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In other words the advance lies in the possibility of reducing some iatrogenic side effects 250 mg flagyl free shipping. The roles of the pharmaceutical industry and the commercial imperative in driving the therapeutic evangelism that surrounds the genuinely exciting advances of pain physiology and pain genetics need to be highlighted generic 250 mg flagyl fast delivery. For pain poses a conundrum for pharmacological advance flagyl 400 mg with amex. The biomedical scientists have provided us with a clear rationale and mechanisms for why culture order flagyl 400 mg fast delivery, society proven flagyl 250mg, affect and cognition, fears and expectations, have such a profound and important influence on the chronicity of pain. And yet some of these same scientists would have us believe that the true virtue of their unveiling of the mechanisms of pain is that we have an array of specific chemical targets for newly fashioned therapies. An equal argument would be that if we can identify anything that alters affect and cognition and beliefs in the right direction – a homoeopathic physician who, say, spends an hour with a patient alleviating fears, creating expectations in an atmosphere of trust, reducing anxiety, addressing domestic topics – then why not bet on that? Indeed there may be less uncertainty in that, since it is all very well to target a piece of the mechanism, but history tells us that upsetting the homeostasis and equilibrium of body systems can have bad as well as good effects. The COX-2 story provides a good example of this, with one of the experts on this class of drugs pointing out that inhibiting COX-2 activity may paradoxically promote some types of inflammatory activity. Brand new agents to treat musculoskeletal pain and nip chronicity in the bud might appear in a side effect-free nirvana of applied pharmacology. But it would be equally foolish to assume that the amazing advances in understanding, imaging and integrating the pain story – which I do believe will be unravelled in all its complexity in the coming decades – will automatically result in great new analgesic drugs. Indeed there are some reasons to suppose that, for pain particularly, the pharmaceutical path, good as it is, should not be seen as the only way in which pain management can advance. In summary, I think it unlikely that new targeted therapies in chronic musculoskeletal pain will produce major advances in management, but I would be happy to be proven wrong. Milder grounds for optimism lie in the continuing advance of opioid science and the refinement of its application. Advances in multiple therapies that harness the endogenous system and reduce the side effects of opioids will allow experiments to address their possible role in chronic musculoskeletal pain. Cannibinoids are another traditional drug group which may have a similarly enhanced role in coming years. What will be the role of the placebo in pain management? My prediction is that there will be many impeccably carried out randomised controlled trials of pain management using complementary therapies, and that they will universally show an overall positive effect which is only a little higher than placebo. The role of expectation and the power of the placebo is becoming a challenge to our capacity to harness and use the placebo effect therapeutically. We have emerged from the end of the twentieth century with strong experiments to show that what may be the most important thing in placebo controlled trials of pain treatments is neither the randomisation, nor the efficacy of the active drug, but the amazingly powerful effect on pain of the placebo itself. Coupled with these is convincing biological science to explain just why suggestion and expectation and fear reduction might be such positive influences in reducing pain. Therapies will not lose respectability because they are little different from placebo, but they may gain respectability from the demonstrable power of their non-specific effect, and perhaps from their lack of side effects, compared with magic bullets from the pharmaceutical industry. But there is a paradox, one that Richard Asher knew and wrote about 40 years ago15: “It is better to prescribe something that is useless, but which you and the patient both believe in, than to admit that you do not know what to do. How can you support something in the knowledge that it is only the belief and not the substance which is effective? One of the optimistic things about all this relates to the fact that the opinions and prophecies of experts who stand at opposite sides of the biological–cultural divide are couched in the same language. This suggests that a major potential advance in chronic pain management in the forthcoming decades will be an ability to talk about the social and cultural in biological terms whilst avoiding solutions which reduce to the exclusively biochemical. Patrick Wall for instance, one of the outstanding figures in biological pain science in the twentieth century, stated: “A crucial component is the patient’s belief that it works – for the patient who benefits, it matters not a toss why it works”. Arthur Kleinman, one of the great figures in anthropological pain research, quotes a physician, Spiro, suggesting that “the placebo effect – the non-specific therapeutic effect of the doctor–patient relationship – although it is despised in medical research because it confounds a clear-cut understanding of the specificity of successful treatments – is in fact the essence of effective clinical care”. And let it do so with a neurobiological model of how it might work, a model which actually asks whether single chemical approaches to the problem of chronic musculoskeletal pain are doomed to failure if taken out of the clinical, social and psychological context of the patient suffering from pain. What will be the role of non-pharmacological pain management? Strong evidence now exists that the psychological status of the individual – emotions and beliefs, attitudes and learned behaviour – as well as the social, cultural and economic circumstances in which they live, are crucial influences on why people develop chronic and 108 MANAGEMENT OF CHRONIC MUSCULOSKELETAL PAIN persisting musculoskeletal pain. The biology of pain presents us with an explanation of the neurological mechanisms as to why this is so. The question now to be addressed is the extent to which therapies and interventions directed at beliefs, attitudes, behaviour and circumstances may be effective.

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Although the spinal Therefore generic flagyl 250mg with amex, as the spinal cord segments do not corre- cord has a functional organization within itself order 250mg flagyl mastercard, these neu- spond to the vertebral segments flagyl 250 mg fast delivery, the nerve roots must rons of the spinal cord receive their “instructions” from travel in a downward direction to reach their proper higher centers generic 400mg flagyl visa, including the cerebral cortex cheap 200 mg flagyl fast delivery, via several entry/exit level between the vertebra, more so for the lower descending tracts. This enables us to carry out normal spinal cord roots (see the photographic view in Figure 2A movements, including normal walking and voluntary and Figure 2C). These nerve roots are collectively called activities. The spinal cord also has a motor output to the the cauda equina, and they are found in the lumbar cistern viscera and glands, part of the autonomic nervous system (see Figure 2A, Figure 2C, and Figure 3). CLINICAL ASPECT UPPER INSET: CERVICAL SPINAL CORD The four vertebral levels — cervical, thoracic, lumbar, and CROSS-SECTION sacral — are indicated on the left side of the illustration. The neurons of the spinal cord are organized as nuclei, The spinal cord levels are indicated on the right side. One the gray matter, and the various pathways are known as must be very aware of which reference point — the ver- white matter. In the spinal cord, the gray matter is found tebral or spinal — is being used when discussing spinal on the inside, with the white matter all around. One of the loca- Figure 32) and motor (see Figure 44) systems. The sensory nerve of the spinal cord are described with the pathways in roots to the perineal region, which enter the cord at the Section B (e. All the sacral level, are often anesthetized in their epidural loca- pathways are summarized in one cross-section (see Figure tion during childbirth. The dura-arachnoid has been The segmental organization of the spinal cord and the opened and the anterior aspect of the cord is seen, with known pattern of innervation to areas of skin and to mus- the attached spinal roots; from this anterior perspective, cles allows a knowledgeable practitioner, after performing most of the roots seen are the ventral (i. There is a large plexus of veins on the the spinal cord with the skin and muscles of the body, give outside of the dura of the spinal cord (see Figure 1), and the cord a segmented appearance. This segmental organi- this is a site for metastases from pelvic (including prostate) zation is reflected onto the body in accordance with tumors. These press upon the spinal cord as they grow and embryological development. Areas of skin are supplied by cause symptoms as they compress and interfere with the certain nerve segments — each area is called a der- various pathways (see Section B). The muscles are supplied usually by two adjacent accidents into shallow water (swimming pools). Other trau- = C5 and C6; quadriceps of the lower limb = L3 and L4). If the This known pattern is very important in the clinical setting spinal cord is completely transected (i. For the ascending There are two enlargements of the cord: at the cervical pathways, this means that sensory information from the level for the upper limb (seen at greater magnification in periphery is no longer available to the brain. On the motor Figure 2B), the roots of which will form the brachial side, all the motor commands cannot be transmitted to the plexus, and at the lumbosacral level for the lower limb, anterior horn cells, the final common pathway for the the roots of which form the lumbar and sacral plexuses. The person therefore is completely cut off The cord tapers at its ending, and this lowermost portion on the sensory side and loses all voluntary control, below is called the conus medullaris. Bowel and bladder control are also of L2 in the adult, inside the vertebral canal, are numerous lost. SPINAL CORD 3 CLINICAL ASPECT SPINAL CORD: CERVICAL REGION Because of its tenuous blood supply, the spinal cord is (PHOTOGRAPH) most vulnerable in the mid-thoracic portion. A dramatic drop in blood pressure, such as occurs with a cardiac This is a higher magnification photographic image of the arrest or excessive blood loss, may lead to an infarction cervical region of the spinal cord. The result can be just as severe as if roots are the motor/ventral roots, coming from the ventral the spinal cord was severed by a knife. The most serious horn of the spinal cord (discussed with Figure 4); a few consequence of this would be the loss of voluntary motor of the dorsal/sensory roots can be seen, which enter the control of the lower limbs, known as paraplegia. These roots exit the vertebral canal clinical picture will be understood once the sensory and and carry a sleeve of arachnoid-dura with them for a very motor tracts of the spinal cord have been explained (in short distance, as they head for the intervertebral spaces Section B). Surgeons who operate on the abdominal aorta, for The somewhat tortuous artery running down the mid- example, for aortic aneurysm, must make every effort to line of the cord is the anterior spinal artery. This artery, preserve the small branches coming off the aorta as these which is the major blood supply to the ventral portion of are critical for the vascular supply of the spinal cord.

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Among Pontine Level these nuclei are those of 10 of the cranial nerves (CN III to CN XII) buy cheap flagyl 250 mg on line. Many basic brain activities are located in the • CN V cheap 250 mg flagyl visa, the trigeminal nerve cheap flagyl 500 mg without a prescription, is a massive nerve brainstem 250 mg flagyl fast delivery, including key vital functions (control of blood attached along the middle cerebellar peduncle discount 250mg flagyl mastercard. Some motor functions • CN VI, the abducens nerve, is seen exiting are found at various brainstem levels, some as part of the anteriorly at the junction between the pons and reticular formation; the reticular formation is also part of medulla. Most • CN VII, the facial nerve, and CN VIII (the important, the ascending sensory and descending motor vestibulocochlear nerve), are both attached to tracts/pathways that connect the spinal cord with “higher” the brainstem at the ponto-cerebellar angle. In addition, many of the connections to the Medullary Level cerebellum, including pathways and nuclei, are found in the brainstem. Finally, each part of the brainstem has a part of the ventricular system. Each of the parts has uppermost region of the spinal cord, enters the distinctive features that allow for the identification of the skull and then exits from the skull as if it were parts, both on the gross brain specimen or a microscopic a cranial nerve; by convention it is included as cross-section. The nuclei of the brainstem, including the cranial nerve • The pons portion is distinguished by its bulge anteriorly, the pons proper, an area that is com- nuclei, will be studied in cross-sections of the brainstem posed of nuclei (the pontine nuclei) that connect in Section C of this atlas (see Figure 64–Figure 67). BRAINSTEM 2 • CN IV, the trochlear nerve, supplies one extraocular muscle. BRAINSTEM AND DIENCEPHALON: Pontine Level VENTRAL (PHOTOGRAPHIC) VIEW • CN V, the trigeminal nerve — its major nucleus This specimen has been obtained by isolating the brain- subserves a massive sensory function for struc- stem (and cerebellum) along with the diencephalon from tures of the face and head. It is the same specimen as in supplies motor fibers to jaw muscles. The • CN VI, the abducens nerve, supplies one three parts of the brainstem can be differentiated on this extraocular muscle. Figure 45), to the brainstem (cortico-bulbar tract, see Figure 46), and to the pontine nuclei Medullary Level (cortico-pontine fibers, see Figure 55). The direct voluntary motor pathway from some of the muscles of the neck. Behind each pyramid is the olive, a pro- trusion of the inferior olivary nucleus (dis- More details concerning the innervation of each of the cussed with Figure 55). For almost all of the cranial nerves, this tion, demarcating the end of the medulla and the begin- attachment coincides with the location of the nucleus/nuclei ning of the spinal cord. Not only does this assist in understanding the neuroanatomy of this region, CRANIAL NERVE FUNCTIONS but this knowledge is critical in determining the localization Knowledge of the attachment of each cranial nerve (CN) of a lesion of the brainstem region (discussed further in to the brainstem is a marker of the location of the cranial Section C of this atlas). In addition, it is necessary one or more sensory or motor pathways as they pass to know the function of each of the nerves. Because of the close relationship with the cerebellum, there may be cerebellar signs as well. Midbrain Level ADDITIONAL DETAIL • CN III, the oculomotor nerve, supplies several of the extraocular muscles, which move the eye- Structures belonging to the cerebellum are explained in ball. A separate part, called the Edinger-West- Figure 54–Figure 57. The nucleus is located in the The cranial nerves are peripheral nerves that supply the head region, except for the olfactory (CN I) and optic (CN lower pontine region. Each cranial nerve is unique and may have one • CN VII, the facial nerve, is a mixed cranial or more functional components, either sensory, motor, or nerve. The motor nucleus, which supplies the both, and some also have an autonomic (parasympathetic) muscles of facial expression, is found at the component. The parasympathetic There are two kinds of motor functions: fibers, to salivary and lacrimal glands, are part of CN VII (see Additional Details below). The motor supply to the muscles derived from somites, including CN III, IV, VI, and XII, and MEDULLARY LEVEL to the muscles derived from the branchial arches, called branchiomotor, including CN V, • CN IX, the glossopharyngeal nerve, and CN X, VII, IX, and X (no distinction will be made the vagus nerve, are also mixed cranial nerves. The parasympathetic supply to smooth mus- and larynx (X), originating from the nucleus cles and glands of the head, a part of CN III, ambiguus. In addition, the parasympathetic VII, and IX, and the innervation of the viscera component of CN X, coming from the dorsal in the thorax and abdomen with CN X. Both nuclei are This diagram shows the location of the motor nuclei found throughout the mid and lower portions of the cranial nerves, superimposed upon the ventral view of the medulla.

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While this has a number of theoretical and practical advantages over conventional radiography in the detection of spinal fractures cheap flagyl 400mg with visa, reservations concerning reference ranges and correctly recognising other causes of vertebral deformity (such as degenerative changes or Scheuermann’s disease) have limited the use of this technique to date purchase flagyl 200mg line. At present buy flagyl 500 mg free shipping, many individuals presenting to accident & emergency or orthopaedic services with fragility fractures are not referred for appropriate investigation and treatment discount 500mg flagyl amex; correcting this deficit is an important priority for the future purchase 250 mg flagyl overnight delivery. Biochemical markers of bone turnover A person’s bone density at a point in time is the product of the rate at which bone density is lost and the peak density attained at skeletal maturity (Figure 6. Biochemical assessment of osteoporosis is not yet in reach, though markers of bone formation and resorption (Table 6. Some markers correlate with rates of change in bone mineral density, and others have been shown to accurately predict fractures in the elderly. However, ongoing difficulties include: G biovariability in the “normal” ranges (i. G variance in the laboratory measurement of these markers (i. G identifying a sufficiently sensitive and specific single test or combination of tests. However, as methodology improves it is likely that bone turnover markers will add to the overall assessment of osteoporosis and may eventually influence treatment decisions. However, it is not possible to directly measure this in vivo. High resolution magnetic resonance imaging of the wrist can assess the cancellous structure, but long scanning times, relatively expensive equipment and the need for expert interpretation of the images preclude the routine use of this technique. Quantitative computed tomography enables measurement of volumetric bone density and separate evaluation of cancellous and cortical bone, and 84 MANAGEMENT OF OSTEOPOROSIS also has the potential to assess cancellous bone structure. This can be applied to the vertebrae (axial quantitative computed tomography) or to peripheral sites (peripheral quantitative computed tomography). While radiation dose in peripheral quantitative computed tomography is quite low, it is unacceptably high in axial quantitative computed tomography for routine clinical use. Furthermore, scanning times are long, and accessibility is limited. Ultrasonography, in use for many years in materials engineering, assesses material elasticity (Young’s modulus) and is related to mineral density and bone architecture – sound propagates more quickly through more dense, intact structures. Expressed as broadband ultrasound attenuation (in dB/MHz) and as speed of sound (in m/s), both values are used in a “stiffness index”. Sound waves must also travel through adjacent soft tissue, and for this and other reasons the calcaneus (heel) is commonly used. Broadband ultrasound attenuation and speed of sound can predict fracture as accurately as BMD, though each detects different aspects of the overall susceptibility to fracture. However, several problems remain to be resolved before both these values can be reliably used for screening or intervention purposes. Ultrasound technology is still grappling with variability between various machines, and with imprecision of measurements. Patient factors (variability in skin temperature, ultrasound beam attenuation at the skin surface, variation in soft- tissue thickness and density) also pose problems. Technological advances (coupling gels, uniformity in sound wave focussing, software to handle soft tissue artefact) are expected to overcome many of these limitations. Being portable, non-ionising and inexpensive, and as ultrasound machines are already widely available to the public, this will have a considerable impact on patterns of self-referral. Unfortunately, commercialisation is likely to hamper future research efforts, particularly in trying to achieve standardisation and improved reliability of measurements across various providers. The clinical value of ultrasound in the future therefore remains uncertain. Genetic influences Genetic factors account for 60–80% of the observed variation in bone mineral density. Osteoporosis is polygeneic (many different genes contributing) and involves a complex interaction between genetic inheritance and the environment (including nutrition, general health, exposure to drugs, etc. Associations between bone mineral density 85 BONE AND JOINT FUTURES and, in some studies fracture, and a number of polymorphisms (variations in the DNA sequence within a gene) have been identified. These are reviewed in detail elsewhere, but the following observations are of interest with respect to future developments: G Polymorphisms in the collagen type I gene (COLIA1) and the gene for transforming growth factor beta (TGF- ) have been directly associated with both bone mineral density and fracture risk. G Several polymorphisms in the vitamin D receptor gene have been identified and associations with bone mineral density reported, although these findings have not always been consistent. There is also evidence that polymorphisms in this gene may affect the response to vitamin D and calcium supplementation.

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