The problem of acute pain and its substantial relief is common for every medical field. This project work deals with mechanisms of pain and the pathogenic treatment

Вид материала

Подобный материал:

1 2 3 4

The problem of acute pain and its substantial relief is common for every medical field. This project work deals with mechanisms of pain and the pathogenic treatment. It goes without saying nobody can discuss such an issue within the frame of a project work so the next step is to underline several key questions. They are a base for practical implementation and, if interested, for keeping on in pain studies.

Pain is аn unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

Nowadays terms used in pain defined by International Association of the study of pain IASP are wide-spread. Next we’re going to list the most common of them.

Allodynia -pain due to a stimulus which does not normally provoke pain.

Analgesia - absence of pain in response to stimulation which would normally be painful.

Complex Regional Pain Syndrome I. CRPS I formerly known as reflex sympathetic dystrophy, consists of continuous pain (allodynia or hyperalgesia) in part of an extremity after trauma including fractures. However, the pain does not correspond to the distribution of a single peripheral nerve. The pain is worse with movement and associated with sympathetic hyperactivity. The patient often complain of cool, clammy skin which later becomes pale, cold, stiff and atrophied. This process often occurs within weeks of trauma, which may be mild.

Complex Regional Pain Syndrome II. CRPS 2 formerly known as causalgia, consists of burning pain in the distribution of a partially damaged peripheral nerve (most commonly median, ulnar or sciatic). Pain may occur within a month of injury and may radiate beyond the nerve’s distribution. The condition results from abnormal sweat and vasomotor sympathetic efferent pathways, possibly due to abnormal connections between efferent sympathetic fibres and somatic sensory fibres at the injury site. The skin is classically cold, moist and swollen, becoming atrophic later.

Central pain - pain initiated or caused by a primary lesion or dysfunction in the central nervous system.

Dysaesthesia - an unpleasant abnormal sensation, whether spontaneous or evoked.

Hyperalgesia - an increased response to a stimulus which is normally painful.

Hyperaesthesia - increased sensitivity to stimulation, excluding the special senses.

Hyperpathia - a painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold.

Hypoalgesia - diminished pain in response to a normally painful stimulus.

Hypoaesthesia - decreased sensitivity to stimulation, excluding the special senses.

Neuralgia - pain in the distribution of a nerve or nerves.

Neuritis - inflammation of a nerve or nerves.

Neuropathic pain - pain initiated or caused by a primary lesion or dysfunction in the nervous system.

Neuropathy - a disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy.

Nociceptor - a receptor preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged.

Noxious stimulus - a noxious stimulus is one which is damaging to normal tissues.

Pain threshold - the least experience of pain which a subject can recognise.

Pain tolerance level the greatest level of pain which a subject is prepared to tolerate.

Paraesthesia - an abnormal sensation, whether spontaneous or evoked.

Peripheral neuropathic pain - pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system.

As pain can be measured it’s important to list several scales. In adults

in the assessment of pain intensity, rating scale techniques are often used. The most commonly used forms are:

The Category Rating Scales
(e.g. none, mild, moderate, severe, unbearable or 1-5)

The Visual Analogue Scales (VAS)
(e.g. 10 cm line with anchor points at each end). The VAS has been shown to be more sensitive to change and is therefore more widely used. These scales may also be incorporated into pain diaries.

McGill Pain Questionnaire (MPQ) (Melzack, 1975) (78 pain adjectives arranged into 20 groups further arranged into sets of words describing sensory aspects of the quality of pain). Very widely used questionnaire.

The McGill Pain Questionnaire consists primarily of three major classes of word descriptors - sensory, affective and evaluative - that are used by patients to specify subjective pain experience. It also contains an intensity scale and other items to determine the properties of pain experience. The questionnaire was designed to provide quantitative measures of clinical pain that can be treated statistically. This paper describes the procedures for administration of the questionnaire and the various measures that can be derived from it. The three major measures are: (1) the pain rating index, based on two types of numerical values that can be assigned to each word descriptor; (2) the number of words chosen; and (3) the present pain intensity based on a 1-5 intensity scale. The data, taken together, indicate that the McGill Pain Questionnaire provides quantitative information that can be treated statistically, and is sufficiently sensitive to detect differences among different methods to relieve pain.

The Illness Behaviour Questionnaire (Pilowsky, Spence 1975) was also developed, to help describe the constituents of abnormal illness behaviour. The major dimensions derived from factors analysis are: phobic concern about one’s health, conviction of disease, perception of somatic versus psychological illness, affective inhibition, affective disturbance, denial of other problems and irritability.

Minnesota multiphasic personality inventory is also used for pain assessment.

In children, pain can be measured by self-report, biological markers and behaviour. Because pain is a subjective event, self-report is best if it is available. Unfortunately, in many infants, young children, or children with cognitive or physical impairments, self-report is not available and behavioural or biological measures must be used.

Let’s study the self-report thoroughly. Children as young as 2 years of age can report pain, although at this age they are not able to rate intensity. Children at any age may deny pain if the questioner is a stranger, if they believe they are supposed to be brave, if they are fearful or if they anticipate receiving an injection for pain.

Children of 4 or 5 years of age can use standardised measures. Hester’s Poker Chip Tool is well validated. Four poker chips are placed in front of the child and the chips are described as pieces of hurt. The first chip is described as "just a little hurt", the second is "a little more hurt", the third chip is "more hurt" and the fourth chip is "the most hurt you could have". The child is asked, "How many pieces of hurt do you have?". The response is then confirmed.

Face scales can often be used in this age group. Children are asked to indicate their pain by pointing to one of the faces. Usually the child is trained by asking how he or she would feel following some minor pain and then a more severe pain.

Wong-Baker FACES Pain Rating Scale belongs to FACES scales.

Children of 6 or 7 years of age can use word-graphic rating scales. Children are asked to indicate how much pain they have on a line with five verbal anchors. At this age, children can use 0-10 or 0-100 scales, with 0 being "no pain" and 10 or 100 being "the worst possible pain". Similarly, a 10 cm line with anchors of "no pain" and "the worst possible pain" (a visual analogue scale) can be used. The data do not suggest that any one scale of this type is better than another.

Now let’s study biological measures.

Heart rate initially decreases and then increases in response to short, sharp pain. Vagal tone and heart rate variability, such as during breathing, have been used as indices of pain and distress. No studies have evaluated heart rate as a measure for longer-term pain, although heart rate is not substantially elevated during postoperative pain in older children. Ill and premature babies have less predictable responses. Heart rate is an easy and generally valid measure of short, sharp pain. Unfortunately, there appear to be no biological measures that can be recommended for use as a clinical pain measure for longer-term pain.

Oxygen saturation decreases during painful procedures such as circumcision, lumbar punctures and intubation, but can occur for other reasons or just during handling of neonates. Children may have normal oxygen saturation despite significant pain over a long period.

Surgery or trauma triggers the release of stress hormones. This cascade may facilitate healing but can have disastrous results in the sick neonate. The stress response is blunted by opioids, probably by several actions at the hypothalamic and pituitary level. The stress response is more than a measure of pain.

Cortisol release, widely studied in infants and children, is not specific to pain and occurs in many adverse situations. Plasma cortisol levels rise significantly during circumcision. However, sick premature babies may have unstable levels, and small changes during painful procedures may not be detectable. Cortisol changes with routine inoculation in healthy infants, but the response depends on a complex interaction of age, behaviour and baseline values. This complexity precludes cortisol as a clinical pain measure, even for short sharp pain.

Next we’re going to discuss pain conductive mechanisms.

Cutaneous sensation is mediated by specific sensory receptors that are located in the skin. These can be broadly classified into low and high threshold primary afferents. Low threshold afferents are myelinated fibres with specialised nerve endings that convey innocuous sensations such as light touch, vibration, pressure (all Ab) and proprioception (Aa). High threshold afferents are thinly myelinated (Ad) or unmyelinated (C) fibres located in the dermis and epidermis, which convey pain and temperature.

Table 1: Comparative properties of primary afferent fibres

Fibre class	Threshold	Main transmitters	Main receptor activated	Laminar location	Target spinal cord neurones	Normal sensation	Pathological sensation
C	High	Peptides	NK1,2	I-II, V	NS	Slow pain	Hyperalgesia
Ad	High	EAA	NMDA AMPA mGlu	I-II, V	WDR	Fast pain	Allodynia
Ab	Low	EAA	AMPA	III-VI	LT WDR	Touch vibration pressure	Mechanical allodynia

Key: EAA = Excitatory amino acids; NS = Nociceptive specific; LT = Low threshold; WDR = wide dynamic range; NK = neurokinin (peptide) receptor; NMDA, AMPA, mGlu are different types of glutamate receptors

Pain and temperature afferents do not have any specialised receptors; they use “free nerve endings”. They are polymodal, i.e. they respond to more than one kind of stimulus, e.g. chemical, thermal or mechanical stimuli. Free nerve endings are found in all parts of the body except the interior of the bones and the interior of the brain itself. In the cornea of the eye, only free nerve endings are found and abrasions of the cornea can be extremely painful. Most of these respond only to tissue damaging stimuli and are called nociceptors. Pain sensations can be broadly divided up into bright, sharp, stabbing types of pain, and dull, throbbing, aching types. Ad fibres mediate the former or ‘fast’ pain, C-fibres signal the latter or ‘slow pain’. Not all Ad and C fibres are nociceptors. Some respond to low threshold stimuli such as touching or brushing the skin. Many C fibres are thermoreceptors, and respond to warm or cold.

Although pain results from damage to these free nerve endings, in reality the pain is a result of substances released by damaged tissues: prostaglandins, histamine and peptides. These activate receptors located on the free nerve endings.

Now let’s study the spinal cord.

The spinal cord consists of grey matter and white matter. The white matter contains ascending and descending fibres, the grey matter contains cells and central terminals of primary afferents from the periphery.

The dorsal horn is divided into 6 layers (laminae) and processes sensory information.

Lamina I is the most dorsal and is a thin layer of large cells, together with small inhibitory interneurons. The axons from the large cells form part of the spinothalamic tract.

The second layer is lamina II or the “substantia gelatinosa”. Many of the cells are inhibitory but excitatory cells exist as well. This region is believed to control the “connectivity” of the other laminae in the dorsal horn. Together, laminae I-II are known as the superficial dorsal horn and receive input from C and Ad fibres. Functionally, they receive input from the nociceptors (high threshold C and Ad fibres) and contain cells that are nociceptive specific, NS (respond only to noxious stimuli) or wide dynamic range, WDR (respond to both innocuous and noxious stimuli).
Laminae III-VI receive input from the cutaneous Ab non-nociceptive afferents and contain cells with low-threshold (LT) receptive fields that respond to innocuous sensations. Some lamina V cells are WDRs that receive input from both low-threshold (Ab) sensory fibres and high-threshold (C, Ad) fibres as their dendrites project dorsally into laminae I-II.

The dorsal horn is not just a relay station for the transmission of innocuous and noxious messages. It has an important role in modulating pain transmission through spinal and supraspinal mechanisms. These regulatory circuits involve primary afferents, spinal interneurons and descending fibres.

Pain fibres terminate mainly in the superficial dorsal horn (laminae I- II). Ad fibres enter lamina I (and V) and synapse on a second set of neurons. These neurons will carry the signal to the thalamus and are part of the spinothalamic tract (STT). The C fibres enter the spinal cord and synapse on lamina I cells and lamina II interneurons - neurons that make synaptic connections with other cells within the local environment. The interneurons convey the signal to the STT cells that reside mainly in laminae I, IV and V. The axons of the STT cells project across the spinal cord to the STT, which is located in the ventrolateral quadrant of the contralateral spinal cord white matter.

The STT transmits information about temperature and pain, as well as “simple” touch (i.e. related to localisation of stimulus) and visceral sensations. It mediates the discriminative and arousal-emotional components of these sensations by separating out the “fast” (discriminative aspect) and “slow” (affective aspect) components of pain into different regions of the tract that are transmitted in parallel to the thalamus. Discriminative pain reaches the thalamus directly without making connections elsewhere in the nervous system, whereas arousal-emotional pain reaches the thalamus indirectly via connections with brainstem regions. Slow pain is also transmitted by other pathways such as the spinoreticular tract.

The STT may be divided into the lateral STT and the anterior STT. Pain and temperature is transmitted mainly in the lateral STT. The lateral-STT transmits the sensations of both fast and slow pain. The anterior STT conveys sensations of simple touch (stimulus localisation). The STT ascends the entire length of the cord and the brainstem, staying in about the same location all the way up. It is here in the brainstem that the different modalities separate out to terminate in different thalamic and brainstem nuclei. The fast pain STT axons terminate in the ventroposterior nucleus, which comprises the ventral posterolateral (VPL) and ventral posteromedial (VPM) and the posterior (PO) nuclei. These axons seem to mediate mainly the sense of “simple touch” and pain. These sensations are separated within the thalamus: neurons in the VPL and VPM do not respond specifically to noxious stimulation, whereas cells in the PO receive inputs from both low- and high-threshold afferents. These cells are associated with the conscious perception of pain.

The slow pain-STT axons innervate the non-specific intralaminar nuclei of the thalamus, and the reticular formation in the brainstem. These axons form at least part of the forebrain pain pathway associated with the affective quality (unpleasantness and fear of further injury) of pain and can be dissociated from the discriminative quality (the type and nature of the injury itself). The projections to the reticular formation may underlie the arousal effects of painful stimuli. The arousal itself may activate noradrenergic neurons in the locus coeruleus, and thus decrease the upward pain transmission. This may be an example of a negative feedback loop in the nervous system.
Table 2: Comparison of central pathways for pain transmission

	Direct (fast)	Indirect (slow)
Tract	Lateral-STT	Lateral-STT Spinoreticular tract (SRT)
Origin	Lamina I & IV, V	Lamina I, IV,V, (and VII, VIII)
Somatotopic organisation	Yes	No
Body representation	Contralateral	Bilateral
Synapse in reticular formation	No	Yes
Sub-cortical targets	None	Hypothalamus Limbic system
Thalamic nucleus	Ventral posterolateral (VPL)	Intra-laminar nuclei Other midline nuclei
Cortical location	Parietal lobe (SI cortex)	Cingulate gyrus
Role	Discriminative pain (quality intensity, location)	Affective-arousal components of pain
Other functions	Temperature Simple touch

It has long been known that the STT is an important pain pathway because when it is damaged, pain and temperature sense is abolished on the contralateral side of the body below the lesion. It has been used, as a last resort, by surgeons to relieve intractable cancer pain. However, pain is not permanently abolished because of preservation of one side of the bilateral indirect pathways. Also, the transmission of simple tactile modalities (detection, location) via the anterior STT explains why touch sensation is preserved in people with dorsal column lesions (although they are unable to discriminate the nature of the stimulus).

Antinociceptive pathways are activated when pain signals in the spinothalamic tract reach the brain stem and thalamus. The periaqueductal gray matter and nucleus raphe magnus release endorphins and enkephalins. A series of physicochemical changes then produce inhibition of pain transmission in the spinal cord.

70% of endorphin and enkephalin receptors are in the presynaptic membrane of nociceptors. Thus, most of the pain signal is stopped before it reaches the dorsal horn. The signal is then further weakened by dynorphin activity in the spinal cord. The site of action of various analgesics is shown.

Dynorphin activation of alpha receptors on inhibitory interneurons causes the release of GABA. This causes hyperpolarisation of dorsal horn cells and inhibits further transmission of the pain signal.

So we’ve studied the main pain principles. Now let’s discuss the implications for pain therapy.

Medications that mimic the effects of endorphins and enkephalins are the mainstays of chronic pain therapy. Newer drugs that mimic or potentiate the effects of GABA or alpha-2 receptor agonists have made it possible to target therapy for chronic pain syndromes.

The transmission of information from primary afferents to secondary neurons in the CNS is subject to “gating” (modulation). Nociceptive sensory information is gated in the substantia gelatinosa of the spinal cord. Gating is of two kinds:
1.

Blog

The problem of acute pain and its substantial relief is common for every medical field. This project work deals with mechanisms of pain and the pathogenic treatment