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Background: Continuous wound infusion (CWI) is effective for post-operative pain management, but the effect of prolonged infusions and the use of steroids in the infused mixture have never been addressed. We investigate the effect of prolonged CWI with ropivacaine 0.2% (R) over seven days and methylprednisolone (Mp) 1 mg/kg infused in the wound in the first 24 hours., Methods: This is a randomized, double blind, phase III trial (RCT) in major abdominal surgery with laparotomy. After a 24-hours pre-peritoneal CWI of R-Mp, patients were randomized to receive either R-Mp or placebo for the next 24 hours. Then, patient-controlled CWI with only ropivacaine 0.2% or placebo (according to the randomization group) was planned between 48 hours and seven days after surgery. Morphine equivalents at seven days were analyzed, together with any catheter- or drug-related side effect and PPSP at 3 months., Results: We enrolled 120 patients (63 in the CWI group, 57 in the placebo group). Prolonged CWI did not reduce opioid consumption in the first seven postoperative days (P=0.08). CWI was associated with reduced consumption of non-opioid analgesics (P=0.03). Most of the patients continued to require bolus in the surgical wound beyond 48 hours. PPSP prevalence was not different between groups., Conclusions: Prolonged infusion with R-Mp is safe and effective but did not reduce opioid consumption in the seven days after surgery or PPSP prevalence.

Background . Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods . Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results . Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups ( P > 0.05). Conclusions . There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested., Competing Interests: The authors declare that they have no competing interests.

Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release.

Neuropathic pain is caused by a lesion or disease affecting the somatosensory system and is difficult to manage, often proving refractory to existing treatments. In more than half of cases, it is localized and affects a specific, clearly circumscribed area of the body (localized neuropathic pain, or LNP). A recently developed screening tool enables patients with probable neuropathic pain/LNP to be identified quickly and easily. In view of the conflicting current treatment recommendations, an advisory board of pain specialists met in June 2015 to develop a complementary treatment guidance algorithm, for use in the primary care setting and by non-pain specialists. The starting point of the algorithm is a diagnosis of LNP and there was consensus that first-line treatment should be a topical analgesic agent, because the benefit/risk ratios are far better than for systemic agents. Topical application offers site-specific delivery, a lower total systemic dose and avoidance of first-pass metabolism, reducing the risk of adverse events and drug/drug interactions. The 5% lidocaine medicated plaster has most evidence supporting its use in LNP, producing effective analgesia and reducing the associated area of allodynia, but other topical agents include capsaicin, clonidine and botulinum toxin type A. Treatment should be commenced with the topical agent of choice, and the patient re-assessed after an appropriate period. Where the response is good the topical agent is continued, with a re-evaluation after 3-6 months. A systemic agent (e.g. gabapentin, pregabalin, duloxetine, venlafaxine) is added if there is only a partial response, or substituted if there is no response, and the patient re-assessed after a month. If there is poor or no response to the systemic agent the patient should be switched to an alternative one and, if this also proves ineffective, referred to a pain specialist.

Background: Inflammatory response is one of the key components of pain perception. Continuous infusion (CWI) of local anesthetics has been shown to be effective in controlling pain and reducing postoperative morphine consumption, but the effect of adding a potent anti-inflammatory drug (such as a steroid) has never been addressed. In our study, we want to investigate the effect of CWI with local anesthetic + methylprednisolone on acute and persistent pain, correlating clinical data with biomarkers of inflammation and genetic background., Methods/design: After approval by their institutional review board, three hospitals will enroll 120 patients undergoing major abdominal surgery in a randomized, double-blind, phase III study. After a 24-h CWI of ropivacaine 0.2 % + methylprednisolone 1 mg/kg, patients will be randomly assigned to receive either ropivacaine + steroid or placebo for the next 24 h. Then, patient-controlled CWI with only ropivacaine 0.2 % or placebo (according to the group of randomization) is planned after 48 h up to 7 days (bolus 10 ml, lock-out 1 h, maximum dose of 40 ml in 4 h). Morphine equivalent consumption up to 7 days will be analyzed, together with any catheter- or drug-related side effect. Persistent post-surgical pain (PPSP) incidence will also be investigated. Our primary endpoint is analgesic consumption in the first 7 days after surgery; we will evaluate, as secondary endpoints, any catheter- or drug-related side effect, genotype/phenotype correlations between some polymorphisms and postoperative outcome in terms of morphine consumption, development of the inflammatory response, and incidence of PPSP. Finally, we will collect, in a subgroup of patients, wound exudate samples by micro-dialysis, blood samples, and urine samples up to 72 h to investigate local and systemic inflammation and oxidative stress., Discussion: This is a phase III trial to evaluate the safety and efficacy of wound infusion with steroid and local anesthetic. The study is aimed also to evaluate how long this infusion has to be maintained in order to maximize effectiveness. Our data are intended to quantify the amount of ropivacaine and methylprednisolone needed by patients undergoing major abdominal surgery, to be stored in a new nanotechnology device for sustained pain treatment after surgery. We also aim to clarify the roles of inflammatory response, oxidative stress, and genetic background on postoperative and persistent pain after major abdominal surgery., Trial Registration: The trial was registered on ClinicalTrials.gov ( NCT02002663 ) on 24 Oct. 2013.

Background: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion., Methods: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 μg/mL or of ropivacaine 0.2% + sufentanil 0.75 μg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses., Results: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups., Conclusions: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.

Study Objective: To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain., Design: Multicenter, randomized, case-control trial., Design Classification: Canadian Task Force Classification I., Setting: University hospitals in Italy., Patients: One hundred forty patients scheduled for laparoscopic ovarian cystectomy., Interventions: Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland)., Measurements and Main Results: One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035)., Conclusion: Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Acute pain remains a tremendous clinical and economic burden, as its prevalence and common narcotic-based treatments are associated with poorer outcomes and higher costs. Multimodal analgesia portends great therapeutic promise, but rarely allows opioid sparing, and new alternatives are necessary. Microparticles (MPs) composed of biodegradable polymers [e.g., poly(lactic-co-glycolic acid) or PLGA] have been applied for controlled drug release and acute pain treatment research. However, foreign particles' presence within inflamed tissue may affect the drug release or targeting, and/or cause a secondary inflammatory reaction. We examined how small alterations in the particulate nature of MPs affect both their uptake into and subsequent activation of macrophages. MPs composed of PLGA and chitosan (PLGA-Chi) loaded with bupivacaine (BP) were engineered at different sizes and their opsonization by J774 macrophages was assessed. Uptake of PLGA-Chi by macrophages was found to be size dependent, but they were not cytotoxic or proinflammatory in effect. Moreover, encapsulation of MPs in a thermoresponsive loading gel (pluronic F-127) effectively prevented opsonization. Finally, MPs displayed sustained, tunable release of BP up to 7 days. These results demonstrate our ability to develop a drug delivery system capable of controlled release of local anesthetics to treat acute/subacute pain while concurrently avoiding enhanced inflammation., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Introduction: Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time., Areas Covered: This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013., Expert Opinion: The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach.

Background: Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion., Materials and Methods: We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 μg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software)., Results: Mean plasma concentration of ropivacaine at the end of epidural infusion (C(48 h)) was 1.69 μg/mL (0.21-3.8 μg/mL). Mean (range) C(max) was 1.82 μg/mL (0.61-4.0 μg/mL); the area under the plasma concentration curve, AUC ((0-60)), was 67.48 ± 30.60 μg·h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0-3.0 μg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 μg/mL, namely 3.8 and 4.0 μg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 μg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h)=15.04-0.148 × age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t(1/2,DP)=0.693 × Vd/CL) was 10.8 h., Conclusions: Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t(1/2,DP) is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.