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Rapidly Dissolving Polymeric Microneedle Skin Patch of Naloxone for Opioid Overdose Treatment Tijani Akeemat1, Maria J. Peláez2, Prashant Dogra2,3, Ashana Puri1 1 Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614. 2 Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA 3 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA Worldwide opioid abuse affects over 16 million people. A major cause of death in abusers is overdosing. Naloxone (NAL) is an opioid inhibitor that reverses its respiratory depressing effect. The use of this drug is limited mostly to invasive delivery: intravenous (IV), intramuscular (IM) and subcutaneous (SC) due to its significant hepatic clearance and poor oral bioavailability (2%). These routes are painful and worse still is the need for frequent injections for patient stabilization due to the short half-life of NAL. Non-invasive intranasal forms exist but this is fraught with a couple of limitations such as nasal damage and epistaxis. The need for alternatives without these limitations is thus evident. The feasibility of the use of metal microneedles (MNs) for the transdermal delivery of NAL was demonstrated in-vitro and through in-vitro in-vivo correlation modeling in our lab. The goal of the current study was to design a rapidly dissolving polymeric MN patch with delivery and pharmacokinetic (PK) properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations. NAL loaded rapidly dissolving polyvinyl pyrrolidone-based MN arrays (500 µm, 100 needles) were fabricated by the mold casting technique. The permeation profile of fabricated MNs over a predetermined time were assessed via an in-vitro permeation set up using porcine ear skin. Samples were analyzed via HPLC. To improve on drug flux and amount permeated, the effect of increasing MN length and density (no. of needles/unit area) were assessed by fabricating MNs 300 µm longer and those with density double that of the initial array. Factors such as drug load and polymer strength influenced the needle fabrication. Compared to passive permeation, a reduced lag time of about 15 min was observed with a significant drug flux of 15.09 ± 7.68 g/cm2/h seen in the first 1 h (pin-vitro in-vivocorrelation we were able to predict an optimized design of the patch that can reproduce the clinical PK of NAL obtained with commercial devices. Increasing needle density and/or patch area was found to be of greater significance. Overall, drug flux seen over 1 h depicts the applicability of fabricated needles in opioid overdose emergencies with delivery properties comparable to that with IM and IN delivery.

With the rise of accidental fentanyl overdoses and recreational opioid use in college-aged populations, the need for campus-based overdose prevention and harm reduction measures is at an all-time high. Naloxone, an opioid antagonist, is an FDA-approved, lifesaving, medication which can be intranasally delivered by laypersons. Naloxone reverses opioid overdose, essentially buying time until an overdosing individual receives emergency medical attention. While some previous studies have examined access to naloxone on college campuses, to my knowledge no study has explored distribution of naloxone in residential college areas, such as dormitories and within Greek housing. Therefore, the purpose of this thesis was to identify themes in student perception surrounding naloxone, as well as potential processes and barriers/facilitators to naloxone distribution within residential areas (e.g., dormitories, sorority housing, and fraternity housing.) This study addresses these issues through qualitative, semi-structured, interviews with a convenience sample of students at the University of Central Florida, with questions informed by the Consolidated Framework for Implementation Research and Proctor et al. implementation outcomes. Seven students (n = 7) participated in the interview, all of whom either had personal experience with substance use disorder (SUD) or were close to someone with SUD. I analyzed data for themes using a mixed deductive-inductive template analysis approach in Dedoose software. Resulting themes relating to barriers to distribution within residential areas were as follows: lack of knowledge; fear of negative consequences from external parties; desire of administrators to maintain image of a “drug free campus”; lack of funding for distribution; student desire to avoid stigmatization. Resulting themes relating to facilitators to distribution in residential areas included the following: active involvement of peers; providing free naloxone; educating students about where to get and how to use naloxone; physical accessibility; and anonymous ways to access naloxone. Targeting residential areas for naloxone distribution was also discussed as a theme. Types of people who could/should be involved in naloxone distribution included the following: residential assistants; secondary distributors; pharmacists; UCF leadership; sorority and fraternity leaders; and student liaisons. Study results could be used to inform efforts at UCF and other colleges to expand naloxone access.

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The ongoing opioid crisis presents a significant public health challenge particularly for people who use opioids (PWUO). Naloxone is an opioid antagonist crucial to reducing opioid overdose mortality. Inconsistencies exist among PWUO in obtaining, carrying, discussing, and administering naloxone. Using sequential mixed methods, this study was aimed at investigating the use of implementation intentions on naloxone use among PWUO. Semi-structured interviews were conducted with 83 PWUO to gather individual experiences with using naloxone and contextual details regarding its use. An essentialist thematic analysis with inductive coding revealed valuable insights into where, for whom, and when naloxone is implemented. The analysis identified major themes such as caring for others' needs, knowledge gaps, reinforcement through overdose experiences, duality of overdose and compassion, and stigma. Minor themes related to syringe services program implementation and drug use were identified. Building on these qualitative findings a quantitative analysis determined the impact of implementation intentions on naloxone implementation. Participants were randomly assigned to develop implementation intentions or goal intentions for the use of naloxone. Follow-up surveys assessed changes in participants' intentions to obtain, carry, discuss, and administer naloxone and their actual implementation over a 6-month period. At the 3-month follow-up the experimental condition exhibited statistically significant positive intentions to obtain naloxone and engage in discussions about naloxone in social contexts of drug use. Changes in the magnitude of naloxone implementation were observed at the 3- and 6-month timepoints. Specifically, the self-reported discussion of naloxone showed noticeable changes in implementation frequency over time. This suggests that while implementation intentions may not have statistically significant effects on the use of naloxone it had some influence on the frequency of discussing naloxone prior to drug use. This work makes a valuable contribution to the existing literature because of its attempt to apply the Theory of Planned Behavior and implementation intentions in a novel way. Though the experimental hypothesis was not supported statistically significant observations were made for some behaviors at the 3-month follow-up. The pragmatic nature of the setting enhances the relevance of the findings and provides valuable insights for future interventions supporting PWUO. / Doctor of Philosophy / The ongoing crisis of opioid addiction poses a significant public health challenge particularly for individuals who use opioids. Naloxone is a medication that can reverse opioid overdoses and it plays a crucial role in saving lives. People who use opioids often face difficulties in accessing, carrying, discussing, and using naloxone consistently. This study was aimed at investigating the use of naloxone by employing qualitative and quantitative methods. We conducted interviews with 83 individuals who use opioids to explore their experiences and gather insights into naloxone use. These interviews provided valuable information about when, where, and for whom naloxone is used. Several important themes emerged including the significance of helping others, knowledge gaps, the influence of personal experiences, the conflict between the fear of overdose and caring for others, and the stigma associated with drug use. We investigated the impact of a specific approach called "implementation intentions" in improving naloxone use. Participants were randomly assigned to create specific plans or general goals for naloxone use. Through surveys conducted over a 6-month period we examined changes in participants' intentions and actions related to naloxone use. Although the specific approach did not yield significant improvements, we observed changes in how people discussed naloxone over time. This study contributes to the existing research by introducing innovative ideas to support positive behavioral changes among individuals who use opioids. The real-world setting in which the study took place enhances the applicability of the findings and offers valuable insights for future programs supporting individuals who use opioids.

Background: The news media has spread misinformation about the toxicity and potency of fentanyl, exaggerating the extent to which bystanders could be harmed by fentanyl when responding to overdose situations. College students are increasingly among the victims of opioid overdose, and their peers may be the nearest person capable of administering naloxone – an overdose reversal medication. However, college students who fear incidental exposure to fentanyl may be worried about administering naloxone. Objective: I sought to understand the relationship between undergraduate college students’ perceptions of the risks of fentanyl and their intentions to administer naloxone in an overdose situation. Methods: An online survey was formulated based on the Health Belief Model to measure beliefs about the harm of fentanyl and the likelihood of administering naloxone. The survey was distributed to students at a major public university in the Southeastern US in 2024. The survey was analyzed using a Spearman Rank Correlation to assess the relationship between the variables: intent to administer naloxone, beliefs about administering naloxone in an overdose, and perceptions about fentanyl. Additional analysis included the differences in beliefs about fentanyl among health versus non health majors and first year versus non first year students. Results: Notable findings include no significant correlation between beliefs about fentanyl and intention to administer naloxone in a fentanyl overdose in the 182 respondents who completed the survey. However, a significant difference was found in intention to administer naloxone in a fentanyl overdose in those who know what action to take in a fentanyl overdose versus those who do not. Conclusions: This study is among the first of its kind to analyze the relationship between fentanyl beliefs and intentions to administer naloxone in a fentanyl overdose. As overdoses and overdose deaths continue to rise and students continue to be among the victims of accidental overdose deaths, universities should use this research to implement early training and resources to improve access to naloxone and naloxone administration.

Five adult male volunteers were studied to investigate the effect of opiate receptor blockade on the physiological response to a maximum of 60 minutes of stationary cycling at 70% V02peak in a hot (33 0 C/65% RH) environment. Exercise bouts were conducted following the administration of naloxone (4mg IV) 5 minutes prior to exercise with a follow-up 4mg dose at 25 minutes of exercise. In the placebo trial, volume-matched doses of saline were administered at the same points. No significant drug effect was observed on rectal or mean skin temperature during exercise. Post-exercise skin temperature was significantly (P<.001) higher on naloxone versus saline. Forearm blood flow (FBF) was consistently higher from minute 25 of exercise until test termination, although only the minute 25 and minute 55 data points were significantly elevated (P<.05, P<.005, respectively) . The rectal temperature threshold at which FBF plateaued was higher on naloxone (P=.054), and the FBF: rectal temperature slope was higher on naloxone throughout the trial. No significant changes were observed in heart rate or estimated mean arterial pressures, although both were consistently lower on naloxone. Gross sweat response was not altered by the drug. Plasma Beta-Endorphin was significantly (P<.Ol) higher on naloxone versus saline, and Beta-Endorphin was significantly elevated in the naloxone trial only. The observation that FBF was significantly higher on naloxone without inducing compensatory heart rate or blood pressure changes suggests that the opioids may be involved in the blood volume shifts that occur during prolonged exercise in the heat. / Master of Science

No / The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of I Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, ip) or morphine (0.1 mg/kg, ip) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, ip) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, ip) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.

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