Quasi-Static, Poiseuille Flow of Analgesics from an Elastomeric Pump: Theoretical Determination of Infusion Times and Toxicity Conditions

Background: Elastomeric pumps (elastic balls into which analgesics or antibiotics can be inserted) push medicines through a catheter to a nerve or blood vessel. Since elastomeric pumps are small and need no power source, they fit easily into a pocket during infusion, allowing patient mobility. Elastomeric pumps are widely used and widely studied experimentally, but they have well-known problems, such as maintaining reliable flow rates and avoiding toxicity or other peak-and-trough effects. Objectives: Our research objective is to develop a realistic theoretical model of an elastomeric pump, analyze its flow rates, determine its toxicity conditions, and otherwise improve its operation. We believe this is the first such theoretical model of an elastomeric pump consisting of an elastic, medicine-filled ball attached to a horizontal catheter. Method: Our method is to model the system as a quasi-Poiseuille flow driven by the pressure drop generated by the elastic sphere. We construct an engineering model of the pressure exerted by an elastic sphere and match it to a solution of the one-dimensional radial Navier-Stokes equation that describes flow through a horizontal, cylindrical tube. Results: Our results are that the model accurately reproduces flow rates obtained in clinical studies. We also discover that the flow rate has an unavoidable maximum, which we call the “toxicity bump”, when the radius of the sphere approaches its terminal, unstretched value—an effect that has been observed experimentally. Conclusions: We conclude that by choosing the properties of an elastomeric pump, the toxicity bump can be restricted to less than 10% of the earlier, relatively constant flow rate. Our model also produces a relation between the length of time that the analgesic fluid infuses and the physical properties of the fluid, of the elastomeric sphere and the tube, and of the blood vessel into which the analgesic infuses. From these, we conclude that elastomeric pumps can be designed, using our simple model, to control infusion times while avoiding toxicity effects.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain(CMP)is a common occurrence in clinical practice and there are a variety of options for the treatment of it.However,the pharmacological therapy is still considered to be a primary treatment.The recent years have witnessed the emergence of opioid crisis,yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly.The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics.The purpose of this consensus is to present the application of nonsteroidal antiinflammatory drugs,serotonin norepinephrine reuptake inhibitors,serotonin and norepinephrine reuptake inhibitors,muscle relaxants,ion channel drugs and topical drugs in CMP.

Design, Synthesis of Analgesics and Anticancer of Some New Derivatives of Benzimidazole

This work, contains some new compounds from benzimidazole derivatives, which are synthesized by condensation of Orthophenylene diamine and Carbon disulfide resulting in 2-Mercapto-benzimidazole which is treated by alcoholic potassium hydroxide forming potassium salt of 2-mercaptobenzimidazole which reacts with different substances (alkyl chloroacetates, chloroacetic chloride, alkyl halides) also the ethoxy carbonyl methyl thiobenzimidazole reacts with different amines. In addition to chloromethyl benzimidazole which resulted from the reaction between orthophenylene diamine and chloroacetic acid, which reacted with different amines. The synthesized compound tested as analgesics and anticancer activity the new derivatives revealed moderate, strong and very strong analgesics and moderate and strong anticancer activity.

Research Progresses in Effects of Analgesics and Sedatives on Intracranial Pressure of Neurointensive Care Patients

At present, there are some concerns and problems to treat neurointensive care patients by using analgesics and sedatives. Conditions of neurointensive care patients change quickly. For neurointensive care patients who cannot have auxiliary examination timely, clinicians judge intracranial conditions mainly through relevant monitoring devices and consciousness and pupil changes of patients. The use of analgesics and sedatives is limited due to worry about influences on consciousness evaluation and judgment and different degrees of inhibition on cardiovascular system and respiratory system. Common sedatives (e.g. benzodiazepines) and common analgesics (e.g. morphine, fentanyl and sufentanil) both may inhibit respiration. The specification often provides taboos for the use of drugs by patients with increase intracranial pressure (ICP) and craniocerebral injuries. Through literature review, the author analyzed influences of analgesics and sedatives on ICP of neurointensive care patients comprehensively.

Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healingassociated genes

Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.

Gender Differences in Usage of Over-the-Counter Analgesics among Norwegian Adolescents

Introduction: Usage of over-the-counter (OTC) analgesic has increased among Norwegian adolescents since 2001. It has been noted that females tend to have a higher usage compared to males. In this paper we explore this gender difference. Data: Our dataset consists of 284,674 from Norwegian adolescents attending junior high school and high school between 2014 and 2017. Methods: The econometric approach consists of applying ordered logistic regressions with usage of OTC analgesics as the dependent variable and a dichotomous gender variable as the independent variable. Control variables include variables such as frequency of physical and mental health problems and other sociodemographic variables. Results: Gender, physical and mental health problems and various sociodemographic variables are found to have a significant effect on usage of OTC analgesics. Females are predicted to use significantly more analgesics. A large proportion of the gender difference evaporates when controlling for various other determinants. Conclusion: A considerable part of the observed gender difference in OTC analgesic usage can be traced back to differences in frequency and severity of physical and mental health problems. Part of the gender difference in usage, however remains unexplained.

Combining Human and Rodent Genetics to Identify New Analgesics

Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacolog- ically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design： the use of controlled inhibition of peripheral tetrahydrobiopterin （BH4） synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially iden- tified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype （present in 25% of Cau- casians） of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 （GCH1）. Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, target- ing the last enzyme of the BH4 synthesis pathway, sepiapterin reductase （SPR）, allows reduction of patholog- ical BH4 production without completely blocking physio- logical BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarker of target engagement, allowing potential quantification of drug efficacy. The emerging development of therapeutics that target BH4 synthesis to treat chronic pain illustrates the power of combining human and mouse genetics： human genetic studies for clinical selection of relevant targets, coupled with causality studies in mice, allowing the rational engineering of new analgesics.

Epoxymicranthols A-N,5,9-Epoxygrayanane Diterpenoids as Potent Analgesics from Rhododendron micranthum

Main observation and conclusion Fifteen 5,9-epoxygrayanane diterpenoids(1-15)including fourteen new ones,epoxymicranthols A-N(1-14),were isolated from the leaves extract of Rhododendron micranthum.Their structures were elucidated via extensive spectroscopic methods and ^(13)C NMR-DP4+analysis,and the absolute configurations of 1,3-10,14,and 15 were confirmed by single-crystal X-ray diffraction analysis.

Gait Assessment of Pain and Analgesics: Comparison of the DigiGait^(TM) and CatWalk^(TM） Gait Imaging Systems

Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors.Recent studies have indicated the superiority of gait analysis over traditional evaluations(e.g., skin sensitivity and sciatic function index [SFI]) in detecting subtle improvements and deteriorations in animal models. Here,pain-related gait parameters, whose criteria include(1)alteration in pain models,(2) correlation with nociceptive threshold, and(3) normalization by analgesics, were identified in representative models of neuropathic pain(spared nerve injury: coordination data) and inflammatory pain(intraplantar complete Freund’s adjuvant: both coordination and intensity data) in the DigiGait^TM and CatWalk^TM systems. DigiGait^TM had advantages in fixed speed(controlled by treadmill) and dynamic SFI, while CatWalk^TM excelled in intrinsic velocity, intensity data,and high-quality 3 D images. Insights into the applicability of each system may provide guidance for selecting the appropriate gait imaging system for different animal models and optimization for future pain research.

Clinical Research on Nourishing Yin and Unblocking Meridians Recipe Combined with Opioid Analgesics in Cancer Pain Management

Objective： To investigate the analgesic effects of Nourishing yin and Unblocking meridians Receipe （NUR） combined with opioid analgesics in managing cancer pain. Methods： All the patients enrolled were differentiated as of yin deficiency and meridian blocked syndrome type of TCM. Forty-one of them in the treated group were treated with NUR combined with opioid analgesics, while 43 of them in the control group were given opioid analgesics alone with successive 14 days as one treatment course for both groups. Results： The indexes of the treated group were superior to those in the control group as to the degree of pain-relieving, the therapeutic effect of analgesia, the occurrence frequency of cancer pain every day and its duration each time, the analgesic initial time, and the quality of life. Conclusion： NUR combined with opioid analgesics in cancer pain management was more effective than opioid analgesics alone. KEY WORDS

Pain management in chronic pancreatitis

Pain in chronic pancreatitis(CP)is difficult to manage.Many patients suffer from inadequate pain relief,completely incapacitating them in their daily activities.Historically,despite their well-known adverse effects,opioids have been the pillar of treatment regimens in painful CP.The management is now gradually evolving with a better understanding of the underlying pathophysiology of CP-related pain.Clinicians should follow a holistic approach to the management of CPassociated pain,which must involve lifestyle changes that are coupled with analgesic medications and other pain-relieving interventions.Furthermore,there is no easy cure for vanquishing CP-associated pain.Each patient must be evaluated on a case-by-case basis by a multidisciplinary team to decide which treatment option is best suited for that individual.

Analgesic and anti-inflammatory activity of Cotinus coggygria Scop.extracts in vivo

Objective:To assess the analgesic and anti-inflammatory effects of standardized extract of Cotinus coggygria(C.coggygria)in different animal models.Methods:C.coggygria extracts(25,50,and 100 mg/kg)were administered to rats and mice(n=6)during hot plate,tail-flick,acetic acid-induced writhing,and formalin tests to determine its analgesic efficacy.The anti-inflammatory activity of C.coggygria extracts was evaluated by histamine and carrageenan-induced paw edema,cotton pellet-induced granuloma,and acetic acid-induced peritoneal capillary dye leakage tests.Results:C.coggygria extracts(50 and 100 mg/kg)significantly alleviated thermal and chemical-induced pain in rodents(P<0.05).It also demonstrated notable anti-inflammatory properties by mitigating histamine and carrageenan-induced paw edema,granuloma deposits,and vascular permeability(P<0.05).Moreover,C.coggygria extracts remarkably reduced TNF-α,IL-1β,IL-6,COX-2,and oxidative stress in rat paws(P<0.05).Carrageenan-induced histological aberrations in hind paw tissues were effectively(P<0.05)mitigated by treatment with C.coggygria extracts.Conclusions:C.coggygria Scop.extracts show analgesic and anti-inflammatory effects via inhibition of COX-2 and inflammatory and oxidative mediators.

Anticancer,Anti-inflammatory,Analgesic,and Anxiolytic Effects of Koumine and Their Molecular Mechanisms

Koumine is an indole alkaloid monomer extracted from the Chinese herb Gelsemium elegans,which has a variety of pharmacological effects.This paper provides a comprehensive summary of the pharmacological effects and molecular mechanisms of koumine,with a particular emphasis on its mechanisms of action in the context of anticancer,anti-inflammatory,analgesic,and anxiolytic properties.The aim is to provide a theoretical foundation for further research and the application of koumine in clinical practice.

Analgesic Effect of Combined Spinal-Epidural Anesthesia and its Effect on TNF-α and CRP Levels in Elderly Patients with Hip Fracture During Surgical Treatment

Objective:To observe the analgesic effect of combined spinal and epidural anesthesia on older patients undergoing hip fracture surgery.Method:One hundred and twenty elderly hip fracture surgery patients treated in our hospital from January 2021 to December 2022 were selected and randomly divided into two groups,with 60 cases in the experimental group and 60 in the control group.The experimental group was given combined spinal-epidural anesthesia intervention measures,while the control group was given epidural anesthesia intervention measures.The analgesic effect,tumor necrosis factor-alpha(TNF-α),C-reactive protein(CRP)levels,and other observation indicators were analyzed after anesthesia intervention.Result:After the intervention,the analgesic effect and the evaluation results of the subjects in the experimental group were better than those in the control group(P<0.05);the obtained values of TNF-αand CRP levels in the experimental group were higher than those of the control group(P<0.05).Conclusion:The combined spinal-epidural anesthesia intervention demonstrated positive outcomes.The analgesic effect of patients during surgery and their inflammatory factor levels improved,which makes this intervention worthy of clinical application and promotion.

电针对佐剂性关节炎大鼠脾细胞IL-1和IL-2活性的影响

To seek for peripheral mechanism of electroacupuncture (EA) analgesia, observed effects of EA on activity of IL 1 and IL 2 in spleem cell in adjuvant arthritic (AA) rats of inflammatory pain model. METHODS Injected Freund’s complete adjuvant into the right hind paw of rats to produce AA model, stimulated Xuanzhong and Kunlun points with EA, adpoted H3 TdR and MTT methods to detect activity of IL 1 and SIL 2. RESULTS EA may raise activity of IL 1 and IL 2 in spleen cell in AA rats while Eaamalgesia. CONCLUSION The peripheral action of EA amalgesia on inflammatory pain is related to rising of IL 1 amd IL 2 activity.

Hyperammonemia,brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

AIM:To study the blood-brain barrier integrity,brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS:Adults male Wistar rats were divided into four groups.Group Ⅰ:sham operation;Ⅱ:Prehepatic portal hypertension,produced by partial portal vein ligation;Ⅲ: Acetaminophen intoxication and Ⅳ:Prehepatic portal hypertension plus acetaminophen.Acetaminophen was administered to produce acute hepatic injury.Portal pressure,liver serum enzymes and ammonia plasma levels were determined.Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity.Reflexes and behavioral tests were recorded. RESULTS:Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ.Uver enzymes and ammonia plasma levels were increased in groups Ⅱ,Ⅲ and Ⅳ.Prehepatic portal hypertension (group Ⅱ),acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia.Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ.Behavioral test (rota rod) was altered in group Ⅳ. CONCLUSION:These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (oltotoxic).Group Ⅳ,with behavioral altered test,can be considered as a model for study at an early stage of portal-systemic encephalopathy.

Pathogenesis and managenent of pain in chronic pancreatitis

INTRODUCTIONOf the three cardinal manifestations of chronic pancreatitis-pain,diabetes mellitus and steatorrhea,it is pain thatbrings the patient to the physician and is the most difficultto manage.The intractabale pain that is quite

Sedation and monitoring for gastrointestinal endoscopy

The safe sedation of patients for diagnostic or therapeutic procedures requires a combination of properly trained physicians and suitable facilities.Additionally,appropriate selection and preparation of patients,suitable sedative technique,application of drugs,adequate monitoring,and proper recovery of patients is essential.The goal of procedural sedation is the safe and effective control of pain and anxiety as well as to provide an appropriate degree of memory loss or decreased awareness.Sedation practices for gastrointestinal endoscopy(GIE) vary widely.The majority of GIE patients are ambulatory cases.Most of this procedure requires a short time.So,short acting,rapid onset drugs with little adverse effects and improved safety profiles are commonly used.The present review focuses on commonly used regimens and monitoring practices in GIE sedation.This article is to discuss the decision making process used to determine appropriate pre-sedation assessment,monitoring,drug selection,dose of sedative agents,sedation endpoint and post-sedation care.It also reviews the current status of sedation and monitoring for GIE procedures in Thailand.

Expert consensus of the Chinese Association for the Study of Pain on pain treatment with the transdermal patch

Chronic pain lasting more than 3 mo,or even several years can lead to disability.Treating chronic pain safely and effectively is a critical challenge faced by clinicians.Because administration of analgesics through oral,intravenous or intramuscular routes is not satisfactory,research toward percutaneous delivery has gained interest.The transdermal patch is one such percutaneous delivery system that can deliver drugs through the skin and capillaries at a certain rate to achieve a systemic or local therapeutic effect in the affected area.It has many advantages including ease of administration and hepatic first pass metabolism avoidance as well as controlling drug delivery,which reduces the dose frequency and side effects.If not required,then the patch can be removed from the skin immediately.The scopolamine patch was the first transdermal patch to be approved for the treatment of motion sickness by the Food and Drug Administration in 1979.From then on,the transdermal patch has been widely used to treat many diseases.To date,no guidelines or consensus are available on the use of analgesic drugs through transdermal delivery.The pain branch of the Chinese Medical Association,after meeting and discussing with experts and based on clinical evidence,developed a consensus for promoting and regulating standard use of transdermal patches containing analgesic drugs.

Translational pain research: Evaluating analgesic effect in experimental visceral pain models

Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can be achieved through stand-ardized experimental human pain models. Experimental pain models in healthy volunteers are advantageous for evaluation of analgesic action, as this is often diff icult to assess in the clinic because of confounding factors such as sedation, nausea and general malaise. These pain models facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic stud- ies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical treatment of visceral pain. To improve treatment of visceral pain, it is important to study the underlying mechanisms of pain and the action of analgesics used for its treatment. An experimental pain model activates different modalities and can be used to investigate the mechanism of action of different analgesics in detail. In combination with pharmacokinetic studies and objective assessment such as electroencephalography, new information re-garding a given drug substance and its effects can be obtained. Results from experimental human visceral pain research can bridge the gap in knowledge between animal studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.