General Principles of Pain Management
There are several different pharmacological options used to treat neonates who are experiencing pain or undergoing a painful procedure. These treatments generally involve opioids, nonopioids, or coanalgesics.
Opioids are natural, endogenous or synthetic compounds that primarily activate the mu receptors. The term opiate refers to a class of alkaloid compounds derived naturally from the poppy, such as morphine and codeine. Heroin, oxycodone, hydromorphone, methadone, and buprenorphine are examples of synthetic opioids (Ries, Fiellin, Miller, & Saitz, 2009). Nonopioids, such as nonsteriodal anti-inflammatory drugs (NSAIDs), among others, refer to drugs that do not bind to opioid receptors. Some may be given with opioids for enhanced effect. Coanalgesics are drugs that do not produce much or any analgesic effect but work to enhance analgesic drugs or offer symptom relief, which leads to pain reduction. These three classifications of medications are discussed specifically in the next chapters and are listed in Table 3.1.
PHARMACOKINETICS AND PHARMACODYNAMICS OF PAIN THERAPY IN NEONATES
Pain can be managed through pharmacological and nonpharmacological means. Although nonpharmacological treatment is preferred in this population, medication is necessary for many of the invasive procedures performed in the neonatal intensive care unit (NICU). The problem with pharmacological measures in the neonate is the lack of study specific to the neonatal population, especially those born prematurely. Most drugs commonly given to neonates are not labeled for use in this population; they are given because they have always been given. A recent study suggests that up to 90% of all medication in the NICU is “off label” (Allegaert, van den Anker, & Naulaers, 2007). Neonates, especially as prematurity increases, are a vulnerable population on which to perform a randomized controlled trial. This off-label drug use does not come without consequences. Research has suggested an increased incidence of kernicterus after widespread use of sulfonamides and of gray baby syndrome from chloramphenicol use in neonates. Despite these experiences, drug therapy in neonates still lacks regular clinical testing and thorough prescribing information (Food and Drug Administration, 2001). Off-label use, although dangerous, is not usually a haphazard use of therapy. It is often a therapy tested through experience and sound judgment in the absence of a controlled trial to use as reference. In 2002, the American Academy of Pediatrics (AAP) Committee on Drugs released a statement on the off-label use of drugs in pediatric patients. The committee stated, “off-label use does not imply an improper use and certainly does not imply an illegal use or a contraindication based on evidence” and “the off-label use of a drug should be based on sound scientific evidence, expert medical judgment, or published literature” (American Academy of Pediatrics Committee on Drugs, 2002).
TABLE 3.1 Modified Drug Classification Reference Table From the Children’s Hospital Association
What we do know is that most drugs will metabolize differently in the neonate and the preterm than in an adult patient. This is because of inherent differences in body surface area, metabolic systems, renal, liver, gut and excretory functions, increased fluid requirement, and concurrent underlying pathologies. These differences become more profound the younger and smaller the neonate.
In the newborn, drug-metabolizing enzymes are immature, particularly CYP2D6 and CYP1A1. CYP3A4 gradually increases with increasing gestational age in preterm infants. The role and substrates of CYP3A7, the fetal form of CYP3A4, remain unknown. In general, phase II or conjugation reactions are inefficient in newborns. They may play an important role in reducing their ability to eliminate xenobiotics. Gastric pH is higher, gastric emptying prolonged, and intestinal absorption is delayed in earlier gestation neonates (Choonara & Conroy, 2002).
Drug distribution is affected by the extreme difference in body composition, especially total fluid and lipid distribution. Differences in developmental expression of metabolic pathways, in addition to immature renal clearance, lead to the profound differences in individual drug biodisposition, especially in very low-birth-weight infants.
In addition to developmental immaturity, these infants may have organ dysfunction related to concomitant disease processes that reduce the clearance or elimination of drugs. This is especially true of hepatic or renal insufficiency. Also, the very measures used to save provide life-saving treatment (e.g., positive pressure ventilation) may reduce hepatic blood flow, which is particularly important for drugs, such as morphine, that have clearance related to hepatic blood flow (Choonara & Conroy, 2002).
A major problem with pharmacology for use in the neonatal population is the limited availability of validated pharmacodynamic endpoints, which are specific testing targets used to see what dosage is safe and effective for this specific population. The situation in neonates is critical because “immaturity of cellular transporters or receptors is likely to alter the effect of drugs, particularly at the low-gestational ages” (Choonara & Conroy, 2002). It is therefore imperative that we are able to see exactly what the effects are for neonates, especially preterms, and not make assumptions based on studies of animals, adults, or even older children. See Box 3.1 for important issues to consider about medication selection and administration.