Hydrogel device for analgesic drugs with in-situ loading and polymerization.

The high prevalence of opioid addiction and the shortcomings of systemic opioids has increased the pace of the search for alternative methods of pain management. The local delivery of pain medications has started to be used as a tool for pain management and to decrease the use of systemic opioids for these patients. Here, we explored an in-situ polymerizable hydrogel system for the local delivery of analgesics and nonsteroid anti-inflammatory drugs (NSAID) for orthopaedic applications. We synthesized a series of methacrylated oligomeric polyethylene glycol-co-lactic acid polymer using microwave radiation for the delivery of bupivacaine hydrochloride as an analgesic and ketorolac tromethamine as an NSAID. We determined drug elution and gel degradation profiles in vitro. Biocompatibility was assessed against osteoblasts in vitro and by histological analysis after subcutaneous implantation for 4 weeks in vivo. Intra-articular and systemic concentrations and pharmacokinetic parameters were estimated using a two-compartment pharmacodynamic model based on in-vitro elution profiles. This type of in-situ applicable hydrogels is promising for extending the local efficacy of pain medication and further reducing the need for opioids.

Evaluation of the Efficacy of Liposomal Bupivacaine in Total Joint Arthroplasty.

BACKGROUND: Appropriate pain control is one of the cornerstones necessary to promote positive clinical outcomes. A new bupivacaine liposomal formulation was designed to extend its analgesic effect for up to 72-hours post-surgery, reportedly leading to significant opioid-sparing. METHOD: Retrospective and prospective chart review conducted in a 178-bed academic institution between January 2013 to December 2013 and August 2014 to November 2014, in 115 patients that receive hip and knee arthroplasty. The primary outcome was the measurement of average daily pain score on post-operative days 1 and 2. Secondary outcomes included length of stay, overall opioid use post-surgery and pain control satisfaction using Press-Ganey® scores. RESULTS: The average pain scores in the HCl group were 4.64 and 4.38 (Likert score: 0-10) for POD 1 and POD 2, compared to 4.72 POD 1 and 4.2 POD 2 in the liposome group (POD 1: p = 0.413; POD 2: p = 0.303). The difference in LOS for knee arthroplasty was statistically significant [HCl group: 1.94 days (± 0.66) versus liposome group: 2.27 days (±0.77) p-value = 0.038)] favoring the standard of care. For hip arthroplasty or bilateral knee arthroplasty the differences in LOS were not statistically significant (p = 0.052 and p = 0.484 respectively). 93% of the patients in the HCl group, pain was well controlled, versus 88.5% in the liposome group with similar oxycodone IR use among groups. CONCLUSION: Liposome bupivacaine did not offer a notable benefit compared to the HCl formulation in our study.

Pharmacokinetics and Safety of INL-001 (Bupivacaine HCl) Implants Compared with Bupivacaine HCl Infiltration After Open Unilateral Inguinal Hernioplasty.

INTRODUCTION: Surgical site infiltration with bupivacaine HCl results in short-lived analgesia for postsurgical pain and carries the risk of systemic bupivacaine toxicity due to accidental intravascular injection. INL-001 is a bupivacaine HCl collagen-matrix implant that provides extended delivery of bupivacaine directly at the site and avoids the risk of accidental injection. Here, we examine the pharmacokinetic (PK) and safety profile of INL-001 placement during unilateral open inguinal hernioplasty. METHODS: This multicenter, single-blind study (NCT03234374) enrolled patients undergoing open inguinal hernioplasty to receive three INL-001 implants, each containing 100 mg bupivacaine HCl (n = 34) or local infiltration of 0.25% bupivacaine HCl 175 mg (n = 16). Acetaminophen was provided in the postsurgical period and supplemented by opioids for breakthrough pain, as needed. PK blood samples were taken before surgery and up to 96 h after drug administration. RESULTS: INL-001 demonstrated a prolonged rate of absorption and clearance of bupivacaine compared with 0.25% bupivacaine HCl 175 mg, as demonstrated by a longer time to peak plasma concentration and terminal elimination half-life. Peak plasma concentration with INL-001 300 mg was comparable to bupivacaine HCl 175 mg and well below levels associated with systemic bupivacaine toxicity. The most common adverse events (AEs) in both groups were associated with general anesthesia and the postsurgical setting. No AE was related to the implant, including those associated with wound healing. CONCLUSIONS: These findings demonstrate that INL-001 provides immediate and extended delivery of bupivacaine and is well tolerated in patients undergoing open inguinal hernioplasty with no adverse effect on wound healing. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT03234374.

Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials.

INTRODUCTION: Surgical site infiltration with bupivacaine results in short-lived analgesia. The MATRIX-1 and MATRIX-2 studies examined the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair. INL-001, designed to provide early and extended delivery of bupivacaine, provides prolonged duration of perioperative analgesia. METHODS: In two phase 3 double-blind studies [MATRIX-1 (ClinicalTrials.gov identifier, NCT02523599) and MATRIX-2 (ClinicalTrials.gov identifier, NCT02525133)], patients undergoing open tension-free mesh inguinal hernia repair were randomized to receive 300-mg bupivacaine (three INL-001 100-mg bupivacaine HCl collagen-matrix implants) (MATRIX-1 n = 204; MATRIX-2 n = 213) or three placebo collagen-matrix implants (MATRIX-1 n = 101; MATRIX-2 n = 106) during surgery. Postsurgical medication included scheduled acetaminophen and as-needed opioids. RESULTS: Patients who received INL-001 in both studies reported statistically significantly lower pain intensity (P ≤ 0.004; primary end point) and opioid analgesic use (P < 0.0001) through 24-h post-surgery versus those who received a placebo collagen-matrix. Patients who received INL-001 reported lower pain intensity through 72 h (P = 0.0441) for the two pooled studies. In both studies, more of the patients (28-42%) who received INL-001 used no opioid medication 0-24, 0-48, and 0-72 h post-surgery versus those who received a placebo collagen-matrix (12-22%). Among patients who needed opioid medication, patients receiving INL-001 used fewer opioids than those who received a placebo collagen-matrix through 24 h in both studies (P < 0.0001) and through 48 h in MATRIX-2 (P = 0.0003). Most adverse events were mild or moderate, without evidence of bupivacaine toxicity or deleterious effects on wound healing. CONCLUSION: These findings indicate that INL-001 results in post-inguinal hernia repair analgesia that is temporally aligned with the period of maximal postsurgical pain and may reduce the need for opioids while offering a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02523599; NCT02525133. FUNDING: Innocoll Pharmaceuticals. Plain language summary available for this article.

Local sustained delivery of bupivacaine HCl from a new castor oil-based nanoemulsion system.

Bupivacaine HCl (1-butyl-2',6'-pipecoloxylidide hydrochloride), an amide local anesthetic compound, is a local anesthetic drug utilized for intraoperative local anesthesia, post-operative analgesia and in the treatment of chronic pain. However, its utility is limited by the relative short duration of analgesia after local administration (approximately 9 h after direct injection) and risk for side effects. This work is aimed to develop a nanoemulsion of bupivacaine HCl with sustained local anesthetics release kinetics for improved pain management, by exhibiting extended analgesic action and providing reduced peak levels in the circulation to minimize side effects. Herein, biodegradable oils were evaluated for use in nanoemulsions to enable sustained release kinetics of bupivacaine HCl. Only with castor oil, a clear and stable nanoemulsion was obtained without the occurrence of phase separation over a period of 3 months. High loading of bupivacaine HCl into the castor oil-based nanoemulsion system was achieved with about 98% entrapment efficiency and the resulting formulation showed high stability under stress conditions (accelerated stability test) regarding changes in visual appearance, drug content, and droplet size. We show herein that the in vitro release and in vivo pharmacokinetic profiles as well as pharmacodynamic outcome (pain relief test) after subcutaneous administration in rats correlate well and clearly demonstrate the prolonged release and extended duration of activity of our novel nanoformulation. In addition, the lower Cmax value achieved in the blood compartment suggests the possibility that the risk for systemic side effects is reduced. We conclude that castor oil-based nanomulsion represents an attractive pain treatment possibility to achieve prolonged local action of bupivacaine HCl.

Treatment of complex regional pain syndrome with stellate ganglion local anesthetic blockade: a case report of one patient's experiences with traditional bupivacaine HCl and liposome bupivacaine.

Complex regional pain syndrome (CRPS) is a poorly understood, debilitating disorder characterized by severe chronic pain in an affected limb or region of the body. This case presentation is the first to describe the effectiveness and prolonged duration of the effect of liposome bupivacaine in stellate ganglion block for CRPS.

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

BACKGROUND: Liposome bupivacaine is a prolonged-release bupivacaine formulation indicated for single-dose administration into the surgical site to produce postsurgical analgesia. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Epinephrine as adjuvant for propranolol produces a marked peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats.

The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the relative potency was bupivacaine [2.05 (1.95-2.21) µmol/kg]>propranolol [9.21 (9.08-9.42) µmol/kg] (P<0.01 for each comparison). Subcutaneous epinephrine (0.012 µmol/kg) did not produce cutaneous analgesia. Mixtures of epinephrine (0.012 µmol/kg) with drugs (propranolol or bupivacaine) at ED50 or ED95, respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED95 with epinephrine (0.012 µmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia.

Safety of liposome extended-release bupivacaine for postoperative pain control.

BACKGROUND: Ideal postoperative pain management requires a multidisciplinary approach in combination with a variety of dosage regimens. Approximately 21-30% of patients experience moderate to severe pain in the postoperative period, which may have a significant impact on recovery rate, standard of living, psychological health, and postoperative complications. OBJECTIVE: Analysis of the incidence and characterization of reported adverse effects with DepoFoam bupivacaine compared to conventional bupivacaine or placebo. METHODS: A systematic review of prospective studies on the use of DepoFoam versus bupivacaine or placebo was performed in order to answer the clinically relevant question: is DepoFoam a safer formulation in place of bupivacaine single injection or continuous local infusion techniques for postoperative pain management? Inclusion criteria required randomized, controlled, double-blind trials in patients 18 years old or older, single dose used for postoperative pain control, and a primary procedure performed. RESULTS: Six studies fitted the inclusion criteria for analysis, DepoFoam bupivacaine used in therapeutic doses was well-tolerated, had a higher safety margin, and showed a favorable safety profile compared to bupivacaine and control groups. CONCLUSION: Extended drug delivery system DepoFoam bupivacaine is a promising drug formulation that may significantly improve postoperative care and pain control in surgical patients.