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At least 19 recordsLinked to original sources

PubMed2004

Pathophysiology of neuropathic pain.

Neuropathic pain is caused by damage to the nervous system. Unlike physiologic pain (also known as nociceptive pain), neuropathic pain is not self-limited and is not as easily treated. The etiologic causes of neuropathic pain are many and varied in their scope. These include infectious agents, metabolic disease, neurodegenerative disease, and physical trauma, among others. Clinically, a high degree of variability exists between patients in their response to treatment. The pathophysiology of neuropathic pain syndromes is complex. However, current research is rapidly expanding our understanding of these syndromes. Numerous cellular mechanisms of pain transmission have been elucidated, and the clinical correlates of these mechanisms are beginning to be recognized. As our knowledge base continues to grow, we anticipate the development of improved treatments for the benefit of our patients with pain.

Afferent Pathways↗

PubMed2005

Antidepressants in the treatment of neuropathic pain.

Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class--may among the antidepressants--favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.

Analgesics, Non-Narcotic↗

PubMed2005

[Assessment of neuropathic pain].

Neuropathic pain is underdiagnosed and, in consequence, not properly treated. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. The term dysfunction is not clearly defined and is suggested not used. The prevalence of neuropathic pain is unknown, but a few detailed studies show that neuropathic pain is more common than previously assumed. Some common causes of neuropathic pain are entrapment/injuries to peripheral nerves, painful neuropathies, infections in the nervous system (i.e. postherpetic neuralgia), spinal cord injuries, multiple sclerosis and cerebral infarcts. Evaluation of neuropathic pain is performed on the basis of a thorough clinical examination which includes detailed questioning of different types of pain. Both spontaneous (ongoing and paroxysmal) as well as evoked pain may occur. The ongoing pain may be described by a large number of adjectives such as burning, aching, throbbing, sore, cutting, but there is no pain descriptor which is diagnostic for neuropathic pain. Pain may usually be evoked by lightly touching the skin or by exposure to cold. A clinical neurological examination is necessary in the evaluation of the level of injury, possibly also electromyography/neurography in case of peripheral nerve lesions or CT/MR in case of central lesions. Neuropathic pain is almost always characterised by changes in sensibility, usually involving the thin-fibre system (peripheral nerve fibres or central projections). Special emphasis is put on the examination of sensory dysfunction.

Central Nervous System Diseases↗

PubMed2005

Challenges in the development of novel treatment strategies for neuropathic pain.

Neuropathic pain might best be considered as a collection of various pain states with a common feature, that being symptoms suggestive of dysfunction of peripheral nerves. The development of therapeutic options for the treatment of neuropathic pain is complicated significantly by several factors. Neuropathic pain may arise from widely diverse etiologies such as physical trauma, disease, infection, or chemotherapy. Symptoms indicative of neuropathic pain may also arise in individuals with no evidence of any type of nerve trauma (idiopathic). Although neuropathic pain is a substantial health care issue, it is relatively uncommon and only occurs in a small fraction (<10%) of individuals with these initiating factors. Moreover, the efficacy of treatment protocols, even against the same type of symptoms, differ depending on the underlying initiating cause of the neuropathy. Although these observations strongly suggest that there are predisposing factors that may impart susceptibility to the development of neuropathic pain, no common predisposing factors or genetic markers have been satisfactorily identified. Because of these vagaries, treatment of neuropathic pain has been based on trial and error. However, recent progress in the understanding of neurophysiologic changes that accompany peripheral nerve dysfunction indicate that regulation of ion channels that maintain membrane potentials or generate action potentials may provide an important therapeutic approach. Neuropathic pain is accompanied by increased activity of peripheral nociceptors, which is produced in part by changes in levels of specific calcium and sodium channels. The identification of sodium and/or calcium channels subtypes that are expressed almost exclusively on nociceptors may provide a way of regulating the activity of exaggerated nociceptor function without altering other sensory modalities. Thus, the selective targeting of ion channels may represent a viable therapeutic target for the management of the neuropathic pain state, regardless of etiology.

Analgesics↗

PubMed2005

Possible involvement of brain-derived neurotrophic factor in the antinociceptive effect of antidepressants in neuropathic pain.

Neuropathic pain, a chronic pain state caused by injury to the nervous system, usually responds poorly to standard pain treatment. Antidepressants have been used to treat neuropathic pain, and animal and clinical studies have showed beneficial effects. However, the mechanisms underlying antidepressant antinociceptive effect in neuropathic pain are still unknown. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent animal and human studies have demonstrated that antidepressants can increase central as well as plasma BDNF levels. In addition: (1) BDNF is produced by a subset of primary sensory neurons that are located in the dorsal root ganglion; (2) BDNF levels change in animal models of neuropathic pain; (3) BDNF can indirectly depress sensory neuron transmission in the dorsal horn. From these findings, it is proposed that BDNF may play an important role in the antidepressant antinociceptive effect in neuropathic pain. The notion of BDNF mediating the therapeutic mechanisms of antidepressant in neuropathic pain may help to select the specific type and the optimal dose of antidepressants for the treatment of neuropathic pain. Exploration of this hypothesis could provide a new direction in the treatment of neuropathic pain, as well as other pain disorders.

Analgesics↗

PubMed2000

Drug treatment of neuropathic pain.

Neuropathic pain results from damage to or dysfunction in the nervous system. The term usually refers to pain caused by a primary abnormality in the peripheral nervous system, while pain caused by damage to the central nervous system tends to be called central pain. Once established, neuropathic pain frequently runs a chronic course and can be severe and difficult to treat. Most doctors (but especially GPs, neurologists, neurosurgeons, oncologists and pain clinic specialists) will encounter patients with neuropathic pain. Management, ideally in a multidisciplinary pain-relief clinic, often involves the combined use of a range of pharmacological and non-drug approaches, the latter including transcutaneous electrical nerve stimulation, psychological treatments, and specialist procedures to stimulate, block or destroy discrete areas of the nervous system. Here, we review just the drug treatments for neuropathic pain.

Aged↗

PubMed2001

Pharmacologic treatment of neuropathic pain.

Neuropathic pain, or pain after nervous system injury, can be very refractory to pharmacologic interventions. Through a better understanding of the pathophysiology of neuropathic pain, it has been suggested that nonopioid agents, such as antidepressants and anticonvulsants, may be more efficacious in the treatment of neuropathic pain than common analgesics, such as opioids or nonsteroidal anti-inflammatory drugs. However, this has not been consistently demonstrated in clinical studies. Conversely, many confounding factors of neuropathic pain make it difficult to interpret clinical studies. Therefore, we must develop a better understanding of the preclinical models of neuropathic pain to better understand the application of new and old drugs to the human neuropathic pain state. This article provides an overview of the commonly used preclinical neuropathic pain models, followed by a summary of the efficacy of currently available agents in preclinical pain models and human correlates.

Analgesics↗

PubMed1998

Cancer-related neuropathic pain.

Neuropathic pain refers to syndromes that may be related to peripheral or central neural structure compression, infiltration, or damage. Cancer-related neuropathic pain results from compression or infiltration of nerves by the tumor, nerve trauma from operative procedures, or neuropathic pain related to cancer treatment. Management of neuropathic pain includes the use of opioids, antidepressants, anticonvulsants, local anesthetics, and other adjuvant medications. Intractable neuropathic pain may require the use of intraspinal delivery or anesthetic and neurosurgical procedures. The nurse practitioner plays an important role in the assessment and "trial and error" management of cancer-related neuropathic pain.

Analgesics↗

PubMed2005

Emerging therapies for neuropathic pain.

Neuropathic pain develops as a result of damage to either the peripheral or central nervous system. It is characterised by spontaneous burning pain and/or ongoing pain with accompanying hyperalgesia and allodynia. Neuropathic pain is difficult to treat as it is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief. At present, there are four major medication categories that are considered first-line treatment for neuropathic pain: antidepressants, anticonvulsants, local anaesthetic/topical agents and opioids. The efficacy of these treatments in neuropathic pain, excepting opioids, has been discovered serendipitously. However, responder rates and overall efficacy is poor with these agents and tolerability or side effects are often limiting. This update will review existing treatment options for neuropathic pain, and highlight more recent advances in the development of novel analgesics to treat this chronic disorder.

Analgesics↗

PubMed2006

Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain.

Neuropathic pain is a major clinical problem unresolved by available therapeutics. Spinal cord glia play a pivotal role in neuropathic pain, via the release of proinflammatory cytokines. Anti-inflammatory cytokines, like interleukin-10 (IL-10), suppress proinflammatory cytokines. Thus, IL-10 may provide a means for controlling glial amplification of pain. We recently documented that intrathecal IL-10 protein resolves neuropathic pain, albeit briefly (approximately 2-3 h), given its short half-life. Intrathecal gene therapy using viruses encoding IL-10 can also resolve neuropathic pain, but for only approximately 2 weeks. Here, we report a novel approach that dramatically increases the efficacy of intrathecal IL-10 gene therapy. Repeated intrathecal delivery of plasmid DNA vectors encoding IL-10 (pDNA-IL-10) abolished neuropathic pain for greater than 40 days. Naked pDNA-IL-10 reversed chronic constriction injury (CCI)-induced allodynia both shortly after nerve injury as well as 2 months later. This supports that spinal proinflammatory cytokines are important in both the initiation and maintenance of neuropathic pain. Importantly, pDNA-IL-10 gene therapy reversed mechanical allodynia induced by CCI, returning rats to normal pain responsiveness, without additional analgesia. Together, these data suggest that intrathecal IL-10 gene therapy may provide a novel approach for prolonged clinical pain control.

Animals↗

PubMed2005

Topical analgesics in neuropathic pain.

Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, alpha-adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of novel topical analgesics for this condition.

Administration, Topical↗

PubMed2003

Neurotrophic factors as novel therapeutics for neuropathic pain.

Neuropathic pain is a chronic condition that is caused by injury to the nervous system. Unlike acute pain, which is protective, neuropathic pain persists and serves no useful purpose, and severely affects quality of life. However, present therapies have modest efficacy in most patients, are palliative rather than curative, and their side effects represent significant limitations. Tremendous progress has been made over the past decade in our understanding of the biology of pain sensory neurons. The recent discovery that neurotrophic factors play an important role in neuropathic pain indicates that these pathways could serve as novel intervention points for therapy. Moreover, neurotrophic factors have the potential to address the underlying pathophysiology of neuropathic pain, thereby halting or reversing the disease process.

Animals↗

PubMed2007

Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain.

Neuropathic pain is typified by injuries to the peripheral and central nervous system and derives from such causes as cancer, diabetes, multiple sclerosis, post-herpetic neuralgia, physical trauma or surgery, and many others. Patients suffering neuropathic pain do not respond to conventional treatment with non-steroidal anti-inflammatory drugs and show a reduced sensitivity to opiates often associated with serious side effects. Recently, it has been demonstrated that botulinum neurotoxin serotype-A (BoNT/A) is able to induce analgesia in inflammatory pain conditions. The goal of this research was to test if BoNT/A was able to relieve also neuropathic pain symptoms. By using chronic constriction injury of the sciatic nerve, a mouse model of neuropathic pain, we observed that peripheral administration of BoNT/A strongly reduced the mechanical allodynia associated with this neuropathy. Remarkably, a single non-toxic dose of BoNT/A was sufficient to induce anti-allodynic effects, which lasted for at least 3 weeks. This result is particularly relevant since neuropathic pain is poorly treated by current drug therapies. This communication enlarges our knowledge on potentially new medical uses of BoNT/A in efforts to ameliorate human health conditions, with very important implications in the development of new pharmacotherapeutic approaches against neuropathic pain.

Analysis of Variance↗

PubMed2002

A role of the ubiquitin-proteasome system in neuropathic pain.

Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.

Action Potentials↗

PubMed2003

Unmet needs in the management of neuropathic pain.

Neuropathic pain is a challenging condition to treat. It is heterogeneous in nature and largely resistant to treatment with commonly prescribed analgesics. Current management strategies fail to achieve adequate or satisfactory pain relief in a high proportion of patients. The four main reasons that treatments for neuropathic pain fail are: inadequate diagnosis and a lack of appreciation of the mechanisms involved; insufficient management of comorbid conditions; incorrect understanding or selection of treatment options; and the use of inappropriate outcomes measures. These unmet needs in the current management of neuropathic pain are reviewed in this article. The review focuses on the need for a methodical and mechanistic approach to diagnosis, and a flexible, interdisciplinary approach to treatment of neuropathic pain conditions, in order to improve pain relief and quality of life in patients with neuropathic pain.

Anti-Arrhythmia Agents↗

PubMed2000

Topical ketamine gel: possible role in treating neuropathic pain.

Neuropathic pain is often resistant to opioids, so other medication classes, such as tricyclic antidepressants, anticonvulsants, and local anesthetics, are often used. Central sensitization, or pain 'wind-up', may perpetuate chronic neuropathic pain even when ongoing peripheral sensory input is absent. Wind-up is thought to cause allodynia, hyperalgesia, and hyperpathia. Receptors such as NMDA, AMPA, and M-glu have recently been identified for their role in central sensitization or pain 'wind-up'. Ketamine has been proposed recently for neuropathic pain secondary to its NMDA receptor activity. The current application as a topical gel stems from the theory that ketamine has peripheral action at both opioid and Na+-K+ channels. This case study involved 5 patients from 25 to 70 years old (3 RSD, 1 lumbar radiculopathy, 1 post-herpetic neuralgia). Dose used was determined by site and surface area of involvement and ranged from 0.093 mg/kg to 9.33 mg/kg. All five patients reported significant pain relief at initial application and wished to continue treatment. The average numerical analogue scale (NAS) score preapplication was 8.8. The average 15 minutes post application NAS was 1.6. Patients reported alterations in temperature sensation, feelings of relaxation and decreased tension in the area of application, and pain relief. Reduction in numerical pain scores postapplication of ketamine gel ranged from 53-100% using a 1-10 numerical pain intensity scale. No significant side effects were reported. Ketamine Gel may provide clinicians with a new option in the battle against chronic neuropathic pain. Until further information is available and larger trials can be conducted, we can only recommend this type of therapy for refractory cases in which all primary and secondary options have been exhausted.

Journal Article↗

PubMed2003

HSV-mediated gene transfer of the glial cell-derived neurotrophic factor provides an antiallodynic effect on neuropathic pain.

Neuropathic pain is a difficult clinical problem that is often refractory to medical management. Glial-derived neurotrophic factor (GDNF) administered intrathecally has been shown to prevent or reduce pain in an animal model of neuropathic pain, but cannot be delivered in the required doses to treat human pain. We have previously demonstrated that peripheral subcutaneous inoculation of a replication-incompetent herpes simplex virus (HSV)-based vector can be used to transduce neurons of the dorsal root ganglion. To examine whether HSV-mediated expression of GDNF could be used to ameliorate neuropathic pain, we constructed a replication-incompetent HSV vector expressing GDNF. Subcutaneous inoculation of the vector 1 week after spinal nerve ligation resulted in a continuous antiallodynic effect that was maintained for 3-4 weeks. Reinoculation of the vector reestablished the antiallodynic effect with a magnitude that was at least equivalent to the initial effect. Vector-mediated GDNF expression blocked the nonnoxious touch-induced increase in c-fos expression in dorsal horn characteristic of the painful state. Gene transfer to produce a trophic factor offers a novel approach to the treatment of neuropathic pain that may be appropriate for human therapy.

Animals↗

PubMed2006

EFNS guidelines on pharmacological treatment of neuropathic pain.

Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools.

AIDS-Associated Nephropathy↗