**1.1. Paediatric pain**

Pain is described as an unpleasant sensory and emotional sensation associated with actual or potential tissue damage [2]. Pain is a normal physiological response to injury that protects an injured area at the time of healing. The experience of pain is the consequence of neuroinflammatory activity and its interaction with complex peripheral and central nervous information-processing networks. It is not a simple hardwired impulse to sense message. The complex sequence of electrochemical events that take place from the site of injury to perception of pain is known as nociception. External noxious energy from the site of injury is converted into electrophysiological activity (transduction). This coded information is relayed via multiple parallel ascending pathways through the spinal cord to the brainstem, thalamus and sensory cortex (transmission). Incoming nociceptive traffic can be modified at any point in this transmission pathway by descending inhibitory pathways (modulation) [3]. The periaqueductal grey region, within the midbrain, and the periventricular grey matter connect anatomically with the rostroventral medulla and send descending excitatory projections to the dorsal horn of the spinal cord. Finally, connections between the thalamus and other higher cortical centres integrate the autonomic, affective and emotional responses to give a cumulative perception of pain [4]. It is important to note that pain pathways show remarkable neuroplasticity, changing phenotype in response to sustained inputs [5].

The paediatric experience of pain is influenced by many factors including the degree of tissue damage, age, sex, pharmacogenetic profile, previous pain experiences, cognitive factors, emotional issues, behavioural aspects, family background, environment, peer groups and culture. Due to the diverse interplay of these factors, there is substantial inter-individual variability in pain perception for different child/youths who have undergone the same surgical insult. In addition inter-individual variability in response to medications due to pharmacogenetic, sex, cultural, cognitive and emotional factors means that the analgesic response to doses of analgesia medication is also not predictable. Hence, the nature of pain as a sensation and its overall significance to a child/youth is unique. The resulting uncertainty in an individual child's pain perception and response to medications dictate that pain therapy is targeted according to ongoing individual assessment and response. Safe clinical practice requires appropriate understanding of pain pathophysiology, different pain models, pain assessment in different aged children and the age-related changes in the pharmacokinetics and pharmacodynamics of analgesics in infants and children. In an effort to comprehend why IVLT is effective, it is essential to understand some the mechanisms integral to pain physiology and pathophysiology.

## **1.2. Pain physiology and pathophysiology**

Nociceptors are the free nerve endings of primary afferent pain nerve fibres responsible for the detection of noxious (unpleasant) stimuli, transforming the stimuli into electrical signals that are conducted to the central nervous system. Nocioceptors are distributed throughout the body and can be stimulated by mechanical, thermal or chemical stimuli.

Tissue injury induces an inflammatory reaction with an increase in acute phase proteins and the release of vasoactive mediators from mast cells and platelets. This inflammatory reaction includes activation of the kinin, complement and cytokine systems with release of inflammatory markers such as endothelin, prostaglandin E2, leukotrienes, substance P, bradykinin, cytokines, serotonin and adrenaline. These inflammatory markers induce peripheral nocioceptor sensitization and increased neuronal excitability [6–8]. These changes are partly caused by a change in levels of growth factors such as nerve growth factor, brain-derived neurotrophic factor, neuotrophin-3 and glial-cell derived neurotrophic factor [5].

**1. Introduction**

64 Pain Relief - From Analgesics to Alternative Therapies

**1.1. Paediatric pain**

**1.2. Pain physiology and pathophysiology**

Pain is described as an unpleasant sensory and emotional sensation associated with actual or potential tissue damage [2]. Pain is a normal physiological response to injury that protects an injured area at the time of healing. The experience of pain is the consequence of neuroinflammatory activity and its interaction with complex peripheral and central nervous information-processing networks. It is not a simple hardwired impulse to sense message. The complex sequence of electrochemical events that take place from the site of injury to perception of pain is known as nociception. External noxious energy from the site of injury is converted into electrophysiological activity (transduction). This coded information is relayed via multiple parallel ascending pathways through the spinal cord to the brainstem, thalamus and sensory cortex (transmission). Incoming nociceptive traffic can be modified at any point in this transmission pathway by descending inhibitory pathways (modulation) [3]. The periaqueductal grey region, within the midbrain, and the periventricular grey matter connect anatomically with the rostroventral medulla and send descending excitatory projections to the dorsal horn of the spinal cord. Finally, connections between the thalamus and other higher cortical centres integrate the autonomic, affective and emotional responses to give a cumulative perception of pain [4]. It is important to note that pain pathways show remarkable neuroplasticity, changing phenotype in response to sustained inputs [5].

The paediatric experience of pain is influenced by many factors including the degree of tissue damage, age, sex, pharmacogenetic profile, previous pain experiences, cognitive factors, emotional issues, behavioural aspects, family background, environment, peer groups and culture. Due to the diverse interplay of these factors, there is substantial inter-individual variability in pain perception for different child/youths who have undergone the same surgical insult. In addition inter-individual variability in response to medications due to pharmacogenetic, sex, cultural, cognitive and emotional factors means that the analgesic response to doses of analgesia medication is also not predictable. Hence, the nature of pain as a sensation and its overall significance to a child/youth is unique. The resulting uncertainty in an individual child's pain perception and response to medications dictate that pain therapy is targeted according to ongoing individual assessment and response. Safe clinical practice requires appropriate understanding of pain pathophysiology, different pain models, pain assessment in different aged children and the age-related changes in the pharmacokinetics and pharmacodynamics of analgesics in infants and children. In an effort to comprehend why IVLT is effective, it is essential to understand some the mechanisms integral to pain physiology and pathophysiology.

Nociceptors are the free nerve endings of primary afferent pain nerve fibres responsible for the detection of noxious (unpleasant) stimuli, transforming the stimuli into electrical signals that are conducted to the central nervous system. Nocioceptors are distributed throughout

the body and can be stimulated by mechanical, thermal or chemical stimuli.

Activation of nocioceptors creates energy that is converted into electrophysiological activity and transduced. Action potentials are created by activity of voltage-gated sodium and potassium channels which then propagate through axons to synapse in the dorsal horn [9]. The spinaldorsal horn receives this nocioceptive information principally from primary afferent A-delta and C fibres. A-delta fibres are medium diameter myelinated axons that transmit acute afferent, localized sharp pain sensation. C fibres are small diameter un-myelinated afferents and convey delayed poorly localized pain. In the dorsal horn depolarization opens voltage-gated calcium channels (VGCC) which release substance P and glutamate that activate second-order neurons.

Following injury, the inflammatory mediators released also activate G-protein-coupled receptors expressed on sensory neurons. These are of fundamental importance for intra- and intercellular communication pathways [10] and play an important role in pain modulation and inflammation [11, 12]. It is relevant to note that cell membranes of injured peripheral nerves can exhibit an increased density in sodium channels and produce ectopic impulse generation and persistent spontaneous discharge in these nerves, their dorsal root ganglia, as well as neighbouring un-injured neurons [13–20]. As these spontaneous discharges have been shown to develop in both myelinated and un-myelinated nerve fibres, it is evident that ectopic activity can arise in both nociceptors and low-threshold mechanoreceptors [21]. Voltage-gated sodium channels (VGSC) with distinct gating and pharmacological properties have been reported to be upregulated in adult neurons by injury or disease [22]. An increased expression of sodium channels in dorsal root ganglia and around the injury site of injured axons contributes to spontaneous firing of nerve fibres after injury [23]. Changes in expression of sodium channels also occur in chronic neuropathic and inflammatory pain states [20, 24–28]. Changes in the properties and expression of voltage-gated calcium channels are also observed in neuropathic pain [29].

The non-selective cation channels, which make up the transient receptor potential (TRP) family of ion channels, are also key components in nocioception [30–32] and neurogenic inflammation [33, 34]. The transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) channels are members of this TRP family. TRPV1 and TRPA1 are expressed on some sensory nerves and dorsal root ganglia [35]. They inter-link considerably with each other in terms of function, except, only TRPV1 is activated by vanilloids, like capsaicin (the piquant component of chili peppers). About 97% of TRPA1-expressing sensory neurons express TRPV1, while 30% of TRPV1-expressing neurons express TRPA1 [36]. TRPA1 is a molecular sensor of potentially toxic chemicals [37, 38] and is also activated by low temperatures [38, 39], mechanical stimuli [40, 41], and elevation of intra-cellular Ca2+ [42]. TRPA1 is, therefore, involved in the generation of pain signals associated with exposure to noxious chemicals, cold and mechanical stimuli [31]. In animal models of inflammatory and neuropathic pain, TRPA1 is up-regulated in sensory neurons [43, 44] and TRPA1 antagonists have been found to exhibit analgesic properties [45–47].

The terminals of C and A-delta fibres are concentrated in the superficial dorsal horn, C and Ad fibres terminate in lamina I (marginal zone) and lamina II (substantia gelatinosa) with some Ad fibres also terminating in lamina V. These fibres activate second-order neurons as well as modulatory inter-neurons (located in laminae V and VI). Primary afferent terminals release a number of excitatory neurotransmitters including glutamate and substance P.

Primary afferent nociceptive inputs synapse in the dorsal horn utilizing alpha-amino-3-hydroxy-5-methyl-4-iso-xazolepropionate (AMPA), neurokinin-1, and calcitonin gene-related peptide. Glutamate has a fundamental role in the activation of both AMPA and N-methyld-aspartate (NMDA) receptors in the dorsal horn, which generate excitatory post-synaptic potentials. Substance P belongs to the neurokinin group of small peptides, its effects are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is present in only a minority of neurons (5–7%) and only in certain areas of the central nervous system. Release of substance P is induced by injurious stimuli, and the extent of its release is proportional to the strength and frequency of stimulation.

Glycine also serves an important role in central neurotransmission. It is an inhibitory neurotransmitter, and a co-agonist with glutamate at the NMDA receptor. These actions depend on extracellular glycine levels, which are regulated by glycine transporters. Ablation or silencing of spinal glycinergic neurons induces hyperalgesia and spontaneous pain behaviours, while their activation evokes analgesia against acute and chronic pain in rodents [48]. During high neuronal activity, glycine released from inhibitory inter-neurons escapes from the synaptic cleft, reaches nearby NMDA receptors and stimulates the NMDA receptor.

It is important to realize that different pain states (i.e. neuropathic/cancer/inflammatory) do create a unique but different set of neurochemical changes within sensory neurons, dorsal root ganglia and the spinal cord [5, 49].

Information from second-order neurons is relayed via the spinal cord to the brainstem and thalamus. Connections between the thalamus and higher cortical centres integrate the affective and autonomic responses to pain perception. In addition, descending axons from the brainstem synapse and release serotonin, noradrenaline and enkephalins in dorsal horn to also modify nociceptive transmission.

Primary afferent A-beta fibres are large-diameter myelinated nerves, which transmit mechanical information such as light touch. A-beta fibres do not usually activate nociceptive neurons and therefore do not transmit pain. The terminals of A-beta fibres are concentrated in the deeper dorsal horn and mainly target excitatory and inhibitory inter-neurons. However, the dorsal horn neuronal interconnections are modified and modulated under pathological conditions, such as peripheral nerve injury or peripheral tissue inflammation from injury or surgery [50–52]. Peripheral injuries may trigger on-going increases in the excitability of neurons (sensitization). This occurs at the level of the primary afferent nociceptive peripheral neuron (peripheral sensitization) and at the dorsal horn of the spinal cord (central sensitization). Reduction in the threshold for activation of nociceptive neurons is manifest as allodynia (a non-painful stimulus perceived as painful) and hyperalgesia (a mild painful stimulus perceived as severe or long-lasting pain). Allodynia or touch-evoked pain is A-beta mediated [53].

In animal models of inflammatory and neuropathic pain, TRPA1 is up-regulated in sensory neurons [43, 44] and TRPA1 antagonists have been found to exhibit analgesic properties [45–47].

The terminals of C and A-delta fibres are concentrated in the superficial dorsal horn, C and Ad fibres terminate in lamina I (marginal zone) and lamina II (substantia gelatinosa) with some Ad fibres also terminating in lamina V. These fibres activate second-order neurons as well as modulatory inter-neurons (located in laminae V and VI). Primary afferent terminals release a

Primary afferent nociceptive inputs synapse in the dorsal horn utilizing alpha-amino-3-hydroxy-5-methyl-4-iso-xazolepropionate (AMPA), neurokinin-1, and calcitonin gene-related peptide. Glutamate has a fundamental role in the activation of both AMPA and N-methyld-aspartate (NMDA) receptors in the dorsal horn, which generate excitatory post-synaptic potentials. Substance P belongs to the neurokinin group of small peptides, its effects are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is present in only a minority of neurons (5–7%) and only in certain areas of the central nervous system. Release of substance P is induced by injurious stimuli, and the extent of its release is

Glycine also serves an important role in central neurotransmission. It is an inhibitory neurotransmitter, and a co-agonist with glutamate at the NMDA receptor. These actions depend on extracellular glycine levels, which are regulated by glycine transporters. Ablation or silencing of spinal glycinergic neurons induces hyperalgesia and spontaneous pain behaviours, while their activation evokes analgesia against acute and chronic pain in rodents [48]. During high neuronal activity, glycine released from inhibitory inter-neurons escapes from the synaptic cleft, reaches nearby NMDA receptors and stimulates the NMDA receptor.

It is important to realize that different pain states (i.e. neuropathic/cancer/inflammatory) do create a unique but different set of neurochemical changes within sensory neurons, dorsal

Information from second-order neurons is relayed via the spinal cord to the brainstem and thalamus. Connections between the thalamus and higher cortical centres integrate the affective and autonomic responses to pain perception. In addition, descending axons from the brainstem synapse and release serotonin, noradrenaline and enkephalins in dorsal horn to

Primary afferent A-beta fibres are large-diameter myelinated nerves, which transmit mechanical information such as light touch. A-beta fibres do not usually activate nociceptive neurons and therefore do not transmit pain. The terminals of A-beta fibres are concentrated in the deeper dorsal horn and mainly target excitatory and inhibitory inter-neurons. However, the dorsal horn neuronal interconnections are modified and modulated under pathological conditions, such as peripheral nerve injury or peripheral tissue inflammation from injury or surgery [50–52]. Peripheral injuries may trigger on-going increases in the excitability of neurons (sensitization). This occurs at the level of the primary afferent nociceptive peripheral neuron (peripheral sensitization) and at the dorsal horn of the spinal cord (central sensitization).

number of excitatory neurotransmitters including glutamate and substance P.

proportional to the strength and frequency of stimulation.

root ganglia and the spinal cord [5, 49].

66 Pain Relief - From Analgesics to Alternative Therapies

also modify nociceptive transmission.

Complex interactions occur in the dorsal horn between afferent neurons, inter-neurons and descending modulatory pathways (see below). These interactions determine activity of the secondary afferent neurons. Glycine and gamma-aminobutyric acid (GABA) are important neurotransmitters acting at inhibitory inter-neurons.

Neuropathic pain may involve anomalous excitability in the dorsal horn, resulting from multiple functional alterations including; loss of function of inhibitory inter-neurons, reduced effectiveness of the inhibitory neurotransmitters, sprouting of wide dynamic neurons and activation of microglia, the immune cells of the CNS [54–56]. Microglia activate, respond and transform to reactive states through hypertrophy and proliferation [57, 58]. These activated microglia induce/enhance production and release of pro-inflammatory cytokines and brain-derived neurotrophic factor [59], which modulate the activity of dorsal-horn neurons [60].

"Wind up" is physiological activation in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses [57, 61]. Central sensitization refers to enhanced excitability of dorsal-horn neurons and is characterized by increased spontaneous activity, enlarged receptive field areas, and an increase in responses evoked by large and small calibre primary afferent fibres. IASP taxonomy defines central sensitization as increased responsiveness of nociceptive neurons in the central nervous system to their normal or sub-threshold afferent input [2]. Secondary hyperalgesia (hyperalgesia in undamaged tissue adjacent to the area of actual tissue damage) is due to an increased receptive field and reduced threshold of wide dynamic neurons in the dorsal horn.

Central sensitization and wind-up intensify pain perception, and both depend on activation of N-methyl-d-aspartate (NMDA) receptors. Pain memories imprinted within the central nervous system by NMDA-receptor activation produce hyperalgesia and allodynia. NMDA glutaminergic synapses do not participate significantly in primary nociceptive transmission, but instead in spinal sensitization. NMDA blockade in the spinal cord does not prevent primary afferent transmission of nociceptive information to the thalamus. Therefore, any attempt to reduce pain needs to target nociception, as well as wind up and central sensitization.

The increased barrage of pain impulses secondary to peripheral and central sensitization confers change within the nervous system known as neuroplasticity. That is, the nervous system undergoes maladaptive changes in response to incoming pain signals by reorganizing its structure, function and connections. Patients with ongoing or chronic pain demonstrate such structural brain changes as well as abnormal functioning of the inhibitory pain-modulatory system [62]. In addition, in chronic-pain conditions, the primary brain areas accessed through classical acute pain pathways decrease in their activation incidence and pre-frontal cortex activity increases [63]. A simplified depiction of acute and chronic pain pathways is depicted in **Figures 1** and **2**. For more detailed information, please review "The Basic Science of Pain" by Philip Peng (https:// itunes.apple.com/ca/book/the-basic-science-of-pain/id1174147456?mt=11).

**Figure 1.** Simplified acute pain pathways.

**Figure 2.** Simplified chronic pain pathophysiology.
