Transport mechanisms in oral transmucosal drug delivery: implications for pain management

The mechanism for the oral transmucosal delivery of fentanyl citrate (OTFC) was investigated in this work. A developed mathematical model included the following transport characteristics: dissolution of the fentanyl citrate lozenge, diffusion through the saliva and oral mucosal membrane and equilibrium between adjacent layers. An orthogonal-collocation-based solution procedure was adopted to discretize the governing equations and boundary conditions. The Mathematica® built-in function, NDSolve, was applied to integrate the equations with respect to time. Simulations were conducted with a 200 μg-dosage. A novel fabrication method, aimed at maintaining a high flux for a prolonged period of time, was proposed based on the calculated delivery rate and cumulative amount of medicament absorbed into the systemic circulation. The model allows drug manufacturers to decide when to replace the unit based on estimated drug concentrations in the saliva and the mucosal membrane. Both the model and solution strategies were validated using serum fentanyl citrate concentration collected from adult subjects. The predicted profiles, based on parameters obtained from the literature, agree well with the experimental data.     

小剂量纳洛酮硬膜外应用对胃癌术后芬太尼静脉自控镇痛效果及胃肠功能的影响

目的:探讨小剂量纳洛酮硬膜外应用对胃癌术后芬太尼静脉自控镇痛效果及胃肠功能的影响。方法:选取我院2010年7月-2015年7月收治的110例胃癌患者为研究对象,将所有患者随机分为试验组和对照组各55例,两组患者均行根治性肿瘤切除术,术后采用芬太尼静脉自控镇痛,试验组于术后硬膜外注入小剂量纳洛酮,对照组注入等量的生理盐水,对两组术后不同时间点(4 h、8 h、12 h、24 h)疼痛程度进行评分,对比两组肠鸣音恢复时间、肛门排气时间、肛门排便时间、胃动力恢复时间,镇痛泵药物消耗量及并发症发生率。结果:术后4 h,试验组疼痛评分明显低于对照组(P0.05),术后8 h、12 h两组患者的疼痛评分均有显著上升(P0.05),且试验组患者的疼痛评分均远低于对照组(均P0.05),术后24 h,试验组与术后12 h比较差异无统计学意义(P0.05),对照组术后24 h疼痛评分与术后12 h分相比有显著差异(P0.01);试验组患者肠鸣音恢复时间、肛门排气时间、肛门排便时间、胃动力恢复时间、镇痛泵药物消耗量、芬太尼用量均远远低于对照组(P0.05);试验组并发症总发生率(7.27%)远远低于对照组(23.64%),差异具有统计学意义(P0.05)。结论:采用小剂量纳洛酮硬膜外应用方法辅助术后镇痛可以有效的减轻患者的疼痛,降低并发症的发生率,促进胃肠功能恢复,疗效显著,值得在临床上推广使用。     

Innate Immune Signalling Genetics of Pain,Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.     

Persistent pain accelerates xenograft tumor growth of breast cancer in rat

Pain occurs at all stages of the patients who suffer from cancer. Owing to surgery and bone metastasis, breast cancer patients were usually disturbed by persistent pain. However, the pain-relief-right has not been respected enough in clinical cancer treatment. Whether pain has any adverse effects on cancer development is still unclear. In order to uncover this question, we established two preclinical animal models to explore the effects of pain on the tumor. For the first model, we mimicked neuropathic pain by sciatic nerve ligation on rats with xenograft tumor subcutaneously. For the second model, we mimicked the bone cancer pain by injecting tumor cell suspension into the tibial medullary cavity of rats with xenograft tumor subcutaneously. The rats with persistent pain showed higher tumor volume and tumor weight compared with the group without pain. Interestingly, when the neuropathic pain and bone cancer pain were relieved by drug administration, both the tumor volume and tumor weight were lowered compared with the group without pain relief. In summary, our study indicated that persistent pain acted as a contributing factor to tumor growth. Moreover, the pain relief could weakened the accelerating role of pain in tumor growth. Thus, we should be paid more attention to the cancer patients with persistent pain as well as cancer treatment.     

Influence of postoperative analgesics on the development of neuropathic pain in rats

Rodent models of neuropathic pain require extensive tissue manipulation to induce the lesion of interest which results in inflammation and postoperative pain that is unrelated to nerve injury per se. We sought to determine whether acute postoperative pain management affects the development of hallmark signs of neuropathic pain. Analgesic regimens (q 24 h x 3 days) were buprenorphine (0.05 and 0.1 mg/kg of body weight, s.c.), flunixin meglumine (1.1 and 2.5 mg/kg, s.c.), and fentanyl citrate (0.01 and 0.1 mg/kg, i.p.). The spared nerve injury model of neuropathic pain was used, and mechanical and cold allodynia as well as body weight gain were measured for 28 days. Buprenorphine and fentanyl alleviated mechanical sensitivity and prevented weight loss associated with the surgery (0 to 3 days), but opioid-related adverse effects were observed. Flunixin reduced wound inflammation and improved weight gain, but had no effect on nociceptive thresholds. Cold allodynia was unaltered by any treatment. By postoperative day 7, control and treatment groups did not differ with respect to weight gain or nociceptive thresholds. Our findings suggest that postsurgical inflammation and pain behavior can be ameliorated without substantially altering the long-term development of neuropathic pain, provided that the selection of agent(s) and treatment regimen(s) is appropriate and the neuropathic pain of interest is evaluated seven days after surgery.     

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。     

Pharmacodynamics of fentanyl citrate in patients undergoing aortocoronary bypass

The pharmacodynamics of fentanyl citrate were studied in two groups of patients. One group underwent surgery with cardiopulmonary bypass (CPB) and the other group had surgery without CPB; the latter group represented the controls. Apneic periods were considerably longer (2.70 +/- 0.90 hr) for the CPB patients than for the control patients (1.75 +/- 0.75 hr). The total plasma fentanyl concentration at which apnea ceased was not statistically different between the two groups. Minor differences were attributed to the massive dilution of plasma proteins after the adding of priming fluid to the heart-lung machine. This prolongation of apnea is of considerable clinical importance because it means that CPB patients must remain mechanically ventilated for longer periods.     

阿片类药物滴定法治疗癌痛的疗效及不良反应分析

目的:探讨阿片类药物滴定法治疗癌痛的疗效及不良反应分析,为临床治疗提供依据。方法:采用回顾性分析选择2012年1月~2015年12月我院收治的肿瘤患者共110例,采用数字评定量表(NRS)和面部表情疼痛分级量表(FRS)进行疼痛评价,采用滴定法从小剂量开始给药,并记录患者的疼痛状况和不良反应发生状况。结果:患者总用药时间为28~170 d,平均用药时间(45.7±19.4)d,中位时间为48d。阿片类药物使用剂量(换算成吗啡剂量计算)40~500 mg,中位剂量74 mg。110例患者中有101例(91.82%)达到中度以上缓解。发生不良反应63(57.27%)例,消化道副反应为最常见的不良反应,主要有便秘48例(43.64%)例和恶心呕吐25例(22.73%)、其次依次为嗜睡15例(13.64%)、头晕9例(8.18%)、排尿困难5例(4.55%)、皮肤瘙痒3例(2.73%)和呼吸抑制2例(1.82%)。结论:阿片类药物能够有效缓解癌症患者的中重度癌痛,其主要不良反应是便秘和恶心呕吐。应合理、安全的使用阿片类药物,从小剂量开始,规范剂量滴定。     

对于可改善癌性疼痛的教育干预的研究进展

疼痛是癌症患者的一种常见症状,全世界每年有超过1000万人被诊断出患有癌症,而与他们病情相关的疼痛是一个严重的问题。尽管在国际上有明确的评估和管理癌症相关疼痛的指南,但是出现癌症相关疼痛的患者并未能得到充分合理的治疗,疼痛症状重。目前,相当一部分患者对癌症止痛药物的使用缺乏认识,针对患者进行合理的教育干预显得尤为重要。本文通过检索多个中外数据库的临床研究,对探讨癌症患者疼痛教育干预的研究进展进行综述,以期为癌性疼痛的教育干预提供新的改进思路。     

Impact of pain,psychological-distress,SARS-CoV2 fear on adults’ OHRQOL during COVID-19 pandemic

Corona virus disease (COVID-19) has crippled life, families and oral health care delivery. Hence, we assessed the impact of dental pain, fear of COVID-19 and psychological distress during lockdown on the oral health related quality of life of individuals visiting a tertiary dental care center during COVID-19 pandemic. Cross sectional study conducted among patients between 18 and 60 years. Demographics, access to pain killers, dental care (yes/no), duration (</> 15 days) and intensity of pain were self reported. Fear of COVID-19 was assessed using fear of corona virus scale (FCV-19S); psychological distress in the last 30 days and oral health related quality of life was evaluated. Oral examination was performed and dental caries status (DMFT) was assessed using the world health organization method. Univariate and multivariate regression analysis was conducted to evaluate significant predictors and 5% was set as level of significance. 2966 patients visited our dental emergency due to painful decayed tooth between March-June 2020. Mean age was 42.7 years, 53.97% were males and most common cause of painful teeth was upper right third molar (7.7%). 73.4% reported lack of pain medication; 95% reported closure of dental clinics close to home. Almost 79% suffered from dental pain for >15 days. Higher self reported pain (OR 2.1; 95% CI 1.36–14.71), >15 days of suffering from pain (OR 6.8; 95% CI 2.18–23.14), greater fear of COVID-19 (OR 4.14; 95% CI 1.98–16.07) and psychological distress (OR 4.41; 95% CI 1.09–16.76) were associated with poorer OHRQOL of adults during COVID-19 pandemic. Our findings strongly suggest that COVID-19 pandemic negatively impacts the mental and oral health of individuals affecting their overall health.     

Prevalencia y etiopatogenia del dolor oncológico neuropático en el anciano

The prevalence of neuropathic pain is difficult to estimate as most studies evaluating chronic pain do not differentiate neuropathic from nociceptive pain. There are only a few studies of neuropathic pain in the elderly, specifically in the oncology population. This article is a non-systematic review of the relevant evidence on the prevalence and aetiopathogenesis of neuropathic cancer pain in the elderly.     

lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral and maxillofacial region, severely affects human health. However, current treatments for OSCC commonly show only a ~60% 5-year survival rate of patients with distant metastases, indicating an urgent need for targeted treatments for patients with advanced metastases. Here, we report a survival-related long non-coding RNA, CYTOR, which is highly expressed in the lesions of oral cancer patients. We found that CYTOR can promote both migration and invasion in oral cancer cells as well as the epithelial–mesenchymal transition (EMT). RNA-sequencing of CYTOR-knockdown oral cancer cells revealed that CYTOR can regulate mitochondrial respiration and RNA splicing. Mechanistically, we found that nuclear-localized CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC. By synthesizing CYTOR-targeting small interfering RNAs (siRNAs) encapsulated in Nanoscale Metal Organic Frameworks (NMOFs), we demonstrate the targeted suppression of CYTOR to inhibit invasion and metastasis of oral cancer cells in a nude mouse model. Cumulatively, this study reveals the potential role of the CYTOR-HNRNPC-ZEB1 axis in regulating mitochondrial metabolism and glycolysis of oral cancer cells, and illustrates the effective use of lncRNA targeting in anti-metastatic cancer therapies.Subject terms: Cancer metabolism, Cancer metabolism, Oral cancer     

Trigeminal neuralgia: a retrospective study of 188 Thai cases

doi: 10.1111/j.1741‐2358.2011.00530.x Trigeminal neuralgia: a retrospective study of 188 Thai cases Objective: To describe the clinical characteristics and treatment of trigeminal neuralgia (TN) in a group of Thai patients. Materials and methods: Records of 188 patients with TN were reviewed retrospectively for patient demographics, the characteristics of the pain and treatment modalities. Results: Of the 188 patients, 37.2% were men and 62.8% were women. The peak incidence (46.8%) was in the age range of 50–69 years. Pain occurred on the right side of the face more often than on the left (1.8:1). The mandibular division of the trigeminal nerve was the most frequently affected (30.3%), followed by the combined maxillary and mandibular divisions (29.3%) and the maxillary division alone (25%). The majority described their attack as a sharp pain (77.6%), and the most common primary locations were at previous extraction sites (40.5%). The most common triggers were chewing (61.2%) and speaking (47.3%). Carbamazepine was the most common prescribed drug (76.1%) for the initial treatment. Combination drug therapy was introduced when the monotherapy failed to control the pain. Surgical intervention was the alternative choice of treatment in refractory cases. Conclusion: TN affected women more than men, and this disorder occurred most frequently in patients aged 50 years and older. The mandibular division of the trigeminal nerve was most commonly involved.     

放射线引导下经椎间盘入路内脏大小神经毁损术治疗上腹部癌痛的临床分析

目的:观察放射线引导下经椎间盘入路毁损内脏神经治疗上腹部癌痛的疗效及安全性。方法:选择上腹部癌痛患者26例,在放射线引导下经T11~12椎间盘入路穿刺,注射无水乙醇5.0 mL毁损内脏大、小神经,观察穿刺成功率,并记录术前、术后1天、1周、2周、1月、2月的疼痛强度(NRS评分)、生活质量评分(QOL),阿片类药物的用量以及手术不良反应的发生情况。结果:所有患者均穿刺到位,无严重并发症出现。和术前相比,术后各时点的NRS评分、每日吗啡消耗量下降,QOL评分增加(P0.05)。其中,6例患者发生暂时性腹泻,一周内恢复;5例患者出现不同程度的腹背部烧灼感,未经特殊处理24 h后症状消失。结论:在放射线引导下经椎间盘入路毁损内脏神经治疗上腹部癌痛的操作简单,疗效好,可显著提高患者的生活质量,且安全性高。     

肝癌疼痛与血浆VEGF、BDNF、FGF-2水平的相关性研究

目的:研究肝癌疼痛与血浆血管内皮生长因子(VEGF)、脑源性神经营养因子(BDNF)、纤维细胞生长因子-2(FGF-2)水平的相关性。方法:选择我院2018年10月～2019年7月收治的30例肝癌疼痛患者作为研究对象,依据疼痛程度分为4例轻度疼痛组、19例中度疼痛组、7例重度疼痛组,同期纳入30例肝癌无痛患者和30例健康对照组,比较各组血浆VEGF、BDNF和FGF-2水平,并分析肝癌疼痛患者血浆VEGF、BDNF和FGF-2水平和数字评分法(NRS)评分的相关性。结果:肝癌疼痛组血浆VEGF、BDNF、FGF-2水平显著高于肝癌无痛组及对照组(P0.05)。重度疼痛组血浆VEGF、BDNF、FGF-2水平显著高于中度疼痛组及轻度疼痛组(P0.05)。治疗后,肝癌疼痛患者血浆VEGF、BDNF、FGF-2水平显著低于治疗前(P0.05)。肝癌疼痛患者血浆VEGF、BDNF、FGF-2水平和NRS评分呈显著正相关(r值分别为0.619、0.571、0.563,P值均0.001)。结论:肝癌疼痛患者血浆VEGF、BDNF和FGF-2水平较肝癌无痛者明显上升,且和疼痛程度显著相关。     

Barrels IX-proceedings

The properties of a newly developed tonic heat pain model (THPM), which makes use of pulsating contact heat, were investigated in 18 young men. The most important feature of this model is that repetitive heat pulses with an intensity of 1°C above the individual pain threshold are employed. This approach was used to tailor the tonic pain stimulation to the individual pain sensitivity. In the first of two experiments, the effects of pulse frequencies ranging from 5 to 30 pulses per minute (ppm) on ratings of pain intensity and pain unpleasantness (visual analogue scales) were examined. At all frequencies, both ratings increased steadily over the 5-min test period. Frequencies of 15 ppm or more appeared to enhance pain intensity throughout the test period compared to the lower frequencies, but did not appear to alter pain unpleasantness. This suggests that only pain intensity is influenced by slow temporal summation and that a sort of frequency threshold exists for this kind of summation. In the second experiment, the THPM was compared to a well-established form of tonic pain stimulation, the compressor test (CPT); visual analogue scales were again used, and in addition the McGill Pain Questionnaire was employed. The CPT appeared to produce stronger tonic pain than the THPM. However, as is typical with tonic pain, both tonic pain models induced relatively higher values on the affective pain dimension than on the sensory pain dimension. The time course of pain was dynamic in the CPT, with an increase followed by a plateau phase, at least in those subjects who could tolerate the CPT for more than 60 sec. In contrast, as in the first experiment, the pain ratings in the THPM were characterized by a slow and steady increase over time. Moreover, there was absolutely no indication of a dichotomy between “pain-sensitive” and “pain-tolerant” individuals in the THPM, although such a dichotomy was evident in the CPT. This implies that the distinction between pain-sensitive and pain-tolerant individuals can be made only with the CPT, and that this distinction represents individual differences in peripheral vascular reactions to cold rather than in pain perception. In conclusion, the THPM appears to produce a stable and predictable temporal pattern of tonic pain with a predominant affective component, and to be suitable for application in the majority of individuals without causing undue discomfort.     

Numerical evaluation of the efficacy of small-caliber colonoscopes in reducing patient pain during a colonoscopy

Patient pain caused by a colonoscope is one of the main complications in completing a colonoscopy. Currently, randomized controlled trial (RCT) is one of the most used methods to evaluate the efficacy of small-caliber (SC) colonoscopes in reducing patient pain during a colonoscopy, compared with a standard colonoscope (SDC). However, many disturbing factors, including endoscopists’ skills, characteristics of patients and new technical features of the colonoscope (passive bending and high force transmission shaft), limit the reliability and generalizability of each finding in current RCTs. This paper focuses on modeling the insertion of colonoscopes within colon models using an explicit finite element method (FEM). Such a numerical model could overcome the limitations in RCTs. At the same time, it is expected to evaluate the efficacy of the small-caliber colonoscopes in reducing patient pain during a colonoscopy, while considering the effects of patient characteristics, including age, region and gender. The simulation results in this work showed that: compared with the SDC, a SC colonoscope may be more helpful in reducing discomfort for older patients, patients with smaller colon diameters and females.     

帕瑞昔布在肺癌手术多模式镇痛效果及其对凝血功能的影响

目的:研究帕瑞昔布在胸部肺癌手术后多模式镇痛效果及其对凝血功能的影响。方法:自2012年1月到2013年12月期间,全麻复合硬膜外麻醉下实施肺癌手术病人120例,分为3组,对照组(C组)和不同帕瑞昔布钠处理组(P1组和P2组)。对照组采用硬膜外镇痛,P1此基础上术前静脉用帕瑞昔布,P2组在P1基础上术后加用帕瑞昔布。观察三组手术时间、术中出血量、术中瑞芬太尼及术后吗啡用量、不同时间段VAS和术前术后凝血功能。结果:C组、P1和P2组术中出血量三组间的差异有统计学意义,P2组出血量最少(p0.05)。C组、P1和P2组术中瑞芬太尼和术后吗啡使用剂量差异有统计学意义(P均0.05)。C组、P1组和P2组术后6个月时间内疼痛发生率和6个月时间内疼痛发生天数差异有统计学意义(P均0.05)。术中PT、APTT在三组间的差异有统计学意义(P0.05)。结论:帕瑞昔布可降低病人开胸术后慢性疼痛综合征的发生,增加凝血功能,减少吗啡用量,且不增加不良反应发生几率,临床应用安全性可靠。     

Citrate enhances in vitro metastatic behaviours of PC-3M human prostate cancer cells: status of endogenous citrate and dependence on aconitase and fatty acid synthase

Prostate is a unique organ that produces and releases large amounts of citrate. This is reduced significantly in cancer and it is possible that citrate is (re)taken up and used as a metabolite to enhance cellular activity. The main purpose of this study was to determine how cytosolic citrate might affect in vitro metastatic cell behaviours (lateral motility, endocytosis and adhesion). Normal (PNT2-C2) and metastatic (PC-3M) human prostate cancer cells were used in a comparative approach. As regards intermediary metabolic enzymes, aconitase and fatty acid synthase, already implicated in prostate cancer, were evaluated. The level of intracellular citrate was significantly higher in PNT2-C2 cells under both control conditions and following preincubation in extracellular citrate. Supply of exogenous citrate enhanced endocytosis, lateral motility, decreased cell adhesion of PC-3M cells but failed to produce any effect on normal cells. Real-time PCR measurements showed that the mRNA levels of mitochondrial and cytosolic aconitases and fatty acid synthase were significantly higher in PC-3M cells. Correspondingly, aconitase activity was also higher in PC-3M cells. Using cerulenin (an inhibitor of fatty acid synthase), oxalomalate and fluorocitrate (inhibiting aconitases), we investigated the dependence of citrate-induced down-regulation of cellular adhesion on aconitase and fatty acid synthase activities. It was concluded: (1) that strongly metastatic PC-3M cells stored less/utilised more cytosolic citrate than the normal PNT2-C2 cells and (2) that cancer cells could metabolise cytoplasmic citrate via aconitase and fatty acid synthase to enhance their metastatic behaviour.