If We Build It, Will They Come? Perspectives on Pharmacy-Based Naloxone Among Family and Friends of People who use Opioids: A Mixed Methods Study

Background: Expanding access to the opioid antagonist naloxone to reduce overdose mortality is a public health priority in the United States. Naloxone standing orders (NSOs) have been established in many states to increase naloxone dispensing at pharmacies, but increased pharmacy access does not ensure optimal uptake among those likely to witness an overdose. In a prior statewide purchase trial, we documented high levels of naloxone access at Massachusetts pharmacies under a statewide NSO. In this study, we characterize barriers to pharmacy-based naloxone uptake among potential opioid overdose “bystanders” (friends or family of people who use opioids) that may be amenable to intervention.Methods: Eligible bystanders were Massachusetts residents >18 years of age, did not use illicit opioids in the past 30 days, and knew someone who currently uses illicit opioids. We used a sequential mixed methods approach, in which a series of semi-structured qualitative interviews (N=22) were conducted to inform the development of a subsequent quantitative survey (N=260). Results: Most survey participants (77%) reported ever obtaining naloxone but few (21%) attempted to purchase it at a pharmacy. Qualitative participants revealed that barriers to utilizing the NSO included low perceived risk of overdose, which was rooted in misconceptions regarding the risks of prescription opioid misuse, denial about their loved one’s drug use, and drug use stereotypes; inaccurate beliefs about the impact of naloxone on riskier opioid use; and concerns regarding anticipated stigma and confidentiality. Many participants had engaged in mutual support groups, which served as a source of free naloxone for half (50%) of those who had ever obtained naloxone.Conclusions: Despite high levels of pharmacy naloxone access in Massachusetts, few bystanders in our study had attempted to obtain naloxone under the NSO. Low perceived risk of overdose, misinformation, stigma and confidentiality were important barriers to pharmacy naloxone uptake, all of which are amenable to intervention. Support groups provided a setting for addressing stigma and misinformation and provided a discreet and comfortable setting for naloxone access. Where these groups do not exist and for bystanders who do not participate in such groups, pharmacies are well-positioned to fill gaps in naloxone availability.

Pattern of Opioid Overdoses and Interventions at the Emergency Department: Impact of COVID-19

BackgroundOpioid-related overdoses cause substantial numbers of preventable deaths. Naloxone is an opioid antagonist available in take-home naloxone (THN) kits as a lifesaving measure for opioid overdose. As the emergency department (ED) is a primary point of contact for patients with high-risk opioid use, evidence-based recommendations from the Society of Hospital Pharmacists of Australia THN practice guidelines include the provision of THN, accompanied by psychosocial interventions. However, implementation of these guidelines in practice is unknown. This study investigated ED opioid-related overdose presentations, concordance of post-overdose interventions with the THN practice guidelines, and the impact, if any, of the SARS-CoV-2 (COVID-19) pandemic on case presentations.MethodsA single-centre retrospective audit was conducted at a major tertiary hospital of patients presenting with overdoses involving opioids and non-opioids between March to August 2019 and March to August 2020. Patient presentations and interventions delivered by the paramedics, ED and upon discharge from the ED were collated from medical records and analysed using descriptive statistics, chi square and independent T-tests.ResultsThe majority (66.2%) of patients presented to hospital with mixed drug overdoses involving opioids and non-opioids. Pharmaceutical opioids were implicated in a greater proportion (72.1%) of overdoses than illicit opioids. Fewer patients presented in March to August 2020 as compared with 2019 (26 vs. 42), and mixed drug overdoses were more frequent in 2020 than 2019 (80.8% vs. 57.1%). Referral to outpatient psychology (22.0%) and drug and alcohol services (20.3%) were amongst the most common post-discharge interventions. Naloxone was provided to 28 patients (41.2%) by the paramedics and/or ED. No patients received THN upon discharge.ConclusionsThis study highlights opportunities to improve ED provision of THN and other interventions post-opioid overdose. Large-scale multi-centre studies are required to ascertain the capacity of EDs to provide THN and the impact of COVID-19 on opioid overdose presentations.

Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose

Opioid use disorder is a well-established and growing problem in the United States. It is responsible for both psychosocial and physical damage to the affected individuals with a significant mortality rate. Given both the medical and non-medical consequences of this epidemic, it is important to understand the current treatments and approaches to opioid use disorder and acute opioid overdose. Naloxone is a competitive mu-opioid receptor antagonist that is used for the reversal of opioid intoxication. When given intravenously, naloxone has an onset of action of approximately 2 min with a duration of action of 60–90 min. Related to its empirical dosing and short duration of action, frequent monitoring of the patient is required so that the effects of opioid toxicity, namely respiratory depression, do not return to wreak havoc. Nalmefene is a pure opioid antagonist structurally similar to naltrexone that can serve as an alternative antidote for reversing respiratory depression associated with acute opioid overdose. Nalmefene is also known as 6-methylene naltrexone. Its main features of interest are its prolonged duration of action that surpasses most opioids and its ability to serve as an antidote for acute opioid overdose. This can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.

The Efficacy and Safety of Methylnaltrexone for the Treatment of Postoperative Ileus

Background Postoperative ileus (POI) is a surgical complication resulting in increased morbidity and length of stay (LOS). Usual care for POI includes bowel rest and gastric decompression. It has been questioned if methylnaltrexone (MNTX), a peripheral opioid antagonist, could be used as treatment for POI. The purpose of this study was to determine if MNTX is effective and safe for POI treatment. Methods This single-center, retrospective cohort study included patients ⩾ 18 years with a POI. Patients with acute colonic pseudo-obstruction, small bowel obstruction, and gastrointestinal malignancy were excluded. The intervention was MNTX administration. The primary outcome was time to ileus resolution. Secondary outcomes included LOS, duration of nasogastric tube, total parenteral nutrition requirement, and incidence of gastrointestinal perforations. Results 110 patients were included in the analysis; 28 received MNTX. Time to ileus resolution was 9.9 days for the MNTX group and 11.4 days for the control group ( P = .38). Duration of gastric decompression was 4.6 days for the MNTX group and 4.2 days for the control group ( P = .71). Length of stay was 19.9 days for the MNTX group and 19.7 days for the control group ( P = .96). The percentage of TPN requirement was 17.9% in the MNTX group and 22.0% in the control group ( P = .65). No gastrointestinal perforations were observed in either group. Conclusion For the treatment of POI, MNTX did not significantly reduce time to resolution of ileus, LOS, duration of gastric decompression, or TPN requirements. However, no gastrointestinal perforations were seen, indicating that MNTX may be safely used in these patients.

Levels of Impulsivity, Hyperactivity, and Inattention and the Association with Mental Health and Substance Use Severity in Opioid-Dependent Patients Seeking Treatment with Extended-Release Naltrexone

The level of impulsivity, hyperactivity, and inattention (IHI) is higher among patients with substance use disorder (SUD) than in the general population. However, the prevalence of such symptoms in patients seeking treatment with an opioid antagonist, such as extended-release naltrexone (XR-NTX), is unknown. We screened 162 patients with opioid use disorder (OUD) seeking treatment with XR-NTX in Norway using the Adult ADHD Self-Report Scale (ASRS) to estimate the prevalence of IHI alongside an assessment of mental and physical health and substance use. Sixty-six patients scored above the clinical cut-off on the ASRS. Higher levels of IHI were significantly associated with a longer history of frequent amphetamine use, current alcohol use, and greater mental distress. Mental distress was the strongest factor associated with higher levels of IHI. The introduction of screening for IHI and mental distress in opioid maintenance treatment and XR-NTX would likely improve the quality of care and enable clinicians to tailor interventions to the needs of patients with high levels of IHI to prevent treatment discontinuation.

Abstract P500: Naltrindole And Naltrindole Derivatives Exhibit Potent Cardioprotection In Myocardial Ischemia Reperfusion Injury

Previously, naltrindole (NTI; selective delta opioid receptor antagonist) was shown to improve post-reperfused cardiac function and reduced infarct size when given prior to ischemia (I)/ reperfusion (R) in ex-vivo rat hearts. Conversely, naloxone (NX, broad-spectrum opioid antagonist) and nor-binaltrophine (BNI, selective kappa receptor antagonist) were similar to control hearts. In this study, the effects of NTI derivatives naltriben (NTB, delta receptor antagonist) and guanidonaltrindole (GNTI, kappa receptor antagonist) were compared to NTI, BNI, and NX. Isolated hearts from male SD rats (300g) were subjected to global I(30min)/R(45min). Treatments were given 5 min before I (preconditioning) and during the first 5 min of R. Left ventricular (LV) cardiac function was measured using a pressure transducer. At the end of reperfusion, infarcted heart tissue was compared to total tissue weight. Data were evaluated using ANOVA. As shown in Table 1, NTI, NTB, and GNTI significantly improved post-reperfused cardiac function and reduced infarct size compared to control hearts. NTI and NTB elicited direct effects on cardiac function when given during preconditioning in contrast to all other study groups and were the most robust at reducing infarct size and restoring post reperfusion cardiac function. The negative inotropic effects of NTI and NTB were correlated with a decrease in the rise of ischemic pressure. GNTI also elicited significant improvement in post-reperfused cardiac function and reduction of infarct size compared to BNI which suggests a separate cardioprotective mechanism that this NTI derivative may exert in contrast to kappa opioid receptor inhibition. Results suggest that NTI and derivatives, GNTI and NTB, are cardioprotective against I/R injury resulting in reduced ischemic peak pressure (NTI/NTB) and infarct size. In future studies, we will examine the mechanism of the protective effects of NTI and derivatives in hearts subjected to I/R injury.

Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men

Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.

Mechanisms Underlying the Anti-Suicidal Treatment Potential of Buprenorphine

Death by suicide is a global epidemic with over 800 K suicidal deaths worlwide in 2012. Suicide is the 10th leading cause of death among Americans and more than 44 K people died by suicide in 2019 in the United States. Patients with chronic pain, including, but not limited to, those with substance use disorders, are particularly vulnerable. Chronic pain patients have twice the risk of death by suicide compared to those without pain, and 50% of chronic pain patients report that they have considered suicide at some point due to their pain. The kappa opioid system is implicated in negative mood states including dysphoria, depression, and anxiety, and recent evidence shows that chronic pain increases the function of this system in limbic brain regions important for affect and motivation. Additionally, dynorphin, the endogenous ligand that activates the kappa opioid receptor is increased in the caudate putamen of human suicide victims. A potential treatment for reducing suicidal ideation and suicidal attempts is buprenorphine. Buprenorphine, a partial mu opioid agonist with kappa opioid antagonist properties, reduced suicidal ideation in chronic pain patients with and without an opioid use disorder. This review will highlight the clinical and preclinical evidence to support the use of buprenorphine in mitigating pain-induced negative affective states and suicidal thoughts, where these effects are at least partially mediated via its kappa antagonist properties.

Prevention of Opioid Addiction

Opioid addiction is classified as a Substance Use Disorder (SUD), a complex and chronic health condition with physical, social, and psychological consequences. While there is no cure for it, we present a novel approach towards preventing a hallmark feature of addiction-- the opiate withdrawal syndrome. Opioids exert numerous effects, acutely and chronically, on the nervous system with physical dependence, tolerance, and withdrawal being the most adverse chronic features. The degree of opioid dependence can be quantified by the frequency and/or intensity of the behavioral expression of withdrawal seen after abrupt termination of opioid consumption or after treatment with an opioid antagonist such as naloxone. Although the Central Nervous System (CNS) is the primary area of opioid impact, the involvement of the immune system in modifying CNS phenomena was suggested nearly two centuries ago and proved by several groups within the last few decades. Through a series of studies with immunomodulators alpha interferon, cyclosporine A, and cortisol, preclinical experiments show that administration of these agents prior to chronic morphine exposure prevents the expression of opiate withdrawal a hallmark feature of addiction. This review provides updates on current developments in the management of the opioid epidemic and an overview of studies on preventative immunomodulation prior to repetitive opioid administration as a means of addressing one of the underlying symptomatology driving the epidemic.

Effects of remifentanil on pharyngeal swallowing and esophageal motility - no impact of different bolus volumes, and partial antagonism by methylnaltrexone

Background Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. Aims To investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Methods Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid state catheter. Data was analyzed from three series of bolus swallows, baseline, during remifentanil exposure, and 15 min after methylnaltrexone. Results Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Conclusions Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction, and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.