阿片受体的晶体结构和基因多态性研究进展

阿片受体是阿片类镇痛药的重要作用靶点,中度至重度疼痛的治疗大部分依赖于阿片类药物的使用。目前临床上常用的吗啡等阿片类镇痛药治疗指数窄并且具有较大的个体差异。而且常常伴随着一些严重的耐受性和成瘾性等副作用。深入认识阿片受体高分辨率结构特点,有助于一些基于结构研发的方法中开发治疗疼痛及成瘾药物。研究阿片受体的基因多态性有助于从分子生物学的角度解释个体间对阿片类药物反应存在的差异。     

阿片类药物不良反应的性别差异

阿片类药物是临床中广泛用于治疗中度至重度疼痛的药物。阿片类药物不良反应的性别差异近年日益受到重视,其中包括药物在呼吸抑制、胃肠道反应、心血管反应、镇痛耐受性及药物依赖性等方面的差异。进一步研究阿片类药物不良反应的性剐差异,将有助于更好地实施个体化用药。     

非阿片类药物改善阿片类药物致呼吸抑制研究进展

阿片类药物通过作用于阿片受体,激活与受体偶联的G蛋白和(或)β-抑制蛋白等信号通路而发挥镇痛和麻醉等效应,但同时阿片类药物致呼吸抑制(OIRD)则是临床常见的严重问题.目前通常采用阿片受体拮抗剂纳洛酮等改善OIRD,但纳洛酮可能会拮抗阿片类药物的镇痛作用,甚至带来许多不可预知的不良反应.近年来,使用非阿片类药物直接和(...     

关注阿片类药物的不良反应

疼痛是癌症患者最常见的症状之一。大约70％的晚期肿瘤患者必须依靠阿片类药物进行止痛治疗。对于阿片类药物,患者及其家属最为担心的就是成瘾性。其实,国内外众多研究显示：慢性癌痛患者长期用阿片类药物作止痛治疗时,成瘾的发生率极为罕见。在长期使用阿片类药物的过程中,亦存在一些不良反应,最常见的不良反应有便秘、恶心呕吐、嗜睡和过度镇静、排尿困难。以及呼吸抑制等。这些不良反应应该引起患者及其家属的重视。     

癌性疼痛药物不良反应的防治

治疗癌性疼痛最常用的的药物是阿片类药物和非甾体消炎药。阿片类药物常见的不良反应包括便秘、恶心、呕吐、呼吸抑制和尿潴留等。非甾体消炎药常见的不良反应包括胃肠道损伤、肝肾损伤、血液系统损害等。治疗时以预防不良反应为主,包括避免用于高危人群、控制剂量与时间、同时使用治疗不良反应的药物等。出现不良反应时应及时采取相应的治疗措施。     

《根据CYP2D6、OPRM1和COMT基因型选择阿片类药物治疗方案的临床药物遗传学实施联盟指南》解读

阿片类药物被广泛用于中度至重度疼痛的治疗，然而其镇痛效果及不良反应存在广泛的个体差异。药物遗传学研究表明，基因多态性与上述个体差异有密切关系，研究较多的为CYP2D6、μ阿片受体(OPRM1)和儿茶酚-O-甲基转移酶(COMT)等基因的多态性。2021年2月，临床药物遗传学实施联盟(CPIC)发布了《根据CYP2D6、OPRM1和COMT基因型选择阿片类药物治疗方案的临床药物遗传学实施联盟指南》。该文对指南进行解读，总结CYP2D6、OPRM1和COMT基因多态性对阿片类药物镇痛效果和不良反应的影响，同时提出基于CYP2D6基因型指导临床使用可待因、曲马多和氢可酮等阿片类药物的治疗建议，以期为临床个体化用药提供参考。     

癌症疼痛患者阿片类药物剂量计算的临床推荐

阿片类药物是肿瘤患者中重度疼痛的主要治疗药物,但由于该类药物存在较大的个体差异性和用药风险,正确进行阿片类药物剂量滴定和换算在有效减轻患者疼痛的同时还可避免过度治疗造成的不良反应。目前临床上常用的阿片类药物剂量计算有阿片初始剂量的滴定,爆发痛剂量计算,不同阿片药物以及不同剂型的换算,肝、肾功能不全患者阿片类药物的给药剂量等。该文结合国内外研究报道,对上述几种剂量计算进行了综述,为临床合理用药提供参考。     

阿片类药物治疗老年中重度癌痛不良反应分析

目的探讨阿片类药物治疗老年中重度癌痛不良反应。方法采用回顾性分析的方法,分析了100例老年肿瘤患者应用阿片类药物治疗中重度疼痛的不良反应。采用面部表情疼痛分级量表和数字评定量表综合评定疼痛强度。初次使用强阿片类药物的患者从小剂量开始药物滴定,未达到满意止痛效果者,根据剂量换算确定起始剂量。每天定时记录患者疼痛强度、部位、性质和毒副反应等。结果 100例患者用药时间中位值50d,阿片类药物剂量中位值60mg。93%(93/100)以上的患者达到中度以上缓解。患者不良反应发生率为61%(61/100)。便秘为最常见的(48%)不良反应,其次为恶心/呕吐(24%),嗜睡(12%)、头晕(5%)、皮肤瘙痒(5%)、排尿困难(4%),呼吸抑制(2%)的不良反应较少见。结论阿片类药物能够有效控制老年癌痛,主要不良反应为便秘和恶心呕吐。     

纳洛酮的抗休克作用

纳洛酮(Naloxone)是阿片类药物和内源性阿片样物质的特异性拮抗剂,至今在临床上尚少应用,国外主要用于治疗阿片类药物过量引起的呼吸抑制,并作为检出潜在阿片瘾患者的诊断剂。近三年来,Holaday等陆续报道纳洛酮对于动物实验性休克有良好效果,此发     

高乌头温敏凝胶外用辅助治疗局部癌性疼痛的临床研究

目的评价高乌头温敏凝胶联合阿片类镇痛药治疗局部癌性疼痛的有效性和安全性。方法将Kamofsky评分50⁸0分的癌症患者随机分为2组,其中治疗组采用高乌头温敏凝胶联合阿片类镇痛药(53例),对照组单用阿片类镇痛药(50例);采用数字评分量表(numerical rating scale,NRS)评分进行疼痛评估;记录2组阿片药物的消耗量以及不良反应的发生率。结果治疗组和对照组的NRS评分基线值无显著性差异(P>0.05),但对照组阿片类药物的消耗量及不良反应和爆发痛发生率显著多余治疗组(P<0.05)。结论高乌头温敏凝胶联合阿片类药物可以更好地治疗癌性疼痛,减少阿片药品的用量,降低由阿片药引起的不良反应,且简单易行,不失为辅助治疗局部癌性疼痛安全、有效、经济的治疗手段。     

Analgesia in PACU: intravenous opioids

Critically ill patients, particularly those under mechanical ventilation, require analgo-sedation to control noxious stimuli and enhance comfort. Despite their harmful side effects, such as respiratory depression, physical dependence and difficult arousal, opioids are effective in providing a good level of analgesia and comfort. Traditional opioids (morphine and fentanyl) have been shown effective in providing analgesia; however, the respiratory adverse effects and their pharmacokinetics, with an high risk of accumulation, limits their use, especially for a long-term sedation. In the last decade, new synthetic opioids with limited side effects and favourable pharmacokinetics profile, such as Sufentanil and Remifentanil, have been investigated to evaluate their efficacy in mitigating pain and enhancing comfort in critically ill patients.     

Epidural analgesia in the Post-Anaesthesia Care Unit

Epidural analgesia is widely used for postoperative pain in a variety of surgical operations and it is recognised to provide superior quality of analgesia when compared with systemic opioids. The combination of low doses of local anaesthetics and opioids appears to provide optimal analgesia with minimal motor blockade. However, side effects have been reported with epidural analgesia such as postoperative nausea and vomiting (PONV), respiratory depression and arterial hypotension. Although the incidence of these side effects is lower than those reported with the use of systemic opioids, they can contribute to a delay in discharging patients from PACU. Epidural analgesia is also associated with perioperative hypothermia. The incidence of cognitive dysfunction is not decreased by using postoperative epidural analgesia. Assessment of the quality of analgesia by using pain visual analogue score (VAS) at rest and with movements or on coughing remains the most preferred in PACU, although there are limitations with this measurement. Epidural failure due to technical failure or malposition of the catheter represents potential problems having direct consequence on the quality of analgesia provided. All epidural catheters have to be checked and the quality of analgesia assessed before patients are discharging from PACU to the surgical wards. With advances in pain pharmacology, multimodal interventions and adjuvants can be used safely with the intent of providing better analgesia and decreasing the side effects associated with one technique.     

Effects of NMDA receptor antagonists on opioid-induced respiratory depression and acute antinociception in rats

Although exogenous opioids alter the responses of animals to tissue-damaging stimuli and therefore are the cornerstone in the treatment of acute antinociception, they have profound side effects on ventilation. To diminish ventilatory effects, combination therapies have been advocated. Recent studies reported the effectiveness of the addition of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine to morphine in the treatment of acute pain. However, NMDA receptors, together with non-NMDA receptors are known to be involved in the neurotransmission of inspiratory drive to phrenic motoneurons. Co-administration of NMDA and non-NMDA receptor antagonists has been shown to be deleterious to respiratory function. The present study investigated the hypothesis that the association of opioids and NMDA receptor antagonists may add to the impairment of respiratory parameters. In male Wistar rats, combinations of opioids (fentanyl or morphine) at antinociceptive doses and NMDA receptor antagonists (ketamine, 40 mg/kg, or dextromethorphan, 10 mg/kg) at subanesthetic doses were administered intraperitoneally. Antinociception was tested with the tail-withdrawal reaction (TWR) test, while the effect on respiratory parameters was investigated with blood-gas analysis. We found that, in rats, co-administration of NMDA receptor antagonists and opioids may result in an increased respiratory depression as compared to the opioids alone. The effect of the NMDA receptor antagonists on opioid-induced antinociception was limited.     

哌替啶用于分娩镇痛的研究进展

众所周知,分娩是一个痛苦的过程。哌替啶为人工合成的阿片受体激动药,便宜易得,是最常用于产科镇痛的阿片类药物,有较好的镇痛效果,但是,由于其可能造成产妇恶心、呕吐、烦躁不安、呼吸抑制等副作用以及其对新生儿的影响,哌替啶对分娩疼痛的缓解效果存在争议。通过检索各国文献,对哌替啶在分娩镇痛中的作用机制、临床研究、系统评价、不良反应以及争议的研究进展进行综述。     

曲马多的临床应用进展

曲马多作为一种中枢性镇痛药,与其他阿片类药物相比,成瘾性和耐药倾向较低,呼吸抑制、尿潴留、胃肠道反应等不良反应发生率较低。目前,已广泛应用于临床。常用于术后镇痛、癌痛治疗、分娩镇痛等,随着对其研究的深入,在抗寒战、镇咳等其他一些治疗方面,曲马多具有较强大作用。本文就其临床运用作一综述。     

Neuraxial morphine and respiratory depression: finding the right balance

Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the 'gold-standard' single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use. Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preB?tzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preB?tzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression. Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event. The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy 'ceiling'. The optimal 'single-shot' intrathecal dose appears to be 0.075-0.15 mg and the ideal 'single-shot' epidural morphine dose is 2.5-3.75 mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioid-induced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists. Early evidence suggests that ampakine (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study.     

Opioids, sleep, and sleep-disordered breathing

Opioid medications are increasingly used to treat chronic pain. Opioid-associated respiratory depression, and their potential to cause nocturnal apneas, is increasingly recognized as a major contributor to nocturnal hypoxemia and sleep-disordered breathing. Given the widespread use of opioids, understanding their mechanism of action and their potential to cause adverse effects particularly during sleep is critical. This article reviews the salient features of the physiologic control of respiration and sleep, and the role opioids play in altering that regulation. Additionally, we summarize the evidence regarding the association between opioid use and sleep-disordered breathing and explore treatment modalities for opioid-associated nocturnal respiratory depression and apneas.