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History and Overview of Neonatal Pain
The study of pain in neonates is relatively new and still evolving. Before the 1980s, pain in the neonate was disputed and often dismissed. The idea that neonates do not experience pain is not new. Charles Darwin, in his famous work The Expression of the Emotions in Man and Animals, wrote that even though newborns exhibit pain reactions, these were only reflexive and babies were incapable of experiencing and expressing true pain (Darwin, 1872). Darwin’s belief, coupled with research by scientists such as Dr. Flechsig, who equated the absence of myelination in some of the baby’s nervous system as the system’s inability to function (Cope, 1998). This idea was so widely believed that even operations, including open-heart surgery, were carried out without the use of analgesics or anesthetics (Cope, 1998). It was thought that neonatal nervous systems were so immature that they did not feel pain and that lack of myelination translated into a decreased or disorganized response to pain. It is now known that incomplete myelination only leads to a slower conduction of pain, not an absence of pain. This decreased speed is offset, however, by the shorter distance the impulse needs to travel to reach the neonatal brain. Myelination is usually complete by the second to third trimester. There was a belief that because the infant would not remember the pain, it was not necessary to provide relief from pain. Another common concern was that the risks of pain relief exceeded the benefits when it came to pharmacologic and anesthetic use. Today, it is understood that pain is detrimental to term and preterm infants and that these patients have a worse pain experience than an adult or older child. This realization began with a landmark paper published by Anand and Hickey in 1987, which was one of the first peer-reviewed trials to study pain in the neonatal population. In this article, it was made clear that even a fetus is capable of experiencing pain and urged clinicians to humanely treat pain in this population as adults and older children would be treated (Anand & Hickey, 1987). In 1987, the American Academy of Pediatrics (AAP) released a statement on neonatal pain control with consensus from three of their committees: the Committee on Fetus and Newborn and the Committee on Drugs, the Section on Anesthesiology and the Section on Surgery. The statement confirmed that there are now ways to safely use anesthesia and analgesia for surgical procedures and such treatment should be given by following the guidelines for any high-risk patient (AAP, 1987). Practice still needed time to catch up though. In 1997, a study was published on neonatal intensive care units (NICUs), which found that 2,134 invasive procedures were performed in 1 week on 239 patients and only 0.8% of these patients received analgesics (Johnson, Collinge, & Henderson, 1997). Then, in 2001, the AAP Committee on Psychosocial Aspects of Children and Family Health, along with the American Pain Society (APS) Task Force on Pain in Infants, Children, and Adolescents, published a call-to-action statement for the treatment of pediatric pain. In this statement, they directly addressed the critical need for pain management with all types of pediatric pain (acute injuries, chronic pain, procedures, surgery, etc.), and some of the barriers keeping patients from receiving the pain control that they deserve (American Academy of Pediatrics, 2001). A few years later a study was published that demonstrated about one third of the study neonates received analgesia for painful procedures (Simons et al., 2003).
Two studies have addressed whether infants can process noxious stimulation at the cortical level. Using real-time, near-infrared spectroscopy to detect changes in cortical blood flow, both studies showed that noxious stimuli activated the primary somatosensory cortex in newborns (Bartocci, Bergqvist, Lagercrantz, & Anand, 2006; Slater et al., 2006). This was shown to occur in even preterm infants, the youngest of whom were tested at 25 weeks gestational age (Slater et al., 2006).
The current movement is toward pain prevention and treatment, rather than treatment alone. Because of the adverse effects stress can have on the developing neonate, eliminating or minimizing as much stress as possible has become standard practice. Standardized policies and procedures regarding pain management have been put into place in many organizations.
Pain assessment and management are one of the most important components of patient care. Pain is often referred to as the “fifth vital sign” (a phrase introduced by The Joint Commission), along with heart rate, respiration, blood pressure, and temperature, because of the powerful indicator pain is of the patient’s current condition.
Pain is a complex topic that is especially difficult to conceptualize in the neonatal population. Practitioners for adult patients typically base treatment on verbal descriptions regarding pain level and tolerance, yet neonates do not yet have the capacity to relay this information. This leads to a high risk of misinterpreted pain responses and inadequate pain relief in this fragile population, who, unfortunately, are most affected by pain. Neonates sometimes offer physiologic cues to signal pain, but this may be masked or confused with concurrent conditions and comorbidities. For this reason, pain should be at the forefront of all clinical practice and pain relief should be administered if any pain signs are noticed or anticipated.
DEFINING PAIN
There are many ways to describe pain. The International Association for the Study of Pain (IASP) definition of pain as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” is derived from a 1964 definition by Harold Merskey (1979, p. 250). If the patient is an adult and a good historian, simply asking him or her to describe the pain, its location, quality, duration, exacerbating and relieving factors, whether there has been previous injury and any other associating symptoms (such as swelling, numbness, erythema, etc.) will give clues as to what is causing the pain and how relief can be provided. But neonates, unlike adults or even older children, are not able to verbalize such sensations. Neonates also give nonspecific and inconsistent cues that may become masked in their underlying pathology (such as a premature infant having an apneic episode in which pain may not be considered as part of the problem). When treating this population, care providers have to be attuned to often subtle or complicated symptoms. In some cases, providers should treat based on the fact that they are performing an invasive procedure known to cause pain. Inability to express pain in a traditional manner in no way negates the fact that pain is being experienced.
ANATOMY AND PAIN PATHWAYS
DEVELOPMENT
Responses to somatic stimuli begin at an early age. Reflex responses to stimuli begin around 7.5 weeks postconception in the perioral skin and continue to develop in the palms of the hands before finally reaching the limbs by about 13 to 14 weeks. Peripheral pain receptors are in place systemically by around 20 weeks postconception (Stevens, 1999). By 21 weeks, there is dendritic arborization. At around 22 weeks postconception, nerve tracts in the spinal cord to the brain stem and connections with the thalamocortical fibers are in place. But it is not until 32 weeks that the descending, inhibitory fibers are complete. These fibers aid in blunting full pain response and experience. Therefore, a lack of neurotransmitters in the descending tract suggests a lack of complete neuromodulating mechanisms in the preterm infant, making the infant more sensitive to pain than older children and adults (Anand et al., 2006).
Nociception is the most common pain pathway. Nociceptors are sensory receptors that are located throughout the body and are activated by physical, chemical, or heat stimuli. First, painful sensory stimuli are introduced; these can be actual tissue damage, muscle spasms, or even anticipated tissue damage.
Most pain originates from damage to body tissues. A stimulus is introduced, perceived by the nociceptors, then sent through the spinal cord and into the brain for interpretation. A stimulus is transmitted first through tiny afferent nerve fibers in the spinal cord. The fibers that are most responsible for pain are the afferent A-delta and C-fibers (Adriaensen, Gybels, Handwerker, & Van Hees, 1983). These fibers are the first-order neurons and they begin the pain-perception process. A-delta fibers are found primarily in the skin and muscle, and C-fibers are found in muscle, periosteum, and visceral organs. A-delta fibers are myelinated fibers that produce rapid sharp, pricking, and piercing sensations. This pain is usually localized. In contrast, C-fibers are unmyelinated (or poorly so), and conduct temperature, chemical, or strong physical signals. Pain elicited from the C-fibers is a dull, aching, or burning pain that is more diffuse. Of note, there are other fibers responsible for sensation related to pain, such as A-alpha and A-beta fibers. A-alpha and A-beta fibers transmit nonpainful sensations such as pressure, soft touch, and vibration. These nonpainful sensations can be either beneficial or detrimental to pain management by either contributing to stimulation overload or by helping to block painful messages.
The stimuli then travel through to the spinal cord, to the dorsal root ganglia, through to the dorsal horn, and up to the thalamus. This begins the involvement of the second-order neurons. The tract from the dorsal horn to the thalamus is called the spinothalamic tract and it is divided into two pathways: the lateral pathway called the neospinothalamic (NST) tract and the medial pathway called the paleospinothalamic (PST) tract. The NST tract transmits pain directly to the sensory cortex, where it is interpreted. The PST tract synapses in other parts of the brain, such as the limbic system and the reticular formation, which are areas of the brain responsible for emotion and circadian rhythm. A-beta fibers make synapses in the spinal dorsal horn close to synapses of the A-delta and C-fibers. This dorsal horn connection means that input from touch fibers can enter the spinal cord and synapse or communicate with cells carrying nociceptive input. This is an important reason that techniques, such as massage, light touch, acupuncture/acupressure, and other alternative measures, work to aid in pain management.
Pain stimuli may be influenced by neuroregulators. Neuroregulators are chemicals that inhibit, enable, or even enhance painful stimuli. There are two types: neurotransmitters and neuromodulators. Neurotransmitters, such as epinephrine, norepinephrine, acetylcholine, and dopamine, work to either slow or accelerate postsynaptic nerve activity. Neuromodulators are endogenous opiates and help in pain relief. They consist of large amino acid peptides, such as alpha-endorphins, beta-endorphins, and enkephalins, which act similarly to morphine with increased potency. Endorphins are produced in the anterior pituitary gland and hypothalamus. They are larger peptides and longer acting than enkephalins. Enkephalins are more diffuse throughout the brain and dorsal horn. Several types of endorphins and enkephalins have been identified and each acts on a highly specific opiate receptor in the central nervous system (CNS).
Once the pain signal reaches the brain, it is processed at three levels: the thalamus, midbrain, and cortex. These areas work together to interpret and respond to stimuli. The thalamus relays sensory data from the NST and PST tracts. The midbrain alerts the cortex to be aware of incoming stimuli. Lastly, the cortex discriminates and interprets the stimuli. This demonstrates that the painful stimuli must pass through many areas of the brain, which sometimes includes behavioral and emotional centers. All of this happens in a matter of seconds (Figure 1.1).
Almost all painful stimuli cause some degree of tissue damage (e.g., heel lancing, venipuncture, catheterization, difficult adhesive tape removal). This damage leads to a release of chemicals, such as noradrenaline, bradykinin, histamine, prostaglandins, purines, cytokines, 5-HT, leukotrienes, nerve growth factor, and neuropeptides, which sensitize the receptors. This sensitization occurs to make sure the body is aware of the painful stimuli and can act to stop the stimuli and begin repair. These chemicals can also lead to a decrease in the nociception threshold, ectopic discharges, and accumulation of sodium (Na) channels, especially with repeated exposure to pain (Devor, 1994).
Pain is processed in four main ways: transduction, transmission, modulation, and perception (Box 1.1).
FIGURE 1.1. Noceptive stimulus received at the periphery → travels through the dorsal horn of the spinal cord to the dorsal root ganglia → thalamus → through the spinothalamic tracts (paleospinothalamic [PST] and neospinothalamic [NST]) → NST goes to the sensory cortex → PST goes to limbic system and reticular formation.
