esters occurs through plasma esterases. Local anesthetics may be administered in the intrathecal or epidural space, around peripheral nerves, or applied topically in creams or ophthalmic drops. The maximum dosages and duration of action of the local anesthetics are listed in Table 2. Tetracaine and bupivacaine are the most commonly used local anesthetics for spinal anesthesia in children. Bupivacaine is the most commonly used local anesthetic for epidural analgesia and peripheral nerve blocks in children, although the newer local anesthetic ropivacaine is being used more frequently. Recent studies reveal ropi-

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pediatric acute pain management Table 2 Local anesthetic maximum doses Local anesthetic

Spinal (mg/kg)

Epidural (mg/kg)

Peripheral (mg/kg)

Tetracaine Lidocaine Bupivacaine Ropivacaine 2-Chloroprocaine

1 NR 0.5 NR NR

NR 5–7a 2.5 2.5–3 20–30a

NR 5–7a 2.5 2.5–3 NR

Abbreviation: NR, not recommended. a Higher dose only with epinephrine 1:200,000.

vacaine has less potential for cardiovascular toxicity compared with bupivacaine [53–55]. Because of the high protein binding of bupivacaine, dosages of this drug must be reduced in neonates and infants to avoid toxicity [56]. 2-Chloroprocaine is an attractive local anesthetic for neonates and infants because it metabolizes through plasma esterases so there is less accumulation and potential for toxicity [48,57]. This property combined with its rapid onset and offset also makes 2-chloroprocaine useful as a testing agent for epidural catheters in cases in which amide local anesthetic infusions such as bupivacaine or ropivacaine are being used, thus avoiding possible toxic levels of the amide local anesthetic [47,58]. Topical anesthetics have enabled caregivers to provide children with analgesia for many painful procedures including venipuncture, IV placement, lumbar punctures, and laceration suturing. Eutectic mixture of local anesthetics (EMLA) cream contains lidocaine and prilocaine. It is meant for intact skin; the onset time is approximately 60 minutes. Liposomal 4% lidocaine cream (LMX4) is a newer topical agent that reportedly has a shorter onset time of 30 minutes. Lidocaine, epinephrine, tetracaine (LET) is a topical gel for open wounds such as lacerations. The onset time of LET is approximately 20 to 30 minutes for excellent analgesia. LET was introduced as a safer preparation than the formerly used tetracaine, epinephrine, cocaine (TAC) compound because of reports of seizures and death with that agent. Lidocaine can be delivered by iontophoresis to achieve dermal anesthesia in 20 minutes. Lidocaine powder can be delivered by pressurized helium to provide topical anesthesia for venipuncture in 1 to 3 minutes [42,59].

Antispasmodics The treatment of muscle spasticity is an essential element of acute postoperative pain management in many children with significant neurological impairment such as cerebral palsy. One of the most common agents used is the benzodiazepine diazepam, 0.1–0.2 mg/kg, rectally or orally, as an adjunct to systemic or regional analgesics. Chronic muscle spasticity is often treated with baclofen, a g-aminobutyric acid (GABA) agonist, given orally or intrathecally through an implanted infusion pump. Another modality is intramuscular botulinum toxin,

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which provides temporary reduction in muscle spasm of contracted muscles for up to 3 months. It works by binding to the presynaptic motor endplate and preventing the release of acetylcholine [60,61]. Epidural clonidine may help reduce postoperative muscle spasticity, although this remains to be proven.

Developmentally appropriate pain assessment In 2001, the JCAHO mandated that all patients have a right to proper pain management. Pain assessment tools are used to quantify and guide the treatment of pain. Self-reported pain assessment tools are the standard, and many validated developmentally appropriate tools are available in which the child rates the pain intensity on a numeric scale, a color scale, or a face picture scale. Preverbal children or cognitively impaired children are unable to provide a self report, so physiologic and behavioral indices must be used as indicators of pain. Numerous pain assessment tools are available for neonates and infants [62]. The recent development of the Non-Communicating Children’s Pain Checklist (NCCPC) by Breau and colleagues [63] has advanced the ability to assess pain by using an observational pain checklist in cognitively impaired children who are unable to communicate their pain. This tool includes a number of common pain behaviors culled from interviews of caregivers of cognitively impaired children. They further adapted their checklist specifically for postoperative patients (NCCPC-Postoperative Version). In Boston, Solodiuk and colleagues [64] have developed the Individualized Numeric Rating Scale for nonverbal, cognitively impaired children, in which caregivers rank their child’s pain behaviors on a scale of 0 to 10 using the facial expression, leg activity, arm activity, crying, and consolability (acronym FLACC) (Table 3). This method provides a patientTable 3 Example pediatric pain scales Scale

Type

Ages

Scoring

CRIES

Infants  1 yr

CHEOPS

Observational (behavioral and physiologic) Observational (behavioral)

FLACC

Observational (behavioral)

Faces

Self-report

Postoperative children 1–7 yrs Children  3 y or children who cannot self-report Children 3–12 y

5 indicators 0 = no pain; 6 indicators 4 = no pain; 5 indicators 0 = no pain;

Numeric VAS

Self-report Self-report

Children  7 y Children  7 y

0, 1, or 2; 10 = max pain scored; 13 = max pain scored 0–2; 10 = max pain

Happy face = no pain; Saddest face = max pain; Each face has numeric value to get score 0–10 0 = no pain; 10 = max pain 10-cm line; 0 = no pain; 10 = max pain

Abbreviations: CHEOPS, Children’s Hospital of Eastern Ontario Pain Score; CRIES, crying, requires oxygen, increased heart rate and blood pressure; VAS, visual analogue scale.

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specific tool that can be used to assess the child’s pain throughout the period of hospitalization. The further development and validation of tools such as these will help greatly in assessing and treating pain in preverbal and nonverbal cognitively impaired children [65].

Postoperative pain management strategies It is well established that pain is not a simple transmission of neural impulses from the periphery to the cerebral cortex [10]. Signals can be augmented or attenuated at many different levels. In addition, nociceptive pathways have multiple synapses in the limbic system, frontal cortex, and medial thalamus where pain is influenced by emotions, behavior, past experiences, cultural orientation, and emotional states. Successful acute pain management targets all of the elements in the complex system of pain transduction, transmission, modulation, and perception. Analgesia balanced with a combination of opioid therapy, regional techniques, and NSAIDs is being used successfully in pediatric patients. Such a balanced approach results in a reduction in systemic opioid administration and opioid-related side effects. Traditionally, moderate to severe pediatric pain was treated with intermittent opioid analgesics on an as-needed basis, either intravenously or intramuscularly. Inadequate dosing, delays in administration, fear of intramuscular injections, and patient variability in analgesic needs resulted in frequent failure in this method of analgesia. There is a wide variability in the amount of pain experienced by different children with similar conditions. Children also have fluctuating analgesic needs. During rest, the child’s analgesic requirements are less than when attempting to change positions, breathe deeply, or undergo dressing changes, diagnostic tests, therapeutic procedures, physical therapy, or nursing care. Effective pediatric pain management includes a proactive plan for managing background and breakthrough pain [9]. The following discussion deals with various techniques to accomplish this task.

Patient-controlled analgesia Patient-controlled analgesia (PCA) has been used for moderate to severe pain in children over 6 years old. It has been used in younger children who have more chronic opioid needs, such as in those with malignancy. PCA is safe, effective, and highly satisfactory to patients, families, and nursing staff [66]. PCA is considered safe because if a patient has a high demand for an opioid, he or she will eventually become somnolent and stop pushing the demand button. If another individual pushes the button, however, there is potential for severe CNS and respiratory depression; thus only the patient is allowed to press the button. In some centers, PCA by proxy (nursing and parent-controlled analgesia) has been

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shown to be safe and effective in children less than 6 years of age or in cognitively impaired children [65,67]. Specific policies and structured orientation of nurses and parents are needed wherever nursing or parent-controlled analgesia is instituted. PCA is effective because it allows patients (or proxies) to titrate the amount of analgesic they desire based on the amount of pain the patient is experiencing. Plasma concentrations of opioid are maintained in a narrower range with lower peak levels and higher trough levels than with intermittent injections. This results in less respiratory and central nervous system depression. PCA is well suited to deal with the variable amount of pain between patients with similar conditions, as well as the different levels of pain an individual patient will experience during their care. Computerized PCA infusion pumps are programmed to deliver a specified (demand) dose of opioid when the patient pushes a button. The pump is programmed to administer only one demand dose in a specified period of time (lockout interval) regardless of how many times the patient pushes the demand button. The pump also is programmed to deliver no more than a specified maximum amount of opioid in the course of 1 hour (1-hour limit). The pump records the patient’s history of attempts and actual opioid injections. This allows precise tailoring of analgesic delivery to need. The infusion pumps may be programmed to deliver a continuous (basal) infusion of opioid regardless of whether the patient uses the demand button. There is debate over the use of PCA basal infusions [67,68]. The argument against using basal infusions is that it circumvents the inherent safety of the patient titrating the analgesic to effect, thus limiting respiratory depression. Also, several studies have indicated that basal infusions increase the risk for adverse events without improving analgesia. The argument for basal PCA infusions is that it allows the patient to sleep without awakening in severe pain from having not pressed the button. Basal PCA infusions may be especially helpful in adolescent patients after spinal fusions. Even with a basal opioid infusion, some children will have severe pain if they have been sleeping for a prolonged period without pressing the demand button. In this situation it is almost impossible for the patient to get adequate pain relief quickly by pressing the demand button. Therefore, in addition to the PCA orders, an intravenous rescue medication (eg, morphine, 50 mg/kg, every 3 hours) is ordered for breakthrough pain. The present authors also use standing orders for Table 4 PCA dosing guidelines

Drug

Demand dose (mg/kg)

Lockout interval (min)

Basal infusion (mg/kg/h)

1-h limit (mg/kg)

As needed IV rescue dose (mg/kg)

Morphine Hydromorphone Fentanyl Nalbuphine

20 4 0.5 20

8–10 8–10 6–8 8–10

0–20 0–4 0–0.5 0–20

100 20 2.5 100

50 10 0.5–1.0 50

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respiratory depression (naloxone, 10 mg/kg IV, as needed), nausea and vomiting (ondansetron, 50 mg/kg IV, every 8 hours), and pruritus (nalbuphine, 50 mg/kg IV, every 4 hours). In addition to helping with pruritus , nalbuphine may also be used for mild breakthrough pain. For children with muscle spasms, an adjunct such as diazepam, 0.1 mg/kg, orally or rectally, every 6 hours, may be needed. Morphine is usually the first-line opioid used in PCA in children. An alternate opioid, usually hydromorphone, is chosen if there are side effects to morphine. Refer to Table 4 for examples PCA dosing guidelines.

Continuous intravenous opioid infusion Continuous intravenous opioid infusion (CIV) is used in patients who are unable to use PCA because of age, physical disability, or cognitive impairment. The advantage of CIV over intermittent opioid administration is the attainment of stable plasma opioid levels without wide fluctuations. There is less reliance on nursing staff. A constant infusion will not cover breakthrough incident pain, so rescue doses of opioid are needed as described with PCA. The most common opioid used for CIV at the authors’ institution is morphine, with doses adjusted for age (Table 5). If a child is at an increased risk of central nervous system or respiratory depression, the infusion rates are reduced 25% to 50%. Morphine infusions are associated with an increased risk of respiratory depression in preterm and full-term neonates, so further reductions are required in this age group [22,23,69].

Continuous epidural analgesia Continuous epidural analgesia (CEA) provides pain relief for surgical procedures below the fourth thoracic dermatome. Patients who receive CEA obtain excellent dermatomal analgesia [56,68]. Epidural catheters may be placed in the caudal, lumbar, or thoracic region. In infants, thoracic dermatomal analgesia is often obtained by threading a catheter from a caudal insertion site to the thoracic region. This technique is believed by many practitioners to be safer than placing a thoracic epidural in an anesthetized child, although this indirect method is often confounded by incorrect dermatomal placement of the catheter. A stylletted catheter can help with placement, although there is an increased risk of vascular or dural puncture. A radiograph in the operating room using nonionic radio contrast agent will confirm catheter location [70]. The introduction of the stimulating catheter by Tsui and colleagues [71,72] is a promising contribution to the reliability of this technique [71–74]. As of this writing, there is no US Food and Drug Administration-approved stimulating epidural catheter available in the United States.

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Table 5 Opioid dosing regimens Opioid Morphine

Route/age group

Oral, immediate release: infants and children Oral, sustained release: infants and children IV bolus: Preterm neonate Full-term neonate Infants and children IV Infusion: Preterm neonate Full-term neonate Infants and children Hydromorphone Oral: infants and children IV bolus: infants and children IV infusion: infants and children Fentanyl Oral transmucosal Intranasal Transdermal IV bolus IV infusion Meperidine IV bolus: infants and children Methadone Oral or IV bolus: infants and children Nalbuphine IV bolus: Preterm neonate Full-term neonate Infants and children IV infusion: Preterm neonate Full-term neonate Infants and children Codeine Oral Oxycodone Oral Hydrocodone Oral

Dose/interval 0.3 mg/kg every 3–4 h 0.25–0.5 mg//kg every 8–12 h 10–25 mg/kg every 2–4 h 25–50 mg/kg every 3–4 h 50–100 mg /kg every 3 h 2–5 mg/kg/h 5–10 mg/kg/h 15–30 mg/kg/h 40–80 mg/kg every 4 h 10–20 mg/kg every 3–4 h 3–5 mg/kg/h 10–15 mg/kg (oralet) 1–2 mg/kg 12.5, 25, 50, 75, 100 mg/h patches 0.5–1 mg/kg every 1–2 h 0.5 mg/kg/h 0.8–1 mg/kg every 3–4 h 0.1–0.2 mg/kg every 12–36 h 10–25 mg/kg every 2–4 h 25–50 mg/kg every 2–4 h 50–100 mg/kg every 2–4 h 5–10 mg/kg/h 10–15 mg/kg/h 20 mg/kg/h 0.5–1 mg/kg every 4 h 0.1–0.15 mg/kg every 4 h 0.1–0.2 mg/kg every 4 h

When placing direct lumbar or thoracic epidural catheters in children, there are significant points to consider: (1) there is a much shorter distance from the skin to the epidural space; (2) the ligamentum flavum is softer in children; and (3) saline should be used for loss-of-resistance technique rather than air to avoid a venous air embolus, cord compression, or a patchy block [70,75]. Because epidural analgesia begins in the operating room, good communication between the anesthesia team and the pain service is essential. The report should include the medical history, surgical procedure, the location of epidural insertion site and the catheter tip, the length of catheter inserted into the epidural space, and epidural medications used. The postoperative epidural analgesic solution may contain a single agent or a combination of different classes of analgesics (Table 6). The administration of CEA requires the ability to immediately respond to problems. Daily rounds should be performed by a team of nurses and physicians

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pediatric acute pain management Table 6 CEA dosing guidelines

Patient Newborn 0–2 months, non-ventilated Newborn 0–2 months, mechanical ventilation Infant Child (lumbar) Child (thoracic)

Bupivacaine or ropivacaine (mg/mL)

Fentanyl (mg/mL)

Morphine (mg/mL)

Clonidine (mg/mL)

Rate (bupivicaine or ropivicaine mg/kg/h)

1 (0.5–1)

NR

NR

NR

0.2 (0.15–0.25)

1 (0.5–1.0)

2

NR

NR

0.2 (0.15–0.25)

1 (0.5–1.25) 1 (0.5–1.25) 1 (0.5–1.25)

2 (2–5) 5 (2–5) 5 (2–5)

25 25–50 NR

0.4 0.4–1 0.4–0.6

0.25 (0.15–0.3) 0.25 (0.2–0.4) 0.2 (0.2–0.4)

NR, not recommended.

who have expertise in CEA to ensure proper analgesia and to proactively address expected adverse effects such as nausea, vomiting, pruritus , motor block, epidural site inflammation, and less frequent and more severe sequelae such as respiratory and CNS depression. Standard orders for CEA should include a warning that additional parenteral or enteral opioid are not to be given while the patient is receiving an epidural opioid. Additional orders include cardiorespiratory monitoring, hourly respiratory rate monitoring for the first 24 hours (and hourly for 24 hours after any increase in epidural infusion rate) and then every 4 hours, and recording of pain scores, blood pressure, heart rate and mental status every 4 hours. A functioning intravenous line is required with CEA. A breathing circuit, mask, oxygen, and suction are to be immediately available at the bedside, with standing orders for the administration of 100% oxygen and naloxone 10 mg/kg IV to be given for respiratory rate  12 or unresponsiveness. The most common problems with CEA are ineffectiveness caused by incorrect dermatomal location, catheter problems (obstruction, kinking, leaking, or breaking), infusion pump failure, inappropriate infusion rate or solution, or accidental displacement of the catheter from its original location. In the event of motor block, the concentration of the local anesthetic can be decreased. If opioidrelated side effects occur, the dose of the epidural opioid should be reduced initially 25% to 50% before discontinuing its use if the symptoms persist. A rare but serous complication is the development of local anesthetic toxicity from systemic absorption. This is very unlikely if the concentrations and infusion rates listed in Table 6 are adhered to, although extra caution is needed in patients with a reduced capacity for local anesthetic metabolism and excretion, such as a neonate with biliary atresia who is undergoing a Kasai procedure [76].

Patient-controlled epidural analgesia Patient-controlled epidural analgesia (PCEA) combines the benefits of epidural analgesia and patient-controlled analgesia. This technique is suitable for

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Table 7 PCEA dosing guidelines Drugs

Demand Lockout Basal infusion 1-h limit Maximum 1-h dose (mL/kg) interval (min) (mL/kg) (mL/kg) dose (mL)

Bupivacaine 0.75 mg/mL 0.05–0.1 or Ropivacaine 0.75 mg/mL Fentanyl 2.5–5 mg/mL (thoracic) or Morphine 25–50 mg/mL (lumbar), and/or Clonidine 0.4 mcg/mL

20–30

0.1–0.2

0.2–0.4

19.9

children over 7 years of age who are capable of using a PCA demand button [77]. PCEA may be of particular benefit for predictable episodes of incident pain such as getting out of bed, physical therapy, or dressing changes. Example dosing regimens are listed in Table 7. Adjuvant medications are listed in Table 8.

Transition to oral analgesics The transition from specialized techniques such as CIV, PCA, CEA, and PCEA is often challenging. Oral analgesic therapy can begin when the child’s pain subsides and oral medications are tolerated. Epidural infusions and CIV are discontinued before oral analgesics are started. Patients on PCA may start oral analgesics and be allowed to use demand-only PCA (no basal infusion) for a brief period to make certain that the dose of oral analgesic is sufficient. A co-analgesic such as acetaminophen, 10 to 15 mg/kg, orally, every 4 hours; ibuprofen, 10 mg/kg, orally, every 4 hours; or ketorolac, 0.5 mg/kg, IV, every 6 hours may be helpful for smoothing the transition. Also, during the transition, a rescue intravenous dosage of morphine, 50 mg/kg, or nalbuphine, 50 mg/kg, every 3 hours, will help prevent sudden setbacks. Oxycodone, 0.1 to 0.15 mg/kg, orally, every 4 hours, with acetaminophen or ibuprofen is a standard regimen, although hydrocodone also is frequently used. In addition, oral hydromorphone and tramadol are ef-

Table 8 Adjuvant medications for patients receiving epidural analgesia Symptom

Medication

Nausea or vomiting Pruritis or mild breakthrough pain Breakthrough pain mod/severe

Ondansetron, 50 mg/kg IV, every 8 h Nalbuphine, 50 mg/kg IV, every 4 h Ketorolac, 0.5 mg/kg IV, every 6 h (maximum 20 doses) Diazepam, 0.1 mg/kg, PO/PR, every 6 h

Muscle spasm

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fective options. Oral codeine with acetaminophen is still commonly used, but as discussed earlier, because of its metabolism and side effects, its uses is declining. An essential element in postoperative analgesia is the instructions given to the parents at discharge about oral analgesic use at home, after an inpatient hospital stay or from the post anesthesia care unit (PACU) after outpatient surgery. It is important that the parents are clear on the medications, doses, and frequency. Parents’ fears abut giving analgesic medications need to be allayed so the analgesics are not withheld unnecessarily. Also, it should be verified that the parents will be able to obtain the prescribed analgesics. Pain management after outpatient pediatric surgery is still an area in need of improvement [9,78].

Regional techniques Many regional techniques are being increasingly used in pediatric anesthesia both as an adjunct to anesthesia and as a modality of postoperative analgesia. The reader is referred to the many texts and articles on regional anesthesia for the technical details of performing regional blocks in children. There has been a lively discussion on the safety of performing regional blocks in anesthetized children, whereas the standard for adults is that blocks are placed while the patient is awake. The consensus of pediatric anesthesiologists is that there is a long record of safety in performing regional blocks in anesthetized children; it is actually safer to perform these blocks in an anesthetized child rather than a struggling child, and children have an equal right to the benefit from the superior analgesia of regional blocks, as do adults [79,80].

Caudal analgesia The caudal block is one of the most commonly performed regional techniques in children [70,75]. It provides excellent analgesia for lower extremity or superficial lower abdominal surgeries using volumes of 0.75 to 1 mL/kg of local anesthetic solution (bupivacaine, 0.125%–0.25%, ropivacaine 0.2%). To reach T10 dermatomal levels, volumes of 1.25 mL/kg are required, but caution is needed to ensure that the dosage of bupivacaine or ropivacaine does not exceed 2.5 mg/kg. Bupivacaine 0.25% provides excellent analgesia, but in ambulatory children, the potential motor block can be avoided by using bupivacaine, 0.125%. The use of clonidine, 1 to 2 mg/kg, as an adjunct significantly prolongs the duration of caudal analgesia [49]. Additional adjuncts such as preservative-free S-ketamine and neostigmine are being studied for their efficacy in augmenting and prolonging analgesia with single-dose caudal administration. These agents show promise in early studies, but to date they are not approved for caudal/ epidural use in the United States [81–83].

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Centroneuraxis opioid Intrathecal morphine (5–10 mg/kg) and epidural morphine (25–50 mg/kg) provides 12 to 24 hours of analgesia. Because of the hydrophilic nature of morphine and its cephalad spread in cerebrospinal fluid, these techniques can be used for all types of surgeries, from lower extremity to craniofacial [84,85]. Patients receiving centroneuraxial opioid require hospitalization for respiratory monitoring for at least 24 hours because of the potential for delayed respiratory depression. When staying within recommended doses of morphine, respiratory depression is rare, but nausea, vomiting, urinary retention, and especially pruritus are common and can be quite annoying. Rescue medications to proactively deal with these side effects are necessary. Ideally, children receiving centroneuraxial opioid will make the transition directly to oral analgesics, making this modality attractive for surgeries involving short hospital stays, such as ureteral reimplantation. In major surgeries such as spinal fusions, patients will also require IV PCA opioid before conversion to oral analgesia [58,68].

Peripheral nerve blocks Peripheral nerve blocks are being used with increasing frequency in children [86,70]. Giaufre and colleagues [79] have presented, in a retrospective study, the relatively low risk of peripheral nerve blocks in children compared with centroneuraxial blocks [79,87]. The potential advantages of using peripheral nerve blocks as adjuncts to general anesthesia and to postoperative analgesia are improved and more prolonged analgesia and less opioid-induced side effects, especially nausea and vomiting. Because these blocks are performed mostly on anesthetized children, a number of safety measures are advised: (1) when using a nerve stimulator, do not insist on a muscle contracture at settings lower than 0.4 to 0.5 mA; (2) aspirate before injecting local anesthetic and inject in fractionated doses; and (3) use the smallest practical syringe and do not inject under pressure to avoid intraneuronal injection [70,88]. Also important is the incomplete myelination in young children and shorter distance between nodes of Ranvier, resulting in an earlier block with less local anesthetic. An additional caveat is that the volume of local anesthetic solution needed to obtain a block in children is relatively higher on a weight basis than in adults, so caution is needed to use the lowest concentration of local anesthetic necessary [87]. Peripheral blocks may be performed as single injection techniques or as a continuous infusion through a percutaneously placed catheter. With the advent of simple elastomeric pumps, children will be allowed to be discharged with a continuous nerve block postoperatively for 3 to 5 days [89]. Peripheral nerve block techniques, especially the brachial plexus block techniques, are frequently being modified for more stable placement of catheters for continuous infusion. Some example peripheral blocks are listed in Table 9. Practitioners will likely see

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Table 9 Example peripheral nerve blocks Region

Block

Areas affected

Upper extremity blocks

Interscalene Infraclavicular Axillary Wrist block Lumbar plexus Femoral; 3-in-1; fascia iliaca Sciatic Ankle block Ilioinguinal/iliohypogastric Pararectus sheath block Penile block Supraorbital/supratrochlear Infraorbital Great auricular Greater occipital

Shoulder/arm/elbow Elbow/forearm/hand Forearm/hand Hand Hip/anterior thigh/knee Anterior thigh/knee Ankle/foot Foot Inguinal hernia/orchidopexy Umbilical hernia Circumcision/hypospadias Scalp procedures/headaches Cleft lip/sinus surgery Otoplasty/tympanoplasty Occipital procedures/headaches

Lower extremity blocks

Miscellaneous blocks

much advancement in regional analgesia in children in the near future. One example is the investigation of the use of ultrasound to locate peripheral nerves rather than the nerve stimulator [90,91]. The ongoing investigation of long-acting local anesthetic microsomal spheres is particularly exciting [92].

Nonpharmacologic methods Nonpharmacologic techniques such as cognitive-behavioral therapies (distraction, guided imagery, and relaxation) and physical therapy are essential modalities of acute pain management, and each technique deserves a much more robust treatment than a perfunctory discussion would provide here. The reader is referred to the many texts and references dealing with these areas. A point worth emphasizing is that institutions that provide care to children in acute pain need to be aware of the overall environment. A child-friendly environment with a strong Child Life Service and parental involvement is essential to provide the many comfort measures needed to complement any pain management strategy [93–95].

Summary Pediatric pain management has made great strides in the past few decades, in the understanding of developmental neurobiology, developmental pharmacology, the use of analgesics in children, the use of regional techniques in children, and of the psychological needs of children in pain. There are reasons to be optimistic that ongoing scientific investigation coupled with political and public pressure will promote further advances in pain management for children.

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