Neuropathic syndromes

TABLE 36-2 Antibody -mediated PNS disorders Neuropathic syndrome... 

Several psychosomatic disorders may respond at least partly to treatment with tricyclic antidepressants, MAO inhibitors, or SSRIs among these are chronic pain disorders, including diabetic and other peripheral neuropathic syndromes (for which tertiary-amine tricyclics probably are... 

Diabetic neuropathy is characterized by a spectrum of clinical neuropathic syndromes, which includes dysfunction of almost every segment of the somatic peripheral and autonomic nervous system. Diabetic neuropathy is classified as either mononeuropathy... 

Antiepileptics are used in neuropathic pain resulting from lesions to the peripheral (e.g., diabetes, heipes) or central nervous system (e.g., stroke). Such syndromes have been attributed to ectopic activity in sensitized nociceptors from regenerating nerve sprouts, recruitment of previously silent nociceptors, and/or spontaneous neuronal activity. This may result in sensitization... 

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

In the peripheral nervous system (PNS), HIV-1 infection and its treatment using HAART are associated with the development of neuropathic pain syndromes characterized by severe lancinating pain as well as parathesias and burning pain in the extremities. Damage to peripheral nerves has been associated with these syndromes. HIV-1-associated polyneuropathy has become the most common neurological complication of HIV-1 infection (Pardo et al. 2001). More than half of individuals with... 

The mechanisms of pain and the ability to control pain may vary in different pain states. This is of particular importance in consideration of a rational basis for the treatment of both inflammatory and neuropathic pain where the damage to tissue and nerve leads to alterations in both the peripheral and central mechanisms of pain signalling. In respect of existing drug therapies, this plasticity, the ability of the system to change in the face of a particular pain syndrome, explains the effectiveness of NSAIDs in inflammatory conditions and yet is also responsible for some of the limitations in the effectiveness of opioids in neuropathic pain. 

Association of Pain, neuropathic pain is defined as pain initiated or caused by a primary lesion, dysfunction in the nervous system". Neuropathy can be divided broadly into peripheral and central neuropathic pain, depending on whether the primary lesion or dysfunction is situated in the peripheral or central nervous system. In the periphery, neuropathic pain can result from disease or inflammatory states that affect peripheral nerves (e.g. diabetes mellitus, herpes zoster, HIV) or alternatively due to neuroma formation (amputation, nerve transection), nerve compression (e.g. tumours, entrapment) or other injuries (e.g. nerve crush, trauma). Central pain syndromes, on the other hand, result from alterations in different regions of the brain or the spinal cord. Examples include tumour or trauma affecting particular CNS structures (e.g. brainstem and thalamus) or spinal cord injury. Both the symptoms and origins of neuropathic pain are extremely diverse. Due to this variability, neuropathic pain syndromes are often difficult to treat. Some of the clinical symptoms associated with this condition include spontaneous pain, tactile allodynia (touch-evoked pain), hyperalgesia (enhanced responses to a painful stimulus) and sensory deficits. 

Neuropathic pain is defined as spontaneous pain and hypersensitivity to pain associated with damage to or pathologic changes in the peripheral nervous system as in painful diabetic peripheral neuropathy (DPN), acquired immunodeficiency syndrome (AIDS), polyneuropathy, post-herpetic neuralgia (PHN) or pain originating in the central nervous system (CNS), that which occurs with spinal cord injury, multiple sclerosis, and stroke. Functional pain, a relatively newer concept, is pain sensitivity due to an abnormal processing or function of the central nervous system in response to normal stimuli. Several conditions considered to have this abnormal sensitivity or hyperresponsiveness include fibromyalgia and irritable bowel syndrome. 

Hereditary triose phosphate isomerase (TPI) deficiency is an autosomal recessive disorder that has the most severe clinical manifestations of the erythroenzy-mopathies, including hemolytic anemia, neurological dysfunction, sudden cardiac death, and increased susceptibility to infection. Since the first description by Schneider et al. (S10), more than 25 unrelated families have been reported (Fll). Cases of decreased TPI activities associated with cat cry syndrome and pancytopenia were reported, whereas the correlation between TPI deficiency and these disorders was not clear. Although the degree of anemia is variable, most patients require blood transfusions. Neurological involvement, such as paraparesis, weakness, and hypotonia, is progressive in most cases. No specific therapy is available for the neuropathic manifestations of the disease, and most severely affected children fail to survive beyond the age of 5 years. 

Features of central sensitization are pain in response to normally innocuous tactile stimuli, and the spread of pain sensitivity beyond the site of tissue injury. Central sensitization plays a major role in acute post-traumatic pain, and also in migraine, neuropathic pain (see below) and some diffuse chronic pain syndromes, such as fibromyalgia and irritable bowel syndrome. In these conditions, which have no detectable peripheral trigger, an autonomous central sensitization may be the pathology, increasing the gain in neuronal activity in the CNS and thereby producing abnormal responses to normal inputs. 

Neuropathic and functional pain is often described in terms of chronic pain. Neuropathic pain (e.g., postherpetic neuralgia, diabetic neuropathy) is a result of nerve damage, but functional pain (e.g., fibromyalgia, irritable bowel syndrome, tension-type headache) refers to abnormal operation of the nervous system. Pain circuits may rewire themselves and produce spontaneous nerve stimulation. 

Milnacipran is currently available for use as an antidepressant in several countries outside the U.S. It is also under clinical development to assess its potential role in the treatment of fibromyalgia syndrome [62,63]. In a rat model of neuropathic pain, milnacipran, administered intrathecally, produced dose-dependent anti-allodynic effects at doses between 3 and 100 gg for up to 7h [64], The anti-allodynic effect of 30 gg of milnacipran was attenuated by intrathecal coadministration of a serotonin receptor antagonist or a norepinephrine receptor... 

One of the metabolites of bupropion, radafaxine (GW 353162, 25), is being studied as a treatment for obesity in clinic trials [76]. It is also reported to be in clinical development for restless leg syndrome, neuropathic pain, bipolar disorder and fibromyalgia [68]. 

The recent approval of the SNRI duloxetine for the treatment of diabetic neuropathy reinforces the utility of this drug class in the treatment of neuropathic pain. Other largely untapped areas which remain to be exploited with this drug class include sexual dysfunction, such as premature ejaculation, irritable bowel syndrome, obesity, neurodegenerative diseases such as Parkinson s disease, restless leg syndrome, and substance abuse and addiction. It is apparent that considerable opportunities for drug discovery will exist in this area for some time to come. 

Neuroanatomically both the locus coeruleus and the raphe nuclei project to the spinal cord where they gate sensory pathways from the skeletomuscular areas. As there is evidence that both noradrenaline and 5-HT are dysfunctional in depression, it is perhaps not surprising to find that the pain threshold is often reduced in patients with depression. Conversely, different types of antidepressants have been shown to have an antinociceptive effect in both rodent models of neuropathic pain, and clinically in fibromyalgia, chronic fatigue syndrome, postherpetic neuralgia and diabetic neuropathy. In general, it would appear that the dual action antidepressants (such as the TCAs and SNRIs) are more effective than the SSRIs. 

Because of sensory neuropathy, deep pain is often experienced by patients given vincristine. Through involvement of the glossopharyngeal nerve, throat pain may occur, as may deep pain of almost any other area of the body (31,32). Neuropathic changes are not always peripheral. Hallucinations and overall mental status changes, such as depression and/or psychosis, are also rarely reported (31,32). Another CNS effect is the syndrome of inappropriate antidiuretic hormone secretion, which is a well-characterized side effect of vincristine (31,32). 

Some authors believe that neuropathic effects of vincristine are greatly exacerbated in patients with underlying neuropathy, such as in those with Marie-Charcot syndrome. This is based on experience with one patient who developed bulbar paralysis following vincristine injection. Some authors believe this reaction to have been idiosyncratic and report successful treatment of patients with underlying neuropathies with vincristine without untoward effects. At the least, extreme caution and careful consideration of alternate therapies seems reasonable in such patients (31,32). In either case, the neurologic symptoms are so common they should not limit the use of this agent, which in early studies was well tolerated at a weekly dose of 3.5 mg. 

Neuropathic disorders Administer with caution in individuals with peripheral motor neuropathic diseases (eg, amyotrophic lateral sclerosis, motor neuropathy) or neuromuscular junctional disorders (eg, myasthenia gravis, Lambert-Eaton syndrome). Patients with neuromuscular disorders may be at increased risk of clinically significant P.787... 

Other Uses in Geriatric Patient Anxiety symptoms and related disorders, dementia-related behavioral problems, neuropathic pain, restless legs syndrome... 

Since local anesthetics have membrane-stabilizing effects, both parenteral (eg, intravenous lidocaine) and oral (eg, mexiletine, tocainide) formulations of local anesthetics have been used to treat patients with neuropathic pain syndromes because these syndromes are thought to involve uncontrolled, rapid, sensory fiber firing. Systemic local anesthetic drugs are commonly used as adjuvants to the combination of a tricyclic antidepressant (eg, amitriptyline) and an anticonvulsant (eg, carbamazepine) in chronic pain patients who fail to respond to the combination of antidepressant and anticonvulsant. 

McQuay, H. J. and Moore, R. A. Antidepressants and chronic pain - effective analgesia in neuropathic pain and other syndromes, Br. Med. J. 1997, 314, 763-764. 

Mexilitine has analgesic properties in several neuropathic pain syndromes and is an alternative agent for treatment of patients who fail to respond to tricyclic antidepressants or who cannot tolerate them... 

Tremont-Lukats, I. W., Megeff, C., Backonja, M. M. Anticonvulsants for neuropathic pain syndromes mechanisms of action and place in therapy, Drugs 2000, 60, 1029-1059. 

This ability to test drugs in contexts other than acute pain models has arisen from good communication between bench scientists, clinicians and industry. Until recently investigations into the mechanisms of clinical pain syndromes all relied on animal studies using acute stimuli. The symptoms of pain arising from nerve injury, neuropathic pain, such as allodynia, spontaneous pain, hyperalgesia, sensory deficits and in some cases a sympathetic component are simply not seen in the older acute models. There are now several animal models which mimic peripheral and central neuropathic states. The same is true for inflammation. 

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