Thresholds of unsensitised nociceptors

Spinal transmission

Primary nociceptors terminate in the dorsal horn of the spinal cord. The dorsal horn consists of numerous layers, which are defined according to the projections and structural and functional properties of their neurones. The majority of nociceptors terminate in laminae I (Aδ fibres usually terminate here), II (C fibres usually terminate here) and V (Aδ, C and Aβ fibres all terminate here). Lamina II neurones project to other laminae and can be excitatory or inhibitory. Because peripheral input onto lamina I fibres is almost exclusively nociceptive (Aδ), the neurones that project from here are called nociceptive-specific second order neurones. Because peripheral input onto lamina V second-order neurones includes Aδ, C and Aβ fibres, lamina V second-order neurones tend to respond over a wide range of stimulus inputs, which is why they are called wide-dynamic range neurones.

Brain transmission

The brain is defined here as that part of the CNS that lies above the spinal cord. There are several important characteristics of how nociception is handled by the brain.

Parallel processing

Many brain areas are involved in pain. Most often, the thalamus, insula, primary (S1) and secondary (S2) somatosensory and prefrontal cortices are involved. These areas are called the pain matrix (Apkarian et al. 2005) (Figure 17.1). However, these areas are never the only areas involved and they are not always all involved – the pattern of brain activation varies greatly between, and within, individuals.

Different aspects of pain seem to involve different brain areas

In an attempt to clarify the potential roles of different brain areas in pain, some authors conceptualise two systems. The medial nociceptive system includes the medial thalamic nuclei, anterior cingulate and dorsolateral prefrontal cortices. It is described as slow and only broadly somatotopic, which means it does not have the capacity to code in detail the location in the body at which the stimulus occurred. Activity in this system has been proposed to subserve the affective-emotional dimensions of pain, i.e. the unpleasantness of pain rather than the intensity and quality. This aspect of pain may have value to the person experiencing pain by triggering behaviour that demands other people’s attention (Goubert et al. 2009).

The lateral nociceptive system includes the lateral thalamic nuclei and the primary (S1) and secondary (S2) somatosensory cortices. It is described as fast and is highly somatotopic, which means it is able to code, in great detail, the tissue location at which the stimulus occurred. Activity in this system is proposed to subserve the sensory-discriminative aspects of pain, i.e. the intensity of the pain and the sensory characteristics of the stimulus (e.g. warm, sharp, deep, superficial). The intensity and unpleasantness of pain can be independently manipulated (e.g. Moseley 2007a).

Multiple inputs: The neuromatrix theory

Melzack (1990) proposed the neuromatrix theory as a way of conceptualising how myriad inputs and factors affect pain and nociception (Figure 17.2). Inputs and factors in that theory include previous learning and past experiences, immune and endocrine states and responses, activity in the autonomic nervous system, and information coming from nociceptors and other sensory receptors. The theory suggests that pain will occur when all these elements are evaluated and a specific network of neurones in the brain is activated. Melzack calls each particular network of neurones a neurosignature (or ‘neurotag’ (described by Butler and Moseley (2003)), which is analogous to the representation concept used in cognitive neuroscience literature (see Damasio (2000) for a review of representation theory). Remember that this is a theory and that the brain physiology underpinning pain and consciousness is not well understood.

Pain is of the brain

Both Melzack’s ‘Neuromatrix Model’ and the International Association for the Study of Pain (IASP) definition of pain highlight the need to use a biopsychosocial approach in evaluating and treating a person’s pain. They also reinforce the concept of pain being created by the brain as a result of multiple influences, in particular the detection or perception of danger to the body’s tissues. Tissue damage and the resultant nociception is just one of these influences. As is suggested by the IASP definition, tissue damage is neither sufficient nor necessary for pain.

Peripheral mechanisms

Peripheral mechanisms that increase the pain evoked by a standardised stimulus include the presence of inflammatory mediators (including proinflammatory cytokines, bradykinin, prostaglandins), decreased circulation (which increases the local concentration of H⁺ ions), the presence of immune mediators and activation of certain genes (Figure 17.2) (see Meyer et al. (2006) for an exhaustive review of peripheral mechanisms of modulation). Inflammatory mediators are released by tissue damage and by activation of nociceptors (neurogenic inflammation). This sensitisation, driven by peripheral mechanisms, is called peripheral sensitisation and the hyperalgesia that follows is called primary hyperalgesia.

Spinal cord mechanisms

Second order nociceptors can also become sensitised. The N-methyl-D-aspartate (NMDA) receptors in the dorsal horn respond to persistent or intense stimulation by opening channels to allow greater post-synaptic activity. This means that the same input from the periphery will result in greater activation of the second order nociceptor, which means that more messages of danger to body tissue will be sent to the brain.

Brain mechanisms

Supraspinal mechanisms that enhance the sensitivity of the CNS include influences, mediated by the rostroventral medulla, on the inhibitory transmission affecting the spinal cord. Current research is looking not only at descending modulation, but also on intracortical modulatory processes. Imaging studies have associated pain processing with activity in multiple brain areas, commonly including the thalamus, anterior and posterior cingulate cortex, other areas of the limbic system and the medial prefrontal cortex (Bushnell and Apkarian 2006; Schweinhardt et al. 2008; Wiech et al. 2008). The attributed function of these brain areas supports a role in the cognitive modulation of pain (see below).

Neuropathic pain

The pain associated with nerve damage is known as neuropathic pain and may include descriptions such as ‘burning’ or ‘electric shock’. CNS damage, such as stroke, can result in centrally-mediated neuropathic pain that reduces the inhibition of the nociceptive system. Peripherally, damage to an axon or the myelin covering of a nerve, can lead to spontaneous transmission of impulses from the damaged area or the dorsal root ganglion (DRG). This may also be driven, in part, by loss of inhibition, specifically through alterations of chloride homeostasis affecting gamma amino-butyric acid (GABA)-mediated inhibition (see review of mechanisms in De Koninck (2009) and also Sandkühler (2009)). Such damage will usually result in hypersensitivity to mechanical input. This sensitivity forms the basis for tests such as Tinel’s sign – sometimes considered as an indicator of neuropathic pain.

There is mounting evidence that interactions between the immune system, the endocrine system and the autonomic nervous system are important in all types of pain, including neuropathic pain (Watkins and Maier 2000).

Pain modulation via psychological and social influences

Anecdotal evidence that somatic, psychological and social factors modulate pain is substantial – sport- and war-related stories are common (see Butler and Moseley (2003) for several examples). However, numerous experimental findings corroborate the anecdotal evidence (see Fields et al. (2006) for a review of CNS mechanisms of modulation and Poleshuck and Green (2008) for a review of the impact of socioeconomic disadvantage and pain).

By far the greatest research efforts in this area have been directed towards the cognitive modulation of pain. Experiments that manipulate the psychological context of a noxious stimulus often demonstrate clear effects on pain, although the direction of these effects is not always consistent.

Despite the wealth of data, consensus is lacking: some data suggest that attending to pain amplifies it and attending away from pain nullifies it; others suggest the opposite. This may be explained by the existence of different modes of selective attention (see Legrain et al. (2009) for review). Most likely, the effect depends on the coping style of the individual and the wider context of the experiment or situation.

Anxiety

Anxiety also seems to have variable effects on pain. Some reports link increased anxiety to increased pain during clinical procedures (Schupp et al. 2005; Klages et al. 2006) and during experimentally-induced pain (Tang and Gibson 2005), but other reports suggest no effect (Arntz et al. 1990; Arntz et al. 1994). Relevant reviews conclude that the influence of anxiety on pain is probably largely dependent on attention (Arntz et al. 1994; Ploghaus et al. 2003).

Expectation

Expectation also seems to have variable effects on pain. As a general rule, expectation of a noxious stimulus increases pain if the cue signals a more intense or more damaging stimulus (Fields 2000; Sawamoto et al. 2000; Keltner et al. 2006; Moseley 2007a; Moseley and Arntz, 2007) and decreases pain if the cue signals a less intense or less damaging stimulus (Pollo et al. 2001; Benedetti et al. 2003). There are several informative reviews on the influence of expectation on pain (Fields 2000; Wager 2005).

The common denominator of the effect of attention, anxiety and expectation on pain seems to be the underlying evaluative context, or meaning, of the pain. That is demonstrated by the consistent effect that some cognitive states seem to have on pain. For example, catastrophic interpretations of pain are associated with higher pain ratings in both clinical and experimental studies (see Haythornwaite (2009)). Believing pain to be an accurate indicator of the state of the tissues is associated with higher pain ratings (Moseley et al. 2004), whereas believing that the nervous system amplifies noxious input in chronic pain states increases pain threshold during straight leg raise (Moseley 2004).

Social context

The social context of a noxious stimulus also affects the pain it evokes. For example, when men have blood taken by a woman, it hurts less than when it is taken by another man (Levine and De Simone 1991). The effects are variable but, again, seem to be underpinned by the underlying evaluative context or meaning (see Butler and Moseley (2003) for a review of pain-related data and Moerman (2002) for exhaustive coverage of the role of meaning in medicine and health-related interactions).

To review the very large amount of literature on somatic, psychological and social influences on pain is beyond the scope of this chapter. However, it is appropriate, and clinically meaningful, to reiterate the theme that emerges from that literature: the influences on pain perception, tolerance and report are variable and seem to depend on the evaluative context of the noxious input.

Behavioural measures

Although self-reporting measures are behavioural measures, they are generally considered as a separate category. Non-self-reporting behavioural measures are useful as a corroborator of self-reporting measures, when the patient is unable to use the measure (e.g. children) or when the clinician considers the patient’s report to be dubious. Behavioural measures include observation (by a covert or overt observer) and performance (e.g. functional, endurance, speed or load tests). Full review of behavioural measures is beyond the scope of this chapter, but the interested reader is referred to the Handbook of Pain Assessment (Turk and Melzack 2001) and Manage your Pain (Nicholas et al. 2007) for examples.

Measures of the impact of pain

Critical to the ICF framework, and to the biopsychosocial model, is evaluation of other factors that might be modulating pain or the behavioural response to pain, or both. Numerous measures have been devised and tested. The following is a brief account of the most widely used and documented.

Measuring potential impact of beliefs and thoughts

The importance of evaluation of the threat to body tissue has been mentioned earlier. Inherent to this evaluation is fear of movement and (re)injury. A large amount of research has investigated the role of pain-related fear avoidance behaviour. There are many specific findings that relate fear and catastrophic thought processes to pain intensity, disability and self-efficacy but the principle can be summarised thus: people who have heightened concerns about pain, its cause and its consequences, often have a sense of helplessness and adopt a passive coping style. As a result, they have a lower criterion for a movement or activity to be considered potentially painful or potentially injurious. They therefore avoid those movements and activities – ‘fear-avoidance’. Avoidance of activity leads to disuse and hampers healing and recovery, leaving the person in a vicious cycle of progressive depression, disuse and disability (Figure 17.3). According to the fear-avoidance model, most people do not follow this path because they have a more accurate and appropriate level of concern and thus do not tend to avoid movement and activity (Vlaeyen and Linton, 2000). See Vlaeyen and Linton (2000) for a review of fear-avoidance beliefs and pain and Sullivan et al. (2001) for a review of catastrophic thought processes and pain.

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