Visceral Pain: Mechanisms of Peripheral and Central Sensitization

This paper describes the responses of peripheral and central visceral nociceptive systems to acute injury and discusses these observations in relation to the concept of 'pre-emptive analgesia'. Visceral nociceptors are known to respond to injury but are also known to become sensitized to non-noxious stimuli during the inflammatory process that follows intense noxious stimulation. The afferent barrages triggered in visceral nociceptors by the acute injury and the enhanced responses evoked in sensitized nociceptors during the repair process can, in turn, increase the excitability of central nociceptive systems. The maintenance of central hypersensitivity is, however, dependant on the continuing presence of afferent volleys from sensitized nociceptors because the central changes cannot be sustained in the absence of a peripheral drive. Therefore it is proposed that the concept of 'pre-emptive analgesia', as such, has no neurophysiological basis. Any analgesic procedure aimed at reducing postoperative pain must not only prevent the arrival in the CNS of the initial afferent barrage evoked in nociceptive endings but also reduce or eliminate the persistent discharges of sensitized nociceptors during the inflammatory repair process that are critically important for the maintenance of the central pain state.     

Neuropathic Pain: Mechanisms and Treatment Options

Abstract : Neuropathic pain results from damage to the nervous system. The diseases responsible for neuropathic pain are diverse but they may have in common pathophysiological mechanisms. This review will focus on these mechanisms both in the peripheral as well as within the central nervous system. In addition, there will be discussion on the various treatment choices including both pharamcological and interventional options.     

Peripheral Acute Pain Mechanisms

Many studies in several species, including humans, have identified a subset of primary afferent nerve fibres that are activated by potential or actual tissue-damaging stimuli. Discharge patterns of these nociceptive afferents faithfully reproduce some aspects of the applied stimuli (e.g. shape of the stimulus-response function) but not others (e.g. time-course of a sustained stimulus). Since primary nociceptive afferents provide the input to the central nervous system, their encoding properties have to be considered when studying central processing. On the other hand, pain perception correlates with some aspects of nociceptor discharges (e.g. fatigue with repetition of brief heat pulses), but not with others (e.g. absolute thresholds). Therefore, the painfulness of a stimulus cannot be deduced from nociceptor discharges alone; central processing needs to be taken into account, particularly central summation. In addition to the immediate responses of nociceptive afferents to external stimulation, acute pain mechanisms also comprise the short-term plasticity of the nociceptive system as a consequence of prolonged noxious stimulation     

Transdermal Buprenorphine for Central Neuropathic Pain: Clinical Reports

Transdermal buprenorphine is an effective analgesic for a variety of pain conditions. Traditionally, neuropathic pain is treated with medications such as tricyclic antidepressants or anticonvulsants, with opioid medications as second or third‐line agents. We present two different painful conditions of presumed neuropathic origin, with complex etiopathogenesis, which were successfully treated with buprenorphine. The results of treatment of these neuropathic pain syndromes with buprenorphine are encouraging, suggesting that it might represent a valid alternative to standard approaches for central neuropathic pain.     

Meteorin Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Mice

Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4 mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (.5 and 1.8 mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin ( .5 and 1.8 mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the dorsal root ganglion. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for chemotherapy-induced peripheral neuropathy treatment.PerspectiveChemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.     

AAPT Diagnostic Criteria for Central Neuropathic Pain

Central neuropathic pain, which is pain caused by a lesion or disease of the central somatosensory nervous system, is a serious consequence of spinal cord injury, stroke, multiple sclerosis, and other conditions affecting the central nervous system. A collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative, invited a working group to develop diagnostic criteria for central neuropathic pain. The criteria for central neuropathic pain that were developed expand upon existing criteria for neuropathic pain and the International Classification of Diseases 11th Revision draft criteria to ensure consistency. This article focuses on central neuropathic pain associated with spinal cord injury, stroke, and multiple sclerosis, but the AAPT framework can be extended to central pain due to other causes such as traumatic brain injury. The classification of central neuropathic pain is organized according to the AAPT multidimensional framework, specifically: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, and functional consequences, and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Central Acute Pain Mechanisms

This account will consider the events occurring in the spinal cord that give rise to acute pain. The transmission and control of acute pain is not immutable but subject to plasticity so that the dividing line between acute and chronic pain is difficult to draw. Very brief acute pain is transmitted in a simple way and rarely produces difficulties in treatment. The situation within the spinal cord changes if the stimulus continues. After only seconds of C-fibre stimulation, additional peptides are released from C fibres, and spinal N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide production occur. Soon after, genes are induced in central neurones, and increases and decreases in diverse pharmacological systems involved in pain transmission and modulation occur over periods of only a few hours. This rapid plasticity has important implications for the pharmacological treatment of acute because both the level of pain transmission and pain modulation will be altering over time.     

Current Approaches to the Management of Peripheral Neuropathic Pain

Symptoms and signs of neuropathic pain can be both positive and negative. Tricyclic antidepressants are the first-line treatment option for neuropathic pain. Opioid agonists have demonstrated efficacy in patients with neuropathic pain. Combination therapy in the management of neuropathic pain is not well researched.

?This report is adapted from paineurope 2015: Issue 1, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be viewed via the Web site: www.paineurope.com, at which health professionals can find links to the original articles and request copies of the quarterly publication and access additional pain education and pain management resources.     

AAPT Diagnostic Criteria for Peripheral Neuropathic Pain: Focal and Segmental Disorders

Peripheral neuropathic pain is among the most prevalent types of neuropathic pain. No comprehensive peripheral neuropathic pain classification system that incorporates contemporary clinical, diagnostic, biological, and psychological information exists. To address this need, this article covers the taxonomy for 4 focal or segmental peripheral neuropathic pain disorders, as part of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS) collaborative to develop a standardized, evidence-based taxonomy initiative: the ACTTION-APS Pain Taxonomy (AAPT). The disorders—postherpetic neuralgia, persistent posttraumatic neuropathic pain, complex regional pain disorder, and trigeminal neuralgia—were selected because of their clinical and clinical research relevance. The multidimensional features of the taxonomy are suitable for clinical trials and can also facilitate hypothesis-driven case-control and cohort epidemiologic studies.

Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain in Rodents

Physical exercise is often recommended to patients who have chronic pain. However, only a small number of studies report exercise-induced analgesia in the setting of inflammatory pain, and even fewer relate long-term exercise to reductions in neuropathic pain. To address these questions, we evaluated the effect of extended swimming exercise in animal models of inflammatory (intraplantar injection of dilute formalin) and neuropathic (partial peripheral nerve injury) pain. We found that 9 days of swimming exercise in 37 degrees C water for 90 min/d decreased licking and flinching responses to formalin, as compared with nonexercised control animals. In addition, 18 to 25 days of swimming decreased nerve injury-induced cold allodynia and thermal hyperalgesia in rats, and 7 days of swimming decreased nerve injury-induced thermal hyperalgesia in mice. Our data indicate that swimming exercise reduces behavioral hypersensitivity in formalin- and nerve injury-induced animal models of persistent pain. PERSPECTIVE: Surprisingly, few animal studies have investigated the effects of extended exercise on chronic pain. Our results support the use of exercise as a nonpharmacological approach for the management of peripheral neuropathic pain.     

A Comprehensive Drug Safety Evaluation of Pregabalin in Peripheral Neuropathic Pain

Pregabalin is a commonly used therapy currently recommended as first‐line treatment for a number of neuropathic pain (NeP) conditions. Since licensure, a number of clinical trials of pregabalin in different NeP conditions have been completed from which additional data on safety and tolerability can be drawn. In this analysis, patient‐level data from 31 randomized clinical trials of pregabalin in peripheral NeP sponsored by Pfizer were pooled and assessed for incidence of adverse events (AEs). Incidence by age, disease condition, and race, together with risk differences and time to onset and resolution of AEs, was assessed. In total, 7,510 patients were included: 4,884 on pregabalin (representing 805 patient‐years treatment) and 2,626 on placebo. Pregabalin vs. placebo risk analysis identified 9 AEs with a risk difference, for which the lower limit of the 95% confidence interval (CI) was > 1%: dizziness (risk difference [95% CI]: (17.0 [15.4 to 18.6]), somnolence (10.8 [9.5 to 12.1]), peripheral edema (5.4 [4.3 to 6.4]), weight increase (4.7 [3.9 to 5.5]), dry mouth (2.9 [2.1 to 3.8]), constipation (2.3 [1.5 to 3.2]), blurred vision (2.2 [1.6 to 2.9]), balance disorder (2.0 [1.5 to 2.5]), and euphoric mood (1.6 [1.2 to 2.0]). The most common AEs, dizziness and somnolence, typically emerged within the first 1 to 2 weeks of treatment and resolved 1 to 2 weeks later, without resulting in cessation of treatment. The data from this review provide information, indicating which AEs may be expected in patients treated with pregabalin, and suggest that careful dose titration to the highest tolerable dose is the most appropriate approach in clinical practice.     

IASP关节痛文献资料,《中国疼痛医学杂志》组织翻译第十七篇:关节痛的神经病理性机制与症状:对评估和处理的影响

<正>关节痛常被认为是一种单纯的伤害性疼痛,也是一种评价伤害性疼痛镇痛药例如非甾体抗炎药和阿片类药物的模型。最新研究表明关节痛患者常伴有神经病理症状,关节痛包含神经病理学机制。这为评价和处理关节痛提供了新的思路。关节痛的神经病理性临床特征很多研究表明,关节痛患者有神经病理性疼痛症状。就骨关节炎而言,一些研究表明疼痛特性显示出一些神经病理性疼痛的特征(Cedraschi et al,2013)。     

Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.     

Neuropathic Pain Syndrome

Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. This article provides information to patients regarding the treatment of neuropathic pain syndrome. It narrates how a doctor might explain neuropathic pain to a patient and particularly discusses the use of anticonvulsants.