ABSTRACT
Opioid-based medications remain the mainstay of post-operative pain management, even though they are associated with a plethora of adverse effects including addiction, nausea, constipation, cognitive impairment, respiratory depression, and accidental death due to overdose. Local anesthetics are effective at controlling the intense pain after surgery but their short duration of effect limits their clinical utility in post-operative pain management. In this manuscript, an optimized injectable oleogel-based formulation of bupivacaine for multi-day post-operative pain management was characterized on the benchtop and assessed in two clinically-relevant porcine post-operative pain models. Benchtop characterization verified the optimized oleogel-based bupivacaine formulation design, demonstrating a homogenous stable oleogel with sufficient injectability due to shear-thinning properties, high drug loading capacity and first-order drug release kinetics over 5 days. In vivo assessment in two pig post-operative pain models demonstrated that the oleogel-based bupivacaine formulation can provide statistically significant multi-day analgesia in two routes of administration: local instillation directly into a surgical site and ultrasound-guided peripheral nerve block injection. Pharmacokinetic assessment of ALX005 found that Cmax values were not statistically different from the bupivacaine HCl control, with no clinical signs of local anesthetic systemic toxicity observed, when administering up to 2.7 and 8.1 times the control dose of bupivacaine HCl. This study demonstrates the pre-clinical safety and efficacy of an injectable oleogel-based bupivacaine formulation and explores its utility as a single-administration long-acting local anesthetic product for post-operative pain management that can be used in both local and regional anesthetic applications.
ABSTRACT
BACKGROUND: Partial-thickness skin wounds are some of the most painful injuries due to large areas of exposed nerve endings. These injuries often require systemic opioid treatments to manage pain adequately. However, in 2021 alone, the CDC reported nearly 17,000 prescription opioid-related deaths in the USA, highlighting the ongoing need for non-opioid treatment strategies. In this manuscript, we developed a novel single-application ropivacaine-eluting primary wound dressing that could provide sustained ropivacaine delivery to partial-thickness wounds and assessed its in vivo feasibility for prolonged non-opioid analgesia. METHODS: Sustained release of ropivacaine from a poly(lactide-co-e-caprolactone) matrix was first optimized in vitro using dissolution testing and a Box Behnken design of experiments. The optimized dressing was then tested against a clinical control silicone dressing in a porcine partial-thickness wound study to assess analgesic effect, pharmacokinetics, and wound healing. RESULTS: The ropivacaine-eluting dressing showed a moderate analgesic effect in vivo, where normalized single pinprick scores significantly improved pain over the testing period (4-168h) (control vs treatment: 232±25% vs 145±16%, p<0.0003). Ropivacaine blood plasma levels peaked at 8 hours post-treatment, with a maximum concentration of 246 ± 74 ng/mL. No significant differences in wound healing were found when compared to control. CONCLUSION: The ropivacaine-loaded poly(lactide-co-e-caprolactone)-based wound dressing provided sustained delivery of ropivacaine to partial-thickness skin wounds and enhanced analgesic effect compared to a clinical standard control dressing.
ABSTRACT
Traditional teaching suggests that prior pelvic operations, including prostatectomy, are a contraindication to laparoscopic inguinal hernia repair. Despite the growing use of robotic platforms in inguinal hernia repair, there are few studies describing robotic-assisted inguinal hernia repairs (RIHR) in this patient population. This study aims to demonstrate that RIHR is safe and effective in repairing inguinal hernias in patients who had previously undergone prostatectomy. We retrospectively reviewed RIHR cases performed from March 2017 to October 2021 by a single surgeon at our university-affiliated community hospital. Cases were reviewed for preoperative considerations, operative times and complications, and postoperative outcomes. A total of 30 patients with prior prostatectomy underwent transabdominal preperitoneal (TAPP) RIHR with mesh. Sixteen of the 30 patients had undergone robot-assisted laparoscopic prostatectomy (RALP), while 14 patients underwent open resection. Seven of the patients had received post-resection radiation and 12 had previous non-urologic abdominal operations. When compared to all RIHRs performed over the same period, duration of surgery was increased. There were no conversions to open surgery. Postoperatively, one patient developed a repair site seroma which resolved after 1 month. Mean follow-up time was 8.0 months. At follow-up, one patient reported experiencing intermittent non-debilitating pain at the repair site and one patient developed an inguinoscrotal abscess of unknown relation to the repair. No patients reported hernia recurrences nor mesh infection. This review suggests that TAPP RIHR can be a safe and effective approach to inguinal hernia repair in patients who have previously undergone prostatectomy, including those who received radiation and those who underwent either open or robotic resections.
Subject(s)
Hernia, Inguinal , Laparoscopy , Robotic Surgical Procedures , Robotics , Male , Humans , Hernia, Inguinal/surgery , Hernia, Inguinal/etiology , Robotic Surgical Procedures/methods , Retrospective Studies , Herniorrhaphy/adverse effects , Prostatectomy/adverse effects , Surgical Mesh , Treatment OutcomeABSTRACT
This manuscript systematically assesses three different glycerides (tripalmitin, glyceryl monostearate, and a blend of mono-, di- and triesters of palmitic and stearic acids (Geleol™)) as potential gelator structuring agents of medium-chain triglyceride oil to form an oleogel-based injectable long-acting local anesthetic formulation for postoperative pain management. Drug release testing, oil-binding capacity, injection forces, x-ray diffraction, differential scanning calorimetry, and rheological testing were serially performed to characterize the functional properties of each oleogel. After benchtop assessment, the superior bupivacaine-loaded oleogel formulation was compared to bupivacaine HCl, liposomal bupivacaine, and bupivacaine-loaded medium-chain triglyceride oil in a rat sciatic nerve block model to assess in vivo long-acting local anesthetic performance. In vitro drug release kinetics were similar for all formulations, indicating that drug release rate is primarily dependent on the drug's affinity to the base oil. Glyceryl monostearate-based formulations had superior shelf-life and thermal stability. The glyceryl monostearate oleogel formulation was selected for in vivo evaluation. It was found to have a significantly longer duration of anesthetic effect than liposomal bupivacaine and was able to provide anesthesia twice as long as the equipotent bupivacaine-loaded medium-chain triglyceride oil, indicating that the increased viscosity of the oleogel provided enhanced controlled release over the drug-loaded oil alone.
Subject(s)
Anesthetics, Local , Bupivacaine , Rats , Animals , Glycerides/chemistry , TriglyceridesABSTRACT
Proper pain management is well understood to be one of the fundamental aspects of a healthy postoperative recovery in conjunction with mobility and nutrition. Approximately, 10% of patients prescribed opioids after surgery continue to use opioids in the long-term and as little as 10 days on opioids can result in addiction. In an effort to provide physicians with an alternative pain management technique, this work evaluates the material properties of a novel local anesthetic delivery system designed for controlled release of bupivacaine for 72 hours. The formulation utilizes solid-lipid microparticles that encapsulate the hydrophobic molecule bupivacaine in its free-base form. The lipid microparticles are suspended in a non-crosslinked hyaluronic acid hydrogel, which acts as the microparticle carrier. Two different particle manufacturing techniques, milling and hot homogenization, were evaluated in this work. The hot homogenized particles had a slower and more controlled release than the milled particles. Rheological techniques revealed that the suspension remains a viscoelastic fluid when loaded with either particle type up to 25% (w/v) particles densities. Furthermore, the shear thinning properties of the suspension media, hyaluronic acid hydrogel, were conserved when bupivacaine-loaded solid-lipid microparticles were loaded up to densities of 25% (w/v) particle loading. The force during injection was measured for suspension formulations with varying hyaluronic acid hydrogel concentrations, particle densities, particle types and particle sizes. The results indicate that the formulation viscosity is highly dependent on particle density, but hyaluronic acid hydrogel is required for lowering injection forces as well as minimizing clogging events.
Subject(s)
Anesthetics, Local , Hyaluronic Acid , Bupivacaine/chemistry , Delayed-Action Preparations/chemistry , Humans , Hyaluronic Acid/chemistry , Hydrogels , Lipids , Microspheres , Particle Size , ViscosityABSTRACT
Robotic surgical technology has the potential to broaden the applicability of minimally invasive approaches into more complex, technically challenging inguinal hernia repairs. A unique patient population requiring inguinal hernia repair are those patients who either have artificial urinary sphincters (AUS) or inguinal bladder herniation (IBH). Traditionally, these patients have not been considered candidates for minimally invasive inguinal hernia repairs. Through this retrospective series, we aim to contribute to the growing body of literature on robotic-assisted inguinal hernia repair (RIHR) by describing our experience with RIHR in this patient subset. We performed a retrospective chart review of RIHR cases performed from June 2017 to April 2019 by a single surgeon at our university-affiliated community hospital. Charts were reviewed for preoperative considerations, operative complications, and postoperative outcomes. A total of three patients with an AUS and six patients with IBH were included, all of whom were male. All the patients received transabdominal preperitoneal (TAPP) approaches, and all received placement of mesh. There were no intraoperative complications and no conversions to open surgery. Postoperatively, one patient with IBH had persistent surgical site pain that resolved after 3 weeks and one patient, also with IBH, had a surgical site seroma that resolved without further intervention. Mean follow-up time was 10.71 and 12.13 months for patients with AUS and IBH, respectively. No patients reported hernia recurrence during this time. This review suggests that the use of robotic assistance for laparoscopic inguinal hernia repair is safe and effective and may provide additional benefits for patients with concurrent urological considerations such as AUS and IBH.