Peripheral nociceptive system

Nociceptive receptors are defined as nerve endings that are sensitive to noxious or potentially noxious (mechanical and chemical) stimuli. The perceptual aspect of the nociceptive system consists of unmyelinated free nerve endings, distributed three dimensionally throughout skin, subcutaneous and adipose tissue, fasciae, aponeuroses, ligaments, tendons, muscles, periosteum and bone.6,7 Clinically, three distinct areas of pain perception may be considered: the skin (superficial somatic pain); the locomotor system (deep somatic pain); and the viscera (visceral pain). Of these, only the skin is adapted to localize pain exactly in the region of injury. Deep somatic and visceral pain are often felt in unusual locations (see Referred pain, p. 6).

In normal circumstances, this nociceptive receptor system remains largely inactive. The unmyelinated free nerve endings are depolarized only by the application of mechanical forces sufficient to deform or damage the tissue that contains them or after exposure to sufficient concentrations of irritating chemical substances (lactic acid, serotonin, prostaglandins and histamine), released from local inflammatory cells and from the peripheral terminals of the primary afferent fibres themselves.8–10

Another important influence on nociceptor sensitivity is the pH of the tissue. High local concentrations of protons are known to occur in inflammation and the consequent reduction in pH contributes to the sensitization of nociceptors.11,12

Afferent nociceptive system

Nerve impulses generated at the nociceptive receptor system are delivered into the spinal cord by small myelinated and unmyelinated nerve fibres (5 µm or less in diameter), that mainly belong to the Ad and C groups of afferent nerve fibres (Fig. 1.1). Their cell bodies are located in the dorsal root ganglia of the spinal nerves. The very small diameter of the C nerves explains their slow conduction velocity (1 m/s), and their extreme sensitivity to blockade by local anaesthetic drugs. The myelinated Ad fibres are slightly larger and have a faster conduction velocity (10 m/s).¹³

The nociceptive afferents enter the spinal cord, where they divide into short ascending and descending branches, before they terminate at synapses on various groups of relay neurones in the dorsal horn of the spinal grey matter. Most of the connections are to the neurones in the basal spinal nucleus (at the base of the dorsal horn).14,15

The efferents of these cross the cord obliquely to turn upwards on the contralateral side and form the anterolateral spinal tract, which connects the basal spinal nucleus with the thalamic nuclei and has therefore traditionally been called the ‘spinothalamic tract’. Most of the fibres in this tract, however, do not directly ascend to the thalamus without interruption, but instead synapse with neurones in the brainstem reticular system, while others re-enter the spinal grey matter to synapse with internuncial neurones.¹⁶ However, the majority of the ascending nociceptive inputs terminate (sometimes after crossing several synapses) in the thalamic nuclear relay sites.¹⁷ It should be emphasized that not only do the neurones in the thalamic centres respond to peripheral noxious stimulation but they can also be activated by mechanoreceptor peripheral stimulation (see Pain modulation systems below).

The axons of the thalamic nuclei then ascend to the neurones of the cerebral cortex. Three thalamocortical projections can be defined: those responsible for perception; those related to the emotional experience; and those responsible for memory.¹⁸

The first project to the superior paracentral region of the cerebral cortex and seem to contribute to the so-called ‘perceptual component’ of pain – the patient’s ability to perceive whereabouts (in which segment of his body) the pain is localized.¹⁹

The activation of the second thalamocortical projection system, projections that pass from the medial and anterior thalamic nuclei to the frontal lobes, evokes the emotional disturbances related with pain.²⁰ Thus, a stimulus ‘hurts’ only when the nociceptive afferent projections arrive at the frontal cortex.

A third thalamocortical projection system links some of the medial thalamic nuclei to the cortex of the ipsilateral temporal lobe. Here the recent and long-term memory storage systems of the brain are located.21,22

A fourth projection system exists which relates some thalamic nuclei to subjacent hypothalamic nuclei in the ventral diencephalon. It is very probable that this thalamohypothalamic system provides the means whereby nociceptive afferent activity entering the brain evokes the complex of visceral reflex (cardiovascular and gastrointestinal) effects and hormonal changes that are so often associated with the experience of pain.²³

In conclusion, activity of nociceptive receptors distributes pain into four different projecting systems in the brain, each contributing to a specific component of the global experience ‘pain’. However, the projection of pain from a peripheral receptor to the brain is not via a straight-line system. The intensity of pain is not only determined by the intensity of peripheral stimulation but also depends largely on peripheral and central modulation systems at the various synaptic stages in the course of the afferent pathway within the central nervous system. These modulation systems account for the large variation in the intensity of pain experienced. Patients with apparently comparable pathological lesions undergo widely different degrees of suffering; even in an individual patient, the intensity of experience of pain varies widely with the prevailing emotional mood, with concentration on the problem or with suggestions from others.

Pain modulation systems

There are both peripheral and central pain modulation systems.

Introduction

When the skin is pricked with a pin, the patient can exactly pinpoint the injury. This ability to localize the pain is limited to skin and does not apply when the source of the pain is in deep tissue. Deep somatic pain and visceral pain are often felt far from their point of source. In consequence, the examiner needs to know the patterns of pain reference so as not to be misled about where to search for the seat of the trouble. Diagnosis of orthopaedic lesions often rests entirely on history and clinical examination and is therefore almost impossible if the rules and conditions relevant to referred pain are not clearly understood.

Those who originally studied pain reference soon noted that although it appeared erroneous and anarchic, some rules of presentation did exist. For instance, pain from specific structures is always referred to the same parts of the body: colic from a ureteral stone to groin and testicle, diaphragmatic disorders typically to the shoulder, angina pectoris to one or both arms, and the pain caused by arthritis of a hip very often to the ipsilateral knee. Also pain is, in the main, referred distally and its localization depends in a certain way on the severity of the lesion.

In 1905, Sir Henry Head described referred pain in the abdominal wall caused by a visceral disease.³¹ Using the dermatological appearances in herpes zoster, he constructed schemes of segmental innervation of the skin.³² He also described dermatomic zones that became painful in the event of provocation of a related visceral structure. His theory of pain reference was built on the concept of the segmental organization of the human body and its nociceptive system. Further experiments in this sphere were conducted by Sir Thomas Lewis in 1936.³³ In 1938 and 1939, Kellgren published the results of a systematic examination of the phenomena of referred pain, demonstrating segmental radiation and failure to cross the midline.^34,35

His experiments were confirmed by others.36–38 Later, the concept of segmental reference of pain was refined^39,40 and exact borders of the different dermatomes mapped out.^41–44

Possible mechanisms

The fact that referred pain is an error in perception was first pointed out by John Hunter in 1835 (cited by Cyriax).⁴⁵ It was obvious that if pain is felt elsewhere than at its true site, the nociceptive mechanism is reacting inappropriately. However, since there seems to be logical consistency in the way the errors are made (pain from specific lesions is always referred to the same areas), there must also be a logical explanation for ‘failures’. (If a machine always makes the same mistake, a structural or functional disorder must exist.) The basis for the inadequacy must therefore be sought in a miscalculation in the pain mechanism. Theoretically, the defect can lie anywhere along the afferent pathway, from the peripheral receptors to the synapses in the spinal cord and the reticular area and projection zones in the sensory cortex.

During the last century, numerous investigators have studied referred pain. Two main hypotheses have been put forward:

As pointed out previously, pain is experienced at three different locations in the cerebral cortex. Perception – of the site of pain – is located in the superior paracentral cortex. The frontal lobes evoke the emotional disturbances related to pain, and the memory store is in the temporal lobes.

The ability to localize pain in the region of injury is limited to skin and does not apply when the source of the pain is in deep tissue. In due course, a certain pain memory is built up in the temporal lobes, and achieves a high degree of anatomical precision. The efficacy of the long-term memory storage system is not simply a function of the intensity of the painful experience but also relates to the length of time a painful experience lasts or to the frequency with which it is repeated.55,56 Since the frequency of painful stimuli coming from the skin is much higher than the frequency of stimuli coming from deeper structures, it will be obvious that pain memory will centre around painful experiences from the skin. When the same cortical cells receive a painful message arriving from a deep-seated structure, the memory will interpret it on the basis of past experience; in that the sensory cortex is arranged segmentally, the pain will be ascribed to the correct segment but the system will fail to localize it accurately at the site of the lesion. The brain therefore ‘places’ it in the tissue it has a reference for – the skin. Pain is thus felt under the surface area connected with the particular cells that belong to the same segment as the tissue from which the nociceptive afferents originate. The pain is felt deep to the skin of the relevant dermatome and not accurately in the skin.

Clinical consequences

The concept of referred pain is extremely important to the orthopaedic physician, who has to deal daily with the problem. If the principles of erroneous localization by the cortex are clearly understood, the examiner can turn a misleading phenomenon to diagnostic advantage. In the Cyriax concept, referred pain obeys certain rules. The inadequacy in the sensory cortex is structural and therefore can easily be accommodated. To a certain degree, referred pain can be compared with the refraction of light when it falls on a water surface. The observer does not see objects under the water surface at their exact localization. However, since the error of perception is structural and obeys particular physical rules and laws, it is easy to correct what is seen (provided the observer knows the correction formula) and so locate the object accurately. The same applies to referred pain. The examiner must constantly ask if the localization of the pain is also the exact localization of the disorder and, if the answer is negative, what corrections must be made to arrive at the exact localization.

Before this discussion of referred pain is continued, it should be stressed that root pain reference does not necessarily mean that a nerve is involved. The false idea that wide radiation of pain is evidence of involvement of nerves is still strongly held by some and is usually the most important obstacle to a logical understanding of referred pain. To approach the problem of referred pain with an open mind, the reader must constantly remember that referred pain is an error of perception. Although the nerve supply to these peripheral structures is distributed on a segmental basis, it does not indicate that referred pain ‘runs down’ a somatic nerve. For instance, pain at the anterior aspect of the leg does not necessarily mean that a nerve structure (L3, femoral nerve or peripheral branches of the femoral nerve) is involved. Although inflammation of the dural sleeve of the L3 nerve root does of course lead to pain extending in the L3 dermatome, the same pain can be provoked by a lesion in any other tissue belonging to the L3 segment (e.g. hip joint or psoas bursa). There will not be any difference in the nature and extent of the pain. The only distinction between pain as the result of a compressed and inflamed nerve root and pain originating from trauma to other structures is the appearance of paraesthesia (see Pressure on nerves, Ch. 2).

Rules of referred pain (Box 1.1)

The first rule – reference of pain within the borders of the skin area that belongs to the same segment as the tissue lesion that causes pain – follows directly from the premise that the nociceptive mechanism is organized on a segmental basis. Nociceptors, afferent fibres and the sensory cortex are all arranged segmentally. Afferents from skin, deep somatic structures and visceral organs from the same segment relay on the same dorsal neurones and project to the same area in the sensory cortex. Pain reference is therefore confined to, and remains within, the borders of the cutaneous area (or dermatome) that belongs embryologically to the same segment as the tissue from which the pain is arising.

To understand the segmental organization of the nociceptive mechanism, it is necessary to reconsider embryogenesis (Fig. 1.4).

Dermatomes

The cutaneous area supplied by one spinal nerve is a dermatome. The first clinicians to draw dermatomic maps were Head and Campbell.⁵⁸ Their diagrams are the basis for the classical drawings in standard neurological textbooks. However, they did not take into consideration the significant degree of variability and overlap in dermatomic borders.^57,58 Later investigators such as Keegan and Garrett, and Fukui et al^59,60 have demonstrated that dermatomes of adjacent spinal nerves overlap markedly.

An example of this is pain at the anterior aspect of the thigh, which can be of second or third lumbar origin. The second lumbar dermatome spreads from the groin, down the front of the thigh, to the patella. Pain of third lumbar origin again spreads along the anterior aspect of the thigh and the patella but it can continue down the anterior aspect of the leg, to just above the ankle. Pain at the anterior aspect of the thigh therefore can be of second or third lumbar origin but if it spreads further down below the patella then its origin is third lumbar.

Another example of overlap between dermatomes is referred pain in the hand and fingers: C6 pain refers to the dorsal aspect of the hand, the thumb and the index finger, whereas C7 refers also to the dorsum of the hand and the index finger, as well as to the long and ring fingers. In a patient complaining of pain at the back of the forearm or at the dorsum of the hand and the index finger, it is difficult to decide whether the pain is of sixth or seventh cervical origin.

We use the charts drawn by Foerster⁴¹ in 1933 and corrected by Cyriax in 1982,⁴⁵ in order to give the broadest possible information about the area to which pain from a particular segment may refer. The extreme importance of accurate localization of pain in orthopaedic medicine requires the physician to use a map of dermatomes that is as close as possible to clinical reality. The figures showing the dermatomes are based on Foerster,⁴¹ Cole et al,⁶¹ Cyriax,⁴⁵ Conesa,⁶² Wakasugi,⁶³ and Mitta.⁶⁴

Discrepancies between dermatomes and myotomes

We have mentioned already that, as the outcome of embryological development, dermatomes do not always precisely cover the underlying myotomes. Cyriax described eight areas in the human body where the skin and the structure it covers have completely different embryological derivations (Cyriax⁴⁵). These are the head, scapular and pectoral region, hand, intrathoracic and intra-abdominal region, buttock and scrotum.

Referred pain in visceral diseases

It is important to emphasize that referred pain is not a phenomenon of orthopaedic medicine only. As described earlier, many visceral diseases also cause referred pain. For the convenience of practitioners often faced with thoracic or abdominal pain, a list of the segmental derivations of the viscera, based on the work of Cyriax⁴⁵ (see his p. 30), William and Warwick,⁶⁷ Lindsay et al⁶⁸ and Guyton (cited by Van Cranenburgh⁶⁹ is given in Box 1.2).

Referred pain is felt deeply and distally in the dermatome

An important difference between local pain and referred pain is that in the latter the pain is felt deeply and vaguely. The patient thus does not point to a localized and precise area, but outlines an approximate one and tends to describe it as ‘deep’.

That pain – with some exceptions – is always referred distally, remains a purely empirical clinical observation and has hitherto not been explained on neurophysiological grounds. The fact that pain that arises from the proximal part of a segment can be felt distally in the dermatome but a distal lesion is not referred proximally within this same segment, remains an inconsistency that is hard to rationalize. However, this clinical observation is very important to the clinician confronted with referred pain, for the lesion must never be sought in a structure that is localized distally of the painful area. Pain at the distal aspect of the L3 dermatome (knee and lower limb) can have a proximal origin (spine, hip), but pain only in the hip or the groin, cannot be caused by a lesion at the knee or the thigh.

Segmentally referred pain does not cross the midline

The segments in the body are arranged in pairs, each of which has its own segmental innervation and its own projection area in the cerebrum. Hence it is obvious that the cerebral cortex will easily differentiate between a left-side or a right-side pain, and no one will question that a C5 pain on the left side has a left-side origin and vice versa. The fact that pain stemming from a unilateral structure does not cross the midline, becomes important in the interpretation of more or less centrally localized pain, for instance in aches in the neck or back. It is evident that a lesion of a unilateral facet joint will not cause pain radiating all over the lower back. Only centrally localized structures (vertebral body, longitudinal ligaments, intra- and supraspinal ligaments and dura mater) can theoretically be responsible for a bilaterally radiating pain at both sides of the midline. A pain felt centrally or bilaterally must originate from a central structure, or from two bilateral structures (two facet joints or two sacroiliac joints) but it can never be the result of a lesion in a unilateral structure.

Dura mater an ‘exception’ to segmental reference

Pain originating from the dura mater has a rather peculiar behaviour. First, in that the dura is a midline structure, it is innervated from both sides, so that pain refers bilaterally. Second, pain stemming from the dura has a very broad reference and seems to cover several consecutive dermatomes. For instance, pressure of a lumbar disc on the dura at the L5 level can cause pain in the back which radiates to the abdomen and groins, down to the anterior and posterior aspect of both thighs and legs, and upwards to the back of the lower chest. This type of pain reference is inexplicable in terms of segments. We therefore call it ‘extrasegmental reference’ of pain. Because in orthopaedic medicine, the dura is the exclusive source of this type of pain radiation, it is also called dural reference. Pain of this nature can be very difficult to interpret if it is felt in a part or parts of the possible reference area. As in purely segmental reference, dural reference can be to only a part of the respective dermatomes. Thus, instead of the broad radiation to the whole back, both glutei and both legs, dural pain sometimes only affects a small part, for instance one groin, or one buttock or the whole posterior aspect of the thigh. The differential diagnosis from a more segmental pain, for instance as the result of a nerve root compression, is then difficult.

A common clinical finding in a cervical disc protrusion that impacts on the dura is unilateral interscapular pain or pain in the trapezius or pectoral area. In the latter instance, suspicion of angina pectoris may then easily arise. Also the removal of an appendix for dural pain of lumbar origin referred extrasegmentally into the iliac fossa and groin is not at all exceptional.

A possible explanation for the misleading pain reference of the dura may lie in its multisegmental origin, which is reflected in the great overlap between the fibres of the consecutive sinuvertebral nerves innervating its anterior aspect.70–73 More recent researchers describe division of the nerves into ascending and descending branches which ramify variously, to give off longitudinally and transversely orientated branches.^74,75 In a recent study that used the very sensitive acetylcholinesterase method, more ramifications between the nerve branches were demonstrated (Fig. 1.19).⁷⁶ Ascending branches up to four segments cranial to the level of entry into the dural nerve plexus and also descending branches extending up to four segments caudally were observed. In addition, many vertical and horizontal interconnections between the various ascending and descending branches were seen. The conclusion is that dural nerves may spread over eight segments and that a great overlap exists between adjacent and contralateral dural nerves.

These findings may form an anatomical explanation for the clinical observations of Cyriax on the limits of extrasegmental reference of dural pain.⁷⁷ Upwards, pain originating in the lower cervical part of the dura may spread to the occiput, skull and forehead (Fig. 1.20). Downwards it can descend to T7 which corresponds with the lower angles of the scapulae. Anteriorly the pain can occupy the whole pectoral area. Extrasegmental pain does not extend beyond the upper half of the arms.

A middle thoracic disc lesion can cause dural extrasegmental pain that may radiate to the base of the neck, and downwards to the whole abdomen and to the upper lumbar region (Fig. 1.21).

Dural extrasegmental reference from a low lumbar level may reach the lower thorax posteriorly, the lower abdomen deep to the umbilicus, the groins, the buttocks, and the sacrum and coccyx (Fig. 1.22). Unlike the cervical dura – which does not radiate far into the arms – extrasegmental reference from a lumbar origin may also involve the legs, both the anterior and the posterior aspects, and descend to the ankles.

Referred tenderness

There seems to be more to referred pain than just mislocation by the patient. Within or near the area of referred pain, it is often possible to find small trigger points which are exquisitely sensitive. Pressure on one of these immediately produces a deep and radiating tenderness which is identified by most patients as the source of their symptoms. Classic localizations of these tender spots are:

If the tender area is palpated without the prior conduct of a proper functional examination of the neck or lumbar spine, the tenderness is regarded as the primary lesion, the more so because the patient insists that it is the apparent origin of the pain. It is no wonder then that ‘fibrositis’, ‘myofibrositis’ or ‘myofascial pain’ syndromes have long been regarded as primary lesions. The ‘fibrositis’ concept has been used to explain the cause of lumbago.⁷⁸ Lewis³³ was the first to recognize that trigger points and myalgic spots were not primary lesions and that the painful area, although tender to the touch, did not contain a focus.

Cyriax considered that the localized tender area is a secondary effect of pressure on the dura mater.79,80 He derived his theory from the simple clinical observation that the tender spot shifted from place to place over a few seconds after a successful manipulation and that, when a full and painless range of motion had been restored, the tenderness disappeared.

However, referred tenderness has also been demonstrated in muscular and fibrous tissue lesions,⁸¹ in visceral lesions such as ischaemic heart attacks⁸² and in pathological viscera. The phenomena are not completely understood as yet but it is reasonable to assume that trigger points are caused by summation mechanisms which can be understood in terms of gate-control mechanisms.⁷⁹

Summation – the excitatory effect of converging inputs – is an important pain mechanism. Pain may be triggered by two sources of nerve impulses: a major one from the lesion; and a minor one from normal skin which add together. If one source is removed, it becomes more difficult for the other to trigger the feeling of pain.⁸³

Factors determining reference of pain

Referred pain is a faulty perception of the origin of a pain. In orthopaedic medicine it is common to see marked differences in the extent of reference between segments, between distinct affected tissues and between different degrees of the same condition.

The degree of reference – that is the distance between the localization of the perception and the site of the lesion – depends on four different factors (Box 1.3). Some can be explained on the basis of the known pathways, others remain unexplained and result purely from clinical observations.

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