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Time to Analgesia Onset and Pharmacokinetics After Separate and Combined Administration of Liposome Bupivacaine and Bupivacaine HCl: Considerations for Clinicians.

ABSTRACT: Liposome bupivacaine is a prolonged-release bupivacaine formulation indicated for single-dose administration into the surgical site to produce postsurgical analgesia.An overview of time to onset of analgesia observed with liposome bupivacaine in human studies is provided, as well as a summary of data from pharmacokinetic studies including those that assessed pharmacokinetics after separate versus coadministration of liposome bupivacaine and bupivacaine HCl.Data from multiple studies show that local administration of liposome bupivacaine is associated with rapid onset and effective analgesia after surgery. However, the efficacy profile observed in controlled settings may not replicate the profile observed in clinical practice; time to onset may be impacted by nonpharmacologic factors, such as amount of drug given, location and relative vascularity, and variances in surgical techniques. Some clinicians coadminister or admix bupivacaine HCl and liposome bupivacaine based on the supposition that adjuvant use will result in more rapid onset of efficacy. To date, no clinical studies have been conducted comparing pain-related outcomes following coadministration versus liposome bupivacaine alone. Preclinical pharmacokinetic studies have assessed the potential impact of combined use, which resulted in predictable, additive systemic exposure without compromising the prolonged-release profile of liposome bupivacaine, and without signs of toxicity.Based on available data and approved package insert, in the setting of wound infiltration, clinicians have the flexibility to administer liposome bupivacaine alone, coadminister separately with bupivacaine HCl, or admix with bupivacaine HCl prior to injection, providing the bupivacaine HCl dose does not exceed 50% of the liposome bupivacaine dose.

SUBMITTER: Gadsden J

PROVIDER: S-EPMC4897097 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Time to Analgesia Onset and Pharmacokinetics After Separate and Combined Administration of Liposome Bupivacaine and Bupivacaine HCl: Considerations for Clinicians.

Gadsden Jeffrey J Long William J WJ

The open orthopaedics journal 20160412

<h4>Background</h4>Liposome bupivacaine is a prolonged-release bupivacaine formulation indicated for single-dose administration into the surgical site to produce postsurgical analgesia.<h4>Methods</h4>An overview of time to onset of analgesia observed with liposome bupivacaine in human studies is provided, as well as a summary of data from pharmacokinetic studies including those that assessed pharmacokinetics after separate versus coadministration of liposome bupivacaine and bupivacaine HCl.<h4> ...[more]

PMID: 27347237

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Project description:BackgroundTransversus abdominis plane (TAP) infiltration has been increasingly used for postsurgical analgesia in abdominal/pelvic procedures; however, duration/extent of analgesia with standard local anesthetics is limited. This pilot study assessed the preliminary efficacy and safety of two volumes of liposome bupivacaine administered via TAP infiltration in patients undergoing robotic laparoscopic prostatectomy.MethodsIn this single-center, open-label, prospective study, patients older than 18 years received TAP infiltration with liposome bupivacaine immediately after surgery. The first 12 patients received a total volume of 20 mL liposome bupivacaine (266 mg); the next 12 received 40 mL liposome bupivacaine (266 mg). The liposome bupivacaine was diluted with 0.9% normal saline. The primary efficacy measure was duration of analgesia, measured by time to first opioid administration. Secondary outcome measures included patient-assessed pain scores, opioid use, and opioid-related adverse events (AEs).ResultsTwenty-four patients received liposome bupivacaine (20 mL, n=12; 40 mL, n=12) and were included in the primary analysis. Three refused participation in a 10-day follow-up visit and did not complete the study. Median time to first opioid administration after surgery was 23 and 26 minutes for the 20 and 40 mL groups, respectively. Mean total amount of postsurgical opioids ranged from 25.4 to 27.3 mg; after hospital discharge to day 10, both groups required a mean of 0.7 oxycodone/acetaminophen tablets/day. Mean pain scores of 4.4 and 5.3 were reported at 1 hour and 3.1 and 3.9 at 2 hours postsurgery, with 20 and 40 mL doses, respectively. Neither group had mean scores higher than 3.0 at any further assessments. No opioid-related or treatment-related serious AEs were reported.ConclusionMedian time to first opioid administration did not differ between the two groups. No differences in secondary outcomes were observed on the basis of volume administered. These initial findings suggest further study of liposome bupivacaine administered via TAP infiltration as part of a multimodal analgesic regimen in laparoscopic robotic prostatectomy may be warranted.

Project description:BackgroundOpioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms.MethodsWe analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs.ResultsEighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine.ConclusionsCompared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.

Project description:ObjectiveSeveral modalities for analgesia after laparoscopic procedures have been used. This study aimed to investigate the efficacy of early versus late bupivacaine/tramadol combination and bupivacaine/dexmedetomidine combination in analgesia for laparoscopic cancer surgeries.MethodsA total of 100 patients of both genders scheduled for elective laparoscopic cancer surgeries were included. Patients were randomly assigned to one of four groups each comprises 25 patients. Group 1: early bupivacaine/tramadol, Group 2: late bupivacaine/tramadol, Group 3: early bupivacaine/dexmedetomidine, and Group 4: late bupivacaine/dexmedetomidine. Early groups received the intraperitoneal instillation before start of surgery and late groups received the instillation after completion of surgery. Perioperative heart rate (HR) and mean arterial blood pressure (MAP) were recorded. The degree of postoperative pain was measured at rest and with cough using Visual analogue scale (VAS) score at 2, 4, 6, 12, 18 and 24 h after surgery. In addition, the total intraoperative fentanyl and postoperative morphine doses were calculated.ResultsBoth late bupivacaine/tramadol, bupivacaine/dexmedetomidine groups had longer time to receive first analgesic requirement (13.4±3.9, 11.3±3.9 h) respectively as compared to early bupivacaine/tramadol, bupivacaine/dexmedetomidine groups (9.8± 3.6, 8.4± 2.8 h), respectively. Between each early and late group, intraoperative fentanyl consumption was higher for the late groups (75± 22.8, 73± 21.55µg) versus (32.7± 10.9, 37.5± 13.3 µg), respectively. As regards to rescue analgesic requirements, both early bupivacaine/tramadol and bupivacaine/dexmedetomidine groups consumed more analgesics (5.2± 2.0 and 6.1± 1.8 mg) as compared to the late groups (3.2± 0.8 and 4.3± 1.5 mg), respectively. The four groups were comparable for their perioperative HR and MAP values.ConclusionIntraperitoneal instillation of bupivacaine/tramadol and bupivacaine/dexmedetomidine could be considered an effective route for analgesic administration during laparoscopic cancer surgeries. Early instillation reduced the intraoperative opioid consumption and late instillation resulted in reduced postoperative opioid consumption.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04813016.

Project description:ObjectiveTo evaluate bupivacaine concentrations in maternal plasma and transfer into breast milk in women undergoing liposomal bupivacaine infiltration in the transversus abdominis plane after cesarean birth.MethodsProspective cohort study of healthy pregnant women who underwent cesarean birth at term followed by a transversus abdominis plane block using 52 mg bupivacaine hydrochloride 0.25% (20 mL) and 266 mg liposomal bupivacaine 1.3% (20 mL). Simultaneous blood and milk samples were collected in a staggered fashion, three to four samples per patient at the following timepoints after block administration: 2, 6, 12, 24, 48, 72, and 96 hours. Quantification of bupivacaine was performed by liquid chromatography-tandem mass spectrometry. Neonatal drug exposure was modeled by calculating milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage of bupivacaine at each sampling time.ResultsThirty patients were enrolled. Concentrations in breast milk peaked at 6 hours (mean 58 ng/mL), followed by constant and steady decline to low levels at 96 hours (mean 5.2 ng/mL). Maternal plasma concentrations had two peaks, first at 6 hours (mean 155.9 ng/mL) and then at 48 hours (mean 225.8 ng/mL), followed by steady decline. Milk/plasma AUC0-t ratios ranged between AUC0-2 of 0.45 (80% CI 0.38-0.52) and AUC0-96 of 0.15 (80% CI 0.14-0.17). Neonatal dosage ranged between a mean of 355.9 ng/kg at 0-2 hours and a mean of 15,155.4 ng/kg at 0-96 hours. Relative neonatal dosage was less than 1% at all time intervals. No serious adverse reactions occurred in any neonate.ConclusionBupivacaine is excreted in breast milk after local infiltration of liposomal bupivacaine and bupivacaine hydrochloride mixture into transversus abdominis plane blocks after cesarean birth. Relative neonatal dosages of less than 1% (less than 10% is considered to be unlikely to be of clinical concern) suggest minimal risks for breastfeeding healthy, term neonates after the administration of this combination of local anesthetics to mothers.Clinical trial registrationClinicalTrials.gov, NCT03526419.

Dataset Information

Time to Analgesia Onset and Pharmacokinetics After Separate and Combined Administration of Liposome Bupivacaine and Bupivacaine HCl: Considerations for Clinicians.

Publications

Time to Analgesia Onset and Pharmacokinetics After Separate and Combined Administration of Liposome Bupivacaine and Bupivacaine HCl: Considerations for Clinicians.

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