Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone.

Developing an effective antidote for fentanyl-induced overdose to achieve timely reversal is an unmet public health need. Previously, we found that naloxone derivative NX90 with mild κ-opioid agonistic properties was three-fold more effective than the parent naloxone in reversing a fentanyl overdose in rats. To investigate whether κ-agonistic properties could indeed augment the robustness of overdose reversal, we evaluated a κ-agonist/µ-antagonist nalbuphine (NB) as well as its combinations with naloxone (NX) in a fentanyl overdose model in rodents. An administration of either NB or NX as single agents at 0.1 mg/kg doses produced a full recovery in 90 ± 9.9 min and 11.4 ± 2.7 min, respectively. A higher dose of NX at 0.2 mg/kg reversed an overdose within 4.8 ± 1.0 min. In contrast to that, the coadministration of NB and NX at 0.1 mg/kg each produced a synergistic effect, with overdose reversal in 3.4 ± 0.2 min. The coadministration of NX and NB at sub-therapeutic doses of 0.05 mg/kg each was also 1.2-fold more effective than NX at 0.2 mg/kg. We further found that co-administration of NB at different doses (0.025, 0.05, 0.1 mg/kg) and ratios (1:4 and 1:1) with NX had differential effects on overdose reversal, cardiorespiratory liabilities, and analgesia.

Opioid overdose prevention education in Texas during the COVID-19 pandemic.

BACKGROUND: Distribution of naloxone and training on its proper use are evidence-based strategies for preventing opioid overdose deaths. In-person naloxone training was conducted in major metropolitan areas and urban centers across Texas as part of a state-wide targeted opioid response program. The training program transitioned to a live, virtual format during the COVID-19 public health emergency declaration. This manuscript describes the impact of this transition through analyses of the characteristics of communities reached using the new virtual training format. CASE PRESENTATION: Training participant addresses were compared to county rates of opioid overdose deaths and broadband internet access, and census block comparison to health services shortages, rural designation, and race/ethnicity community characteristics. CONCLUSIONS: The virtual training format reached more learners than the in-person events. Training reached nearly half of the counties in Texas, including all with recent opioid overdose deaths. Most participants lived in communities with a shortage of health service providers, and training reached rural areas, those with limited broadband internet availability, and majority Hispanic communities. In the context of restrictions on in-person gathering, the training program successfully shifted to a live, online format. This transition increased participation above rates observed pre-pandemic and reached communities with the need for equipping those most likely to witness an opioid overdose with the proper use of naloxone.

Risks and overdose responses: Participant characteristics from the first seven years of a national take-home naloxone program.

BACKGROUND: In 2014, the Norwegian government funded a large-scale take-home naloxone (THN) program to address high overdose mortality rates. The aims of this study are to describe characteristics among persons trained to receive THN, describe actions taken following THN use at an overdose event and to explore factors associated with naloxone use. METHODS: This was a prospective cohort study of individuals who received THN from 2014 to 2021. Descriptive characteristics were collected at initial training. When returning for refill, participants reported on their previous naloxone use. In a multivariable logistic regression model exploring associations with naloxone use: gender, age, opioid use history, concomitant drug use, injecting, history of experienced or witnessed overdose were included. RESULTS: In total, 3527 individuals were included in this study. There were 958 individuals who returned for refills 2303 times. Most participants were male (63.6%), with a history of opioid use (77.5%). Those who reported naloxone use were more likely to have a history of opioid use (aOR= 4.1; 95% CI=2.77,6.1), were younger (aOR=0.98; 95% CI=0.97,0.99) and had witnessed overdoses (aOR=3.3; 95% CI=1.98,5.34). Among current opioid users, the odds were higher for injectors (aOR=1.57; 95% CI=1.18,2.1). Naloxone use was reported 1282 times. Additional actions such as waking the person and calling the ambulance were frequently reported. Survival was reported in almost all cases (94%). CONCLUSION: People who use drugs are a suitable target group for THN-programs, as they seem to be willing and capable to reverse overdoses effectively. Given their personal risk factors for overdosing, recipients will likely also benefit from overdose prevention education.

Treatment of opioid overdose: current approaches and recent advances.

BACKGROUND: The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs). METHODS: This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans. RESULTS AND CONCLUSIONS: The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.

Modifying naloxone to reverse fentanyl-induced overdose.

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.

Willingness to use a wearable device capable of detecting and reversing overdose among people who use opioids in Philadelphia.

BACKGROUND: The incidence of opioid-related overdose deaths has been rising for 30 years and has been further exacerbated amidst the COVID-19 pandemic. Naloxone can reverse opioid overdose, lower death rates, and enable a transition to medication for opioid use disorder. Though current formulations for community use of naloxone have been shown to be safe and effective public health interventions, they rely on bystander presence. We sought to understand the preferences and minimum necessary conditions for wearing a device capable of sensing and reversing opioid overdose among people who regularly use opioids. METHODS: We conducted a combined cross-sectional survey and semi-structured interview at a respite center, shelter, and syringe exchange drop-in program in Philadelphia, Pennsylvania, USA, during the COVID-19 pandemic in August and September 2020. The primary aim was to explore the proportion of participants who would use a wearable device to detect and reverse overdose. Preferences regarding designs and functionalities were collected via a questionnaire with items having Likert-based response options and a semi-structured interview intended to elicit feedback on prototype designs. Independent variables included demographics, opioid use habits, and previous experience with overdose. RESULTS: A total of 97 adults with an opioid use history of at least 3 months were interviewed. A majority of survey participants (76%) reported a willingness to use a device capable of detecting an overdose and automatically administering a reversal agent upon initial survey. When reflecting on the prototype, most respondents (75.5%) reported that they would wear the device always or most of the time. Respondents indicated discreetness and comfort as important factors that increased their chance of uptake. Respondents suggested that people experiencing homelessness and those with low tolerance for opioids would be in greatest need of the device. CONCLUSIONS: The majority of people sampled with a history of opioid use in an urban setting were interested in having access to a device capable of detecting and reversing an opioid overdose. Participants emphasized privacy and comfort as the most important factors influencing their willingness to use such a device. TRIAL REGISTRATION: NCT04530591.

The role of overdose reversal training in knowing where to get naloxone: Implications for improving naloxone access among people who use drugs.

Background: Naloxone distribution and training programs have been implemented to combat the opioid overdose crisis. While many individuals are trained, ongoing naloxone access is not ensured by these programs. We explored whether people who use drugs (PWUD) in Baltimore City, Maryland could identify a location where they would go to obtain naloxone and how training changed where they would be willing to access naloxone. Methods: We surveyed 574 PWUD as to whether they had heard of, been trained to use, and knew where to get naloxone. Among participants who had heard of naloxone, we tested for differences in knowing where to get naloxone by training. Results: The majority (95.3%) had heard of naloxone. Of these, 84.0% could name a location where they would access naloxone, but only 11.7% named multiple. Pharmacies (32.3%) and medical providers (excluding drug treatment providers) (22.9%) were the most commonly identified sources. Participants who had been trained to use naloxone were more likely to report that they would obtain naloxone from the needle exchange and were less likely to report they did not know where they would go to get it or that they would go to a medical provider (excluding drug treatment providers) for naloxone. Conclusions: Naloxone training was associated with participants' ability to name a location where they would obtain naloxone. Medicalized sources of naloxone remained the most commonly reported. These sources, however, may be associated with significant barriers to access, such as cost. Trainings should provide comprehensive education about low-cost/free sources to ensure ongoing naloxone access among people who use drugs.

"You've got to care to carry this stuff" Community implications from take-home naloxone use: A qualitative study.

BACKGROUND: In New Mexico, drug overdose rates have been among the highest in the nation for the past two decades, with 332 overdose deaths involving opioids in 2017. While interventions aimed at enhancing distribution and uptake of take-home naloxone (THN) have identified people who use opioids as viable candidates, there exists a gap in applying these findings to underserved, ethnic minority women. METHODS: We conducted qualitative interviews with participants recruited from a parent study which recruited 395 women diagnosed with OUD who participated in a two year study (April 2016-May 2018) during which they received opioid overdose education and two free THN kits for their use. RESULTS: Findings characterize the social dynamics of persistent opioid exposure, accidental overdose, and take home naloxone use to reverse overdose, and we identified three overarching themes: 1) Crisis management and community responsibility; 2) Complex social networks as informal channels for family to family and peer to peer naloxone distribution and education; and 3) Participant preferences and strategies for THN distribution and education. CONCLUSIONS: Participants in the ASAP program demonstrated an unquestionable willingness to distribute naloxone when they had access to it, and the ability to replace it. Further research is warranted to apply these findings in interventional contexts to refine strategies toward prioritizing distribution of THN, enhance training tools and optimize community locations for engagement.

Opioid overdose reversals using naloxone in New York City by people who use opioids: Implications for public health and overdose harm reduction approaches from a qualitative study.

BACKGROUND: Adverse reactions to naloxone, such as withdrawal symptoms and aggression, are widely recognised in the literature by pharmaceutical manufacturers and clinical practitioners as standard reactions of individuals who are physically dependent upon opioid drugs following the reversal of potentially fatal opioid overdose. This paper seeks to provide a differentiated view on reactions to naloxone that may have important implications for public health and harm reduction approaches. METHODS: Analyses from a qualitative investigation embedded within a 5-year Randomised Controlled Trial (RCT) examined the risks and benefits of Overdose Education and Naloxone Distribution (OEND) training models (brief or extended training) in various populations of people who use opioids in New York City. The qualitative experiences (obtained through semi-structured interviews) of 46 people who use opioids and who were each involved in the delivery of naloxone, during 56 separate overdose events that occurred throughout 2016-2018, were studied. Situational analysis and inductive content analysis of interview data focused upon overdose reversals in an attempt to provide understandings of the various adverse effects associated with naloxone from their perspective. These analyses were supplemented by data sessions within the research team during which the findings obtained from situational analysis and inductive content analysis were reviewed and complemented by deductive (clinical) appraisals of the various physical and psychological effects associated with the overdose reversals. RESULTS: People who use opioids recognise three distinct and interconnected outcomes that may follow a successful opioid overdose reversal after intramuscular or intranasal administration of naloxone. These outcomes are here termed, (i) 'rage' (describing a wide range of angry, hostile and/or aggressive outbursts), (ii) 'withdrawal symptoms,' and (iii) 'not rage, not withdrawal' (i.e., a wide range of short-lived, 'harmless' conditions (such as temporary amnesia, mild emotional outbursts, or physical discomfort) that do not include rage or withdrawal symptoms). CONCLUSION: Physical and psychological reactions to naloxone should not be understood exclusively as a consequence of acute, opioid-related, withdrawal symptoms. The three distinct and interconnected reversal outcomes identified in this study are considered from a harm reduction policy perspective and are further framed by concepts associated with 'mediated toxicity' (i.e., harm triggered by medicine). The overall conclusion is that harm reduction training programmes that are aligned to the policy and practice of take home naloxone may be strengthened by including awareness and training in how to best respond to 'rage' associated with overdose reversal following naloxone administration by people who use opioids and other laypersons.

Findings from the recovery initiation and management after overdose (RIMO) pilot study experiment.

This pilot study evaluated the feasibility of the Recovery Initiation and Management after Overdose (RIMO) intervention to link individuals to medication-assisted treatment (MAT) following an opioid overdose. The study team worked with the Chicago Fire Department to train Emergency Medical Service (EMS) teams to request permission from individuals after an opioid overdose reversal to release their contact information; individuals were subsequently contacted by the study team for participation. A mixed-methods study design comprised: (1) an experimental pilot study that examined participation at each stage of the intervention and compared the odds of treatment received for individuals who were randomly assigned to either the RIMO intervention (n = 16) or a passive referral control (n = 17); and (2) a focus group that was subsequently conducted with participants in the RIMO group to obtain their feedback on the intervention components. Quantitative data was collected on participant characteristics at study intake and treatment received was based on self-report at a 30-day follow-up. The RIMO group had higher odds of receiving any treatment for opioid use (OR = 7.94) and any MAT (OR = 20.2), and received significantly more days of opioid treatment (Ms=15.2 vs. 3.4) and more days of MAT in the 30 days post-randomization (Ms=11.2 vs. 0.76), relative to the control group (all p < .05). Qualitative data illustrated that participants valued the assertive outreach, engagement, and persistent follow-up components of RIMO, which differed from their prior experiences. The pilot study suggests that the RIMO intervention is able to address the challenges of linking and engaging individuals into MAT after an opioid overdose.

Predicting pharmacy naloxone stocking and dispensing following a statewide standing order, Indiana 2016.

BACKGROUND: While naloxone, the overdose reversal medication, has been available for decades, factors associated with its availability through pharmacies remain unclear. Studies suggest that policy and pharmacist beliefs may impact availability. Indiana passed a standing order law for naloxone in 2015 to increase access to naloxone. OBJECTIVE: To identify factors associated with community pharmacy naloxone stocking and dispensing following the enactment of a statewide naloxone standing order. METHODS: A 2016 cross-sectional census of Indiana community pharmacists was conducted following a naloxone standing order. Community, pharmacy, and pharmacist characteristics, and pharmacist attitudes about naloxone dispensing, access, and perceptions of the standing order were measured. Modified Poisson and binary logistic regression models attempted to predict naloxone stocking and dispensing, respectively. RESULTS: Over half (58.1%) of pharmacies stocked naloxone, yet 23.6% of pharmacists dispensed it. Most (72.5%) pharmacists believed the standing order would increase naloxone stocking, and 66.5% believed it would increase dispensing. Chain pharmacies were 3.2 times as likely to stock naloxone. Naloxone stocking was 1.6 times as likely in pharmacies with more than one full-time pharmacist. Pharmacies where pharmacists received naloxone continuing education in the past two years were 1.3 times as likely to stock naloxone. The attempted dispensing model yielded no improvement over the constant-only model. CONCLUSIONS: Pharmacies with larger capacity took advantage of the naloxone standing order. Predictors of pharmacist naloxone dispensing should continue to be explored to maximize naloxone access.

Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations.

OBJECTIVE: Naloxone hydrochloride, an opioid antagonist, has been approved as a concentrated 4 mg dose intranasal formulation for the emergency treatment of known or suspected opioid overdose. This new formulation is easier to use and contains a higher dose of naloxone compared with earlier, unapproved kits. A survey of first responders and community-based organizations was conducted to understand initial real-world experiences with this new formulation for opioid overdose reversal. METHODS: In August 2016, 152 US organizations known to have received units of the approved 4 mg dose/unit naloxone nasal spray (Narcan®1 nasal spray 4 mg; NNS) were surveyed regarding experiences using this formulation and availability of recorded data on these cases. Descriptive statistics were calculated based on the number of responses received for each item. RESULTS: Eight first-responder or community-based organizations provided case report data on 261 attempted overdose reversals using NNS, with survival reported for 245 cases. Successful overdose reversals were reported in 98.8% (242/245) of cases; most cases (73.5%; 125/170) reported a time to response of ≤5 minutes after NNS administration. Heroin was the substance reportedly involved in a majority (95.4%; 165/173) of these cases; fentanyl was reported to be involved in 5.2% (9/173) of the cases. Many reversals (97.6%; 248/254) involved administration of ≤2 units of NNS. Three deaths were reported (NNS was reported to have been administered too late for two cases [the individuals were deceased prior to NNS administration]; details were not provided for the third case). The most commonly reported observed events were "withdrawal" (14.3%; 28/196); "nausea", "vomiting", or "gagging/retching" (10.2%; 20/196); and "irritability" or "anger" (8.7%; 17/196). CONCLUSION: This survey of data provided by first-responder and community-based organizations indicated that NNS was successful at reversing the effects of opioid overdose in most reported cases.

Characteristics of persons who inject drugs and who witness opioid overdoses in Vietnam: a cross-sectional analysis to inform future overdose prevention programs.

BACKGROUND: Persons who use opioids have a high risk of overdose and associated mortality. In Vietnam, little is known about the characteristics of this population and the persons who are witness to those overdoses. One approach to combatting fatal overdose has been the use of peer interventions in which a friend or injecting partner administers overdose reversal medication, but availability in Vietnam of these medications is limited to pilot programs with aims to expand in the future (Le Minh and V.F. Go, Personal Communication, 2016). The primary objective of this paper is to explore the characteristics associated with witnessing three or more overdoses in a lifetime. METHODS: This cross-sectional analysis used baseline data from a four-arm randomized control trial conducted in Thai Nguyen, Vietnam, known as the Prevention for Positives project. One thousand six hundred seventy-three PWID were included in the analysis. We conducted bivariable and multivariable logistic regression to identify characteristics associated with witnessing three or more overdoses in a lifetime. Characteristics explored included education, employment, marital status, risky drug use behaviors, locations for accessing syringes, recent overdose, history of incarceration, drug treatment, and having slept outside in the past 3 months. RESULTS: Seventy-two percent (n = 1203) of participants had witnessed at least one overdose in their lifetime, and 46% had witnessed three or more overdoses (n = 765). In the multivariable model, having less than secondary education (AOR 0.70; 95% CI 0.57, 0.86), having slept outside in the past 3 months (AOR 1.77; 95% CI 1.31, 2.40), having a history of incarceration (AOR 1.33; 95% CI 1.07, 1.65), having a history of drug treatment (AOR 1.41; 95% CI 1.12, 1.77), experiencing a recent non-fatal overdose (AOR 3.84; 95% CI 2.36, 6.25), injecting drugs daily (AOR 1.79; 95% CI 1.45, 2.20), receptive needle sharing (AOR 1.30; 95% CI 1.04, 1.63), and number of years injecting (AOR 1.04; 95% CI 1.02, 1.07) were significantly associated with witnessing three or more overdoses. CONCLUSIONS: Targeted interventions are needed to train persons witnessing an overdose to administer overdose-reversal medication. This includes targeting persons prior to release from prisons, drug treatment centers, and those accessing syringe exchange programs. Additional research should assess the burden of witnessing an overdose as well as locations for medication distribution. Assessments of the training capacity and needs for implementing these programs among drug using peers in Vietnam are of the utmost importance.