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4 Articles in Volume 2, Issue #1
Effective Approaches: Multidisciplinary Pain Management
Head Pains
Managing Pediatric Pain
Mastering Medications

Managing Pediatric Pain

Pharmacological techniques are quite useful for treating pain in children.

During the past two decades, pain treatment in children has received a considerable amount of attention. Numerous books and papers have been published on the management of pediatric pain. Guardiola and Barios, in a published review, revealed that there has been an increased published interest in pediatric pain issues.1 Nevertheless, there exists a culture that allows the under-treatment of pain in children to exist. Outdated methods of restraint, such as strapping a child down in a papoose fashion, without the benefit of sedation, are still being used for procedures such as circumcisions. Documentation of this inadequate care persists.2,3,4 Children who have pain that is not adequately treated have less satisfactory medical outcomes.5-6 The recent evidence that pre-emptive, perioperative pain management in infant males undergoing circumcision has an impact on their future physiological and behavioral pain responses to vaccination, may guide practitioners to new and better ways of thinking about pain in children and treating pain in children.7-8

Pain Assessment in Children

The International Association for the Study of Pain (IASP) defines pain as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”9-10 The definition has been criticized because of its lack of utility when being applied to the neonate or non-verbal patient. The definition speaks more specifically to adult patients because it assumes an ability to verbalize which is not present in a large, very vulnerable segment of the pediatric population. Even though some aspects of pain in the neonate and young infants (and some adults) may be subcortical or reflexive (not cortically processed or associated with emotions), we have assumed that children have pain and are subjected to the beneficial protective aspects of pain.11 It is also assumed, in those cases where the child cannot verbalize, they can suffer the untoward sequelae of unrelieved pain. There are compelling reasons why a more expansive conceptualization of pain with respect to infants is necessary. Our current knowledge base for objectively and efficiently measuring pain in infants is very limited. Therefore, for at least humanitarian reasons, we should assume the presence of the pain experience in the neonate and infant, just as we do in the laboratory animal.

Assessment of pain in children is challenging and with regard to the neonate presents an especially formidable task to the uninitiated. The problematic nature of defining pain in children makes the assessment of pain in this age group even more enigmatic. Some older children may have difficulty describing their pain because of inexperience and a limited vocabulary. The developmental psychology issues in the pediatric population also serve to confound pain assessment. Perrin and Gerrity found that young children tend to blame themselves for illness, thus associating punishment with painful medical procedures.12 Adolescents are able to think in the abstract, so a more complex understanding of illness is usually reached during this period of development. Whether old or young, the assessment of pain is needed to determine the presence of pain. It is also important for the determination of the magnitude of pain present, the impact of pain on homeostasis, and very importantly, the effectiveness of therapy.

Pain assessment measures may be classified as behavioral, physiological, or self-report, depending on the nature of the response that is measured. Pain may be assessed by displays of distress (e.g. grimaces, cries, and protective guarding gestures). It may also be assessed by measuring a child’s physiological state (e.g. heart rate, sweating, blood pressure, and cortisol level), or even by obtaining a child’s direct self-report (e.g. words, numerical ratings, and drawings). To be useful, pain measures must have: (1) validity; (2) reliability; and (3) minimal bias. To be valid, pain measure must unequivocally measure a specific aspect of a child’s pain (e.g. intensity) so that changes in a child’s pain rating represent a meaningful and proportional change in the child’s pain experience. The measure must be reliable in that it provides trustworthy and consistent pain ratings that do not change over time. The measure must be free from response bias, in that children use it similarly regardless of how they may wish to please the questioner or how adults administer the tool. In addition, the pain measure should be practical for assessing different types of pain, (acute, recurrent, and persistent) for many different children (according to age, cognitive level, and cultural background), and versatile for use in a variety of settings (clinic, postoperative recovery room, emergency room, and home). A thorough review of pain assessment in children can be found in, Pain in Children: Nature, Assessment, and Treatment, by Patricia McGrath.13

Analgesic Techniques

An increased understanding of analgesic and anesthetic pharmacology, and familiarity with new drug delivery technologies, means that a profound impact on a patient’s level of pain, as well as his or her potential to develop chronic pain can be made. A new therapy and an old therapy implemented in a new way to attack the problem of pediatric pain are discussed.

Figure 1. Ear Piercing with EMLA

EMLA and Other Topical Analgesics

One of the most terrifying childhood experiences is receiving a shot, a needle stick, or a venipuncture. The pain and anxiety provoked by these early childhood experiences crosses cultural and ethnic boundaries and can have an impact in later life. For several decades, researchers have tried to find methods to eliminate the pain caused by this mechanical stimulation to the skin and underlying structures. Localized skin pressure, cold, ischemia, and topical agents have been utilized to lessen the discomfort associated with many medical procedures. EMLA, a eutectic (a combination of drugs with a lower melting point than the individual agent property is termed, eutectic) mixture of local anesthetics, and more recently Amethocaine, an aqueous gel, have gained acceptance as a means of providing topical pain relief.

To attain the requisite high concentration of local anesthetic in the skin, to block the transmission of pain signals, a topical drug has to not only penetrate the surface of the skin, it most then transit through to the dermis and block the A-delta and C fibers. Local anesthetics, generally, are weak bases. They are marketed as water-soluble hydrochloride salts because the free bases are insoluble or are poorly soluble and unstable in water. The hydrochloride salts are usually acidic leading to a higher proportion of the drug existing in the cation form. The concentrations of the hydrophilic, cation (charged) form and the lipophilic, uncharged species are dependent upon the pKa of the drug. The pKa of most local anesthetics ranges from 7.5-9.0. It is the cation form of the local anesthetic that blocks the transmission of pain sensation, however, it is the uncharged lipophilic base that diffuses through the skin, across a concentration gradient, to the site of action.

Several factors lead to the development of EMLA. It was known that the base form of amide local anesthetics was soluble in oils. If emulsified, the resulting oil-in-water form of the drug has a high concentration of the active base of the local anesthetic. A mixture of lidocaine and prilocaine, crystaline bases, were noted to have a lower melting point than either drug alone. When mixed with an emulsifier, the resulting mixture of lidocaine and prilocaine contained a high concentration of active local anesthetic base that could go directly to the site of action and block pain transmission. Several studies have investigated the efficacy of a lidocaine-prilocaine eutectic mixture applied to the skin of pediatric patients for a venous cannulation.14,15 These researchers have found this combination of local anesthetics to be useful in reducing pain associated with venous catheterization. Other uses of this preparation could include skin grafting, suturing of lacerations, circumcisions, venipuncture, ear piercing or performance of a lumbar puncture (Figures 1 and 2).

A number of studies have investigated the efficacy of a lidocaine-prilocaine eutectic mixture applied to the skin of pediatric patients for a venous cannulation.14,15 These researchers have found this combination of local anesthetics to be useful in reducing pain associated with venous catheterization. However, there appears to be an age-related correlation with the amount of pain reduction seen with EMLA. Rovieux and co-workers found a reduction in pain scores in infants and toddlers undergoing venipuncture.16 However, the reduction in pain was not as significant in older children having the same procedure. Other uses of this preparation could include skin grafting, suturing of lacerations, circumcisions, venipuncture, or lumbar puncture. To be effective, topical anesthesia agents must diffuse through the skin. The use of local anesthetics to infiltrate the skin can provide relief of pain from surgical incisions, wound debridements, and instrumentation of orifices. Toxicity is not usually a problem if one adheres to the safe limits in the amount of drug infiltrated. Bupivacaine is generally used at our institution because of its long duration. The amount used is usually 1.0 cc/kg of 0.25 percent bupivacaine or 0.5 cc/kg of 0.5 percent bupivacaine. This is based on 2.5-3.0 mg/kg being the upper limit for dosing. Lidocaine in solution or as a jelly is very useful. The solution can be given for nerve, gingivostomatitis, wound care, and more nerve blocks. The jelly comes as a two percent concentration, is used in conjunction with urethral instrumentation. The amount used should be based on the patient’s weight and the maximum recommended dose for lidocaine. A reduction in the amount of drug used in premature infants or infants with hyperbilirubinemia for any type of procedure is prudent, since these infants may have more free drug in their systems.

Figure 2. Lumbar Puncture Site Pretreated with EMLA.

Amethocaine

Amethocaine, a tetracaine derivative, is classified as an ester local anesthetic. This gel has gained in popularity recently as a topical anesthetic for painful procedures. After absorption into the blood stream, this ester local anesthetic is rapidly hydrolyzed by plasma cholinesterase. The by-product of its metabolism is para-aminobenzoic. This molecule produces allergic reaction in a small number of patients. The abundance of the cholinesterase limits the toxic side effects. In four percent gel form, under an occlusive dressing, its onset time is about 30 minutes. It appears to provide good analgesia in children for veinipunctures. Initially mixed in DMSO, Amethocaine was found to work quickly and produce no detectable blood levels with a 10 percent preparation.17 This was however, discontinued due to the irritation from the DMSO. The current gel preparation appears to rival EMLA in its effectiveness and to have a shorter onset. Studies are currently under way to evaluate Amethocaine in the United States.

Acetaminophen

Acetaminophen has been in clinical use for more than 100 years and is one of the most widely used analgesics in the world. Though it is well known for its safety, it is also one of the most frequent pharmaceutical agents responsible for poisoning. In 1994, overdose from acetaminophen was responsible for 135 deaths.18 In 1996, it associated with more than 72,000 cases of toxicity and 29 deaths.19 Perhaps it is because of its reputation as a safe and well-tolerated drug with infrequent adverse effects, it has not been treated with as much caution as it deserves.

Site of Action

Acetaminophen has both analgesic and antipyretic effects but has only very weak anti-inflammatory action. It inhibits cyclooxygenase in the brain producing antipyresis. In the presence of high concentration of peroxide, as found in inflammatory tissues, acetaminophen becomes a very weak inhibitor of cyclooxygenase. Cycloxygenase is an enzyme in the body responsible for prostaglandin synthesis. Acetaminophen acts peripherally by blocking pain impulse generation. A study by Bjorkman et al suggests that acetaminophen analgesic effect may be related to blockage of spinal hyperalgesia N-methy-D-aspartate (NMDA) and substance P.20

Acetaminophen has been in clinical use for more than 100 years and is one of the most widely used analgesics in the world. Though it is well known for its safety, it is also one of the most frequent pharmaceutical agents responsible for poisoning.

Absorption

Acetaminophen is ionized in the alkaline duodenum and is absorbed rapidly. Absorption is complete within one hour when given orally. In children, acetaminophen is at times given rectally when the child is fasted during perioperative period or when they have nausea or vomiting. Several studies using different doses of acetaminophen rectally have shown that absorption through this route is slow and variable.21,22,23 Rectal absorption depends on dissolution of the suppository, which in turn depends of factors such as patient temperature, content in the rectum, the base composition, and size of the suppository. Peak plasma concentration after a rectal dose is not reached for two to four hours after administration.

Bioavailability

Bioavailability of orally given acetaminophen is high. In adults, its first pass metabolism is low and its hepatic extraction ratio varies between 0.11-0.37.24 Rectal to oral bioavailability ratio varies between 6.5 to 92.2 percent depending on suppository formulation.25 In neonates it may be as high as one (9).26 Courthard et al showed that the rectal bioavailability of Panadol brand of acetaminophen is 78 percent.27

Effective serum concentration

Serum concentrations necessary for analgesia have been assumed to be similar to that associated with antipyresis, i.e., 10-20 mcg/cc. Anderson et al in 1996 were the first to demonstrate a relationship between plasma concentration and analgesia.28 They showed that at serum levels of 10.5 mcg/cc, there was significant analgesia and opioid sparing effect. Higher serum concentrations also resulted in better analgesia.

Oral Dose

Acetaminophen’s usual recommended dose is 10-15 mg/kg every four to six hours, orally or rectally. At an oral dose of 10 mg/kg, serum level was less than 10 mcg/cc.29 Walsha et al and Berta et al have shown that 10 mg/kg of po acetaminophen gave no more analgesic effect than placebo.30,31 When acetaminophen is given at a dose of 15 mg/kg po, it provides a serum concentration of 10-20 mcg/cc, i.e., within the target serum concentration,32 Walson et al showed that this dose provides effective analgesia.33 Since the daily maximum recommended dose of acetaminophen is 90 mg/kg, giving acetaminophen 15mg/kg every four hours would add up to 90mg/kg per day, which is the same as the maximum dose. This allows no margin for error.

Methods of Pain Treatment for Pediatric Patients
Method Advantage Disadvantage Procedure
Continuous IV more stable plasma levels no peaks and valleys appropriate for all ages less labor intensive equipment costs careful titration required no patient control possible all except for very short procedures major reconstruction nephrectomy
PCA exquisite patient control safe enhances nursing time good for episodic pain pump costs requires patient cooperation not useful below age 4 years all procedures where age is not a concern and hospital stay is sufficiently long
Opioid boluses good for episodic pain less costly for short stays can be used for all ages unstable plasma levels if dosing interval is not appropriate expensive if hospital stay is long all procedures
Peripheral Nerve Block (Ilioinguinal Iliohypogastric ordorsal penile n.) very effective inexpensive requires very little training preemptive analgesia short duration vascular injection nerve damage circumcision repair hypospadias repair
Caudal (one shot) very effective inexpensive requires very little training preemptive analgesia lowers anesthetic requirement if done at beginning of surgery vascular injection intraosseous injection nerve damage epidural hematoma bowel or bladder perforation dural puncture postdural puncture headache good for any procedure below the clavicle cystoscopy inguinal hernia circumcision hypospadias
Epidural (caudal or lumbar) constant level of analgesia safe enhances nursing time muscle relaxation with concentrated local anesthetics or patients can ambulate with dilute epidural solutions lumbar approach is technically difficult in children nerve damage epidural hematoma bowel or bladder perforation dural puncture postdural puncture headache vascular injection good for any procedure below the clavicle revascularization major hypospadias/nephrectomy/ureteral vaginoplasty urethroplasty
Wound infiltration constant level of analgesia safe enhances nursing time technically easy requires very little training requires no special equipment very localized effects visceral pain will not be treated higher local anesthetic absorption less attachments i.e., pumps/poles procedures where somatic pain is most
Topical safe effective technically easy requires no special equipment very localized effects vasoconstriction at site methemoglobinemia in high doses limited availability in some hospitals circumcision skin grafting
 

Rectal dose

Recent studies have shown that a higher rectal acetaminophen dose than 15 mg/kg is necessary to achieve serum level of 10-20 mcg/cc. Montgomery et al showed that 45 mg/kg of rectal acetaminophen is necessary to achieve a serum concentration equivalent of 10-15 mg/kg of acetaminophen po. Korpela et al showed that the ED 50 of rectal acetaminophen is 35mg/kg.34 Birmingham et al showed that 30 mg/kg of rectal acetaminophen resulted in mean serum concentration of 14.2 mcg/cc. Birmingham et al in 2001 found that a 40 mg/kg loading dose followed by 20 mg/kg q6h resulted in serum concentration range of 10-20 mcg/cc.35 The peak serum level during the first 24 hours was less than 40 mcg/cc, well below the toxic level of 120 mcg/cc. With this regimen, the child would receive a total of 100 mg/kg during the first 24 hours. The current daily maximum recommended dose is 90 mg/kg. However, rectal acetaminophen delivery may be less than oral administration so perhaps the maximum daily dose should be adjusted accordingly.

Metabolism and Toxicity

Approximately two percent of acetaminophen is excreted unchanged by the kidneys.36 In adults, approximately 60 percent of acetaminophen is metabolized by glucoronidation while approximately 30 percent is metabolized by sulfation. This ratio is age dependent with sulfation taking a larger role in infants and children under the age of 12. These two pathways to nontoxic metabolites metabolize more than 90 percent of acetaminophen. About five percent of acetaminophen is metabolized by hepatic cytochrome P450 mixed function oxidase to NAPQI (N-acetyl-p-benzoquinone-imine). This metabolite is very toxic and is usually immediately neutralized by anti-oxidant, glutathione, to nontoxic conjugates that are then excreted by the kidneys. NAPQI has a half-life of nanoseconds and can only produce damage to the cells where it is formed. Most of the NAPQI are formed in hepatocyte and hepatic damage is the most common toxic effect. There have been a few reports of kidney, myocardial, and pancreatic damage which may not be the result of hepatic damage. Conditions that lead to an increase in production of NAPQI or decrease store of gutathione to less than 70 percent will allow NAPQI to bind to hepatocytes leading to cell death and centrilobular necrosis. Toxicity may be increased when glutathione is decreased. Causes of decreased glutathione include: starvation, gastroenteritis, liver disease, and AIDS. Substances that induce mixed function oxidase can increase the formation of NAPQI therefore increasing the chance of developing hepatotoxicity after overdose. Inducers of mixed function oxidase include alcohol, cigarette smoke, and medications such as isoniazid, rifampin, phenytoin, and carbamazepine. Children under the age of five have a much lower incidence of hepatotoxicity.37,38 This could be due to differences in their ability to detoxify NAPQI or perhaps due to earlier intervention.

Phases of overdose

There are four phases of acetaminophen poisoning. In phase 1 (0.5-24 h) when glutathione stores are sufficient, patients may appear normal. Usually there is nausea, vomiting, and anorexia. Transaminases may be elevated. In phase 11 (24-72h), glutathione stores have been decreased because of NAPQI binding to hepatocyte. There is right upper quadrant (RUQ) pain and tenderness, elevated transaminase level and prothrombin time may be prolonged. Phase III (72-96h) is characterized by signs of hepatic necrosis with jaundice, coagulation defect, renal failure, and hepatic encephalopathy. Phase IV (4-14d) is when patient either recovers from liver failure with complete resolution or succumbs to fulminant liver failure.

Assessment of overdose

Acute acetaminophen overdose is defined as taking more than 150mg/kg dose in children and max = 4g/day more than 7.5 gm in adult. Dose history cannot be reliably used to determine the risk of hepatic damage. The Remack Matthew nomogram, where serum acetaminophen concentration is plotted against time in hours after ingestion, has been used to assess probability for hepatic damage. In the US, adaptation of this nomogram with a line running parallel to the original but lowered by 25 percent is used to add greater safety.39 Patients with acetaminophen value below the lowered line do not need to be treated for their overdose.

Treatment with gastric lavage is sometimes not necessary depending on the time of ingestion. Activated charcoal should be given. The antidote for acetaminophen overdose NAC (N-Acetycysteine) NAC acts by enhancing glutathione synthesis and by increasing sulfation. It is most effective when given within eight hours of acetaminophen ingestion. Late treatment with NAC does not improve liver function but a recent study showed improved survival with patients who received late NAC.40 Mechanism for this benefit could include antioxidant effect, decreased neutrophil accumulation, and improved microcirculation and oxygen delivery.41

Recommendations

The maximum recommended dose of acetaminophen is 90 mg/kg/day in children. This about the same or slightly lower than what is shown in recent studies to be an effective pain dose. Perhaps the maximum recommended dose could be higher but there are reports of toxicity even with doses within the therapeutic guidelines.42 Acetaminophen comes in many formulations. Accidental overdose in children may occur when parents misread the label, substitute one formulation for another, or overzealously administer more 15 mg/kg medication when the child is not responding to the recommended dose. It is very important for us as physicians to give careful instructions to parents even when only acetaminophen is prescribed.

Summary

Pain has become a priority in many aspects of health care. Pain has been targeted for intensive study and management. Through the establishment of clinical guidelines and standards the Agency for Health Care Policy and Research (AHCPR), the American Pain Society (APS), the World Health Organization (WHO), and most recently the Joint Commission on Accreditation of Health Organizations (JCAHO) have raised the importance of good pain control to patient wellness. The well-informed caregiver has the opportunity to dramatically alter the pain experience of children undergoing medical procedures and surgery by making pain treatment a priority. This includes dispelling the misconception amongst anesthesiologists surgeons and nurse colleagues that pain is unimportant in the pediatric population and that the treatment of pain is unnecessary and unsafe.

No patient should be denied safe and effective postoperative analgesia. This is especially true when we identify those problems that can be addressed through education and training by pain medicine practitioners. The American Academy of Pediatrics has urged clinicians to use the same medical criteria applied to older patients when deciding whether to provide anesthesia and analgesia to infants. The variety of new drugs and refined techniques that allow the pain to be better managed enables patients to receive safe and effective analgesia 24 hours a day.

Psychological methods of pain relief for children and adolescents are not as widely used and understood as they might be. Both pleasant imagery and progressive muscle relaxation have been shown to decrease self-reported pain intensity and pain distress. Pain management in children and adolescents seems best addressed with an integrated multidisciplinary approach that begins in the postoperative period or initial acute phase of injury and extends through the patients convalescence period. Hopefully, the guidelines presented will enable health care providers to make more educated decisions about analgesic use and particularly about the need for opioid narcotics in the pediatric patient. Pain management based on a good working knowledge of pharmacokinetic principles and safe practices will help prevent the establishment of terrible pain cycles and lead to greater patient satisfaction.n

Last updated on: November 18, 2013
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