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 adultsin 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 EAA NMDAAMPAmGlu WDR Fast pain Allodynia Ab Low EAA AMPA III-VI LTWDR Touchvibrationpressure 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-STTSpinoreticular 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 HypothalamusLimbic system Thalamic nucleus Ventral posterolateral (VPL) Intra-laminar nucleiOther midline nuclei Cortical location Parietal lobe (SI cortex) Cingulate gyrus Role Discriminative pain (quality intensity, location) Affective-arousal components of pain Other functions TemperatureSimple 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. Local – segmental antinociception2. Widespread – supraspinal antinociception which utilises descending pathways from the brainstem.The Gate Control Theory was devised by Patrick Wall and Ronald Melzack in 1965. This theory states that pain is a function of the balance between the information travelling into the spinal cord through large nerve fibres and information travelling into the spinal cord through small nerve fibres. If the relative amount of activity is greater in large nerve fibres, there should be little or no pain. However, if there is more activity in small nerve fibres, then there will be pain. According to the Gate Control theory, this neuronal circuitry is present in the posterior roots of the spinal cord: Ab and C fibres coming from the skin, for example, stimulate the neuron N implicated in nociception, but this stimulation cannot occur when the peripheral stimulus is weak because enkephalinergic interneurons (E) stimulated by sensory somesthetic fibres Ab inhibit nociceptive transmission. It is only when the stimulus is strong that the nociceptor C fibres lower the efficacy of this inhibitory control. According to the theory, lamina II inhibitory interneurons can be activated directly or indirectly (via excitatory interneurons) by stimulation of non-noxious large sensory afferents from the skin that would then block the projection neuron and therefore block the pain. Thus rubbing a painful area relieves the pain.Not only medicines can relieve the pain. TENS – trans-electrical nerve stimulators – are devices commonly used by physiotherapists (or during labour) to stimulate the large (Ab) sensory fibres in peripheral nerves, in the hope that they will in turn activate the inhibitory neurons of lamina II and block pain transmission. Importantly, these devices work best when placed on/near the skin of the injured/painful region. They use high frequency, low intensity stimuli to activate the low threshold fibres. They are ineffective if they are positioned far away from the painful site. In practice, most counter-stimulation techniques require the use of “near noxious” stimulation intensities (felt as a buzzing, or tingling sensation), which recruit both Ab and Ad afferents, to be maximally effective. From the spinal cord, the messages go directly to several places in the brain, including the thalamus, midbrain and reticular formation. It may be that Ad fibres rather than Ab fibres are best at exciting lamina II inhibitory interneurones because the Ad fibres are able to recruit the help of the supraspinal control systems.Some brain regions that receive nociceptive information are involved in perception and emotion. Also, some areas of the brain connect back to the spinal cord - these connections can change or modify information that is coming into the brain. This is one way that the brain can reduce pain, by a mechanism known as supraspinal (descending) analgesia. It uses feedback loops that involve several different nuclei in the brainstem reticular formation. Two important areas of the brainstem that are involved in reducing pain are the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM). The PAG is important in the control of pain. This region surrounds the cerebral aqueduct in the midbrain. Stimulation of parts of the PAG produces more pronounced analgesia than stimulation of either the NRM or the locus coeruleus (LC). Neurosurgeons can implant electrical stimulating electrodes near the PAG of intractable (chronic) pain patients so that a small electrical shock can be delivered through a device. This is wired so that the patient can control the level of self-stimulation and hence level of analgesia. This is known as stimulus-induced analgesia. The PAG contains enkephalin-rich neurons that excite the NRM and/or LC neurons by disinhibiting GABAergic interneurons in the PAG. This allows PAG (anti-nociceptor) neurons to excite the amine-containing cells in the NRM and LC that in turn project down to the spinal cord to block pain transmission by dorsal horn cells by different mechanisms:1. Direct postsynaptic inhibition of projection cells causing hyperpolarisation of the membrane potential due to activation of G protein-linked receptors that cause the opening of potassium channels.2. Presynaptic inhibition of neurotransmitter release from primary afferent terminals. This works by activating G protein-linked receptors that cause closing of calcium channels, thus reducing transmitter release.A second descending system of serotonin-containing neurons exists. The cell bodies of these neurons are located in the raphe nuclei (NRM) of the medulla and, like the noradrenaline-containing neurons, the axons synapse on cells in lamina II. They also synapse on cells in lamina III. Stimulation of the raphe nuclei produces a powerful analgesia and it is thought that the serotonin released by this stimulation activates the inhibitory interneurons even more powerfully than the noradrenaline and thus blocks pain transmission. However, serotonin may not be specifically involved in inhibition of pain transmission. Serotonergic agonists do not have significant analgesic effects. Serotonin neurons appear to inhibit all somatosensory transmission, and may have a function in the initiation of sleep. A complicating factor is that serotonin receptors are found in many places in the dorsal horn, including on primary afferents from C fibres. Serotonin may act to presynaptically inhibit pain by blocking C fibre terminals. C fibres release not just the excitatory amino acid glutamate but also a peptide known as “substance P”. Substance P is a neuromodulator, like most peptides. Although it can alone activate lamina I neurons, it seems mainly to amplify the effect of the glutamate that is released. Substance P and glutamate appear to be co-released from C fibres, but the proportions of each may vary.Some of the interneurons of lamina II contain enkephalins. Enkephalins have been shown pharmacologically to bind to the same receptors as opiate drugs like morphine and heroin. Therefore, it seems likely that opiate drugs may act by mimicking the activity of the interneurones of lamina II. It has not yet been fully established how endogenous enkephalins work at the spinal level. They may act as ‘trophic factors’, somehow amplifying the response of the post-synaptic dendrites to the action of GABA. Enkephalin-containing neurons have also been found in the medulla, mid-brain and hypothalamus. (People probably become addicted to opiates because of their effects at these mid-brain and hypothalamic sites). Analgesics may act at different sites: They may act at the site of injury and decrease the pain associated with an inflammatory reaction (e.g. non-steroidal anti-inflammatory drugs) They may alter nerve conduction (e.g. local anaesthetics) They may modify transmission in the dorsal horn (e.g. opioids and some antidepressants) They may affect the central component and the emotional aspects of pain (e.g. opioids and antidepressants)The terms “opioid” and “opiate” are often used interchangeably. However, their meaning is slightly different. “Opiate” means that a substance/drug is extracted from opium or is similar in structure to such substances. This is an older term, which refers mainly to morphine-like compounds, which have a non-peptide structure. Opium is a dried exudate from unripe seed pods of the poppy Papaver somniferum, and it contains morphine, codeine and various other alkaloids, some not related to morphine. The opiates available for use in the clinic are either natural or synthetic compounds. “Opioid” is a term that has been used mainly to designate substances that are not derived from opium, and in particular opioid peptides, i.e. natural substances that bind to opioid receptors and mimic the effect of morphine-like compounds. However, the term “opioid” is now used increasingly to designate all agents that act on opioid receptors, irrespective of their nature (natural or synthetic, peptide or non-peptide). Although morphine has been used for many centuries, it was only in 1973 that specialised receptors for this drug, the opioid receptors, were shown to be present in the central nervous system (and also in peripheral organs, like the gut). This was followed in 1975 by the discovery of the first endogenous opioid peptides, the enkephalins. The list of opioid peptides has become longer over the years, and the classification of these peptides is complex. The following are just a few examples: Beta-endorphin Leucine-enkephalin Methionine-enkephalin Dynorphin A Dynorphin B Endomorphin-1 Endomorphin-2Other peptides, more recently discovered, such as nociceptin and nocistatin, are related structurally to opioid peptides. Interestingly, these two peptides are derived from the same precursor, and appear to have mutually antagonistic actions in terms of analgesia/ hyperalgesia. Opioid peptides bind to opioid receptors, which are G-protein coupled receptors. These receptors have been subdivided into three main categories:1. Mu receptors 2. Delta receptors 3. Kappa receptorsEach of these receptor categories can be further subdivided, defining various opioid receptor subtypes. Opioid peptides act as agonists at opioid receptors, and generally have limited selectivity for a given receptor type.The activation of the opioid receptors is associated at the cellular level with inhibition of the cell. Opioid agonists reduce neuronal excitability (by decreasing potassium conductance), and inhibit neurotransmitter release (by decreasing calcium influx, required for exocytotic release). From the functional systemic point of view, opioid agonists induce a range of effects, including analgesia. One could associate each type of opioid receptor with certain predominant effects. Most of the opioid drugs presently used (in particular morphine, as a prototype drug) are agonists with significant affinity at mu opioid receptors. If used appropriately, the relief of pain can be significant, but is often accompanied by unwanted effects, some of which may become life-threatening, such as the significant respiratory depression seen at high doses of morphine.Morphine - can be used via the oral, intravenous, intramuscular or subcutaneous route. Slow-release preparations are available. Morphine has significant first-pass (or pre-systemic) metabolism; therefore, the fraction reaching the systemic circulation is much less than that absorbed after oral administration. One of its metabolites, morphine-6-glucuronide, is analgesic in its own right. Morphine induces significant analgesia, but also a host of other effects: respiratory depression, euphoria and sedation, nausea/vomiting, constipation, pupillary constriction (“pin-point” pupil), histamine release (leading to bronchoconstriction and itching).Heroin (diamorphine) – is a pro-drug, which is metabolised to morphine (that is ultimately responsible for its effects). It is more lipid soluble than morphine; therefore, the effect after intramuscular administration has a more rapid onset. Its properties make it particularly suitable for epidural administration, to relieve postoperative pain after major surgery. Its higher solubility also constitutes an advantage for continuous subcutaneous infusion.Codeine – is an analgesic with lower efficacy than morphine. Its analgesic effect is due to demethylation in the liver to morphine. It may be used in combination with aspirin or paracetamol and it also has a significant antitussive effect. Like morphine, it induces constipation.Pethidine- is a synthetic substance, which is more sedative and has a more rapid onset and a shorter duration of action than morphine. Its metabolite, norpethidine, is active and may accumulate to toxic levels in patients with renal impairment. Methadone – is a synthetic compound with a half-life of >24 hours. It leads to a much milder physical abstinence syndrome than morphine but can induce psychological dependence. It is used in maintenance programmes for morphine and heroin addicts.Fentanyl – is a highly potent compound, with a half-life of 1-2 hours. It can be used for severe acute pain and during anaesthesia.Buprenorphine – is a very lipid soluble compound, which acts as a partial agonist at mu receptors. It is a potent compound but has less efficacy than morphine. Consequently, it may lead to a re-emergence of pain in patients who have received more efficacious opioids, such as morphine. It can be used sublingually and it has a longer duration of action than morphine, but is more emetic. It may induce dysphoria.Opioid antagonists - naloxone is used in the management of opioid overdose, or to relieve respiratory depression in apnoeic infants after opioids (e.g. pethidine) administered to the mother during labour.Tolerance and dependence are very common for opioids. Tolerance (the necessity to increase the dose in order to achieve the same effect) may develop during chronic administration of drugs, and it may be due to both pharmacokinetic and pharmacodynamic changes. Tolerance to opioids can develop rapidly, especially under experimental conditions. Physical and psychological dependence can also develop. Physical dependence is associated with a withdrawal syndrome when the administration of the drug is stopped abruptly. Psychological dependence leads to craving for the drug.Next we’re going to study non-opioids.In this category, the non-steroidal anti-inflammatory drugs (NSAIDs) represent a widely used group of drugs. Examples of such drugs are: aspirin, paracetamol, ibuprofen and diclofenac. Paracetamol is included in this group but has very weak anti-inflammatory effects. These drugs are mainly used to treat mild or moderate pain, in general associated with inflammatory processes. It is also important to note that NSAIDs can be used to treat the severe pain associated with bone metastasis in cancer. It is believed that the analgesic/antipyretic/anti-inflammatory effects of NSAIDs are largely due to inhibition of cyclo-oxygenase (COX), and the resulting inhibition of the synthesis of prostaglandins, which are pro-inflammatory. COX has two forms: COX-1 and COX-2. COX-1 is a constitutive enzyme, whereas COX-2 is induced at sites of inflammation. The existing NSAIDs are not selective. In particular, it is the inhibition of COX-1 that underlies the majority of unwanted effects of NSAIDs, such as gastrointestinal irritation and bleeding, and nephrotoxicity. In the stomach, the prostaglandins PGE2 and PGI2 inhibit acid secretion and have a gastroprotective action, whereas in the kidney PGE2 and PGI2 act as local vasodilators. Therefore, inhibition of their synthesis reduces renal blood flow and may precipitate acute renal failure. In addition, the prolonged use of NSAIDs is associated with risk of chronic renal failure due to development of interstitial nephritis. For all these reasons, much effort is being devoted at present to the development of better NSAIDs, in particular highly selective COX-2 inhibitors, such as the new drug rofecoxib.Aspirin – is analgesic and anti-inflammatory. This is due to the irreversible inhibition of the synthesis of prostaglandins peripherally, at the site of injury. It is unclear whether the effect of aspirin also has a central component.Paracetamol – is antipyretic and analgesic, but with negligible anti-inflammatory effects. It is well absorbed after oral administration and does not irritate the gastric mucosa. However, its prolonged use and the ingestion of high doses is associated with significant risk of hepatotoxicity.Ibuprofen – has analgesic and anti-inflammatory properties. It may cause less gastric irritation than other NSAIDs.Some types of pain do not respond to either opioid analgesics or NSAIDs. For example, neuropathic pain appears to be relatively insensitive to opioids. It can be significantly relieved with tricyclic antidepressants (e.g. amitryptiline) or anticonvulsant agents (e.g. carbamazepine). Carbamazepine can also be used to treat the paroxysmal pain experienced by patients who suffer from trigeminal neuralgia. Corticosteroids (e.g. dexamethasone) may produce substantial improvement in some cases in neuropathic pain associated with cancer.Local anaesthetics (e.g. lidocaine, amethocaine, bupivacaine, prilocaine) are agents which are used to block the initiation and propagation of nerve action potentials, by blocking Na+ channels. Their mode of administration varies: surface anaesthesia, infiltration, spinal or epidural anaesthesia. They are used for pain associated with localised surgery, childbirth or in dentistry. However, newer drugs, such as tocainide and mexiletine, may be used in future as oral analgesics for neuropathic pain. The main problem associated with local anaesthetics is the risk of systemic toxicity (e.g. hypotension, bradycardia and respiratory depression).The management of pain associated with migraine consists of the management of acute attacks, and prophylaxis. Acute attacks may respond to NSAIDs such as aspirin and paracetamol, or to agonists at 5-HT1D receptors, such as sumatriptan. Prophylaxis may be achieved by use of 5-HT2 receptor antagonists (methysergide, cyproheptadine), calcium channel blockers (e.g. verapamil), or tricylic antidepressants (e.g. amitriptyline).Several new approaches in the management of pain are still at an experimental stage, such as use of antagonists of substance P receptors (i.e. NK1 receptors), inhibitors of the enzymatic degradation of enkephalins, analogues of adenosine or agonists at nicotinic receptors, agonists or antagonists at excitatory amino acid receptors. If proved active in the clinic, these new drugs may diversify the management of pain in the future.References:www.anaesthesiauk.comCold E.G., Dhal B.L. Topics in neuroanaesthesia and neurointensive care. – Berlin – Helderberg – New York: Springer-Verlag, 2002. – 416p.Deshpande J.K.,Tobias J.D. Pediatric pain handbook. 2000; 387 p.Peoples’ Friendship University of RussiaMedical SchoolGeneral MedicineProject Work.Acute Pain. Острая боль.Student: Botchaeva Tatiana (ML-401)Supervisor: Startseva E.O.Moscow 2006Проблема острой боли и ее эффективного купирования присутствует в каждой области медицины. Данная работа посвящена механизмам развития боли и патогенетическим методам ее лечения. Естественно вопрос подобного рода невозможно полностью раскрыть в объеме реферата, далее будут изложены лишь ключевые моменты, на основе которых читатель самостоятельно сможет сделать заключения практического характера и, при желании, продолжить изучение темы. Боль – это неприятные ощущения или эмоции, связанные с повреждением тканей или возможностью такового, или описываемые с данной позиции. В настоящее время общепринята терминология, разработанная Международной ассоциацией изучения боли (МАИБ). Далее целесообразно привести значения наиболее часто употребляемых понятий. Аллодиния – боль, возникающая при действии раздражителя, который в норме не является болевым. Анальгезия – отсутствие боли при действии болевого раздражителя. Комплексный местный болевой синдром I (старое название – рефлекторная симпатическая дистрофия) – его основным компонентом являются постоянные боли (аллодиния или гиперальгезия) в травмированной (в том числе вследствие перелома) конечности. Однако, боль локализуется не только в зоне иннервации одного периферического нерва. Также она усиливается при движении. Это связано с гиперактивностью симпатической нервной системы. Пациенты жалуются на чувство холода в поврежденной конечности, которая позднее бледнеет, становится одеревенелой и атрофируется. Чаще это происходит в течение недель после травмы, которая могла быть и легкой. Комплексный местный болевой синдром II (старое название – каузалгия) – его основным компонентом является жгучая боль в зоне иннервации частично поврежденного периферического нерва (в основном, это n. medianus, n. ulnaris et n. ischiadicus). Боль может развиться в течение месяца после травмы. Возможна иррадиация за пределы зоны иннервации данного нерва. Причиной данного болевого синдрома является патологическая активность эфферентных сосудодвигательных симпатических нервов (характерным признаком является патологическое потоотделение), возможно, вследствие образования патологических связей между эфферентными симпатическими и чувствительными соматическими волокнами в области повреждения. Классическими клиническими признаками процесса являются холодная, влажная на ощупь, отечная кожа, впоследствие она атрофируется. Центральная боль – боль, возникшая при первичном повреждении или нарушении функций центральной нервной системы. Дисэстезия – неприятные патологические ощущения, спонтанные или вызванные. Гиперальгезия – усиление ответной реакции на болевой стимул. Гиперэстезия – повышение чувствительности организма, исключением являются специальные виды чувствительности. Гиперпатия – синдром с развитием патологической болевой реакции (особенно, на повторное действие раздражителя) при повышении порога раздражения. Гипоальгезия – снижение ответной реакции на болевой стимул. Гипоэстезия – снижение чувствительности организма, исключением являются специальные виды чувствительности. Невралгия – боль, локализующаяся в зоне иннервации данного нерва(-ов). Неврит – воспаление нерва -ов). Нейропатическая боль – боль, возникшая при первичном повреждении или нарушении функции нервной системы. Нейропатия – нарушение функции или структуры нерва: одного – мононейропатия, нескольких – сложная мононейропатия, двусторонняя диффузная – полинейропатия. Ноцицептор – рецептор, воспринимающий болевые раздражения или раздражения, становящиеся таковыми при длительном воздействии. Болевой раздражитель – раздражитель, действие которого вызывает повреждение здоровых тканей. Нижний болевой порог – минимальный воспринимаемый уровень болевого раздражения. Верхний болевой порог – максимально возможный для восприятия уровень болевого раздражения. Парэстезия – патологическая чувствительность, спонтанная или вызванная. Периферическая нейропатическая боль – боль, возникшая при первичном повреждении или нарушении функции периферической нервной системы. Так как боль является количественной характеристикой, необходимо привести некоторые системы для ее оценки. У взрослых для оценки интенсивности боли часто используют специальные шкалы. Наиболее распространены:Шкала категорий боли (например, боль отсутствует, болезненность, боль умеренной интенсивности, сильная, непереносимая, или 1-5)Шкала зрительных аналогий (ШЗА) (например, линейка, длиной 10 см, где пациенту предлагается отметить уровень интенсивности боли). Доказано, что чувствительность ШЗА к изменениям в состоянии пациента выше, чем у других шкал, вследствие чего она нашла более широкое применение. Применение подобных шкал также можно сочетать с ведением дневников боли.Словесная шкала Мак-Гилла (СШМ) (Мелзак, 1975) (78 прилагательных, характеризующих боль, распределенные в 20 групп и далее объединяемые в новые группы, согласно собственным ощущениям) используется очень широко. Словесная шкала Мак-Гилла первоначально состоит из трех основных классов слов, обозначающих ощущения, эмоции и оценочные характеристики соответственно. Они используются для определения характерных черт собственных болевых ощущений. Также она включает шкалу интенсивности и оценку многих других параметров. Шкала была разработана для определения клинических характеристик боли, которые можно обработать статистически. В данном реферате описаны правила пользования шкалой и интерпретации полученных данных. Среди последних тремя основными являются: 1) болевой индекс, вычисляемый на основе двух типов числовых значений, соответствующих словесным характеристикам боли; 2) количество выбранных слов; 3) интенсивность боли, вычисленная по шкале интенсивности 1-5. Соотнесение данных многих исследований убеждает в том, что словесная шкала Мак-Гилла дает количественную оценку боли, доступную для статистической обработки. Ее чувствительность значима для определения различий эффективности методов противоболевой терапии.Словесная шкала «Поведение во время болезни» (Пиловски, Спенс, 1975) была разработана с целью выявления патологических компонентов поведения во время болезни. Основными характеристиками последнего, которые были получены при факториальном анализе, являются: страх, тревожность по поводу состояния собственного здоровья, осуждение болезни, как факта, контрвосприятие соматического заболевания психологическому состоянию, торможение, тревога, инициированные лимбической системой, отрицание существования других проблем и раздражительность.Многофазная шкала характеристик личности Миннесота также применяется в качестве системы оценки боли. У детей параметры боли можно определить количественно, используя метод самооценки, биологические показатели и на основе характеристики поведения. Поскольку боль является субъективным ощущением, метод самооценки является наилучшим, если, конечно, его применение возможно. К сожалению, у большинства детей младшего возраста или у детей с когнитивными или соматическими нарушениями его применение невозможно, и тогда используются биологические или поведенческие методы оценки. Давайте подробно рассмотрим метод самооценки. Начиная с двухлетнего возраста, ребенок может описать испытываемую боль, хотя еще пока не может определить ее интенсивность. В любом возрасте дети могут отрицать наличие боли, если о ней спрашивает незнакомый человек, а также ,если считают, что должны быть храбрыми, или если боятся или не хотят делать уколы от боли. При работе с детьми в возрасте 4-5-и лет можно использовать стандартный подход, каким является применение палочек Хостера. Благодаря собственной конкретности, он является высокоэффективным при работе в данной возрастной группе. Ребенку показывают четыре палочки, называя их частичками боли. Одна – это когда «немного болит», две – «болит сильнее», три – «сильно болит», четыре – «боль, самая сильная в мире ». Затем ребенка спрашивают: «А сколько палочек у тебя?». Затем ответ проверяют. В этой возрастной группе часто используется шкала «Лица». Детей просят указать на изображение лица, которое, по их мнению, похоже на испытываемую боль. Далее обычно с ребенком занимаются, задавая вопросы, как бы он (она) себя чувствовал, если бы боль была слабее, сильнее. Одной из шкал «Лица» является шкала Вонг-Бейкера. При работе с детьми 6-7-и лет можно использовать словесно-графические шкалы. Ребенка просят показать, как сильно у него болит, выбрав одно из пяти слов. Для работы с этой возрастной группой можно использовать шкалы 0-10 или 0-100, где 0 – «не болит», 10 или 100 – «самая ужасная боль на свете». Также можно использовать линейку, длиной 10 см, с такими же крайними отметками (шкала визуальных аналогий). По данным исследований, ни одна из шкал этого типа не уступает остальным. Теперь обратимся к биологическим методам оценки. В ответ на кратковременную острую боль частота сердечных сокращений (ЧСС) вначале понижается, а затем повышается. Изменения тонуса n. vagi и ЧСС, как во время различных фаз дыхательного цикла, используются в качестве болевого и дистресс-индекса. Ни в одном из исследований ЧСС не оценивалась в качестве количественной характеристики хронической боли, хотя ЧСС значимо повышалась при болях в постоперационном периоде у детей старшего возраста. У детей с соматической патологией или недоношенных реакции менее предсказуемы. Изменения ЧСС являются легко измеряемой общепринятой количественной характеристикой в системе оценки кратковременной острой боли. К сожалению, оказалось, что нет достоверных клинических характеристик хронической боли. Во время проведения болезненных процедур, таких как обрезание, люмбальная пункция или интубация, кривая насыщения гемоглобина кислородом снижается. Это может происходить и по другим причинам или наблюдаться в норме у новорожденных. У детей даже во время сильных болей в течение долгого периода кривая насыщения гемоглобина кислородом может оставаться нормальной. Травма или хирургическое вмешательство провоцирует выброс гормонов стресса. Они могут способствовать заживлению, но могут и повлечь тяжелые последствия у новорожденных с соматической патологией. Опиоиды тормозят стресс-реакцию, возможно, на уровне гипоталамуса или эпифиза. Но, следует отметить, что по уровню стресс-реакции можно судить не только об интенсивности боли. Выброс кортизола не является специфическим компонентом в патогенезе боли, это было тщательно исследовано у детей и новорожденных. Выброс кортизола происходит и при других неблагоприятных ситуациях. Уровень кортизола в плазме значимо повышается при проведении процедуры обрезания. Однако, у недоношенных детей с соматической патологией уровень кортизола колеблется, и небольшие его изменения во время проведения болезненных процедур можно просто пропустить. У здоровых детей уровень кортизола меняется даже во время обычных прививок, но реакция организма зависит от комплексного взаимодействия таких параметров, как возраст, темперамент и базовый уровень гормона. Такое сложное соотношение не дает кортизолу стать клиническим параметром оценки интенсивности боли, даже кратковременной и острой. Далее будут рассмотрены механизмы проведения боли в нервной системе. Кожная чувствительность опосредована специфическими рецепторами и нервными волокнами. Последние широко классифицируют на низко- и высокопороговые. Низкопороговые афферентные волокна миелинизированы, имеют специальные нервные окончания, отвечают за передачу нейтральных сигналов, таких как тактильные, вибрация, давление (все Ab-волокна), и проприоцепцию (Аа-волокна). Высокопороговые афферентные волокна имеют тонкую миелиновую оболочку (Ad-волокна) или немиелинизированы (С-волокна), расположены в эпидермисе и дерме, отвечают за болевую и температурную чувствительность.Таблица 1. Сравнительная характеристик афферентных волокон первого порядка. Тип волокон Порог Основные переносчики Основные рецепторы Локализация в слоях задних рогов спинного мозга Нейроны-мишени в спинном мозге Вид чувствительности в норме Патологическая чувствительность C Высокий Пептиды Нейрокининовые (пептидные) 1,2 I-II, V Специфические ноцицептивные Медленная боль Гиперальгезия Ad Возбуждающие аминокислоты Глутаматные (NMDA, AMPA, mGlu) Широкого спектра Быстрая боль Аллодиния Ab Низкий Глутаматные (AMPA) II-IV Низкопороговые, широкого спектра Тактильная, вибрационная Механическая аллодиния Волокна болевой и температурной чувствительности не имеют специфических рецепторов, только свободные нервные окончания. Они полимодальны, то есть воспринимают различные типы стимулов, например химические, термические или механические. Свободные нервные окончания есть везде, кроме внутренних отделов костей и мозга. В роговице есть только они, поэтому ее повреждения могут быть чрезмерно болезненными. Большинство из свободных нервных окончаний реагируют только на стимулы, повреждающие ткани, это ноцицепторы. Боль можно широко классифицировать на внезапную, острую, кинжальную и тупую, пульсирующую. Ad-волокна опосредуют первую, «быструю», С-волокна – последнюю, «медленную». Не все Ad – и C-волокна являются ноцицептивными. Некоторые реагируют на низкопороговые стимулы, такие как прикосновение. У многих С-волокон есть терморецепторы, они реагируют на тепло и холод.