Effect of Opium Versus Methadone on Polysomnographic Characteristics of Patients With Obesity Hypoventilation Syndrome.

Introduction: There are studies about polysomnographic (PSG) characteristics of patients with either obesity hypoventilation syndrome (OHS) or addiction. We aimed to investigate the PSG characteristics of obstructive sleep apnea (OSA) patients with opium addiction, those on methadone maintenance treatment (MMT), and non-addicts for the treatment of addiction. Methods: In this cross-sectional study, we enrolled 75 patients with OHS in the Bamdad Respiratory and Sleep Research Center affiliated with the Isfahan University of Medical Sciences between January 2020 and February 2021. The patients were categorized into three groups: Opium addicts (OA), MMT, and non-addicts (NA). All patients completed screening questionnaires for OSA. This included the Epworth sleepiness scale (ESS), stop-bang questionnaire, and Berlin questionnaire and the data analyzed by SPSS software, version 24. Results: A total of 75 OHS patients (54 men [72%] and 21 women [28%]) were studied in three groups, including OA (n=30), MMT (n=15), and NA (n=30). The apnea hypopnea index was not significantly different between the three groups. The longest apnea duration was higher in the OA than in other groups (P=0.001). Central apnea index (P=0.01), longest hypopnea duration (P=0.04), PaCO2 (P=0.04), and time with SpO2<90% (T90) (P=0.009) were higher in the MMT than in other groups. Furthermore, the minimum SpO2 was lower in the MMT than in other groups (P=0.03). Conclusion: Some of the sleep disturbances were worse in the MMT than in the OA group. This suggests the need for further studies to compare the effects of opium and methadone on sleep in OHS patients.

Reframing conceptualizations of primary care involvement in opioid use disorder treatment.

BACKGROUND: Opioid-related harms and opioid use disorder (OUD) are health priorities requiring urgent policy responses. There have been many calls for improved OUD care in primary care, as well as increasing involvement of primary care providers in countries like Canada and Australia, which have been experiencing high rates of opioid-related harms. METHODS: Using Starfield's 4Cs conceptualization of primary care functions, we examined how and why primary care systems may be suited towards, or pose challenges to providing OUD care, and identified health system opportunities to address these challenges. We conducted 14 semi-structured interviews with 16 key informants with experience in opioid use policy in Canada and Australia. RESULTS: Primary care was identified to be an ideal setting for OUD care delivery due to its potential as the first point of contact in the health system; the opportunity to offer other health services to people with OUD; and the ability to coordinate care with other health providers (e.g. specialists, social workers) and thus also provide care continuity. However, challenges include a lack of resources and support for chronic disease management more broadly in primary care, and the prevailing model of OUD treatment, where addictions care is not seen as part of comprehensive primary care. Additionally, the highly regulated OUD policy landscape is also a barrier, manifesting as a 'regulatory cascade' in which restrictive oversight of OUD treatment passes from regulators to health providers to patients, normalizing the overly restrictive nature and inaccessibility of OUD care. CONCLUSIONS: While primary care is an essential arena for providing OUD care, existing sociocultural, political, health professional, and health system factors have led to the current model of care that limits primary care involvement. Addressing this may involve structurally embedding OUD care into primary care and strengthening primary care in general.

Recreational Drug Overdose-Clinical Value of Toxicological Analysis.

BACKGROUND: Toxicological analysis of patients with acute recreational drug poisoning can improve our understanding of substance use patterns, clinical symptoms, and improve treatment. Patient history alone may be incomplete or misleading. The objective was to assess the differences in patient history and analytical results, to describe the clinical characteristics, implications and hospital management, and to describe the drug use pattern over time. METHODS: A retrospective study including all patients admitted to our toxicology unit with recreational drug toxicity and analytical testing from October 2014 to December 2022. RESULTS: 872 patients were included. Patient history revealed a median of one ingested substance class: opiates/opioids, benzodiazepines/Z-drugs, and Pregabalin were predominant. Urine analysis revealed a median of three ingested substance classes (p < 0.001). Benzodiazepines/Z-drugs, Pregabalin, and THC were severely underreported. Agitation and aggression, anxiety, hallucinations, and psychosis were frequent, associated with cocaine, cathinone/phenethylamine, and amphetamine/MDMA detection and required sedation. Coma was also frequent, associated with opiate/opioid, benzodiazepine/Z-drug, GBL/GHB, and Pregabalin detection and required intubation, and/or application of Naloxone and/or Flumazenil. Twelve patients arrived in cardiac arrest; all were positive for opiates/opioids. Four patients died: three with Benzodiazepines/Z-drugs, Pregabalin and opiates/opioids detected, one with cathinones/phenethylamines detected. While cathinones/phenethylamines and synthetic cannabinoid receptor agonists were mainly detected between 2014-2016, detection decreased significantly between 2017-2022 after NPS legislation passed. Pregabalin detection increased. CONCLUSIONS: Patient history is inaccurate, and patients frequently underreport ingested drugs. Opiates and opioids are still the main cause of morbidity and mortality. Pregabalin is increasingly abused. NPS legislation effectively decreased cathinone/phenethylamine and synthetic cannabinoid receptor agonist overdoses.

Prevalence and predictors of HIV among patients presenting to US emergency departments with opioid overdose.

INTRODUCTION: Opioid overdose deaths in the U.S. have risen dramatically in the past decade, largely due to the surge in illicitly manufactured fentanyl. Injection drug use is a known risk factor for HIV, further complicating the long-term consequences of opioid use. The baseline prevalence of HIV among adults in the US is 0.46 %. The primary purpose of this study was to determine the prevalence and risk factors of HIV among patients presenting to the emergency departments (ED) with an acute opioid overdose. METHODS: This study is a prospective observational cohort study from the ToxIC Fentalog Study group. Patients age 18 years of age or older are included if they present to one of 10 participating U.S. hospitals in 9 states between September 2020 and May 2023 with a suspected opioid overdose and had waste serum available after routine laboratory testing. Clinical data is collected from the medical record and patient serum is sent for comprehensive toxicologic analysis via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect the presence of over 1200 substances including illicit opioids, novel synthetic opioids, medications, and adulterants. Logistic multivariable regression was performed to examine the association between demographic, behavioral, and serum toxicology data with risk factors and HIV status. RESULTS: Among the total cohort (n=1690), 1062 cases had known HIV status (62.8 % of total sample). Among patients with a known HIV status, 60 (5.6 % [95 % CI: 4.2 %, 7.0 %]) were HIV positive. Patients with HIV reported stimulant use more frequently (13.3 %) than those without HIV (6.8 %; p=0.003). After controlling for confounding, bipolar psychiatric history was a significant independent predictor of HIV positivity (aOR: 1.08; 95 % CI: 1.02, 1.13) in this population. CONCLUSIONS: In this large multicenter cohort, the prevalence of HIV for ED patients with illicit opioid overdose was 9 times higher than that expected by the general population. Bipolar disorder appears to be a novel risk factor for HIV positivity in this patient population.

The Impact of Sedative Choice in the Management of Aneurysmal Subarachnoid Hemorrhage: A Scoping Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high mortality and morbidity. This scoping review assesses the current evidence regarding the use of sedatives and analgesics in the acute intensive care unit management of aSAH. We conducted a systematic search of Ovid MEDLINE, Ovid Embase, Ovid EmCare, APA PsycInfo, CINAHL, and the Cochrane Database of Systematic Reviews from inception to June 2023. Studies were included if they enrolled intensive care unit patients aged 18 or older with a significant proportion (> 20%) who had aSAH and evaluated the impact of one or more commonly used analgosedatives on physiological parameters in the management of aSAH. The methodological quality of the studies was assessed using the Methodological Index for Nonrandomized Studies score. Of 2,583 articles, 11 met the inclusion criteria. The median sample size was 47 (interquartile range 10-127), and the median Methodological Index for Nonrandomized Studies score was 9.5 (interquartile range 8-11). The studies' publication years ranged from 1980 to 2023. Dexmedetomidine and ketamine showed potential benefits in reducing the incidence of cortical spreading depolarization and delayed cerebral ischemia. Propofol and opioids appeared safe but lacked robust evidence for efficacy. Benzodiazepines were associated with increased delayed cerebral ischemia-related cerebral infarctions and cortical spreading depolarization events. The evidence available to guide the use of analgosedative medications in aSAH is critically inadequate. Dexmedetomidine and ketamine warrant further exploration in large-scale prospective studies because of their potential benefits. Improved study designs with consistent definitions and a focus on patient-centered outcomes are necessary to inform clinical practice.

Novel insights into mechanisms of inhibition of colonic motility by loperamide.

Background: It is well known that opiates slow gastrointestinal (GI) transit, via suppression of enteric cholinergic neurotransmission throughout the GI tract, particularly the large intestine where constipation is commonly induced. It is not clear whether there is uniform suppression of enteric neurotransmission and colonic motility across the full length of the colon. Here, we investigated whether regional changes in colonic motility occur using the peripherally-restricted mu opioid agonist, loperamide to inhibit colonic motor complexes (CMCs) in isolated mouse colon. Methods: High-resolution video imaging was performed to monitor colonic wall diameter on isolated whole mouse colon. Regional changes in the effects of loperamide on the pattern generator underlying cyclical CMCs and their propagation across the full length of large intestine were determined. Results: The sensitivity of CMCs to loperamide across the length of colon varied significantly. Although there was a dose-dependent inhibition of CMCs with increasing concentrations of loperamide (10 nM - 1 µM), a major observation was that in the mid and distal colon, CMCs were abolished at low doses of loperamide (100 nM), while in the proximal colon, CMCs persisted at the same low concentration, albeit at a significantly slower frequency. Propagation velocity of CMCs was significantly reduced by 46%. The inhibitory effects of loperamide on CMCs were reversed by naloxone (1 µM). Naloxone alone did not change ongoing CMC characteristics. Discussion: The results show pronounced differences in the inhibitory action of loperamide across the length of large intestine. The most potent effect of loperamide to retard colonic transit occurred between the proximal colon and mid/distal regions of colon. One of the possibilities as to why this occurs is because the greatest density of mu opioid receptors are located on interneurons responsible for neuro-neuronal transmission underlying CMCs propagation between the proximal and mid/distal colon. The absence of effect of naloxone alone on CMC characteristics suggest that the mu opioid receptor has little ongoing constitutive activity under our recording conditions.

The autoimmune nature of morphine addiction.

The onset of the disease as a morphine addiction is associated with the appearance in the patient's body of antibodies directed against opiate receptors (ORs). Once anti-opiate receptor antibodies (anti-OR antibodies) appear in the blood they will tend to bind to ORs. Such binding will cause blocking of physiological functions of OR. The blockage is felt by a morphine addict as withdrawal syndrome. To get rid of this harmful condition, the addict increases the dose of morphine taken. This is where tolerance manifests itself. The drug addict is forced to increase the dose of morphine from time to time because of the body responds by producing the more and more anti-OR antibodies. The immunological nature of morphine addiction is the reason for lifelong changes in the body's reactivity to the drug. An addict can be cured if he gets rid of B- and T-memory cells, which specifically react to ORs.

Buprenorphine Induction in Trauma Patients With Opioid Use Disorder - A Single Center Experience?

INTRODUCTION: Buprenorphine is a Food and Drug Administration-approved therapy for opioid use disorder, with proven efficacy in treatment retention and reduction in opioid use and mortality. Low-dose buprenorphine initiation or microinduction is a novel means of initiation that may allow for an easier transition in patients. Trauma patients have high rates of opioid use disorder and patient directed discharges (PDD). We hypothesized that patients initiated on a buprenorphine microinduction program would have increased protocol completion and fewer PDD compared with patients initiated historically on a traditional induction. METHODS: Our retrospective cohort study compared buprenorphine microinduction and traditional induction in trauma patients at an urban level one trauma center between December 2020 and June 2022. Patients aged 18-89 y with traumatic injuries who received buprenorphine were included. Our primary outcome was in-hospital protocol completion, defined as reaching 16 mg of buprenorphine within 24 h or a documented stable dose. Statistical analysis was performed using chi-square for categorical variables and two sample t-tests for continuous variables. RESULTS: Ninety-eight patients were included, with 46 initiating with microinduction and 52 initiating with traditional induction. There was no difference in protocol completion, (P = 0.29) and 83% of subjects who started an induction protocol completed it. Those who completed a protocol were more likely to be discharged home (P = 0.0002), had less PDD (P = 0.001), and had an increased likelihood of attending outpatient addiction clinic follow-up (P = 0.038). CONCLUSIONS: Regardless of the protocol type, buprenorphine induction can be implemented in trauma patients with high protocol completion rates. In our population, those who complete a protocol had a higher likelihood of discharge home and postdischarge follow-up in addiction medicine clinic.

Physicians, pharmacists and take-home naloxone: What practices? The SINFONI study.

OBJECTIVE: For several years, both the French Addictovigilance Network and French health authorities have consistently emphasized the need to provide opioid users with take-home naloxone (THN), the specific antidote for opioid overdoses. In March 2022, the French Health Authority recommended systematically assessing the appropriateness of prescribing THN to all opioid users, regardless of the context, and identified 8 high-risk situations. However, at present, THN distribution remains limited, particularly among primary care healthcare professionals. This study, conducted by the Pays de la Loire Centre for Evaluation and Information on Drug Dependence-Addictovigilance and supported by the Regional Health Agency, aims to explore healthcare professionals' practices and perceptions of these high-risk situations. METHODS: An ad-hoc questionnaire was distributed via mail by the project's regional institutional partners to the target healthcare professionals: pharmacists, general practitioners (GPs), physicians practicing in specialities other than general medicine (SPs: algologists, psychiatrists and addictologists). It was completed online from 20/10/2022 to 30/12/2022. RESULTS: Out of the 355 participants (158 pharmacists, 167 GPs and 30 SPs), nearly all were managing patients on opioids. In total, 47.7% of physicians and 27.8% of pharmacists reported experiencing difficulties in dealing with the risk of overdose when prescribing or dispensing opioids to their patients. In the 12months preceding the study, only 8 pharmacists and 34 physicians had prescribed/dispensed THN, primarily due to a lack of awareness of its existence (52% of pharmacists and 72% of physicians) and challenges in addressing the eight overdose risk situations listed by the HAS (ranging from 54% to 83% for all professionals). The best-trained healthcare professionals were those who prescribed the most THN (P<0.001). CONCLUSION: The identification of barriers related to THN distribution in the regional SINFONI study, conducted among primary care healthcare professionals managing patients on opioids, highlights the need to develop a training tool specifically tailored for these professionals.

Housing status and accidental substance-related acute toxicity deaths in Canada, 2016-2017. / Recherche quantitative originale Statut résidentiel et décès accidentels attribuables à une intoxication aiguë liée à une substance au Canada, 2016-2017.

INTRODUCTION: There is a complex relationship between housing status and substance use, where substance use reduces housing opportunities and being unhoused increases reasons to use substances, and the associated risks and stigma. METHODS: In this descriptive analysis of people without housing who died of accidental substance-related acute toxicity in Canada, we used death investigation data from a national chart review study of substance-related acute toxicity deaths in 2016 and 2017 to compare sociodemographic factors, health histories, circumstances of death and substances contributing to death of people who were unhoused and people not identified as unhoused, using Pearson chi-square test. The demographic distribution of people who died of acute toxicity was compared with the 2016 Nationally Coordinated Point-In-Time Count of Homelessness in Canadian Communities and the 2016 Census. RESULTS: People without housing were substantially overrepresented among those who died of acute toxicity in 2016 and 2017 (8.9% versus <1% of the overall population). The acute toxicity event leading to death of people without housing occurred more often in an outdoor setting (24%); an opioid and/or stimulant was identified as contributing to their death more frequently (68%-82%; both contributed in 59% of their deaths); and they were more frequently discharged from an institution in the month before their death (7%). CONCLUSION: We identified several potential opportunities to reduce acute toxicity deaths among people who are unhoused, including during contacts with health care and other institutions, through harm reduction supports for opioid and stimulant use, and by creating safer environments for people without housing.

Outcomes of ST-Elevation Myocardial Infarction in Patients With Opioid Dependence: A National Inpatient Sample Study.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is a critical condition characterized by the sudden obstruction of one or more coronary arteries, resulting in diminished blood flow to the heart muscle. This acute ischemic event demands swift and precise intervention to minimize myocardial damage and preserve cardiac function. Opioids, a class of potent analgesic medications, are frequently utilized in the management of STEMI-related chest pain. Despite their efficacy in alleviating discomfort, their use in this context warrants careful consideration due to potential adverse effects and interactions.  Methods: In this large nationwide retrospective observational study, we evaluated the effect of opioid dependence on inpatient mortality, length of hospitalization, and cost of hospitalization of patients with STEMI. Data was collected for 2019 from various hospitals across the United States using the National Inpatient Sample (NIS) through the Healthcare Cost and Utilization Project (HCUP). Using the International Classification of Diseases-10 codes (ICD-10), we identified a primary diagnosis of STEMI in patients over the age of 18, as well as a secondary diagnosis of opioid dependence.  Complex samples and multivariable logistic and linear regression models were used to determine the association of opioid dependence on inpatient mortality, length of hospitalization, and cost of hospitalization of patients with STEMI. Of the patients who fit our criteria, we identified other comorbidities and diagnoses associated with them as potential confounders including drug abuse, hypertension, diabetes, alcohol use, obesity, peripheral vascular disease, and chronic lung disease. Other confounders that were adjusted for include race, Charlson Comorbidity index, median household income, insurance, hospital region in the US, hospital bed size, and teaching status of the hospital.  Results: A total of 661,990 patients presented to a hospital with a primary diagnosis of STEMI in 2019. The majority of the patients were male with a mean age of 62.5+/-3.4 and were Caucasian American. Patients who were opioid dependent were found to be on average younger, earned less than the 25th percentile household income, had a higher history of illicit drug and alcohol use, and had Medicaid. They were also found to have higher rates of chronic lung disease at 39.2%, compared to 21.4.% in patients who were not opioid-dependent. Patients who were not opioid dependent were found to have higher rates of hypertension and type 2 diabetes mellitus. Inpatient mortality and cost of hospitalization in STEMI patients with opioid dependence were not statistically different compared to those who were not opioid dependent. However, STEMI patients who were opioid dependent did have an associated longer length of hospitalization.  Conclusion: Opioid use for pain relief in acute coronary syndrome, particularly STEMI, is a mainstay of treatment. Our retrospective cohort dived into assessing the relationship between opioid dependence on its effect on inpatient mortality, length of stay, and cost of hospitalization in STEMI patients. Our study showed that opioid dependence has no significant impact on inpatient mortality. However, it was associated with a longer length of hospital stay in STEMI patients. Further studies may be warranted into the effects of opioid dependence on the length of hospitalization in STEMI patients. .

Combined impact of local anaesthetic infiltration through wound catheter and epidural analgesia following surgical hepatectomy: a meta-analysis.

Introduction: A meta-analysis was performed to examine the effects of wound catheter (WC) local anaesthetic infiltration (LAI) and epidural analgesia (EA) in open hepatectomy (OH). Material and methods: A systematic literature review was performed, which found 350 subjects with OH at the baseline of the studies; 159 of them were treated with WC local anaesthetic infiltration, and 191 used EA. Results: WC LAI substantially reduced the functional recovery time (MD = -0.64; 95% CI, -1.02 to -0.26, p < 0.001) and increased the pain score on the second postoperative day (MD = 0.25; 95% CI: 0.10-0.40, p < 0.001) compared to EA in OH patients. WC LAI did not vary from EA in OH patients in second postoperative opiate use (MD = -14.86; 95% CI: -32.88 to 3.16, p = 0.11) or overall complication rate (OR = 0.66; 95% CI: 0.41-1.04, p = 0.07). Conclusions: WC LAI showed a non-significant difference in opiate consumption on the second postoperative day and in the overall complication rate, compared with EA, but it showed a lower functional recovery time and higher pain score.

Opioid-Related Emergency Department Visits Before and During COVID-19: Association with Community-Level Factors.

Background: The purpose of the study was to investigate the relationship between community-level variables and emergency department (ED) visit rates before and during COVID-19. The focus was on opioid-related ED visits. Despite large declines in overall ED visits during COVID-19, opioid-related visits increased. While visits for avoidable conditions decreased, the opposite was true for opioid-related visits. Methods: We combined data from Florida EDs with community-level variables from the 2020 American Community Survey. The outcome measures of the study were quarterly ZIP code tabulation-area-level ED visit rates for opioid-related ED visits as well as visit rates for all other causes. Associations with opioid-related visit rates were estimated before and during COVID-19. Results: The associations between community-level variables and opioid-related visit rates did not match those found when analyzing overall ED visit rates. The increase in opioid-related visits during COVID-19 was not unique to or more prevalent in areas with a larger percentage of racial/ethnic minority populations. However, socioeconomic status was important, as areas with higher unemployment, lower income, lower home ownership, and higher uninsured had higher overall ED visit rates and opioid visit rates during the pandemic. In addition, the negative association with income increased during the pandemic. Conclusion: These results suggest socioeconomic status should be the focus of prevention and treatment efforts to reduce opioid-related visits in future pandemics. Healthcare organizations can use these results to target their prevention and treatment efforts during future pandemics.

Willingness to Provide Naloxone Resources for Patients at Risk of Opioid Overdose: A National Survey of Emergency Registered Nurses.

INTRODUCTION: Opioid-related events continue to claim lives in the United States at alarming rates. Naloxone-dispensing rates fall dramatically short of national expectations. Emergency registered nurses are uniquely poised to connect at-risk patients with naloxone resources. This study sought to (1) describe the emergency registered nurses' willingness to provide naloxone resources and (2) explore variables that may influence the nurse's willingness to provide resources. METHODS: A cross-sectional, survey-based design was deployed using an online branch logic approach to include a national sample of emergency registered nurses. The Willingness to Provide, a validated questionnaire, measured the registered nurse's willingness to provide naloxone resources for patients at risk of opioid overdose. Eight variables were assessed for potential influence on willingness. RESULTS: A total of 159 nurses from 32 states and the District of Columbia completed the online survey via the Research Electronic Data Capture platform. The results revealed a mean Willingness to Provide score of 38.64 indicating a willingness to provide naloxone resources. A statistically significant relationship was identified between the nurse's willingness and years of nursing experience (P = .001), knowledge (P = .015), desire (P = .001), and responsibility (P < .001). DISCUSSION: In this representative sample, emergency nurses are willing to provide naloxone resources; furthermore, results indicate that higher knowledge, desire, and responsibility scores increase the nurse's willingness to provide naloxone resources; with education and clear expectations, emergency nurses may be able to improve the connection of patients at risk of opioid overdose with naloxone, a potentially lifesaving connection.

Impact of a new state law and electronic health record prompt on naloxone prescribing in an academic medical center.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To evaluate the impact of a best-practice advisory (BPA) and South Carolina legislation on naloxone prescribing patterns. The primary objective was to assess the change in naloxone prescription rates following BPA implementation. The secondary objective was to analyze the performance of the BPA. METHODS: Naloxone prescriptions generated before (July 28, 2020, through July 27, 2021) and after (July 28, 2021, through July 28, 2022) BPA implementation were analyzed via retrospective chart review. Lists of patients at risk for opioid overdose and patients for whom the BPA fired were generated for March 2022. The BPA's effectiveness was evaluated based on the proportion of at-risk patients missed by the alert, the frequency with which the BPA resulted in a naloxone prescription, and the reasons for not prescribing naloxone when the BPA fired. RESULTS: Following BPA implementation, there was a significant increase in the average monthly naloxone prescribing rate from 66.1 to 625.5 prescriptions per month. Overall, 2,086 patients were considered at risk for opioid overdose and 1,101 had a BPA alert during March 2022, with 32.7% of BPA alerts resulting in naloxone prescribing. The most common reasons selected for not prescribing naloxone were "patient refusal" and "criteria not met." Only 354 patients (17.1%) at risk for opioid overdose also had a BPA alert. CONCLUSION: State legislation and implementation of the BPA significantly increased naloxone prescribing rates. However, a significant proportion of patients identified as being at risk did not have a BPA alert and most BPA alerts did not result in naloxone prescribing, suggesting a need for improvement of the BPA.

Activation of µ receptors by SR-17018 through a distinctive mechanism.

Agonists at µ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve ß-arrestin2. Agonists biased against ß-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed µ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted µ receptor availability in PathHunter CHO cells using the irreversible antagonist, ß-funaltrexamine (ß-FNA), and compared efficacies and apparent potencies of twelve agonists, including several previously reported as biased, in ß-arrestin2 recruitment and cAMP assays. With full receptor availability all agonists had partial efficacy for stimulating ß-arrestin2 recruitment relative to DAMGO, while only TRV130 and buprenorphine were partial agonists as inhibitors of cAMP accumulation. Limiting receptor availability by prior exposure to ß-FNA (100 nM) revealed morphine, oxycodone, PZM21, herkinorin, U47700, tianeptine and U47931e are also partial agonists in the cAMP assay. The efficacies of all agonists, except SR-17018, correlated between ß-arrestin2 recruitment and cAMP assays, with depleted receptor availability in the latter. Furthermore, naloxone and cyprodime exhibited non-competitive antagonism of SR-17018 in the ß-arrestin2 recruitment assay. Limited antagonism by naloxone was also non-competitive in the cAMP assay, while cyprodime was competitive. Furthermore, SR-17018 only negligibly diminished ß-arrestin2 recruitment stimulated by DAMGO (1 µM), whereas fentanyl, morphine and TRV130 all exhibited the anticipated competitive inhibition. The data suggest that SR-17018 achieves bias against ß-arrestin2 recruitment through interactions with µ receptors outside the orthosteric agonist site. This article is part of the Special Issue on "Ligand Bias".

Loperamide positive deaths in Sweden 2012-2022 and Finland 2017-2022: Fatal loperamide intoxication exclusively for Sweden.

Loperamide, a potent µ-opioid receptor agonist used as an antidiarrheal drug, exhibits increased bioavailability at supratherapeutic doses, causing potential central nervous system effects. Its misuse for opioid withdrawal relief and euphoria can lead to dangerously elevated blood levels, causing severe cardiac dysrhythmias and death. This study aimed to compare loperamide positive autopsy cases in Sweden and Finland after the introduction of postmortem toxicological analysis of loperamide, focusing on loperamide's role in fatalities and identifying common characteristics among those affected. All cases with detected loperamide in femoral blood at forensic autopsies in Sweden (2012-2022) and Finland (2017-2022) were included. In Sweden, loperamide was detected in 126 individuals, and in Finland, in 111 individuals. The incidence of individuals positive for loperamide in postmortem femoral blood increased steadily over the study duration in both Sweden and Finland. Loperamide related fatalities were observed exclusively in Sweden (n=80), predominantly involving younger males with histories of substance abuse, typically classified as accidental deaths. The group of loperamide nonrelated deaths in Sweden mirrored the entirety of cases in Finland. The concentration of loperamide in postmortem femoral blood was significantly higher in cases where loperamide was considered the cause of death (median 0.140 µg/g) compared to cases where loperamide contributed (median 0.080 µg/g), as well as in deaths unrelated to loperamide in both countries (Sweden: median 0.029 µg/g; Finland: median 0.010 µg/ml). The high limit of quantification for loperamide in Sweden may underestimate therapeutic users in epidemiological assessments. This study underscores the absence of loperamide misuse in Finland and indicates a rising trend of loperamide abuse in Sweden.

Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption.

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD.

Regimes of pain: The geopolitics of cancer palliation in Pakistan.

This article examines how militarized regimes of narcotics and price control sustain unpalliated cancer pain in Pakistan. It shows how these regimes of control-reimagined as "regimes of pain"-render morphine, a cheap, effective opiate analgesic, scarce in hospitals. Meanwhile, heroin, morphine's illegal derivative, proliferates in illicit circuits. The article highlights a devastating consequence of the global wars against drugs and "terror": the consignment of cancer patients to agonizing end-of-life pain. Widening the analytic lens upon palliation beyond bodies and their clinical encounters, the article offers a geopolitics of palliation. It shows how narcovigilance targeting illicit drugs has the perverse effect of throttling morphine's licit supply. It shows further how unviably low price ceilings, purported to ensure a poor population's access to morphine, render it scarce on the official market. These mutually reinforcing regimes of control thus thwart their own purported objectives, consigning cancer patients to preventable, yet unpalliated, pain.

Early Hospice Consultation Team Engagement for Cancer Pain Relief: A Case Report.

This case report explores the challenges and complexities associated with opioid management of cancer pain, emphasizing the importance of early involvement of a hospice consultation team and the adoption of a multidisciplinary approach to care. A 56-year-old man with advanced pancreatic cancer experienced escalating pain and inappropriate opioid prescriptions, highlighting the shortcomings of traditional pain management approaches. Despite procedural intervention by the attending physician and increased opioid dosages, the patient's condition deteriorated. Subsequently, the involvement of a hospice consultation team, in conjunction with collaborative psychiatric care, led to an overall improvement. The case underscores the necessity of early hospice engagement, psychosocial assessments, and collaborative approaches in the optimization of patient-centered palliative care.