Naloxone Administration and Survival in Overdoses Involving Opioids and Stimulants: An Analysis of Law Enforcement Data from 63 Pennsylvania Counties.

Background: In consideration of rising deaths from opioid-stimulant-involved overdoses in the United States, this study explored rates of naloxone administration and survival in opioid overdoses with versus without stimulants co-involved. Methods: The study used data from the Pennsylvania Overdose Information Network, focusing on 26,635 suspected opioid-involved overdose events recorded by law enforcement and other first responders in 63 Pennsylvania counties from January 2018 to July 2024. Relative frequencies and chi-square tests were first used to compare suspected opioid overdoses with, versus without, stimulants (cocaine or methamphetamine) co-involved. Next, mediation analyses tested naloxone administration as a mediator of the association between stimulant co-involvement (in opioid overdoses) and survival. Results: Naloxone was reportedly administered in 72.2% of the opioid-no-cocaine overdoses, compared to 55.1% of the opioid-cocaine-involved overdoses, and 72.1% of the opioid-no-methamphetamine overdoses vs. 52.4% of the opioid-methamphetamine-involved overdoses. With respect to survival rates, 18.0% of the opioid-no-cocaine overdoses ended in death, compared to 41.3% of the opioid-cocaine overdoses; 18.1% of the opioid-no-methamphetamine overdoses ended in death, versus 42.9% of the opioid-methamphetamine overdoses. In mediation analyses (adjusted for demographics, county, year, and other drug co-involvement), naloxone administration mediated 38.7% (95% Confidence Interval [CI], 31.3%-46.0%) of the association between cocaine co-involvement and survival and 39.2% (95% CI, 31.3%-47.1%) of the association between methamphetamine co-involvement and survival. Conclusions: Among suspected opioid overdose events recorded in the Pennsylvania Overdose Information Network, stimulant co-involvement was associated with lower naloxone administration and higher fatality, with naloxone partially mediating the association between stimulant co-involvement and death.

Design and implementation of a Type-2 hybrid, prospective randomized trial of opioid agonist therapies integration into primary care clinics in Ukraine.

INTRODUCTION: Ukraine has high HIV prevalence, concentrated among people who inject drugs (PWID), mostly of opioids. Maintenance on opioid agonist therapies (OAT) is the most effective evidence-based treatment for opioid use disorder. As PWID experience high morbidity and mortality from preventable and treatable non-communicable diseases, international agencies recommend integrating OAT into primary care centers (PCC). METHODS: A randomized, type-2 hybrid implementation trial was carried out to compare outcomes of OAT integration in PCC to OAT delivery at specialty treatment centers (STC) - standard-of-care. Tele-education supporting PCC providers in managing OAT, HIV, tuberculosis and non-communicable diseases along with pay-for-performance incentives were used to facilitate implementation. Consenting patients underwent 1:2 randomization to either STC or PCC. Quality health indicators (QHIs), a composite percentage of recommended primary and specialty services accessed by patients (blood/urine tests, cancer screenings, etc.), were defined as efficacy outcomes and were assessed by participant self-report at baseline and every 6 months over 24 months and electronic chart reviews after the completion of the follow-up. The primary outcome is defined as the difference in composite QHI scores at 24 months, in which a repeated measures likelihood-based mixed model with missing at random assumptions will be used. Providers at PCC completed surveys at baseline, 12 and 24 months to assess implementation outcomes including changes in stigma and attitudes towards OAT and PWID. PRELIMINARY RESULTS: Among the 1459 participants allocated to STC (N = 509) or PCC (N = 950), there were no differences in clinical and demographic characteristics. Self-reported prevalences were available for HIV (42 %), HCV (57 %), and prior tuberculosis (17 %). Study retention at 6, 12, 18, and 24 months was as 91 %, 85 %, 80 %, and 74 %, respectively. CONCLUSION: PWID have a high prevalence of medical comorbidities and integrating OAT into primary care settings has the potential to improve the health of PWID. Findings from this study can help guide implementation of integrated care in Ukraine and throughout similar low-resource, high-burden countries in the Eastern European and Central Asian region.

Social homeostasis and psychoactive drugs: What can we learn from opioid and amphetamine drug challenge studies in humans?

BACKGROUND: Social disequilibrium, or disrupted social homeostasis, underlies many behavioral disorders, including problematic drug use. One way to study the relationship between drug use and social homeostasis is to determine whether single doses of psychoactive drugs relieve some of the discomfort of social isolation and promote social connection. METHODS: In this narrative review, we discuss challenges and opportunities in studying the relationship between psychoactive drugs and social homeostasis. Using the examples of opioids and amphetamines, we discuss the evidence that drugs alleviate dysphoria related to lack of social connection or produce pro-social effects that improve connection. RESULTS: With regard to opioid drugs, we report that mu opioid agonists and kappa opioid antagonists reduce distress from social isolation, and mu opioid agonists enhance social reward. Amphetamine-like stimulant drugs, including MDMA, do not seem to act by reducing the distress of social isolation, but they have notable prosocial effects that increase both motivation for social contact and the pleasure derived from interacting socially. CONCLUSIONS: Many questions remain in understanding interactions between drugs and social equilibrium, including whether these effects contribute to problematic drug use. We identify gaps in knowledge, including the effects of drug withdrawal or dependence on social function, or the responses of individuals with psychiatric symptomatology. Understanding these actions on social processes will help to develop novel pharmacologic treatments for clinical problems related to social disequilibrium.

Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness.

Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.

Association of OPRD1 Gene Variants with Changes in Body Weight and Psychometric Indicators in Patients with Eating Disorders.

Objectives: This study aimed to investigate whether genetic variations in the OPRD1 gene affect psychopathological symptoms and personality dimensions in eating disorders (ED) patients and/or contribute to ED risk. Methods: The study involved 221 female patients with anorexia nervosa (AN), 88 with bulimia nervosa (BN), and 396 controls. Sixteen tag-single nucleotide polymorphisms (SNPs) in OPRD1 were identified. Psychometric evaluations were conducted using the Symptom Checklist 90 Revised (SCL-90R) and the Eating Disorders Inventory Test-2 (EDI-2). p-values obtained by regression models were corrected for multiple testing by the False Discovery Rate (FDR) method. Results: In AN patients, genotypes rs204077TT and rs169450TT were linked to lower body-mass index (BMI) values (FDR-q = 0.035 and 0.017, respectively), as was rs2234918 in a log-additive model (BMI: 18.0 ± 0.28, 17.22 ± 0.18 and 16.59 ± 0.39 for TT, TC and CC carriers, FDR-q = 0.012). Additionally, AN patients carrying the rs72665504AA genotype had higher scores in interpersonal distrust (FDR-q = 0.030), whilst BN carriers of rs513269TT and rs2873795TT showed lower scores in ineffectiveness (FDR-q = 0.041 and FDR-q = 0.021). In the AN group, BMI correlated with variability in a distal haplotype (rs508448/rs204077/rs223491, FDR-q = 0.028), which was also associated with the global positive symptom total (PST) index of SCL-90R (FDR-q = 0.048). Associations were more noticeable in BN patients; again, the distal region of the gene was linked to EDI-2 total scores (FDR-q = 0.004-0.048 for the four last haplotypes) and two global SCL-90R indices (GSI: FDR-q = 0.011 and positive symptom distress index (PSDI): FDR-q = 0.003 for the last s204077/rs2234918/rs169450 combination). No associations with ED risk were observed. Conclusions: Genetic variation in the OPRD1 gene, particularly in its distal region, is associated with BMI and psychopathological comorbidities in ED patients.

A brainstem circuit amplifies aversion.

Dynamic gain control of aversive signals enables adaptive behavioral responses. Although the role of amygdalar circuits in aversive processing is well established, the neural pathway for amplifying aversion remains elusive. Here, we show that the brainstem circuit linking the interpeduncular nucleus (IPN) with the nucleus incertus (NI) amplifies aversion and promotes avoidant behaviors. IPN GABA neurons are activated by aversive stimuli and their predicting cues, with their response intensity closely tracking aversive values. Activating these neurons does not trigger aversive behavior on its own but rather amplifies responses to aversive stimuli, whereas their ablation or inhibition suppresses such responses. Detailed circuit dissection revealed anatomically distinct subgroups within the IPN GABA neuron population, highlighting the NI-projecting subgroup as the modulator of aversiveness related to fear and opioid withdrawal. These findings unveil the IPN-NI circuit as an aversion amplifier and suggest potential targets for interventions against affective disorders and opioid relapse.

Evaluation of a Drug Deactivation System for Safe Disposal of Opioids After Ambulatory Surgery.

BACKGROUND: Prescription opioids are commonly prescribed postoperatively and increase the risk of diversion or misuse when left unused and accessible. Despite awareness of the risks associated with unused opioids, harm reduction strategies like safe storage and drug take-back events may be limited by inconvenience and patient-specific barriers to access. OBJECTIVES: To evaluate a quality improvement project designed to facilitate at-home disposal of unused opioids after day surgery. METHODS: An observational, prospective quality improvement project was conducted in patients undergoing elective outpatient surgery at Newton-Wellesley Hospital from December 2019 to June 2020. Upon discharge, eligible patients received a Deterra® drug disposal packet, which deactivates unused medication. Follow-up surveys assessed packet use and reasons for nonuse one to two weeks after surgery. RESULTS: 106 participants received a disposal packet and responded to the survey. Among the 67 respondents with unused medication, 30% used the packet. Women were more likely to use the packet than men (predicted probability 30.2% vs. 10.4%, p = .033), and patients aged 18-25 were more likely to use the packet than those aged 26-40 (40.0% vs. 9.5%, p = .049). The most common reasons for packet nonuse included procrastination, holding onto prescriptions in case of future pain, and waiting to dispose of multiple medications. CONCLUSION: The majority of patients surveyed had unused opioids one to two weeks after surgery, and approximately one in three patients with unused doses utilized the disposal packet. Common reasons for nonuse included procrastination and concerns about needing future medication for pain. Going forward, safe drug disposal efforts may emphasize improved patient education, partial prescription fill options, or alert systems to remind patients to safely dispose of unused medication.

Patient and navigator experiences with the opioid use disorder treatment system in Philadelphia, PA.

BACKGROUND: In 2022, 1413 people in Philadelphia died of an unintentional drug overdose. Addressing the complex challenges within the opioid use disorder (OUD) treatment system requires a comprehensive grasp of multiple system-level siloes from the perspective of patients who are accessing services and certified recovery specialists. Identifying facilitators and barriers to treatment entry and retention are critical. METHODS: We conducted 13 focus groups with 70 people with a history of opioid use in Philadelphia, Pennsylvania. The study recruited participants from non-profit organizations, OUD treatment programs, and street intercept. Certified Recovery Specialists (CRS), people with experience in residential, outpatient, methadone, and buprenorphine programs in Philadelphia, identity-specific groups with Black women, Black men, and Latino men, pregnant and parenting people, and people accessing harm reduction services participated in focus groups. Focus group guides varied by group, but the overarching focus remained on understanding participants' experiences in navigating the OUD treatment system. The research team summarized and edited CRS focus groups and coded all other focus groups for thematic analysis. RESULTS: Most focus group participants (mean age = 45.1 years; 52.9 % men, 40 % Black) had a history with multiple treatment types and reported experiences with different modalities. Salient themes that emerged from analysis included frustrations with the assessment process; reflections on facilitators and barriers by treatment type (residential, methadone, and buprenorphine); and recommendations across treatment modalities. Assessment centers, rather than being easy points of treatment entry, were identified as a major barrier to OUD treatment initiation; issues discussed included length of assessment, limited operating hours, and inadequate withdrawal management. DISCUSSION: The data from the present study were used to develop recommendations for policymakers and other stakeholders of OUD treatment programs to improve care across the spectrum of services. Expansion of residential programs that can support patients with complex comorbid conditions and wounds is needed to prevent delays for patients deemed ineligible for lower levels of care. Housing and income were identified as significant deterrents to initiating drug treatment and greater resources are needed. Greater investment in the OUD workforce is needed, especially expanding staff with lived experience. Findings can enhance OUD treatment programs elsewhere.

Mother's little helper turned a foe: Alprazolam use, misuse, and abuse.

Benzodiazepines are effective in managing anxiety and related disorders when used properly (short-term). Their inappropriate use, however, carries significant risks, involving amnesia, rebound insomnia, rebound anxiety, depression, dependence, abuse, addiction, and an intense and exceedingly prolonged withdrawal, among other complications. Benzodiazepines also amplify the effects of opioids and, consequently, have been implicated in approximately 30 % of opioid overdose deaths. Despite their unfavorable profile, sharp increases in medical and non-medical use of benzodiazepines have been steadily reported worldwide. Alprazolam (Xanax®), a potent, short-acting benzodiazepine, is among the most prescribed and abused anxiolytics in the United States. This medication is commonly co-abused with opioids, increasing the likelihood for oversedation, overdose, and death. Notwithstanding these risks, it is surprising that research investigating how benzodiazepines, such as alprazolam, interact with opioids is severely lacking in clinical and preclinical settings. This review therefore aims to present our current knowledge of benzodiazepine use and misuse, with an emphasis on alprazolam when data is available, and particularly in populations at higher risk for developing substance use disorders. Additionally, the potential mechanism(s) surrounding tolerance, dependence and abuse liability are discussed. Despite their popularity, our understanding of how benzodiazepines and opioids interact is less than adequate. Therefore, it is now more important than ever to understand the short- and long-term consequences of benzodiazepine/alprazolam use.

Predictors of Postoperative Morphine Milligram Equivalents in Cardiac Surgery.

OBJECTIVES: Given both the short- and long-term deleterious effects of opioids, there has been an increased focused on reducing the use of postoperative opioid analgesia. As patients undergoing cardiac surgery often require high levels opioids postoperatively, understanding risk factors for increased postoperative opioid use may be helpful for the development of patient-specific opioid-sparing pain regimens for this patient population. DESIGN: A retrospective analysis of data from our electronic medical records and the Society of Thoracic Surgeon's database. SETTING: A single-institution study at an academic medical center. PARTICIPANTS: All patients undergoing open adult cardiac surgery were included. Exclusion criteria were patients with continuous intravenous narcotic drips and operative mortality. INTERVENTIONS: As this was a retrospective study, no interventions were conducted on the participants. MEASUREMENTS AND MAIN RESULTS: Data for patient postoperative opioid requirements were extracted from the electronic medical record. Total opioid use on postoperative days 0 to 3 was converted to morphine milligram equivalent (MME) via standard conversion factors. The study cohort comprised 1604 patients, including 456 females and 1066 coronary artery bypass grafting (CABG) recipients. MME was 31.0% greater in patients undergoing CABG (p < 0.001), 76.3% greater in patients with liver disease (p = 0.005), and 48.8% greater in patients with patient-controlled analgesia (p <0.001) during postoperative days 0 to 3. Younger age (p < 0.001) and higher body mass index (BMI) (p < 0.001) also were associated with increased MME prescription. CONCLUSIONS: CABG, liver disease, patient-controlled analgesia, younger age, and higher BMI are associated with increased narcotic use after cardiac surgery. Implementation of more aggressive perioperative multimodal opioid-sparing regimens should be considered for these patient groups.

Practice review: Pharmacological management of severe chronic breathlessness in adults with advanced life-limiting diseases.

BACKGROUND: Severe and refractory chronic breathlessness is a common and burdensome symptom in patients with advanced life-limiting disease. Its clinical management is challenging because of the lack of effective interventions. AIM: To provide practice recommendations on the safe use of pharmacological therapies for severe chronic breathlessness. DESIGN: Scoping review of (inter)national guidelines and systematic reviews. We additionally searched for primary studies where no systematic review could be identified. Consensus on the recommendations was reached by 75% approval within an international expert panel. DATA SOURCES: Searches in MEDLINE, Cochrane Library and Guideline International Network until March 2023. Inclusion of publications on the use of antidepressants, benzodiazepines, opioids or corticosteroids for chronic breathlessness in adults with cancer, chronic obstructive pulmonary disease, interstitial lung disease or chronic heart failure. RESULTS: Overall, the evidence from eight guidelines, 14 systematic reviews and 3 randomised controlled trials (RCTs) on antidepressants is limited. There is low quality evidence favouring opioids in patients with chronic obstructive pulmonary disease, cancer and interstitial lung disease. For chronic heart failure, evidence is inconclusive. Benzodiazepines should only be considered for anxiety associated with severe breathlessness. Antidepressants and corticosteroids should not be used. CONCLUSION: Management of breathlessness remains challenging with only few pharmacological options with limited and partially conflicting evidence. Therefore, pharmacological treatment should be reserved for patients with advanced disease under monitoring of side effects, after optimisation of the underlying condition and use of evidence-based non-pharmacological interventions as first-line treatment.

The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150 mg/kg, SC) for 36 h and continuous intravenous infusion of vehicle (20 µL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) for the full 36 h. NLX elicited pronounced withdrawal signs in rats treated for 48 h with morphine (150 mg/kg, SC), plus continuous infusion of vehicle (20 µL/h, IV) that began at the 36 h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12 h infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) that began at the 36 h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.

Design and Implementation of an Opioid Scorecard for Hospital System-Wide Peer Comparison of Opioid Prescribing Habits: Observational Study.

Background: Reductions in opioid prescribing by health care providers can lead to a decreased risk of opioid dependence in patients. Peer comparison has been demonstrated to impact providers' prescribing habits, though its effect on opioid prescribing has predominantly been studied in the emergency department setting. Objective: The purpose of this study is to describe the development of an enterprise-wide opioid scorecard, the architecture of its implementation, and plans for future research on its effects. Methods: Using data generated by the author's enterprise vendor-based electronic health record, the enterprise analytics software, and expertise from a dedicated group of informaticists, physicians, and analysts, the authors developed an opioid scorecard that was released on a quarterly basis via email to all opioid prescribers at our institution. These scorecards compare providers' opioid prescribing habits on the basis of established metrics to those of their peers within their specialty throughout the enterprise. Results: At the time of this study's completion, 2034 providers have received at least 1 scorecard over a 5-quarter period ending in September 2021. Poisson regression demonstrated a 1.6% quarterly reduction in opioid prescribing, and chi-square analysis demonstrated pre-post reductions in the proportion of prescriptions longer than 5 days' duration and a morphine equivalent daily dose of >50. Conclusions: To our knowledge, this is the first peer comparison effort with high-quality evidence-based metrics of this scale published in the literature. By sharing this process for designing the metrics and the process of distribution, the authors hope to influence other health systems to attempt to curb the opioid pandemic through peer comparison. Future research examining the effects of this intervention could demonstrate significant reductions in opioid prescribing, thus potentially reducing the progression of individual patients to opioid use disorder and the associated increased risk of morbidity and mortality.

Pain Management in Animals with Oncological Disease: Opioids as Influencers of Immune and Tumor Cellular Balance.

Advancements in understanding pain physiopathology have historically challenged animals' absence of pain senses. Studies have demonstrated that animals have comparable neural pain pathways, suggesting that cats and dogs likely experience pain similarly to humans. Understanding brain circuits for effective pain control has been crucial to adjusting pain management to the patient's individual responses and current condition. The refinement of analgesic strategies is necessary to better cater to the patient's demands. Cancer pain management searches to ascertain analgesic protocols that enhance patient well-being by minimizing or abolishing pain and reducing its impact on the immune system and cancer cells. Due to their ability to reduce nerve sensitivity, opioids are the mainstay for managing moderate and severe acute pain; however, despite their association with tumor progression, specific opioid agents have immune-protective properties and are considered safe alternatives to analgesia for cancer patients.

Discharge Opioid Prescription and Consumption Following Surgery: The POPCORN Observational Study.

Background: Few studies have evaluated opioid consumption after various inpatient surgical procedures. Objectives: To describe opioid prescription patterns and to characterize patient-reported use of opioids after surgery. Methods: This single-centre prospective observational study was conducted between February and October 2021 at the Jewish General Hospital in Montréal, Quebec. Patients 18 years of age or older who underwent a surgical procedure, were hospitalized for 24 hours or longer after the procedure, and had an opioid prescription at the time of discharge were included. Data were collected for the quantity of opioids prescribed, as documented in hospital records, and the quantity consumed, as reported by participants. Various potential predictors of opioid consumption were explored, and data were also collected on patients' use of non-opioid coanalgesia, scores on the Numeric Rating Scale for pain, opioid renewal requests, and proper opioid disposal during the 30-day follow-up period. Results: A total of 150 participants completed the study. The median dose prescribed was 10 opioid pills (75.0 morphine milligram equivalents). By the end of the follow-up period, a median of 1 pill (7.5 morphine milligram equivalents) had been consumed from the total amount in the discharge prescription. Overall, 66 participants (44.0%) did not consume any of the opioids prescribed at discharge. Of the total number of pills prescribed, 58.2% (1193/2050) were unused, and 7.0% (5/71) of participants with unused pills disposed of them properly. Conclusions: Following discharge from hospital, postoperative patients consumed a median proportion of only 10% of prescribed opioid pills. More than half of all prescribed pills were unused. Protocols implementing specific prescribing strategies warrant further investigation to evaluate their potential impact on opioid prescription and consumption.

Contexte: Peu d'études ont évalué la consommation d'opioïdes après diverses interventions chirurgicales en milieu hospitalier. Objectifs: Décrire les schémas de prescription d'opioïdes et caractériser leur utilisation déclarée par les patients après une intervention chirurgicale. Méthodologie: Cette étude observationnelle prospective monocentrique a été menée entre février et octobre 2021 à l'Hôpital général juif de Montréal, au Québec. Les patients d'au moins 18 ans ayant subi une intervention chirurgicale, ayant été hospitalisés pendant au moins 24 heures après l'intervention et qui avaient une prescription d'opioïdes au moment de leur congé ont été inclus dans l'étude. Des données ont été recueillies sur la quantité d'opioïdes prescrite, telle que documentée dans les dossiers de l'hôpital, et sur la quantité consommée, telle que déclarée par les participants. Divers prédicteurs potentiels de la consommation d'opioïdes ont été étudiés et des données ont aussi été recueillies, sur une période de suivi de 30 jours, sur l'utilisation de coanalgésie non opioïde par les patients, leurs scores sur l'échelle d'évaluation numérique de la douleur, les demandes de renouvellement d'opioïdes et l'élimination appropriée de ces dernières. Résultats: Au total, 150 participants ont complété l'étude. La dose médiane prescrite était de 10 comprimés d'opioïdes (75,0 équivalents en milligrammes de morphine). À la fin de la période de suivi, une moyenne de 1 comprimé (7,5 équivalents en milligrammes de morphine) avait été consommée sur la quantité totale indiquée dans l'ordonnance remise au moment du congé. Dans l'ensemble, 66 participants (44,0 %) n'ont consommé aucun des opioïdes prescrits au moment du congé. Sur le nombre total de comprimés prescrits, 58,2 % (1193/2050) n'ont pas été utilisés et 7,0 % (5/71) des participants ayant des comprimés inutilisés s'en sont débarrassés correctement. Conclusions: Suite au congé de l'hôpital, les patients postopératoires ne consommaient qu'une proportion médiane de 10 % des comprimés d'opioïde prescrits. Plus de la moitié de tous les comprimés prescrits n'ont pas été utilisés. Les protocoles mettant en oeuvre des stratégies de prescription spécifiques justifient des recherches plus approfondies pour évaluer leur incidence potentielle sur la prescription et la consommation d'opioïdes.

Synthetic opioids have disrupted conventional wisdom for treating opioid overdose.

More than 90 % of opioid overdose deaths in North America are now caused by synthetic opioids, and while they are not as prevalent in the European illicit drug market, there are indications that they may become so in the near future. Multiple publications have argued that neither higher doses of naloxone nor more potent opioid receptor antagonists are needed to reverse a synthetic opioid overdose. However, the unique physicochemical properties of synthetic opioids result in a very rapid onset of respiratory depression compared to opium-based molecules, reducing the margin of opportunity to reverse an overdose. While intravenous administration rapidly delivers the high naloxone concentrations needed to reverse a synthetic opioid overdose, this option is often unavailable to first responders. A translational mechanistic model of opioid overdose developed by the FDA's Division of Applied Regulatory Science provides an unbiased approach to evaluate the effectiveness of overdose reversal strategies. Reports using this model demonstrated the naloxone tools (2 mg intramuscular and 4 mg intranasal) used by many first responders can result in an unacceptable loss of life following a synthetic opioid (fentanyl, carfentanil) overdose. Moreover, sequential (2.5 minutes between doses) administration of up to four doses of intranasal naloxone was no more effective at reducing the incidence of cardiac arrest (a surrogate endpoint for lethality) than a single dose, suggesting that attempts at titration may not provide the rapid absorption required to reverse a synthetic opioid overdose. This model was also used to compare the effectiveness of intranasal naloxone to intranasal nalmefene, a recently FDA-approved opioid receptor antagonist with a more rapid absorption and a higher affinity at mu-opioid receptors compared to intranasal naloxone. Intranasal nalmefene resulted in large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone. Furthermore, simultaneous administration of four doses of intranasal naloxone was needed to reduce the incidence of cardiac arrest to levels approaching those produced by a single dose of intranasal nalmefene. These data are consistent with evidence that synthetics have indeed disrupted conventional wisdom in the treatment of opioid overdose.

Sex differences in opioid response: a role for the gut microbiome?

Opioid drugs have been long known to induce different responses in males compared to females, however, the molecular mechanisms underlying these effects are yet to be fully characterized. Recent studies have established a link between the gut microbiome and behavioral responses to opioids. Chronic opioid use is associated with gut dysbiosis, or microbiome disruptions, which is thought to contribute to altered opioid analgesia and reward processing. Gut microbiome composition and functioning have also been demonstrated to be influenced by sex hormones. Despite this, there is currently very little work investigating whether sex differences in the gut microbiome mediate sex-dependent responses to opioids, highlighting a critical gap in the literature. Here, we briefly review the supporting evidence implicating a potential role for the gut microbiome in regulating sexually dimorphic opioid response and identify areas for future research.

[Pain relief after abdominal oncologic surgery. Evaluation of the effectiveness and safety of a fixed combination of diclofenac and orphenadrine]. / Obezbolivanie posle abdominal'nykh onkokhirurgicheskikh vmeshatel'stv. Otsenka effektivnosti i perenosimosti fiksirovannoi kombinatsii diklofenaka i orfenadrina.

OBJECTIVE: Evaluation of the analgesic, opioid-sparing, anti-inflammatory and adverse effects of the diclofenac and orphenadrine (Neodolpasse) fixed combination for analgesia in the postoperative period of surgical cancer patients. MATERIAL AND METHODS: A randomized, single-center, prospective, comparative study evaluated two analgesic regimens in 40 cancer patients undergoing various open cavity surgeries, including extensive combined interventions associated with the resection of 3 or more organs. The study was conducted following the transfer from the ICU to the surgical department during the early activation period, within the first two postoperative days. In the first group N (n=20), "Neodolpasse" (a fixed combination of 75 mg Diclofenac and 30 mg Orphenadrine) was administered as an infusion, twice daily. In the second group K (n=20) analgesia was performed with ketoprofen as an intravenous infusion at a daily dose of 200 mg. Patients in both groups received scheduled prolonged epidural analgesia with 0.2% ropivacaine, and when the severity of pain in a visual analogue scale (VAS) increased to more than 40 mm, so an additional dose of 100 mg tramadol was administered intramuscularly. Daily measurments of blood creatinine level and C-reactive protein were taken, postoperative blood loss was accounted for, as well as postoperative complications according to the Clavien-Dindo classification. RESULTS: The comparative analysis of the indicators of pain syndrome severity showed that the patients in group N exhibited a more pronounced analgesic effect, so on the second postoperative day 30% of patients reported moderate pain (from 50 to 60 mm on the pain scale), on the third day - 15%, and by the fourth day - all 100% of patients experienced pain of low intensity. The additional analgesia with tramadol in group N was required twice less than in the comparison group, and such adverse effects as nausea, drowsiness, and weakness were significantly more common in the ketoprofen group. In both groups, the average blood creatinine level did not exceed permissible values, and the C-reactive protein was elevated at all stages of the study but tended to decrease by the fourth day. The analysis of postoperative complications according to the Clavien-Dindo scale at the time of discharge did not reveal a direct correlation between the occurred complications and the use of NSAIDs. Adverse effects such as anastomotic failure, gastrointestinal complications, or other hemorrhagic manifestations were not recorded. CONCLUSION: The inclusion of Neodolpasse into multimodal analgesic regimens resulted in the most pronounced analgesic and opioid-sparing effects in surgical cancer patients using laparotomy access. Additionally, the application of short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a favorable safety profile.

Perceptions Towards Naloxone among Patients with Cancer Receiving Opioids.

CONTEXT: Naloxone nasal spray is recommended for patients with risk factors for opioid overdose. However, cancer patients' perceptions and beliefs regarding naloxone prescriptions and their self-perceived risks for overdose are understudied. OBJECTIVE: To determine the proportion of cancer patients at risk for overdose who perceived naloxone as beneficial. METHODS: Between July 2020 and April 2022, we surveyed 150 adult patients from the supportive care ambulatory clinic at a tertiary cancer center in the United States who received a co-prescription of naloxone nasal spray. We measured patients' knowledge of overdose risk-factors, attitudes, beliefs, and education received on naloxone. Risk-factors between beneficial vs. non-beneficial groups were analyzed. The survey was administered on paper or via a telephone interview. RESULTS: Of the 150 patients, 55% were male, 70% were white, and 81% had advanced cancer. The majority of patients believed naloxone was beneficial (100/150, 67%). When compared to the non-beneficial group, more patients from the beneficial group agreed that the concurrent use of alcohol (100% vs. 90%;p=0.004) or sedating drugs (96% vs.85%;p=0.04) with opioids could result in overdoses and felt safe having naloxone at home (95% vs. 60%;p<0.0001). More patients from the non-beneficial group associated naloxone prescription with being suspected of misusing opioids (12/50 vs. 8/100;p=0.01), and fewer had confidence in their caregivers' ability to administer naloxone (69% vs. 95%;p<0.0001). CONCLUSION: Most patients understood the benefits of naloxone and felt safe having one at home. More research is needed to identify knowledge gaps and develop educational strategies for those who find it non-beneficial.