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European Journal of Hospital Pharmacy :... Mar 2020The objective of this study was to evaluate the physical and chemical stability of hydromorphone hydrochloride and bupivacaine hydrochloride in concentrations of 15...
OBJECTIVES
The objective of this study was to evaluate the physical and chemical stability of hydromorphone hydrochloride and bupivacaine hydrochloride in concentrations of 15 mg.ml and 10 mg.mL in 0.9% sodium chloride injection. Test samples of hydromorphone/bupivacaine mixtures were stored at 37°C, body temperature encounterd during continuous intrathecal infusion, for 90 days. The solutions were packaged in 20 ml plastic syringes. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by visual observation. The chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. In addition, pH and osmolarity were measured electronically.
METHODS
This study determines the stability and compatibility of hydromorphone (15 mg.ml) and bupivacaine (10 mg.ml) mixture after 3 months at 37°C using a validated method by HPLC-UV. A simple, precise, specific and accurate reversed phase high performance liquid chromatographic (RP-HPLC) method was developed and validated. The different analytical performance parameters such as linearity, accuracy, specificity, precision and sensitivity (limit of detection and limit of quantitation) were determined according to International Conference on Harmonisation ICH Q2 (R1) guidelines. RP-HPLC was conducted on a nucleoshell RP18plus (C18 150×4.6 mm with 2.7 µm particle size) column. The mobile phase consisted of buffer A (phosphate buffer (0.05M) pH 4.5) and acetonitrile B. The gradient used for the elution is the following one: time (min)/% of B: 0 min/20%; 1.9 min/50%; 2.5 min /40%; 4.5 min/40%; 5.5 min/20%; and 8 min /20%, and the flow rate was maintained at 1.0ml.min and performed at 35°C. The molecules were monitored using Dionex ultimate 3000, equipped with photo diode array detector (λ=210 nm). Linearity was observed in concentration range of 9-21 mg.l for hydromorphone and 6-14 mg.l for bupivacaine. All the system suitability parameters were found within the range.
RESULTS
The degradation study shows a photolytic degradation compound for hydromorphone and an oxidative degradation compound found for bupivacaine. The stability study shows no visible haze or particulate formation or gas evolution. pH and osmolarity were stable during the 3 months. Colour changed after 2 months, although this colouring is due to hydromorphone, proportional to hydromorphone concentrations and increases with time but it is a well known modification. The quantitative study by HPLC method revealed no significant change in hydromorphone and bupivacaine concentration. There is less than 5% of variability during the 3-month period.
CONCLUSIONS
Hydromorphone (15 mg.ml) and bupivacaine (10 mg.ml) were physically and chemically compatible and analysed with HPLC, which revealed no significant change in hydromorphone and bupivacaine concentration in this simulated compatibility study.
Topics: Analgesics, Opioid; Anesthetics, Local; Bupivacaine; Chromatography, High Pressure Liquid; Drug Combinations; Drug Compounding; Drug Stability; Hydromorphone
PubMed: 32133135
DOI: 10.1136/ejhpharm-2018-001553 -
American Journal of Veterinary Research Jan 2022To compare the efficacy and duration of action for perineural analgesia with liposomal bupivacaine (LB) versus bupivacaine hydrochloride (BHCl) in a sole-pressure...
OBJECTIVE
To compare the efficacy and duration of action for perineural analgesia with liposomal bupivacaine (LB) versus bupivacaine hydrochloride (BHCl) in a sole-pressure induced model of forelimb lameness in horses.
ANIMALS
6 healthy adult research horses.
PROCEDURES
In 1 randomly assigned forelimb, grade 3/5 lameness was induced by use of a sole-pressure lameness model. Objective lameness (vector sum [VS]) was determined with an inertial sensor system at 0, 1, 6, and 24 hours after lameness induction to evaluate the model. Mechanical nociceptive thresholds (MNTs) and objective lameness (VS and force platform kinetics) were recorded prior to and at 1, 6, 24, 48, and 72 hours after perineural anesthesia of the palmar nerves at the level of the proximal sesamoid bones with LB or BHCl in random order, with a 1-week washout period between crossover treatments. Data analysis was performed with mixed-model ANOVA.
RESULTS
When evaluating the lameness model, there was a decrease in lameness at 24 hours in at least 1 limb of each horse (7/12 limbs); thus, screw length was increased by 1 to 2 mm at each 24-hour interval to maintain lameness. Compared with results at baseline, horses treated with BHCl had significant improvements in median MNT and VS identified at only 1 hour after injection, whereas treatment with LB yielded significantly improved median MNT, VS score, and peak vertical force for up to 24 hours.
DISCUSSION
In this experimental model of forelimb lameness, LB provided longer analgesia when compared with BHCl and should be further investigated for treatment of pain in horses.
Topics: Analgesia; Animals; Bupivacaine; Forelimb; Horse Diseases; Horses; Lameness, Animal; Pain
PubMed: 35092669
DOI: 10.2460/ajvr.21.08.0132 -
British Journal of Anaesthesia Aug 1982
Topics: Anesthesia, Local; Anesthesia, Spinal; Bupivacaine; Humans
PubMed: 7104129
DOI: 10.1093/bja/54.8.799 -
Trials May 2021Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the... (Randomized Controlled Trial)
Randomized Controlled Trial
Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): statistical analysis plan for a randomised controlled trial assessing the effectiveness of peri-articular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone.
BACKGROUND
Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement.
METHODS/DESIGN
The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published.
RESULTS
The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests.
DISCUSSION
The paper provides details of the planned statistical analyses for the SPAARK trial and aims to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report.
TRIAL REGISTRATION
ISRCTN54191675 . Registered on 13 November 2017.
Topics: Anesthetics, Local; Arthroplasty, Replacement, Knee; Bupivacaine; Humans; Knee Joint; Pain, Postoperative
PubMed: 34001205
DOI: 10.1186/s13063-021-05293-7 -
The Cochrane Database of Systematic... Feb 2017Despite multi-modal analgesic techniques, acute postoperative pain remains an unmet health need, with up to three quarters of people undergoing surgery reporting... (Review)
Review
BACKGROUND
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.
OBJECTIVES
To assess the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain.
SEARCH METHODS
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.
SELECTION CRITERIA
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.
DATA COLLECTION AND ANALYSIS
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.
MAIN RESULTS
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.
AUTHORS' CONCLUSIONS
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.
Topics: Anesthetics, Local; Arthroplasty, Replacement, Knee; Bupivacaine; Humans; Liposomes; Mammaplasty; Pain Measurement; Pain, Postoperative; Randomized Controlled Trials as Topic
PubMed: 28146271
DOI: 10.1002/14651858.CD011419.pub2 -
Journal of the American Veterinary... May 2020To compare liposome-encapsulated bupivacaine (LEB) and (nonliposomal) 0.5% bupivacaine hydrochloride (0.5BH) for control of postoperative pain in dogs undergoing tibial...
OBJECTIVE
To compare liposome-encapsulated bupivacaine (LEB) and (nonliposomal) 0.5% bupivacaine hydrochloride (0.5BH) for control of postoperative pain in dogs undergoing tibial plateau leveling osteotomy (TPLO).
ANIMALS
33 client-owned dogs.
PROCEDURES
In a randomized clinical trial, dogs undergoing TPLO received LEB (5.3 mg/kg [2.4 mg/lb]) or 0.5BH (1.5 mg/kg [0.68 mg/lb]) by periarticular soft tissue injection. All dogs received carprofen (2.2 mg/kg [1 mg/lb], SC, q 12 h) beginning at extubation. Signs of pain were assessed at extubation and predetermined times up to 48 hours later with the Colorado State University-Canine Acute Pain Scale and Glasgow Composite Pain Scale-Short Form. A pressure nociceptive threshold device was used at the affected stifle joint before surgery and at 5 postoperative time points. Methadone (0.1 mg/kg [0.05 mg/lb], IV) was administered if the Colorado State University pain scale score was ≥ 2 (scale, 0 to 4). Surgical variables; pain scores; pressure nociceptive thresholds; times to first administration of rescue analgesic, first walk, and first meal consumption; and total opioid administration were compared between treatment groups.
RESULTS
28 dogs completed the study. Dogs administered LEB were less likely to require rescue analgesia and received lower amounts of opioids than dogs administered 0.5BH. There were no significant intergroup differences in other measured variables.
CONCLUSIONS AND CLINICAL RELEVANCE
The LEB appeared to provide adequate analgesia after TPLO with lower requirements for opioid treatments, which may allow dogs to be discharged from the hospital earlier than with traditional pain management strategies.
Topics: Anesthetics, Local; Animals; Bupivacaine; Colorado; Dog Diseases; Dogs; Osteotomy; Pain, Postoperative; Stifle
PubMed: 32301662
DOI: 10.2460/javma.256.9.1011 -
American Journal of Veterinary Research Jul 2020To evaluate the analgesic and tissue effects of liposomal bupivacaine administered SC as an abaxial sesamoid nerve block in horses with experimentally induced lameness.
Comparison of analgesic and tissue effects of subcutaneous perineural injection of liposomal bupivacaine and bupivacaine hydrochloride in horses with forelimb lameness induced via circumferential clamp.
OBJECTIVE
To evaluate the analgesic and tissue effects of liposomal bupivacaine administered SC as an abaxial sesamoid nerve block in horses with experimentally induced lameness.
ANIMALS
6 healthy mature light-breed horses.
PROCEDURES
In a randomized crossover study, a circumferential hoof clamp was applied to a forelimb to induce reversible lameness. An abaxial sesamoid nerve block of the lame forelimb was performed by SC perineural injection of 10 mg of liposomal bupivacaine or bupivacaine HCl/site. Quantitative gait data were objectively obtained with a body-mounted inertial sensor system before (baseline) and at 30-minute intervals after treatment. Time to return to 85% of baseline lameness was determined. After a minimum 4-day washout period, procedures were repeated with the alternate limb and treatment. Lastly, the palmar digital nerves and perineural tissues were collected and examined histologically.
RESULTS
SC perineural injection of liposomal bupivacaine ameliorated forelimb lameness in 5 of 6 horses. The median duration of analgesia was not significantly different between liposomal bupivacaine (4.5 hours) and bupivacaine HCl (3.0 hours). Histologically, mild inflammation was noted in 3 of 10 sites injected with liposomal bupivacaine and in none of the sites injected with bupivacaine HCl.
CONCLUSIONS AND CLINICAL RELEVANCE
SC perineural injection of 10 mg of liposomal bupivacaine/site ameliorated experimentally induced forelimb lameness in some horses. At milligram-equivalent doses, liposomal bupivacaine had a similar duration of analgesia to that of bupivacaine HCl. Further investigation is required before recommending clinical use of liposomal bupivacaine for nerve blocks in horses.
Topics: Analgesics; Animals; Bupivacaine; Cross-Over Studies; Forelimb; Gait; Horse Diseases; Horses; Lameness, Animal
PubMed: 32584174
DOI: 10.2460/ajvr.81.7.551 -
Anesthesiology Feb 2021Liposomal bupivacaine is purported to extend analgesia of peripheral nerve blocks when administered perineurally. However, evidence of the clinical effectiveness of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Liposomal bupivacaine is purported to extend analgesia of peripheral nerve blocks when administered perineurally. However, evidence of the clinical effectiveness of perineural liposomal bupivacaine is mixed. This meta-analysis seeks to evaluate the effectiveness of perineural liposomal bupivacaine in improving peripheral nerve block analgesia as compared with nonliposomal local anesthetics.
METHODS
The authors identified randomized trials evaluating the effectiveness of peripheral nerve block analgesic that compared liposomal bupivacaine with nonliposomal local anesthetics. The primary outcome was the difference in area under the receiver operating characteristics curve (AUC) of the pooled 24- to 72-h rest pain severity scores. Secondary outcomes included postoperative analgesic consumption, time to first analgesic request, incidence of opioid-related side effects, patient satisfaction, length of hospital stay, liposomal bupivacaine side effects, and functional recovery. AUC pain scores were interpreted in light of a minimal clinically important difference of 2.0 cm · h.
RESULTS
Nine trials (619 patients) were analyzed. When all trials were pooled, AUC pain scores ± SD at 24 to 72 h were 7.6 ± 4.9 cm · h and 6.6 ± 4.6 cm · h for nonliposomal and liposomal bupivacaine, respectively. As such, perineural liposomal bupivacaine provided a clinically unimportant benefit by improving the AUC (95% CI) of 24- to 72-h pain scores by 1.0 cm · h (0.5 to 1.6; P = 0.003) compared with nonliposomal bupivacaine. Excluding an industry-sponsored trial rendered the difference between the groups nonsignificant (0.7 cm · h [-0.1 to 1.5]; P = 0.100). Secondary outcome analysis did not uncover any additional benefits to liposomal bupivacaine in pain severity at individual timepoints up to 72 h, analgesic consumption, time to first analgesic request, opioid-related side effects, patient satisfaction, length of hospital stay, and functional recovery. No liposomal bupivacaine side effects were reported.
CONCLUSIONS
Perineural liposomal bupivacaine provided a statistically significant but clinically unimportant improvement in the AUC of postoperative pain scores compared with plain local anesthetic. Furthermore, this benefit was rendered nonsignificant after excluding an industry-sponsored trial, and liposomal bupivacaine was found to be not different from plain local anesthetics for postoperative pain and all other analgesic and functional outcomes. High-quality evidence does not support the use of perineural liposomal bupivacaine over nonliposomal bupivacaine for peripheral nerve blocks.
Topics: Analgesia; Anesthetics, Local; Bupivacaine; Humans; Liposomes; Nerve Block; Pain Management; Peripheral Nerves; Treatment Outcome
PubMed: 33372953
DOI: 10.1097/ALN.0000000000003651 -
Minerva Anestesiologica Apr 2017
Topics: Anesthesia, Spinal; Anesthetics, Local; Arthroplasty, Replacement, Hip; Bupivacaine; Levobupivacaine
PubMed: 28177207
DOI: 10.23736/S0375-9393.17.11874-2 -
Acta Cirurgica Brasileira Jul 2015To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. (Comparative Study)
Comparative Study
PURPOSE
To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility.
METHODS
Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation.
RESULTS
Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2.
CONCLUSIONS
Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine.
Topics: Amides; Anesthetics, Local; Animals; Bupivacaine; Depression, Chemical; Male; Muscle Tonus; Myocardial Contraction; Papillary Muscles; Rats, Wistar; Reference Values; Ropivacaine; Stereoisomerism; Time Factors
PubMed: 26270140
DOI: 10.1590/S0102-865020150070000006