Effective Home Remedy to Cure Peripheral Neuropathy

The Peripheral Neuropathy Program

Neuropathy Solution Program was a natural healing developed by Dr. Labrum an expert and previous Neuropathy researcher. Diabetes patients ought to care for his or her feet a lot more than they normally do. When your blood sugar levels remains uncontrolled for an prolonged period of time you are able to expand neuropathy. To help the smarting deadness in your reduced arms and legs, Neuropathy Solution Program is using compression stockings to offer help to blood vessels and induce each of them to more efficiently send blood stream going back to cardiovascular. By revitalizing the blood flow frequently and managing glucose levels, you can actually reduce the condition of your neuropathy. Randall Labrum, the author confidently and personally guarantees that customers will see the effectiveness of the Neuropathy Solution program within the very first days after using it. In case it does not work for them, he will instantly refund their total investment within 8 weeks from the date of purchase. More here...

The Peripheral Neuropathy Solution Overview

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Animal Models Of Neuropathic Pain

Unravelling the mechanisms involved in neuropathic pain requires the use of laboratory animal models that replicate as far as possible, with the above caveats, the different pathophysiological changes present in patients. For reasons of reproducibility and simplicity, most studies of neuropathic pain are based upon animal models of traumatic nerve injury, usually in the rat sciatic nerve (Figure 1.2). Before exploring what is known about the pathophy-siology of neuropathic pain, three major caveats as to the nature of the existing literature need to be stated. First, the overwhelming bulk of the literature related to neuropathic pain mechanisms has emerged from rodent studies in which the major outcome measure is hypersensitivity of spinal withdrawal reflexes evoked by sensory stimuli. Thus, in this chapter, it will actually only be possible to discuss the putative mechanisms of evoked hypersensitivity, a relatively minor component of the spectrum of clinical neuropathic pain. Second,...

Imaging Of The Brain In Neuropathic Pain

Neural correlates of allodynia have been examined in various conditions, including patients with neuropathic pain, central pain, or experimentally provoked allodynia. However, the existing data are controversial with some suggesting that allodynia is processed differently than nociceptive pain and others suggesting they share a common neural basis. Areas shown to be involved in allodynia include the parietal association cortex,194 medial thalamus, putamen, and prefrontal cortex.195 The ACC, which is almost always activated during acute pain in normal subjects and is involved in the affective (cognitive-evaluative) component of pain, has been differentially associated with processing of allodynia.196197, 198,199 This suggests that A-p-mediated pain may have a unique cortical representation in some situations which may aid further understanding of the phenomenon that is tactile allodynia. The amygdala, which plays an important role in fear-conditioning and affective disorders, such as...

Classification Of Neuropathic Pain

Neuropathic pain has usually been classified on the basis of the underlying etiology, e.g. peripheral diabetic neuropathy, postherpetic neuralgia, nerve damage due to Table 11.2 Recording of various parameters in neuropathic pain. Although a mechanism-based classification is an attractive approach, it is not known at present whether this provides a reliable, reproducible method for classifying neuropathic pain. However, it will be of interest to determine the possible additional clarification provided by a hierarchical structured system that classifies pain on the basis of (1) symptoms (2) symptoms plus signs (3) symptoms plus signs plus mechanisms and (4) symptoms plus signs plus mechanisms plus pharmacological analysis. However, a considerable overlap between symptoms and signs was found in a large group of patients with increasing clinical suspicion of neuropathic pain. Superficial ongoing pain intensity, brush-evoked allodynia, and cold-provoked pain intensity was higher in...

Assessment Of Neuropathic Pain History

The examination of a patient with suspected neuropathic pain begins with the history. Patients may describe the quality of their pains in a variety of ways they may complain of unpleasant pricking or sticking sensations in parts of the body. They may have a burning, scalding, aching, or deep sore pain. Many patients with neuropathic pain suffer from allodynia following exposure to nonpainful cold. In such cases, patients may describe their pain in a paradoxical manner as burning hot or ice-burning or as if holding a snowball in the hand. Some patients with central pain complain of pain evoked by movement in which the movement itself elicits a tightening, squeezing, or burning sensation in the skin. At other times, the pain is one of paroxysms with stabbing, shooting, lancinating types of pain. Paroxysms last seconds, but can be repeated with ultrashort intervals, giving a false impression of continuous types of pains. An important point concerns the possible classification of pain...

Painful peripheral diabetic neuropathy

Five randomized, placebo-controlled, parallel group trials on painful DPN involving 1463 patients in total were reported between 2004 and 2007. In four of them, multiple doses were used ranging from 75 to 600 mg day. No concomitant neuropathic pain medications were permitted. In one study a group with flexible dosing of 150-600 mg day was included. The titration period varied from one to three weeks. The shortest maintenance period was four weeks, the longest 11 weeks.56 II , 57 II In another study both patients with DPN and PHN were included, with similar results reported between groups and presented as a single group.51 II Of the tested doses, 600 mg day reduced pain in all four studies. The mean treatment difference (from placebo) on the visual analog scale (VAS) scale of 0-10 ranged from -1.45 (-2.1, -0.9) to -0.97 (-1.6, -0.3). NNT for 50 percent pain relief ranged from 3.3 to 6.3. Superior efficacy of a lower dose of 300 mg day over placebo was found in two of three studies.56...

Peripheral Nerves as a Therapeutic Target

Peripheral nerves can be a source of significant pain after trauma or ligation precipitates the formation of a neuroma or abnormal growth of the nervous tissue. The neural tissue may be resected by a procedure called neurectomy, but motor deficit may result since most nerves have both sensory and motor components. This procedure is not highly successful for nerve ligations in amputations, but may be effective for meralgia paresthetica and post-herniorrhaphy pain. Pain signals can also be targeted peripherally at a level closer to the CNS,

Painful Diabetic Peripheral Neuropathy

Like PHN, painful diabetic peripheral neuropathy (PDPN) is prevalent in society and treated with nearly identical pharmacologic agents. These drug therapies are often ineffective, and SCS has been attempted in previous trials for that reason. PDPN may be related to ischemia of the small vasa nervorum, metabolic impairments, or other causes. In a study of ten PDPN patients who were unresponsive to conventional treatments, eight of ten had positive responses to SCS trials and received implants. A control group received sham placebo screening. Mean duration of neuropathy was five years. Improvement was noted in both background and peak neuropathic pain, and exercise tolerance. These results were statistically significant in comparison to the sham group. The authors recommended SCS for drug-refractory patients.64 III In another study, eight male patients with long-term treatment of PDPN were followed over a three-year or greater period. Although some patients developed diabetes-related...

Neurotrophins In Diabetic Neuropathy

Decreased capture and retrograde transport of iodinated NGF in the sciatic nerve was observed in diabetic rats many years ago (34). Reduced retrograde transport of iodinated NGF in ileal mesenteric nerves has also been demonstrated (35). These observations imply that even in the absence of any deficit in production of NGF in diabetes, a deficit in the amount delivered to the cell body might be expected. In diabetic rats, there are reduced levels of NGF in the submandibular gland, superior cervical ganglion, and sciatic nerve (3638). NGF levels have also been shown to be decreased in the serum of diabetic patients with symptomatic peripheral neuropathy (39). Work in our laboratory has shown that with increasing duration of diabetes, progressive reductions in NGF mRNA appear in leg muscle and sciatic nerve followed by reductions in skin. There is a profound reduction in the retrograde transport of NGF in the sciatic nerve, which can be reversed by intensive insulin treatment, and...

Mechanisms Of Pain In Peripheral Neuropathy

Propagate toward both the central nervous system and the periphery. Such ectopic discharges may also arise from local patches of demyelination, neuromas, and soma in the dorsal root ganglia. The mechanisms underlying neuropathic pain have been reviewed elsewhere.1,2,3 Persistent primary pain is attributed to activity in noci-ceptor C-fibers, which in turn leads to central changes. Similar activity in large myelinated A-fibers may produce paresthesiae, and they mediate secondary allodynia and hyperalgesia in the setting of central changes. The mechanism of ectopic discharges is attributed to changes in the expression and distribution of membrane ion channels, especially sodium channels. Two types of sodium channel are found in sensory neurons. The first are sensitive to a neurotoxin derived from the puffer fish - tetrodotoxin (TTX) - and are found in all sensory neurons. The second types are resistant to tetrodotoxin, and are found predominantly in nociceptor sensory neurons. The...

Human immunodeficiency virusassociated painful peripheral neuropathy

Human immunodeficiency virus (HIV) infection may be complicated by various forms of peripheral neuropathy. Distal symmetrical polyneuropathy is the most common type of neuropathy that occurs in patients with HIV infection and is a result of HIV infection itself.37 It is a predominantly sensory neuropathy and burning feet is the most common symptom. The signs are those of distal axonal sensorimotor polyneuropathy. Similar neuropathy in HIV-positive subjects could result from antiretroviral drugs29, 30 and vitamin B12 deficiency, and these need to be excluded before diagnosis could be established. Painful mononeuropathy multiplex related to focal vasculitis or subacute cauda equina syndrome due to cytomegalovirus infection are other painful neuropathies that are associated with HIV infection. Neuropathies associated with HIV infection are discussed elsewhere.38

Role Of Oxidative Stress In Diabetic Neuropathy Clinical And Experimental Evidence

In experimental diabetic neuropathy, oxygen free radical activity in the sciatic nerve is increased (9). Treatment with a-lipoic acid, a potent lipophilic free radical scavenger (14), results in prevention of neurovascular abnormalities associated with experimental diabetic neuropathy (15). It has been demonstrated that reduced digital nerve conduction velocity (NCV), nerve blood flow, and glutathione levels in diabetic rats are normalized and in vitro lipid peroxidation of neural tissue reduced by a-lipoic acid in a dose-dependent manner (15,16), suggesting that the improvement in neurovascular changes were induced by improving oxygen free radical scavenging activity. One mechanism of reduced nerve blood flow is the inhibitory effect of superoxide anion on nitric oxide synthase. Because nitric oxide synthase is reduced in experimental diabetic neuropathy (17), a-lipoic acid might prevent this inhibition by reducing oxidative stress (15). A recent study has also demonstrated that...

Neuropathic Pain In Hiv Infection

HIV disease is associated with a number of painful neuropathies (Box 26.2), some of which have overlapping clinical features. Electrophysiological studies can reveal changes in the peripheral nervous system even in asymptomatic individuals with HIV.18 Of the painful neuropathies, the most common are distal symmetrical polyneuropathy (DSP) and antiretroviral toxic neuropathy (ATN).15'16'17 These two sensory neuropathies are found in over 40 percent of HIV-positive individuals. This figure has not changed in the era of HAART.19

Central Neuropathic Pain Pathophysiology

Further discussion of the applied physiology of neuropathic pain can be found in Chapter 1, Applied physiology neuropathic pain and Chapter 24, Pain in neurological disease. The pathogenesis of the various central neuropathic pain syndromes may or may not be the same. However, it appears that the site of the lesion and the affected pathways are more important than the etiology of the lesion (ischemia, hemorrhage, demyelination, trauma). Much of the work in humans has been carried out in CPSP, but the results appear to be largely applicable to post-SCI pain and MS-related central pain. Involvement of the spinothalamic pathways also appears critical, although not sufficient in and of itself, for the development of MS-related pain and post-SCI below-level central neuropathic pain.8,1649 5051,5253 Given spinothalamic tract dysfunction appears necessary, although not necessarily sufficient independently, to cause central neuropathic pain the concept of an associated denervation...

Treatment Of Central Neuropathic Pain

If one were to include case studies and small, non-randomized series, there may appear a wide breadth of experience on the treatment of central neuropathic pain. Unfortunately, prospective cohort series and randomized, double-blind, placebo-controlled trials are limited. Systemic reviews of multiple grade II studies and subsequent recommendations do not exist. While the mechanisms of action may vary in the various central neuropathic pain states, the evidence suggests overall that there is considerable overlap in the end pathways leading to below level SCI, MS-related, and CPSP central neuropathic pain states. Therefore, particularly in the context of limited high quality studies for low prevalence pain syndromes, it is rational to extrapolate data suggesting efficacy in one central pain state to justify clinically treating a patient with another central pain state. Some general principles apply to treating central neuropathic pain, as to all types of neuropathic pain. Set realistic...

Atlevel Neuropathic Pain

At-level neuropathic pain refers to pain with the features typical of neuropathic pain and present in a band or segmental pattern within the dermatome at, and two dermatomes above or below, the neurological level of injury. This type of pain has also been referred to as segmental, transitional zone, border zone, end zone, and girdle zone pain, names that reflect its characteristic location in the dermatomes adjacent to the neurological level of injury. It is often associated with allodynia (pain from a normally nonpainful stimulus) or hyperalgesia (an exaggerated pain response) in the affected dermatomes. At-level neuropathic pain may be due to damage to either nerve roots (including the cauda equina) or the spinal cord itself. Syringomyelia (cyst formation within the spinal cord) must always be considered in the person who has delayed onset of at-level neuropathic pain, especially where there is a rising level of sensory loss. Loss of pain and temperature sensation is typical, but...

Belowlevel Neuropathic Pain

This type of pain, which is also referred to as central dysesthesia syndrome, central pain, phantom pain, or deafferentation pain, presents with spontaneous and or evoked pain which is present often diffusely caudal to the neurological level of SCI. It is characterized by sensations of burning, aching, stabbing, or electric shocks, often with hypersensitivity and it may develop some time after the initial injury. It is typically constant, varying with mood, distraction, and physical pathology (e.g. infections) and is not usually related to position or movement. Sudden noises or jarring movements may trigger this type of pain. Differences in the nature of below-level neuropathic pain may be apparent between those with complete and incomplete spinal cord lesions. Both complete and incomplete spinal cord injuries may be associated with the diffuse, burning pain that appears to be associated with spinothalamic tract damage. However, incomplete injuries are more likely to have an...

Atlevel and belowlevel neuropathic pain

At-level neuropathic pain is located adjacent to the neurological level of injury and has neuropathic pain descriptors, e.g. burning, tingling, evoked by brushing.43 Below-level neuropathic pain is located diffusely below the neurological level of injury, but does not include the dermatomes immediately caudal (see Figure 29.1). At-level neuropathic pain may be due to peripheral nerve injury and nerve root impingement. This may be suggested by a pattern of pain in the region of a nerve or dermatomes that correspond to suspected trauma. Although not definitive, nerve root pain may be suggested by a unilateral distribution. Diagnosis is assisted by radiographic, CT, or MRI evidence of compression of the nerve root in the foramen by bone or disk that correlates with the location of the pain. If investigations fail to find evidence of a peripheral nerve lesion, the pain is possibly due to central changes and further assessment is unlikely to be helpful or provide further benefit in...

Abovelevel neuropathic pain

The treatment of complex regional pain syndromes is itself complex and the reader is referred to other texts that deal with this condition in more detail.54 Sympathetic blockade may provide complete relief of pain in some individuals, but effectiveness is unpredictable.55 Physical rehabilitation may also be helpful in some people with complex regional pain syndromes. Nerve root or peripheral nerve compression may require surgical decompression. Syringomyelia may require drainage and shunting or a detethering procedure.

Novel drug treatments for neuropathic pain

Active treatment of neuropathic pain can be either for long-term management or for acute flare-ups of pain. It is hoped that administration of medication on an ongoing basis may have a prophylactic effect in that it may curtail the frequency, magnitude, and duration of any flare-ups. When medication is used in the long term it should be chosen because of its tolerability being mindful that side effects of medication can be of slow onset and insidious as well as immediate and obvious. Table 17.1 Novel drug treatments for neuropathic pain. **Where neuropathic pain has resulted from postlaminectomy scar tissue epidural fibrosis.

Peripheral Nerve Blocks of the Upper Extremity

The ultrasound appearance of peripheral nerves in the brachial plexus seen in short axis with high-frequency linear transducers can be described as multiple, round, hypoechoic areas seen within a hyperechoic stroma corresponding to nerve fascicles with intervening connective tissue separating the fascicles. In long axis, the fascicular pattern of nerve tissue is seen as longitudinal, discontinuous hypoechoic tubules separated by hyperechoic lines. High-frequency probes have better axial resolution to discriminate this fascicular pattern. Tendons have the closest ultrasound appearance to nerves, but can be distinguished from them by a smaller and more homogeneous fibrillar pattern, described as a fine pattern of alternating hyperechoic and hypoechoic areas in short axis (Silvestri et al. 1995). In addition, tendons can be seen to evolve to muscle when followed proximally or distally and display a greater tendency to anisotropy.

Peripheral Nerve Blockade

When pain is refractory to pharmacologic treatment, peripheral nerve blockade may be an option (Raj 1996). Somatic nerve blocks are used in patients with intractable pain, generally from cancerous invasion of parts of the body, including the nervous system. At times, these blocks are employed in peripheral nerve pain, sciatica, and carpal tunnel syndrome. In addition, peripheral nerve blocks are employed to provide analgesia during localized surgery so that the patient can avoid general anesthesia.

Mechanisms of Neuropathic Pain

In terms of the experience of pain, it must be remembered that noxious stimuli are not just passively conducted from the periphery to the central nervous system as a large number of mechanisms serve to attenuate, magnify, and extend the organism's perception and experience of pain. The current understanding of the pathogenesis of neuropathic pain suggests that multiple mechanisms appear to mediate the symptoms of neuropathic pain including, but not limited to, temporal and spatial summation, recruitment of inactive neurons, peripheral and central sensitization, phenotypic switching, and central neuronal reorganization. Although a systematic review of the pathophysiological mechanisms underlying neuropathic pain is beyond the scope of this chapter, they have been reviewed extensively within recent years by others in the field (Baron 2000, Besson 1999, Pace et al. 2006, Pasero 2004, Waxman 2006). Normal activity in the peripheral nervous system involves a reciprocal balance between...

Assessment and Diagnostic Evaluation of Patients with Neuropathic Pain

The assessment and differential diagnosis of neuropathic pain syndromes is complex and challenging for the clinician. In patients presenting with chronic pain, the underlying pain mechanism or mechanisms are often difficult to diagnose and a distinction between noci-ceptive and neuropathic types of pain is sometimes challenging because conditions such as diabetes mellitus, cancer, and other neurological diseases can produce mixed pain pictures. It is important, of course, that the clinical assessment of a patient with suspected neuropathic pain focus on ruling out treatable conditions (e.g., spinal cord compression, neoplasm), confirming the diagnosis of neuropathic pain, and identifying clinical features (e.g., insomnia, autonomic neuropathy) that might help individualize treatment. Crucial to any pain assessment is the clinician's acknowledgment that the patient is experiencing pain and that the pain is real. This validation of the patient's pain is critical in developing rapport...

Sympathectomy Neuraxial and Peripheral Nerve Blocks

Sympathectomy with radiofrequency ablation or chemical sympathectomy is reported to be effective for severe refractory ischemic pain. Reduction in pain, increased sleep, and low incidence of side effects have been reported with transdermal buprenorphine plus epidural (or intrathecal) infusion of morphine with ropivacaine or bupivacaine. Peripheral nerve block (PNB) with inpatients with chronic ischemic lower extremity pain showed that continuous PNB is an effective, safe, and comfortable modality for long-term use in the home setting for patients with intractable chronic pain.

Assessing Neuropathic Pain

Thiere are some pain assessment tools that are specific for neuropathic pain. They are designed to evaluate the specific elements of a neuropathic pain condition. In clinical practice, a tool for diagnosing neuropathic pain may not be needed, but there are several that are specifically designed for assessing the patient with suspected neuropathic pain. The Neuropathic Pain Scale (NPS), the Leeds Neuropathic Pain Scale (S-LANSS), and the revised Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) are three tools that have been developed specifically to assess the neuropathic components of a pain complaint. The new revised SF-MPQ-2 has the ability to differentiate between a neuropathic pain and a non-neuropathic pain. When assessing a neuropathic pain complaint, it is important to use not only a recognized pain scale but also a variety of physical tests. Subjecting the painful area to heat and cold and testing sensation with cotton wisps, manual pressure, pinprick, or alcohol wipes can...

Treatment Options For Neuropathic Pain

There are a variety of treatment options for neuropathic pain. The most recent recommendations are included in the stepwise management of neuropathic pain from a guideline designed to direct medication and therapeutic choices using evidence-based recommendations (Exhibit 15.2). The guideline is available at www.guideline.gov. Stepwise Pharmacologic Management of Neuropathic Pain (NP) Step 1

Epidemiology and natural history of chronic painful diabetic neuropathy

Estimates of the prevalence of chronic painful diabetic neuropathy (CPDN) vary substantially. In a hospital diabetic clinic population, 8 of patients had typical lower limb neuropathic symptoms, over twice that of a control group 2 . One study found that 11 of insulin-treated patients aged 15-59 years had painful symptoms 3 while another reported that 20 of patients with type 2 diabetes had neuropathic pain after 10 years of diabetes 4 , although details of pain duration and severity were not given. In a community-based study of patients with type 1 and 2 diabetes attending primary or secondary care clinics 5 , using a structured questionnaire and examination, 350 people with diabetes were assessed and compared with 344 age- and sex-matched controls from the same locality. This is the largest study to date in which well-defined criteria of painful diabetic neuropathy and validated measures of pain severity and quality have been used, giving a better representation of the extent of the...

Pathogenesis of neuropathic pain in chronic pain diabetic neuropathy

Data from basic research indicate that multiple patho-physiologic mechanisms may underlie neuropathic pain and that different mechanisms may co-exist in a single patient and perhaps change over time 15 . There is considerable agreement that both peripheral and central processes contribute to the chronic neuropathic pain in CPDN, and that these different mechanisms may explain the qualitatively different symptoms and signs that patients experience 16 . There is now mounting evidence that not only the damaged neurones but also the altered properties of the nondamaged sensory neurones projecting into damaged neurons play a crucial role in the generation of neuropathic pain. However, the precise nature of the mechanisms underlying these changes remains to be fully elucidated 17 . At the molecular level, some of the important changes that occur and may contribute to the generation and maintenance of chronic neuropathic pain can be summarized as follows 18

Management of Neuropathic Pain

Pain caused by a lesion of the peripheral or central nervous system is commonly termed neuropathic pain. This could be a source of pain in the teeth along the course of the nerve which innervates the teeth on the ipsilateral side of the jaw. Fractures of jaw bones can cause injury to the nerves. This can result in neuropraxia or neurotmesis leading to paresthesia, resulting in patient biting on the tongue and causing traumatic ulcers.

Chemotherapyinduced neuropathic pain

While this type of neuropathic pain can respond in the same way to treatment as any other type of neuropathic pain, the patient has the twin burdens of the cancer illness and disability produced as a temporary side effect of chemotherapy to endure, and so the imposition of neuropathic pain treatment related side effects needs to be avoided if at all possible. Therefore, the simpler the treatment the better. Particular treatments stand out in this respect. The dietary supplement L-carnitine has the advantages of a low risk of producing side effects and a relatively high chance of helping. Time to effect is also sort. Anecdotal evidence would also suggest that IV lidocaine and oral lamotrigine can both be efficacious and relatively well tolerated by the patient.

A common mechanism in inflammatory and neuropathic pain

Pain Pathway Feedback Loops Spinal Cord

As outlined above, AMPA and NMDA receptors are critically involved in activity-dependent changes in spinal nociceptive processing. Their contribution to the pathogenesis of inflammatory pain or to pain originating from peripheral nerve damage, however, is less clear. Accordingly, recent evidence points to a critical role of disinhibition that is, a reduction in the activity of glycinergic and GABAergic neurons and receptors rather than direct exaggerated excitation as the dominant source of inflammatory and neuropathic pain.

Neuropathic Pain Scale

Thie NPS (Exhibit 15.1) was developed as a result of two research protocols in which pain descriptors were assessed for four different pain conditions PHN, CRPS, PDN, and traumatic peripheral nerve injury. A second, more diverse group of patients being treated with either lidocaine or phentolamine infusions used the scale to rate their pain. Interestingly, the second protocol outcome identified a positive response for pain that was described as unpleasant or deep. This finding led researchers to believe that the descriptors that are used by patients are really clues to the specific mechanisms that are producing the pain. More research is needed to correlate the various descriptors with individual mechanisms. It is a reliable and valid tool for measuring neuropathic pain, and it can also differentiate between nociceptive and neuropathic pain. The higher the score, the more intense the neuropathic pain. In a study of chronic pain patients having a nociceptive or neuropathic pain...

Sequence of Resulting in Neuropathic Pain

Because long-term pain may also result in apoptotic degeneration of interspinal neurons with their attached opioid receptor sites, resulting in a opioid resistance to any exogenous narcotic analgesic (Figure I-42). It is for this reason that up to 35 of all patients with neuropathic pain of peripheral or central origin may be opioid non-responders. The following disorders with associated pain states may show focal diffuse neuropathic pain (Table I-1). Table I-1. Classification of neuropathic pain disorders - Painful diabetic neuropathy (PDN), interventional blocks with local anesthetic (sodium-channel blockers), topical therapy with lidocaine or capscaicin are used as adjuncts in neuropathic pain. Certain cases will respond to neuromodulation with TENS (transcutaneous electrical nerve stimulation) or SCS (spinal cord stimulation), while physical and occupational therapy as well as psychobiological treatment, regularly are implemented in the therapeutic armamentarium of neuropathic...

Pathways of Glucose Mediated Oxidative Stress in Diabetic Neuropathy

Diabetic distal symmetric sensorimotor polyneuropathy (DPN), the most common peripheral neuropathy in developed countries (1-3), affects up to 6070 of diabetic patients (4) and is the leading cause of foot amputation (5). The typical slowing of nerve conduction and the advancing distal symmetrical sensorimotor deficits are thought to reflect an underlying slowly progressive distal axonopathy of the dying-back type primarily affecting sensory nerve fibers (6). Improved blood glucose control substantially reduces the risk of developing DPN in insulin-dependent (type 1) diabetes (7,8), thereby strongly implicating hyperglycemia as a causative factor. and inhibition of DAG kinase (15-18). These metabolic initiators are compartmentalized within the rich anatomical complexity and cellular heterogeneity of the peripheral nervous system (PNS) and its supporting vasculature and connective tissue elements. This compartmentalization channels and shapes the physiological response to metabolic...

Synaptic disinhibition in the dorsal horn as a possible source of neuropathic pain

Neuropathic pain results from the damage of neurons or nerves through trauma, poisoning, or metabolic diseases. Damage of peripheral nerves through mechanical injury or metabolic diseases is probably the most frequent cause of neuropathic pain. As in inflammatory pain, the initial focus of research was on peripheral processes. It could be demonstrated that damaged nerves become spontaneously active (Sheen and Chung 1993) and that irregular electric contacts may be formed between nerve fibers (e.g., Seltzer and Devor 1979). Both processes probably explain some aspects of neuropathic pain, but they cannot fully account for all aspects of neuropathic pain syndromes. Central processes have therefore become the center of present research. During the last decade, a number of cytokines and other mediators have been identified that contribute to the development of pain after peripheral nerve injury (Sommer 2003). However, insight into how these mediators affect sensory information processing...

Prevalence Of Neuropathic Pain

Neuropathic pain is much more common than previously suspected. The overall prevalence of neuropathic pain is thought to be approximately 1,765,000 people, excluding those patients with lower back pain radiculopathy (Irving, 2005). If the back pain The types of neuropathic pain syndromes are generally organized into peripheral neuropathic pain syndromes and central neuropathic pain syndromes. The peripheral neuropathic pain syndromes are further classified into categories, including the following Painful diabetic neuropathy (600,000 patients) The central neuropathic pain syndromes are further classified into the following categories Although these numbers seem large, they will continue to grow. War-related injuries to members of the armed services requiring amputations will increase the number of patients with phantom limb pain. The increase in obesity and resultant diabetes will increase the number of patients who have the potential to develop PDN. Additionally, previously...

Is opioid responsiveness different for nociceptive or neuropathic pain central or peripheral

Kalso et al.14 I provide some help here. They reviewed 15 randomized placebo controlled trials. Four looked at intravenous opioid testing and included 120 patients, the other 11 compared oral opioids with placebo in 1025 patients. The opioids tested were described as World Health Organization (WHO) step 3 analgesics, including fentanyl, hydromorphone, methadone, morphine, oxy-codone, and oxymorphone and a wide variety of nociceptive and neuropathic pain disorders were treated. The mean reduction in pain intensity with opioids was approximately 30 percent for both nociceptive and neuropathic pain. Five of the studies that assessed function reported no change in a range of measures with one17 II reporting significant improvement in pain-related disability and two18 II , 19 II reporting disability scores lower during treatment with oxycodone over placebo. In summary, the review by Kalso et al.14 suggests that short-term, moderate-dose opioid therapy can produce a modest reduction in both...

Vasculitis in focal and multifocal diabetic neuropathy

In a recent study on nerve lesions of the intermediate cutaneous nerve of the thigh and of the superficial peroneal nerve in patients with multifocal and proximal diabetic neuropathy, we found occlusion of epineural blood vessels associated with vasculitis and inflammatory in filtration in some patients.70 These findings come as a surprise in this setting. Clinically, the neuropathy was not accompanied by general signs or symptoms of inflammation. The lesions spared muscle blood vessels of the same size, and the cellular infiltration was made up of mono-nuclear cells only, without polymorphonuclear cells, leukocytoclasia or recanalization, as observed in PAN, This possibly, however, stresses the need for studying nerve and muscle biopsy specimens in this context. The link between the occurrence of inflammatory infiltrates, vasculitis and diabetes is not clear, but small inflammatory infiltrates have been occasionally encountered in sural nerve biopsy specimens of diabetic patients...

Experimental Diabetic Neuropathy Oxidative Stress and Antioxidant Therapy

There is ample evidence of oxidative stress in both experimental (EDN) and human diabetic neuropathy. Most studies have been done on plasma, with limited study on neural tissues. We briefly review and update our studies. There is a perfusion deficit of approximately 50 that affects peripheral nerve endoneurium (1) and the parent cell bodies in relevant dorsal root and sympathetic ganglia (2). The onset of ischemia occurs within the first week (3) and is due to a reduction in nutritive rather than arteriovenous flow. There is attendant hypoxia, seen in both experimental (4) and human diabetes (5).

Neuropathic pain

Multiple randomized, placebo-controlled trials have demonstrated the efficacy of tricyclics for treatment of neuropathic pain syndromes. These pain syndromes can be generally categorized as painful polyneuropathy,33'34'35' 36,37,38,39,40,41,42 including diabetic peripheral neuropathy, postherpetic neuralgia,43,44,45,46,47 I and centrally mediated pain.48,49 II The outcomes of these trials have been summarized in several systematic reviews.50,51 525354 I The number needed to treat (NNT) in order to achieve greater than 50 percent pain relief among individuals with neuropathic pain has been shown to be 3.1 (95 percent CI, 2.7-3.7).52

Diabetic Neuropathy

Diabetes mellitus is the most common cause of neuropathy in the western world,16 affecting approximately 50 percent of diabetic patients over time.17 It is usually seen in diabetics over 50 years of age and is uncommon in children. Diabetes can affect different components of the PNS. As a result, diabetic neuropathy is not a uniform disorder, but rather a group of distinct clinical syndromes, each reflecting the site and components of the PNS affected by the pathological process. Several clinical syndromes have been delineated.

Peripheral nerves

Acute involvement of most individual peripheral nerves has been described. The most commonly involved nerves are the median, ulnar, radial, femoral, lateral cutaneous nerve of the thigh, and common peroneal nerves. Onset is often sudden, presumably due to infarction of the nerve, and pain may be a prominent feature in such cases. Isolated peripheral nerve lesions tend to occur at the common sites for pressure palsies, and nerves in diabetic subjects are more susceptible to compression injury.17

Experimental evidence Adenosine receptors

At peripheral nerve terminals in rodents, adenosine Aj receptor activation produces antinociception by decreasing, while adenosine A2 receptor activation produces pronociception by increasing cyclic Adenosine Monophosphate (AMP) levels in the sensory nerve terminals. Adenosine A3 receptor activation produces pain behaviors due to the release of histamine and 5HT from mast cells and subsequently activates the sensory nerve terminal. Caffeine acts as a non-specific adenosine receptor antagonist. When systemic caffeine is administered with systemic amitriptyline, the normal effect on thermal hyperalgesia is blocked. When amitriptyl-ine is administered into a neuropathic paw, an antihyperalgesic effect is recorded (but not when it is given into the contralateral paw). This anti-hyperalgesic effect is blocked by caffeine, suggesting that at least part of the effect of peripherally applied amitriptyline is mediated through peripheral adenosine receptors.

Animal evidence of an antinociceptive effect of peripherally applied TCAs

Neuropathic pain A variety of experimentally induced neuropathic pain models exist. In one of these a constricting suture is applied around lumbar nerve roots which results in measurable signs of neuropathic pain such as allodynia and hyperalgesia. When amitriptyline is applied to rodent paws made neuropathic by a chronic nerve constriction injury, an antinociceptive effect is observed. When the amitriptyline is applied to the contralateral paw, no antinociceptive effect is observed in the paw on the injured side. When desipramine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine are considered, desipramine has a similar antinociceptive effect when applied topically whereas fluoxetine does not.

Topical Glutamate Receptor Antagonists

More recently it has been appreciated that multiple glutamate receptors are also expressed on peripheral nerve terminals, and that these may contribute to peripheral nociceptive signaling (Table 8.1). Table 8.1 Excitatory and inhibitory influences on peripheral nerve activity by mediators released by tissue injury and inflammation and by agents acting on neuroreceptors. Table 8.1 Excitatory and inhibitory influences on peripheral nerve activity by mediators released by tissue injury and inflammation and by agents acting on neuroreceptors. Inflammation of the hindpaw or the knee joint produces a local release of glutamate that appears to originate from A and C fibers. An additional indirect mechanism, via activation of glutamate receptors on sympathetic afferents to release norepinephrine and other substances from postganglionic efferents (e.g., ATP, neuropeptide Y), can occur as NMDA, AMPA, and KA receptors are also present on postganglionic sympathetic efferents, and inflammation...

Clinical use of lamotrigine

Undoubtedly there are fewer pain studies on lamotrigine than there are with gabapentin or pregabalin. Of course, since the manufacturers of lamotrigine did not pursue a product licence for lamotrigine in the treatment of neuropathic pain, they sponsored fewer studies, and none of the size that were undertaken with gabapentin or pregabalin. Painful diabetic neuropathy Case report evidence also suggests that it can reduce the neuropathic pain associated with multiple sclerosis and complex regional pain syndrome It could be argued that if there is controlled trial evidence to suggest a pain-relieving effect of lamotrigine in at least six neuropathic pain syndromes then it is likely that this effect is replicated in many other conditions where neuropathic pain is evident. However, not all studies have shown a positive effect with lamotrigine use. This may be partially due to inadequate doses being administered. In a study of 100 patients with neuropathic pain of mixed etiology, I found...

Other potential effects of CCK antagonists

A single animal study examined the effect of a CCK antagonist on the antinociceptive effect of the tricyclic antidepressant clomipramine in rats with streptozocin-induced diabetic neuropathy. Clomipramine on its own has the expected antinociceptive effect, as did the CCK antagonist. However, when both were given together the effect is compounded. Whether this effect is replicated in humans has not been examined, although with the well-known side effects associated with tricyclic use, the prospect of being able to enhance their analgesic effect while reducing the dose administered suggest that human studies are definitely needed.

Human clinical pain

Challapalli and colleagues (2005) concluded Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Tremont-Lukats and colleagues (2005) concluded Lidocaine and mexiletine produced no major adverse events in controlled clinical trials, were superior to placebo to relieve neuropathic pain, and were as effective as other analgesics used for this condition. Kalso and colleagues (1998) concluded in relationship to IV lidocaine that Neuropathic pain In no other type of pain has IV lidocaine been more extensively studied than in neuropathic pain. Reports of its effects have been published in a range of conditions where this type of pain is manifest. Perhaps one of the most extensively studied of such conditions is painful diabetic neuropathy. When infused over several hours a definite pain-relieving effect is produced. In the study by Viola and colleagues (2006) 4-h infusions were...

Oral local anesthetics

It can be seen, therefore, that the use of IV lidocaine has been found to offer hope of pain reduction in a broad range of conditions giving rise to pain. Indeed, this is one of the major advantages of its use. Its effect is not dependent on the cause of the pain as it can reduce neuropathic pain, which arises from surgical trauma, burns muscles and so on.

Animal experimental evidence of antinociceptive effect of carnitine

A number of experimental techniques have shown that carnitine can have an antinociceptive effect. These studies have concentrated on examining the actions of carnitine in chemotherapy-induced and diabetic neuropathic pain as well as on an acute pain model. An unfortunate consequence of the use of certain chemotherapeutic agents in cancer patients is their propensity to cause neuropathy and indeed neuropathic pain. A positive effect has been demonstrated when animals are treated with carnitine and these chemotherapeutic agents are administered. Among the chemotherapy agents known to cause neuropathic pain which can be lessened by carnitine are paclitaxel, oxaliplatin, cisplatin, and vincristine.

Carnitine in human pain

An increasing number of human studies demonstrate that carnitine treatment reduces neuropathic pain and that its use is uncomplicated by severe adverse effects. Particular examination has been made into the effect of carnitine on the pain associated with human immunodeficiency virus (HIV). Infection with HIV can be complicated by a painful symmetrical neuropathy the pain of which can be lessened by parenteral and oral car-nitine. More commonly the treatments for HIV can lead to a significant neuropathy and neuropathic pain. Nucleoside analog reverse transcriptase inhibitors (NRTIs) disrupt mitochondrial DNA synthesis impairing energy metabolism and are widely used in the management of patients with HIV. Their use is also complicated by an antiretroviral toxic neuropathy. Studies have shown that long-term carnitine treatment produces symptomatic improvement in most patients with neuropathic pain while allowing the continued use of the antiretroviral medication. Furthermore, significant...

Treatment of specific fractures

When nerve impingement occurs, a radiated neuropathic pain is the consequence and is suggested by the usually diagnostic symptoms and signs of neuropathic pain (e.g., paresthesia, numbness, allodynia, and lancinating pain). Therefore, adequate treatment of the longer-term pain that can occur with a vertebral collapse fracture requires a diagnosis as to which structure, or structures, are giving rise to the pain. Only then can there be significant hope of good quality pain relief.

Muscle Spasm and Pain

Those drugs which can reduce muscle spasm do so by effects on the central or peripheral nervous system or on the muscle itself. Where the action is on the central nervous system, sedation is a common-side effect. Where the action is on the muscle itself, this adverse effect should be less problematical.

Clinical presentation of muscle spasm

Particular varieties of muscle spasm give rise to identifiable conditions. For example, spasm of the sternomastoid muscle gives rise to torticollis or rye neck where the head is held rotated to the side of the muscle spasm. A further example would be piriformis muscle spasm where pain is felt over the greater trochanter, sciatic notch, and sacral area. This pain is worse on abduction and external rotation of the leg on that side as well as on passage of a bowel motion. Neuropathic pain may also accompany the piriformis muscle spasm as the sciatic nerve is compressed as it passes with the piriformis muscle through the sciatic notch. The tender, tense piriformis muscle can be palpated on digital rectal examination because of the close proximity of the piriformis muscle to the rectum.

Side effects of antiepileptic drugs

When we consider drug side effects, much of the available evidence comes from drug studies which are almost universally of short duration. Therefore side effects recorded are the acute side effects and not those associated with long-term therapy. Since neuropathic pain, the primary indication for AED use is often long term if not lifelong, consideration should be given not only to the acute side effects associated with the use of a particular drug, but also to the long-term consequences of its use. In terms of their effect on cognition, as with much of the data on other potential side effects, it is based on work done largely in subjects with epilepsy. Given that epilepsy may itself cause CNS abnormalities due both to the underlying cause of the epilepsy and to the effect of previous seizures, the interpretation of this data is problematical. That said, it can give some insight into the possible CNS side effects in patients with, for example, neuropathic pain. Aldenkamp and colleagues...

Parenteral Antiepileptics

Historically the first AED to be used in the treatment of pain was when phenytoin was used in the treatment of facial neuralgia in the early 1940s. Since that time oral phenytoin has been shown to be effective for the treatment of, among other conditions, painful diabetic neuropathy and so it is likely that it may be effective for other neuropathic pain conditions as well. Some concern must exist about the long-term use of oral phenytoin in view of its enzyme inducing, tachyphylactic, and gingival hyperplastic effects. With the advent of newer generation AEDs the long-term oral use of phenytoin must be questionable. On the other hand, one is left with the problem of how to treat a patient with a flare-up of neuropathic pain, in whom a quick onset of treatment is desirable, or in whom the oral route is unavailable. What drugs can we use Logically one would assume that if an oral formulation of a drug can be effective then the IV or intramuscular use of that same drug should have the...

Clinical use of 5HT3 antagonists

Neuropathic pain Use of a 5HT3 antagonist in the treatment of neuropathic pain may be reserved for management of a flare-up in view of the considerable cost if more long-term therapy were instituted and the risk of severe constipation. Ondansetron 8 mg intravenously or orally (either as a tablet or the lyophilisate) can be used, repeated up to three times a day. It is suggested that ondansetron be used for neuropathic pain and fibromyalgia treatment and granisetron for tender point, intra-articular, and nerve block injections. There is no logic to why a differing 5HT3 antagonist is used in these circumstances and why other 5HT3 antagonists are not used. It merely reflects habit.

Topical Tricyclic Antidepressants

Few classes of drugs are more extensively used in the management of chronic pain conditions than the tricyclic antidepressants (TCAs). Substantial and convincing evidence supports their use in a variety of pain conditions including neuropathic pain and the pain associated with fibromyalgia. Their use is so common that it is now normal for them to be initiated by General Practitioners. The pain relief that may be apparent is independent of their antidepressant effects but any mood improvement that may occur is often welcome. In addition to pain reduction and mood improvement, muscle relaxation and normalization of sleep pattern may also occur. All oral TCA used for a pain indication is off label.

Intravenous

Relatively few general guidelines exist for musculoskeletal pain management. As with neuropathic pain, they tend to concentrate on one particular type and source of pain. One example is a guideline formulated by the American Academy of Orthopedic Surgeons (2003). In terms of pharmacological therapy they suggest a trial of an analgesic, non-steroidal anti-inflammatory or acetaminophen. If this fails a further option is that of joint aspiration and injection of cortisone, although they rate the strength of evidence for this recommendation as little or no systematic empirical evidence. They go on to state that the role of chondroprotective agents such as glucosamine and chondroitin sulfate in the treatment of OA is not yet clear.

Human pain

Human evidence of an analgesic effect with the topical application of TCAs is, however, limited but suggestive. A small randomized, placebo controlled trial (RCT) of 40 subjects with neuropathic pain of mixed etiology produced a reduction of 1.18 on a 0-10 linear visual analogue score (LVAS) relative to placebo use with the application of a doxepin 5 cream. Minor side effects were seen in only three subjects. A larger RCT involving 200 subjects, again with neuropathic pain of mixed etiology, suggested that 5 doxepin cream reduced LVAS by about one relative to placebo and that time to effect was about 2 weeks. Again side effects were minor and infrequent. A pilot study examining the effect of topical amitriptyline application failed to produce any pain relief, but the maximum therapy duration was 7 days and so the study may have been terminated before the time to maximal effect had been reached.

Topical Opioids

The use of opioids of varying strengths is now a fundamental part of all aspects of pain management. The evidence supporting their use is impressive and increases with the passage of time. We now have opioids available in a wide range of formulations including several strong opioids in patch forms. When these are used the drug is administered transdermally with the aim of producing systemic concentrations of the drug to achieve central nervous system receptor activation. However, it is now becoming clear that the opioid receptors, at which opioids interact, are not only located in the central nervous system but also in peripheral nerve tissue. This being the case it may be that topically applied opioids may have a peripheral, as well as central, effect.

Lamotrigine

Currently just three of the AEDs have a specific pain indication. Carbamazepine is indicated for trigeminal neuralgia with gabapentin having a US licence for postherpetic neuralgia (neuropathic pain in the UK) and pregabalin for fibromyalgia, postherpetic neuralgia and painful diabetic neuropathy (peripheral neuropathic pain in the UK). The gulf between what is officially licensed and what can be effective is as wide among the AEDs as any other drug group. The possession of a marketing authorization or specific indication does not suggest that a particular drug is superior than any other drug which may be used off-label. It merely suggests that evidence of efficacy has been sought and presented in an acceptable way to the licensing authorities. From a purely scientific perspective, we lack the comparative studies that would advise us as to the best drug choices in an individual drug class.

Fibromyalgia

In an intriguing aside, it is universally acknowledged that the tricyclic antidepressants can reduce neuropathic pain and that of fibromyalgia. At least some of this effect is mediated by their effects on augmenting the descending bulbo-spinal serotinergic inhibitory drives. It has been shown in animal models that amitriptyline dosing of rats with neuropathic pain caused by spinal nerve ligation reduces the allodynia in the paw on the side of injury. But when these animals are treated with amitriptyline, the paw on the contralateral side to the injury becomes hyperesthetic, where previously they were normal after commencement of the amitriptyline Could this be because it augments the descending bulbo-spinal facilitatory drive in the absence of spino-cerebral nociceptive signaling If so, logic would suggest that co-administration of a 5HT3 antagonist could ablate this response, but work on the potential augmentative effect of a 5HT3 antagonist on tricyclic antidepressants remains to be...

Animal pain models

The use of spinal nerve root ligation in rats is a conventional method for producing allodynia, a cardinal feature of neuropathic pain, and allows the efficacy of pharmacological entities to be assessed as potential antineuro-pathic pain agents. When lidocaine is systemically infused for a defined period of time in rats with surgically induced allodynia, paw-withdrawal thresholds, a measure of allodynia, are increased for the period of infusion when low doses of lidocaine are administered. When larger doses are given, the reduction in allodynia persists well beyond the period of infusion. It has been noted that in some animals a dramatic reduction in allodynia is observed while in others absolutely no effect is generated at all. This parallels human clinical practice closely. An alternative model involves the creation of neuromas in rat sciatic nerves. Electrophysiological measurements can then be made to quantify the amount of spontaneous electrical activity that emanates from the...

LCamitine

L-Carnitine is a quaternary ammonium compound synthesized from the amino acids lysine and methionine primarily in the liver and kidneys. In vivo it has a role in transporting fatty acids from the cytosol to the mitochondria but an increasing body of evidence suggests that it may also have a useful effect on the neuropathic pain produced by a number of conditions. In the UK it is widely sold as a nutritional supplement to which a number of benefits are attributed, including weight loss, reduction in depression, and even an effect on the mental decline that accompanies aging. In other countries, such as Canada, products containing L-carnitine cannot be marketed as natural health products, as it is not considered a natural ingredient.

Clonazepam

Clonazepam is recognized as a treatment for epilepsy and in particular status epilepticus where it is given as an IV infusion. In addition to its anticonvulsant properties, clonazepam has several other potentially useful properties. Clonazepam can reduce muscle spasm, induce sleep, and reduce neuropathic pain with an impression that it is most effective for lancinating pain. In addition, it has amnesic and anti-anxiety effects. One would expect that with its long half-life that if taken on a regular basis, even if only at night, the day-time sedation would complicate its use. In practice, while such sedation may occur, it is not universal.

Suggested algorithm

There are some circumstances where treatment with drugs not normally utilized for neuropathic pain treatment can indirectly reduce neuropathic pain. For example, the muscle relaxant baclofen can reduce the pain of Peripheral neuropathic pain - area of pain relatively small Topical lidocaine patch or Topical doxepin or Topical capsaicin Central neuropathic pain or peripheral neuropathic pain felt over large area Acute flare-up of neuropathic pain trigeminal neuralgia, while glyceryl trinitrate patches can be useful in the patient with ischemic neuritis caused by peripheral vascular disease or painful diabetic neuropathy where tissue ischemia can exacerbate neuropathic pain. The vasodilatory effects of nitrates can be used to maximize tissue perfusion and therefore indirectly reduce neuropathic pain.

HT3 antagonists

It has earlier been described how 5HT3 antagonists can be used to treat fibromyalgia, irritable bowel syndrome, and neuropathic pain. It is now known that they can also be used by the intra-articular route and that the pain relief that is produced is at par with that produced by corticosteroid injection. When given into a joint, there is a clinical impression that they cause a flare of pain that can last for several days, before pain relief is produced. The benefit of use of this class of medication is that it is devoid of the risks associated with repeated corticosteroid injection.

LCarnitine

Both animal and human studies have shown that carnitine can reduce neuropathic pain and in particular that associated with cancer chemotherapy. It can also have a useful effect in patient with fibromyalgia. In the UK carnitine is sold in health food shops and has a suggested indication of weight loss (it has an effect on fat metabolism) and depression. Many patients like the concept of using something that is freely available over the counter and perceive that type of availability as indicating safety with use. We know that carnitine has an effect of glutamate receptors and this is probably what endows it with pain-relieving properties. Side effects with use are few and any antidepressant effect in a patient group in whom depression is a frequent accompaniment is welcome. A number of the drugs used conventionally in fibromyalgia treatment, such as the tricyclic antidepressants, and certain anti-epileptics are known to cause weight gain, so the propensity of carnitine to achieve weight...

Gabapentinoids

The gabapentinoids, gabapentin, and pregabalin exert their analgesic effect by interaction with the a-52 sub-unit of the calcium channel and are known to have an anti-allodynic and anti-hyperalgesic effect when used in the treatment of neuropathic pain. It is now known that these drugs can also reduce postoperative pain, reduce postoperative opioid requirement, and consequently reduce opioid-related side effects. Interestingly, the current evidence would suggest that the opioid-sparing effect of gabapentin is not dependent on the dose of gabapentin used.

Human studies

A number of human studies have examined the effect of the mixed CCK A and B antagonist proglumide. They have shown that it enhances the analgesic effect of morphine and dihydrocodeine when being used to treat chronic neuropathic pain. Further studies show it to enhance the analgesic effect and duration action of morphine when used for third molar surgery. A single human study failed to find any opioid enhancing effect of proglumide when it was used in patients after major abdominal or gynaecological surgery. One issue from the human studies is that a great range of doses have been used from fractions of a milligram to 200 mg twice daily. Clearly proper dose finding studies are required to define the optimum dose of proglumide, particularly as there is some evidence with other CCK antagonists of a bell-shaped dose-response curve. The other CCK antagonist that has been studied in humans is the CCK B antagonist L365,260. A study in patients taking strong opioids for neuropathic pain...

Tropisetron

Tropisetron belongs to the 5HT3 antagonist group of drugs. This group has been marketed for its antiemetic effect which is most well established in the fields of postoperative nausea and vomiting and in chemotherapy-induced nausea. More recently it has been shown that 5HT3 antagonists, when given systemically, can also have an analgesic effect on the pain associated with fibromyalgia and irritable bowel syndrome and even in patients with neuropathic pain. This effect is produced by their specific action on the NKl-expressing neurones in the superficial laminae of the dorsal horn. These NKl-expressing neurones contain receptors for substance P.

Introduction to Clinical Pain Management Chronic Pain

Chronic pain has traditionally had the negative connotation of psychogenic etiology and an arbitrary time domain. It has also been a pejorative term to the extent that chronic pain syndrome was deliberately omitted from the IASP Taxonomy of Chronic Pain Syndromes. This new volume gathers together the scientific and clinical evidence that confirms chronic pain as an identifiable syndrome, the final common path of many etiologies. Consistent with any clinical syndrome, there are common neurophysiological, neuroanatomical, and functional changes throughout the organism regardless of the precipitating factors. These changes are addressed in the early chapters of this volume. In addition, there is physical, psychological, and psychiatric deconditioning resulting from central and peripheral nervous system dysfunction. Socioeconomic impairment and reduction in quality of life almost invariably accompany these changes. This volume contains 46 chapters in three parts. The first part, General...

Recent developments in rodent models of neuropathy

The activation of the chemokine receptors CXCR4 and CCR5 expressed by neurons and glial cells.23 Finally, drug-induced neuropathies are becoming more prevalent clinically with painful peripheral neuropathy presenting as an unfortunate side effect of treatment with chemother-apeutics, including taxols and vinca alkaloids, or with antiretroviral agents which form part of the highly active antiretroviral therapy (HAART) for the treatment of HIV disease. Rats treated systemically with such drugs develop signs of a neuropathic phenotype and are therefore important, clinically relevant models that are currently being investigated for the understanding of underlying mechanisms.22'24'25'26'27 The aforementioned models are important as they model some aspects of the diseases most frequently associated with neuropathic pain. The majority of neuropathic pain models were originally described in rats, but more recently have adapted to the mouse. The translation of these models from rat to mouse is...

Mechanisms Of Neuropathic Hypersensitivity

A variety of pain-related phenomena, both central and peripheral, have been associated with peripheral nerve injury (Table 1.2). These are generally not mutually exclusive and it is entirely possible that any one of these (or more likely a combination) contribute to symptomatology in individual patients suffering from neuropathic pain. It is therefore inappropriate to attempt to generate a unifying hypothesis of pathophysiology for all neuropathic pain states. The next challenge is to diagnose which of these phenomena may be operative in an individual patient and to interpret each symptom within the mechanistic framework arising from work with neuropathic pain models. In this regard, neuropathic pain is ideally suited to the mechanistic-based approach to

Primary Afferent Excitability

Table 1.2 An overview of pathophysiological events which are likely to be related to the generation of neuropathic pain. Peripheral nervous system However, following a nerve injury, many injured axons and associated cell bodies in the DRG undergo an increase in their intrinsic electrical excitability. As a result they begin to generate impulse discharge spontaneously or with only minimal stimulation linked to the injury site.35 This has been termed ectopic discharge36 and has also been demonstrated in humans, suffering from neuropathic pain.37 Ectopic discharge originating in the peripheral nervous system (PNS) can result in excess spontaneous and stimulus-evoked electrical impulses feeding into the central nervous system (CNS) (Figure 1.4).39 Ectopic afferent activity may also trigger and maintain central sensitization amplifying the afferent signal from the remaining afferents that innervate the partly denervated skin and deep tissues leading to tenderness to touch (tactile...

The Role Of Peripheral Inflammatory Mediators

Nerve injury, trauma, and or infection evoke a cascade of cellular events in the PNS, including a neuroin-flammatory response with the release of chemical mediators, including many proinflammatory cytokines and chemokines.86,87 Cytokines and chemokines (small che-moattractant cytokines) are growth factor proteins secreted primarily from leukocytes as part of the immune and inflammatory response88 and have been demonstrated to play a role in the pathogenesis of pain.87 These factors can act on neurons to induce changes in gene expression, which in turn lead to the emergence of abnormal electrical activity, known to be essential for the manifestation of neuropathic pain behavior. Following nerve trauma, tumor necrosis factor-a (TNFa) is released from Schwann cells and infiltrating and resident macrophages, and in turn stimulates the sequential production and release of interleukin-1 p (IL-1p) and interleukin-6 (IL-6) (Figure 1.6).86 Accordingly, neutralizing antibodies to TNFa and IL-1p...

Excitatory Mechanisms

The afferent barrage associated with peripheral nerve injury is associated with the development of a sustained state of hyperexcitability of dorsal horn neurons, a process NMDA receptors are also involved in the maintenance of central sensitization. Nerve injury induces increased release of excitatory amino acids into the spinal dorsal horn which is associated, in an NMDA receptor-dependent manner, with increased intracellular calcium concentration ( Ca21 i) in dorsal horn neurons.114 Initial NMDA receptor activation contributes to further increased concentrations of glutamate and aspartate, representing a continual positive feedback loop which maintains sensitization. The increased Ca21 could also form a positive feedback loop, potentially through indirect activation of protein kinase C (PKC), a hypothesis supported by the antihypersensitivity effect of a PKC inhibitor in the SNL model of neuropathic pain,115 as well as the evidence that deletion of genes for isoforms of adenylate...

Spinal Inhibitory Systems yAminobutyric acid and glycine

The g-aminobutyric acid (GABA) pathway forms a major inhibitory neurotransmitter system in the CNS. Depression of such spinal inhibitory mechanisms are thought to be important for sustained enhancement of excitatory transmission and central sensitization.129 In support of this, administration of GABA-mimetics reduces neuropathic hypersensitivity and antagonism of the GABA receptors is associated with hypersensitivity.130 Moreover, peripheral nerve injury results in a substantial loss of GABA-mediated inhibitory currents,131 decreased extracellular levels of GABA,132 a decrease in dorsal horn levels of the GABA synthesizing enzyme glutamic acid dec-arboxylase (GAD) 65kDa,131 and decreased GABA receptor levels in the spinal cord, probably due to degeneration of the primary afferent neuron terminals on which the receptor is localized.133 Apoptosis in the dorsal horn following nerve injuries may correlate to selective death of GABAergic inhibitory interneurons131 due to excessive...

The Role Of Nonneuronal Cells

Peripheral nerve injury produces molecular and cellular changes that result in multiple forms of neuronal plasticity and anatomical reorganization at various levels of the peripheral and central nervous systems. Oligo-dendrocytes, astrocytes, and microglia form a large group of CNS glial cells. Although often underappreciated, a substantial body of evidence has accumulated showing that peripheral nerve injury leads to activation of glia in the spinal cord implicating astrocytes and particularly microglia.89,123 Microglia are immune-derived cells and represent 5-10 percent of glia in the CNS.154 Microglia are said to be resting under normal conditions and do not actively influence nociceptive processing. However, microglia become activated by events such as CNS injury, microbial invasion, and in some pain states. Following peripheral nerve lesions, spinal microglia appear to migrate to the relevant spinal segments, thus increasing the local micro-glial population, and become activated...

Descending Modulation

In addition to the peripheral and spinal mechanisms discussed, supraspinal mechanisms are thought to play an important role in neuropathic pain.173,174 The periaqueductal gray (PAG) is the most characterized part of a CNS circuit that controls nociceptive transmission at the level of the spinal cord.175 The PAG integrates inputs from areas such as the limbic forebrain, diencephalon, amygdala, and hippocampus with ascending nociceptive input from the dorsal horn176 and is therefore associated with the affective and autonomic responses to pain. Facilitatory cells within the RVM are classed as ON cells, whereas cells that have inhibitory influences on the spinal cord are termed OFF cells.179 Following nerve injury, there is enhanced descending excitatory drive from the RVM180 which may represent a central compensatory mechanism for the loss of normal sensory input following peripheral nerve damage.174 The brainstem areas involved are also implicated in autonomic responses, emotions, and...

Emergence Of Modern Genetics And Experimental Pharmacogenetics

Working with various chromatographic technologies that became available in the 1950s, and drawing on various pharmacological and biochemical studies performed on patients and members of their families, pharmacologists disclosed new relationships between genetically conditioned differences in drug response and their metabolic fate. ''Primaquine sensitivity,'' ''succinylcholine sensitivity, and isoniazid-induced neuropathy were the drug-related traits first to be intensely scrutinized in this fashion. Primaquine, an antimalarial drug that was used in the South Pacific during World War II, caused hemolysis of red blood cells in a large fraction of black Africans succinylcholine (also called suxamethonium), a muscle relaxant drug used as an adjunct in general anesthesia, caused prolonged paralysis and apnea (''succinylcholine or suxamethonium sensitivity'') in Caucasian subjects and isoniazid (isonicotinyl hydrazide), a new, highly effective drug in trial for treatment of tuberculosis,...

Types Of Chronic Pain And Differences Between Acute And Chronic Pain

There are several different types of chronic pain. Exhibit 1.1 identifies the two main categories, nociceptive and neuropathic pain. Figure 1.1 further classifies chronic pain into mixed and visceral pain. Differences Between Nociceptive and Neuropathic Pain Nociceptive Diabetic neuropathy Cancer pain Thie stimulus for nociceptive pain is generated from various sources and specialized sites located throughout the body. Activation of thermoreceptors (heat), mechanoreceptors (tissue injury, pressure), and chemoreceptors (chemical irritants) can all create nociceptive pain. This means that when a patient burns a hand, has a crush injury, or has an infection, a nociceptive pain stimulus is produced. The pain stimulus is then passed along the peripheral nervous system by a voltage-gated sodium channel that allows an influx of sodium ions into the neural cell, also creating an action potential that allows the stimulus to pass to the central nervous system. Once the pain stimulus reaches the...

The Role Of Antibodies In Multiple Sclerosis

Oligoclonal immunoglobulin bands in the cerebro-spinal fluid (CSF) serve as an additional pathologic hallmark of MS.9 The appearance of these immunoglobulin bands in the majority of patients with MS was initially interpreted as evidence for involvement of the humoral immune response in the pathogenesis of the disease. This notion has been supported by observations in rodents with experimental autoimmune encephalitis (EAE), using antibodies directed against the myelin oligodendro-cyte glycoprotein (MOG). In these animals, intravenous injection of monoclonal antibodies (mAbs) against MOG has been shown to increase the severity of the disease, inducing relapses and enhancing demyelination.10,11 In further support of the idea that antibodies might play a pathogenic role in demyeli-nating disease is the potential involvement of pathogenic autoantibodies in peripheral neurologic disorders, especially Guillain-Barre syndrome, an inflammatory demyelinating disease of peripheral nerves which...

Clinical trial design for chronic pain treatments

We focus on clinical trials of treatments for chronic pain, conventionally defined as pain that persists beyond 3 months or the normal time of healing 2 . Chronic pain is typically classified based on its presumed etiology, specifically, neuropathic pain versus non-neuropathic inflammatory and musculoskeletal pain. Neuropathic pain is caused by a lesion or disease affecting somatosensory pathways of the peripheral or central nervous system 3 , whereas non-neuropathic (i.e. nociceptive) pain reflects stimulation of specialized nociceptors in somatic tissue, with visceral pain often classified separately. We focus on trials of phar-macologic interventions for both of these types of chronic pain in this chapter, although many of the issues we address are also relevant to studies of psychologic therapies, nerve blocks, spinal cord stimulation,

Understanding The Basic Principles Of Epidemiology

When the prevalence of cases of pain in a population is low, the odds ratio approximates the relative risk (i.e. a+cffid and b+dffid). For relative risks greater than 1, the odds ratio overestimates the relative risk however, the odds ratio is nearly unbiased when studying uncommon events such as the risk of neuropathic pain. The odds ratio is a measure used to estimate the relative risk for several reasons. For example, in case-control studies, if a disease is uncommon, the odds ratio gives a nearly unbiased estimate of its relative risk. Also, commonly used data analysis tools, such as logistic regression, readily provide estimates of odds ratios.

Detection Of Apoptotic Cell Death In Eae And Ms

It has been shown in several studies that human autoreactive T-cells specific for CNS antigens are increased and activated in MS patients.5,6 In vitro experiments have also demonstrated that cells from MS patients grown in the presence of apoptosis-blocking antibodies against the CD95 ligand show high numbers of myelin-specific T-cells.7 The T-cells' CD95 system was also shown to be associated with apoptosis induced by interferon beta (IFN-p), which is widely used in MS therapy. Moreover, when IFN-p treatment failed, deterioration of the disease was associated with the increase in neutralized INF-p antibodies and soluble CD95.8 Apoptotic T-cells were observed in the CNS in chronic-progressive EAE during recovery, while the antibodies prevented the generation and penetration of new inflammatory cells.9 Nguyen et al10 also reported that the beneficial clinical effect of gluco-corticoid therapy in myelin basic protein (MBP)-induced EAE in rats is associated with the induction of...

General Physical Examination

The patient's skin should then be evaluated for color, temperature, and signs of rashes or edema. The practitioner should also be attentive to a patient's hair and nails, as patients with complex regional pain syndrome may present with hair loss over the affected extremity and the nails may show abnormalities in texture and smoothness. The skin's color and temperature allow the physician to assess the vascular status of a patient, as poorly perfused regions may appear cyanotic and cool to the touch. Often times, patients with vascular abnormalities will suffer from concurrent neuropathic pain.

Transporters as Targets for Drug Discovery

Whitlock et al. describe progress in the discovery of SSRIs, noradrenaline reuptake inhibitors (NRIs), and SNRIs from 2000 to the present day. Whilst Chen et al. focus on recent developments in the search for triple SERT, NET and DAT reuptake inhibitors. The interest in these areas stems not only from the potential for improved antidepressant efficacy and side effect profiles, as has been proposed for the triple reuptake inhibitors 38 , but the recognition that by tweaking the transporter profile potential therapies for other diseases associated with neurotransmitter imbalance can be developed. For example, although duloxetine 6 (Fig. 1), a dual SNRI, was initially launched in 2004 for the treatment of major depressive disorder (MDD) 39 , since 2004 additional approvals have been granted for pain associated with diabetic neuropathy 40 and fibromyalgia 41 , for stress urinary incontinence 42 and generalised anxiety disorder 43 . NRIs have been licensed for the treatment of attention...

Neurologic Examination

A neurologic examination should be performed on every new patient regardless of the region or type of pain. The neurologic exam should focus on an examination of the cranial nerves, motor strength, sensory system, and deep tendon reflexes. Except for strength, the right and left sides of the body should be identical on testing. Neurologic deficits should follow the distribution of peripheral nerves, dermatomes, or hemibody and should not end abruptly at the midline as nerves partially overlap from either side (Shea et al. 1973).

Advantages and Limitations of LCLs for Evaluating the Pharmacogenomics ofAnticancer Agents

One limitation of LCLs or other human-derived cell lines is that they represent only one specific tissue type, which may or may not be appropriate when assessing a toxic effect that occurs in a different tissue (e.g., peripheral neuropathy, diarrhea). Another limitation is that EBV transformation can introduce phenotypic changes or expression changes that may affect the phenotype of interest. One must consider different ethnic populations when evaluating phenotype-genotype relationships, and the large pedigrees currently available are Caucasian. Despite these limitations, the cell model provides an opportunity for initial identification of important genes and variants that can be validated in further studies.

Differential Diagnosis

In contrast, neuropathic pain results from injury or disease to the peripheral or central nervous system and is characterized by pain out of proportion to tissue injury, dysesthesia, and signs of nerve injury detected during neurologic examination. As mentioned previously, psychogenic pain is characterized by pain existing with no apparent organic pathology despite extensive evaluation and commonly presents with pain inconsistent with the likely anatomic distribution. Many disease processes present with pain, thus associated pain syndromes should be part of the physician's differential diagnosis (Overcash et al. 2001). Diabetic neuropathy (Tesfaye et al. 1994) is a frequently encountered pain, characterized by burning, muscle cramps, lancinating pain, metatarsalgia, hyperalgesia, allodynia, loss of proprioception, tingling, and numbness in lower extremities. Human immunodeficiency virus (HIV) patients present with pain including neuropathic, somatic, visceral, and headache symptoms....

Alternative Therapeutic Targets in Pain Therapy

Protein Kinase C (PKC) appears to contribute to the long-term changes that underlie injury-associated allodynia and hyperalgesia. Specifically, repeated or prolonged noxious stimulation leads to activation of the PKCy isoform in the dorsal root ganglia 17 . Inhibitors of PKCy may thus possess therapeutic potential in alleviating hyperalgesia and neuropathic pain.

Opiate Receptors and Descending Inhibition of Pain Pathways

The -receptor produces more analgesia than the other types of receptors. It is also responsible for changes in respiratory activity, gastrointestinal motility, and sphincter tone produced by opiates. The -receptor is abundantly present in the dorsal horn, medulla, and the PAG. It is also responsible for pain modulation at peripheral nerve endings. Its abundance in the myenteric plexus is likely responsible for the effects of the opiates on gastrointestinal motility and sphincter tone. to become chronic. Peripheral nerves may be dysfunctional. Motor reflexes may potentiate pain. Dorsal horn can become sensitized.

Pain Augmenting Mechanisms and the Emergence of Chronic Pain

Ongoing abnormalities in peripheral tissues, with resultant inflammation, can result in activation of nociceptive pathways, rendering pain chronic. In such cases, treatment is best directed at the inflammatory mechanisms (e.g., aspirin or nonsteroidal anti-inflammatory agents). Peripheral nerves may become dysfunctional due to injury or disease (e.g., diabetes, infection, toxin exposure). Damaged neurons may fire spontaneously. Nociceptive fibers firing in this way are perceived in the CNS as signaling pain, yet in the peripheral tissues there may be no current injury. In such cases, antidepressants and anti-convulsants might be the most helpful treatment. Commensurate alterations in the thalamus and somatosensory cortex can occur after peripheral nerve injury. Thus, even after an amputation, the area of the somatosensory cortex corresponding to the amputated limb increases. Other cortical and limbic events can contribute to pain. The experience of pain can be shaped and influenced by...

Chemistry And Structureactivity Relationships Noncovalent Inhibitors

These agents share mechanism (above and Figure 8-1) but differ in their disposition in the body and their affinity for the enzyme. Edrophonium, a quaternary drug whose activity is limited to peripheral nervous system synapses, has a moderate affinity for AChE. Its volume of distribution is limited and renal elimination is rapid, accounting for its short duration of action. By contrast, tacrine and donepezil (Figure 8-2) have higher affinities for AChE and are more hydrophobic, contributing to their longer durations of action they readily cross the blood-brain barrier to inhibit AChE in the central nervous system (CNS).

Adjuvant Analgesics In Pain Therapy

Adjuvant analgesics are compounds that are not classified as analgesics, but are used clinically for the relief of pain. This class of analgesics contains a wide range of compounds that belong to a variety of chemical families. They are classified according to their use and their mechanisms of action are often not well defined. For example, antidepressants are used to control neuropathic pain, a2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine) potentiate the anti-inflammatory and analgesic effects of COX inhibitors, while corticosteroids block inflammation and may directly modulate the nociceptive action of substance P. Compounds that have been especially beneficial in the treatment of neuropathic and phantom limb pain include local anesthetics (e.g., mexiletine, flecainide), anticonvulsants (gabapentin, carbamazepine, phenytoin, valproate, clonazepam, lamotrigine), GABA agonists, neuroleptics and calcitonin. Other analgesics such as muscle relaxants and benzo-diazepines are...

Central excitatory systems

The long-term increase in pain sensitivity frequently seen following injury or peripheral nerve damage is thought to be due to both alterations in transmission within the spinal cord and to changes in descending controls that run back to the spinal cord from the brainstem. Within this circuit, nocic-eptive information is also relayed to higher centers in the brain via projection neurones. The neuroanatomy of these ascending pain pathways is highly complex, and supraspinal contacts include centers involved with the sensory-discriminative aspects of pain such as the intensity, location and duration of the stimulus as well as centers involved in the affective-cognitive aspects including anxiety, emotion and memory 61 . Importantly, these are the same areas of the brain that modulate descending serotonergic and noradren-ergic inputs from the brainstem that regulate nocic-eptive processing at spinal levels. Thus, a network of spinal and brain circuits can change spinal sensitivity Several...

Central inhibitory systems

To be responsible for both the analgesic and adverse effects of morphine 70 . The actions of clinically used opioids can now be explained in terms of their acting as agonists at one of the four opioid receptors found in the brain, spinal cord and peripheral nervous system. All opioid receptors are inhibitory. The receptors are for the endogenous opioid peptides that function as transmitters in the nervous system. Like all other peptides, they are synthesized as large inactive precursors in the neuronal cell body and transported to the terminal, with processing en route yielding the active fragment which is then released into the synapse and activates the appropriate receptors. Morphine activates opioid receptors to a much greater extent than the opioid peptides and so produces profound analgesia. Most of the data concerning morphine analgesia have been derived from studies of patients with cancer pain, since its therapeutic potential for the treatment of neuropathic pain has been...

Delta Knockout Mice Behavior Nociceptive and Emotional Responses

Nociceptive thresholds have been examined in response to acute painful stimuli. First studies showed no change in responses to thermal, mechanical, visceral, and inflammatory pain 52,53 . A more extensive study with separate gender analysis later indicated modest but significant increased nociception in the tail pressure test, as well as in the late phase of the formalin test, but in females only 69 . These data, together with results using mice lacking mu and kappa receptors see 56,69 , suggest a modest opioid tone in modulating acute noxious information, with delta receptors contributing the least. In the future, models of chronic inflammation or neuropathic pain applied to the knockout animals may reveal a significant contribution of delta receptors in adaptive

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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