21 - Pain - pharmacological management
Editors: Goldman, Ann; Hain, Richard; Liben, Stephen
Title: Oxford Textbook of Palliative Care for Children, 1st Edition
Copyright 2006 Oxford University Press, 2006 (Chapter 34: Danai Papadatou)
> Table of Contents > Section 3 - Symptom care > 19 - Pain: An introduction
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19
Pain: An introduction
John J. Collins
Suellen Walker
Introduction
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 [1]. Implicit in this definition is that pain is a subjective experience and is based on self-report of the experience. Anand and Craig [2] have critically examined the definition of pain in the context of the infant or child who cannot give self report. In its present form, the definition of pain does not apply to living organisms incapable of self-report. They propose a broader definition of pain that applies also to those diverse, special populations, that communicate in a unique and effective manner through their biobehavioural responses [2]. These populations include infants and the cognitively impaired.
Clinicians and researchers have long observed the lack of co-relation between the extent of tissue injury and the intensity of pain or suffering. The experience of pain is subjective, and, as such is modulated not only by biological factors, but also by previously painful experiences, the meaning and context of the pain, fear, anxiety, depression, and a range of other factors. It is essential to assess the extent to which one or more of these modulating factors require specific interventions.
Pain is one of the most common symptoms experienced in children receiving palliative care, and one of the most feared. The severity of this symptom may increase with time, especially when the terminal phase is reached. Palliative therapeutics should generally only be implemented once the underlying causative mechanisms have been established, since therapies directed at the primary cause may ultimately have a more effective outcome for symptom management.
The following Chapter outlines the historical concepts of pain, the myths and misperceptions about pain in children, the epidemiology of pain in dying children, the mechanism of pain perception in humans, the changes in nociceptive processing during development, the long term consequences of early pain and injury, and the mode of action of opioids and adjuvant analgesics.
Historical concepts of pain
It is an integral component of the survival process to recognise a relationship between pain and physical experiences that are harmful to the body. However, there has been much debate about the concept of pain over the centuries. The main controversy has surrounded the relative components of the response to external injury, and the contribution of inner emotions and psychological factors. Homer thought pain was due to arrows shot by Gods, and thus an external physical insult was seen as the determinant of pain. Aristotle, who was the first to distinguish the five senses of sight, hearing, smell, taste, and touch, did not regard pain as a sensation, but rather an emotion. He classed it as one of the passions of the soul , and felt that pain may result from unduly violent forms of wave motion due to the other sensations. Plato argued that pain and pleasure were perceived in the heart and liver, and resulted from violent impacts of the four elements earth, air, fire and, water on the soul. In Roman times, Galen (131 200 AD) investigated sensory physiology and concluded that the brain was the centre of sensation [3, 4, 5].
Over the centuries the relative contributions of injury and emotion, continued to be debated. During the seventeeth century, Descartes developed a mechanistic concept of a neural connection from the periphery to the brain. According to this Cartesian model , one unit of pain stimulus, secondary to a peripheral insult would pass to the brain and result in one unit of pain being perceived centrally [5]. The ninteenth century saw great advances in physiology and anatomy. Specific
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end-organs, peripheral nerve fibres and nerve tracts were identified, and the electrical activity of sensory nerves was studied. As in the Cartesian model, pain was seen as a physiological process within a fairly hard-wired system, which did not allow for modulation of transmission by peripheral, spinal cord or cortical mechanisms. If there was no clearly identifiable physical source of pain, pain was presumed to be due to emotional causes and was seen as imaginary [3], as distinct from pain due to observable physical causes.
The Gate Control theory of Melzack and Wall [6], published in 1965, suggested that activity generated by large myelinated primary afferent fibres (A-beta fibres) would act via inhibitory circuits in the superficial laminae of the dorsal horn, to inhibit the transmission of activity in the small unmyelinated primary afferent C fibres thus closing a gate on pain transmission. Although aspects of the original Gate Control theory have been disputed [7], it provided the framework for directing attention to the active modulation of pain transmission. Thus, the intensity and quality of pain perceived does not bear a push-button, straight-through, one-to-one relationship to the intensity of the stimulus, but is influenced by a multiplicity of physiological, psychological and environmental variables [5].
The epidemiology of pain in dying children
The symptom prevalence, characteristics and distress of 30 children (mean age 8.9 years) dying in hospital have been described [8]. Data from the last week of life were obtained from the medical records and symptoms and their characteristics during the last day of life were determined by nurse interview. The dominant disease process was cancer (n= 18), most likely location of death intensive care (n= 20) and the major physiological disturbances at the time of death were respiratory failure (n= 9) and encephalopathy (n= 9).
The mean ( SD) number of symptoms per patient in the last week of life was 11.1 5.6 and six symptoms, including pain, irritability and fatigue, occurred with a prevalence of 50% or more. The location of death had a significant (p< 0.02) impact on the mean number of symptoms; ward (14.3 6.1) vs. intensive care (9.5 4.7). The prevalence of pain in intensive care was half that of those patients located in the ward (40% vs. 80%). Only fatigue and dry mouth were more prevalent and more distressing to those who experienced these symptoms [8].
These data indicate that pain is both prevalent and highly distressing to many dying children. This raises the importance of paediatric palliative care physicians to be soundly trained in comprehensive pain management strategies. Otherwise, the memory of poorly controlled symptoms in their dying child may be retained for many years in the memory of their parents (Table 19.1).
Myths and misperceptions about pain in children
The myths
The myth that children either do not experience pain, or do not experience pain as much as adults, have inhibited progress in pain management for children until recent times (Table 19.2). Since the 1980s there has been a growing movement towards improved pain control for infants, children, and adolescents. This movement was partly a response to the weight of evidence indicating that poor pain control negatively influenced outcome in post-operative neonates [9]. It was also partly due to improved measures of pain severity in infants and children and a critical mass of clinicians with developing expertise in this area. This latter has seen the development of multidisciplinary pain services in many paediatric centres around the world.
The misperceptions
Although there is an increasing consciousness towards improved pain control for children in general, there are some particular issues pertaining to children receiving palliative care. For example, the meaning of increasing pain severity for some families is that this is a marker of disease progression. Some children and families defer opioid dose increases because of the meaning associated with increasing pain. The names of the opioids have certain meanings for some families. Methadone, for example, can sometimes be an appropriate analgesic for children in certain circumstances. The mere mention of methadone can cause anxiety for some care-givers because of its association with the treatment of opioid drug addiction.
There is confusion about the terms tolerance, dependence, and drug addiction.
Analgesic tolerance refers to the progressive decline in potency of an opioid with chronic use, so that increasingly higher doses are required to achieve the same analgesic effect. Parents are sometimes reluctant to increase opioid doses in their child because of a fear that tolerance will make opioids ineffective later. Reassurance should be given that tolerance, in the majority of cases, can be managed by simple dose escalation, use of adjuvant medications, or perhaps by an opioid switch in the setting of dose-limiting side-effects.
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Table 19.1 Symptom prevalence (n = 29) and characteristics (n = 27) of dying children on the last day of life
Degree when symptom was present
Symptom
Overall prevalence (%)
Frequency A lot-AA (%)a
Intensity mod-VSev (%)b
Distress QB-VM (%)c
a Percentage a lot to almost always.
b Percentage moderate to very severe.
c Percentage quite a bit to very much.
Source: Drake, R., Frost, J., and Collins, J.J. The symptoms of dying children. Pain Symptom Management 2003;27(7):6 10.Skin changes
51.7
NE
60.0
21.4
Lack of energy
48.3
92.8
78.6
30.7
Dry mouth
41.4
66.7
25.0
27.3
Swelling of arms/legs
41.4
NE
50.0
9.1
Feeling drowsy
31.0
88.9
66.7
0.0
Pain
31.0
33.3
11.1
25.0
Problems with urination
27.6
87.5
87.5
0.0
Difficulty swallowing
27.6
75.0
62.5
12.5
Lack of concentration
27.6
62.5
50.0
0.0
Cough
27.6
25.0
12.5
12.5
Lack of appetite
24.1
85.7
85.7
0.0
Diarrhoea
24.1
42.9
28.6
33.3
Dyspnoea
20.7
66.7
33.3
16.7
Feeling irritable
20.7
16.7
16.7
16.7
Weight loss
20.7
NE
50.0
0.0
Mouth sores
20.7
NE
33.3
20.0
Vomiting
20.7
0.0
0.0
16.7
Feeling nervous
13.8
50.0
25.0
75.0
Feeling sad
13.8
50.0
25.0
25.0
Sweating
13.8
50.0
25.0
0.0
Worrying
10.3
100.0
33.3
100.0
Insomnia
10.3
33.3
33.3
0.0
Itching
10.3
33.3
0.0
0.0
Numbness/tingling in hands/feet
6.9
50.0
100.0
100.0
Headache
6.9
50.0
50.0
50.0
Nausea
6.9
50.0
0.0
0.0
Dizziness
6.9
50.0
0.0
0.0
Constipation
6.9
NE
50.0
0.0
Hair loss
6.9
NE
0.0
0.0
Change in the way food tastes
3.4
NE
0.0
0.0
I don't look like myself
0.0
NE
0.0
0.0
Note:NE=not evaluated
Physical dependence is a physiologic state characterized by withdrawal (abstinence syndrome) after dose reduction or discontinuation of the opioid, or administration of an opioid antagonist. Initial manifestations of withdrawal include yawning, diaphoresis, lacrimation, coryza and tachycardia.
Addiction is a psychological and behavioural syndrome characterized by drug craving and aberrant drug use. Some parents fear that an exposure to an opioid will result in their child subsequently becoming a drug addict. The incidence of opioid addiction was examined prospectively in 12,000 hospitalized adult patients, who received at least one dose of a strong opioid [10]. There were only four documented cases of subsequent addiction in patients without a prior history of drug abuse. These data suggest that iatrogenic opioid addiction is an uncommon problem in adults. This observation is also consistent with a large worldwide experience with opioid treatment of cancer pain in childhood.
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Long-term consequences of early pain and injury
Pain and injury in early life are occurring on the background of a developing nervous system. This not only leads to changes in baseline nociceptive processing, but also changes pharmacodynamic responses to analgesic agents. In addition, structural and functional reorganisation of synaptic connections occurs in the postnatal period, and is dependent on activity within developing sensory pathways. As a result, abnormal or excessive activity related to pain and injury may alter normal development, and has the potential to produce behavioural and structural changes that are not seen when similar injuries occur in the adult. Although the laminar distribution of A fibres changes during development, the segmental distribution of the terminal fields of peripheral nerves is somatotopically precise from early in development and allows localisation of a stimulus. However, nerve injury in the first postnatal week in rat pups produces sprouting of remaining terminal afferents into the denervated area [11], while early inflammation can produce an expansion of terminal fields [12, 13]. Clinical studies suggest that early pain related to surgical and procedural interventions during intensive care management of premature neonates can have long term consequences upon pain behaviour, and perception in later life [14, 15]. Further investigation of the plasticity of developing pain pathways is required to evaluate potential long-term effects of pain and injury experienced in early life.
Table 19.2 Myths and misperceptions about pain in children | ||
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How do humans experience pain?
The somatosensory system has the ability to detect noxious stimuli that are potential sources of tissue injury, and then to process this information to elicit the perception of pain and appropriate behavioural responses. Lack of protective sensation can lead to a variety of medical complications, including compartment syndromes or decubitus ulcers. Conversely, there is often no protective significance to some types of pain, such as that of metastatic cancer, or migraine. Neuropathic pain refers to pain associated with abnormal excitability in peripheral or central neurons. Neuropathic pain may persist even after tissue injury or inflammation have subsided. Neuropathic pain often is described as burning, shooting, or stabbing in character, and it is often associated with paraesthesiae. The term allodynia refers to a condition in which pain can be elicited by normally nonpainful stimuli, such as light stroking of the skin. In the absence of acute inflammation of the skin, allodynia generally implies the existence of an underlying neuropathic condition.
Peripheral mechanisms
The detection of noxious stimuli requires activation of peripheral sensory organs (nociceptors), and transduction of the energy into electrical signals for conduction to the central nervous system. Nociceptive afferents are widely distributed throughout the body (skin, muscle, joints, viscera, meninges), and encode stimulus modality, intensity, location and duration. The most numerous subclass of nociceptor is the C-fibre polymodal nociceptor (PMN), which responds to a variety of stimuli, including:
Chemical stimuli A large range of chemical stimuli and inflammatory mediators activate and/or sensitise PMNs [16, 17]. These may act either directly via ligand-gated ion channels (e.g. capsaicin and the vanilloid receptor 1, (VR1), or via metabotropic receptors linked to second messenger systems (e.g. bradykinin at the B2 receptor activates intracellular protein kinase C, (PKC). ATP acts via a number of ligand- gated cation channels (P2X receptors) to excite nociceptors, and the P2X3 subtype is expressed selectively in small diameter
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non-peptidergic, dorsal root ganglion (DRG) neuron [18]. The pH of injured and inflamed tissue is often low, and protons enhance the responsiveness of VR1 [19, 20] and P2X receptors, and also excite nociceptors directly [21]. In addition, a number of acid-sensing ion channels (ASIC1, ASIC2b, and ASIC3) which are selective ligand-gated cation channels, are activated by extracellular acidification [22].
Thermal stimuli The transition from a sensation of warmth, to that of heat pain occurs at approximately 45 C in mammals. This correlates with the threshold for action potential generation in PMNs and a steep increase in firing frequency is seen with further increases in temperature [23]. The transduction mechanism is not dependent on a signal molecule and is not gated by diffusible messengers, and it is likely that heat is signalled through a number of channels [24, 25, 26]. The VR1 capsaicin sensitive receptor responds to thermal stimuli in the noxious heat range (>43 C) [27]. The capsaicin-insensitive vanilloid receptor-like protein subtype 1 (VRL1) is activated by temperatures higher than about 52 C, but is most prominently expressed by medium to large-diameter rather than small diameter DRG neurons [27].
Mechanical stimuli With brief noxious mechanical stimuli, the discharge rate of PMNs increases with the force and pressure applied. With repetitive stimulation, temporal or spatial summations of the nociceptive discharge signal the magnitude of sensation [16]. A different subpopulation (mechano-insensitive nociceptors) may also become active with tonic sustained pressure [28]. The transduction mechanism for mechanical stimuli may involve a stretch-activated channel [29].
Once transduced into electrical stimuli, conduction of neuronal action potentials is dependent on voltage gated sodium channels (VGSCs). However, the sodium current from nociceptive afferents reflects activation of a number of distinct ion channels. A rapidly inactivating, fast sodium current which is sensitive to block by tetrodotoxin is present in all sensory neurons. In addition, PMN neurons express TTX-R currents. The channels responsible for TTX-R currents vary in their subtype, distribution and number in different pain states, and represent an endogenous mechanism to modulate excitability [25].
The cell body of C-fibre PMNs resides in the dorsal root ganglion (DRG), and the axon bifurcates into both the peripheral branch that innervates the skin, and a central branch that enters the spinal cord. Two subtypes of DRG cell have been identified: one group synthesizes peptides [substance P (SP); calcitonin gene related peptide (CGRP)], and expresses the high affinity nerve growth factor (NGF) receptor tyrosine kinase A (trkA); while the second group express the purinergic P2X3 receptor, an IB4-lectin binding site, and receptors for glial derived neurotrophic factor (GDNF) [30, 31]. Both groups respond to similar types of noxious stimulation, and synapse within lamina I and II of the dorsal horn.
Following the synapse of the primary afferent neuron with the second order cell body in the dorsal horn, multiple ascending pathways relay pain transmission. Nocispecific fibres from lamina I neurons that express NK1 receptor ascend to the parabrachial area of brainstem, and a large number of fibres (with connections via lamina V) project in the spinothalamic tract [30]. Small diameter afferents have an orderly somato-topic arrangement in which each portion of the skin surface is innervated by afferent fibres that terminate in preferred localities within the dorsal horn [29]. This somatotopic map is maintained by second order neurones within the ascending tracts in the spinal cord, and is finally represented in the somatosensory cortex, thus allowing localisation of the painful stimulus.
Peripheral sensitization
An increase in peripheral noxious stimulus intensity is encoded in PMNs by an increase in action potential firing. Nociceptors must reach a certain discharge frequency (about 0.5 impulses/sec) for pain to be perceived [16]. A progressive increase in primary afferent firing correlates with the level of pain experienced until tissue damage is produced. A subgroup of C fibres (silent nociceptors) that are chemically sensitive, but initially insensitive to mechanical and thermal stimuli, can be recruited following injury [32], and once activated have features of PMNs.
In the presence of inflammation, nociceptors acquire new characteristics and are said to be sensitized [33, 34]; that is:
they spontaneously discharge and therefore contribute to the continuing pain following tissue injury;
their threshold for activation is decreased, such that innocuous stimuli may cause pain (allodynia) and contribute to the tenderness experienced in an injured region;
their stimulus-response curves are shifted to the left, such that a noxious stimulus causes more pain than normal (hyperalgesia). Primary hyperalgesia is characterised by a decrease in pain threshold and increased response to supra-threshold stimuli within an area of injury [23].
A number of inflammatory mediators induce peripheral sensitisation in PMNs with a resultant increase in C fibre afferent discharge. Prostaglandins, serotonin and adenosine activate adenylate cyclase and increase cyclic AMP, leading to activation of protein kinase A (PKA). One target for PKA is the TTX-R sodium channel [35]. Phosphorylation of the
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channel decreases the action potential threshold, increases the activation rate and increases the current magnitude, thus resulting in more rapid depolarisation. In addition, the inactivation rate of the channel is increased, allowing a decrease in inter-spike interval and the potential for increased discharge frequency [36].
Spinal cord mechanisms
The spinal cord is an important site for modulation of pain transmission. The central terminals of C-fibre nociceptors project predominantly to lamina I and II in the superficial dorsal horn of the spinal cord. However, dorsal horn neurones not only receive information via synaptic transfer from primary afferent neurones, but also from interneurons and descending neural pathways. These multiple inputs have both excitatory and inhibitory influences on the subsequent output from the dorsal horn neuron. The nature and amount of transmitter released, the density and identity of pre- and post-synaptic receptors, the kinetics of receptor activation and ion-channel opening and closing, and the rate of removal or breakdown of transmitter can all modify sensory processing in the spinal cord.
Depolarization of the primary afferent terminal results in glutamate release. If the stimulus intensity is high enough, substance P is also released from dense core vesicles [37]. Glutamate receptors are widely distributed throughout the spinal cord dorsal horn [38], and are of three types: the kainate/AMPA (L-amino-3-hydroxy-5-methylsoxasolepropionoc acid) receptor; the ionotropic n-methyl-D-aspartate (NMDA) receptor; and the metabotropic (mGluR) receptor. Fast synaptic currents (tens of milliseconds) mediated by glutamate acting on ionotropic AMPA receptors signal information relating to the location, intensity, and duration of afferent fibre input. In this normal mode where a high intensity stimulus elicits brief localized pain, the sensory processing, and the stimulus-response relationship between afferent input and dorsal horn neuron output is predictable and reproducible [39].
Central sensitization
Ionotropic NMDA receptors are blocked by magnesium under resting conditions. Repeated C-fibre input results in a progressively more depolarised postsynaptic membrane and removal of the magnesium block. Slow currents mediated by glutamate acting on ionotropic NMDA receptors and mGluR, and by substance P acting on neurokinin1 (NK1) receptors, allow temporal and spatial summation of C fibre input [39]. As a result, there is in an amplified response to each subsequent stimulus, and this rapid progressive increase in dorsal horn neuron responsiveness, during the course of a train of inputs has been termed wind-up [40]. Tissue damage, and persistent primary afferent input also induce more generalized, and long-term changes in the sensitivity of the dorsal horn neuron, termed central sensitisation. Central sensitisation manifests as a reduction in threshold, increase in the responsiveness of dorsal horn neurons, and expansion of the receptive field. This is the result of a number of changes at the primary afferent synapse and within the dorsal horn neuron, which include:
Enhanced transmitter release from the pre-synaptic terminal. Glutamate acts on pre-synaptic NMDA and kainate GluR5 receptors, resulting in a positive feedback loop [41, 42]. Nitric oxide is synthesised following activation of nitric oxide synthase in the dorsal horn cell, and diffuses back to influence pre-synaptic release [43]. A reduction in pre-synaptic inhibition (via adenosine, serotonin, opioid and GABA) will also increase transmitter release.
Increased post-synaptic depolarisation and activation of intracellular cascades. Ongoing activation of ionotropic NMDA receptors, voltage gated calcium channels, and metabotropic mGluR and NK1 receptors results in an increase in intracellular calcium, both via calcium inflow, and release from intracellular stores. A number of enzyme cascades are subsequently activated via PKC, PKA and mitogen-activated kinase (MAPK) [17, 39]. Phosphorylation of the NMDA receptor further reduces the voltage-dependent Mg block and enhances the channel kinetics [38]. These post-translational changes increase the basal sensitivity of dorsal horn neurons, and result in hyperalgesia that extends beyond the site of the initiating stimulus [17]. This surrounding zone of secondary mechanical hyperalgesia occurs in uninjured tissue, and is dependent on both spinal and supraspinal mechanisms.
Activation of transcription factors, with resultant changes in gene and protein expression. Increased PKC is associated with increased expression and insertion of AMPA receptors into the post-synaptic membrane of DH neurons [44]. Changes occurring in DRG and DH neurons often act together. For example, production of substance P increases in DRG neurons and is matched by an increased expression of NK1 receptors in dorsal horn cells [39]. NGF is upregulated in peripheral inflamed tissues, and increases the firing rate of nociceptors. NGF is also retrogradely transported to the DRG of trkA expressing C fibre nociceptors, and contributes to upregulation of TTX-R channels and VR1 receptors, which further increases excitability [31]. Brain-derived neurotrophic
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factor (BDNF) is also upregulated in DRG neurones in the presence of NGF and inflammation [45]. BDNF transport to the dorsal horn increases [46], leading to increased phosphorylation of the NMDA receptor and potentiation of C-fibre mediated spinal reflexes [45, 47]. These changes contribute to longer-term alterations in the relationship between the peripheral stimulus and the dorsal horn neuron response.
The area of tissue that responds to an applied stimulus and generates a neural response within a nerve fibre is described as its receptive field. Each primary afferent, branches on to many central cells (divergence), and dorsal horn neurons receive inputs from many primary afferents (convergence). Therefore, the receptive field of dorsal horn neurones is relatively large and complex, but each central neuron has its own unique temporal and spatial input of activity. Receptive fields can be altered by persistent afferent input [48], with increases in the spatial extent of the receptive field and recruitment of previously subthreshold components. In the presence of inflammation and increased central excitability, cells in the superficial dorsal horn of the rat spinal cord that are normally nociceptive specific respond to low threshold primary afferent mechanoreceptors [49]. This effect is mediated via increased N-methyl-D-aspartate (NMDA) receptor activity as the increase in dorsal horn neuron receptive field size induced by C-fibre stimulation can be blocked by NMDA antagonist [50]. NMDA-receptor antagonists depress central sensitisation in both laboratory and clinical studies [51, 52, 53, 54]. Dextromethorphan, dextrorphan, ketamine, memantine and amantadine, among others have been shown to have NMDA-receptor antagonist activities. The clinical usefulness of some of these medications is compromised by an adverse effect to side effect ratio.
Inhibitory mechanisms
As a result of inhibitory modulation, dorsal horn neurones can also reduce their output with time. Inhibitory effects within the dorsal horn can be activated by a large number of mechanisms that include: non-nociceptive peripheral inputs; local interneuronal fibres with inhibitory transmitters glycine and GABA; descending bulbospinal noradrenergic, serotonergic, and opioid projections; and higher order brain function (distraction, cognitive input etc.). Descending pathways from the brainstem modulate pain transmission in the spinal cord [55, 56]. Activation of presynaptic inhibitory receptors (e.g. mu and delta opioid, alpha-2 adrenergic) reduces transmitter release. Post-synaptic inhibitory receptors on the dorsal horn neuron (e.g. mu, delta and kappa opioid, adenosine, GABA) reduce the excitation evoked by glutamate via a G-protein coupled increase in potassium conductance that hyperpolarizes the membrane [57]. Opioids reduce the slope of the intensity-response curve, and diminish the magnitude of the response evoked in the dorsal horn by C-fibre activity [58]. These inhibitory mechanisms are activated endogenously to reduce the excitatory responses to persistent C-fibre activity [59], and are also targets for exogenous analgesic agents [60].
Table 19.3 How do humans experience pain? | ||||||||
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A unique and different set of neurochemical changes occurs in the spinal cord and the DRGs as a result of inflammatory, neuropathic, and cancer pain states and many of these changes might be involved in generating or maintaining each pain state and might potentially influence therapeutics. For example, it is known clinically that chronic inflammatory pain, cancer pain, and neuropathic pain are best treated with different types of analgesia. While there is a significant upregulation of substance P and CGRP in the dorsal horn in inflammation, these same neurotransmitters are downregulated in neuropathic pain states. In metastatic bone pain there is no changes in these neurotransmitters [61]. The greatest change observed in the spinal cord in response to metastatic bone cancer pain is the upregulation of glial fibrillary acidic protein (GFAP) which is significantly greater than that induced by neuropathic pain (Table 19.3).
Development and changes in nociceptive processing
The reader is referred to previous reviews of the impact of the developing nervous system on nociceptive processing and response to tissue injury [62, 63].
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Peripheral mechanisms of nociception
C-fibre polymodal nociceptors are mature in their pattern of firing at birth, and are capable of being activated by exogenous stimuli [64]. Although peripheral C fibres are initially less able to produce neurogenic oedema, primary hyperalgesia has been demonstrated in a number of early developmental models [65, 66]. Cutaneous withdrawal reflexes can be elicited by low intensity stimuli (that is have lower mechanical and thermal thresholds) early in development as receptive fields are large and inhibitory mechanisms are immature [63]. Developmental changes in the pattern of withdrawal reflexes in rat pups have been correlated with changes in human neonates [67], and the threshold and magnitude of the reflex EMG response correlate with the intensity of the cutaneous stimulus [68]. Similarly, both laboratory and clinical studies have established changes in reflex withdrawal thresholds and the development of hyperalgesia following tissue injury. In neonates, repeated heel prick blood sampling produces primary hyperalgesia in the area of injury with a reduction in the mechanical threshold for limb withdrawal [67] and these changes can be abolished by topical analgesia [69].
Spinal cord nociceptive processing
In the adult, C-fibre polymodal nociceptors project to the superficial dorsal horn (lamina I and II), while larger myelinated A-beta fibres which subserve light touch and pressure project to deeper layers of the dorsal horn (lamina III and IV). Developmentally regulated changes in the functional and anatomical relationships between C and A fibres have signifi-cant effects on nociceptive processing. C fibre afferents enter the spinal cord late relative to A fibre innervation [70], and the density of substance P containing fibres in the dorsal horn is initially low. Early in development, A-beta fibres extend up into laminae I and II and only withdraw to the deeper laminae as C fibres mature [71, 72]. This initial overlap of terminals contributes to the large receptive fields of dorsal horn neurones in early development. Electrical stimulation of the hind-paw at C fibre strength does not evoke post-synaptic activity in dorsal horn cells in the first postnatal week [73], although this does not exclude the presence of subthreshold responses.
Recordings from spinal cord slices confirm that capsaicin increases glutamate release at synapses in the superficial dorsal horn during the first postnatal week, although the frequency of miniature excitatory postsynaptic currents is less at post-natal day (P) 1 5 than at P9 10 [74]. From P10, repetitive C fibre stimulation at three times the C fibre threshold produces wind-up , but is observed in an increased proportion of cells with further increases in age. Sensitisation can be observed early in development, but is produced by repeated A fibre (rather than C fibre) stimulation which evokes activity in both superficial and deep laminae at P3 [73].
Mechanisms of central sensitisation and secondary hyperalgesia differ according to age, as there are developmental changes in the dorsal horn responses evoked by C or A fibre stimulation, alterations in NMDA receptor distribution and function, and variable maturation of post-synaptic intracellular cascades. NMDA receptor activation is an important component of central sensitisation, and this receptor is present throughout the gray matter of the dorsal horn in a higher concentration and more generalised distribution early in development [75]. In addition, the receptor has a higher binding affinity for NMDA, and activation results in a greater influx of calcium ions [76] during the first postnatal week. This may relate to changes in the sub-unit composition of the receptor, as increased NR2A subunit expression increases channel open time and ion flow in developing neocortex [77]. A proportion of NMDA receptors in the developing spinal cord have been considered to be silent as they are not co-localised with AMPA receptors, but repetitive stimulation can drive action potential firing and affect neuron excitability in the absence of AMPA [78]. The influx of calcium ions following NMDA receptor channel opening activates a number of intracellular enzyme cascades, which further modulate activity. Nitric oxide synthase expression does not reach adult levels in lamina II until P20, and this parallels a delay in the development of c-fos expression in response to peripheral mustard oil application [79].
Descending inhibitory pathways and diffuse noxious inhibitory controls are not functional in the first two postnatal weeks in rat pups [80, 81]. Descending fibres are present in the dorsolateral funiculus, but initially do not extend collateral branches into the dorsal horn. Inhibition of dorsal horn cell responses by stimulation of the dorsolateral funiculus is not present until P10 12, and until P22 24 is only activated by high-intensity stimulation [80]. Stimulus-produced analgesia from the peri-acqueductal gray is also not effective until P21 [82]. In addition, local interneuronal inhibitory mechanisms are initially immature, and GABA has excitatory rather than
Table 19.4 Development and changes in nociceptive processing | |||||||
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inhibitory actions early in development [83]. Therefore in early development, there is a relative excess of excitatory mechanisms, immature inhibitory mechanisms, and large receptive fields, which contribute to more generalized responses to lower intensity pain stimuli (Table 19.4).
From laboratory to bedside:the mode of action of opioids, nmda antagonists, antidepressants, and anticonvulsants
Opioids
It is now recognized that opioid actions are subject to changes within the nervous system ( plasticity ), and also modulation by a number of other transmitters, which may enhance or decrease the action of exogenous opioids. Opioid analgesia may be decreased by anti-opioid peptides such as CCK and F8a, or by activity of excitatory amino acids on the NMDA receptor [84]. Degeneration and loss of pre-synaptic opioid receptors following nerve damage will reduce opioid responsiveness, but this should be overcome by titration of opioid and dose escalation [85] as supraspinal sites of action will not be affected by primary afferent damage.
Hyperalgesia and morphine tolerance are interrelated at the level of NMDA receptor activation in the dorsal horn of the spinal cord. Post-synaptic mu opioid receptor activation by an exogenous ligand such as morphine may mediate protein kinase C activation, leading to removal of the magnesium blockade and allowing activation of the NMDA receptor. It has been proposed that exogenous opioid administration may result not only in tolerance, but also lead to hyperalgesia by increasing the efficacy of NMDA-receptor activated calcium channels [86]. Clinically, hyperalgesia has developed following high doses of morphine administered orally, parenterally [87] and intrathecally [88]. Therefore, escalation to massive doses of opioids in patients with pain may not always be appropriate, and alternative routes of administration, or alternative drugs may be preferable. Similar excitatory amino acid receptor-mediated cellular and intracellular mechanisms have also been implicated in the development of morphine tolerance [86].
Early research suggested that a subtype of mu receptor agonist may improve analgesia without associated respiratory depression, but this has not been supported by subsequent studies. Endorphins, enkephalins, and dynorphins are endogenous opioid peptides which bind with only low to moderate specificity to the mu, delta and kappa opioid receptors. Recently, two peptides (endomorphin-1 and endomorphin-2) have been identified in mammalian brain and have the highest specificity and affinity for the mu receptor of any endogenous substance so far described [89]. Cloning of opioid receptors led to the recognition of a novel G-protein coupled opioid-like receptor. Nociceptin/orphinan FQ, a 17 amino acid peptide resembling dynorphin, acts as a potent endogenous ligand of the opioid receptor-like 1 (ORL1) receptor. The ORL1 receptor is expressed widely in the nervous system [90]. The actions of nociceptin/orphinan FQ are site specific and in animal studies hyperalgesia and opioid antagonism was demonstrated at supraspinal sites, while analgesia was shown at spinal sites [91]. Its efficacy varies in neuropathic and inflammatory models [92]. The clinical application of these findings is yet unclear, but they may provide tools for further elucidation of nociceptive pathways [93], and the development of more specific opioid agonists.
NMDA antagonists
NMDA receptor antagonists have been shown to prevent and reverse opioid tolerance, reduce opioid withdrawal effects, and may have a role in patients whose pain is inadequately controlled with high dose opioids [94]. Therefore, clinically useful NMDA antagonists with a reduced side-effect profile would have potential advantages in combination with opioids for the management of chronic pain [95].
The NMDA receptor clearly has an important role in pain transmission, and NMDA receptor antagonists reduce the effects of wind-up and central sensitisation. Ketamine, a non-competitive NMDA antagonist, has analgesic effects at subanaesthetic doses, but its use remains limited by psychomimetic side-effects. Preoperative administration of small doses of ketamine has been shown to improve postoperative analgesia [96], reduce opioid requirements [97], and reduce postoperative wound hyperalgesia [97, 98]. Ketamine has also been shown to benefit patients with chronic neuropathic pain [99, 100], and cancer pain. Currently available oral agents with NMDA antagonist activity, such as dextromethorphan and memantine, appear to have limited efficacy [101, 102], but further studies are required to determine dose ranges. More specific NMDA receptor antagonists with improved side-effect profiles are required.
Antidepressants
Antidepressants potentiate the effect of biogenic amines in endogenous analgesic systems. The efficacy in neuropathic pain may rely on both noradrenergic and serotonergic effects, as the specific serotonin reuptake blocker fluoxetine was no more effective than placebo [103]; and paroxetine and mianserin were less effective than imipramine in adult studies
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[104]. Controlled trials supports a moderate effect for tricyclic antidepressant drugs in neuropathic pain which is not selective for the nature or quality of the pain. Pain relief is independent of their action on mood as the analgesic effect occurs at a lower dose and with more rapid onset than mood effects, and the analgesic efficacy is similar in depressed and non-depressed patients [105].
Anticonvulsants
The mode of action of the anticonvulsants is sodium channel blockade which suppresses ectopic neural firing and may offer relief from neuropathic pain. Anticonvulsants such as carbamazepine and sodium valproate have a long history of use for trigeminal neuralgia and other neuropathic pain states. Newer anticonvulsant drugs such as gabapentin [106, 107] and lamotrigine [108], may have improved side-effect profiles but this remains to be confirmed by controlled trials in a larger number of patients.
Conclusion
Pain is a common symptom in dying children. Fears and concerns surrounding its management are often based on myths and misperceptions. The mechanisms by which pain is perceived in infants, children, and adolescents and the consequences of improperly managed pain is increasingly being understood. The changes in pharmacokinetic and pharmaco-dynamic parameters with development suggest that clinical analgesic administration should take into consideration the type of pain, weight and clinical status of the child, and also his/her developmental stage. In addition, genetic factors contribute to responses to opioid agonists. This variability emphasises the importance of ongoing assessment of pain, and adjustment of analgesic regimes according to individual needs. This developing body of knowledge combined with a greater understanding of the developmental aspects of analgesia may lead to improved palliative analgesic therapeutics in the future.
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