This dissertation has been submitted by a student. This is not an example of the work written by our professional dissertation writers.

1. Neurologic Aspects of Pain

1.1. Functional Properties of Nerve Fibres

1.1.1. Properties of Peripheral Somatic Nerves

Peripheral somatic nerves consists generally of somatic-motor, autonomic-motor and sensible fibres.

1.1.1.1. Somatic-motor fibres for the striated musculature

The cell bodys of somatomotor fibres for the striated musculature are always lying in the brainstem (12 pare cerebral nerves) or the fore horn of the whole spinal medulla. The stimulus runs from central to peripheral (efferent). The lateral cutaneous femoral nerve consists of sensible fibres and no motor fibres. The shiatic nerve consists of 20% motor fibres, 30% sensible, and 50% sympathetic fibres. The gluteal nerves consist of pure motor fibres, sympathetic fibres and no sensible fibres. 1,2

1.1.1.2. Autonomic-motor fibres for the smooth muscles of blood- and lymphatic vessels

The autonomic-motor fibres for the smooth muscles of the blood and lymphatic vessels are of sympathetic origin. Venes are not innervated. They function by the musculare pump system and in some cases by valves. The cells bodies of the autonomic-motor fibres are situated in the lateral horn between C8-L2. They are termed: the centro-ganglionar neurons. All motor neurons, situated in the spinal medulla go via the fore horn to the peripheral nerve. It must be mentioned that all smooth muscles can contract without external innervation (for example: heart, gut). This is due to the intrinsic nerve system with is influenced by the sympathetic and parasympathetic nervous system. 3-5

1.1.1.3. Sensible fibres for somatic structures

The sensible fibres for somatic structures originate from muscles, tendons, capsules, joints, ligaments and bones. Their cell bodies are lying in the spinal ganglions of the corresponding nerve (= afferent). 2,6

1.1.1.4. Sensible fibres for autonomic structures: blood- en lymphatic vessels

The cell bodies of the sensible fibres for autonomic structures are situated in the spinal ganglions of the segments where the sympathetic neurons start (SI-joint: T11-L1). The peripheral autonomic nerve contains generally autonomic-motor and sensible fibres and serves for the innervation of organs. Glands are always dubble innervated (sympathetic and parasympathetic), except for the adrenals. 2 Examples:

- The femoral arterie contains sensible fibres which go to the spinal ganglions and arrive in the dorsal horn where connections exist, via intercalar neurons, with the origins of the sympathethic fibres of the levels T10-T11.

- Knee joint: is sensible innervated via the sciatic nerve (posterior side of the knee), but in the knee capsule, sensible fibres exist which connect via the femoral arterie the levels T10-T12.

1.1.2. Properties of Peripheral Autonomic Fibres

Peripheral autonomic nerves consist of autonomic-motor and sensible fibres. They innervate organs and glands.

1.1.2.1. Viscero-sensible fibres

The cell bodies of viscero-sensible nerve fibres are situated in the spinal ganglions of those segments from where the sympathetic and parasympathetic neurons start. Example: the pelvis organs: S2-S4 and/or TLJ (= thoracolumbar junction). The TLJ receives a lot of information. Some of those stimuli go via the nervous supply in the blood vessel wall. 2

1.1.2.2. Motor fibres for smooth muscles

The parasympathetic primary cells are situated in the brain stem to the level of C2 and the lateral horn of S2-S4. The sympathetic origin is situated in the lateral horn of C8-L2. 2,7,8

1.1.3. Axoplasma Flow of the Axons

Materials and substances are moved within the cytoplasm of all cells. In the axoplasm (= cytoplasm of neurons), structures such as the smooth endoplasmic reticulum, ribosomes, microtubules and neurofilaments likely take part of the axoplasmic transport mechanism. Perhaps the human movement plays a role in this intracellular motility 9. In the cytoplasm of nerve fibres nutrients and transmitters are moved. At the nerve ends vesicles are located, that continue the transport into the gap junction. The transport in the axoplasma is termed antidrome and orthodrome transport. Antidrome (antegrade) transport occurs from central to the periphery and orthodrome (retrograde) transport in the opposite direction.1,10,11 For the sciatic nerve the antidrome transport is rather fast (12 hours), the orthodrome transport is slower (48 hours).

1.1.3.1. Signal transfer of the peripheral nerve fibres

Ion-channels and receptors play an important role in the signal transfer of the peripheral nerve fibres. The ion-channels are located on the extremities of the fibres. They make the transport for the neurotransmitters possible. Receptors are specified. Every cell has ± 1 million receptors. The gates of the ion-channels (mostly proteins) can be inhibitory or excitatory. The Swann-cells are spread over the axon and form de myelin sheet. The myelin sheets are interrupted by the knots of Ranvier. In the CNS they are termed glial cells. The glial cells have several functions. The myelin sheets have a certain thickness. Unmyelinated axons have Schwann-cells as well. In myelinated axons the stimulus progresses salutatory and in unmyelinated axons the stimulus progresses slowly. The signal transfer of the peripheral nerve fibres has 3 kinds of stimulus progress being chemical transport, electric stimuli progression and axoplasm flow.

Chemical transport occurs at the nerve ends, and consists of neurotransmitters. The transport depends of the kind of ion-channel, the neurotransmitter and the receptor.

Electric stimuli progress over the axon and occur by opening of the ion-channels stimulation the own nerve ends due to production of the neurotransmitters. The speed of transmission depends of the presence of a myelin sheet and the diameter of the fibres.

The axoplasm flow of the neurotransmitter in axoplasma (= chemical) occurs in 2 directions. Sometimes the pain can occur 24 hours after injury! It can also be very slow (up to 48 hours) and be resposible for the “delayed onset of pain?. 1,11

1.1.3.2. Morphologic and functional classification of nerve fibres:

Understanding pain phenomen the morphologic and functional properties of nerve fibres is important. In time several classification systems have been investigated and proposed.

1.1.3.3. Classifying axons according to their conduction velocity

In the 1920s and 1930s, there was a virtual use of classifying axons according to their conduction velocity 13. Three main categories were discerned, called A, B and C fibres:

C fibres are the smallest and slowest. Mechanoreceptors generally fall in category A. The A group is further broken down into subgroups designated:

- the a fibres: the fastest

- the b fibres

- the d fibres: the slowest

The muscle afferents axons are usually classified into four additional groups:

- I: the fastest

- II, III and IV: the slowest, with subgroups designated by lower case roman letters.

1.1.3.4. Properties of the A-d, A-b sensors or type I en II fibres

The A-a and A-b fibres have low threshold properties. They are low threshold afferents/efferents, they have a quick adaptation, are bi- or monosynaptic and unimodal (= mechanosensors: only sensible for mechanical stimuli). They cross the midline in the spinal medulla. The A-b provides information about normal pressure or strain tension and the A-a provides information about position changes of joints in space. They give information about the smooth touch and kinesaesthesis in the skin.

1.1.3.5. Properties of the A-d and C sensors or type III en IV fibres

1.1.3.5.1. The A-d sensors or type III fibres

The A-d or type III fibres are selective and have a slightly higher threshold than the A-a and the A-b sensors. They have a longer adaptation time. After a pin prick the pain keeps going on for a time which is a specific property of the A-d sensors. They are multisynaptic and cross the midline in the spinal medulla. A-d sensors are polymodal. They provide information about mechanical stretch and pressure forces from normal to noxious. They give information about temperature from normal to noxious stimuli. From 36,5°C tot 42°C especially C-fibres are involved. From 36,5°C tot 38°C the A-d fibres are responsible. A quantity of those fibres is noxious. They are termed: “nocisensors? but not all. Some measure only normal temperatures and they become nocisensors in case of tissue injury. 11

1.1.3.5.2. The C sensors or type IV fibres

The C or type IV fibres are selective and have a high till very high threshold. They are slow to very slow with a long adaptation time. They have tonic and continuous activity properties. They cross the midline in the medulla medulla and are polymodal. The C fibres measure the chemical consistence of tissues from normal to noxious. They measure temperature from normal till abnormal (= noxious). Some of those fibres are nocisensors but not all of them. Example: the sensibility of the knee consists of 80% normal sensibility sensors and 20% nocisensors. 11

1.1.3.5.3. Difference between “nocisensor?- stimulation and “pain?

A nocisensor measures the damage of injured tissue. A nocisensor can but must not necessarily provoke pain. A part of the A-d and C-fibres are nocisensors. They measure the damage or the almost-damage (mechanic, temperature, chemical). Their noxious stimulation does not always lead to pain perception. Here fore the stimulus must attain the thalamus and cerebral cortex, otherwise there is no pain sensation. Not all nociceptory stimuli rise so high to the midbrain or cortex. A lot of stimuli “extinguish? in the spinal medulla, the ascending pathways or in the brainstem. The stimulus attains the “pain centres? when the intensity of one stimulus is sufficient or when summation occurs of several stimuli in parts of the dorsal horn. As well reflectory (unconscious) as cognitive (conscious) reactions occur and the nocisensors will provoke “pain?, in case of severe damage. Thus, not all nocisensors provoke pain but they can be considered as normal pain fibres. It is logic that if a nocisensor is sufficiently stimulated it will provoke the sensation of pain. A-d en C fibres can give pain that’s not only caused by the damage itself, but as a result of the damage as well. A pain feelin which is more intense than normally expected is termed hyperalgesia. For example, when ice is applied on the skin it “hurts? but ice applied on a burned skin does hurt even more. When punctuated stimuli are applied on the course of the sciatic nerve it “normally? hurts but in case of sciatica it hurts even more (= hyperalgesia). Hyperalgesia is hypersensitivity on a stimulus that normally hurts, due to over stimulation of the nocisensors. The A-a and A-b fibres normally do not give pain, because they are not nocisensors. They register only “normal? values. Under certain circumstances they provoke pain. This happens in case of injured tissues or nerves or when the nocisensors become active. When nocisensors already give pain as a result of a decreased threshold, then the A-a and A-b fibres become sensitive as well. A light pressure on the pain area will also be painful. A low pressure- or strain force on the skin, tendons or muscles normally provoke no pain, but in case of damage it will well provoke pain. This is termed allodynia. Allodynia is pain that is caused by a stimulus that normally doesn’t hurt due to an increased sensitivity of the the A-a and A-b fibres. This phenomon gives an opportunity to test the pain perception of the nervous system by use of pricking or brushing tests on the painfull area. There is a difference between nocisensor stimulation and the pain interpretation. 11 Table 5: Difference between nocicensor stimulation and pain.

By use of selective stimulation the A-a and A-b fibres can be stimulated without that the A-d and C-fibres become active. This is caused by the low threshold of the A-a and A-ß fibres compared with the A-d and C-fibres. A-d en C-fibres can’t be stimulated selectively by use of mechanical stimuli because at the moment those fibres are stimulated; already the A-a and A-ß fibres are active. When those become active, all fibres were stimulated. Also in case of nociception all those fibres are active. Selective stimulation can be used during TENS application or during active en passive mobilisations applied under the pain threshold level. 11

1.1.4. Hierarchy of the Nervous System

The information processing in the nervous system happens on 4 levels. As well as the peripheral nerve ends, the dorsal horn, the brainstem and sub cortical and cortical levels are involvend. 1,7,11

1.1.4.1. The peripheral nerve ends

The peripheral nerve ends are responsible for the uptake of information. The receptors are modulated by the state of surrounding tissue and the condition of the peripheral nerve.

1.1.4.2. The dorsal horn of the spinal medulla

The dorsal horn modulates the incoming signals and is influenced by the state of the dorsal horn and the quantity and kind of gathered stimuli.

1.1.4.3. The brainstem

The brainstem provides the primary responses with autonomic and hormonal modulations as a response to stimulation.

1.1.4.4. Sub cortical and cortical levels

The sub cortical and cortical area provides the conscious cognitive and psycho-emotional modulation.

The processing of the information and response on stimulation depends on the hierarchic manner, but always occurs with a total integration of the whole nerve system.

1.1.4.5. The Archi-, Paleo- and Neo level of the nervous system

The nervous system can be ordered depending on a hierarchic manner in an archi, paleo and a neo level. 7

1.1.4.5.1. The Archi level

The archi level consists of the gray matter (dorsal horn) of the spinal medulla, the ascending multisynaptic pathways in and around the gray matter, the medial pathways of the anterolateral quadrant, the mid part of the cerebellum and the brainstem (reticular formation). It is responsible for the “most automatic movements? after Hughlings Jackson. 7

1.1.4.5.2. The Paleo level

The paleo level consists of the ascending pathways of the anterolateral quadrant, the descending pathways in the ventro-lateral quadrant, the hormonal and vestibular nuclei in the brainstem, the hypothalamus, certain parts of the cerebellum and the limbic system. Humoral influences from the liquor can influence (endofins) the sensibility of the pain system. 7

1.1.4.5.3. The Neo level

The neo level consists of the dorsal ascending pathways, the dorso-lateral and ventral descending pathways, the cerebellar cortex, the lateral thamalus nuclei and the cerebral cortex. It is responsible for the cognitive mental processes, accurate skills and “least automatic functions?. 7

1.1.4.6. Phylogenetic development of the nervous system

The phylogenetic development of the nervous system differs in time for the different levels.

The archi-system is the oldest and is identical to that of the lower vertebrates. It is completely developed when born. The paleo-system is younger than the archi-system. It is identical of that of the lower vertebrates but only half developed when born. The neo-system is het youngest system in the phylogenetic evolution. It is much more developed than that of the lower vertebrates and not developed when born. 7

1.1.4.7. Functional properties of the different hierarchic systems of the nervous system

Specific properties can be indicated to the different hierarchic levels of the nervous system.

1.1.4.7.1. Functional properties of the Archi level

The archi level consists of C and A-d fibres. It is a relatively slow and tonic (continuous) working system that stands for the basic needs of life e.g.: “basic survival? or “most automatic movements? and autonomic functions such as basic tonus regulation in the brainstem and medial cerebellum. It is responsible for primary pain modulation e.g.: redraw reflex and increased tonus.

1.1.4.7.2. Functional properties of the Paleo level

The paleo level consists especially of A-d, A-b, and C-fibres as well. It is a relative quicker system but also has tonic activity properties. The paleo level supports the archi-level by use of hormonal adaptation and psycho-emotional adaptation. It takes part of the autonomic function (hormonal function), fight/flight reactions in case of stress and pain and posture regulation (static posture balance).

1.1.4.7.3. Functional properties of the Neo level

The neo level consists especially of A-a and A-b fibres and is very quick with phasic responses on stimulation. It analyses the information of the archi- and paleosystem and is guided by use of cognitive responses. The least automatic movements are “guided? and “conscious? movements. It regulates the dynamic posture balance and automatisation of movements. It is responsible for the organ sense perception and dissociated movement.

1.1.4.7.4. Interaction and control of the different hierarchic systems in the nervous system

General principles of interaction among the different hierarchic systems in the nervous system can be summarized as follows. The paleo-system controls the archi-system and guides it. The neo-level controls the archi- and paleo system and guides both. The neo-level surrounds literally the archi and paleo level. The grey matter is situated medially in the nervous system medial in spinal medulla, the white matter laterally. The neo-system keeps the paleo-level and archi-level “in harness?. The hierarchic construction of the nervous system can be seen as a gate control system that exists on all levels. 7

1.1.4.7.5. Gate-control in the peripheral nerve fibres

Axo-axonal connections between lower and higher fibres exist. The A-a and A-b fibres give off collaterals in the dorsal horn. The A-a and A-b attain the spinal medulla faster and “prepare it? for the arrival of A-d and C-stimuli. Selective stimulation of higher fibres (A-a and A-b fibres) inhibits the working of the fibres of lower order (A-d and C-fibres).

1.1.4.7.6. Gate control in the dorsal horn

At the level of the dorsal horn interaction and control mechanisms exist and this phenomen known as “Gate-control in the dorsal horn? is also known as the gate theory of Melzack en Wall. The outlets of the A-a en A-b neurons shunt on the outlets of the A-d and C-neurons and their neurotransmitters close the ion-channels of these. The descending pathways of the paleo- and neosystem do the same and work on the interneurons and inhibit the A-d and C-neurons. 11

1.1.4.7.7. Gate-control in the brain

The cortical pathways control the sub cortical pathways. They inhibit the brainstem reflexes. “Conscious? movements and intentions inhibit “unconscious? tonic reflexes (Example: relaxation). The cortical and sub cortical pathways regulate a directed and conscious life. The brainstem provides the autonomic support. This is all controlled by neurotransmitters. The perception of nociceptive pain not only involves the sensation transmitted and regulated by peripheral and central neurons, but is also affected by higher brain functions. 11

1.1.4.7.8. The uptake of nociception information

A-d and C-fibres are the only fibres that can registrate nociception. The A-d fibres are quicker and give “epicritic? pain when the stimulus is attaining the pain centres. Epicritic pain means precise localisation with immediate redraw reflexes. The kind of pain is described as stabbing, boring, tearing or pulling. The impulses of the C-fibres attain the pain centres much later. They give “protopathic? pain, which is a continuous pain. That pain is not precisely located. Protopathic pain is burning, booring of a kind and continues much longer. It goes together with autonomic reactions, for expample: oedema. 11

1.1.5. The dorsal horn of the spinal medulla

1.1.5.1. General survey of the classification of the grey matter of the spinal medulla

The grey matter is divided in the 10 layers of Rexed. This system is named by Rexed who discovered that the neurons in the dorsal horn where organised in “layers? depending on their function. Every layer is present in different segments and forms rostro-caudal nuclear columns. The counting happens from the dorsal horn to the anterior horn. Every layer is in contact with another by interneurons and dendrites.

- Layer I and II: nocisensory outlets of both: musculo-skeletal and visceral structures

- Layer III: intersegmental ascending pathways (dorsal proprium tract) and outlets to the spinothalamic tract (anterolateral quadrant)

- Layer IV: exclusive nocisensors from the musculoskeletal system

- Layer V-VI: fibres arriving from the nocisensors of the skin and viscera

- Layer VII: lateral horn: interneurons and sympathetic neurons

- Layer VIII en IX: motoneurons for musculoskeletal system

- Layer X: hormonal neurons

In all levels descending pathways arrive from diverse levels of the brain.

1.1.5.2. Somatotopic ordering of nocisensors in the dorsal horn

In layer I-II the nocisensors of viscera and musculo-skeletal structures are laying next to each other. They are ordered in a sagittal way from medial to lateral. The medial structures project medial and lateral structures project laterally.

In layer V the nocisensors of certain skin areas are lying next to the nocisensors of viscera. Those are ordered in “horizontal? layers. For example: the organ-nocisensors under the level of the diafragm are lying next to the skin sensors from Th7-Th10.

1.1.5.3. Segmental interactions in the dorsal horn

Normal reactions in musculo-skeletal influence the nocisensoric function. Outlets of nocisensors stimulate interneurons. There exists interaction with the spinothalamic tract and interaction with motoric anterior horn cells (somato-somatic relation).

Normal reactions in musculo-skeletal nocisensoric function and influence the outlets of nocisensors stimulate the interneurons causing interaction with spinothalamic tract and with the sympathetic lateral horn cells (viscero-visceral relation). 11

Abnormal reactions can occur when the outlets of nocisensors “infect? the other nocisensors. Those react in turn causing interaction between motoric and visceral responses. This results in a somato-visceral relation, a somato-sympathetic relation and a viscero-somatic relation.

1.1.5.4. The Importance of Wide Dynamic Range Neurons

In layer III, wide dynamic range neurons (WDR-neurons) exist. 21 Those WDR-neurons are interneurons that connect all the A-d en C-fibres from the dorsal horn. They project on the spinothalamic tract (antero-lateral quadrant). The ventral pathways go to the reticular formation, medial thalamus and the medial limbic system. The lateral pathways go to the lateral thalamus and cortex. They connect all visceral and motoric stimuli (= summation) with as consequences that motoric and visceral stimuli are sent together to the brain. The brain receives “segmental? information and no “individual? information. The brain can project pain to segmental connected structures. This is termed “referred pain?. Examples are: the stomach ulcer can provoke inter scapular pain or cardiac complaints and can give ulnaris nerve pain. Pain does not always indicate the exact location and origine. Anamnesis, assessment and clinical reasoning are very important.

1.1.5.5. Inhibition and excitation of the dorsal horn

Inhibition and excitation of impulses in the dorsal horn can be caused by outlets of peripheral nerves. For example the A-a and A-b can inhibit the A-d and C fibres (pre-synaptic inhibiton). The outlets of the descending pathways can influence the the nerve ends and the interneurons (postsynaptic inhibition/excitation). The interneurons themselves can cause pre- or postsynaptic inhibition/excitation. Summation of stimuli defines the state of the dorsal horn. If a segment is excited or inhibited depends on the som of stimuli. Nocisensory impulses of the peripheral nerves always excite the dorsal horn. Summation of exciting nocisensoric impulses is defined by “spatial? and “temporal? facilitation. Temporal facilitation means the timing; spatial facilitation, the diverse structures that are involved. Impulses of A-a and A-b neurons act “generally? inhibiting. The impulses from the descending pathways can act in both ways. They are also regulated by temporal and spatial factors. The sum of stimulating and inhibiting stimuli defines the state of the dorsal horn. An excitated dorsal horn provokes a lot of irradiating pain.

1.2. Assessment of Primary and Secondary Hyperalgesia

1.2.1. Definition of primary hyperalgesia

“Changes in the local sensibility of the afferent neurons as a result of a lesion in the peripheral tissues are termed hyperalgesia?. In case of an increased sensibility of the A-a and A-b fibres the primary hyperalgesia is termed allodynia. In case of an increased sensibility of the A-d and C fibres the primary hyperalgesia is termed hyperalgesia. The lesion in the peripheral tissue can be of inflammation or neurogenic origin. 22

1.2.1.1. Pathophysiology of primary hyperalgesia

In case of tissue injury bradykinin and ATP is produced at the site of lesion. Those mediators stimulate the blood- and lymphatic vessels, the mast cells and nociceptors. In the circulation inflammatory mediators are released aswell as histamine, serotonin, NGF, leucocytes, trombocytes and others. C-fibres released neuropeptides such as SP and CGRP. Those modulate and stimulate the release of other inflammatory mediators aswell. All those mediators are termed the “inflammatory soup?. Those mediators also stimulate the C-fibres which causes a vicious circle. The sympathetic nerve terminals are stimulated by inflammation and release noradrenalin which also stimulates the C-fibres. The “sympathetic coupling? between C-fibres and sympathetic end neurons occurs. The presence of inflammatory mediators decreases the threshold of all types of endneurons with as a result local allodynia and hyperalgesia. The allodynia and hyperalgesia can spread in the surrounding tissue, by stimulating the surrounding neurons. This is termed the flair zone. 22,23

Figure 16: Consequences of tissue injury: the inflammatory soup. 14

1.2.1.2. Primary hyperalgesia and the dorsal horn

The A-d mechanoreceptors and nociceptors, and C-nocisensors stimulate the dorsal horn of somatic connected segments. As a consequence a temporary wind-up can occur. A wind-up is an over stimulation that can hold on for 72 hours. A refectory muscular reaction occurs around the lesion aswell. As a result the stimulation via the ascending pathways (antero-lateral quadrant) to the brain increases. Protopatic pain (quick, stabbing pain) followed by epicritical pain (boring, continuous pain) occurs. The brainstem regulates the autonomic reactions further such as sympathetic, hormonal, and emotional. The C-nocisensors give stimuli to the sympathetic connected segments. As a result the sympathetic system stimulates the C-endneurons (= sympathetic coupling) and vasoconstriction on the arterioles and lymphatic vessels. 20,24

1.2.1.3. Primary hyperalgesia and nerve injury

When compressed inflammation occurs as prescribed above. In case of long standing injury, an ectopic injury occurs. This can be located on different locations on the peripheral nerve with the result that hyperalgesia and allodynia occurs on the course of the nerve, the connected dermatomes and this from the nerve root! In the spinal ganglion of the nerve, the sympathetic endneurons grow round the nerve cells with the occurrence of basket formations as a result. Consequently sympathetic maintained pain (SMP) occurs, also termed causalgia. This phenomon can continue for 7 to 10 weeks after the lesion but can also continue afterwards. 10 25

To summarize we can state that inflammation provokes a “local? hyperalgesia and allodynia, which spreads over the flair zone. Locally a vicious circle between the inflammatory soup and C-fibres takes place and sympathetic coupling between sympathetic end-neurons and C-fibres occurs. This continues until the tissue heals. Normally the medulla reacts with a temporary wind-up and a normal stimulus-response reaction. In case of neurogenic injury, causalgia may occur and sensitisation of the dorsal horn is possible. 22

1.2.1.4. Clinical pain assessment in case of primary hyperalgesia

During the pain assessment, in case of primary hyperalgesia, when brushing or by use of punctuate stimuli the following properties are local allodynia and hyperalgesia restricted to the flair zone. In case of a nerve injury the flair zone is restricted to the course of the nerve root. Local sympathetic reactions occur when inflamed but are restricted in time. In case of allodynia and hyperalgesia when brushing and applying punctuated stimuli on the course of the nerve or a part of it, sympathetic reactions in the dermatome of the nerve can occure aswell. 22

1.2.2. Definition of Secondary Hyperalgesia

“An increased sensibility of all types of nerve fibres that continues outside the flair zone of the original lesion, linked to the course of the hyperalgesia and allodynia around the tissue, is termed secondary hyperalgesia?. 22

1.2.2.1. Pathophysiology of secondary hyperalgesia

When tissue is injured, nociceptors stimulate the interneurons by use of neurotransmitters such as SP, CGRP, NO, Ca, etc. The A-a and A-b neurons provide inhibiting neurotransmitters and the descending pathways give exciting or inhibiting mediators. The WDR-neurons receive al those impulses and send them to the spino-thalamic tract. WDR-neuron receptors differ. Some open ion-channels using inhibiting neurotransmitters, others open ion-channels using exciting neurotransmitters depending on the kind of receptor. If the stimulus acts inhibiting or exciting depends on the quantity of the opened inhibiting- or exciting ion-channels. In case of secondary hyperalgesia, more excitatory stimuli exist and insufficient inhibiting ways are activated. The WDR-neurons will work exiciting as well because of the fact they do not only activate the spino-thalamic pathways but also on the incoming stimulating neurons. As a result a vicious circle occurs in the dorsal horn. This provokes a decreased threshold of the present neurons. The sensors are also stimulated by the dorsal horn and not only by the local lesion. They become sensitized over their whole course with the consequence that the central hyperalgesia is linked to the lesion. When the local lesion is healing, the central allodynia will also disappear. Hyperalgesia is not as much linked to the course of the lesion but can last longer. Its origin is mostly caused by temporal and spatial summation of exciting stimuli. 22

1.2.2.2. Clinical pain assessment in case of secondary hyperalgesia

During the pain assessment, when touching (brushing) and applying punctuate stimuli local hyperalgesia en allodynia and extending hyperalgesia and allodynia can be observed.

When the pain occurs outsite the spinal column area the touching (brushing) and applied punctuate stimuli starting from the lesion and over the dermatome near by. The application must be enlarged to the neighbouring dermatomes and also to the corresponding segments of the spine. Always compare with the opposite side. Differentiate allodynia and hyperalgesia. 22

In case of primary hyperalgia the allodynia and/or hyperalgesia is restricted to the lesion area and flair zone. The allodynia disappears before the hyperalgesia when healing.

In case of secondary hyperalgesia the allodynia and or hyperalgesia is present in several dermatomes and sometimes occurs up to the spinal segments. The allodynia disappears sooner than the hyperalgesia when healing.

When the pain occurs at the level of and around the spine, the touching (brushing) and applying punctuate stimuli must first be applied on the painful segments and continued to higher and lower segments. The findings in the different segmental zones must be compared with each another. The conclusions are identical as case of peripheral pain. 22

1.2.3. Sympathethic maintained pain

1.2.3.1. Definition of sympathetic maintained pain:

“Pain, which is maintained by local or central over stimulation of the sympathethic nervous system, is termed sympathetic maintained pain?.

Sympathetic maintained pain can occur as a consequence of local maintained inflammation and provoke phenomons such as sympathetic reflex dystrophy or complex regional pain syndrome (= CRPS). 26-28

1.2.3.2. Pathophysiology of sympathetic maintained pain

In case of sympathetic maintained pain, local inflammation is maintained by local sympathetic coupling. This can be caused by a continuous stimulation of the secondary neurons in the lateral horn. This stimulation can be the result of stress situations or local input from organs. In pain physiology sympathetic reflex dystrophy (CRPS) is described as CRPS type I of II. CRPS I is the classic algoneuro dystrophy and CRPS II is the earlier described causalgia. Both types have a different pathophysiology. CRPS I is caused by a continuous sympathetic coupling as seen in maintained inflammation. The CRPS II is caused by the presence of basket formations in the spinal ganglion in case of a nerve lesion. Sympathethic maintained pain can be mild to extreme. In both cases of pain, the sympathetic system is involved. It depends from case to case, if its role becomes dominating. 26-28

1.2.3.3. Clinical pain assessment of sympathetic activity

When assessing patients with chronic pain it is important to evaluate the sympathetic activity. This can be done with superficial observation and palpation of the skin. Herefore the therapist strikes softly over the skin of the back with the dorsal side of the hand. Look for colour changes, connective tissue abnormalities (strings), sweaty skin, pilo erection (chicken skin reaction). Afterword the Kibler-skin roll test can be applied. Hereby the skin is taken up between the thumb and index or mid finger. Lift and roll out the skin softly while proceeding in the paravertebral area over the whole spinal column. This must be repeated about 4 times. During the assessment; special attention must be made for possible presence of adhesions, the elasticity and dampness of the skin. Pain and red colouring may occur. The Headsche zones can be disturbed. Deep irritation of the skin can occure accompanied with muscular tension (McKenzie zones). To assess deeper tissues, enforced circularly frictions around the paravertebral musculature can be applied over the whole spine and repeated sufficiently. When palpating for hypertonic paravertebral musculature, also look for sweat reactions, the red colour and Headsche zones, pain, hypertonia (Mc Kenzie zones). Sometimes the Headsche zones and the Mc Kenzie zones can correlate and indicate an underlying pathology. 7,26-28

1.2.3.4. Clinical neurodynamic pain assessment

During clinical pain assessment special attension must be made for peripheral nerve lesions. While neurodynamic testing, the “mobility? of the peripheral nerve is assessed when elongated. The sensibility or “irritability? of the peripheral nerve must be evaluated and the involvement of the peripheral nerve in case of a locomotoric lesion must be investigated. The neurodynamic testing involves “mobility? or sensibility assessment of the dura mater aswell. The sympathetic chains must be must also been assessed. More details are described in literature 10,29-35.

1.2.4. Organisation of the Sympathetic Nervous System

The functional properties of the sympathetic- en parasympathetic system are the regulation of the physiological basic functions such as: blood pressure, heart- and lung function, energy regulation and the functioning of organs. The function of the exo- and endocrine glands are regulated. The autonomic nervous system plays an important role regulating the the balance of the “milieu interne? (homeostasis). 2 Table 6: Organisation of the autonomic system.

1.2.4.1. Sympathetic nervous system: musculo-skeletal distribution

1.2.4.1.1. Primairy or first order neurons

The primary or first order neurons are situated in locus coerolus (b-fibres) and in the reticular formation. The axons or first order neurons attain the whole spinal medulla and have collaterals to the dorsal horn. They produce catecholamine provoking inhibition. They have collaterals to cells in the lateral horn between C8-L2 as well. The first order neurons are stimulated by the limbic system, the cerebellum and the hormonal system. 22,36

1.2.4.1.2. Secondary or second order neurons

The secondary or second order neurons are situated in the lateral horn (intermedio-lateral tract (ILT)) between C8-L2 (b-fibres). The axons go externally via the ventral horn together with the spinal nerves through the intervertebral foramen attaining the paravertebral ganglions. The secondary neurons are stimulated by the first neurons, the interneurons from the dorsal horn and from impulses of visceral or motoric origin. Before they attain the paravertebral ganglia, the second order neurons go as close as possible to the target tissue. 24,37

This phenomen can be summerized in 3 golden rules. Figure 7 Musculoskeletal distribution of sympathetic origin: 3 golden rules.

1.2.4.1.3. Tertiary or third order neurons

The tertiary or third order neurons are situated in the paravertebral ganglia. They go direct to the target tissue. They are postganglionic end neurons (C-fibres). The teriary neurons go from every ganglion fibre back to the spinal channel (recurrent nerves). From every ganglion fibres go back to the spinal ganglion. Tertiary fibres follow the local blood- and lymphfatic vessels: radical arterial nerves. They follow peripheral nerves to muscles, joints and skin aswell (grey rami communicantes). 2

1.2.4.1.4. Functions of the sympathetic system on somatic structures

The general action occurs from the locus coerulus. It is responsible for the activation of the alert state. Those conditions are also termed: fight/flight reactions. A sympathetic state also provokes an increased basic-tonus, vasodilatation of the large arteries, except for the vertebral arteries, an increased heart beat (tachycardia), increased respiratory volume, and increased adrenaline- and cortisol levels. It inhibits the digestion, provokes pupil dilation (mydriasis), constriction of the arterioles and lymphatic vessels and stimulates sweat- and talg glands. Sympathetic facilitation provokes segmental or general reactions on the skin, in general: on the pilomotoric stimulation (chickenskin reaction), sudomotoric stimulation (sweating) and vasomotoric (vasoconstriction: pale skin). The clinical signs at rest or when touched softly are: pale skin, chickenskin reaction and sweating. When stimulated a red skin, swelling and sweating occurs. By working on the musculature (segmental or general) the Headsche areas can be palpated. Ischemic contractures can appear (Mc-Kenzie areas). 7,38-43

1.2.4.2. Autonomic Nervous system: anatomical considerations

The nervous system can be devided in a somatic and autonomic nervous system. Both systems have afferent and efferent properties. The autonomic nervous system receives afferent information of all kind. The efferent part of the autonomic system consists of sympathetic and parasympathetic division. The answer on stimulation depends of the tuning of the nervous system itselve. 7 Table 8: Classification of the nervous system.

1.2.4.3. Anatomical difference between the somatic and autonomic nervous system

1.2.4.3.1. The origin of the somatic and autonomic nervous system in the CNS

The peripheral part of the somatic nervous system starts over the whole length of the spinal medulla and medulla oblongata. The peripheral origine of the autonomic nervous system differs for the sympathetic and parasympathetic division.

The sympathetic division originates in the medullar segments from C8 to L2 and the parasympathetic division originates in the medulla oblongata and the medullar segments of the sacral medulla. 2,7

1.2.4.3.2. The configuration of the reflex bow

The configuration of the reflex bow differs in the somatic and autonomic nervous system. In the reflex bow of the somatic nervous system there exist an afferent and an efferent neuron. The traject of afferent viscerosensible pathways differs from the traject of the somatic sensible pathways. For both systems the perikarion is situated in the spinal ganglions.

The autonomic nervous system has a receptor neuron, a centroganglionar neuron and an effector neuron in its reflex bow. The centroganglionar neuron is situated between the receptor and effector neuron. The centroganglionar neurons originate in the lateral horn. It synapses with the effector neuron outside the CNS. The effector neuro connects the centroganglionar neuron with smooth muscles, glands or organs. 2

The receptor neuron or afferent neuron is the same for both divisions of autonomic nervous system.

1.2.4.3.3. Anatomical differences between the sympathetic and parasympathetic nervous system

1.2.4.3.3.1. Position of centroganglionar neuron

The centroganglionar neuron is the second autonomic neuron which does not exist in the somatic nervous system.

In the sympathetic division, the origin of the centroganglionar neuron is situated between C8-L2 in the lateral horn (intermedio lateral and medial nucleus). 2

In the sympathetic division the origin of the centroganglionar neuron is situated cranial and sacral. The cranial parasympathetic origin is situated in the medular levels C3-C4 of the medulla oblongata and consists of the accessory (Edinger-Westphal) nucleus of the ocullomotor nerve (CN III) (visceral motor), the superior (CN VII) and inferior (CN IX) salivatory nuclei, and the posterior (dorsal) vagal nucleus (CN XI). The sacral parasympathetic origin is situated in the medullar segments S2-S3-S4 of the medio-ventral grey matter of the sacral medulla.

1.2.4.3.3.2. Difference in position of the ganglion or synapse between the 2nd and 3rd autonomic endganglion

In the sympathetic division the synapse (ganglion) between the 2nd and 3rd neuron can be situated close to the spinal medulla in the sympathetic chain, or halfway between the spinal medulla and the end organ (splanchnic ganglia, celiac plexus, hypogastric plexus), or close to the organ (parenchymatic gangliae).

In the parasympathetic division the synapse (ganglion) between the 2nd and 3rd neuron is never situated in or around the sympathetic chain. Fibres of the parasympathetic system even do not go through the sympathetic chain. The synapse between the preganglionar and postganglionar neuron is situated halfway between the CNS and the target organ (for example: the cardiac, pulmonar, celiac, mesenteric or hypogastric plexus). Mostly the synapse between the 2nd and 3rd neuron is situated close to or into the target organ. All those are parasympathetic exept for the adrenals.

Therefore the sympathetic division has typical short preganglionar neurons and long postganglionar neurons. The parasympathetic division has an opposite configuration with long preganglionar neurons and short postganglionar neurons. 2

The grey rami communicantes exist at every medullar level. The white rami communicantes are situated at the level of C8-L2. Sympathetic efferent impulses that must attain higher or lower areas follow the sympathetic chain to their target. The fibres follow the wall of blood vessels. The sympathetic chain attains cranial structures via the internal carotic arterie that enters the skull via the carotic formamen in the temporal bone.

1.2.4.3.3.3. Neurotransmitter properties of the autonomic nervous system

The sympathetic neurotransmitters are adrenalin, noradrenalin, amfetamin, dopamine etc. The parasympathetic neurotransmitter is acethylcholin.

At the end of the postganglionar neurons of the autonomic nervous system, a different neurotransmitter is used. The postganglionar parasympathetic nerve fibres secrete acethylcholine; the postganglionar sympathetic nerve fibres secrete noradrenalin. In the synapse between the 2nd and 3rd autonomic neuron for both systems acethylcholine is secreted. Therefore the sympathetic nervous system is termed adrenergic and the parasympathetic nervous system is termed cholinergic.

1.2.4.3.4. The sympathetic division

The cell bodies of the sympathetic nerves are situated in the lateral horn of the thoracal and upper part of the lumbar medullar segments. The axons leave the spinal medulla via the anterior roots together with the efferent nerves from the somatic system. They connect the the sympathetic chain. The connections between the spinal nerve and the sympathetic chain are termed: the white rami communicantes. The preganglionar fibres can connect the second on different locations.

They can connect the 2nd neuron in the sympathetic chain. After synapsing they follow the peripheral nerves of the somatic nervous system. The connections between the sympathetic chain and the peripheral nerve are termed the grey rami communicantes. In the white rami communicantes myelinated fibers are present. In the grey rami communicantes the fibres are unmyelinated.

When the preganglionar fibres attain the sympathetic chain they can attain higher or lower medullar segments where they synapse in higher or lower sympathetic chain ganglions. From there they connect the peripheral nerve via the grey rami communicantes. The second neurons can follow the wall of bloodvessels aswell in the periphery.

Preganglionar fibres can go through the sympathetic chain without making any synapse to attain the preganglionar plexusses e.g.: the celiac, mesenteric or hypogastric ganglions situated in the prevertebral plexus where they synapse.

The sympathetic division provides the cardiac and pulmonary plexus from the medullar levels T1-T6. Via the celiac plexus (T5-T9) the stomach, liver, gallbladder, spleen, kidney (T10-L1), adrenals (T11) and a part of the duodenum and pancreas is supplied. The superior mesenteric plexus (T10-T12) supplies a part of the pancreas and duodenum, the jujenum, ilium, the colon ascendens and the proximal 2/3rd of the transverse colon. The inferior mesenteric plexus (T12-L2) supplies the distal 1/3rd of the transverse colon, the colon descendens, sigmoid and rectum. The hypogastric plexus (T12-L2) supplies the distal 1/3rd of the colon, the colon descendens, sigmoid, rectum, bladder and gender organs. 2,8,43-45

From the level of T5-T9 the n. splanchnicus major occurs and supplies the upper gastrointestinal tract, the duodenum and pancreas via the celiac ganglions. The minor splanchnic nerves occur from the medullar levels T10-T11. Via the superior mesenteric plexus they supply the intestinum tenue, the right colon, the adrenals, the testes, ovaria, kidney, and upper half of the ureters. The nervus spanchnicus minimus occurs from T12 and joins the lumbar splanchnic nerves (L1-L2) in the inferior mesenteric plexus to supply the left colon, the lower half of the ureters, the pelvis, the bladder and gender organs. The sympathetic supply for the arterial blood vessels of the upper limb is provided from the medullar levels T2-T6 and for the lower limb from T11-L2.

1.2.4.3.5. The parasympathetic division

The parasympathetic division of the autonomic nervous system originates from fibres that start from the brainstem and the sacral medullar segments. The parasympathetic fibres are joining the cranial nerves such as the occulomotory nerve (III), the fascial nerve (VII), the glossopharyngeal nerve (IX) and the vagal nerve (X). The vagal nerve is considered to be the most important parasympathetic nerve but is discussed further. The parasympathetic preganglionar fibres are long, the postganglionar fibres short because the ganglions where they synapse are situated close to the target organ in the cranium. The parasympathetic fibres that originate from the brainstem and join the cranial nerves (III, VIII, IX) serve the supply for the innervation of the pupil and the glands in the cranium. 2,8,43-45

1.2.4.3.5.1. The ciliar ganglion

The ciliar ganglion is situated in the orbital fossa between the lateral rectus muscle and the optic nerve. The preganglionar fibres occur from the autonomic accessory nucleus (nucleus of Edinger Westphal) in the brainstem. They join the occulomotory nerve to the ciliar ganglion where they synapse. From the ciliar ganglion the ciliar breves nerves occur that go through the sclera to the constrictor pupillae muscle and the ciliar body. The sympathetic fibres originate form the cavernous plexus and innervate the dilatator pupillae muscle. 2,8,43-45

1.2.4.3.5.2. The pterygopalatinum ganglion

The ganglion pherygopalatinum is situated in the fossa pterygopalatinum under the maxillar part of the trigeminal nerve. The preganglionar fibres originate from the superior salivatory nucleus, which is part of the fascial nerve nucleus. The fibres attain the pterygopalatinum ganglion via major petrosus nerve and the canalis pterygoideal nerve (Vidian nerve). The postganglionar supply the mouth, nose cavities and pharynx. 2,8,43-45

1.2.4.3.5.3. The otic ganglion

The otic ganglion is situated medial of the mandibular nerve. The preganglionar fibres occur from the inferior salivatorius nucleus and attain the otic ganglion via the minor petrosus nerve. Theire most important supply is the parotis gland. 2,8,43-45

1.2.4.3.5.4. Submandibular ganglion

The submandibular ganglion is situated near by the tube of submandibular gland. The preganglionar fibres occur also from the superior salivatori nucleus. The fibres join the fascial nerve (intermedius n.) and leave it with taste fibres in the tympanic chord. From here they go via the lingual nerve to the base of the mouth where they become a ganglion. They supply the submandibular and submaxillary glands and the anterior part of the tongue.

1.2.4.3.5.5. The vagal nerve

The vagal nerve leaves the skull via the jugular formamen and goes through the cervical area near by the oesophagus and provides supply for the heart and lungs. Together with the oesophagus they go through the respiratory diaphragm into the abdomen. Under the diaphragm the vagal nerve joins the celiac plexus and goes via the mesenteric plexus to its target organs.

1.2.4.3.5.6. The pelvic nerve

The sacral part of the parasympathetic division exists of branches from S2-S3-S4 that form the pelvic nerve that supplies the pelvis organs. It provides the vesical and uterovaginal plexus. 2,8,43-45

1.2.5. References

  1. Loeser JD, Butler SH, Chapman CR, Turk DC. Bonica's Management of Pain. 3th ed. Philadelphia: Lippincott Williams & Wilkins, 2001.
  2. Lignon A. Schématisation Neuro-Végétative en Ostéopathie. 2nd ed: editions de verlaque, 1989.
  3. Gebhart GF. Visceral pain. Seattle, Wash.: International Association for the Study of Pain, 1995.
  4. Tortora GJ. Anatomy and Physiology. Laboratory Manual. 5th ed. London: Prentice-Hall, 1998.
  5. Korr IM. Somatic dysfunction, osteopathic manipulative treatment, and the nervous system: a few facts, some theories, many questions. J Am Osteopath Assoc 1986;86(2):109-14.
  6. Smith JW, Murphy TR, Blair JSG, Lowe KG. Regional Anatomy Illustrated. New York: Churchill Livingstone, 1983.
  7. Van Cranenburgh B. Inleiding in de toegepaste neurowetenschappen Deel 1. 2de ed. Gent: De tijdstroom, 1987.
  8. Netter FH. Atlas of Human Anatomy. 2th ed. East Hanover, New Jersey: Novartis, 1997.
  9. Butler DS. Mobilisation of the Nervous System. 7th ed. Melbourne: Churchill Livingstone, 1996.
  10. Butler DS. The sensitive nervous system. Adelaide, Australia: NoiGroup publications, 2000.
  11. McMahon SB, Koltzenburg M. Textbook of Pain. Wall and Melzack's. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006.
  12. Bernards JA, Bouman LN. Fysiologie van de mens. 6de ed. Diegem: Bohn Staffleu Van Loghem, 1996.
  13. Purves D, ed. Neuroscience. Sunderland, USA: Sinauer Associates, Inc, 1997.
  14. Pauly N, Rondel G. Syllabus: Manuele Neurotherapie. IRSK-WINGS 2006:Graad I,II,III,IV.
  15. Melzack R, Wall PD. Handbook of pain management. Edinburgh: Churchill Livingstone, 2003.
  16. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150(699):971-979.
  17. Netter FH. Nervensystem I: Neuroanatomie und Physiologie. Günter Krämer ed. New York: Georg Thieme Verlag Stuttgart, 1987.
  18. Netter FH. Farbatlanten der Medizin. The Ciba Collection of Medical Illustrations. Band 5: Nervensystem I. Neuroanatomie und Physiologie. New York: Georg Thieme Verlag Stuttgart, 1987.
  19. Duus Peter. Topical Diagnosis in Neurology. 2nd ed. New York: Thieme, 1989.
  20. Todd AJ, Koerber HR. Neuroanatomical substrates of spinal nociception. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 90-73.
  21. Ossipov MH, Lai J, Porreca F. Mechanisms of experimental neuropathic pain: integration from animal models. Wall and Melzack's Textbook of Pain 2006:929-905.
  22. Meyer RA, Ringkamp M, Campbell JN, Raja SN. Peripheral mechanisms of cutaneous nociception. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 3-34.
  23. McMahon SB, Bennett DLH, Bevan S. Inflammatory mediators and modulators of pain. In: McMahon SB, Koltzenburg M, eds. Textbook of Pain. Wall and Melzack's. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 72-49.
  24. Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 105-91.
  25. Devor M. Response of nerves to injury in relation to neuropathic pain. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 905-887.
  26. Harden RN, Baron R, Jèanig W, International Association for the Study of Pain. Complex regional pain syndrome. Seattle, Wash.: IASP Press, 2001.

  27. Stanton-Hicks M BR, Boas R, Gordh T, Harden N, Hendler N, Koltzenburg M, Raj P, Wilder R. Complex Regional Pain Syndromes: guidelines for therapy. Clin J Pain 1998;14(2):155-66.
  28. Baron R. Complex regional pain syndromes. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 1011-1001.
  29. Butler DS. Mobilisation of the Nervous System. New York, NY: Churchill Livingstone Inc, 1991.
  30. Coppieters MW, Butler DS. In defence of neural mobilization. J Orthop sports Phys Ther 2001;31:520-1.
  31. Coppieters M BP, Stappaerts K,. Incorporating nerve gliding techniques in the conservative treatment of cubital tunnel syndrome. Journal of Manipulative and Physiological Therapeutics 2004:1-10.
  32. Coppieters MW. Hst 14. In: Dijkstra PE , et al, eds. Jaarboek kinesitherapie. Houten: Bohn Stafleu van Longum, 2003: 181-202.
  33. Elvey RI, Idozak RM, Dewhurst I, et al. Aspects of manual therapy. Brachial plexus tension tests and the pathoanatomical origin of arm pain. Melbourne: Lincoln Institute of Heath Sciences, 1979.
  34. Elvey RL. Pathophysiology of radiculopathy: A clinical interpretation. Fifth Biennial M.T.A.A. Conference 1987, Melbourne.
  35. Elvey RL, Quintner JL, Thomas AN. A clinical study of RSI. Aust Family Physician 1986;15:1314-1319.
  36. Meyer RA, Campbell JN, Raja SN. Peripheral Neural Mechanisms of Nociception. In: Wall PD, Melzack R, eds. Textbook of Pain. 3th ed. Edinburgh, UK: Churchill Livingston, 1994.
  37. Bielefeldt K, Gebhart GF. Visceral pain: basic mechanisms. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone, 2006: 721-709.
  38. Korr IM. The emerging concept of the osteopathic lesion. 1948. J Am Osteopath Assoc 2000;100(7):449-60.
  39. Korr IM. The spinal cord as organizer of disease processes: III. Hyperactivity of sympathetic innervation as a common factor in disease. J Am Osteopath Assoc 1979;79(4):232-.
  40. Korr IM. The spinal cord as organizer of disease processes: II. The peripheral autonomic nervous system. J Am Osteopath Assoc 1979;79(2):82.
  41. Willard FH, Patterson MM. Nociception and the Neuroendocrine-Immune Connection. International Symposium 1992 1992: 327-1.
  42. Patterson MM, Howell JN. The Central Connection: Somatovisceral/Viscerosomatic Interaction. International Symposium 1989 1989: 298-1.
  43. Ward RC. Foundations for Osteopathic Medicine. 1st ed. Baltimore: Williams and Wilkins, 1997.
  44. Quaghebeur J. Neurologie van het visceraal systeem. FICO. Antwerp, 2006.
  45. Bonica JJ, Loeser JD. Applied Anatomy Relevant to Pain. In: Loeser JD, ed. Bonica's Management of Pain. 2th ed. Philadelphia: Lippingcott Williams & Wilkins, 2001: 196-191.

Writing Services

Essay Writing
Service

Find out how the very best essay writing service can help you accomplish more and achieve higher marks today.

Assignment Writing Service

From complicated assignments to tricky tasks, our experts can tackle virtually any question thrown at them.

Dissertation Writing Service

A dissertation (also known as a thesis or research project) is probably the most important piece of work for any student! From full dissertations to individual chapters, we’re on hand to support you.

Coursework Writing Service

Our expert qualified writers can help you get your coursework right first time, every time.

Dissertation Proposal Service

The first step to completing a dissertation is to create a proposal that talks about what you wish to do. Our experts can design suitable methodologies - perfect to help you get started with a dissertation.

Report Writing
Service

Reports for any audience. Perfectly structured, professionally written, and tailored to suit your exact requirements.

Essay Skeleton Answer Service

If you’re just looking for some help to get started on an essay, our outline service provides you with a perfect essay plan.

Marking & Proofreading Service

Not sure if your work is hitting the mark? Struggling to get feedback from your lecturer? Our premium marking service was created just for you - get the feedback you deserve now.

Exam Revision
Service

Exams can be one of the most stressful experiences you’ll ever have! Revision is key, and we’re here to help. With custom created revision notes and exam answers, you’ll never feel underprepared again.