Publications

Drug abuse and misuse have been a public health issue for many years. To curb this problem, abuse-deterrent formulations (ADFs) have been developed. The present research aimed to develop an ADF using a simple yet effective, scalable, and cost-effective technique. The combination of hydrophobic and hydrophilic materials was used to develop the ADF. The hydrophilic drug molecule was coated with a hydrophobic wax material (hydrogenated castor oil-HCO). This hydrophobic coating retards drug extraction and release from the crushed formulation. A hydrophilic polymer, polyethylene oxide (PEO), was included in ADF. It provides mechanical strength to the formulation and deters from physical manipulation. It can also form a gel-like structure by rapid uptake of solvent, which deters -intravenous abuse. In this research, HCO was explored as a hydrophobic material. A 32 full factorial design was utilized to optimize the formulation, in which the quantity of HCO and PEO has a significant impact on the abuse-deterrent features of the formulation. The optimized formulation was tested using a range of real-life conditions. Stability study proves that the prepared formulation is stable at accelerated and long-term conditions for 6 months.

OBJECTIVE: The objectives were to examine changes in kinesiophobia, pain self-efficacy, and knowledge of the neurophysiology of pain. We hypothesized that implementing an adapted-pain neuroscience education (a-PNE) curriculum, as a single intervention, for patients who experience chronic musculoskeletal pain and concurrent opioid dependence, would demonstrate positive change in kinesiophobia and self-efficacy regarding pain management, which may translate to improvements in functional ability.

DESIGN: This study used a pretest-post-test, quasi-experimental design.

SETTING: A formal opioid management program (OMP) within a clinic associated with the University of Kentucky.

PARTICIPANTS: Patients actively participating in the OMP.

INTERVENTIONS: Pain neuroscience education.

MAIN OUTCOME MEASURES: The Tampa Scale for Kinesiophobia-11, the Pain Self-Efficacy Questionnaire (PSEQ), and the Neurophysiology of Pain Questionnaire (NPQ) were utilized during this study. Subjects completed each questionnaire at three time points: preintervention, post-intervention, and 90 days post-intervention.

RESULTS: No significant interactions between groups and the three time points were found. The a-PNE group significantly improved their knowledge between pre- and post-intervention on the NPQ and PSEQ according to paired-samples t-tests. The a-PNE group scored significantly higher at post-intervention and 90-day post-intervention than the general health education control group on the NPQ according to independent-samples t-tests.

CONCLUSION: An a-PNE curriculum may be beneficial in assisting patients to understand the neurophysiology behind their pain experience. Furthermore, positive changes were noted in pain self-efficacy. The results also indicate that an a-PNE curriculum intervention was acceptable in terms of approach and understandability for the participating patients.

BACKGROUND: There is a paucity of data depicting post-operative opioid consumption in pediatric solid organ transplant (SOT) recipients, limiting ability to perform power analyses in designing prospective trials focusing on analgesia or adjuvant therapies in these populations. There is additionally unclear effect magnitude of various confounders of analgesic and sedative medications encountered in the pediatric intensive care unit (PICU).

METHODS: Retrospective review of pediatric patients aged 2 months-18 years at a single institution was performed on 137 SOT recipients (cardiac, liver, renal, total pancreatectomy with islet cell autotransplantation [TPIAT]) to evaluate post-operative opioid consumption in the PICU, analgesic confounders, pain scores, and opioid-related adverse effects (constipation, ileus, pruritus, nausea, urinary retention, delirium, respiratory depression, withdrawal). Values for correlative and multiplicative effect magnitude were analyzed for planned variables.

RESULTS: Average daily opioid requirement in oral morphine equivalents per kilogram was (cardiac) 12.5 (median 6.98, interquartile range [IQR] 14.3), (liver) 12.6 (median 10.1, IQR 15.3), (renal) 1.47 (median 0.614, IQR 0.95), and (TPIAT) 4.1 (median 3.44, IQR 2.6). Mechanical ventilation dependence, extracorporeal membrane oxygenation use, and open abdomen or chest demonstrated the highest correlation and effect magnitudes with opioid consumption of variables evaluated. No trends were identified for opioid-related adverse effects.

CONCLUSION: Children receiving SOT have high opioid consumption relative to many populations in the PICU. Control for and evaluation of pain confounders such as mechanical ventilation and extracorporeal membrane oxygenation should be utilized in prospective studies analyzing opioid use, adjuvant analgesics, or outcomes in critically ill transplant recipients.

OBJECTIVE: In the context of increased use of buprenorphine for pain management, comparison of real-world data (RWD) on prescription opioid nonmedical use (NMU) based on their controlled substance schedule may assist providers in providing effective pain management therapy while mitigating the risk of opioid NMU.

DESIGN: A systematic literature review of articles reporting RWD on prescription opioid NMU involving Schedule II (CII), Schedule III (CIII), and Schedule IV (CIV) opioid medications was conducted using PubMed®.

PATIENTS/PARTICIPANTS: Human RWD collected in the United States from January 2010 to December 2023.

MAIN OUTCOME MEASURE(S): Articles reporting RWD of prescription opioid NMU. Exclusions included buprenorphine/methadone medications for opioid use disorder, chronic use, or overdose without clearly established NMU (could not rule out legitimate medical use).

RESULTS: There were 2,585 articles screened for inclusion, 102 articles were assessed with a validated data extraction form, and 16 articles were reviewed that compared NMU and/or secondary NMU-related outcomes. Of these, only five articles contained RWD on NMU; all showed more NMU associated with CII than CIII or CIV opioids. Two articles evaluated buprenorphine (CIII) for analgesia and found lower rates of CIII NMU than comparator CII opioids.

CONCLUSIONS: Results of this systematic review support the differentiation in scheduling between CII and CIII/CIV opioid medications with RWD. This study also reveals a research gap in comparing CIII opioid medications for analgesia to CII and CIV opioids, an area of current and future interest, considering the growing use of buprenorphine for pain management, along with initiatives to curb opioid NMU.

BACKGROUND: Spinal opioids are frequently coadministered with local anesthetics for analgesia, allowing the use of a lower dose of each agent, thus minimizing side effects. Most opioid-induced side effects, such as nausea, vomiting, and respiratory depression, are usually encountered with systemic use, while pruritus is more common with intrathecal or epidural administration.

OBJECTIVES: To compare the action of gabapentin versus metoclopramide in prevention of intrathecal opioid-induced pruritus.

STUDY DESIGN: After ethical committee approval and informed patient' consent, this prospective randomized comparative clinical trial was conducted at Ain Shams University Hospitals on 62 adult patients undergoing elective operations under spinal anesthesia. The subjects were randomly divided into two groups: Group G (received 300 mg of oral gabapentin) and group M (received 10 mg of oral metoclopramide) 2 hours before spinal anesthesia.

RESULTS: The overall incidence of pruritus in both groups was 31.5 percent (48.8 percent in group G and 45.2 percent in group M). There was no statistically significant difference between the two groups. As for the severity, both drugs showed low visual analog scale scores from the first hour after intrathecal fentanyl administration. Gabapentin showed more potency in decreasing the severity of pruritus as only two patients in group G needed rescue treatment compared to five patients in group M (but the difference was of no statistical significance).The overall incidence of nausea was 17.7 percent (22.58 percent in group G and 12.9 percent in group M), while the incidence of vomiting was 11.29 percent (16.13 percent in group G and 6.45 percent in group M). There was no statistically significant difference between the two groups.

CONCLUSION: Gabapentin is as effective as metoclopramide in prevention of intrathecal opioid-induced pruritus. Moreover, gabapentin proved to be slightly more effective in reducing the severity of pruritus than metoclopramide.

INTRODUCTION: Prevention of oral overdose of opioids is a critical unmet need. PF614-Multi-Pill Abuse Resistance (MPAR®) was designed to deliver desired opioid-level analgesia at therapeutic dose levels while providing overdose protection if consumed at higher-than-intended doses, through a unique trypsin-activated prodrug approach. PF614, a prodrug of oxycodone, releases oxycodone only after oral ingestion and exposure to trypsin in the small intestine. PF614-MPAR, a combination of PF614 and a potent trypsin inhibitor, nafamostat, will reduce oxycodone release if taken at higher-than-intended doses. The goal of this Phase 1 study was to determine the optimal PF614-nafamostat formulation to optimize the overdose protection that PF614-MPAR should provide.

METHODS: Healthy subjects received oral PF614 25 mg alone or in combination with 10 nafamostat formulations (1-10 mg each), which included immediate-release (IR) solutions, slow or fast extended-release (ER) beads, or a combination of IR/ER nafamostat. Plasma oxycodone concentrations were measured to determine PF614 activation and to identify a nafamostat formulation that would reduce the release of oxycodone only when more than two doses were consumed orally. Once an optimal nafamostat formulation was identified, "PF614-MPAR 25 mg," -overdose protection was evaluated by administering one to eight escalating oral doses to naltrexone-blocked subjects.

RESULTS: The selected PF614 MPAR 25 mg formulation delivered therapeutic oxycodone concentrations equivalent to PF614 alone when administered as one or two doses. However, oxycodone release was suppressed when PF614-MPAR was delivered at 3×, 5×, or 8× doses simultaneously.

CONCLUSION: PF614-MPAR may be the first opioid with both abuse resistance and oral overdose protection.

Opioids remain a central element of perioperative pain management despite increased utilization of multimodal adjuvant strategies intended to reduce their use. Contemporary use of methadone and buprenorphine, both conceived as opioid analgesics, is dominated by their essential roles in the treatment of opioid use disorder. Compared to usual care opioids, however, they provide improved post-operative pain control while reducing analgesic requirements. These findings argue for their expanded role within perioperative multimodal analgesia strategies.

OBJECTIVE: To investigate whether gradually discontinuing chronic opioid therapy (COT) affects quality of life (QOL), depression, and anxiety.

DESIGN: Double-blinded, randomized controlled trial.

SETTING: Ten primary care clinics in Wisconsin.

PARTICIPANTS: Adults on stable doses of COT for chronic noncancer pain.

INTERVENTIONS: Participants were blinded and randomized to either a slow taper or to continue their COT. Participants were assessed at baseline, 3, 6, 9, and 12 months post-enrollment.

OUTCOME MEASURES: Primary outcomes were study completion and QOL, measured by the Medical Outcomes Study Questionnaire Short Form 36 Health Survey version 2. Secondary outcomes were depression and anxiety symptoms, measured using the Patient Health Questionnaire-9 Depression Scale and the Generalized Anxiety Disorder-7 Anxiety Scale, respectively.

RESULTS: Of the 1,140 patients invited to participate, 18 enrolled-all prescribed tramadol or hydrocodone at the time of enrollment (median morphine milligram equivalents per day [MMED] of 17.5 mg; range: 5-40 MMED). Both groups had similar QOL and depression symptoms. The tapering group reported increased anxiety (p = 0.04).

CONCLUSION: Our findings suggest that opioids can be slowly tapered without affecting QOL or depression. Tapering led to a slight increase in anxiety. Larger-scale studies are needed to confirm our findings.

TRIAL REGISTRATION NUMBER: 21-009836 (ClinicalTrials.gov, Home | ClinicalTrials.gov). The trial was registered on March 22, 2022, "Slow Opioid Tapering Pilot Study of Patients Using Chronic Opioid Therapy."

PURPOSE: To investigate the therapeutic potential of Curcuma longa-derived extracellular vesicle-like particles (CL-EVLPs) in a benzalkonium chloride (BAC)-induced corneal injury model.

METHODS: CL-EVLPs were isolated via ultracentrifugation and characterized. A murine dry eye model was induced by topical application of BAC. Corneal injury and repair outcomes were assessed using clinical scoring, histopathology, and proteomic analysis. Western blotting and real-time quantitative polymerase chain reaction were conducted to quantify protein or mRNA levels. Bioinformatics analysis was performed using STRING and Cytoscape software.

RESULTS: CL-EVLPs, with a typical saucer- or cup-shaped structure with a peak diameter of 104 nm and an average diameter of 138.4 ± 64.3 nm, were efficiently taken up by corneal epithelial cells. Treatment with CL-EVLPs significantly accelerated corneal epithelial repair, reduced pathologic neovascularization, promoted corneal nerve regeneration, and suppressed inflammatory responses in a dry eye mouse model. Proteomic analysis revealed that CL-EVLPs are involved mainly in biological processes such as inflammation, oxidative stress, and immune regulation. Mechanistically, CL-EVLPs upregulated the cornea-specific protein keratin 12 but downregulated the hyperproliferation-associated protein Keratin 10. Additionally, we confirmed that key factors such as proangiogenic VEGFA, proteolytic MMP9, the inflammatory mediators IL-1β and S100A8/A9, and the related transcription factor NF-κB were significantly suppressed, whereas the expression levels of the transcription activator Nrf2 increased.

CONCLUSIONS: CL-EVLPs represent a novel natural nanobiologic that restores ocular surface homeostasis, effectively enhancing corneal epithelial regeneration and neural repair in the ocular surface microenvironment. This study provides a foundation for the development of plant-derived EVLPs as a safer and more economical therapeutic strategy for ocular surface disorders.