Renal impairment and analgesia: From effectiveness to adverse effects

Kidney pain is one of the clinically significant features of renal dysfunction. Mild to severe pain is seen in the lower back area. Painkillers are mostly recommended in these cases to relieve the symptom. Yet, several analgesics are associated with side effects that can worsen the state of the disease. This review is based on the studies conducted in these aspects analgesics used to treat kidney pain and their effectiveness, renal consequences of postoperative analgesia, and pharmacogenetics of these palliatives are briefly summarized in this paper.     

Intracellular Signaling in Primary Sensory Neurons and Persistent Pain

During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Aδ-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-α, IL-1β), PGE₂, bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Na_v1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source. Special issue article in honor of Dr. Ji-Sheng Han.     

四肢骨折矫形术后患者慢性手术后疼痛的发生率及其危险因素分析

目的:研究四肢骨折矫形术后患者慢性手术后疼痛的发生率及其危险因素。方法:以2014年12月-2017年10月于我院接受四肢骨折矫形术患者300例为研究对象,于术后6个月分析慢性手术后疼痛的发生率。收集所有患者年龄、性别、体重、术前疼痛程度、二次手术、麻醉方式、术后镇痛、术后引流、合并骨质疏松、骨折类型以及骨折部位等资料,并采用单因素以及多因素Logistic回归分析术后疼痛的危险因素。结果:术后6个月内有96名患者术后发生慢性手术后疼痛,发生率为32.00%(96/300)。单因素分析结果显示:慢性手术后疼痛患者与术前疼痛程度、是否二次手术、麻醉方式、术后有无镇痛、是否合并骨质疏松、骨折类型、骨折部位有关(P0.05),与患者的性别、年龄、体重、术后是否引流无关(P0.05)。多因素Logistic回归分析结果显示:术前重度疼痛、二次手术、麻醉方式为非全麻、术后无镇痛、合并骨质疏松、开放性骨折以及下肢骨折均是四肢骨折矫形术后发生慢性手术后疼痛的独立危险因素(P0.05)。结论:四肢骨折矫形术后患者慢性手术后疼痛的发生率较高,术前重度疼痛、二次手术、麻醉方式为非全麻、术后无镇痛、合并骨质疏松、开放性骨折以及下肢骨折均增加了慢性手术后疼痛的发生风险,临床应根据危险因素给予针对性的干预措施。     

NO在脊髓痛觉传递过程中的作用

一氧化氮(nitric oxide,NO)是神经元细胞内一种新型的神经递质,它参与多种生命活动,包括脊髓水平的伤害性信息传递过程。研究NO在伤害性信息传递过程中的作用及其机制,有利于阐明痛觉生理和发现疼痛治疗的新手段。本文将NO在慢性痛脊髓伤害性信息传递中的作用及其机制的相关研究进展作一综述。     

Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain

BACKGROUND: Chronic established pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. New insights are urgently required, and we reasoned that endogenous processes such as cooling-induced analgesia may point the way to novel strategies for intervention. Molecular receptors for cooling have been identified in sensory nerves, and we demonstrate here how activation of one of these, TRPM8, produces profound, mechanistically novel analgesia in chronic pain states. RESULTS: We show that activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of specific pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, thereby inhibiting the characteristic sensitization of dorsal-horn neurons and behavioral-reflex facilitation. TRPM8 expression was increased in a subset of sensory neurons after nerve injury. The essential role of TRPM8 in suppression of sensitized pain responses was corroborated by specific knockdown of its expression after intrathecal application of an antisense oligonucleotide. We further show that the analgesic effect of TRPM8 activation is centrally mediated and relies on Group II/III metabotropic glutamate receptors (mGluRs), but not opioid receptors. We propose a scheme in which Group II/III mGluRs would respond to glutamate released from TRPM8-containing afferents to exert an inhibitory gate control over nociceptive inputs. CONCLUSIONS: TRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states.     

癌症痛的神经生物学机制研究进展

癌症痛是影响癌症病人生活质量的一个严重问题 ,但长期以来由于缺乏合适的动物模型 ,对其神经机制的研究甚少。近年出现的小鼠股骨、跟骨、肱骨和大鼠胫骨癌症痛模型 ,极大地推动了癌症痛的基础研究。初步研究表明 ,癌症痛有其独特的神经化学机制 ,骨质破坏、外周敏化、中枢敏化及神经侵蚀都参与了癌症痛的产生。本文综述了癌症痛动物模型、癌症痛的产生机制及其药物治疗等方面的研究进展。     

Comparing the efficacy of pain managements after total hip arthroplasty: A network meta-analysis

The aim of our current study is to compare efficiency of various interventions implemented for pain management after total hip arthroplasty (THA). PubMed and EMBASE were searched for randomized clinical trials (RCTs) reporting the pain scales for evaluate the efficacy of pain control after THA including at least one pair of direct control groups. Pain scale values and the associated 95% credible interval (CrI) were used to describe efficacy. Surface under the cumulative ranking curve (SUCRA) of each means of pain control was calculated to compare the relative ranking of different interventions. Thirty-five eligible literatures were involved in data analysis. The interventions for postoperative pain management we examined were psoas compartment block (PCB), posterior nerve block (PNB), fascia iliaca block (FIB), periarticular injection (PAI), femoral nerve block (FNB), lumbar plexus block (LPB), spinal anesthesia (SA), epidural analgesia (EPI), intrathecal morphine (IA), intravenous patient-controlled analgesia (IV-PCA), patient-controlled analgesia (PCA), onsteroidal anti-inflammatory drug (NSAID), local infiltration analgaesia (LIA), and reverse LIA (rLIA). In 0 to 6 hours analysis, patients under SA were found to have significantly lower pain score and SA was ranked the best. In 6 to 12 hours analysis, SA was found to be significantly more effective than other interventions and its SUCRA was the highest. No intervention showed a significant effect on reducing pain score for 12 to 24 hours and 24 to 48 hours after THA. SA is the best intervention to reduce THA postoperative pain in the first 24 hours. LPB is a better choice to reduce pain 12 to 48 hours after THA.     

胶质细胞与病理性疼痛

胶质细胞是中枢神经系统内的一类有别于神经元的细胞,可表达多种神经递质或细胞因子受体,在神经系统的多种功能中扮演着重要角色。组织损伤或炎症引起脊髓胶质细胞大量激活,激活的胶质细胞分泌多种细胞因子和神经-胶质兴奋物质,参与病理性疼痛的产生与维持。以胶质细胞为靶点可能为病理性疼痛的治疗另辟蹊径。     

布托啡诺复合右美托咪定抑制剖宫产术后宫缩痛的临床效果观察

目的:观察布托啡诺复合右美托咪定抑制剖宫产术后宫缩痛的临床效果及安全性。方法:将2015年7月到2016年10月在我院进行建档分娩的剖宫产产妇84例作为研究对象,根据随机信封抽签原则分为观察组与对照组,每组各42例。两组都给予腰硬联合麻醉,对照组给予术后右美托咪定镇痛,观察组给予术后布托啡诺复合右美托咪定镇痛,记录和比较两组产妇的宫缩痛情况。结果:两组新生儿的Apgar评分对比差异无统计学意义(P0.05),所有新生儿都存活。术后2h、4h与24h,观察组的宫缩痛评分分别为0.46±0.14分、0.82±0.19分和2.44±0.92分,都明显低于对照组的5.44±0.98分、5.63±0.78分和6.09±0.99(P0.05)。观察组术后恶心、呕吐、皮肤瘙痒、呼吸抑制等不良反应发生率为9.5%,对照组为11.9%,两组对比差异无统计学意义(P0.05)。观察组与对照组出院时镇痛满意度分别为100.0%和90.5%,观察组的满意度明显高于对照组(P0.05)。结论:布托啡诺复合右美托咪定能更好抑制剖宫产术后宫缩痛,对新生儿无明显影响,且安全性较高。     

Effects of intrathecal opioids combined with low-dose naloxone on motilin and its receptor in a rat model of postoperative pain

Aims

To investigate the effects of intrathecal morphine and fentanyl combined with low-dose naloxone on the expression of motilin and its receptor in a rat model of postoperative pain.

Main methods

An intrathecal catheter was implanted, and saline, opioids (morphine and fentanyl) and naloxone were intrathecally administered 7 days later. An incisional pain model was established to induce pain behaviors in rats by unilateral plantar incision. Thermal hyperalgesia and mechanical allodynia were measured by using a radiant heat and electronic Von Frey filament, respectively. The expression of motilin in the hippocampus, stomach, duodenum, and plasma was determined by ELISA; and the expression of motilin receptor in the hippocampus was detected by Western blot assay.

Key findings

Motilin and its receptor were detected in the hippocampus. Acute incisional pain increased the motilin expression in the hippocampus and duodenum, while decreasing its expression in the gastric body and plasma. Postoperative analgesia with morphine + fentanyl upregulated the expression of motilin in the hippocampus; however, motilin was downregulated in peripheral sites. Naloxone at 1 ng/kg restored motilin to baseline levels. Acute pain, morphine + fentanyl, and naloxone all induced the expression of motilin receptor in the hippocampus.

Significance

Acute pain, postoperative analgesia with opioids, and naloxone significantly impacted the expression of hippocampal and peripheral motilin. Variation trends in all sites were not identical. Intrathecal injection of low-dose naloxone upregulated paw withdrawal thermal latency and enhanced the analgesic effects of opioids. The findings presented here provide a new basis for central and peripheral regulations in GI motility, clinical postoperative analgesia, and management of analgesic complications.     

辣椒辣素对大鼠急性切割痛的作用

目的:研究辣椒辣素对足底切开大鼠疼痛相关行为的影响.方法:32只Wister雄性大鼠随机分为四组:生理盐水组、0.05％辣椒辣素组(C0.05)、0.1％辣椒辣素组(C0.1)、赋形剂组(吐温80),各200微升.切开前一天足底给药,分别测定给药前的基础值,给药后24小时,术后2小时及1、2、3天对热刺激的反应,并记录累积疼痛得分,术后三天进行组织病理学评估.结果:预先给予的辣椒辣素能够减弱热痛觉过敏和降低累积疼痛得分.组织病理学检查证实:与生理盐水比较辣椒辣素影响切口的恢复.结论:辣椒辣素预处理具有预防术后痛的作用.对切口组织学的影响可能与药物抑制疼痛行为有关,而不一定是药物的局部作用.     

Analgesia Induced by Microwave Irradiation of an Acupuncture Point under Conditions of Visceral Pain in Mice: Role of the Serotonergic Cerebral System

We studied behavioral manifestations of analgesic effects induced in mice by irradiation of the E36 acupuncture point (AcP) by low-intensity microwaves under conditions of visceral pain evoked by i.p. injections of 0.08 ml of a 2% solution of acetic acid. We also examined changes in these analgesic effects resulting from a drop in the level of serotonin after i.p. injection of 300 mg/kg of a blocker of synthesis of serotonin, DL-parachlorophenylalanine (PChPhA). Two modes of irradiation were tested, with a wide frequency range (30 to 300 GHz) and amplitude modulation (mode 1) and with a stable frequency (61 ± ± 4 GHz, mode 2). Irradiation in mode 1 provided a higher level of analgesia than that in mode 2 (decreases in the duration of manifestations of the pain reaction were, on average, 35.7 and 20.4%, respectively). The level of analgesia dropped after injections of PChPhA; the durations of behavioral pain manifestations 24 h after such injections were greater than those in the group with no injections of the blocker by 41.3 and 12.1% in irradiation modes 1 and 2, respectively. The respective figures 48 h after PChPhA injections were 52.0 and 16.1%. Thus, under conditions of visceral pain, irradiation of the AcP by low-intensity microwaves provides noticeable analgesia, and the serotonergic brain system mediates the development of analgesia under the above-mentioned conditions. Neirofiziologiya/Neurophysiology, Vol. 37, No. 3, pp. 250–256, May–June, 2005.     

多模式术后镇痛在腹腔镜结肠手术中的应用

目的:理论上联合使用不同机制镇痛药较镇痛药单独使用镇痛效果更完善,在妇科、骨科等手术中已有结论;笔者观察比较腹腔镜结肠手术术使用单一止痛药及联合使用不同机制镇痛药在术后镇痛的效果以及各自不良反应的发生率。方法:择期腹腔镜结肠手术患者90例,随机分为3组,每组30例。A组使用地佐辛+氟比洛酚酯行术后镇痛为多模式镇痛组;B组使用地佐辛行术后镇痛;C组使用氟比洛酚酯行术后镇痛。记录每组术后4、8、12、24 h视觉模糊评分(VAS)及术后不良反应包括嗜睡、躁动、恶心呕吐的发生率。结果:A组术后4 h、8 h的VAS评分低于B、C两组,差异有显著性,A组无嗜睡及躁动发生,发生呕吐1例,不良反应发生率A组低于B、C两组,差异有显著性。结论:地佐辛+氟比洛酚酯联合用药可安全有效应用于腹腔镜结肠手术术后镇痛,是一种有效的多模式术后镇痛方式,在减弱疼痛的放大效应及对中枢神经的作用两方面起效,因而较单独使用地佐辛及氟比洛酚酯有更好的镇痛效果,且不良反应低于单独使用地佐辛及氟比洛酚酯。     

Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation

Neuropathic pain is a well‐known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c‐Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain.     

胸外科手术术后神经病理性疼痛的发生情况及相关因素分析

目的:探讨胸外科手术术后神经病理性疼痛的发生情况及相关危险因素。方法:回顾性分析2015年至2016年就诊于我院行胸外科手术的患者的临床资料,包括患者的年龄、性别、吸烟史、BMI、术前是否使用催眠药物、术前诊断、手术侧别、手术方式、是否为微创、硬膜外自控镇痛泵使用情况、术中失血量、手术持续时间、引流管引流时间及是否发生神经病理性疼痛,对比分析是否发生神经病理性疼痛患者的临床资料,对有差异的临床资料进行多因素Logistic回归分析探讨发生神经病理性疼痛的危险因素。结果:共有123例患者纳入研究,33例(26.8%)患者的患者术后出现神经病理性疼痛,6例(4.9%)患者在术后一年仍有持续性神经性病理疼痛,术后出现神经病理性疼痛的平均时间为术后第7天,平均持续时间为75天,发生神经病理性疼痛的患者吸烟比例(81.8%)、术前使用催眠药比例(57.6%)、开胸手术比例(81.8%)、术中失血量(185 mL)、手术时间(196分钟)、术后引流时间(2.5天)均高于没有发生神经病理性疼痛的患者。多因素分析显示术前使用催眠药(OR=2.322,P<0.001)、手术时间延长(OR=3.703,P<0.001)和术后引流时间延长(OR=2.675,P=0.002)均是神经病理性疼痛发生的危险因素,电视辅助胸腔镜手术方式是保护性因素(OR=0.453,P=0.002)。结论:术前使用催眠药物、延长的手术时间及术后引流时间增加了神经病理性疼痛发生的风险,电视辅助胸腔镜技术可减少其发生率。     

Can women in labor give informed consent to epidural analgesia?

There are reasons to believe that decision‐making capacity (mental competence) of women in labor may be compromised in relation to giving informed consent to epidural analgesia. Not only severe labor pain, but also stress, anxiety, and premedication of analgesics such as opioids, may influence women’s decisional capacity. Decision‐making capacity is a complex construct involving cognitive and emotional components which cannot be reduced to ‘understanding’ alone. A systematic literature search identified a total of 20 empirical studies focused on women’s decision‐making about epidural analgesia for labor pain. Our review of these studies suggests that empirical evidence to date is insufficient to determine whether women undergoing labor are capable of consenting to epidural analgesia. Given such uncertainties, sufficient information about pain management should be provided as part of prenatal education and the consent process must be carefully conducted to enhance women’s autonomy. To fill in the significant gap in clinical knowledge about laboring women’s decision‐making capacity, well‐designed prospective and retrospective studies may be required.     

Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques

Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery.     

平行侧入法硬膜外穿刺CSEA对剖宫产术后腰背痛的影响

目的:探讨平行侧入法硬膜外穿刺腰硬联合麻醉对剖宫产术后腰背痛的影响。方法:选择2014年10月至2016年9月在我院行剖宫产的产妇95例,将其随机分为两组。对照组45例,产妇接受平行直入法硬膜外穿刺腰硬联合麻醉,观察组50例产妇接受平行侧入法硬膜外穿刺麻醉。比较两组产妇术后宫缩、伤口、腰背疼痛VAS评分、术中穿刺情况、术后使用镇痛泵的有效按压次数及术后3 d、7 d、14 d和2个月后腰背疼痛的情况。结果:观察组产妇术后宫缩、伤口以及腰背疼痛评分、术后使用镇痛泵的有效按压次数均显著低于对照组(P0.05),且术中一次性穿刺成功率显著高于对照组(P0.05),且术后7 d、14 d以及2个月腰背痛的发生率显著低于对照组(P0.05)。结论:平行侧入穿刺法行腰硬联合麻醉可有效提高剖宫产产妇一次穿刺成功率,显著缓解产妇的术后疼痛,并降低术后腰背疼痛的发生率。     

综述与专论: 认知行为疗法和虚拟现实疗法干预神经性疼痛的作用及机制

神经性疼痛（neuropathic pain，NP）是由外周或中枢躯体感觉系统的损伤或疾病导致的疼痛。药物治疗在镇痛中占据重要地位，但是过量药物治疗往往会引起严重的副作用，或在可耐受剂量下仅提供了部分的疼痛缓解。认知行为疗法（cognitive-behavioral therapy，CBT）和虚拟现实（virtual reality，VR）干预作为新的、非侵入性的，以及更为安全的疼痛替代治疗方法引起了广泛的关注。CBT和VR疗法可通过转移注意力、改变神经可塑性和神经环路，以及调节促炎和抗炎因子水平缓解神经性疼痛。本文旨在对神经性疼痛的发病机制以及CBT和VR疗法的镇痛效果和机制做出解析，从而为神经性疼痛的治疗干预提供重要的理论指导。     

Synergistic interactions between cannabinoid and opioid analgesics

Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models. In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia, and some of these findings are presented below. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.