Acute Pain Management in Children

Myron Yaster, M.D.
Richard J. Traystman Professor,
Department of Anesthesiology/Critical Care Medicine and Pediatrics
The Johns Hopkins Hospital
Baltimore, MD 21287
myaster@jhmi.edu

Sabine Kost-Byerly, M.D.
Clinical Director, Pediatric Pain Management
Assistant Professor,
Department of Anesthesiology/Critical Care Medicine and Pediatrics
The Johns Hopkins Hospital
Baltimore, MD 21287
skbyerly@jhmi.edu
 

INTRODUCTION

The The treatment and alleviation of pain is a basic human right that exists regardless of age.1;2 Although much of this chapter is directed at pediatric pain which is our area of clinical practice and research, much, if not all, is applicable to adult patients as well. Unfortunately in our quest to treat and cure the underlying disease processes that cause pain, we as physicians have often forgotten about the symptom, pain, that brings patients to us in the first place. What is pain? It is more than simply the physiologic transmission of nociceptive input from a site of injury to the brain. Rather it is a complex sensation that is integrated and given value at higher, conscious brain centers. No two people experience it the same way. Think of symphonic music. Despite the fact that the physiology of sound transmission is the same in all of us, symphonic music to some is simply awful and to others it is glorious. We integrate the neural transmissions and give it personal value based on our age, culture, experience, values, and state of mind. The same is true for pain.

Unfortunately, even when their pain is obvious, children frequently receive no treatment, or inadequate treatment, for pain and for painful procedures. The newborn and critically ill child are especially vulnerable to no treatment or under-treatment.3;4 No other group would be allowed to undergo surgery without anesthesia and yet even in the year 2005 the newborn male typically undergoes circumcision by being tied down to a papoose. The conventional "wisdom" that children neither respond to, nor remember, painful experiences to the same degree that adults do is simply untrue. Indeed, many of the nerve pathways essential for the transmission and perception of pain are present and functioning by 24 - 29 weeks of gestation.5;6 Recent research in newborn animals has revealed that the failure to provide analgesia for pain results in “rewiring” the nerve pathways responsible for pain transmission in the dorsal horn of the spinal cord and results in increased pain perception for future painful insults. This confirms human newborn research in which the failure to provide anesthesia or analgesia for newborn circumcision resulted not only in short term physiologic perturbations but also in longer term behavioral changes, particularly during immunization. 7;8

Nurses are taught to be wary of physicians' orders (and patients' requests) as well. The most common prescription order for potent analgesics, "to give as needed" (pro re nata, "PRN"), in reality means "to give as infrequently as possible". The "PRN" order also means that either the patient must know or remember to ask for pain medication or the nurse must identify when a patient is in pain. Neither of these requirements may be met by children in pain. Children less than 3 years of age, or critically ill children, may be unable to adequately verbalize when or where they hurt. Alternatively, they may be afraid to report their pain. Many children will withdraw or deny their pain in an attempt to avoid yet another terrifying and painful experience-the intramuscular injection or "shot". Finally, several studies have documented the inability of nurses, physicians, and parents to correctly identify and treat pain even in post-operative pediatric patients.

Societal fears of opioid addiction and lack of advocacy are also causal factors in the under-treatment of pediatric pain. Unlike adult patients, pain management in children is often dependent on the ability of parents to recognize and assess pain and on their decision to treat or not treat it. Parental misconceptions concerning pain assessment and pain management, as well as a fear of inducing addiction, may therefore result in inadequate pain treatment. This is particularly true in patients who are too young or too developmentally handicapped to self report their pain. Even in hospitalized patients, most of the pain that children experience is managed by the patient’s parents. Parents may fail to report pain either because they are unable to assess it, or are afraid of the consequences of pain therapy. In one study, false beliefs about addiction and the proper use of acetaminophen and other analgesics resulted in the failure to provide analgesia to children.9 In another, the belief that pain was useful or that repeated doses of analgesics lead to medication not working well resulted in the failure of the parents to provide or ask for prescribed analgesics to treat their children’s pain.10 Parental education is therefore essential if children are to be adequately treated for pain. Unfortunately, the ability to properly educate parents about this issue is often limited by insufficient resources, time, and personnel.

Fortunately, the past 25 years have seen an explosion in research and interest in pediatric pain management and in the development of pediatric pain services, primarily under the direction of pediatric anesthesiologists. The pain service teams provide the pain management for acute, post-operative, terminal, neuropathic and chronic pain. Never the less, the assessment and treatment of pain in children is an important aspect of pediatric care, regardless of who provides it, and failure to provide adequate control of pain amounts to substandard and unethical medical practice.

Pain Assessment

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."11 As discussed above, the perception of pain is a subjective, conscious experience; operationally, it can be defined as "what the patient says hurts" and exists "when the patient says it does". Infants, pre-verbal children, and children between the ages of 2 and 7 may be unable to describe their pain or their subjective experiences. This has led many to conclude incorrectly that children don't experience pain in the same way that adults do. Clearly, children do not have to know (or be able to express) the meaning of an experience in order to have the experience. On the other hand, because pain is essentially a subjective experience, it is becoming increasingly clear that the child's perspective of pain is an indispensable facet of pediatric pain management and an essential element in the specialized study of childhood pain. Indeed, pain assessment and management are inter-dependent and one is essentially useless without the other. The goal of pain assessment is to provide accurate data about the location and intensity of pain, as well as the effectiveness of measures used to alleviate or abolish it.

Instruments currently exist to measure and assess pain in children of all ages.8;12-18 Indeed, the sensitivity and specificity of these instruments has been widely debated and has resulted in a plethora of studies to validate their reliability and validity. The most commonly used instruments measure the quality and intensity of pain and are "self-report measures" that make use of pictures or word descriptors to describe pain. Pain intensity or severity can be measured in children as young as 3 years of age by using either the Oucher scale (developed by Dr. Judy Beyer), a two part scale with a vertical numerical scale (0-100) on one side and six photographs of a young child on the other, or a visual analogue scale, or a 10 cm line with a smiling face on one end and a distraught, crying face on the other. In fact, this scale has been validated even by sex and race! In our practice, we use the 6 face pain-scale developed by Dr. Donna Wong primarily because of its simplicity (figure 1).16 This scale is attached to the vital sign record and nurses are instructed to use it or a more age-appropriate self-report measure whenever vital signs are taken.

Figure 1: Pain intensity scale using faces to rate the intensity of the pain in children16

Pain Management

Acute pediatric (and adult) pain management is increasingly characterized by a multi-modal or “balanced” approach in which smaller doses of opioid and non-opioid analgesics, such non-steroidal antiinflammatory drugs, local anesthetics, NMDA antagonists, and alpha 2 adrenergic agonists, are combined to maximize pain control and minimize drug induced adverse side effects. Additionally, a multi-modal approach utilizes non-pharmacologic, complimentary and alternative medicine therapies as well. These techniques include distraction, guided imagery, transcutaneous nerve stimulation, acupuncture, therapeutic massage, etc. 19

Analgesics with Anti-Pyretic Activity or Non-opioid (or "Weaker") Analgesics

The "weaker" or "milder" analgesics with anti-pyretic activity, of which acetaminophen [paracetamol] (Tylenol®), salicylate (aspirin), ibuprofen (Motrin®), naproxen (Aleve®, Naprosyn®), diclofenic are the classic examples, comprise a heterogenous group of non-steroidal anti-inflammatory drugs (NSAID) that are non-opioid analgesics (Table 1).20-22 They provide pain relief primarily by blocking peripheral and central prostaglandin production by inhibiting cyclooxygenase types I and II. These analgesic agents are primarily administered enterally via the oral or, on occasion, the rectal route and are particularly useful for inflammatory, bony, or rheumatic pain. Parenterally administered NSAIDs, such as ketorolac (Toradol®), are available for use in children in whom the oral or rectal routes of administration are not possible.23 Unfortunately, regardless of dose, the non-opioid analgesics reach a "ceiling effect" above which pain can not be relieved by these drugs alone. Indeed, because of this, these weaker analgesics are basic building blocks in a multi-modal therapeutic approach and are often administered in oral combination forms with opioids such as codeine, oxycodone, or hydrocodone.

Table 1: Oral Dosing Guidelines for Commonly Used Non-Opioid Analgesics

Drug (Brand name)	Dose (mg/kg) (<60 kg)	Dose (mg) (> 60 kg)	Interval (hours)	Daily Maximum Dose (mg/kg) (<60 kg)	Daily Maximum Dose (mg) (>60 kg)	Side Effects
Acetaminophen (Tylenol®)	10-151	650-1000	4	1001	4,000	Toxic doses hepatotoxicity Lacks anti-inflammatory activity
Ibuprofen (Motrin®)	5-10	400-6003	6	402,3	2,4003	GI irritation, bronchospasm,  interferes with platelet function, hematuria
Naproxen (Naprosyn®)	5-63	250-3753	12	242,3	1,0003	see ibuprofen
Aspirin4	10-153,4	650-10003	4	802,3,4	3,6003	Reye syndrome4, see ibuprofen
Choline Mg Tri-Salicylate5	7.5-152,3	500-10003	4-8	802,3,4	3,6003	see aspirin
Maximum daily doses for acetaminophen should be reduced to 80 mg/kg in term neonates and infants and to 60 mg/kg in preterm neonates. Supplied in multiple liquid formulations ranging from 20-100 mg/mL making accidental overdosage easy. Rectal suppositories available, dosing 25-40 mg/kg every 6 hours Dosing guidelines for neonates and infants have not been established. Higher doses may be used in selected cases for treatment of rheumatologic conditions in children. Aspirin carries a risk of provoking Reye’s syndrome in infants and children. If other analgesics are available, aspirin use should be restricted to indications where anti-platelet or anti-inflammatory effect is required, rather than as a routine analgesic or antipyretic in neonates, infants, or children. Dosing guidelines for aspirin in neonates have not been established. Aspirin like compound that does not affect platelet adhesiveness or aggregation

Aspirin, one of the oldest and most effective non-opioid analgesics, has been largely abandoned in pediatric practice because of its possible role in Reye's syndrome, its effects on platelet function, and its gastric irritant properties. Despite these problems, a relatively new salicylate product, choline-magnesium trisalicylate (Trilisate®) is increasingly being used in our pediatric pain management practice, particularly in the management of post-operative pain and in the child with cancer. Choline-magnesium trisalicylate is a unique aspirin-like compound that does not bind to platelets and therefore has minimal, if any, effects on platelet function. 21 It is a convenient drug to give to children because it is available in both a liquid and tablet form and is administered either twice a day or every 6 hours. The association of salicylates with Reye syndrome limits its use, even though the risk of developing Reye syndrome post-operatively or in cancer is extremely unlikely.

The most commonly used non-opioid analgesic in pediatric practice remains acetaminophen [paracetamol]. Unlike aspirin and the other NSAIDs, acetaminophen works primarily centrally and has minimal, if any, anti-inflammatory activity. When administered in normal doses (10-15 mg.kg-1, PO), acetaminophen is extremely safe and has very few serious side effects. It is an antipyretic and like all enterally administered NSAIDs, takes about 30 minutes to provide effective analgesia. Several investigators have reported that when administered rectally, acetaminophen should be given in significantly higher doses than previous recommendations suggested.24;25 These authors recommend acetaminophen doses as high as 30-40 mg.kg-1 when the drug is administered rectally. Follow-up rectal doses are 30 mg.kg-1 every 8 hours. Regardless of route of delivery, in order to prevent hepatotoxicity, the daily maximum acetaminophen dose in the preterm, term, and older child is 60, 80, 90 mg/kg respectively (Table 1). The maximum adult dose is 4 grams a day.

The discovery of at least 2 cyclo-oxygenase (COX) isoenzymes, referred to as COX-1 and COX-2, has updated our knowledge of NSAIDs.26-29 The 2 COX isoenzymes share structural and enzymatic similarities, but are specifically regulated at the molecular level and may be distinguished apart in their functions. Protective prostaglandins, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1.26;27;30 COX-2 is an inducible isoform. The inducing stimuli include pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. Prostaglandins made by COX-2 are also important in ovulation and in the birth process.26;27;30 The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective prostaglandins in the stomach and kidney made by COX-1. In fact, developing a more specific COX-2 inhibitor has been the “holy grail” of drug research because this class of drug will have all of the anti-inflammatory and analgesic properties that one desires in a drug and none of the gastrointestinal and anti-platelet side effects. Unfortunately, the growing controversy regarding the potential adverse cardiovascular risks of prolonged use of the COX-2 inhibitors has dampened much of the enthusiasm for these drugs and has led to the removal of rofecoxib from the market by its manufacturer.31;32 Finally, many orthopedic surgeons are also concerned about the negative influence of all NSAIDs, both selective and non selective COX inhibitors, on bone growth and healing.33-35 Thus, most pediatric orthopedic surgeons have recommended that these drugs not be used in their patients in the postoperative period.

Opioid Drug Selection

Many factors are considered when deciding which is the appropriate opioid analgesic to administer to a patient in pain. These include pain intensity, patient age, co-existing disease, potential drug interactions, prior treatment history, physician preference, patient preference, and route of administration. The idea that some opioids are “weak” (e.g., codeine) and others “strong” (e.g., morphine) is outdated. All are capable of treating pain regardless of its intensity if the dose is adjusted appropriately. And at equipotent doses most opioids have similar effects and side effects (Table 2) Characteristics of selected mu opioid agonist drugs are listed for quick reference in table 2. Meperidine is worth a special note of discussion. An entire generation of physicians believe that meperidine causes less respiratory depression and less biliary spasm than morphine. This is simply untrue and was based on a study of postoperative adult patients in which half received 10 mg morphine and the other half 10 mg of meperidine. The meperidine group had less respiratory depression and biliary spasm than morphine. They also had more pain. The equianalgesic dose of meperidine is 100 mg. When the study was repeated with appropriate dosing the investigators found that meperidine had the same side effect profile as morphine.36 Although meperidine was once among the most commonly prescribed mu-agonist opioids, it no longer is. Meperidine has a neurotoxic metabolite, normeperidine, that possesses no analgesic properties and relies on the kidney for its excretion. Normeperidine accumulation causes CNS excitation, resulting in a range of toxic reactions from anxiety and tremors to grand mal seizures.

Table 2: Opioid Analgesic Initial Dosage Guidelines

DRUG	Equianalgesic dose (mg)		Usual starting IV (SC) Doses and Intervals		Parenteral/ Oral ratio	Usual starting Oral Doses and Intervals
	IV, IM, SC	oral	< 50 kg	> 50 kg		< 50 kg	> 50 kg
Codeine	120	200	NR	NR	1:2	0.5-1 mg/kg every 3-4 hrs	30-60 mg every 3-4  hours1
Fentanyl	0.1	NA2	Bolus: 0.5-1 mcg/kg every 0.5-2  hrs Infusion: 0.5-2 mcg/kg/hr	Bolus: 25-50 mcg every 1-2 hrs Infusion: 25-100 mcg/hr	NA	NA	NA
Hydrocodone	NA	10-20	NA	NA	NA	0.1mg/kg every 3-4 hrs	5-10 mg every 3-4 hrs1
Hydromorphone	1.5-2	3-53	Bolus: 0.02 mg/kg every 0.5-2  hrs Infusion: 0.004 mg/kg/hr	Bolus: 1 mg every 0.5-2 hrs Infusion: 0.3 mg/hr	1:2   1:43	0.03-0.08 mg/kg every 3-4 hrs	2-4  mg every 3-4 hrs
Meperidine4	75-100	150-200	Bolus: 1 mg/kg every 2-3 hrs	Bolus: 50 - 100 mg every 2-3 hrs	1:2	1 - 2 mg/kg every 3-4 hrs	100-150 mg every 3-4 hrs
Methadone	10	10-20	0.1 mg/kg every 4-8 hrs	5-10 mg every 4-8 hrs	1:2	0.2 mg/kg  every 4-8 hrs.	10 mg  every 4-8  hrs
Morphine	10	30-50	Bolus: 0.1  mg/kg every 0.5-2  hrs Infusion: 0.025  mg/kg/hr	Bolus: 5-10  mg every  0.5-2 hrs Infusion: 2 mg/hr	1:3 chronic   1:5 single	Immediate Release: 0.3 mg/kg every  3-4 hrs Sustained Release 20-35 kg:  10-15 mg  every 8-12 hrs 35-50 kg: 15-30 mg  every 8-12	Immediate Release: 15-20 mg every  3-4 hrs Sustained Release: 30-45 mg every 8-12 hrs
Oxycodone	NA	10-20	NA	NA	NA	0.1mg/kg every 3-4 hrs	5-10 mg every 3-4 hrs1,5
Commercial preparations are often combined with acetaminophen or ibuprofen; must be converted to morphine by CYP 2D6 for analgesic effect Oral transmucosal form available (Actiq®): dose 10-15 mcg/kg The equianalgesic oral dose and parenteral/oral dose ratio is not well established Also called pethidine. Meperidine should generally be avoided if other opioids are available, especially with chronic use, because its metabolite, nor-meperidine can produce seizures. A sustained release preparation is available

Commonly Used Oral Opioids: Codeine, Oxycodone, Hydrocodone, and Morphine

Codeine, oxycodone (the opioid in Tylox® and Percocet®) and hydrocodone (the opioid in Vicodin ® and Lortab®) are opioids which are frequently used to treat pain in children and adults, particularly for less severe pain or when patients are being converted from parenteral opioids to enteral ones (table 2). Morphine is commonly used in regimens for chronic pain (e.g. cancer.) Codeine, oxycodone, and hydrocodone are most commonly administered in the oral form, usually in combination with acetaminophen or aspirin.37 Unfortunately, very few, if any, pharmacokinetic or dynamic studies have been performed in children and most dosing guidelines are anecdotal.

In equipotent doses, codeine, oxycodone, hydrocodone, and morphine are equal both as analgesics and respiratory depressants (Table 2). In addition, these drugs share with other opioids common effects on the central nervous system including sedation, respiratory depression, and stimulation of the chemoreceptor trigger zone in the brain stem. Indeed, the latter is particularly true for codeine. Codeine is very nauseating; indeed, many patients claim they are "allergic" to it because it so commonly induces vomiting. There are much fewer nausea and vomiting problems with oxycodone and hydrocodone. Indeed, because of this, oxycodone or hydrocodone are now our preferred oral opioids. Codeine, hydrocodone, and oxycodone have a bioavailability of approximately 60% following oral ingestion. The analgesic effects occur as early as 20 minutes following ingestion and reach a maximum at 60-120 minutes. The plasma half-life of elimination is 2.5 - 4 hours. Codeine undergoes nearly complete metabolism in the liver prior to its final excretion in urine. Approximately 10% of codeine is metabolized into morphine (CYP 2D6) and it is this 10% that is responsible for codeine's analgesic effect. Interestingly, approximately 10% of the population and most newborn infants can not metabolize codeine into morphine and in these patients codeine will produce little, if any, analgesia.

Like oxycodone, codeine, and oxycodone, morphine is also very effective when given orally, but only about 20-30% of an oral dose of morphine reaches the systemic circulation. In the past this led many to conclude that morphine was ineffective when administered orally. This simply isn’t true; it was the result of failing to provide sufficient morphine. Therefore, when converting a patient’s intravenous morphine requirement to oral maintenance, one must multiply the intravenous dose by a factor of 3 to 4.

Whereas oral morphine is prescribed alone, oral codeine, hydrocodone, and oxycodone are usually prescribed in combination with either acetaminophen or aspirin (Tylenol and codeine elixir, Percocet®, Tylox®, Vicodin®, Lortab®). Typically, codeine is prescribed in a dose of 0.5-1 mg/kg. Elixirs, which are available in virtually every pharmacy, contain 120 mg acetaminophen and 12 mg codeine per teaspoon (5 mL).37 Acetaminophen potentiates the analgesia produced by codeine (and other opioids) and allows the practitioner to use less opioid and yet achieve satisfactory analgesia.. Codeine and acetaminophen are also available as “numbered” tablets, e.g. Tylenol® number 1, 2, 3, or 4. The number refers to how much codeine is in each tablet. Tylenol® number 4 has 60 mg codeine, number 3 has 30 mg, number 2 has 15 mg, and number 1 has 7.5 mg. In all “combination preparations”, beware of inadvertently administering a hepatotoxic acetaminophen dose when increasing opioid doses for uncontrolled pain.38 Acetaminophen toxicity may result from a single toxic dose, from repeated ingestion of large doses of acetaminophen (e.g., in adults, 7.5-10 g daily for 1-2 days, children 60-420 mg/kg/day for 1-42 days) or from chronic ingestion. Because of this we prefer to prescribe the opioid and acetaminophen (or ibuprofen) separately. Although it is an effective analgesic when administered parenterally, intramuscular codeine has no advantage over morphine or any other opioid. Why it is used in neurosurgical and some ENT practices defies logic.

Hydrocodone is prescribed in a dose of 0.05-0.1 mg/kg. The elixir is available as 2.5 mg/5 mL combined with acetaminophen 167 mg/ 5 mL. As a tablet, it is available in hydrocodone doses between 2.5-10 mg, combined with 500-650 mg acetaminophen. Oxycodone is prescribed in a dose of 0.05-0.1 mg/kg. Unfortunately, the elixir is not available in most pharmacies. When it is, it comes either as 1 mg/mL or 20 mg/mL. This can obviously result in catastrophic dispensing errors. In tablet form, oxycodone is commonly available as a 5 mg tablet or as Tylox® (500 mg acetaminophen and 5 mg oxycodone) or Percocet® (325 mg acetaminophen and 5 mg oxycodone.)

Oxycodone is also available without acetaminophen in a sustained-release tablet for use in chronic pain. Like many other time-release tablets, it must not be crushed and therefore cannot be administered through a gastric tube. Breaking the tablet results in the immediate release of a huge amount of oxycodone. Drug addicts have discovered this and have made this drug a drug of abuse. Like sustained-release morphine (see below), sustained-release oxycodone is only for use in opioid tolerant patients with chronic pain, and not for routine postoperative pain. Also note that in patients with rapid GI transit, sustained-release preparations may not be absorbed at all (liquid methadone may be an alternative.)

Oral morphine is available as a liquid in various concentrations (as much as 20 mg/mL), a tablet (such as MSIR, for ‘morphine sulfate immediate release’; available in 15 and 30 mg tablets), and as a sustained-release preparation (MSContin and Oramorph tablets, and Kadian “sprinkle capsules”, which may be opened and sprinkled on applesauce.) Because it is so concentrated, the liquid in particularly easy to administer to children and severely debilitated patients. Indeed, in terminal patients who cannot swallow, liquid morphine will provide analgesia when simply dropped into the patient’s mouth.37

Patient (Parent and Nurse) Controlled Analgesia

Among the many reasons for the under-treatment of pain is the lack of familiarity of physicians (and nurses) with appropriate drugs, drug dosing, and routes of administration. When drugs are given on demand (“PRN”), there is a lag time between the time the patient’s nurse responds, prepares, and administers analgesia. Around the clock administration interval administration (e.g., q 4 hours) is not the answer either because of the enormous individual variations in pain perception and opioid metabolism. Indeed, fixed doses and time intervals make little sense. Based on the pharmacokinetics of the opioids, it should be clear that intravenous boluses of morphine may need to be given at intervals of 1-2 hours in order to avoid marked fluctuations in plasma drug levels. Continuous intravenous infusions may provide steady analgesic levels and are preferable to intramuscular injections and have been used with great safety and effectiveness in children. However, they are not a panacea because the perception and intensity of pain is not constant. For example, a post-operative patient may be very comfortable resting in bed and may require little adjustment in pain management. This same patient may experience excruciating pain when coughing, or voiding, or getting out of bed. Thus, rational pain management requires some form of titration to effect whenever any opioid is administered. In order to give patients, and in some cases parents and nurses, some measure of control over their, or their children’s, pain therapy, demand analgesia or patient controlled analgesia (PCA) devices have been developed.39;40 These are micro-processor driven pumps with a button that the patient presses to self administer a small dose of opioid.

PCA devices allow patients to administer small amounts of an analgesic whenever they feel a need for more pain relief. The opioid, usually morphine, hydromorphone, or fentanyl is administered either intravenously or subcutaneously. The dosage of opioid, number of boluses per hour, and the time interval between boluses (the "lock-out period") are programmed into the equipment by the pain service physician and nurse to allow maximum patient flexibility and sense of control with minimal risk of overdosage. Generally, because older patients know that if they have severe pain they can obtain relief immediately, many prefer dosing regimens that result in mild to moderate pain in exchange for fewer side effects such as nausea or pruritus. Typically, we initially prescribe morphine, 20 μg/kg per bolus (or hydromorphone 3-4 μg/kg/hour or fentanyl 0.5 μg/kg/hour), at a rate of 5 boluses/hour, with a 6-8 minute lock-out interval between each bolus . Variations include larger boluses (30-50 μg/kg), shorter time intervals (5 min), etc.

The PCA pump computer stores within its memory how many boluses the patient has received as well as how many attempts the patient has made at receiving boluses. This allows the physician to evaluate how well the patient understands the use of the pump and provides information to program the pump more efficiently. Most PCA units allow low "background" continuous infusions (morphine, 20-30 μg/kg/hour, hydromorphone 3-4 μg/kg/hour, fentanyl 0.5 μg/kg/hour) in addition to self administered boluses. A continuous background infusion is particularly useful at night and often provides more restful sleep by preventing the patient from awakening in pain. It also increases the potential for overdosage. 39-41 Although the adult literature on pain does not support the use of continuous background infusions, it has been our experience that continuous infusions are essential for both the patient and us (fewer phone calls, problems, etc.). Indeed, in our practice, we almost always use continuous background infusions when we prescribe IV (or epidural) PCA.

PCA requires a patient with enough intelligence and manual dexterity and strength to operate the pump. Thus, it was initially limited to adolescents and teenagers, but the lower age limit in whom this treatment modality can be used continues to fall. In fact, it has been our experience that any child able to play Nintendo® can operate a PCA pump (age 5-6). Allowing surrogates such as parents or nurses to initiate a PCA bolus is controversial. We recently demonstrated that nurses and parents can be empowered to initiate PCA boluses and to use this technology safely in children less than even a year of age.41 In this study, the incidence of common opioid-induced side effects is similar to that observed in older patients. Interestingly, respiratory depression is very rare, but does occur, reinforcing the need for close monitoring and established nursing protocols. Difficulties with PCA include its increased costs, patient age limitations, and the bureaucratic (physician, nursing, and pharmacy) obstacles (protocols, education, storage arrangements) that must be overcome prior to its implementation. Contraindications to the use of patient controlled analgesia include inability to push the bolus button (weakness, arm restraints), inability to understand how to use the machine, and a patient's (or parent’s) desire not to assume responsibility for his/her own care.

Transmucosal, Intranasal and Transdermal Fentanyl

Because fentanyl is extremely lipophilic it can be readily absorbed across any biologic membrane including the skin. Thus, it can be given painlessly by new, non-intravenous routes of drug administration including the transmucosal (nose and mouth) and transdermal routes. The transmucosal route of fentanyl administration is extremely effective for acute pain relief. When given intranasally (2 mcg/kg), it produces rapid analgesia that is equivalent to intravenously administered fentanyl.42 Alternatively, fentanyl has been manufactured in a candy matrix (Actiq®) attached to a plastic applicator (it looks like a lollipop) for transoral/transmucosal absorption. As the child sucks on the candy, fentanyl is absorbed across the buccal mucosa and is rapidly (10-20 min) absorbed into the systemic circulation. 43-48 If excessive sedation occurs, the fentanyl is removed from the child’s mouth by the applicator. It is more efficient than ordinary oral-gastric intestinal administration because transmucosal absorption bypasses the efficient first-pass hepatic metabolism of fentanyl that occurs following enteral absorption into the portal circulation. Actiq® has been approved by the FDA for use in children for premedication prior to surgery and for procedure related pain (lumbar puncture, bone marrow aspiration, etc.). 49 It is also useful in the treatment of cancer pain and as a supplement to transdermal fentanyl. 50 When administered transmucosally, fentanyl is given in doses of 10-15 μg/kg, is effective within 20 minutes, and lasts approximately 2 hours. Approximately 25-33% of the given dose is absorbed. Thus, when administered in doses of 10-15 μg/kg, blood levels equivalent to 3-5 μg/kg IV fentanyl are achieved. The major side-effect, nausea and vomiting, occurs in approximately 20-33% of patients who receive it.51

The transdermal route is frequently used to administer many chronically administered drugs including scopolamine, clonidine, and nitroglycerin. Many factors, including body site, skin temperature, skin damage, ethnic group, or age will affect the absorption of transdermally administered drug. Placed in a selective semi-permeable membrane patch, a reservoir of drug provides slow, steady state absorption of drug across the skin. The patch is attached to the skin by a contact adhesive which often causes skin irritation.

The use of transdermal fentanyl has revolutionized adult cancer pain management. As fentanyl is painlessly absorbed across the skin, a substantial amount is stored in the upper skin layers which then act as a secondary reservoir. The presence of skin depot has several implications: It dampens the fluctuations of fentanyl effect, needs to be reasonably filled before significant vascular absorption occurs, and contributes to a prolonged residual fentanyl plasma concentration after patch removal. Indeed, the amount of fentanyl remaining within the system and skin depot after removal of the patch is substantial: At the end of a 24-h period a fentanyl patch releasing drug at the rate of 100 mg/h, 1.07 ± 0.43 mg fentanyl (approximately 30% of the total delivered dose from the patch) remains in the skin depot. Thus removing the patch does not stop the continued absorption of fentanyl into the body.52

Because of its long onset time, inability to rapidly adjust drug delivery, and long elimination half-life, transdermal fentanyl is CONTRAINDICATED for acute pain management. And as stated above, the safety of this drug delivery system is compromised even further, because fentanyl will continue to be absorbed from the subcutaneous fat for almost 24 hours after the patch is removed. In fact, the use of this drug delivery system for acute pain has resulted in the death of an otherwise healthy patient. Transdermal fentanyl is applicable only for patients with chronic pain (e.g., cancer) or in opioid tolerant patients. Even when transdermal fentanyl is appropriate, the vehicle imposes its own constraints: the smallest ‘denomination’ of fentanyl “patch” delivers 25 micrograms of fentanyl per hour; the others deliver 50, 75, and 100 micrograms of fentanyl per hour. Patches cannot be physically cut in smaller pieces to deliver less fentanyl. This often limits usefulness in smaller patients, and like other opioids, this drug delivery system has neither been tested nor approved for use in children.

A new noninvasive method of transdermal PCA is on the horizon. Using iontophoresis (electrotransport), small doses of fentanyl (40 mcg) can be self administered across the skin (E-Trans, ALZA Corp, Mountain View, CA).53 Transdermal PCA may offer logistic advantages for patients and nursing staff by eliminating the need for venous access, IV tubing, and specialized pumps.

Complications

Regardless of method of administration, all opioids produce common, unwanted side effects, such as pruritus, nausea and vomiting, constipation, urinary retention, cognitive impairment, tolerance, and dependence.54 Indeed, many patients suffer needlessly from agonizing pain because they would rather suffer than experience these opioid-induced side effects.55 Additionally, physicians are often reluctant to prescribe opioids because of these side effects and because of their fear of other less common, but more serious side effects such as respiratory depression. Several clinical and laboratory studies have demonstrated that low-dose naloxone infusions (0.25 - 1 mcg/kg/H) can treat or prevent opioid-induced side effects without affecting the quality of analgesia or opioid requirements.56 We recently confirmed this in a study in children and adolescents and now routinely start a concomitant low dose naloxone infusion (0.25 mc/kg/hour) whenever we initiate IVPCA therapy.57

Transition to Oral Medication

Successful transition from intravenous (or epidural) analgesics to oral medication depends on the clinician’s ability to provide alternative therapy that is palatable, acceptable, and above all, equally effective in treating pain. There are many advantages in providing pain medication by the oral route. Enteral therapies are a less invasive route of drug administration and enables children to more rapidly return to their “normal” lives. Additionally, they are easier and cheaper to deliver than the routes of drug administration they are replacing.

Certain criteria are essential for the successful transition to oral medication. Obviously, normal gastrointestinal function must be present before attempting enteral therapy. Thus, the child must be able to drink and/or eat (or have a functioning gastric tube). A child who is nauseous or vomits after eating will simply not tolerate oral analgesics. Second, severe pain is difficult, if not impossible, to control with oral analgesics alone. Therefore, oral analgesics should be reserved for the treatment of mild to moderate pain during the latter part of the recovery process. Assessment of the degree of pain and existing treatment modalities are steps that aid the transition process. Third, an oral formulation that is palatable and appropriate must be available. Finally, one must convert the current parenteral opioid dosing into a roughly equianalgesic oral dose.

This conversion is fairly straight forward even when patients are receiving multiple forms and doses of parenteral opioids. As a first step, we convert the entire daily dose of administered opioids into IV morphine equivalents (Example 1). We then convert that morphine dose to an equianalgesic dose of oxycodone, our preferred oral opioid, using the formula: 0.1 mg/kg IV morphine = 0.1 mg/kg PO oxycodone. As an astute reader, you should realize that this formula actually underestimates the bioequivalence of the drugs. We do this to minimize the risk of overdosing patients during the transition. Finally, in our practice, we use the IVPCA pump to ease the transition to oral medication. Indeed, the PCA pump provides the child with the option to self administer a bolus demand dose as a “rescue dose”if the equianalgesic dosing calculations are in error and thereby acts as a “safety net” during the transition.

Example 1: A 5 year old, 20 kg male was the victim of a motor vehicle accident and sustained a pelvic fracture. He has been on IVPCA morphine for 2 weeks and will be discharged home for further outpatient therapy and recovery. He receives morphine 2 mg/hour and averages 1 bolus of 0.5 mg morphine every hour. He cannot swallow pills.
Step 1: 2 mg/hour * 24 hours = 48 mg morphine/24 hours
Step 2: 0.5 mg/bolus * 24 bolus/day = 12 mg morphine
Step 3: total 24 hour morphine = 48 + 12 mg = 60 mg
Step 4: 60 mg IV morphine = 60 mg PO oxycodone (actually this represents a 25-40% decrease in bioequavalence)
Step 5: Prescribe oxycodone elixir (1 mg/mL), 10 mg every 4 hours and an analgesic with antipyretic activity (such as acetaminophen or ibuprofen).
Step 6: 20- 30 minutes after administering the first oral analgesic dose stop the basal opioid infusion.
Step 7: The IVPCA device is discontinued if no further IVPCA demand doses are used in the next 6 - 12 hours. Increase the oral analgesic dose by approximately 25% if 1-3 demand doses are recorded in six hours.

Local Anesthetics

Over the past 25 years, the use of local anesthetics and regional anesthetic techniques in pediatric practice has undergone a dramatic change. Unlike most drugs used in medical practice, local anesthetics must be physically deposited at their site of action by direct application. This requires patient cooperation and the use of specialized needles and equipment. Because of this, for decades children were considered poor candidates for regional anesthetic techniques because of their overwhelming fear of needles. However, once it was recognized that regional anesthesia could be used as an adjunct, and not a replacement for general anesthesia, its use has increased exponentially. Regional anesthesia offers the anesthesiologist and pain specialist many benefits. It modifies the neuro-endocrine stress response, provides profound post-operative pain relief, insures a more rapid recovery, and may shorten hospital stay. Furthermore, since catheters placed in the epidural, upper or lower extremity or lumbar plexii, and other spaces can be used for days or months, local anesthetics are increasingly being used not only for postoperative pain relief, but also for medical (e.g., sickle cell vaso-occlusive crisis), neuropathic, and terminal pain.58-60 61;62 Peripheral nerve blocks can also provide significant pain relief after many common pediatric procedures. These techniques range from simple infiltration of local anesthetics to neuraxial blocks like spinal and epidural analgesia. To be used safely, a working knowledge of the differences in how local anesthetics are metabolized in infants and children is necessary (Table 4).58;63;64

Effects of Age on Metabolism of Local Anesthetics

The ester local anesthetics are metabolized by plasma cholinesterase. Neonates and infants up to six months of age have less than half of the adult levels of this plasma enzyme. Clearance may thereby be reduced and the effects of ester local anesthetics prolonged. Amides, on the other hand, are metabolized in the liver and bound by plasma proteins. Neonates and young infants (less than 3 months of age) have reduced liver blood flow and immature metabolic degradation pathways. Thus, larger fractions of local anesthetics are unmetabolized and remain active in the plasma than in the adult. More local anesthetic is excreted in the urine unchanged. Furthermore, neonates and infants may be at increased risk for the toxic effects of amide local anesthetics because of lower levels of albumin and alpha-1 acid glycoproteins which are proteins essential for drug binding.65 This leads to increased concentrations of free drug and potential toxicity, particularly with bupivacaine. On the other hand, the larger volume of distribution at steady state seen in the neonate for these (and other) drugs may confer some clinical protection by lowering plasma drug levels.

The metabolism of the amide local anesthetic prilocaine is unique in that it results in the production of oxidants that can lead to the development of methemoglobinemia. This occurs in adults with doses of prilocaine greater than 600 mg. Because premature and full term infants have decreased levels of methemoglobin reductase, they are more susceptible to developing methemoglobinemia.66 An additional factor rendering newborns more susceptible to methemoglobinemia is the relative ease by which fetal hemoglobin is oxidized compared to adult hemoglobin. Because of this, prilocaine has not been recommended for routine use in neonates. 67-69 Unfortunately, this has limited the use of the topical local anesthetic, EMLA (eutectic mixture of local anesthetics), in the newborn.

Recent evidence suggests that this fear of using EMLA in neonates may be unfounded. Single doses have been shown to be safe and effective in the management of newborn circumcision.65;70 In 1999, Essink-Tjebbes et al published an efficacy and safety review of studies involving EMLA in neonates (excluding circumcision) and found that EMLA was safe when used once a day in both term and pre-term neonates.71 They subsequently showed that using 0.5 g up to four times a day on heels of preterm infants did not raise methemoglobin levels.72 A study in term neonates using 1 g of EMLA on intact skin found that methemoglobin concentrations were significantly higher in the EMLA group in the intervals from 3.5 to 13 hours after application but were well below potentially harmful levels.73 Fortunately there are now several alternative topical local anesthetics (lidocaine 4% creams) available (and more are coming to the marketplace) that are equally effective and do not have prilocaine.74;75

Local Anesthetic Dosing

It is beyond the scope of this chapter to discuss in detail the many nerve blocks and regional anesthetic that can be easily and safely performed in pediatrics. However, a brief discussion of local anesthetic dosing is warranted, particularly for the most commonly used local anesthetics for local infiltration, topical application, and neural blockade. These include lidocaine, bupivacaine, ropivacaine, and chloroprocaine.

As in adults, local anesthetic toxicity is primarily related to how rapidly and how much local anesthetic is absorbed (or deposited) in the blood. Toxicity can be limited by careful attention to dose, route of administration, and by limiting the rate of rise of local anesthetic into the systemic circulation. Therefore, careful attention to detail is mandatory, particularly when these drugs are used in newborns and younger infants. Usually, no more than 2-2.5mg/kg of bupivacaine (and ropivacaine) or 5-7 mg/kg lidocaine should be used (Table 3). When given by continuous infusion, the maximum hourly bupivacaine infusion rate should not exceed 0.4 mg/kg/hour in the older child and adolescent and 0.2 mg/kg hour in the newborn.76 Dilute solutions of the local anesthetics can be used to provide adequate spread of the anesthetic solution without exceeding the maximum dose. Epinephrine can also be added to the solution in vascular areas to slow the uptake of the anesthetic and to prolong its action. However, epinephrine must never be used in procedures involving end-arteries, such as the penis or distal extremities, in order to avoid ischemic injury to these areas.

Table 3: Maximum Local Anesthetic Dosing Guideline

Drug	Dose mg/kg without epinephrine	Dose mg/kg with epinephrine	Duration (hours)	Contraindications	Comments
Bupivacaine 1	2	3	3-6		reduce dose by 50% in neonates
Chloroprocaine 2	8	10	1	plasma cholinesterase deficiency	short acting, rapid metabolism, useful in neonates and ? patients with seizures or liver disease
Lidocaine	5	7	1
Ropivacaine	2	3	3-6		Less cardiotoxicity than bupivacaine

Finally, the pain of local anesthetic administration can be minimized by using small gauge needles (25-30), warm, buffered anesthetic solutions, and by injecting slowly. Adding bicarbonate to local anesthetic solutions shortens the onset time (faster block) and reduces the pain of injection.77;78 This is best accomplished by adding 1 mL (1 mEq) of 8.4% sodium bicarbonate to 9 mL lidocaine or by add 1 mL (1 mEq) of 8.4% sodium bicarbonate to 29 mL bupivacaine.63;79

Conclusion

The past 25 years have seen an explosion in research and interest in pediatric (and adult) pain management. In this brief review we have tried to consolidate in a comprehensive manner some of the most commonly used agents and techniques in current practice.
 

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