Interplay between RAS and opioids: Opening the Pandora of complexities

Angiotensin and endogenous opioids are important bioactive neuropeptides, which are widely distributed in the brain and peripheral regions to produce diverse biological and neurobiological activities. An endogenous opioid system includes proopiomelanocortin-derived enkephalin, dynorphin and endorphin that act on their specific receptors such as delta (δ), kappa (κ) and mu (μ) receptors. Research evidence demonstrates significant positive as well as negative interactions between renin angiotensin system (RAS) and endogenous opioids in the brain and periphery. The diverse actions of Ang II are possibly mediated indirectly through endogenous opioids, while opioids are also shown to activate RAS components suggesting the up-regulation of each system in concern with each other. On the contrary, there are reports suggesting a negative correlation between RAS and opioid system. Research evidence also supports the notion that Ang II acts as anti-opioid peptide to decrease the actions of opioids. Moreover, opioids-induced decline in angiotensin release and functioning has also been reported. Co-administration of ACE inhibitors with opioids exhibits significant interactions possibly due to decreased metabolism of opioids leading to potentiation of their actions. The present review describes the complexities of positive and negative interactions between RAS and opioids along with possible mechanisms responsible for these interactions.     

Systemic Naloxone Infusion May Trigger Spasticity in Patients With Spinal Cord Injury: Case Series

Abstract

Background/Objective: Three patients with spinal cord injury (SCI) and 3 able-bodied (AB) patients were infused with naloxone during a study to examine their neuroendocrine function. An unanticipated side effect occurred during the naloxone infusion. All 3 patients with SCI, but none of the AB patients, experienced profoundly increased spasticity during the naloxone infusion. Our report describes this side effect, which has potential implications for the clinical treatment or scientific evaluation of individuals with SCI.

Methods: All patients were in good general health and medication free for 11 days or longer before the study. Each patient was placed on a 30-hour protocol to analyze pulsatile release of gonadotropins. Physiologic saline was intravenously infused on day 1 to serve as a control period for naloxone infusion on day 2.

Results: AB patients experienced no muscle spasm activity or any other side effects at any time during the study. In contrast, all 3 patients with SCI experienced a profoundly increased frequency and duration of spasticity in muscles innervated by the nerve roots caudal to their level of injury. In all 3 patients with SCI, spasticity increased only during the period of naloxone infusion. Within 1 hour of stopping naloxone, spasticity returned to baseline levels.

Conclusions: Naloxone infusion produced a differential effect on the muscle activity of men with SCI compared to AB men with intact spinal circuits. Consistent with previous studies, the results of this study indicate a relationship between opioid neuromodulation and spasticity after SCI.     

Who receives naloxone from emergency medical services? Characteristics of calls and recent trends

Abstract

Background: With the rapid rise in opioid overdose-related deaths, state policy makers have expanded policies to increase the use of naloxone by emergency medical services (EMS). However, little is known about changes in EMS naloxone administration in the context of continued worsening of the opioid crisis and efforts to increase use of naloxone. This study examines trends in patient demographics and EMS response characteristics over time and by county urbanicity. Methods: We used data from the 2013–2016 National EMS Information System to examine trends in patient demographics and EMS response characteristics for 911-initiated incidents that resulted in EMS naloxone administration. We also assessed temporal, regional, and urban–rural variation in per capita rates of EMS naloxone administrations compared with per capita rates of opioid-related overdose deaths. Results: From 2013 to 2016, naloxone administrations increasingly involved young adults and occurred in public settings. Particularly in urban counties, there were modest but significant increases in the percentage of individuals who refused subsequent treatment, were treated and released, and received multiple administrations of naloxone before and after arrival of EMS personnel. Over the 4-year period, EMS naloxone administrations per capita increased at a faster rate than opioid-related overdose deaths across urban, suburban, and rural counties. Although national rates of naloxone administration were consistently higher in suburban counties, these trends varied across U.S. Census Regions, with the highest rates of suburban administration occurring in the South. Conclusions: Naloxone administration rates increased more quickly than opioid deaths across all levels of county urbanicity, but increases in the percentage of individuals requiring multiple doses and refusing subsequent care require further attention.     

纳洛酮联合依达拉奉治疗脑血管疾病的疗效及其机制研究

目的 探讨纳洛酮联合依达拉奉治疗脑血管疾病的疗效及其机制。方法 将180例缺血性脑血管疾病患者随机分为两组,每组各90例,对照组给予依达拉奉注射液30 mg静脉滴注,每日2次,研究组在对照组基础上给予盐酸纳洛酮注射液2 mg静脉滴注,每日2次。两组均连用14 d。分别在治疗前、治疗后检测血清丙二醛（MDA）、超氧化物岐化酶（SOD）浓度以及血液流变学指标。比较两组的临床疗效和不良反应。结果 治疗后,两组血清MDA浓度均较治疗前降低,SOD浓度均较治疗前升高,同组治疗前后比较差异有统计学意义（P<0.05）;且研究组MDA浓度明显低于对照组,SOD浓度明显高于对照组,组间比较差异有统计学意义（P<0.05）。研究组治疗后血液流变学指标改善情况明显优于对照组,差异有统计学意义（P<0.05）。研究组总有效率94.4%,明显高于对照组83.3%,差异有统计学意义（P<0.05）。两组均无明显不良反应。结论 纳洛酮联合依达拉奉治疗脑血管疾病能增进疗效,其机制可能与提高SOD,降低MDA,改善脑组织供血有关。     

Stimulus-evoked opioid inhibition in guinea-pig longitudinal muscle-myenteric plexus strip is modulated by NMDA receptors

Longitudinal muscle-myenteric plexus (LMMP) strips of the guinea-pig ileum were used to investigate the stimulus-evoked endogenous opioid inhibition and its modulation by ionotropic glutamate receptors. Regular cholinergic twitch responses evoked by a short 3-s-field stimulation in intervals of 80s were found reduced after an interposed period of prolonged 40-s-field stimulation. In the presence of a peptidase-inhibitor-cocktail, the cholinergic twitch response following the period of prolonged stimulation was even further reduced as compared to normal Tyrode solution without peptidase inhibitors. In both instances, the impairment of the cholinergic twitch response was completely abolished by naloxone thus demonstrating its opioidergic nature. This endogenous inhibitory opioid effect was significantly mitigated by the NMDA-receptor antagonist MK-801, but not by the AMPA/kainate receptor antagonist CNQX. These results demonstrate by functional experiments that there is a significant opioid-mediated inhibition in guinea-pig LMMP preparations evoked by a prolonged electrical stimulation, and that an NMDA antagonist can mitigate the opioid inhibition.     

A content review of online naloxone Continuing Education courses for pharmacists in states with standing orders

Background

Many community pharmacists are uncomfortable educating patients about naloxone, an opioid reversal agent.

纳洛酮联合小牛血清去蛋白治疗急性颅脑损伤的临床研究

目的探讨纳洛酮联合小牛血清去蛋白治疗急性颅脑损伤的临床效果。方法选取2015年8月—2017年8月重庆市开州区人民医院收治的急性颅脑损伤患者122例,随机分为对照组(61例)和治疗组(61例)。对照组静脉滴注小牛血清去蛋白注射液,30 m L加入5%葡萄糖注射液250 m L,1次/d。治疗组在对照组基础上静脉滴注盐酸纳洛酮注射液,0.3mg/(kg·d)。两组患者均连续治疗7 d。观察两组临床疗效,比较治疗前后两组格拉斯哥昏迷量(GCS)评分、血液流变学指标、及肿瘤坏死因子(TNF)-α、IL-6和神经元特异性烯醇化酶(NSE)水平。结果治疗后,对照组和治疗组临床总有效率分别为78.7%、93.4%,两组比较差异具有统计学意义(P0.05)。治疗后,两组GCS评分中运动、语言、睁眼及GCS总评分均显著升高(P0.05);且治疗组GCS评分明显高于对照组(P0.05)。治疗后,两组全血黏度(WBV)、血浆黏度(PV)和红细胞聚集指数(EAI)值均显著下降(P0.05);且治疗组比对照组降低的更显著(P0.05)。治疗后,两组血清TNF-α、IL-6、NSE水平均明显降低(P0.05);且治疗组比对照组降低的更明显,(P0.05)。结论纳洛酮联合小牛血清去蛋白治疗急性颅脑损伤可迅速缓解患者症状体征,减轻炎性损伤,改善神经功能,具有一定的临床推广应用价值。     

纳洛酮对脑出血大鼠抓握能力的改善及血清S100B水平的影响

目的：探讨纳洛酮对脑出血大鼠抓握能力的改善及血清S100B水平的影响，为其临床应用提供理论依据。方法：40只SD大鼠随机分成假手术组，手术组，纳洛酮组，脑复康组，参照Rosenberg法制作大鼠脑出血模型，造模第二天测定大鼠抓握能力，用ELISA法检测造模后24小时及48小时血清S100B水平。结果：（1）纳洛酮组大鼠抓握能力明显好于手术组，两者比较有显著差异（P<0.05）。（2）纳洛酮组大鼠血清S100B水平明显低于手术组, 两者比较有显著差异（P<0.05）。结论：纳洛酮能明显改善脑出血大鼠抓握能力，降低血清S100B水平，具有神经保护作用。     

洗胃对酒精中毒患者应用纳洛酮加速尿治疗的效果

目的探讨洗胃与不洗胃对急性酒精中毒应用纳洛酮和速尿抢救的效果。方法将60例急性酒精中毒患者随机分为2组，即实验组和对照组。实验组给纳洛酮催醒、速尿促排泄、补液及对症支持的抢救和护理措施。对照组除采用上述抢救护理措施外，还按中毒常规方法给予洗胃。观察2组患者清醒时间和酒后症状持续时间，并进行比较。结果实验组患者和对照组患者清醒时间及酒后症状持续时间无明显差异（P〉0．05）。结论纳洛酮和速尿抢救急性酒精中毒免去洗胃不影响催醒效果，而且减少了患者痛苦及护理工作的风险性。     

Brief overdose education can significantly increase accurate recognition of opioid overdose among heroin users

BackgroundIn an effort to increase effective intervention following opioid overdose, the New York State Department of Health (NYSDOH) has implemented programs where bystanders are given brief education in recognizing the signs of opioid overdose and how to provide intervention, including the use of naloxone. The current study sought to assess the ability of NYSDOH training to increase accurate identification of opioid and non-opioid overdose, and naloxone use among heroin users.MethodsEighty-four participants completed a test on overdose knowledge comprised of 16 putative overdose scenarios. Forty-four individuals completed the questionnaire immediately prior to and following standard overdose prevention training. A control group (n = 40), who opted out of training, completed the questionnaire just once.ResultsOverdose training significantly increased participants’ ability to accurately identify opioid overdose (p < 0.05), and scenarios where naloxone administration was indicated (p < 0.05). Training did not alter recognition of non-opioid overdose or non-overdose situations where naloxone should not be administered.ConclusionsThe data indicate that overdose prevention training improves participants’ knowledge of opioid overdose and naloxone use, but naloxone may be administered in some situations where it is not warranted. Training curriculum could be improved by teaching individuals to recognize symptoms of non-opioid drug over-intoxication.