Natural Peripheral Neuropathy Treatment Systems

Neuropathy Solution Program

Within The Peripheral Neuropathy Solution, you will discover a breakthrough 6-step proven extensive treatment program that can help you finally heal your ruined nerves and end your own case of neuropathy. Irrespective of your age, background and gender and the cause of your peripheral neuropathy, this program can meet your needs. To assist the smarting deadness in your lower limbs, Neuropathy Solution Program Dr. Labrum is applying compression stockings to offer help to blood vessels and stimulate each of them to more effectively send bloodstream returning to cardiovascular. Do exercises assists you to manage your glucose levels. With six easy steps that include changes in diet, exercise and lifestyle habits, a peripheral neuropathy sufferer can have permanent relief from the many painful, debilitating symptoms in as little as a month, often times even less. Continue reading...

The Peripheral Neuropathy Solution Overview


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Diabetic Neuropathy and Digestive System Dysfunction

Diabetic neuropathic cachexia is a much rarer form of peripheral neuropathy and is characterised by profound weight loss, painful dysaes- thesias over the limbs and trunk with spontaneous resolution usually occurring within a year. In 1974, Ellenberg reported on six patients with diabetic neuropathy who complained of profound weight loss and severe neuropathic pain. These patients were all males, chiefly in the sixth decade of life, had bilateral symmetrical peripheral neuropathy, severe emotional disturbance, anorexia, impotence, mild diabetes, simultaneous onset of neuropathy and diabetes, the absence of other specific diabetic complications, and a uniformly spontaneous recovery in about 1 year. Neurologic examination revealed severe muscle wasting and atrophy in all patients. Motor nerve conduction velocity studies and electromyographic studies corroborated the presence of neuropathy in all cases. Biopsies of muscle and nerve showed neu-rogenic atrophy in muscle and marked...

Neuropathic Pain Syndromes

In primary care as well as many types of specialty practice, the term neuropathic pain has been most often thought of as simply meaning painful peripheral neuropathy, as commonly occurs in severe diabetes mellitus (DM). This association may have developed based on the high incidence of diabetes, the bilateral, distal distribution of other symptoms (sensory loss), and signs (reduced temperature, circulatory compromise) commonly seen in this illness. In general clinical practice, the pains of well-known neurologic disorders, such as those created by herpes zoster and inflammatory involvement of the trigeminal nerves, are more likely to be thought of as focal neuralgias, rather than neuropathic pain. Similarly, the pain created by local compression of nerve roots is considered to represent just one aspect of a radiculopathy rather than being part of a neuropathic pain syndrome. Even when contralateral pain is created by unilateral thalamic or other deep hemispheric infarctions, the...

Pathophysiologic Processes Subserving Neuropathic Pain

As one might expect, there is substantial evidence that abnormal nerve activity is an important mechanism underlying the spontaneous pain typical of neuropathic pain states (10,11,12). It is hypothesized that sites of ectopic foci develop on injured or regenerating nerves in the periphery, at the level of the nociceptor, neuromas, or segments of injured nerves at the dorsal root ganglion and in the dorsal horn of the spinal cord. Indeed, after nerve transection, increased sensitivity occurs, followed in a few days by spontaneous activity. These abnormal ectopic foci may be thought of as spontaneous pain generators, resulting in paroxysmal and spontaneous pain (see Chapter 3 for more detail). TABLE 1 Common Causes of Neuropathic Pain Chemotherapy (vincristine, cisplatinum, paclitaxel, metronidazole) Anti-HIV drugs B12 and folate deficiencies Small-fiber neuropathy Mononeuropathy Entrapment syndromes Traumatic injury Diabetes Vasculitis Plexopathy Diabetes Avulsion Tumor Precise...

Peripheral Nerve Injury Produces an Increased Expression of Clusterin in CNS Neuronal Perikarya

From these observations we conclude that peripheral nerve injury produces an increased expression of clusterin in neurons situated in the central, but not in the peripheral nervous system. Furthermore, our findings show that there is no distinct relationship between clusterin upregulation and neuronal death or survival after axotomy.

Neuropathic Pain Disorders Diabetic Neuropathy

The most recent International Association for the Study of Pain (IASP) definition of neuropathic pain, as noted earlier, is pain initiated or caused by a primary lesion or dysfunction in the nervous system (15). These mechanisms may be activated in a different order, which would help to explain the clinical differences between nociceptive and neuropathic pain. In nociceptive pain, tissue damage occurs, activation of phase 1 is noted, after peripherally occurring pain, which is conducted to the CNS pain modulation in phase 2 occurs, including peripheral and central sensitization these changes may last hours to days and then modification of pain sensation (in phase 3) can occur, particularly in disorders involving chronic inflammatory processes, causing prolonged changes to responsiveness, leading to chronic pain (17). In neuropathic pain, damage to the nervous system induces the changes to phase 3 first, secondary to loss of function, inducing modification of pain sensation, which is...

Peripheral Nerve Injury Produces an Increased Expression of Clusterin in Perineuronal Astrocytes

Immunohistochemical preparations demonstrate a distinct increase in clusterin staining intensity in astrocytes in the vicinity of axotomized motoneurons2 and mesencephalic trigeminal nucleus neurons (Pfaller, Liu, Aldskogius, unpublished observations). Similarly, in the spinal cord dorsal horn where primary sensory fibers terminate, astrocytes increase their expression of clusterin and clusterin mRNA following peripheral nerve injury.4 In all these situations the increased immunoreactivity appears to reasonably well match the as-trocytic hypertrophy following peripheral nerve injury. With in situ hybridization for clusterin mRNA, the neuropil labeling is typically relatively weak compared to that of the

Mechanisms Of Diabetic Peripheral Neuropathy

Insulin is not responsible for glucose uptake in the peripheral nerves. For this reason, high glucose levels in the blood cause high nerve glucose concentrations. The polyol pathway, via reactions catalyzed by aldose reductase, converts glucose to sorbitol. Nerve fructose levels are also increased. Excess fructose and sorbitol induce a decrement in the expression of the sodium myoinositol cotransporter, which causes decreased myoinositol levels. This, in turn, creates decreased levels of Na K ATPase activity. Aldose reductase, when activated, depletes its cofactor nicotinamide adenine dinucleotide phosphate (NADPH), which causes decreased levels of nitric oxide and glutathione, which work to stop oxidative injury. The lack of nitric oxide stops vascular relaxation, which helps in the induction of chronic ischemia (60-65). Finally, circulating NGF is decreased in diabetic patients with neuropathy (75). Treatment with NGF has shown improvements in peripheral nerve growth and function...

Hivassociated Neuropathic Pain

A direct mechanism is proposed in which the HIV viral envelope glycoprotein gp120 directly invades the peripheral nerve and the dorsal root ganglion, which induces neurotoxicity (112,113). The activity of chemokines and gp120 glycoprotein can act on the chemokines receptors of nociceptive neurons and induce both hyperesthesia and allodynia (114). HIV may induce indirect damage by promoting macrophage infiltration in peripheral nerves and the dorsal root ganglia (115,116). The macrophages, once in the peripheral nerve, can cause local release of proinflammatory neurotoxic cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6, which can induce axonal degeneration (117-119).

Malignant Peripheral Nerve Sheath Tumors Grades

These grade 3 and 4 tumors, previously called neuro-genic sarcoma, are malignant schwannomas that may arise primarily from peripheral nerves or secondarily from neurofibromas. They involve large- and medium-sized nerves. Grossly, the tumors appear as a fusiform or globoid enlargement of the nerves. Histologically, they are highly cellular, with spindle-shaped cells forming interlacing bundles. Mitoses are frequent, and necroses and hemorrhages are common. Metaplasia with bone, cartilage, and muscles may occur (Fig. 11.36).

Complex Regional Pain Syndromes As Neuropathic Pain

Following peripheral nerve injury, concomitant alternations may be evident in dorsal root ganglia, including transmitter changes and increased density of sympathetic nerve terminals (169). Tyrosine hydroxylase positive cell terminals that produce norepinephrine migrate from vessels supplying the dorsal root ganglion to nerve ganglion cells following sciatic nerve injury. The dorsal root ganglia then express a-adrenergic receptors. This may be a putative link between peripheral tissue injury, nerve injury, and SMP states, such as reflex sympathetic dystrophy and causalgia (complex regional pain syndromes types 1 and 2, respectively). In the periphery, sprouting nerve terminals may exhibit sensitivity to prostaglandins, cytokines, and catecholamines. These kinds of changes further increase the complexity of the neuropathic pain picture and blur the distinctions between nociceptive and neuropathic pain. It should be noted that not all stimulus-independent pain is mediated by spontaneous...

Glial Activation In Neuropathic Pain

In almost a counterpoint to the above noted mechanisms of neuropathic pain, it has been reported that astrocytes and microglia in the CNS spinal cord can be activated and induce the creation and maintenance of pain facilitation secondary to inflammation and damage to peripheral nerves, other peripheral tissues, spinal nerves, and the spinal cord. Glial cells appear to be of immune cell origin (203,204).

Diagnostic Evaluation Of Neuropathic Pain

There exist two lines of thought relative to the clinical diagnosis of pain syndromes of this type one suggests that, since the symptom characteristics of neuropathic pain are not pathognomonic for the condition, their lack of specificity make the diagnosis difficult to reach (213). Another provides evidence to support certain symptom characteristics as strong indicators of neuropathic pain (213a,215). Regardless of which attitude is correct, the pain practitioner hoping to differentiate neuropathic from non-neuropathic disorders must begin, as always, with the clinical history.

Physical Examination Of Patients With Neuropathic Pain

In general, all major parts of the physical examination are important for adequate determination of the presence of local disease, which may cause pain. (8,216). Any patient in whom the symptom characteristics suggest neurologic origin may also demonstrate regional abnormalities of motor or reflex functions. However, the portions of the examination, which are most relevant to the evaluation of neuropathic pain, are those which are related to sensory dysfunction, such as hypoesthesia, hyperesthesia, hyperalgesia, and allodynia (1,5,215,216). There are three important aspects in performing the sensory examination in patients with neuropathic pain (i) the information that is obtained is still subjective, (ii) stimulation with different modalities may create a mixed or uninter-pretable response pattern, and (iii) that there may also be hypoesthesia or even areas of total anesthesia in the middle of areas that the patient describes as being so painful.

Integration Of Historyphysical Data For Neuropathic Pain Evaluation

It is evident from the preceding paragraphs that the duration and complexity of the clinical evaluation of human neuropathic pain are very dependent upon the patient's ability to tolerate long and potentially uncomfortable procedures. For screening purposes however, different methods have been developed to provide a combination of individual components of the history and physical examination. The more simple and direct methods are exemplified by Galer and Jensen (220), and Krause and Backonja (214). Development of a Neuropathic Pain Questionnaire demonstrates burning pain, shooting pain, numbness, electric pain, tingling pain, squeezing pain, freezing pain, and significant sensitivity to touch. Analysis of the elements reveals that the three most valuable features were the symptoms of numbness, tingling pain, and the mixed response of symptoms signs expressed as increased pain due to touch on physical examination.

Mechanistic Basis Of Neuropathic Pain Management

Management of neuropathic pain is a complicated endeavor and often is frustrating to patient and physician alike. This stems from our relatively poor understanding of mechanisms and the limited efficacy of currently available analgesics. Therapeutic approaches vary greatly among physicians, which reflects the paucity of randomized clinical trials, particularly those comparing different drug regimens. Given our current level of understanding of neuropathic pain mechanisms and the limitations of available drugs, nonpharmacologic methods may be as effective as pharmacologic approaches. Recalcitrant chronic pain syndromes warrant an interdisciplinary approach, which may include attempts to treat the underlying disease (e.g., causes of the peripheral neuropathy) as well as formulation of a rational approach to medications, interventions such as nerve blocks, and psychologic and physical therapies.

Stimulusevoked Neuropathic Pain And Opioid Analgesics

Various studies suggest that stimulus-evoked neuropathic pain is more sensitive to opioids than stimulus-independent pain (227). Opioid responsiveness may be maintained in some forms of stimulus-evoked pain, because opioid receptors in the substantia gelatinosa are preserved. On the other hand, segmental loss of presynap-tic central opioid receptors occurs following injury or loss of C fibers, typically seen after deafferentation injury. However, the magnitude of receptor loss is minimal and largely segmental, and only partly explains the diminished opioid-responsiveness characteristic of neuropathic pain (172). Supraspinal facilitative mechanisms may also be involved in maintenance of neuropathic pain and opioid resistance. Evidence suggests that sustained afferent drive induces facilitation of spinal cord pain transmission involving a descending pathway from the rostroventral medial medulla (RVM) (172). Tonic facilitation may involve supraspinal cholesystokinin (CCK), traditionally...

Development of Gabapentin for Neuropathic Pain

Lakhbir Singh and Mark Field performed initial studies of gabapentin for use as an analgesic in animal models in 1992-1993 at the Parke-Davis Cambridge (UK) Research Centre. They found that gabapentin was active in several rat models of antihyperalgesic action (formalin test, carrageenan test),37,38 although at rather high dosages. Gary Bennett obtained a sample of gabapentin in 1993, and tested it in his model of neuropathic pain from sciatic nerve ligation in rats.39 These results from animal models were presented by Bennett at a national meeting in 1994, and at about the same time, the first case reports of gabapentin use for neuropathic pain appeared in the literature.40,41 Subsequently, a large number of investigators found gabapentin to be active in animal models of pain states14,38,42-61 and also in several clinical studies.62-65 In 1995 and 1996, Parke-Davis began two large placebo-controlled parallel group studies of gabapentin for treating neuropathic pain. Clinical trials...

Neuropathic Pain

Neuropathic pain affects a small proportion of the population - 17 - About 30 of patients referred to a pain clinic have symptoms of neuropathic pain. Neuropathic pain usually has one or more recognizable symptoms which can help make the diagnosis. These include shooting pain, burning pain and other sensory symptoms such as tingling. It may be initiated by trauma, surgery, infections (e.g. shingles) or be part of a peripheral neuropathy such as diabetic neuropathy. Careful assessment is needed to check for possible underlying causes. Neuropathic pain is often a difficult diagnosis for the non-specialist to make and may be mistaken for a musculoskeletal pain. This can lead to unsuccessful therapy and frustration on the part of the patient and physician. Neuropathic pain responds very variably to treatment, even for the most experienced practitioners.

Diabetic Neuropathy

Diabetes is the commonest cause of neuropathy in the West 18 . It is most commonly seen in diabetic patients over the age of 50 and affects up to 50 of patients. It can be present in many different forms depending upon the particular part of the peripheral nervous system affected. In diabetes, damage and loss of peripheral nerve fibers may occur. This may be due to poor circulation to the nerves. Most patients are seen within diabetic clinics and services, especially if they have acute symptoms. Most if not all services regularly monitor their patient population for the complications of diabetes, of which the development of peripheral neuropathy is an important one. A number of patients with chronic or persistent pain associated with their neuropathy may be referred to a pain clinic.

Acquired immune deficiency syndrome dementia

A number of autoimmune neuroinflammatory disorders (see 6.09 Neuromuscular Autoimmune Disorders) affect either the central or peripheral nervous system. Many of these disorders are exceptionally rare such as Moersch-Woltman syndrome (stiff-man), Lambert-Eaton myasthenic syndrome, and myasthenia gravis (MG). While uncommon, these disorders tend to be highly debilitating as they directly alter neuromuscular transmission. The most common of these disorders is MG which affects an estimated 60 000 people in the USA. The primary pathology underlying MG appears to be the production of autoantibodies directed against the alpha subunit of the neuromuscular nicotinic acetylcholine receptor. Through direct interference and complement-mediated lysis of the postsynaptic muscle membrane, the autoantibodies cause disruption in the motor endplate that leads to a weakness in skeletal muscle throughout the body. The autoimmune disorder systemic lupus erythematosus (SLE) and the neuroinflammatory...

Peripheral Pain Pathways

All tissues other than the CNS itself contain nociceptors, especially the skin, which is heavily innervated. The sensation of pain usually occurs when the peripheral nervous system's sensory neurons are activated by noxious stimulation to the free nerve endings of primary afferent neurons. They may be stimulated by mechanical, thermal, or chemical stimuli. The peripheral nerves contain sensory, motor, and autonomic fibers. They are classified by their size, conduction velocity, and the absence or presence of a myelin

Neuroanatomy Of Visceral Pain

Basic science studies have demonstrated that from the level of gross anatomy to the microscopic determination of both peripheral and central afferent terminals, visceral sensory pathways are diffusely organized and distributed (diagrammatic summary in Fig. 1). Rather than mimicking the precise organization of cutaneous sensory afferent pathways, which travel in defined peripheral nerves and extend into a limited number of spinal segmental nerves organized in a unilateral, somatotopic fashion, visceral sensory afferent nerve fibers originate from multiple branchings of nerve fascicles organized into weblike plexuses scattered through the thoracic and abdominal cavities that extend from the prevertebral region to reach the viscera by predominantly perivascular routes. Injection of neuronal tracing agents into focal sites within viscera may easily result in the labeling of cell bodies in the dorsal root ganglia of 10 or more spinal levels in a bilaterally distributed fashion (27). The...

Principles of Pediatric Pain Management

Fourth, pain management should consider the patient. Drug choice and administration should be tailored to the patient's age, health, and activity. For example, in the neonate, the physiological and behavioral responses are sensitive indicators of pain, but they have poor specificity. Therefore, pain assessment is affected by the sleep-wake cycle, disease-related stress, or apprehension. When the assessment is equivocal in determining the presence of pain in the neonate, it is better to assume that pain is present and to treat accordingly. Preemptive administration of analgesics is appropriate before the onset of known painful procedure (46). Older infants metabolize and eliminate opioids similar to adults. Continuous infusions of opioids are safe in infants older than 6 months. Plasma levels of morphine remain consistent with stable dosing even when the infusion is continued for several days (47). The use of multimodal techniques and agents potentially decreases the side effects of...

Nmethyldaspartate Receptors

Associated with NMDARs in the periphery, local injections of glutamate or NMDA result in pain behaviors that can be attenuated by peripheral administration of NMDAR antagonists (12,13). Peripheral administration of MK-801 (dizocil-pine), a noncompetitive NMDAR antagonist, produces local anesthetic-like effects (14). The number of NMDARs on peripheral nerve fibers increases during inflammation, and this may contribute to peripheral sensitization in inflammation (15). Another study found a dose-dependent antihyperalgesic effect for IV ket-amine in patients with neuropathic pain, with only minimal CNS side effects encountered (18). Observed changes in the NR subunit expression may represent an adaptive response aimed to reduce excessive neuronal excitability resulting from tissue injury. The dose-response curve of NMDAR currents were consistent with a relative increase in NR2B expression, which is important in neuropathic pain (21). Peripheral inflammation may alter the properties of...

Transient Receptor Potential Channel Receptors

Of equal interest is the fact that TRPV1 receptors appear to be upregulated during inflammatory processes. The TRPV1 is present on neurons that normally do not express them in the presence of experimental models of nerve injury and diabetic neuropathy (43). These findings appear to imply that aberrant TRPV1 expression is found in neuropathic pain and hyperalgesia (43). Small molecule agonists of TRPV1 capsaicin and resiniferatoxin (RTX) are used for a number of clinical syndromes in animal studies, including intractable neuropathic pain, spinal detrusor hyperreflexia, and bladder hypersensitivity. Vanilloid receptor 1 (VR1) antagonists have yet to reach the clinic. Capsazepine is the classic TRPV1 antagonist but it demonstrates poor pharmacokinetics and significant species selectivity issues in the laboratory (47). A study has demonstrated morphological evidence for the distribution of TRPV1 along unmyelinated axons in peripheral nerve giving the first view of vesicular neuropeptide...

Use in Prevention and Therapy

Because thiamin deficiency can reduce pain tolerance, supplemental thiamin may ease chronic pain. Thiamin may be effective in peripheral neuropathy,5 particularly in inflammatory nerve disorders (such as trigeminal neuralgia). It may also be effective in diabetic neuropathy.

Mechanisms of SensitizationCNS Changes

Many of the processes underlying central sensitization are analogous to those observed in the peripheral nervous system. For example, there is evidence that central sensitization reflects an increase in synaptic strength (analogous to transduction in the periphery), which reflects changes in the biophysical properties (144), density (145-148), and or distribution of receptors critical to enabling postsynaptic neurons in the spinal cord dorsal horn (or at higher sites) to respond to excitatory input from nociceptive afferents. Similarly, there is evidence of changes in VGSCs (149) and VGPCs (150) associated with tissue injury, which mediate increases in the excitability of dorsal horn neurons. Interestingly, upregulation of a VGSC a subunit NaV1.3 occurs in both the spinal cord and the thalamus following spinal cord injury, where it appears to be critical for mediating sensitization of these CNS neurons (151). There is also evidence of phenotypic changes in CNS neurons following injury...

Neurochemical Milieu Of Muscle Nociceptors Or Afferent Units

SP, produced in the dorsal root ganglia, is transported to the peripheral nerve endings (3). When released from nociceptive endings, SP triggers a cascade of events that induce neurogenic inflammation (also called a sterile inflammatory response), secondary to antidromic neuronal activity in sensory nerve fibers from the release of endogenous substances with both vascular and cellular actions (4,5). A nociceptor therefore acts both as a passive sensor of painful stimuli and it is also capable of inducing a change in the chemical milieu around the afferent unit as part of its reaction to noxious stimuli (6).

Peripheral And Central Nervous System Aspects Of Noncancer Pain

Pain can be generated from the peripheral nervous system (PNS) and CNS, including the autonomic aspects of the CNS. The attributes of these forms of pain are different from those seen in myofascial pain. They can be seen in addition to myo-fascial pain. The diagnosis of neuropathic, or nerve-related, pain is made via both history and examination. Neuropathic Pain Manifestations Various changes in the physiology of the peripheral nerves can induce pain. These changes include peripheral nerve lesions inducing pathological changes in the dorsal root ganglia, causing spontaneous discharge of neurons without reception of peripheral stimulation, abnormal ectopic impulses produced from new sites (previously injured) in peripheral nerve axons, Even if the majority of peripheral nerve function is restored, some sprouts may become trapped somewhere along the nerve and form neuroma in continuity. If a nerve is only partially transected, axonal regrowth may develop into multiple microneuromas....

Inflammatory Vascular Diseases

Polyarteritis nodosa usually occurs in middle-aged adults and involves the medium-sized and small lepto-meningeal and parenchymal arteries and the nutrient arterioles of the peripheral nerves. In the acute stage, the vessel wall undergoes fibrinoid necrosis, with massive polymorphonuclear infiltration. In the chronic stage, dense fibrosis with residual inflammatory cells replaces the vessel wall (Fig. 4.29). The kidneys, liver, and gastrointestinal tract are commonly involved.

Hereditary Arteriopathies

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) affects young and middle-aged adults. It is associated with mutations of Notch 3 gene on chromosome 19. The disease involves the leptomeningeal and small paren-chymal arteries, and the small arteries of the peripheral nerves, muscles, and skin. The vessel walls are fibrotic and hyalinized, and basophilic and PAS-positive granules are deposited in the media. Skin biopsy and genetic studies confirm the diagnosis.

Chemical Mediators of Pain

The nervous system is rich in potent chemical substances that are released, detected and broken down in an ornate sequence that scientists are only beginning to understand. The excitement for researchers in this area is that thoroughly understanding which compounds are in action in a pain state raises the possibility of delivering drugs that affect their action and result in pain relief. An example of this is the amino acid glutamate, which is thought to be part of the sequence of events that results in neuropathic pain. The discovery by laboratory scientists that the action of glutamate can be blocked at a receptor known as NMDA by existing medications resulted in their more widespread use in the treatment of this debilitating condition and has set in motion efforts to develop new drugs that might do

Contribution of Non Neuronal Cells to Nociception

Recently, we have become aware that direct neuronal signaling to other neurones is not the only process that leads to long-term changes. Immune cells within the spinal cord, which were long thought to only have a protective and nutritive role, have also recently been found to contribute to alterations in neuronal hyperexcit-ability -5-6 - These immune cells, mainly microglia and astrocytes, are activated from their normal quiescent state by injury to peripheral nerves and also by inflammation or injury within the spinal cord or brain. In fact, rather than increasing excitability of spinal nociceptive neurones the processes thought to occur are through removal of an inhibitory influence, or disinhibition 7 .

Transient Receptor Potential Vanilloid Receptor

TRPV1 belongs to the transient receptor potential (TRP) channel family and is activated by heat, protons, and vanilloid ligands such as capsaicin (94-96,142-149). Studies have localized the expression of TRPV1 receptors on small diameter primary afferent neurons (C-fibers) in DRG, usually with P2X3, while functionally TRPV1-mediated currents have been detected in these same neurons. As such, TRPV1 receptors have been strongly implicated in nociception and pain (94-99), including thermal nociception and inflammatory hyperalgesia and allo-dynia (97), and neuropathic pain (150). Although as is the case with P2X3 receptors, it should be noted that the majority of these studies have been performed in levels of DRG, which are devoid of colonic innervation (39,43). A recent report demonstrated differences in TRPV1 expression between cutaneous and visceral afferents. This study showed, using immunohisto-chemistry, that 69 of rat DRG neurons innervating the urinary bladder expressed TRPV1, in...

Pain and its alleviation monitored by the neuroscience portfolio

Of an amino acid neurotransmitter, g-aminobutyric acid (GABA), which leads to the activation of chloride channels. Interestingly, another compound used to treat neuropathic pain, gabapentin, is very similar in structure to GABA however, it is not an anesthetic and it does not produce the same effects, following repeated stimulation, as do the two anesthetics (Fig. 4). These data suggest that loss of awareness with anesthesia does not depend on any one transmitter, such as GABA, but on some higher-order property of neuronal organization, such as macro assembly formations, and most importantly, their duration. Indeed, given that anesthesia itself is well known to be graded in stages (i.e., not all or none) (Rang and Dale, 1991), it would be appropriate for its neural correlate to be correspondingly analogue too (Fiset, this volume, Alkire, this volume). A current monitor for depth of anesthesia relies on a number of collated parameters from a patients EEG trace, which provides a...

Patient Related Factors

The most robust finding to emerge from the surgical pain literature is that pain intensity immediately after the operation predicts the intensity and duration of future pain 1, 4, 33, 34 . This appears to be true days 17, 22, 35-37 and weeks 38 after surgery, as well as for the duration of post. surgical convalescence 17, 18, 26, 35, 38-41 . In addition, the severity of acute postoperative pain in the days and weeks after surgery is also a risk factor for development of CPSP 5, 7, 12, 18, 42-46 . No other patient factor is as consistently related to the development of future pain problems as is current pain. Younger age 38, 46, 47 and female gender 38, 47 predict CPSP but not with the consistency or magnitude with which pain predicts pain. What is yet to be determined, however, is the aspect(s) of pain that is predictive. There are several non- mutually exclusive possibilities for why pain predicts pain including those that propose a causal or associative role (1) intraoperative nerve...

C Effect of co on Nerve Terminals and Neurotransmitters within Vascular Walls

The interaction of CO and the peripheral nerve system may influence vascular contractility in at least two ways. First, chronic CO exposure may affect the development and function of the nerve system.4243 Tetrodotoxin (TTX) inhibited the contraction of rat mesenteric vascular beds evoked by electrical perivascular nervous stimulation. This inhibitory effect of TTX was significantly increased in vascular tissues from prenatal pups after exposing the pregnant mother rats to 150 ppm CO for 5 to 7 days.44 TTX blocks voltage-gated Na+ channels in the nerve endings and inhibits the neurotransmitter release upon the electrical depolarizing stimulation. A reduced TTX effect indicates that chronic CO treatment somehow altered the elec-trophysiological properties of pre-synaptic membranes and facilitated the neurotrans-mitter release. Moreover, in the chronic CO-treated prenatal pups, the ACh-induced relaxation of the mesenteric arterial beds with intact endothelium appeared about 4 days...

Preemptive Preventive Analgesia

Recent studies have demonstrated that preventive analgesia is associated with clinically important reductions in CPSP incidence and intensity. For example, the use of bone graft from the hip is a necessary expedient in certain types of reconstructive surgery, but CPSP at the graft removal site is reported in up to 37 of patients at one year and 19 at two years 66-68 . Reuben et al. 69 showed that infiltration of morphine into the bone graft harvest site reduced acute and chronic donor site pain sixfold. Another study 70 demonstrated that chronic donor site pain was reduced from 30 to 10 simply by giving a non- steroidal antiinflammatory drug one hour prior to surgery and for five days afterwards. Pre-treatment of a similar nature in patients having outpatient anterior cruciate ligament repair -71 was associated with fewer complications and higher activity levels when measured six months postoperatively, an example of how a simple preventative measure taken at the time of surgery can...

Myofascial Pain Syndrome

The localized, hypersensitive regions of muscle associated with trigger points are secondary, at least in part, to sensitization of the afferent peripheral nerve endings in the muscle by prostoglandins, bradykinin, histamine, substance P, and other nociceptive or algetic neurochemicals. Histologically and conceptually, there is evidence of an energy crisis found, which is identified by a decrease in high-energy phosphates and an associated increase in low-energy phosphates, as well as local hypoxia, secondary to local vascular and microvascular disturbances. The local, peripheral sensitization also is associated with a central, spinal cord sensitization in regions of the dorsal horn.

Nitroimidazole Compounds

Danish investigators have looked at the role of pure hypoxic cell radiosensitizers such as misonidazole and nimorazole in improving overall survival. Misonidazole was initially evaluated in a randomized study of split-course radiotherapy in the DAHANCA 2 study (Danish Head and Neck Cancer Study). Overall, the study failed to demonstrate an improvement with misonidazole in comparison to placebo with 26 of patients developing profound peripheral neuropathy resulting in its discontinuation for further investigation (19). Overgaard and colleagues proceeded to evaluate nimorazole, a less toxic hypoxic cell radiosensitizer, in comparison to placebo in a phase Ill randomized study of conventional radiotherapy in supraglottic and pharyngeal head and neck tumors (20). The nimorazole group had improved locoregional control vs placebo (49 vs 33 , p 0.002) with a trend toward improved survival at 10 yr (26 vs 16 , p 0.32) warranting further study.

Changing Therapeutics in the Management of Intractable Pain in Children at the End of Life 19952005

A retrospective study published in 1995 examined the opioid requirements of children with terminal malignancy (27). Twelve (6 ) of the patients in this study required therapies beyond conventional pediatric opioid dosing. The majority of the patients had neuropathic pain related to tumor location as the basis of their intractability. Eleven patients had spinal cord compression, solid tumor metastatic to the spinal nerve roots, nerve plexus, or large peripheral nerves. Of the patients, 50 had adequate analgesia with either regional anesthesia or high-dose opioid infusion alone. The remaining patients required the prescription of sedation to control refractory pain. of their utility in pediatrics other than for procedural pain management. Despite this, clinical usage is increasing, particularly in the setting of severe neuropathic pain and rapid opioid dose escalation and perceived tolerance.

Sympathetically Maintained Pain

Sympathetically maintained pain, as described by Roberts (1), may begin after even minor soft-tissue or peripheral nerve trauma. The initial nociceptive impulses are transmitted via the unmyelinated C fibers to the Rexed layers in the dorsal horns, where they stimulate fibers of the wide-dynamic-range neurons and induce hyper-sensitivity in that region. The wide-dynamic-range neurons also become sensitized, or more responsive to all subsequent afferent stimuli.

Nicotinic acetylcholine receptors nAChRs

NAChRs are homo- or heteropentameric ligand-gated ion channels present in the CNS, peripheral nervous system, and neuromuscular junction. Various subunits can combine to provide a diversity of receptor subtypes with unique brain and neuron-specific distributions.37 Activation of nAChRs mediates calcium influx and neurotransmitter release, again specific to the neuronal subtype (i.e., cortical, hippocampal). Interest in nAChRs comes from observations that they are reduced in AD and that nicotine improves attention in AD patients. Also A 42 can bind to a7 nAChRs and antagonists of this receptor promote neuron survival. Several nAChR agonists have entered the clinic (e.g., ABT-418 14, SIB-1553A 15, GTS-21 16, TC-1734 17). The progress of these agents has been slow due to efficacy issues and side effects, including emesis, motor dysfunction, and hallucinations, although these are reduced in comparison to nicotine due to improved receptor subtype selectivity. The first a4b2 agonist to...

Common Pain Conditions

Pain may be divided into different types, depending on the underlying mechanisms. It may be musculoskeletal if it arises from muscles, bones, or joints. It may be visceral if it arises from hollow organs within the body, such as the gut. It may be neuropathic if it arises from damaged nerves or nerves that are not functioning normally. In practice, most pains are a mixture often involving more than one mechanism. This may be seen in spinal pain, which often presents with both a musculoskeletal pain and a neuropathic pain.

Von Hippel Lindau Syndrome

Table 10.3 Genetic predisposing conditions. CHRPE Congenital hypertrophy of the retinal pigment epithelium, MPNST malignant peripheral nerve sheath tumor Table 10.3 Genetic predisposing conditions. CHRPE Congenital hypertrophy of the retinal pigment epithelium, MPNST malignant peripheral nerve sheath tumor

Spinocerebellar Degenerations

The cerebellum, brainstem, and spinal cord are usually affected. Additional lesions occur in various subcortical gray structures and peripheral nerves. The presence of neuronal nuclear inclusions that derive from aggregations of expanded polyglutamine-containing proteins are characteristic of triplet-repeat diseases.

Clinical Implications

Patients with painful neuromas have abnormal expression of voltage-sensitive sodium channels. Similar changes in sodium channel expression have been identified in animal models of gastrointestinal diseases associated with pain. Patients with neuromas or neuropathic pain often benefit from anticonvulsive drugs, many of which block sodium channels. A similar mechanism may contribute to the effect of tricyclic anti-depressants or opioid agonists, both of which are effective in patients with chronic visceral pain.

Failed Back Surgery Syndrome

Failed back surgery syndrome (FBSS) is the general term used to describe cases in which back surgery performed for back pain has left the patient with pain and those in which decompressing a nerve has failed to resolve nerve pain in the leg. The patient will typically have had symptoms for many months and several imaging studies and surgical opinions. There is usually activity-dependent pain, which may limit activities of daily living and work, a constriction of social life and pleasurable activity and often a considerable burden of side-effects from drugs given to ease the symptoms. FBSS patients are often reluctant to exercise, believing that this may worsen their predicament, and this often becomes a self-fulfilling prophecy as lack of exercise leads to physical deconditioning and yet more disability.

Functionalized Polymer Matrices for Tissue Regeneration

As discussed in this chapter, the modification of material surfaces is an attractive route to develop new and improved smart biomaterials. A natural extension of this technology is to move from two-dimensional surfaces to three-dimensional (3D) polymer matrices, or scaffolds, to accelerate tissue regeneration by fabrication with various bioactive molecules (e.g., peptides, growth factors). 3D polymer matrices have been studied extensively in numerous tissue engineering initiatives, including the regeneration of bone (111,112), cartilage (113,114), blood vessels (115), and peripheral nerves (116). When isolated cells are seeded into the scaffolds, the 3D structures guide the cells' organization and development into tissue both

Autonomic Nerve System

In the peripheral nervous system, NO functions as a neurotransmitter. The most prominent evidence come from studies on the autonomic nerve system, including the digestive system. nNOS is selectively localized in the myenteric plexus and NOS inhibitors selectively block nonadrenergic- and noncholinergic (NANC)-mediated relaxation of the gastrointestinal tract (2), indicating that NO is the NANC neurotransmitter (40). This is further supported by studies using mice with targeted disruption of the nNOS gene (41). These mice are normal in most respects despite their lack of NOS catalytic activity in the brain and loss of NOS immunostaining in the central and peripheral nervous systems. No morphological abnormalities were observed in the brain or in most peripheral tissue at the gross and microscopic level. However, these mice have the markedly enlarged stomachs and histological examination reveals hypertrophy of the inner circular muscle layer. NO is thought to mediate relaxation of the...

Functions of Lipoproteins and Their Receptors in the CNS

These two functions of apoE-containing lipoproteins may explain the up-regulation of apoE seen in models of peripheral nerve damage67-69 and CNS damage.2,18 Apolipoprotein E is synthesized by non-neuronal cells around the site of injury, and delivers cholesterol to the damaged axons, a process necessary for regeneration. Apolipoprotein A-I is also found

Guillain Barre syndrome

Clinical data support the hypothesis that autoantibodies are involved in GBS pathogenesis the efficacy of plasma exchange (PE) and intravenous immunoglobulin (IVIg) therapies and the case of flaccid paralysis in a newborn of a mother with GBS. There is also strong support for a specific role for ganglioside antibodies the identification of GBS-like symptoms in some patients treated with gangliosides approximately 40 of GBS patients have anti-ganglioside antibodies in their plasma disease subtypes or symptoms correlate with the ganglioside antibody subtype, as well as with the differential expression of those subtypes in the PNS and rabbits sensitized with C. jejuni lipooligosaccharide developed anti-GMl IgG antibody, flaccid limb weakness, and peripheral nerve pathology identical to GBS.11 The last study provides the strongest and most direct evidence that at least some types of GBS are the result of carbohydrate mimicry between an infectious agent and peripheral nerve ganglioside...

The Evidence for Prescription Drug Use in the Management of Chronic Pain

Recent reviews have identified several key groups of medication for which there is high quality evidence supporting efficacy in the management of chronic pain 6-9 . This evidence has been used to develop recommendations and treatment algorithms for pharmacologic management of chronic neuropathic pain 6, 9 and chronic pain in general 7, 8 . The classes of agents for which there is well-established evidence of analgesic (pain-relieving) efficacy include the non-steroidal anti-inflammatories (NSAIDs), the tricyclic antidepressants (TCAs), specific anticonvulsants and the opioids (narcotic or morphine-like drugs). The cannabinoids (cannabis derivatives) have good support to justify their use as second or third line treatment and there is growing evidence that specific topical preparations are effective as sole agents in mild to moderate pain with potential to be used in combination with systemic therapy in moderate to severe pain 8 . A generally similar approach to selecting medication...

Tricyclic Antidepressants

Table 9.1 Average of number needed to treat among placebo-controlled trials examining tricyclic and SNRI antidepressants for neuropathic pain for benefit (50 reduction of pain), minor and major harm. Reprinted with permission of Pulses Publishing (Lynch and Watson 2006 8 ). Table 9.1 Average of number needed to treat among placebo-controlled trials examining tricyclic and SNRI antidepressants for neuropathic pain for benefit (50 reduction of pain), minor and major harm. Reprinted with permission of Pulses Publishing (Lynch and Watson 2006 8 ). effective in diabetic neuropathy, postherpetic neuralgia, tension headache, migraine, atypical facial pain, fibromyalgia and low back pain. In neuropathic pain, TCAs relieve brief lancinating pain, constant dysesthetic pain, allodynia and spontaneous pain. The pain relief from TCAs is generally moderate in degree. Side effects such as sedation, postural hypotension, dry mouth and constipation are common. The sedative property of this class of...

Other Antidepressants

There are six randomized controlled trials examining the analgesic effects of venlafaxine. The largest trial of 244 patients with painful diabetic neuropathy found a significant reduction in pain with a NNT of 4.5 for 50 pain reduction at week 6 16 . Several smaller studies demonstrated mixed results 17-21 . At present there is initial evidence indicating that venlafaxine in a dose range of 150-225 mg day may exhibit some analgesic effect in painful diabetic neuropathy, however the NNT in order to obtain an analgesic effect is higher than with the TCA group. Further controlled trials are necessary. One potential advantage of venlafaxine is its less troublesome side effect profile compared to TCAs. To date there are five published randomized controlled trials examining the efficacy of duloxetine in the treatment of pain. In three multidose trials involving a total of 1139 patients with diabetic neuropathy, duloxetine 60 and 120 mg day significantly reduced pain severity as compared...

Urge Urinary Incontinence and Overactive Bladder

In August 2004, duloxetine was given marketing authorization for SUI in Europe (Table 1). It will be marketed under the trade names Yentreve and Aricept. The FDA issued an approvable letter for Yentreve in September 2003. However, Eli Lilly and Co. withdrew its application from the FDA in January 2005 but did not stop clinical trials. Duloxetine is already approved for neuropathic pain and depression in the USA and for incontinence (as well as depression and neuropathic pain) in Europe and Mexico.

HIVRelated Nervous System Diseases

The viruses may infect the brain, spinal cord, and peripheral nerves. Involvement of the peripheral nerves manifests as bilateral distal symmetric neuropathies and, less often, as sensory or autonomic neuropathies, polyradiculopa-thies, and mononeuropathy multiplex. Segmental demy-elination, axonal degeneration, perivascular lymphocytic infiltrations, and vasculitis are common (Fig. 6.16). Several etiologies include direct infection by HIV or cytomegalovirus, an immunologic mechanism, and nutritional, metabolic, and toxic factors.

VCR Mechanisms Indications and Toxicities

CNS ascending peripheral neuropathy (axo-nopathy), seizures, encephalopathy, autonomic dysfunction paralytic ileus, atonic bladder hypothalamic stimulation fever and syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatre-mia and intravascular volume overloading. Bone marrow Myelosuppression, VB > VCR.

Platinoid Mechanism and Toxicity Platinoid Overdose Management

CNS Seizures, encephalopathy, heavy-metal induced sensory peripheral neuropathy-axonopathy, retinal toxicity, reduced color vision, ototoxicity (high-frequency). Renal Distal tubular necrosis with subsequent acute renal failure (ARF). Bone marrow Myelosuppression anemia, thrombocytopenia.

Topical Lidocaine Patch

Subequent to initial data suggesting that a topical gel containing 5 lidocaine led to a significant decrease in the pain of post herpetic neuralgia, a topical 5 lidocaine patch has been developed. There are three randomized controlled trials examining the lidocaine patch in post herpetic neuralgia 77-79 and one in patients with a variety of peripheral neuropathic pain syndromes 80 , all have found the lidocaine 5 patch provides significantly better analgesia than a vehicle placebo patch. The lidocaine patch is not available in Canada.

Newer Anticonvulsant Drugs

Becampanel (Figure 3) is an aminomethylquinoxalinedione AMPA receptor antagonist (IC50 11 nM). It is under development for the potential treatment of status epilepticus and other types of seizures. It is also being evaluated for use in the treatment of neuropathic pain and cerebrovascular ischemia.

Unmet Medical Needs

An alternative to this somewhat pessimistic situation is the considerable potential, discovered in the clinic by serendipity, for the use of AEDs in neuropathic pain (see 6.14 Acute and Neuropathic Pain) and BAPD (see 6.03 Affective Disorders Depression and Bipolar Disorders), which has increased interest in advancing AEDs to the clinic as multifactorial therapeutic agents and a renewed focus on understanding the mechanism(s) of action of these agents as anticonvulsants in order to understand the role of aberrant and spontaneous neuronal firing via epileptogenic-like foci in neuropathic pain (neuromas) and BAPD. Like chronic convulsive episodes, outcomes from chronic pain states include cell death, aberrant neuronal sprouting, and neuronal pathway remodeling (see 6.14 Acute and Neuropathic Pain).

Adenosine Producing Stem Cell Therapy

Adenosine (Figure 4) is an endogenous neuromodulatory agent that has anticonvulsant activity in a variety of animal models.45 Using hippocampal microdialysis probes, adenosine levels were found to be increased 6-31-fold in patients with intractable complex partial epilepsy during seizures,46 suggesting that compounds that mimic adenosine effects, e.g., synthetic adenosine analogs, or facilitate its actions, e.g., adenosine kinase (AK) inhibitors, may be potent and effect AEDs.47 However, as in many other therapeutic areas where modulation of adenosine function has been viewed as a therapeutic option, e.g., neuropathic pain, stroke, asthma, chronic obstructive pulmonary disease (COPD), sleep promotion (see 6.06 Sleep), etc., the efficacy of adenosine and its analogs have been accompanied by unmanageable side effects including sedation and hypotension.48 A novel approach to circumventing the side effects of adenosine has been an 'ex vivo gene therapy' approach, tailoring the local...

Death Associated With Gp120 Binding To Cxcr4

T tropic or X4 gp120 and virus may bind to and signal through the CXCR4 chemokine receptor alone without infecting the cell. Because the X4 form of the virus is present in the end stages of HIV infection and, therefore, is associated with a more rapid disease progression as well as CD8+ T cell depletion, the mechanism of the CXCR4-mediated death has been closely investigated. In contrast to CD4- or CCR5-mediated cellular killing, CXCR4 activation by gp120 causes a non-Fas-mediated caspase-independent CD4+ T cell death.960 The death signal is independent of G-protein signaling.61 The CXCR4 death is blocked by anti-CXCR4 antibodies by SDF1a, the natural ligand of CXCR4 and by small molecule inhibitors of gp120 binding. The chemokine SDF1a signals cellular chemotaxis to the T cell but does not cause apoptosis.6263 The T cell death is independent of caspase activation and, therefore, is not prevented by general caspase inhibitors. Interestingly, direct contact of R5 gp120 with a CD8+ T...

Advantages of Combining Visual Analog Scale Measures with Sensory Tests

It is not widely recognized that the VAS has measurement properties that are superior to other commonly used scales such as the NRS. Unlike VAS, the 11 point-NRS definitely does not have ratio scale properties and has no distinct zero point Fig. 4 of Ref. 13 . Compared to VAS ratings, NRS ratings have been shown to be artificially higher for both clinical and experimental pain (13). The notion that NRS ratings can easily substitute for VAS ratings because they are highly correlated with each other is very misguided. For example, both are monotonic functions of heat stimulus intensity and are likely to be highly correlated, yet the 11 point-NRS stimulus-response curve is displaced above the VAS curve. Only the latter reflects accurate ratios or proportions of pain intensity and appears to have a true zero point (3,13). Given the superior psychometric characteristics of VAS, it is astonishing that NRS has been recommended over other pain scales, including VAS, in clinical research and...

Motivation For Cell Transplantation Therapies In Chronic Pain And

Despite improvements (1) in surgical management, physical therapy, and the availability of pharmacological agents with a variety of delivery systems, many patients following peripheral and central neural injuries continue to suffer from intractable chronic pain (2). Although opioids are the most commonly used agent to control pain, only about 32 of patients receive any significant relief with long-term use (3). This often leads to untoward effects associated with tolerance, tolerability, drug diversion, and other side effects (4), including opioid-induced neurotoxicity. Nonopioid medications can attenuate some types of neuropathic pain but seldom remove the painful sensation completely (5). Recent attempts at classification of neuropathic, nociceptive, and other pain, aided by an IASP Taskforce (6), has helped the understanding of mechanisms and improvement of better treatments for chronic pain. Yet, with the frequency of inadequate or failed clinical trials, especially for chronic...

Psychophysical Characterization Of Pathophysiological Pain

The psychophysical attributes of pain that relate to pathophysiological pain have been characterized using several measurement methods, including direct scaling methods. These include thresholds for pain, adaptation, noxious stimulus intensity-pain intensity relationships, discri-minability, and temporal and spatial summation of suprathreshold pain. Here we focus on a few tests that we consider to be simple and yet the most useful in characterizing hyperalgesia and allodynia in pain patients, including neuropathic pain, fibromyalgia, and IBS patients. Responses to these tests have been useful in characterizing the variability in severity of these pain conditions and their central pathophysiological mechanisms.

Clinical Trial Issues

Traditionally, the assessment of novel analgesics has been based on methods and models based on the clinical utility of opioid analgesics.14 Many of the endpoints measured involve the use of self-report methodologies including the classical visual analog scale (VAS) with which patients rate their pain from a score of 0 (no noticeable pain) to 10 (worst pain imaginable). For the specific assessment of neuropathic pain, clinical studies have used tools like the McGill Pain Questionnaire, Neuropathic Pain Scale, and the Neuropathic Pain Symptoms Inventory. While the use of many of these analgesic endpoints has been validated in the clinical setting, the use of specific combinations of these scales may be useful to enhance the sensitivity of clinical outcomes for new analgesic compounds.

For Cellbased Interventive Therapies

Chronic neuropathic pain following damage to the peripheral or CNS has been difficult to treat clinically (14). As an illustration of the severity of pain following spinal cord injury (SCI), patients often report pain, rather than immobility, as the major deterrent to good quality of life (15). Pharmacological pain management is based on nonopioid and opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX-2) inhibitors (16), calcium channel blockers (17), capsaicin (18), nicotine receptor agonists (19), and opioids (20) (e.g., morphine and its derivatives). Adjunct drugs, such as antidepressants and anticonvulsants, often accompany more antinociceptive agents in certain types of pain, like diabetic neuropathy (21). Gabapentin, an anticonvulsant, has become the most common medication for SCI pain (22), probably owing to its calcium channel-blocking functions (23). Combination of medications, such as NSAIDs with opioids, seems to be more...

Alcohol and Sedatives

Alcohol is rapidly absorbed from the duodenum with blood alcohol concentrations of 100-200 mg , causing impaired motor function and judgment concentrations of200-400 mg lead to stupor and coma. Alcohol activates GABA receptors, inhibits NMDA receptors, and has additional effects on 5-HT3, nico-tinic, and opioid receptors. It is metabolized by alcohol dehyrogenase at a constant rate of 100 mg kg hour. Medical complications of alcohol dependence are listed in Table 8.3. Problems such as anemia, peripheral neuropathy, and dementia are of particular concern in HIV patients, who are already predisposed to these complications. More importantly, alcohol-induced liver disease may be worse in those coinfected Peripheral neuropathy

New Research Areas

Activation of neuronal nicotinic receptors (NNRs) represents a novel approach to pain management supported by the observation that epibatidine (isolated from Epipedobates tricolor) had significantly greater analgesic potency than morphine in assays of acute thermal pain.61,62 While the mechanism of action of epibatidine was unknown, it was subsequently found to be a picomolar agonists at NNRs. NNR agonists with higher affinity for the a4b2 subunit (the predominant subtype in the CNS) relative to the aipiSy nicotinic acetylcholine receptor subunit (located at the neuromuscular junction) had analgesic efficacy with a larger therapeutic window from severe side effects than did epibatidine.63-67 These observations facilitated the discovery of ABT-594 (Figure 7), an a4b2-preferring NNR agonist that was synthesized independently of the identification of the mechanism of action of epibatidine. ABT-594 has broad-spectrum analgesic activity in both acute (hot plate, tail flick, formalin)...

Beta and High Threshold Mechanical Allodynia

Studies of neuropathic pain patients have shown pathological conditions characterized by zones of skin in which heat hyperalgesia is present in some patients, and larger zones in which mechanical hyperalgesia and or allodynia is present in all or most patients (17,21,37). Two distinct types of mechanical allodynia have been characterized in neuropathic pain patients. The first is termed low threshold A-beta allodynia (17,37). Its presence is based on several lines of evidence. First, it occurs in response to electrical stimulation of the lowest threshold axons in nerves supplying the pathological zone. Second, it occurs in response to very gentle mechanical stimuli. Third, it is abolished by blockade of the largest fastest conducting axons within nerves (21). Finally, it has a reaction time consistent with conduction in myelinated afferents (21). It is also commonly characterized by the fact that moving stimuli or stimulus onset or offset is more painful than static mechanical stimuli...

Rosmediated Cytotoxicity Of Antitumor Drugs

Peripheral neuropathy.3132 The mechanism of nephrotoxicity is still not understood completely, but generation of free oxygen radicals by the proximal tubular cells has been proposed as a major pathogenic mechanism.33 Cisplatin treatment resulted in depletion of glutathion (GSH) and protein thiols34 in the kidney. Studies performed on renal cortical slices revealed that depletion of mitochonrial GSH was an early event after cisplatin treatment that was followed by increased lipid peroxidation (measured by the amount of thiobarbituric acid reactive substance) and decreased mitochondrial protein concentration.35 The imbalance of the antioxidant system was partly caused by decreased activity of the antioxidant enzymes, as decreased levels of superoxide dismutase (SOD), catalase, and GSH peroxidase activity (GSH-Px) were detected in vivo in cisplatin-treated kidney.36 The dysfunction of mitochondria caused by oxidative damage may maintain a prolonged increase of oxygen free radical...

Relationships of Temporal Summation of Mechanical Allodynia to Severity of Clinical Pain

Regardless of the exact mechanisms by which temporal summation of allodynia is generated, the phenomenon is likely to be at least part of the basis for CRPS patients' ongoing ''spontaneous'' pain. It has been suggested that temporal summation of A-beta allodynia provides at least part of the basis for ongoing background pain in neuropathic pain patients (17). This relationship could occur if continuous input from A-beta low threshold afferents (evoked in the normal course of mechanical stimulation from walking, sitting, or even contact with clothes) activated slow temporal summation of a type of burning, aching, or throbbing pain that built up slowly and dissipated slowly over time. This possibility was explicitly tested in a group of 31 CRPS patients by comparing intensities of ongoing pain between 10 patients who demonstrated slow temporal summation with 17 who did not (17). The former had significantly higher intensities of ongoing pain (mean 7.02 on visual analog pain scale) than...

Testing Peripheral Sources of Secondary Hyperalgesia in Irritable Bowel Syndrome Patients

A test of the role of tonic peripheral impulse input is suggested by a model of neuropathic pain, in which ongoing afferent input from a peripheral source maintains altered central processing that accounts for spontaneous pain, allodynia, hyperalgesia, and other motor abnormalities (21). In their study, the potential role of ongoing afferent input was demonstrated in CRPS patients. Peripheral anesthetic blockade of nociceptive input from a few critical foci effectively abolished both spontaneous and elicited pain and cold mechanoallodynia within widespread body regions in these patients, including regions that were remote from these critical foci. A similar reversal occurs with sympathetic blocks in some CRPS patients (37,61). Given the presence of widespread zones of hyperalgesia in neuropathic pain, fibro-myalgia, and IBS patients, it is possible that hyperalgesia of these of patients is maintained to some extent by tonic impulse input from nociceptive and or non-nociceptive primary...

Lumbar Sympathetic Block

There is possibly a place for lumbar sympathetic blockade in patients with severe peripheral ischemia, rest pain and ulcers. The use of neurolytic agents in such cases is justified as the patients are often not fit enough to undergo surgical sympathectomy 32 . Neurolytic sympathectomy cannot otherwise be recommended in non-cancer neuropathic pain.

Spinal Cord Stimulation

Spinal cord stimulation involves placement of an electrode or electrodes in the epidural space overlying the spinal cord, usually in the lower thoracic or cervical regions. It is used in a number of conditions including failed back surgery syndrome, CRPS, angina, lower limb ischemia and peripheral neuropathic pain syndromes.


AT patients rarely have functional abnormalities as infants. However, the vast majority develop gait abnormalities in their second year of life. All patients lose cere-bellar function over time, resulting in progressive ataxia, ocular apraxia, dysarthric speech, drooling, and choreoathetoid movements (4,5). Most index cases are initially thought to have a form of cerebral palsy (6). The classic AT patient is wheelchair-bound by the end of the first decade of life, and older AT patients may develop intellectual arrest. Dysphagia and silent aspiration become major problems when the neurodegeneration reaches an advanced stage (7). Functional neurological abnormalities in AT patients are accompanied by a continual loss of neurons from both the central and peripheral nervous system (reviewed in Ref. 4). The cerebellum is particularly affected owing to the cumulative effects of ongoing Purkinje cell death (Fig. 1).

Central Sensitization

This phenomenon has been termed central sensitization'' and is believed to be responsible for the pain hypersensitivity that occurs in surrounding healthy tissues (secondary hyperalge-sia, or allodynia). Central sensitization is characterized by a decrease in threshold and an increase in response duration and magnitude to noxious stimuli and an expansion of the mechanosensitive receptive field of dorsal horn neurons (22). Both peripheral sensitization and central sensitization are the major mechanism in the development of neuropathic pain.

Brain and Nervous System

There are two major parts of the nervous system the CNS and the peripheral nervous system. The CNS consists of the brain and the spinal cord. Once messages leave the CNS, they are carried by the peripheral nervous system. The peripheral system includes the cranial nerves (nerves branching from the brain) and the spinal nerves (nerves branching from the spinal cord). These nerves convey sensory messages from receptor cells in the body to the CNS. They also transport motor impulses from the CNS out to the body, where muscles and glands can respond to the impulses.

Modulation of Pain by Genotypic Profile

Certainly research on rodent populations has demonstrated large and heritable differences in both nociceptive and analgesic sensitivity, with genotypic differences being implicated in mediating basal pain sensitivity, the likelihood of developing neuropathic pain following neural injury, and in determining the sensitivity to pharmacological agents and endogenous antinociception (89,90). It is known that mice lacking the gene for TrkA, a tyrosine kinase receptor for nerve growth factor (NGF) have a loss of responsiveness to painful stimuli such as heat or pinpricks (91). NGF is important for the survival of embryonic sensory and sympathetic neurons. Patients with congenital insensitivity to pain with anhidrosis (CIPA) share phenotypic traits with TrkA knockout mice, and indeed Indo et al. recently demonstrated mutations in the Trk NGF receptor gene in patients with CIPA (92). This suggests that mutations of certain genes may be involved in certain pain pathologies, particularly if they...

Etiology Of Neurodegeneration In At

The one facet of the AT phenotype with the greatest clinical impact is neurodegeneration due to the gradual but inexorable loss of Purkinje cells, and, to a lesser extent, other neurons in the brain and the peripheral nervous system. Why mutations in a gene that controls cell cycle checkpoints should affect the fate of post-mitotic neurons remains a major unanswered question in AT research. Several hypotheses have been proposed over the years. Building on histopathologic analyses of cerebella from AT patients, Vinters et al. (192) proposed that AT Purkinje cells are placed at risk for cell death by abnormal positioning within the cerebellum during embryonic development. Although this hypothesis accounts for the fate of Purkinje cells, it does not provide a ready explanation for the ongoing loss of other neurons in AT patients (4). Meyn (84), noted that AT cerebella contain a high frequency of abnormal Purkinje and granule cells that exhibit the highly condensed, pyknotic nuclei...

Adult Adrenomyeloneuropathy

Adult adrenomyeloneuropathy presents with a slowly progressive spastic paraparesis and peripheral neuropathy. It may be associated with cerebral ALD. Demyelin-ation is prominent in the spinal cord, particularly in the posterior columns and pyramidal tracts, but lympho-cytic infiltrations are rare or absent.

Effects of Nucleoside Reverse Transcriptase Inhibitors

The DNA polymerase hypothesis explains the mitochondrial toxicity of NRTIs as an effect of the inhibition of mtDNA polymerase-y 121, 158, 159, 150 . Mitochondrial structure and function are altered and energy production impaired with intracellular lipid accumulation, hepatic steatosis, lactic acidosis, myopathy, pancreatitis, peripheral neuropathy, nephrotoxicity, and lipodystrophy.

Canavans Disease or Spongy Degeneration

Juvenile metachromatic leukodystrophy. The disease of an 8-year-old boy began with a decline in his school performance, daydreaming, and aimless scribbling. At age 11, he had his first grand mal seizure. Over the ensuring years, his mental and motor functions rapidly deteriorated. First, he became speechless and unable to stand or walk then he became bedridden, with his extremities in flexion contractures. After a 12-year course, at age 20 years, he died. His younger sister developed a similar illness and died before him. A and B. On transverse sections the hemispheric white matter from the frontal to the occipital lobes is reduced in volume, sunken, yellow, and gelatinous. C. Occipital lobe shows total loss of myelin and relative sparing of arcuate fibers. D. Myelin loss is total in the cerebellum and almost total in the pons (Weil stain). E. Brown, metachromatically stained myelin breakdown products are abundant in the subcortical white matter. F. Peripheral nerve shows myelin...

Evidence for Alterations in Descending Pain Modulation

Since the beginning of the 20th century it has been known that the brain can tonically inhibit spinal cord excitability, thereby regulating the amount of peripheral sensory information reaching the central nervous system. More recent evidence has demonstrated the activity of both pain-inhibitory and -facilitatory mechanisms that can tonically and phasically regulate spinal cord excitability (55,62,63). While top-down tonic pain-inhibitory modulation appears to predominate in healthy individuals, an upregulation of descending pain-facilitatory systems has been demonstrated in the maintenance of hyperalgesia in animal models of peripheral nerve injury (64). An alteration in the balance between inhibitory and facilitatory pain-modulatory systems has been proposed as a possible mechanism underlying chronic pain syndromes such as fibromyalgia (65) and IBS (66,67). Zambreanu et al. were the first to

Myoclonus Epilepsy with Ragged Red Fibers

Myoclonus epilepsy with ragged red fibers (MERRF) affects children and adults. Cardinal clinical manifestations include short stature, seizures, polymyoclonus, optic atrophy, sensory-neuronal hearing loss, cerebellar ataxia, peripheral neuropathy, and myopathy. The disease is maternally transmitted and is associated with point mutations in tRNA gene.

Polyglucosan Diseases

Round or spheroid filamentous aggregates, measuring 1 to 30 microns in diameter, occur in the central and peripheral nervous system and various organs. They have a basophilic core in hematoxylin-eosin (HE)-stained section, stain intensely with PAS and Alcian blue, and immunoreact for ubiquitin.

Infantile Neuroaxonal Dystrophy

Grossly, the brain shows moderately severe generalized atrophy. Histologically, axonal spheroids are distributed widely in the gray matter of the cerebrum and spinal cord, in the peripheral nerves, and in the auto-nomic ganglia. Additional findings are moderate neuronal losses in the cerebral cortex, neuronal and myelin losses in the pallidum, and Purkinje and granule cell degenerations in the cerebellar cortex. The clinical diagnosis is supported by demonstration of axonal spheroids in sural nerve biopsy.

Neuroaxonal Dystrophy with Brain Iron Deposition

Neuroaxonal dystrophy with iron deposition. An infant girl developed normally until 1 year of age, when she began to stumble and gradually lost her ability to walk. At 3 years of age, she was speechless, had pale optic discs, searching nystagmus, and stiff extremities. Over the ensuing years, she developed seizures and myoclonic jerks. At nine and a half years of age, she died. Thalamus shows (A) eosinophilic (HE) and (B) argyrophilic axonal spheroids (Bodian stain). C. Basophilic-iron-positive granules are deposited in basal ganglia (HE). D. The cerebellum shows extensive Purkinje cell losses (HE). E. Peripheral nerve shows myelin degeneration and small axonal spheroids (LFB-CV). Neuroaxonal dystrophy with iron deposition. An infant girl developed normally until 1 year of age, when she began to stumble and gradually lost her ability to walk. At 3 years of age, she was speechless, had pale optic discs, searching nystagmus, and stiff extremities. Over the ensuing years, she developed...

CASE 1 Coronary Artery Disease Case Description

Complications related to diabetes to date include microalbuminuria and mild peripheral neuropathy. Concomitant medical problems include mitral valve prolapse and fibromyalgia. She was on no other medications besides insulin, particularly no estrogen replacement. She has had intermittent chest pain previously, including a hospital admission in 1992 with dyspnea and a positive electrocardiogram (ECG). Follow-up exercise thallium perfusion study was unremarkable therefore, symptoms were attributed to an acute panic attack.

Symptom Assessment Close to the Patients Endof Life Multidimensional Issues

Querading (i.e. loss of appetite or fatigue stands for depressive symptoms or dyspnoea) 9 of symptoms. Since these and other symptom-specific phenomena complicate assessment of the patient's symptoms, attempts have been undertaken to identify risk factors for increased or altered symptom expression that result in refractory symptoms. For pain, the main risk factors include incident pain, neuropathic pain, psychosocial suffering, substance abuse, and impaired cognition 10 . A staging system for pain is currently in the multi-centre evaluation phase 11 .

CASE 3 Changing Insulin Regimen Case Description

Despite close follow-up, he continued to have elevated blood sugars, particularly overnight, checking RMG at 3 AM. He had no defined exercise program, but leads an active lifestyle as a farmer. His current laboratory profile includes a fasting glucose of 234 mg dL and a glycosylated hemoglobin of 10.5 . A lipid profile showed a total cholesterol of 240 mg dL, an HDL cholesterol of 51 mg dL, an LDL cholesterol of 148 mg dL, and triglycerides of 60 mg dL. His creatinine was 0.9 mg dL. His examination was essentially normal with no evidence of diabetic neuropathy or diabetic retinopathy. In January 2000, he was started on an insulin infusion pump.

Systemic Amyloidosis See Also Chapter

AL amyloidosis complicates the course of myeloma in 7-10 of patients.185 It is more commonly associated with myeloma of X light-chain type. Amyloidogenic light chains preferentially involve certain Vk and VA germline genes. The specific V gene is often associated with a propensity for a specific pattern of organ infiltration, suggesting an organ tropism of amyloidogenic light chain.86 87 Amyloid protein may deposit in many organs in the body.88 Serious organ dysfunctions develop when the kidneys, peripheral nervous system, and heart are involved. Cardiac amyloidosis results in arrhythmia, conduction defect, and restrictive cardiomyopathy. Involvement of the GI tract may produce mobility disorders and malabsorption. Pulmonary amyloidosis precipitates respiratory failure. Amyloid angiopathy causes spontaneous skin and mucosal bleeding. Amyloid may also deposit in the skin, endocrine organs, joints, and other tissues, occa

Maple Syrup Urine Disease

Labs LP increased protein in CSF (vs. cerebral palsy). Iteore sed peripheral nerve conduction velocity. Discussion Metachromatic leukodystrophy is an autosomal-recessive disorder of sphingolipid metabolism that is due to a deficiency in the enzyme aryLsulfatase A with accumulation of sulfatides in the central and peripheral nervous system as well as fif the kidneys. Intrauterine diagnosis is possible.

Does Cav2 or 3 Play a Role in Tumor Angiogenesis

Presumably due to strictly muscle, glial, and peripheral nerve-specific expression of Cav-3 47 , no data suggesting involvement of Cav-3 in tumor angiogenesis have so far been reported. However, unlike Cav-3, Cav-2 is ubiquitously co-expressed with Cav-1 and is particularly abundant in ECs. A potential role for Cav-2 in ECs and tumor angiogenesis is thus certainly plausible. Although no direct evidence supporting a role for Cav-2 in regulating tumor angiogenesis is available, there are a few reports involving studies on Cav-2 KO mice and Cav-2 ECs that suggest a possible role for Cav-2 in regulating physiological angiogenesis in the lung and perhaps also pathological angiogenesis in vivo. For example, studies of Woodman et al. 19 revealed more hematoxylin eosin positive structures in bFGF loaded matrigel plugs implanted in Cav-2 KO relative to WT mice, suggesting enhanced bFGF-induced angiogenesis in the absence of Cav-2. This data implies that Cav-2 is involved in regulating...

Clinical Features

Peripheral neuropathy was present in all of our 99 patients and usually dominates the clinical picture.52 Symptoms usually begin in the feet and consist of tingling or paresthesias. Motor involvement follows the sensory symptoms. Both begin distally and are symmetric and progress proximally. More than half of the patients have severe weakness and may have difficulty in climbing stairs, rising from a chair, or gripping objects firmly. In contrast to the neuropathy associated with primary amyloidosis (AL), autonomic symptoms are not a feature. Bone pain and pathologic fractures are major findings in symptomatic myeloma, but occur rarely in POEMS syndrome.

Arsenic trioxideassociated toxicities

The most prominent adverse events with ATO in APL have included weight gain and fluid retention, leukocytosis, the APL differentiation syndrome, and prolongation of the QTc interval on the electrocardiogram (Table 3). Peripheral neuropathy, hyperglycemia, and cutaneous reactions have also been described (37,63).

Neuropathic Lowback Pain

After the onset of discogenic abnormalities that can initiate pain, after the nociceptors in the disc have been stimulated, the somatosensory system can increase its sensitivity secondary to constant stimulation, causing a nonfunctional response peripheral sensitization can occur. If the disc degeneration progresses to disc herniation, the nerve roots or dorsal root ganglion, adjacent nervous system structures, may be affected, leading to neuropathic pain of either mechanical or biochemical origin (122). Disc degeneration can also influence other spinal structures including the facet joints, ligaments, and muscles, which individually or as a group can develop into pain generators. This can lead to disc degeneration leading to the development of chronic LBP without being the actual focus of the pain, with both nociceptive and neuropathic pain being modulated at higher centers (spinal and supraspinally) to develop central sensitization (122). The central sensitization can be associated...

The Clinically and Histologically Atypical Melanocytic Nevi The SoCalled Dysplastic Nevus

Melanocytic neoplasms originate from melanocytes neural crest-derived cells defined by their unique property of synthesis of melanin pigments. The melanins are synthesized in unique organelles the melanosomes, which are also transferred to keratinocytes. Melanocytes seem to originate from pluripotential cells that migrate from the neural crest to the skin via the paraspinal ganglia and their peripheral nerves and become terminally differentiated after migration to the local microenvironment of the dermis and basal layer of the epidermis.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

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