For many years, the term pain could not be found in the index of any major pediatric medicine or pediatric surgical textbook.66 The prevailing wisdom was that neonates did not experience pain because of their inadequately developed neuroendocrine systems and nerve pathways. During the last years of the 20th century, however, many research and clinical studies were performed in the areas of pain management and assessment of neonates, infants, children, and adolescents. Today, results of these discoveries have been incorporated into clinical practice, making effective pain therapy a standard of care and pain assessment the fifth vital sign in modern pediatric practice.67
The basic mechanisms of pain perception in infants and children are similar to those of adults, except that pain impulse transmission in neonates occurs primarily along slow-conducting, unmyelinated C fibers rather than along myelinated A-delta fibers. In addition, pain signal transmission in the spinal cord is less precise, and descending inhibitory neurotransmitters are lacking. As a result, neonates and young infants may perceive pain more intensely and be more sensitive to pain than older children or adults.68 It is now known that previous pain experience leads to long-term consequences such as alterations in response to a subsequent painful event.69 Taddio et al.70,71 reported that boys circumcised with the topical anesthetic eutectic mixture of local anesthetics (EMLA) had lower pain responses to subsequent immunizations than those who were circumcised without topical anesthesia. An inadequately treated initial painful procedure may decrease the effect of adequate analgesia in subsequent procedures as a result of altered pain response patterns.
Children consistently report that needles and shots are what they fear most. However, with the current immunization schedule that recommends 14 to 33 injections before adolescence, interventions to decrease injection pain need to be performed (Table e6-1).72,73,74,75,76,77
TABLE e6-1Techniques for Minimizing Pain Caused by Injection |Favorite Table|Download (.pdf) TABLE e6-1 Techniques for Minimizing Pain Caused by Injection
|Pharmacologic Methods |
|EMLA72,110 || |
Advantages: Penetrates the skin to provide anesthesia to a depth of 5 mm; effective in decreasing the pain of IM and subcutaneous injections, venipuncture, IV cannulation, lumbar puncture, circumcision, skin-graft harvesting, and laser dermal therapy; safe and effective in newborns >37 weeks’ gestation. Disc formulation is easier to apply; no need for an occlusive dressing
Disadvantages: Requires 1 hour before onset of adequate anesthesia, has a vasoconstrictive effect that may make starting IV catheters difficult, may induce methemoglobinemia
|J-tip with buffered lidocaine73,78 || |
Advantages: Provides dermal anesthesia to a depth of 5-8 mm within 1-3 minutes; effective in decreasing the pain of IV cannulation
Disadvantage: Makes a popping noise; this can scare a patient who is not properly prepared
|Vapocoolant sprays (ethyl chloride or dichlorodifluoromethane)74 || |
Advantages: Vapocoolant is sprayed directly onto the skin or applied to a cotton ball that is held on the area to be anesthetized; provides local anesthesia within 15 seconds; effective in reducing injection pain in children 4–6 years of age
Disadvantages: Brief duration of action, so procedure should be completed in 1 or 2 minutes; may not be effective in reducing injection pain in infants age 2-6 months
|Local anesthetic (lidocaine)75 || |
Advantage: Reduces the pain of subsequent needle insertion
Disadvantage: Local anesthetic injection itself is associated with pain and burning sensation
|Pacifier with sucrose76 || |
For preterm neonates: 0.1-0.4 mL of a 12%-24% sucrose solution (place on pacifier or the tongue 2 minutes before procedure); for term neonates: 1-2 mL of a 12%-24% sucrose solution (place on pacifier or the tongue 2 minutes before procedure)
Advantage: Noninvasive method to reduce pain associated with needle insertion in infants
Disadvantage: Sucrose solution’s effect in reducing pain gradually decreases over time; loses efficacy by 4 to 6 months of age
|Other Techniques |
|Site selection77 ||For children older than 18 months: Use of the deltoid muscle for IM injections is associated with less pain than injections administered in the thigh; for children older than 3 years: Use of the ventrogluteal area for injection is associated with less pain than the anterior thigh or dorsogluteal area |
|Z-tract technique ||Z-tract IM injection technique is less painful (pull skin taut at the injection site, give injection, and then release the skin); use a higher-gauge needle when the injectable solution is not viscous |
|Behavioral ||Use of distraction methods (eg, blowing bubbles, providing music by headphones, relaxation, imagery, self-hypnosis, or having parents present for the procedure) can be helpful |
Pharmacologic pain management for medical conditions and surgical and postoperative events has progressed considerably over the past decade with the use of continuous opioid infusions, epidural anesthesia, peripheral nerve blockade, local anesthetics, nonsteroidal antiinflammatory drugs, different routes for traditional agents (ie, transmucosal and transdermal), and nonopioid adjuvant drugs (Table e6-2).79,80,81,82 New pain management techniques, education, research, and increasing awareness of pain management options have helped to improve the quality of life in children.
TABLE e6-2Opioid Administration for Acute and Severe Pain |Favorite Table|Download (.pdf) TABLE e6-2 Opioid Administration for Acute and Severe Pain
|Intermittent IV or PO bolus administration (not as needed) || |
Weak opioids (eg, codeine, hydrocodone, and oxycodone) often are combined with acetaminophen or an NSAID for moderate pain. With dose escalation of combination oral products, be aware that the dose does not exceed recommended daily amounts for acetaminophen or ibuprofen. 1%-7% of the general population and up to 28% of some ethnic groups have a genetic variation in the enzyme cytochrome P450 2D6 that causes codeine to be converted to morphine faster and more completely. In 2012, the FDA issued a Drug Safety Communication stating that codeine use in certain children after tonsillectomy or adenoidectomy for obstructive sleep apnea syndrome has lead to deaths and life-threatening respiratory depression. Consider alternative analgesics for children undergoing tonsillectomy or adenoidectomy. If codeine or codeine-containing products are prescribed, use the lowest effective dose for the shortest period of time on an as-needed basis.83 IV administration of codeine has been associated with allergic reactions related to histamine release. Parenteral administration of codeine is not recommended. Intermittent opioid administration is associated with wide fluctuation between peak and trough levels, so the patient may alternate between peak blood levels associated with untoward effects and trough levels associated with inadequate pain relief when being treated for severe pain.
Oxycodone and morphine are available in a sustained-release formulation for use with chronic pain (not acute pain). The tablet must be swallowed whole and cannot be administered to patients through gastric tubes.
|IV continuous infusion79,80 ||Loading dose is administered to achieve rapidly a therapeutic blood level and pain relief (ie, morphine loading dose of 0.05-0.15 mg/kg in children; 0.1 mg/kg infused over 90 minutes in neonates). Loading dose is followed by a maintenance continuous infusion. Doses that are considered safe in children can cause respiratory depression and seizures in neonates because of decreased clearance, immature blood–brain barrier at birth that is more permeable to morphine, and an increased unbound fraction of morphine that increases CNS effects of the drug. |
|PCA81 ||Gives patient some control over his or her pain therapy. PCA allows the patient to self-administer small opioid doses. The PCA-Plus (Abbott, Chicago, IL) pump allows the patient to receive a continuous infusion together with a set number of self-administered doses per hour. PCA helps to eliminate wide peak and trough fluctuations so that levels remain in a therapeutic range. Children as young as 6 or 7 years of age can master the use of PCA. |
|Epidural and intrathecal analgesia82 || |
Effective in the management of severe postoperative, chronic, or cancer pain. Spinal opioids can be administered by a single bolus injection into the epidural or subarachnoid space or by continuous infusion via an indwelling catheter. Dosage requirement by these routes is significantly less than with IV administration (epidural opioid doses: 10-fold lower than IV doses; intrathecal opioid doses: 100-fold lower than IV doses). Morphine, hydromorphone, fentanyl, and sufentanil are effective when administered intrathecally. Bupivacaine is the most commonly used local anesthetic in continuous epidural infusions. Fentanyl, morphine, or hydromorphone usually is combined with bupivacaine for epidural infusions.
Fentanyl and buprenorphine are available as a transdermal formulation. Multiple patches of an agent may be applied for patients who require higher doses. Disadvantage of transdermal administration is the requirement for an alternative short-acting opioid for break-through pain.
|Transmucosal administration ||Fentanyl lozenge is absorbed transmucosally. It is useful for providing analgesia during painful procedures. Advantages include rapid onset of action (within 15 minutes), short duration of action (60-90 minutes), and painless administration because no injection is needed. Common side effects are vomiting and mild to moderate oxygen desaturation. Doses of 10-15 mcg/kg provide blood levels equivalent to 3-5 mcg/kg IV. |
Drugs often are given by the IV route to seriously ill patients. Syringe pumps are widely used for administration of IV drugs. Important steps in successfully administering IV drugs include selecting the drug, calculating the dose, preparing the infusion, programming the infusion pump, and delivering the infusion. Use of “smart” pumps is preferred because they can recognize syringes and have drug libraries and dose limits as safety features. The pumps should be accurate, precise, and easy to use; accept syringes and administration sets from various manufacturers; offer extensive delivery mode combinations, including milliliters per hour, body weight, mass, volume over time, custom dilution and intermittent, loading dose, bolus dose, standby, and volume limit; have wide-ranging flow rates and rate to keep vein open; and have an adequate internal battery capacity.
No single infusion system is ideal for delivery of all drugs in all institutions for all patients. Each facility must be cognizant of problems of drug delivery and develop specific guidelines for IV infusions. At each institution, specific guidelines should be provided for administration of each drug. These guidelines take into account various infusion rates and provide consistency of delivery with each dose. As long as the time for actual delivery is known, times to obtain blood samples for measurement of drug concentration can be adjusted accordingly to generate meaningful data.
Alteration of Dosage Forms
Many drugs used in pediatric patients are not available in suitable dosage forms. This necessitates dilution of high concentrations of drugs intended for adult patients. Examples of these drugs include atropine, diazepam, digoxin, fentanyl, epinephrine, hydralazine, insulin, morphine, phenobarbital, and phenytoin. Volumes ranging from 0.01 to 0.1 mL must be measured to dispense these drugs for use in infants. This obviously can be associated with large errors in measurements, and such errors have caused intoxication with digoxin84 and morphine85 in infants. One solution to this problem is to dilute these concentrated products, but such alterations can influence the stability or compatibility of these drugs. Because of limited data, pharmacists justifiably may be reluctant to alter dosage forms of certain drugs.
Selection of the appropriate vehicle to dilute the adult dosage forms for use in pediatric patients can be difficult. Phenobarbital sodium contains propylene glycol in the original product to improve drug stability. Because propylene glycol can cause hyperosmolality in infants,36 further addition of this vehicle may not be wise. Because of limited access to IV sites in pediatric patients, drugs must be administered through the same site; however, data on drug compatibilities often are missing. Newborn infants often require aminoglycosides for presumed or proven sepsis and calcium gluconate for correction of hypocalcemia or calcium supplementation. Tobramycin and calcium gluconate have been found to be compatible, at least during a 1-hour administration at the same site.85
Administration of oral drugs continues to challenge parents and nurses. Alteration of these drugs by crushing or mixing, refusal of patients to accept the medication, and loss of drug during administration are some factors that can affect pediatric therapy. A common practice is to mix medications in applesauce, syrup, ice cream, or other vehicles just before administration to make the drugs palatable. In 2015, the FDA has approved levetiracetam (Spritam) that uses 3D printing technology, paving the way for potential customization of drugs to meet the needs of pediatric patients. It uses a delivery system that creates premeasured doses which disintegrate in the mouth with a small volume of liquid.
A number of extemporaneous formulations for oral, IV, and rectal administration are included in a compilation of products for use in pediatric patients.86 However, a specific reference on the stability of many drug formulations is lacking and emphasizes the need for continued research in this area.
Drug administration into the middle ear, nose, or eye of a child requires special attention. Certain drugs (eg, sodium valproate and morphine) can be administered rectally to infants who have limited access for IV drug administration or if oral drug administration cannot be accomplished.
Transdermal drug delivery can be used in pediatric patients (a) to avoid problems of drug absorption from the oral route and complications from the IV route and (b) to maximize duration of effect and minimize adverse effects of drugs. As discussed earlier in this chapter, methylphenidate (Daytrana) now is available as a transdermal patch for children with ADHD. Unfortunately, the commercially available transdermal dosage forms (eg, clonidine and scopolamine) are not intended for pediatric patients; these would deliver doses much higher than needed for infants and children.
The issue of medication adherence is more complex in pediatric patients than in adults. Caregivers of young patients must appreciate the importance of understanding and following the prescribing information.
In one study, medication adherence was considered to be a problem in nearly 60% of adolescents (age 12-15 years) with asthma. Approximately 40% of patients had severe denial regarding their asthma and its severity. Nearly 80% of patients had preventable asthma exacerbations.87
Among the factors that can negatively affect adherence are poor communication between the physician and patient or parent, insufficient prescribing information, lack of understanding about the severity of illness by the patient or parent, lack of interest (eg, among adolescents), fear of side effects, failure of the patient or parent to remember to administer the drugs, inconvenient dosage forms or dosing schedules involving administration of three or more doses daily, and unpalatability of drug products.88 Studies in pediatric volunteers have compared the palatability of antibiotics,89 and the data may have important implications for adherence in children.
Medication doses often are based on the body weight of neonates, infants, and children (eg, milligrams per kilogram of body weight per day to be given in one or more portions daily). However, certain drugs, including antineoplastic agents, may be given based on BSA (eg, milligrams per square meter in one or more doses daily). In either case, the total amount of weight- or surface area-based individual or daily dose in a pediatric patient, especially an adolescent, should generally not exceed the amount of drug indicated in an adult patient.
An additional challenge in managing pediatric drug therapy is understanding the effects of obesity on a population that relies on weight-based dosing. As mentioned earlier, the number of children who are overweight or obese has increased markedly over the past 4 decades.51,52 Using ideal body weight versus total body weight to calculate a weight-based dose or to determine BSA can result in a large variance in obese patients. Additional pharmacokinetic studies are needed to study the effects of obesity on drug distribution, protein binding, and clearance and to identify whether dosing should be adjusted according to total body weight or ideal body weight to achieve consistent drug exposure for individual drugs.90,91 Generally, the highest drug dose recommended for a child is the maximum dose approved for adults. However, determining the highest dose of certain drugs for use in children without a known maximum dose for adults (eg, IV immunoglobulin, infliximab, rituximab, and liposomal amphotericin B [AmBisome]) can be difficult.
Drug interaction studies in pediatric age groups generally are lacking. The data often are extrapolated from studies in adult populations. Special attention should be given to adolescents, who may concurrently use alcohol, recreational or illicit drugs, or other prescription or nonprescription medications without the knowledge of the primary healthcare provider, who must attempt to determine their use to avoid drug interactions.
Complementary and Alternative Therapy
In a study of patients between 3 weeks and 18 years (mean, 5.3 years) of age, 45% of caregivers gave a complementary or alternative treatment to the children; 27% had given three or more products in the past year. The most commonly used products were aloe plant or juice (44% of those reporting use of herbal therapies), Echinacea (33%), and sweet oil (25%). The most dangerous combination was ephedra (which was withdrawn from the US market in 2004) with albuterol given to adolescents with asthma. Most caregivers did not recognize potential adverse effects or drug interactions associated with herbs. Friends or relatives were the main sources of information for 80% of caregivers.92
Little is known about the efficacy of herbal products in infants, children, and adolescents. Healthcare professionals must ask caregivers specifically about the use of complementary and alternative treatments to minimize the adverse effects and costs associated with ineffective therapies.
Marijuana has been used in pediatric patients with life-limiting or severely debilitating conditions (eg, cancer and epilepsy) when other treatments were ineffective. It should be noted, however, that no studies have documented the efficacy of marijuana for medical purposes in the pediatric population. A 2015 policy statement of AAP cited several studies documenting the adverse effects of marijuana in adolescents.111 These have included impaired learning due to decreased short-term memory, attention span and problem solving ability; risks with motor vehicle driving associated with changes in motor control, coordination, judgement, and tracking ability; brain development; and drug dependence or addiction which may develop later in adulthood. AAP also recommended changing marijuana from schedule I to schedule II to facilitate research and development under FDA regulations to ensure standards including purity and potency, as well as short-term and long-term effectiveness and safety among children and adolescents.
The Institute of Medicine reported that between 44,000 and 98,000 Americans each year die as a result of medical errors in hospitals.93 According to this report, the vast majority of medical errors that cause harm to patients are preventable. Healthcare professionals have a responsibility for creating a safe medication environment and reducing risk to a vulnerable pediatric population.
Pediatric medication errors commonly occur at the medication-ordering step because of the multiple calculations required for weight-based dosing and the adjustments needed for providing therapy to the developing pediatric patient.94,95,96 The United States Pharmacopeia (USP) Center for the Advancement of Patient Safety states that risk to patients when performing repeated calculations involving multiple steps can be minimized using computer-based algorithms.97 Because the medication-preparation step is also a high-hazard point owing to the need for dilution or manipulation of commercially available products only available in adult doses, the USP recommends that compounded pediatric medications be prepared and labeled in the pharmacy and verified by a pharmacist. In 2006 and 2007, there were several reports of heparin-dispensing errors to neonatal patients caused by different concentrations of the same medication used to service the needs of neonates and adults (neonatal and adult product mix-up).98,99,100,101,102 In 2008, The Joint Commission issued an alert on preventing errors related to commonly used anticoagulants.103 Among drug administration–related errors, wrong dose, wrong technique, and wrong drug are the three most common errors and may be related to an inability to access pediatric drug information. In 2001, the Agency for Healthcare Research and Quality published an evidence-based assessment of patient safety practices that prevent or reduce medication errors.98 Risk-reduction strategies include placing a clinical pharmacist on pediatric wards in hospitals, simplifying the medication-use system, ordering standardized concentrations and doses, implementing computerized physician order-entry systems with dose range checking, dispensing pharmacy-prepared or ready-to-administer doses, standardizing infusion equipment, using smart infusion pumps, using bar-coded medications and bar-coding systems that check the medication at the point of care, and implementing computerized adverse event detection systems.96,98,99,100 Identifying and understanding the high-hazard areas or points of failure in the medication-use process will help in designing strategies that prevent problems before they arise.