Pain Syndromes in Neurology: Butterworths International Medical Reviews

Canada

1

Introduction

H.L. Fields

Publisher Summary

This chapter reviews neural mechanisms relevant to pain perception and also reviews neuropathic pain. The treatment and analysis of pain requires an understanding and appreciation of the mechanisms thorough which the sensations of pain is transmitted to the receptors and thereafter to the brain where the sensation is interpreted as pain; along with this, an appreciation of the systems that the body employs in dealing with pain. In the somatosensory system, the transduction process normally occurs in the peripheral terminals of dorsal root ganglion cells—primary afferents. Primary afferents fall into distinct classes determined by the specific types of stimuli they respond to and the conduction velocity of their axons. Those that respond with increased discharge to stimuli that are tissue damaging or potentially tissue damaging are termed primary afferent nociceptors (PANs). The peripheral terminals of PANs are sensitive to one or more of the following types of stimulus: thermal, mechanical, or chemical. Clinical pains are accompanied by tenderness and, often hypersensitivity. In part these two reflect the sensitization of PANs. PANs enter the spinal cord via the dorsal root, and synapse with second-order neurons, some of which project to supraspinal nuclei implicated in pain sensation, such as the ventrobasal nucleus of the thalamus. The major ascending pathway for pain transmission lies in the antero-lateral white matter of the spinal cord. The pain-modulating system consists of a network of neurons running from the cortex and hypothalamus via the mid-brain periaqueductal gray, and rostral medulla to the dorsal horn.

INTRODUCTION

The major objective of this book is to present an overview of the clinical features, pathophysiology and treatment of certain painful conditions that neurologists are often called upon to see. The focus will be upon those syndromes for which there have been advances in treatment, clinical description, or relevant areas of basic research. Of particular importance are advances in understanding of the pain associated with dysfunction of the nervous system. These conditions (e.g. nerve entrapments and neuromas, postherpetic neuralgia, causalgia, thalamic syndrome) take a terrible toll on the patients afflicted by them because they are often severe, unremitting and refractory to treatment. Fortunately, over the past two decades significant progress has been made in unravelling the processes set in motion by neural injury. The search for effective treatments has also started. This chapter reviews neural mechanisms relevant to pain perception and ends with a brief review of neuropathic pain.

PAIN PATHWAYS

Three major processes underly sensory experiences that are produced by stimuli: transduction, transmission and perception. In this context transduction refers to the process by which a stimulus is converted to receptor membrane depolarization and then nerve impulses. In the somatosensory system this process normally occurs in the peripheral terminals of dorsal root ganglion cells (primary afferents). Primary afferents fall into distinct classes determined by the specific types of stimuli they respond to and the conduction velocity of their axons. Those that respond with increased discharge to stimuli that are tissue damaging or potentially tissue damaging are termed primary afferent nociceptors (PANs). Once impulses are generated in the PANs the process of transmission begins. Transmission includes the conduction of nerve impulses in PAN axons to the spinal cord (or trigeminal nucleus in the brain stem), synaptic activation by the PANs of second-order pain-transmission neurons (e.g. spinothalamic tract cells) and the conduction of impulses in these central pain-transmission neurons to the brain structures that underly subjective perception.

Primary afferent nociceptors

A peripheral nerve contains axons that differ widely in their cross-sectional diameter, degree of myelination and conduction velocity (CV). The axons of the primary afferents fall into three distinct groups: A-β (diameter 6–22 μm, heavily myelinated, CV 33–75 m/s), A-δ (diameter 2–5 μm, thinly myelinated, CV 5–30 m/s) and C fibers (diameter 0.3–3 μm, unmyelinated, CV 0.5–2 m/s) [1,2]. To which of these axonal groups classes do the primary afferent nociceptors belong?

At one level, there is a straightforward experimental approach to this question. One needs only to determine the response properties of an afferent and measure its conduction velocity. In fact, cutaneous nociceptors are defined by their characteristic discharge pattern. Using mechanical or thermal stimuli, PANs discharge when the stimulus intensity is at or above the level reported as painful when delivered to the normal skin of a human subject. Characteristically, PANs discharge with increasing frequency to stimuli of increasing intensity within the range reported as painful (Figure 1.1). Using these criteria most PANs fall into one of two groups of afferents: the unmyelinated C fibers and small-diameter myelinated or A-δ group (see Chapter 2 for details). Few, if any, belong to the A-β group.

Figure 1.1 Comparison of response properties of thermal nociceptor and non-nociceptive thermoreceptor. At non-noxious temperatures, both types of receptors may fire. Then, as the temperature is raised into the noxious range, only the nociceptor continues to increase in discharge frequency. Both receptors can signal warming but only the nociceptor can transmit the message that the temperature is in the noxious range. (Adapted from Fields, H. L. Pain, McGraw-Hill, New York, p. 19 (1987) with permission) McGraw-Hill

The large myelinated primary afferents in the A-β group respond to low-intensity mechanical stimuli and show no increase in discharge frequency to more intense stimuli. Thus the A-β fibers cannot selectively signal the presence of potentially tissue-damaging stimuli. Consistent with this is the observation that in awake human subjects, electrical stimulation of A-β afferents elicits sensations that are not painful. In fact, there is evidence that selective activation of A-β afferents may actually inhibit nociceptive transmission at the spinal level [3,4].

Despite the evidence against a positive contribution of A-β afferents to pain perception, recent studies suggest that, under certain conditions, especially when there is nerve damage, activity in A-β afferents can elicit pain (e.g. see the discussions by Roberts and Kramis in Chapter 4 and by Raja, Meyer and Campbell in Chapter 2 in this book). Thus, although activity of PANs is sufficient to elicit the sensation of pain, it is likely that activity of PANs is not always required for a stimulus to evoke pain. This illustrates the crucial point that the term nociceptor refers to the type of stimuli to which a particular primary afferent responds, as opposed to the type of sensation it produces when it is active. Under normal conditions, nociceptors respond to intense stimuli and, when they are active, consistently elicit the sensation of pain. Under pathological conditions, activity in afferents that are not nociceptors can elicit pain.

The peripheral terminals of primary afferent nociceptors are sensitive to one or more of the following types of stimulus: thermal, mechanical or chemical. The most ubiquitous PAN can be activated by all three types of stimuli and is thus termed the polymodal nociceptor. Most polymodal nociceptors have axons that are unmyelinated. The other major classes of PAN respond only to relatively intense mechanical (high-threshold mechanoreceptors) or to both intense mechanical and thermal stimuli (mechanothermal nociceptors). The latter two classes of nociceptor usually have axons that are myelinated.

Normally, PANs have no spontaneous activity in the absence of stimulation and do not discharge in response to stimuli that are innocuous when applied to normal skin [5]. However, the response properties of primary afferent nociceptors are dependent on previous stimuli. Most nociceptors become sensitized by tissue-damaging stimuli in the region of their terminals. This property of nociceptors is reviewed extensively in Chapter 2 of this book. Suffice it to say that, in a region of injury, some PANs undergo prolonged changes which result in a lowering of their threshold for activation (producing tenderness and hyperalgesia) and others become spontaneously active (producing continuous pain that outlasts the stimulus producing it).

Pain-producing substances

Most clinically significant pains have a time course of hours to days, far beyond the duration of the usual stimuli employed to study nociceptors in the experimental situation. In addition, clinical pains are accompanied by tenderness and, often, hypersensitivity. Tenderness and hyperalgesia simply mean that stimuli that are normally painful are even more painful. There are several contributors to tenderness and hyperalgesia. In part they reflect the sensitization of PANs (a shift to the left of the stimulus intensity–PAN discharge curve). It is likely that intense stimuli also elicit long-lasting changes in the central nervous system that enhance pain transmission [6]. In addition, tissue damage causes the release of a variety of chemical substances into the extracellular space around the receptor terminals (see Chapter 2 for a more complete discussion). These substances persist locally and can elicit pain and/or hypersensitivity. Table 1.1 lists the best-studied of the substances that appear in areas of tissue damage and that can either activate or sensitize PANs.

Table 1.1

Chemical intermediaries in nociceptive transduction

From Fields, H. L. Pain, McGraw-Hill, New York, p. 134 (1987) with permission. McGraw-Hill

Bradykinin is one of the most potent pain-producing substances [7,8]. It is a 9-amino-acid peptide produced by cleavage of certain plasma proteins and is present in sites of injury, especially when there is visible inflammation. Bradykinin produces pain when injected into human skin. It activates polymodal nociceptors directly and causes them to become sensitized. Bradykinin could thus contribute to both the pain and tenderness of clinically significant injuries.

The prostaglandins and leukotrienes are among the most potent and ubiquitous of the inflammatory mediators. They are metabolic breakdown products of arachidonic acid. Prostaglandins sensitize, but do not activate, PANs and thus could have an important role in tenderness and hyperalgesia. It is currently assumed that the analgesic action of aspirin and non-steroidal anti-inflammatory drugs results from their inhibition of the enzyme cyclo-oxygenase, which is required for synthesis of prostaglandins from arachidonic acid [9,10].

Substances released from the peripheral terminals of primary afferent nociceptors: neurogenic inflammation

It is generally accepted that noxious stimuli can raise the level of pain-producing substances by damage to local tissues. It is not as well appreciated that substances contributing to nociception are present in the terminals of primary afferent nociceptors and that they can be released by those terminals when the nociceptor is active. The clearest evidence of this is from experiments in which the sensory axons are electrically stimulated near the spinal cord (see Figure 1.2). Impulses will propagate from the site of stimulation in both directions along the axon: toward the spinal cord (the normal, or orthodromic direction) and toward the peripheral terminals (opposite of normal, or antidromic direction). When the antidromic impulses arrive at the region of skin innervated by the activated PANs they produce neurogenic ‘inflammation’, which consists of reddening (vasodilatation), edema and hyperalgesia. Neurogenic inflammation is produced by a diffusible substance or substances released from the terminals of PANs [11,12].

Figure 1.2 Effect of antidromic impulses in primary afferents. Stimulating the peripheral cut end of a primary afferent (S) results in impulses being conducted in an antidromic direction (opposite of normal, in this case outward toward the sensitive terminals). The antidromic impulses cause vasodilatation (flare), edema (wheal) and sensitize nociceptor terminals (hyperalgesia), presumably by the release of a chemical intermediary. (From Fields, H. L. Pain, McGraw-Hill, New York, p. 31 (1987) with permission) McGraw-Hill

It is by no means certain what these substances are. PANs contain a variety of neuropeptides including substances P and calcitonin gene-related peptide (CGRP). There is evidence that antidromic impulses cause the release of substance P from the peripheral terminals of primary afferents. Both substance P and CGRP are potent vasodilators. In addition, substance P has been shown to cause the release of histamine from mast cells. There is some evidence that histamine can also cause pain and/or sensitize PANs [12]. Thus the sensitizing effect of substance P on the PAN terminal may be indirect (via release of histamine). It is not clear whether other neuropeptides or non-peptide transmitters released from the PAN terminal are involved in neurogenic inflammation; however, it is clear that the PAN is not simply a passive messenger signalling the occurrence of a noxious stimulus but an active player in the peripheral events set in motion by tissue-damaging processes.

Central pain pathways

Primary afferent nociceptors enter the spinal cord via the dorsal root, and synapse with second-order neurons, some of which project to supraspinal nuclei implicated in pain sensation, such as the ventrobasal nucleus of the thalamus. It is important to point out that the nociceptive message is not relayed unchanged to supraspinal sites but undergoes a significant transformation in the gray matter of the spinal cord.

All segmental primary afferents involved in somatic sensation have synaptic connections within the dorsal horn of the spinal gray and each central pain-transmission neuron receives input from many PANs. In addition, many central pain-transmission neurons also receive input from non-nociceptive primary afferents. In contrast to PANs, which are only excited by stimuli within their receptive fields, central neurons frequently have inhibitory inputs, presumably via interneurons. In addition to this massive direct and indirect input from primary afferents, the spinal pain-transmission neurons also receive significant inputs from supraspinal nuclei that provide a tonic control over their firing. Thus, the activity elicited in spinal neurons by PANs is modified by activity in other PANs, activity in non-nociceptive primary afferents, and activity in descending projections from supraspinal structures. The descending connections that control pain transmission can be activated under specific behavioral conditions such as stress and conditioning [13,14]. Understanding the anatomic and physiologic complexity of the neural systems underlying pain perception, and the changes that occur in it following injury to the nervous system, is crucial to improved understanding and care of the patient with chronic pain.

Dorsal horn lamination and pain-transmission neurons

The dorsal horn of the spinal cord (and trigeminal nucleus caudalis) has five or six anatomically distinct layers (Figure 1.3) [15]. This anatomic lamination is of physiologic significance in that the neuronal populations in the different layers have different physiologic properties. Of major importance for nociception are laminae I, II and V. Layer I, or the marginal zone, forms a cap over the top of the dorsal horn. It is a major termination site for the small myelinated or A-δ PANs. Most of the cells in lamina I are nociceptive specific (NS), so named because they only respond to stimuli in the noxious range. A smaller percentage of lamina I neurons are wide dynamic range, which means that they are excited by innocuous mechanical or thermal stimuli but then increase their discharge frequency as the stimulus intensity is increased into the noxious range. Wide-dynamic-range (WDR) neurons must have inputs from non-nociceptive primary afferents as well as PANs. A large proportion of both NS and WDR lamina I cells project to the contralateral mid-brain and thalamus and are considered to be prime candiates for mediating pain sensation [16,17].

Figure 1.3 Rexed’s Scheme for Lamination of the Spinal Gray. (a) Outline of 5th lumbar (L5) segment of the adult cat. In the segments that innervate the limbs (e.g. L5), the cytoarchitectural divisions of the ventral horn do not have an obvious laminar arrangement. (b) Photomicrograph of the L5 spinal segment that corresponds to the diagram of L5 in (a). This is a stain for cell bodies (From Rexed, B. A cytoarchitectonic atlas of the spinal cord in the cat. Journal of Comparative Neurology, 96, 415–495 (1952), by permission)

Lamina II (also known as the substantia gelatinosa) is the major site of termination of the unmyelinated or C PANs. Few of the A-δ PANs terminate in lamina II. The neuronal population in lamina II differs from that in lamina I. Although there are many WDR and NS neurons in lamina II, a substantial number have response properties that do not fall into either group. Furthermore, very few lamina II neurons project to supraspinal sites. Most project within the spinal cord and are thus local interneurons that modify the response properties of the projection neurons.

Lamina V receives some direct input from A-δ PANs. In contrast to lamina I it has a predominance of WDR neurons. The receptive fields of lamina V cells are larger than those in lamina I, suggesting greater convergence of afferent input. It is important to point out that many lamina V neurons have dendrites that extend dorsally into laminae I and II. Thus lamina V cells could receive both direct inputs from C and A-δ PANs and indirect inputs via interneurons in laminae I and II.

Cells in deeper layers of the spinal gray undoubtedly contribute to pain perception. These cells are more varied in their response properties and usually have very complex receptive fields with inputs from wide areas of skin as well as deep tissues [17]. Because of their variability and complexity it has been more difficult to assign them a definite role in nociception.

Segmental and distant afferent inhibition

In addition to their excitatory effects on dorsal horn neurons, primary afferents also have powerful inhibitory effects. The concept of afferent inhibition is important for understanding how injuries of peripheral nerves can result in pain and hyperalgesia because it can be used to explain how impaired sensation and hyper-reactivity to stimuli can coexist.

Experimental observations are quite clear on this matter. In human subjects, selective blockade of myelinated axons in a peripheral nerve results in an elevated threshold for stimuli to produce sensation. Pinpricks are dull, slight changes in temperature are not detected and stereognosis is completely lost. Nevertheless, if a stimulus is of sufficient strength to produce any sensation, that sensation is typically unpleasant or frankly painful. Even light, normally innocuous stimuli in the cutaneous distribution of the blocked nerve are felt as unpleasant and stimuli which would produce mild pain in normally innervated skin produce a severe, poorly localized pain with a burning, stinging quality [18–20]. Thus, although the block of myelinated axons produces an impairment of sensory function, there is also a paradoxical increase in the painfulness of all stimuli.

That myelinated afferents have a net inhibitory effect on pain transmission is supported by the observation that selective activation of myelinated afferents in a peripheral nerve has a pain-relieving effect, i.e. transcutaneous electrical stimulation of nerve (TENS) [20,21]. Furthermore, parallel studies in experimental animals reveal that the selective blockade of myelinated primary afferents results in a greatly enhanced response of pain-transmission cells in the dorsal horn to a constant afferent input over unmyelinated axons [22]. Thus, even though many dorsal horn neurons also have excitatory inputs from some myelinated primary afferents (both A-δ and/or A-β), the predominant effect of input from a large number of simultaneously active myelinated afferents is inhibition.

In addition to the inhibition exerted by these myelinated afferents upon nociceptive dorsal horn neurons, there is also an inhibitory effect produced by input from primary afferent nociceptors innervating distant parts of the body [23]. Thus a dorsal horn cell excited by noxious stimulation of the foot may be inhibited by noxious stimulation of the face (and vice versa). Although the physiologic function of this ’diffuse noxious inhibitory control’ is unknown, it has been proposed to underly such phenomena as acupuncture and counter-irritation.

In summary, it is clear that in addition to activation of pain-transmission neurons in the spinal cord dorsal horn, primary afferents, particularly those with myelinated axons, exert significant inhibitory actions. When myelinated afferents are blocked, the responses of dorsal horn neurons to noxious stimuli are greatly exaggerated. In human subjects, the same maneuvers result in hyperalgesia.

Ascending pathways for pain

It is well established that the major ascending pathway for pain transmission is in the antero-lateral white matter of the spinal cord. This fact is the basis for the well-known surgical procedure antero-lateral chordotomy, which is commonly used for the treatment of intractable pain. Surgical interruption of the antero-lateral quadrant results in a profound contralateral loss of pain sensation in areas innervated by spinal segments below the level of the lesion [24]. The analgesia is virtually complete for cutaneous stimuli and many patients will burn their feet after this operation because they are unaware of potentially injurious stimuli such as touching a hot surface. Loss of pain sensibility from deep structures is also profound, although usually incomplete. Over a period of months the majority of patients with damage of their spinothalamic tract experience a partial recovery of pain sensation: the upper level of the deficit drops and there is some return of pain sensitivity in more caudal segments. As functional regeneration does not occur in the spinal cord, the return of pain sensation must involve pathways outside the antero-lateral quadrant.

Consistent with these clinical observations, many of the neurons in the spinal laminae implicated in pain transmission send their axons via the contralateral antero-lateral quadrant to supraspinal targets. Many of these axons terminate in the contralateral thalamus. Lesions of this spinothalamic pathway anywhere along its trajectory through the brain stem impair pain sensation and electrical stimulation of it produces pain in conscious human subjects [24–26]. Thus, activity in spinothalamic tract neurons is both necessary and sufficient for normal pain sensation.

Brain-stem projections of spinal nociceptive neurons

In addition to their direct projection to the thalamus there are several brain-stem targets for axons of spinal nociceptive neurons. The two brain-stem areas that receive the most prominent input from spinal nociceptive neurons are the reticular formation of the rostral medulla (nucleus reticularis gigantocellularis) and the dorsolateral mid-brain (periaqueductal gray, nucleus cuneiformis and the parabrachial region). A significant part of the nociceptive spinal input to these brain-stem areas derives from collaterals of spinothalamic tract axons but much of the input terminates only in the brain stem [27,28]. Large numbers of neurons in both of these brain-stem areas project to the thalamus and there is reason to believe that they function, in part, as relay nuclei for pain transmission [17,29]. However, it should be pointed out that the significance of these brain-stem relays in human pain perception has not been established.

Thalamic nuclei and their cortical projections [29]

Four thalamic nuclei receive input from nociceptive spinal neurons: these are the ventrobasal, posterior, central lateral and submedius. The spinothalamic tract divides into a medial and lateral component as it approaches the thalamus. The medial component terminates in the central lateral and submedius nuclei, the lateral division in the ventrobasal and posterior nuclei (Figure 1.4).

Figure 1.4 Conglomerate diagram of major thalamic nuclei that receive direct input from the spinal cord. These include the ventrobasal nucleus (VB) (striped), the posterior nuclear complex (PO) (stipple), the central lateral nucleus (CL) (crosshatch) and submedius (SM) (black). Adjacent nuclei [dorsomedial (MD), lateral posterior (LP), ventral lateral (VL), ventral anterior (VA), medial geniculate (MG), lateral geniculate (LG) and pulvinar (P)] do not receive significant direct spinal input. (From Fields, H. L. Pain, McGraw-Hill, New York, p. 66 (1987) with permission)

The ventrobasal nucleus (VB) has the clearest role in pain transmission. Clinically, lesions of the VB cause analgesia and its electrical stimulation causes pain. Experimental studies have shown that the VB receives input from lamina I and V and both nociceptive-specific and wide-dynamic-range neurons similar to their spinal cord counterparts are found in VB. The VB projects to the somatosensory cortex where similar nociceptive neurons are found.

Although it seems likely that the other thalamic nuclei which receive input from spinothalamic tract neurons play a part, it is less clear what it is that they contribute to pain sensation. The nucleus submedius receives its input primarily from nociceptive neurons in lamina I of the spinal cord; however, it projects to the orbitofrontal cortex which does not have a clearly defined role in pain perception [30].

The central lateral nucleus (CL) receives its spinal input primarily from neurons in the deeper laminae of the spinal gray. These neurons have very large complex receptive fields and can often be excited by stimuli on both sides of the body. There is also a major input to CL from that region of the medullary reticular formation which receives the largest nociceptive input from the cord. The CL projects to a variety of cortical areas, including frontal and somatosensory areas, but it is not certain to which area the nociceptive CL neurons project [31].

Sensory and affective components of pain

One way to make sense of the apparent multiplicity of pathways and thalamic and cortical targets for nociceptive input is to consider that there are multiple aspects to the experience of pain and that the different pathways contribute to these different aspects. In fact, Melzack and Casey [32] proposed that pain has two major components: the sensory and the affective. The sensory aspect has to do with quality (in other words the ability to identify the feeling as pain), intensity, location and time course. Pain threshold, for example, is a sensory measure. In contrast, affect relates to the characteristic emotional tone which is distinctly unpleasant. This unpleasantness is associated with a desire to terminate the sensation and/or to escape from the stimulus and, if this is not possible, anxiety.

There is some reason to believe that the sensory and affective aspects of pain are subserved in part by separate neural mechanisms. Clearly, the spinothalamic projection to the ventrobasal thalamus and its projection to the somatosensory cortex are required for the discriminative sensory aspects of pain. A lesion anywhere along that pathway impairs pain sensation. In contrast, the pathway which includes direct and indirect projections from spinal cord to medial thalamus and from medial thalamus to frontal cortex seems to have more to do with the affective aspects of pain. Supportive evidence for this comes from clinical studies of patients with severe pain who underwent frontal lobotomy as a treatment of last resort [33]. Interestingly, these patients usually obtained striking relief of their clinical pain problem but with no impairment in their ability to detect and identify noxious stimuli as painful. When asked about their pain they would say that it was of the same intensity as before the operation; however, they exhibited no ‘appropriate’ emotion and did not request pain medication. The suffering was apparently eliminated, with no effect on the ‘purely sensory’ aspect of their pain. These clinical observations not only support the neuro-anatomic separability of sensation and affect, they indicate that the affect is of greater importance to the