Different Volumes of Local Anesthetics in Ultrasound-Guided Combined Interscalene-Supraclavicular Block for Traumatic Humeral Fracture

Background: Procedures that require anesthesia of entire length of the arm should have combined Interscalene block (ISB) and Supraclavicular block (SCB) to ensure adequate block. However, dual block requires high dose of local anesthetic (LA). We examined if Ultrasound (U/S) guided block helps to decrease the required volume of LA by visualizing trunks, so we only need injection of LA toward cervical nerve roots C5 and C6 aiming to block branches escaped from supraclavicular block. Patients and methods: Ninety-three patients were randomly allocated into one of three equal groups, each included 31 patients. All patients received SCB 20 ml (10 ml Bupivacaine 0.5% plus 10 ml lidocaine 2%) and ISB with different volumes of LA according to the group as follow: group A: 20 ml, group B: 15 ml, and group C: 10 ml. Result: No significant difference in onset of block (sensory and motor) and duration of block (motor only) between the three groups (P value > 0.05). The duration of sensory block was significantly longer in group A (760.65 ± 30.87 minutes) than in either group B (740.48 ± 21.15 minutes, P value P value P value P value P value P value < 0.001). Conclusion: A reduced volume of LA can be used in ultra sound guided ISB in combined with SCB to give satisfactory level of anesthesia to entire length of the arm, but the sensory block duration and duration of post-operative analgesia will be decreased significantly with decreasing the volume.

Effects of Repeated Injection of Local Anesthetic on Sciatic Nerve Blocks Response

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3 % chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aα/β, Aδ, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aα/β, Aδ, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3 % chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Aδ fiber mediated CAP was 108±20 and 92±14 min respectively (P>0.05). In normal rats the duration of first and third blocked Aδ fiber mediated CAP was 110±20 and 75±16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Kinetics of Local Anesthetic Interactions with Model Membranes: Adsorption and Permeation

Introduction: Local anesthetics (LAs) must be adsorbed to and permeate through membranes to reach their sites of action. The rates of these processes critically affect drug actions at the cellular level and also the in vivo pharmacokinetics of perineurally injected drugs. Therefore, we measured the adsorption equilibria and permeation kinetics of two LAs local anesthetics with markedly different hydrophobicities: tetracaine (TTC, Poctanol:buffer = 3.6 × 103) and procaine (PRO, Poctanol:buffer = 8.1 × 101), in unilamellar membranes of different composition and fluidity. Methods: Interactions with unilamellar vesicles made of dipalmitoylphosphatidylcholine (DPPC), at 23°C (solid gel state) or 45°C (liquid crystal state), without or with cholesterol (Chol), were investigated by a combination of fluorescence and stopped-flow techniques. Membrane adsorption was monitored by the LA’s fluorescence. Membrane permeation was monitored by the decrease of fluorescence intensity of intra-vesicular pyranine, when quenched by neighboring TTC or PRO. Results: Ionized TTC (TTCH+) and procaine (PROH+) adsorb to membranes more slowly and weakly than their neutral counterparts (time constant τ ~ 0.1 sec). Fluidizing of membranes, at the higher temperature (45°C) or by Chol inclusion, accelerated LA adsorption (faster than the mixing time of the stopped-flow device, 0.008 s). Permeation of protonated TTCH+ through the solid gel DPPC membranes (23°C) occurred far more slowly than adsorption, (τ = 36.7 ± 0.7 s, n = 9), and 3 times slower than neutral TTC (τ = 10.9 ± 0.7 s, n = 9);neutral PRO permeated these membranes at the same rate as TTC. Inclusion of Chol with DPPC, disordering the fatty acyl tails of membrane phospholipids while crowding their polar headgroups, slowed permeation of TTC and of PRO to an even greater degree. Conclusions: Local anesthetic permeation through membranes is limited by the transport across the membrane core and not by the initial binding. Drug ionization greatly slows permeation, but greater hydrophobicity does not facilitate it. Lipid crowding caused by Chol, a normal membrane component, slows permeation by disorienting the LA bound at the surface.

Pharmacological modulation of brain Nav1.2 and cardiac Nav1.5 subtypes by the local anesthetic ropivacaine

Objective The present study was aimed to investigate the pharmacological modulatory effects of ropivacaine,an amide-type local anesthetic,on rat Nav1.2（rNav1.2）and rNav1.5,the two Na＋channel isoforms heterologously expressed in Xenopus oocytes and in HEK293t cell line,respectively.Methods Two-electrode voltage-clamp（TEVC）and whole-cell patchclamp recordings were employed to record the whole-cell currents.Results Ropivacaine induced tonic inhibition of peak Na＋ currents of both subtypes in a dose-and frequency-dependent manner.rNav1.5 appeared to be more sensitive to ropivacaine.In addition,for both Na＋channel subtypes,the steady-state inactivation curves,but not the activation curves,were significantly shifted to the hyperpolarizing direction by ropivacaine.Use-dependent blockade of both rNav1.2 and rNav1.5 channels was induced by ropivacaine through a high frequency of depolarization,suggesting that ropivacaine could preferentially bind to the 2 inactivated Na＋channel isoforms.Conclusion The results will be helpful in understanding the pharmacological modulation by ropivacaine on Nav1.2 subtype in the central nervous system,and on Nav1.5 subtype abundantly expressed in the heart.

The effects of local anesthetics on intracellular Ca2+ release from ryanod ine-sensitive Ca2+ stores in gerbil hippocampal neurons

OBJECTIVE: To examine the effects of procaine and lidocaine on intracellular Ca(2+) release from sarcoplasmic reticulum ryanodine-sensitive Ca(2+) stores. METHODS: The experiment was performed on hippocampal slices from 60-80 g male Mongolian gerbils. Levels of intracellular Ca(2+) concentration in the slices were measured by microfluorometry. The slices were perfused with 50 mmol/L KCl containing medium for 30 seconds. Then, the medium was switched to physiological medium. After 5 min of incubation, the slice was perfused with 20 mmol/L caffeine containing physiology medium for 2 min. Following incubation, the slice was superfused with physiological medium until the end of the experiment. The effects of procaine and lidocanin (100 micro mol/L) on caffeine-evoked Ca(2+) release were evaluated by adding them to the medium after high K(+) medium perfusion. RESULTS: Caffeine induced a marked increase in intracellular Ca(2+) concentration which was then decreased 12% upon the addition of procaine (P

Minimum effective local anesthetic dose of intrathecal hyperbaric ropivacaine and bupivacaine for cesarean section

Background Intrathecal anesthesia is commonly used for cesarean section. Bupivacaine and ropivacaine have all been used as intrathecal drugs. The minimum effective local anesthetic dose （MLAD） of intrathecal ropivacaine for nonobstetric patients has been reported. However, few data are available on the MLAD of hyperbaric ropivacine for obstetric patients and the relative potency to bupivacaine has not been fully determined. In this study, we sought to determine the MLAD of intrathecal ropivacaine and bupivacaine for elective cesarean section and to define their relative potency ratio.Methods We enrolled forty parturients undergoing elective cesarean section under combined spinal-epidural anesthesia and randomized them to one of two groups to receive intrathecal 0.5% hyperbaric ropivacaine or bupivacaine.The initial dose was 10 mg, and was increased in increments of 1 mg, using the technique of up-down sequential allocation. Efficacy was accepted if adequate sensory dermatomal anesthesia to pin prick to T7 or higher was attained within 20 minutes after intrathecal injection, and required no supplementary epidural injection for procedure until at least 50 minutes after the intrathecal injection.Results The intrathecal MLAD was 9.45 mg （95%confidence interval （CI）, 8.45-10.56 mg） for ropivacaine and 7.53 mg （95%CI, 7.00-8.10 mg） for bupivacaine. The relative potency ratio was 0.80 （95% Cl, 0.74-0.85） for ropivacaine/bupivacaine when given intrathecally in cesarean section.Conclusion Ropivacaine is 20% less potent than bupivacaine during intrathecal anesthesia for cesarean delivery.

A Spiral History of the Development of Ways to Identify the Correct Position of the Injection Needle in Relation to the Peripheral Nerve: A Brief Historical Essay

The first way to identify the needle in relation to the peripheral nerve W. Halsted and R. Hall in 1884 performed the first regional blockade (using direct visualization). However, Vassily von Anrep was a few months earlier described the blockade of the peripheral nerve by anatomical landmarks. In 1912, the blockade of the brachial plexus was first performed using electrical stimulation, but this technique has been widely used only since 1962. The most popular way to identify the needle relative to the nerve at the moment remains US guidance. A promising direction may be optical coherence tomography. But this method is under development. In the last decade, a method for determining the pressure of a local anesthetic has been introduced into practice to determine the position of the needle relative to the nerve.

Extracts from rabbit skin inflamed by the vaccinia virus attenuate bupivacaine-induced spinal neurotoxicity in pregnant rats

Extracts from rabbit skin inflamed by the vaccinia virus can relieve pain and promote repair of nerve injury. The present study intraperitoneally injected extracts from rabbit skin inflamed by the vaccinia virus for 3 and 4 days prior to and following intrathecal injection of bupivacaine into pregnant rats. The pain threshold test after bupivacaine injection showed that the maximum possible effect of tail-flick latency peaked 1 day after intrathecal injection of bupivacaine in the extract-pretreatment group, and gradually decreased, while the maximum possible effect in the bupivacaine group continued to increase after intrathecal injection of bupivacaine. Histological observation showed that after 4 days of intrathecal injection of bupivacaine, the number of shrunken, vacuolated, apoptotic and caspase-9-positive cells in the dorsal root ganglion in the extract-pretreatment group was significantly reduced compared with the bupivacaine group. These findings indicate that extracts from rabbit skin inflamed by the vaccinia virus can attenuate neurotoxicity induced by intrathecal injection of bupivacaine in pregnant rats, possibly by inhibiting caspase-9 protein expression and suppressing nerve cell apoptosis.

Effect of Nalbuphine as Adjuvant to Bupivacaine for Ultrasound-Guided Supraclavicular Brachial Plexus Block

Background: Nalbuphine is a derivative of 14-hydroxymorphine which is a strong analgesic with mixed k agonist and μ antagonist. Nalbuphine was studied several times as adjuvant to local anesthetics in spinal, epidural and local intravenous block. The aim of this study was to evaluate the effect of nalbuphine as an adjuvant to local anesthetics in supraclavicular brachial plexus block. Patients and Methods: Fifty-six patients undergoing elective forearm and hand surgery under supraclavicular brachial plexus block were allocated randomly into one of two groups of 28 patients each to receive either 25 ml (0.5%) bupivacaine with 1 ml of NS or 25 ml (0.5%) bupivacaine with 1 ml (20 mg) nalbuphine. Onset time and duration of both sensory and motor block, and post-operative analgesia were observed. Result: Nalbuphine group showed significant increase in the duration of motor block (412.59 ± 18.63), when compared to control group (353.70 ± 29.019) p-value < 0.001, also, there was significant increase in sensory duration in nalbuphine group (718.14 ± 21.04) when compared to control group (610.18 ± 26.33) p-value < 0.001, without affecting the onset time of the blockade. And also, there was a significant increase in the duration of analgesic effect in nalbuphine group (835.18 ± 42.45) when compared to control group (708.14 ± 54.57) p-value < 0.001. Conclusion: The present study demonstrates that addition of 20 mg nalbuphine to bupivacaine in supraclavicular brachial plexus block is associated with significant increase in the duration of both sensory and motor block and also prolong the duration of analgesia.

Regional anesthesia for orthopedic procedures:What orthopedic surgeons need to know

Regional anesthesia is an integral component of successful orthopedic surgery.Neuraxial anesthesia is commonly used for surgical anesthesia while peripheral nerve blocks are often used for postoperative analgesia.Patient evaluation for regional anesthesia should include neurological,pulmonary,cardiovascular,and hematological assessments.Neuraxial blocks include spinal,epidural,and combined spinal epidural.Upper extremity peripheral nerve blocks include interscalene,supraclavicular,infraclavicular,and axillary.Lower extremity peripheral nerve blocks include femoral nerve block,saphenous nerve block,sciatic nerve block,iPACK block,ankle block and lumbar plexus block.The choice of regional anesthesia is a unanimous decision made by the surgeon,the anesthesiologist,and the patient based on a risk-benefit assessment.The choice of the regional block depends on patient cooperation,patient positing,operative structures,operative manipulation,tourniquet use and the impact of postoperative motor blockade on initiation of physical therapy.Regional anesthesia is safe but has an inherent risk of failure and a relatively low incidence of complications such as local anesthetic systemic toxicity(LAST),nerve injury,falls,hematoma,infection and allergic reactions.Ultrasound should be used for regional anesthesia procedures to improve the efficacy and minimize complications.LAST treatment guidelines and rescue medications(intralipid)should be readily available during the regional anesthesia administration.

Safety of upper endoscopy in patients with active cocaine use

BACKGROUND Cocaine is a synthetic alkaloid initially viewed as a useful local anesthetic,but which eventually fell out of favor given its high addiction potential.Its predominantly sympathetic effects raise concern for cardiovascular,respiratory,and central nervous system complications in patients undergoing procedures.Periprocedural cocaine use,often detected via a positive urine toxicology test,has been mostly addressed in the surgical and obstetrical literature.However,there are no clear guidelines on how to effectively risk stratify patients found to be positive for cocaine in the pre-operative setting,often leading to costly procedure cancellations.Within the field of gastroenterology,there is no current data available regarding safety of performing esophagogastroduodenoscopy(EGD)in patients with recent cocaine use.AIM To compare the prevalence of EGD related complications between active(≤5 d)and remote(>5 d)users of cocaine.METHODS In total,48 patients who underwent an EGD at John H.Stroger,Jr.Hospital of Cook County from October 2016 to October 2018 were found to have a positive urine drug screen for cocaine(23 recent and 25 remote).Descriptive statistics were compiled for patient demographics.Statistical tests used to analyze patient characteristics,procedure details,and preprocedural adverse events included ttest,chi-square,Wilcoxon rank sum,and Fisher exact test.RESULTS Overall,20 periprocedural events were recorded with no statistically significant difference in distribution between the two groups(12 active vs 8 remote,P=0.09).Pre-and post-procedure hemodynamics demonstrated only a statistically,but not clinically significant drop in systolic blood pressure and increase in heart rate in the active user group,as well as drop in diastolic blood pressure and oxygen saturation in the remote group(P<0.05).There were no significant differences in overall hemodynamics between both groups.CONCLUSION Our study found no significant difference in the rate of periprocedural adverse events during EGD in patients with recent vs remote use of cocaine.Interestingly,there were significantly more patients(30%)with active use of cocaine that required general anesthesia as compared to remote users(0%).

Sciatic Nerve Block with Ropivacaine and Prilocaine in a Patient with Chronic Progressive External Ophthalmoplegia(CPEO)

The anesthetic implications of caring for patients with mitochondrial myopathies (MM) are not well defined, and the few case reports that have been published are contradictory. Local anesthetics particularly have the potential to worsen neuromuscular manifestations via direct effects on mitochondrial bioenergetics. Here we describe the anesthetic management of a patient with chronic progressive external ophthalmoplegia (CPEO) in which a sciatic nerve block with ropivacaine and prilocaine was performed and review the available related literature.

Dose-response study of spinal hyperbaric ropivacaine for cesarean section

Background： Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind, randomized, dose-response study determined the ED50 （50% effective dose） and ED95 （95% effective dose） of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods： Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1-L2 vertebral interspace then lumbar puncture was performed at the L3-L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels （pinprick） were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective if an upper sensory level to pin prick of T7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results： ED50 （95% confidence interval） of spinal hyperbaric ropivacaine was determined to be 10.37 （5.23-11.59） mg and ED95 （95% confidence interval） to be 15.39 （13.81-23.59） mg. The maximum sensory block levels and the duration of motor block and the rate of hypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion： The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery.

Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats

AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,suggests that an additional pathway could mediate the cholinergic contraction.The involvement of more than one muscarinic receptor(functionally predominant type 3 over type 2)also suggests more than one pathway mediating the cholinergic contraction in rat antrum.

Effects of mixture of lidocaine and ropivacaine at different concentrations on the central nervous system and cardiovascular toxicity in rats

Background Lidocaine and ropivacaine are often combined in clinical practice to obtain a rapid onset and a prolonged duration of action. However, the systemic toxicity of their mixture at different concentrations is unclear. This study aimed to compare the systemic toxicity of the mixture of ropivacaine and lidocaine at different concentrations when administered intravenously in rats. Methods Forty-eJght male WJstar rats were randomly divided into 4 groups （n=12 each）： 0.5% ropJvacaine （group Ⅰ）; 1.0% ropivacaine and 1.0% lidocaine mixture （group Ⅱ）; 1.0% ropivacaine and 2.0% lidocaine mixture （group Ⅲ）; and 1.0% lidocaine （group Ⅳ）. Local anesthetics were infused at a constant rate until cardiac arrest. Electrocardiogram, electroencephalogram and arterial blood pressure were continuously monitored. The onset of toxic manifestations （seizure, dysrhythmia, and cardiac arrest） was recorded, and then the doses of local anesthetics were calculated. Arterial blood samples were drawn for the determination of local anesthetics concentrations by high-performance liquid chromatography. Results The onset of dysrhythmia was later significantly in group IV than in group Ⅰ, group Ⅱ, and group Ⅲ （P 〈0.01）, but there was no significant difference in these groups （P 〉0.05）. The onset of seizure, cardiac arrest in group Ⅰ （（9.2±1.0） min, （37.0±3.0） min） was similar to that in group Ⅱ（（9.1±0.9） min, （35.0±4.0） min） （P 〉0.05）, but both were later in group Ⅲ （（7.5±0.7） min, （28.0±3.0） min） （P 〈0.05）. The onset of each toxic manifestation was significantly later in group Ⅳ than in group Ⅰ （P 〈0.01）. The plasma concentrations of the lidocaine-alone group at the onset of dysrhythmia （DYS）, cardiac arrest （CA） （（41.2±6.8） min, （59.0±9.0） min） were higher than those of the ropivacaine alone group （（20.5±3.8） min, （38.0±8.0） min） （P 〈0.05）. The plasma concentrations of ropivacaine inducing toxic manifestation were not significantly different among groups Ⅰ, Ⅱ, and Ⅲ（P 〉0.05）. Conclusions The systemic toxicity of the mixture of 1.0% ropivacaine and 2.0% lidocaine is the greatest while that of 1.0% lidocaine is the least. However, the systemic toxicity of the mixture of 1.0% ropivacaine and 1.0% lidocaine is similar to that of 0.5% ropivacaine alone.

改良低浓度长效骶管阻滞用于药物中期引产的疗效观察

目的探讨改良低浓度长效骶管阻滞用于药物中期引产的疗效。方法将63例中期引产产妇按照数字表法随机分为对照组和治疗组，对照组无镇痛要求，治疗组给予镇痛治疗。对照组产妇给予米非司酮、复方雌孕片以及乳酸依沙吖啶注射液进行引产；治疗组产妇则在对照组基础上给予0．75％盐酸布比卡因4-7ml＋2％盐酸利多卡因5ml＋0．9％氯化钠注射液15ml＋硫酸吗啡注射液2mg骶管阻滞镇痛。观察并比较两组产妇产程及出血量，并对疼痛程度进行评估。结果治疗组产程为（5．33±3．77）h，短于对照组的（7．88±2．62）h（t=8．01，P〈0．05）；治疗组疼痛分级均优于对照组（均P〈0．05）；两组出血量差异无统计学意义（t=4．63，P〉0．05）。结论在药物引产后采用改良骶管阻滞，镇痛效果显著，可使产程缩短，且不增加产后出血，值得临床推广应用。

Analgesic nanomedicines for the treatment of chronic pain

Chronic pain is a major cause of suffering that often accompanies diseases and therapies,affecting approximately 20%of individuals at some point in their lives.However,current treatment modalities,such as anesthetic and antipyretic analgesics,have limitations in terms of efficacy and side effects.Nanomedical technology offers a promising avenue to overcome these challenges and introduce new therapeutic mechanisms.This article reviews the recent research on nanomedicine analgesics,integrating analyses of neuroplasticity changes in neurons and pathways related to the transition from acute to chronic pain.Furthermore,it explores potential future strategies using nanomaterials,aiming to provide a roadmap for new analgesic development and improved clinical pain management.By leveraging nanotechnology,these approaches hold the potential to revolutionize pain treatment by delivering targeted and effective relief while minimizing side effects.