Despite multi-modal analgesic techniques, acute postoperative pain remains an unmet health need, with up to three quarters of people undergoing surgery reporting significant pain. Liposomal ...bupivacaine is an analgesic consisting of bupivacaine hydrochloride encapsulated within multiple, non-concentric lipid bi-layers offering a novel method of sustained-release analgesia.
To assess the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain.
On 13 January 2016 we searched CENTRAL, MEDLINE, MEDLINE In-Process, Embase, ISI Web of Science and reference lists of retrieved articles. We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched clinical trials databases for ongoing trials.
Randomised, double-blind, placebo- or active-controlled clinical trials in people aged 18 years or over undergoing elective surgery, at any surgical site, were included if they compared liposomal bupivacaine infiltration at the surgical site with placebo or other type of analgesia.
Two review authors independently considered trials for inclusion, assessed risk of bias, and extracted data. We performed data analysis using standard statistical techniques as described in the Cochrane Handbook for Systematic Reviews of Interventions, using Review Manager 5.3. We planned to perform a meta-analysis and produce a 'Summary of findings' table for each comparison however there were insufficient data to ensure a clinically meaningful answer. As such we have produced two 'Summary of findings' tables in a narrative format. Where possible we assessed the quality of evidence using GRADE.
We identified nine studies (10 reports, 1377 participants) that met inclusion criteria. Four Phase II dose-escalating/de-escalating trials, designed to evaluate and demonstrate efficacy and safety, presented pooled data that we could not use. Of the remaining five parallel-arm studies (965 participants), two were placebo controlled and three used bupivacaine hydrochloride local anaesthetic infiltration as a control. Using the Cochrane tool, we judged most studies to be at unclear risk of bias overall; however, two studies were at high risk of selective reporting bias and four studies were at high risk of bias due to size (fewer than 50 participants per treatment arm).Three studies (551 participants) reported the primary outcome cumulative pain intensity over 72 hours following surgery. Compared to placebo, liposomal bupivacaine was associated with a lower cumulative pain score between the end of the operation (0 hours) and 72 hours (one study, very low quality). Compared to bupivacaine hydrochloride, two studies showed no difference for this outcome (very low quality evidence), however due to differences in the surgical population and surgical procedure (breast augmentation versus knee arthroplasty) we did not perform a meta-analysis.No serious adverse events were reported to be associated with the use of liposomal bupivacaine and none of the five studies reported withdrawals due to drug-related adverse events (moderate quality evidence).One study reported a lower mean pain score at 12 hours associated with liposomal bupivacaine compared to bupivacaine hydrochloride, but not at 24, 48 or 72 hours postoperatively (very low quality evidence).Two studies (382 participants) reported a longer time to first postoperative opioid dose compared to placebo (low quality evidence).Two studies (325 participants) reported the total postoperative opioid consumption over the first 72 hours: one study reported a lower cumulative opioid consumption for liposomal bupivacaine compared to placebo (very low quality evidence); one study reported no difference compared to bupivacaine hydrochloride (very low quality evidence).Three studies (492 participants) reported the percentage of participants not requiring postoperative opioids over initial 72 hours following surgery. One of the two studies comparing liposomal bupivacaine to placebo demonstrated a higher number of participants receiving liposomal bupivacaine did not require postoperative opioids (very low quality evidence). The other two studies, one versus placebo and one versus bupivacaine hydrochloride, found no difference in opioid requirement (very low quality evidence). Due to significant heterogeneity between the studies (I
= 92%) we did not pool the results.All the included studies reported adverse events within 30 days of surgery, with nausea, constipation and vomiting being the most common. Of the five parallel-arm studies, none performed or reported health economic assessments or patient-reported outcomes other than pain.Using GRADE, the quality of evidence ranged from moderate to very low. The major limitation was the sparseness of data for outcomes of interest. In addition, a number of studies had a high risk of bias resulting in further downgrading.
Liposomal bupivacaine at the surgical site does appear to reduce postoperative pain compared to placebo, however, at present the limited evidence does not demonstrate superiority to bupivacaine hydrochloride. There were no reported drug-related serious adverse events and no study withdrawals due to drug-related adverse events. Overall due to the low quality and volume of evidence our confidence in the effect estimate is limited and the true effect may be substantially different from our estimate.
Chronic postsurgical pain (CPSP) occurs in 12% of surgical populations and is a high priority for perioperative research. Systemic lidocaine may modulate several of the pathophysiological processes ...linked to CPSP. This systematic review aims to identify and synthesize the evidence linking lidocaine infusions and CPSP. The authors conducted a systematic literature search of the major medical databases from inception until October 2017. Trials that randomized adults without baseline pain to perioperative lidocaine infusion or placebo were included if they reported on CPSP. The primary outcome was the presence of procedure-related pain at 3 months or longer after surgery. The secondary outcomes of pain intensity, adverse safety events, and local anesthetic toxicity were also assessed. Six trials from 4 countries (n = 420) were identified. Chronic postsurgical pain incidence was consistent with existing epidemiological data. Perioperative lidocaine infusions significantly reduced the primary outcome (odds ratio, 0.29; 95% confidence interval, 0.18-0.48), although the difference in intensity of CPSP assessed by the short-form McGill Pain Questionnaire (4 trials) was not statistically significant (weighted mean difference, -1.55; 95% confidence interval, -3.16 to 0.06). Publication and other bias were highly apparent, as were limitations in trial design. Each study included a statement reporting no adverse events attributable to lidocaine, but systematic safety surveillance strategies were absent. Current limited clinical trial data and biological plausibility support lidocaine infusions use to reduce the development of CPSP without full assurances as to its safety. This hypothesis should be addressed in future definitive clinical trials with comprehensive safety assessment and reporting.
Objectives
We aimed to assess the efficacy of greater occipital nerve (GON) blockade at chronic migraine (CM) treatment.
Materials and methods
Patients with CM were randomly divided into two groups ...of 42. GON blockade was administered four times (once per week) with saline in group A or bupivacaine in group B. After 4 weeks of treatment, blinding was removed; in group A, GON blockade was achieved using bupivacaine, while group B continued to receive bupivacaine, and blockade was administered once per month, then followed for 2 months. Primary endpoint was the difference in number of headache days, duration of headache, and pain scores.
Results
Seventy‐two of 84 patients completed the study. After 1 month of treatment, number of headache days had decreased from 16.9 ± 5.7 to 13.2 ± 6.7 in group A (P = 0.035) and from 18.1 ± 5.3 to 8.8 ± 4.8 in group B (P < 0.001), (P = 0.004, between groups); duration of headache (hour) had decreased from 24.2 ± 13.7 to 21.2 ± 13.4 in group A (P = 0.223) and from 25.9 ± 16.3 to 19.3 ± 11.5 in group B (P < 0.001), (P = 0.767, between groups). VAS score decreased from 8.1 ± 0.9 to 6.7 ± 1.6 in group A (P = 0.002) and from 8.4 ± 1.5 to 5.3 ± 2.1 in group B (P < 0.001), (P = 0.004, between groups). After blinding was removed (in 2nd and 3rd month), group A exhibited similar results like group B in 3rd month.
Conclusions
Our results suggest that GON blockade with bupivacaine was superior to placebo and was found to be effective, safe, and cost‐effective for the treatment of CM. According to our knowledge, this is the first randomized, multicentre, double‐blind, and placebo‐controlled study in the literature in this field of work.
Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications ...of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations.
The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer.
Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system.
All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.
The aim of this review was to compare the effects of postoperative epidural analgesia with local anesthetics to postoperative systemic or epidural opioids in terms of return of gastrointestinal ...transit, postoperative pain control, postoperative vomiting, incidence of gastrointestinal anastomotic leak, hospital length of stay, and cost after abdominal surgery.
Trials were identified by computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 12), Medical Literature Analysis and Retrieval System Online (MEDLINE) (from 1950 to December, 2014) and Excerpta Medica dataBASE (EMBASE) (from 1974 to December 2014) and by checking the reference lists of trials retained. We included parallel randomized controlled trials comparing the effects of postoperative epidural local anesthetic with regimens based on systemic or epidural opioids. The quality of the studies was rated according to the Cochrane tool. Two authors independently extracted data. We judged the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group scale.
Based on 22 trials including 1138 participants, an epidural containing a local anesthetic will decrease the time required for return of gastrointestinal transit as measured by time required to observe the first flatus after an abdominal surgery standardized mean difference (SMD) -1.28 (95% confidence interval CI, -1.71 to -0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportional to the concentration of local anesthetic used. Based on 28 trials including 1559 participants, we also found a decrease in time to first feces (stool): SMD -0.67 (95% CI, -0.86 to -0.47; low quality of evidence; equivalent to 22 hours). Based on 35 trials including 2731 participants, pain on movement at 24 hours after surgery is also reduced: SMD -0.89 (95% CI, -1.08 to -0.70; moderate quality of evidence; equivalent to 2.5 on a scale from 0 to 10). Based on 22 trials including 1154 participants, we did not find a difference in the incidence of vomiting within 24 hours: risk ratio 0.84 (95% CI, 0.57-1.23); low quality of evidence. Based on 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak: risk ratio 0.74 (95% CI, 0.41-1.32; low quality of evidence). Based on 30 trials including 2598 participants, epidural analgesia reduces length of hospital stay for an open surgery: SMD -0.20 (95% CI, -0.35 to -0.04; very low quality of evidence; equivalent to 1 day). Data on cost were very limited.
An epidural containing a local anesthetic, with or without the addition of an opioid, accelerates the return of the gastrointestinal transit (high quality of evidence). An epidural containing a local anesthetic with an opioid decreases pain after an abdominal surgery (moderate quality of evidence). An epidural containing a local anesthetic does not affect the incidence of vomiting or anastomotic leak (low quality of evidence). For an open surgery, an epidural containing a local anesthetic would reduce the length of hospital stay (very low quality of evidence).
Summary
We present a novel ultrasound‐guided regional anaesthetic technique that may achieve complete paraesthesia of the hemithorax. This technique may be a viable alternative to current regional ...anaesthetic techniques such as thoracic paravertebral and central neuraxial blockade, which can be technically more challenging and have a higher potential side‐effect profile. We performed the serratus block at two different levels in the midaxillary line on four female volunteers. We recorded the degree of paraesthesia obtained and performed fat‐suppression magnetic resonance imaging and three‐dimensional reconstructions of the spread of local anaesthetic in the serratus plane. All volunteers reported an effective block that provided long‐lasting paraesthesia (750–840 min). There were no side‐effects noted in this initial descriptive study. While these are preliminary findings, and must be confirmed in a clinical trial, they highlight the potential for the serratus plane block to provide analgesia following surgery on the thoracic wall. We suggest that this novel approach appears to be safe, effective, and easy to perform, and is associated with a low risk of side‐effects.
This article is accompanied by an Editorial by Tighe and Karmakar, pp 1103–1106 of this issue.
Microneedles offer a convenient transdermal delivery route with potential for long term sustained release of drugs. However current microneedle technologies may not have the mechanical properties for ...reliable and stable penetration (e.g. hydrogel microneedles). Moreover, it is also challenging to realize microneedle arrays with large size and high flexibility. There is also an inherent upper limit to the amount and kind of drugs that can be loaded in the microneedles. In this paper, we present a new class of polymeric porous microneedles made from biocompatible and photo-curable resin that address these challenges. The microneedles are unique in their ability to load solid drug formulation in concentrated form. We demonstrate the loading and release of solid formulation of anesthetic and non-steroidal anti-inflammatory drugs, namely Lidocaine and Ibuprofen. Paper also demonstrates realization of large area (6 × 20 cm
) flexible and stretchable microneedle patches capable of drug delivery on any body part. Penetration studies were performed in an ex vivo porcine model supplemented through rigorous compression tests to ensure the robustness and rigidity of the microneedles. Detailed release profiles of the microneedle patches were shown in an in vitro skin model. Results show promise for large area transdermal delivery of solid drug formulations using these porous microneedles.
Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to ...dentists.
Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention.Our secondary objective was to report on patients' experience of the procedures carried out.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research.
We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or cross-over design.
We used standard Cochrane methodological approaches for data collection and analysis.
We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for meta-analysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing.We assessed the included studies as having low risk of bias in most domains. Seventy-three studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion.We reported results for the eight most important comparisons.Success of anaesthesiaWhen the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; low-quality evidence).When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderate-quality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; low-quality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine.Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very low-quality evidence).Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 cross-over studies; 37 participants; low-quality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 cross-over studies; 31 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction are uncertain.Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 cross-over study; 110 participants; low-quality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain.For remaining outcomes, assessing success of dental local anaesthesia via meta-analyses was not possible.Onset and duration of anaesthesiaFor comparisons assessing onset and duration, no clinical studies met our outcome definitions.Adverse effects (continuous pain measured on 170-mm Heft-Parker visual analogue scale (VAS))Differences in post-injection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI -1.98 to 11.46 mm; 3 cross-over studies; 314 interventions; moderate-quality evidence). Lidocaine probably resulted in slightly less post-injection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 cross-over studies; 309 interventions; moderate-quality evidence) on the same VAS.For remaining comparisons assessing local and systemic adverse effects, meta-analyses were not possible. Other adverse effects were rare and minor.Patients' experiencePatients' experience of procedures was not assessed owing to lack of data.
For success (absence of pain), low-quality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderate-quality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed.Adverse events were rare. Moderate-quality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection.Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible.Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow meta-analysis. Once assessed, results of the 34 'Studies awaiting classification (full text unavailable)' may alter the conclusions of the review.
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•NTM-COFs was prepared and used in matrix effect-free on-line pass-through cleanup procedure.•LC-MS/MS method was developed for the fast detection of local anesthetic in plasma ...samples.•The cleanup and analysis procedures are carried out simultaneously.•The developed method can be applied to the clinical studies.
A novel nano-titania modified covalent organic frameworks (NTM-COFs) has been synthesized and characterized by transmission electron microscopy (TEM) and scanning electron micrographs (SEM). Besides, NTM-COFs, as efficient sorbent, has also been evaluated in the on-line pass-through cleanup procedure prior to the analysis of local anesthetic drugs (lidocaine, bupivacaine and tetracaine) in human plasma by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). Under optimum conditions, the level of matrix effects can be dramatically reduced by the NTM-COFs based on-line pass-through cleanup procedure, with acceptable recoveries ranging from 88.8% to 103%. Satisfactory trueness and precision of the proposed method were also obtained, with the within- and between-run RSDs less than 7.0% and relative error (REs) less than 12%. The limits of detections (LODs) of lidocaine, bupivacaine and tetracaine were 0.029 μg·L−1, 0.027 μg·L−1 and 0.016 μg·L−1, respectively. The analytical method has been successfully applied for the determination of the plasma concentrations of bupivacaine in five parturients who received an epidural administration of bupivacaine hydrochloride during vaginal delivery. Results demonstrate the applicability of the developed NTM-COFs on-line pass-through cleanup procedure coupled with LC-MS/MS method to clinical studies.
Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably ...overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article.
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