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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

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Local – segmental antinociception
2. 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-2

Other 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 receptors

Each 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:

  1. ссылка скрыта
  2. Cold E.G., Dhal B.L. Topics in neuroanaesthesia and neurointensive care. – Berlin – Helderberg – New York: Springer-Verlag, 2002. – 416p.
  3. Deshpande J.K.,Tobias J.D. Pediatric pain handbook. 2000; 387 p.



Peoples’ Friendship University of Russia

Medical School

General Medicine


Project Work.

Acute Pain. Острая боль.


Student: Botchaeva Tatiana (ML-401)

Supervisor: Startseva E.O.


Moscow

2006


Проблема 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: