Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.

Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-ß were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier.

A review on abuse-deterrent formulations: formulation technology and regulatory stands in approval process.

Drug abuse has become a global health problem over the past few years. Opioid abuse increased with an increase in the prescription of opioids for pain management. Many other classes of drugs are also abused and misused like anti-depressants, stimulants, hallucinogens, anti-psychotic, and anticholinergic drugs. One of the major reasons is that patients falsely diagnosed with depression, anxiety, and severe pain are prescribed these drugs, which are likely to be addictive. Abuse-deterrent formulations are one means to control drug abuse and overdose of prescription opioids. In this review, we explained how abuse-deterrent technology works, key ingredients used in abuse-deterrent formulations, a brief about marketed opioid drug products with abuse-deterrent properties, and the stand of regulatory agencies in the approval process of opioid drug products. In the end, it summarized that pharmaceutical industries and the FDA put their efforts into reducing drug abuse by encouraging the development of ADFs. Most available drug product having abuse-deterrent features contains Polyethylene oxide, which degrades at high temperatures. It requires the attention of the researcher to find an alternate ingredient or process to overcome said problem. From a regulatory point of view, only a few regulatory agencies have published their guidance on ADFs. It is important to convey other regulatory organizations' perspectives on ADFs as well.

Opioid abuse and SIV infection in non-human primates.

Human immunodeficiency virus (HIV) and drug abuse are intertwined epidemics, leading to compromised adherence to combined antiretroviral therapy (cART) and exacerbation of NeuroHIV. As opioid abuse causes increased viral replication and load, leading to a further compromised immune system in people living with HIV (PLWH), it is paramount to address this comorbidity to reduce the NeuroHIV pathogenesis. Non-human primates are well-suited models to study mechanisms involved in HIV neuropathogenesis and provide a better understanding of the underlying mechanisms involved in the comorbidity of HIV and drug abuse, leading to the development of more effective treatments for PLWH. Additionally, using broader behavioral tests in these models can mimic mild NeuroHIV and aid in studying other neurocognitive diseases without encephalitis. The simian immunodeficiency virus (SIV)-infected rhesus macaque model is instrumental in studying the effects of opioid abuse on PLWH due to its similarity to HIV infection. The review highlights the importance of using non-human primate models to study the comorbidity of opioid abuse and HIV infection. It also emphasizes the need to consider modifiable risk factors such as gut homeostasis and pulmonary pathogenesis associated with SIV infection and opioid abuse in this model. Moreover, the review suggests that these non-human primate models can also be used in developing effective treatment strategies for NeuroHIV and opioid addiction. Therefore, non-human primate models can significantly contribute to understanding the complex interplay between HIV infection, opioid abuse, and associated comorbidities.

Modeling Opioid Abuse: A Case Study of the Opioid Crisis in New England.

For the past two decades, the USA has been embroiled in a growing prescription drug epidemic. The ripples of this epidemic have been especially apparent in the state of Maine, which has fought hard to mitigate the damage caused by addiction to pharmaceutical and illicit opioids. In this study, we construct a mathematical model of the opioid epidemic incorporating novel features important to better understanding opioid abuse dynamics. These features include demographic differences in population susceptibility, general transmission expressions, and combined consideration of pharmaceutical opioid and heroin abuse. We demonstrate the usefulness of this model by calibrating it with data for the state of Maine. Model calibration is accompanied by sensitivity and uncertainty analysis to quantify potential error in parameter estimates and forecasts. The model is analyzed to determine the mechanisms most influential to the number of opioid abusers and to find effective ways of controlling opioid abuse prevalence. We found that the mechanisms most influential to the overall number of abusers in Maine are those involved in illicit pharmaceutical opioid abuse transmission. Consequently, preventative strategies that controlled for illicit transmission were more effective over alternative approaches, such as treatment. These results are presented with the hope of helping to inform public policy as to the most effective means of intervention.

Algorithms to Identify Nonmedical Opioid Use.

The rise in nonmedical opioid overdoses over the last two decades necessitates improved detection technologies. Manual opioid screening exams can exhibit excellent sensitivity for identifying the risk of opioid misuse but can be time-consuming. Algorithms can help doctors identify at-risk people. In the past, electronic health record (EHR)-based neural networks outperformed Drug Abuse Manual Screenings in sparse studies; however, recent data shows that it may perform as well or less than manual screenings. Herein, a discussion of several different manual screenings and recommendations is contained, along with suggestions for practice. A multi-algorithm approach using EHR yielded strong predictive values of opioid use disorder (OUD) over a large sample size. A POR (Proove Opiate Risk) algorithm provided a high sensitivity for categorizing the risk of opioid abuse within a small sample size. All established screening methods and algorithms reflected high sensitivity and positive predictive values. Neural networks based on EHR also showed significant effectiveness when corroborated with Drug Abuse Manual Screenings. This review highlights the potential of algorithms for reducing provider costs and improving the quality of care by identifying nonmedical opioid use (NMOU) and OUD. These tools can be combined with traditional clinical interviewing, and neural networks can be further refined while expanding EHR.

A Safe Number of Perioperative Opioids to Reduce the Risk of New Persistent Usage Among Opioid-Naïve Patients Following Total Joint Arthroplasty.

BACKGROUND: Higher initial opioid dosing increases the risk of prolonged opioid use following total joint arthroplasty (TJA), and the safe amounts to prescribe are unknown. We examined the relationship between perioperative opioid exposure and new persistent usage among opioid-naïve patients after total knee and hip arthroplasty. METHODS: In this retrospective cohort study, 22,310 opioid-naïve patients undergoing primary TJA between 2018 and 2019 were identified within a commercial claims database. Perioperative opioid exposure was defined as total dose of opioid prescription in morphine milligram equivalents (MME) between 1 month prior to and 2 weeks after TJA. New persistent usage was defined as at least one opioid prescription between 90 and 180 days postoperatively. Multivariate regression analyses were performed to examine the relationship between the perioperative dosage group and the development of new persistent usage. RESULTS: For the total patient cohort, 8.1% developed new persistent usage. Compared to patients who received <300 MME, patients who received 600-900 MME perioperatively had a 77% increased risk of developing new persistent usage (odds ratio 1.77, 95% CI, 1.44-2.17), and patients who received ≥1,200 MME perioperatively had a 285% increased risk (odds ratio 3.85, 95% CI, 3.13-4.74). CONCLUSION: We found a dose-dependent association between perioperative MME and the risk of developing new persistent usage among opioid-naïve patients following TJA. We recommend prescribing <600 MME (equivalent to 80 pills of 5 mg oxycodone) during the perioperative period to reduce the risk of new persistent usage. LEVEL OF EVIDENCE: Level III.

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model.

Peripheral mechanoreceptor-based treatments such as acupuncture and chiropractic manipulation have shown success in modulating the mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) of the midbrain and projecting to the nucleus accumbens (NAc) of the striatum. We have previously shown that mechanoreceptor activation via whole-body vibration (WBV) ameliorates neuronal and behavioral effects of chronic ethanol exposure. In this study, we employ a similar paradigm to assess the efficacy of WBV as a preventative measure of neuronal and behavioral effects of morphine withdrawal in a Wistar rat model. We demonstrate that concurrent administration of WBV at 80 Hz with morphine over a 5-day period significantly reduced adaptations in VTA GABA neuronal activity and NAc DA release and modulated expression of δ-opioid receptors (DORs) on NAc cholinergic interneurons (CINs) during withdrawal. We also observed a reduction in behavior typically associated with opioid withdrawal. WBV represents a promising adjunct to current intervention for opioid use disorder (OUD) and should be examined translationally in humans.

Suicidal ideation and attempts following nonmedical use of prescription opioids and related disorder.

BACKGROUND: Since 1999, the rate of fatal prescription opioid overdoses and of suicides has dramatically increased in the USA. These increases, which have occurred among similar demographic groups, have led to the hypothesis that the opioid epidemic contributed to increases in suicidal behavior, though the underlying association remains poorly defined. We examine the association between nonmedical use of prescription opioids/opioid use disorder and suicidal ideation/attempts. METHODS: We used longitudinal data from a national representative sample of the US adult population, the National Epidemiologic Survey on Alcohol and Related Conditions. Participants (n = 34 653) were interviewed in 2001-2002 (wave 1) and re-interviewed approximately 3 years later (wave 2). A propensity score analysis estimated the association between exposure to prescription opioids at wave 1 and prevalent/incident suicidal behavior at wave 2. RESULTS: Heavy/frequent (⩾2-3 times a month) prescription opioid use was associated with prevalent suicide attempts [adjusted risk ratio (ARR) = 2.75, 95% CI 1.35-5.60]. Prescription opioid use disorder was associated with prevalent (ARR = 1.98, 95% CI 1.20-3.28) and incident suicidal ideation (ARR = 2.59, 95% CI 1.25-5.37), and prevalent attempts (ARR = 4.19, 95% CI 1.71-10.27). None of the exposures was associated with incident suicide attempts. CONCLUSIONS: Heavy/frequent opioid use and related disorder were associated with prevalent suicide attempts; opioid use disorder was also associated with the incident and prevalent suicidal ideation. Given population increases in nonmedical use of prescription opioids and disorder, the opioid crisis may have contributed to population increases in suicidal ideation.

Minimally invasive, benign foregut surgery is not associated with long-term, persistent opioid use postoperatively: an analysis of the IBM® MarketScan® database.

BACKGROUND: It is unknown if opioid naïve patients who undergo minimally invasive, benign foregut operations are at risk for progressing to persistent postoperative opioid use. The purpose of our study was to determine if opioid naïve patients who undergo minimally invasive, benign foregut operations progress to persistent postoperative opioid use and to identify any patient- and surgery-specific factors associated with persistent postoperative opioid use. METHODS: Opioid-naïve, adult patients who underwent laparoscopic fundoplication, hiatal hernia repair, or Heller myotomy from 2010 to 2018 were identified within the IBM® MarketScan® Commercial Claims and Encounters Database. Daily drug logs of the preoperative and postoperative period were evaluated to assess for changes in drug use patters. The primary outcome of interest was persistent postoperative opioid use, defined as at least 33% of the proportion of days covered by opioid prescriptions at 365-day follow-up. Patient demographic information and clinical risk factors for persistent postoperative opioid use at 365 days postoperatively were estimated using log-binomial regression. RESULTS: A total of 17,530 patients met inclusion criteria; 6895 underwent fundoplication, 9235 underwent hiatal hernia repair, and 1400 underwent Heller myotomy. 9652 patients had at least one opioid prescription filled in the perioperative period. Sixty-five patients (0.4%) were found to have persistent postoperative opioid use at 365 days postoperatively. Lower Charlson comorbidity index scores and a history of mental illness or substance use disorder had a statistically but not clinically significant protective effect on the risk of persistent postoperative opioid use at 365 days postoperatively. CONCLUSIONS: Only half of opioid naïve patients undergoing minimally invasive, benign foregut operations filled an opioid prescription postoperatively. The risk of progression to persistent postoperative opioid use was less than 1%. These findings support the current guidelines that limit the number of opioid pills prescribed following general surgery operations.

Postoperative Discharge Opioid Consumption, Leftover, and Disposal after Obstetric and Gynecologic Procedures: A Systematic Review.

OBJECTIVE: To perform a systematic review on consumption, leftover, and disposal of prescribed opioids after surgery in obstetrics and gynecology (The International Prospective Register of Systematic Reviews ID 249856). DATA SOURCES: Electronic database searches on PubMed, Embase, Cochrane Library, and MEDLINE and other search methods including all studies published between the years 2000 and 2021 were used. METHODS OF STUDY SELECTION: We included all randomized trials, cohorts, case-control studies, and clinical trials. The search was limited to studies related to obstetrics and gynecology. Studies that pertained to opioid consumption, leftover, and disposal patterns were selected. We excluded review articles, meeting abstracts, case series and case reports, and abstracts without access to full texts. The search was limited to trials in humans and published in English language. Study population included women who were prescribed opioids after obstetric and/or gynecologic procedures. Information on opioid consumption, leftover, and disposal patterns were extracted and compared among different procedures. Potential risk of bias was evaluated using the Newcastle-Ottawa Scale for cohort studies and the National Heart, Lung, and Blood Institute Study Quality Assessment Tool of Controlled Interventional Studies for clinical trial. TABULATION, INTEGRATION, AND RESULTS: Of 2343 articles, 10 were used in the analysis: 9 cohorts and 1 randomized clinical trial. We found that among patients who underwent obstetric and gynecologic procedures, a considerable number of opioids are unused. The total number of consumed opioids after discharge in patients who underwent cesarean delivery was 21.8 oral morphine equivalent (OME); vaginal hysterectomy, 55.7 OME; abdominal hysterectomy, 105.8 OME; and laparoscopic hysterectomy, 89.0 OME. The number of opioids leftover in the vaginal, abdominal, and laparoscopic hysterectomy groups was 67.6 OME, 115.5 OME, and 95.3 OME, respectively. On average, 77.5% of leftover opioids were not disposed/kept, whereas only 20% discarded their medication through a disposal program. Five studies were deemed to have fair quality, and the rest were rated as good quality. CONCLUSION: Compared with those after cesarean delivery, patients undergoing gynecologic procedures consumed a large number of opioids, especially after abdominal hysterectomies. Abdominal hysterectomy was also associated with a high number of opioids leftover. Most patients did not use the entire prescribed opioids and were either keeping their unused opioids or unsure about what to do with them. We recommend perioperative opioid-specific counseling and education on opioid consumption, potential hazards of unused medication, and proper disposal for patients. Strategies to reduce opioids prescription by physicians should be considered.

Identifying the risk of opioid misuse in a chronic pain population: the utility of the MMPI-2-RF personality psychopathology five (PSY-5-RF) and higher-order scales.

Prescription-related opioid misuse, especially in chronic pain populations, is an ongoing problem and is related to increased mortality. The purpose of this study was to assess the utility of two restructured scales of the MMPI-2-RF: the Personality Psychopathology Five (PSY-5-RF) and the Higher-Order Scales to determine which of their subscales may be beneficial for identifying the risk of opioid misuse in a chronic pain population. A sample of 136 patients with chronic disabling occupational musculoskeletal disorders completed the MMPI-2-RF and the Current Opioid Misuse Measure (COMM) upon admission to a functional restoration program. The PSY-5-RF and H-O subscales were correlated with the baseline COMM scores. Correlation analyses, ROC curve analyses, and multiple binary logistic regression models were developed to determine which subscales were most associated with elevated COMM scores. The results of the regression analyses suggest that Scale elevations on two of the PSY-5-RF Scales and two Higher-Order Scales of the MMPI-2-RF demonstrated significant associations with elevated COMM scores, thus exhibiting the utility of these subscales in identifying the risk of opioid misuse among chronic pain patients. These findings are clinically meaningful in underscoring the importance of identifying specific personality traits as potential predictors of opioid misuse, and identifying those at risk through careful screening. Clinical implications based on each of the PSY-5-RF and H-O scales significantly associated with elevated COMM scores are discussed.

Does Maternal Incarceration Impact Infants with Neonatal Abstinence Syndrome?

OBJECTIVES: Opioid exposed infants born to incarcerated women represent a vulnerable and understudied subset of infants with neonatal abstinence syndrome (NAS). The impact of maternal incarceration on length of stay (LOS) for infants with NAS is unknown. We hypothesized that infants with NAS born to incarcerated women have longer hospitalizations compared to infants with NAS born to non-incarcerated women. METHODS: This is a retrospective cohort study of infants with NAS born between 2011 and 2018 at the primary delivery site for Connecticut's only women's prison. Opioid exposed infants were assessed by Finnegan Scores for withdrawal and received morphine as a first line agent and phenobarbital as a second line agent. LOS was compared using Poisson regression. RESULTS: Of 206 infants identified, 166 were included in the analysis, with 28 born to incarcerated women and 138 to non-incarcerated women. Incarcerated women were more likely to report prenatal alcohol use, 14.3% vs 2.2% p = 0.016 and benzodiazepine use 21.4% vs 7.3% p = 0.032. Infants of incarcerated women were less likely to be fed breast milk at discharge, 3.6% vs 37% p < 0.001. Adjusted mean LOS was longer among infants born to incarcerated women, 18.5 vs 16.6 days (p = 0.009). CONCLUSIONS FOR PRACTICE: Infants with NAS born to incarcerated women in Connecticut had longer LOS, lower rates of being fed breast milk, and different prenatal substance exposures than infants with NAS born to non-incarcerated women. Supporting the maternal-infant dyad until infant discharge may mitigate the potential negative impact of maternal incarceration on the care of infants with NAS.

Opioid Prescribing Risk Factors in Nonoperative Ankle Fractures: The Impact of a Prospective Clinical Decision Support Intervention.

Opioids are frequently used for acute pain management of musculoskeletal injuries, which can lead to misuse and abuse. This study aimed to identify the opioid prescribing rate for ankle fractures treated nonoperatively in the ambulatory and emergency department setting across a single healthcare system and to identify patients considered at high risk for abuse, misuse, or diversion of prescription opioids that received an opioid. A retrospective cohort study was performed at a large healthcare system. The case list included nonoperatively treated emergency department, urgent care and outpatient clinic visits for ankle fracture and was merged with the Prescription Reporting With Immediate Medication Mapping (PRIMUM) database to identify encounters with prescription for opioids. Descriptive statistics characterize patient demographics, treatment location and prescriber type. Rates of prescribing among subgroups were calculated. There were 1,324 patient encounters identified, of which, 630 (47.6%) received a prescription opioid. The majority of patients were 18-64 years old (60.3%). Patients within this age range were more likely to receive an opioid prescription compared to other age groups (p < .0001). Patients treated in the emergency department were significantly more likely to receive an opioid medication (68.3%) compared to patients treated at urgent care (33.7%) or in the ambulatory setting (16.4%) (p < .0001). Utilizing the PRIMUM tool, 14.2% of prescriptions were provided to patients with at least one risk factor. Despite the recent emphasis on opioid stewardship, 14.2% of patients with risk factors for misuse, abuse, or diversion received opioid analgesics in this study, identifying an area of improvement for prescribers.

A Multifaceted Approach to Opioid Education, Prescribing, and Disposal for Patients with Breast Cancer Undergoing Surgery.

BACKGROUND: Standardized prescribing practices are recommended to decrease opioid abuse, however, data regarding the handling and disposal of leftover narcotics are lacking. This quality improvement project and analysis evaluated implementation of standardized prescribing, opioid education, and a narcotic disposal system. METHODS: This initiative was implemented over a 1-y period among patients who underwent breast surgery. The project included the following: 1) implementation of standardized prescribing, 2) voluntary and anonymous survey analysis, and 3) preoperative education regarding risks of opioids, charcoal disposal bag distribution, and follow-up survey to assess use and use of intervention. RESULTS: Preintervention surveys were completed by 53 patients, and 60% (n = 32) underwent lumpectomy. Narcotic prescriptions were filled by 90%; median number of pills taken was 3 (range 0-24), however 93% felt that a non-narcotic was more effective. Eighty three percentage of patients had unused pills, and 58% kept these pills in an unlocked cabinet. Postintervention surveys were completed by 66 patients, and 48% (n = 32) underwent lumpectomy. Narcotic prescriptions were filled by 88%, median number of pills taken was 4 (range 0-40), and 89% of patients had pills leftover. Sixty seven percentage of patients found the education handout useful and charcoal bag use was reported by 37% (n = 17). The median postoperative pain control satisfaction score was 4.5 (5-point Likert scale, 1 = very dissatisfied, 5 = very satisfied) on both preintervention and postintervention surveys. CONCLUSIONS: This study, which included standardized prescribing parameters, opioid education, and implementation of a disposal method, was found to be feasible, beneficial, and did not compromise postoperative pain control.

Opioid prescribing practices in academic otolaryngology: A single institutional survey.

OBJECTIVES: Opioids are highly addictive medications and otolaryngologists have a responsibility to practice opioid stewardship. We investigated postoperative opioid prescribing patterns among resident and attending physicians as an educational platform to underscore the importance of conscientious opioid prescribing. METHODS: This quality improvement study was designed as a cross-sectional electronic survey. Residents and attending clinical faculty members at a single academic institution were queried from February through April 2020. An electronic survey was distributed to capture postoperative opioid prescribing patterns after common procedures. At the conclusion of the study, results were sent to all faculty and residents. RESULTS: A total of 29 attending otolaryngologists and 22 residents completed the survey. Resident physicians prescribed on average fewer postoperative opioid pills than attendings. Among attendings, the largest number of opioids were prescribed following tonsillectomy (dose varied by patient age), neck dissection (12.6 pills), brow lift (13.3 pills), facelift (13.3 pills), and open reduction of facial trauma (10.7 pills). For residents, surgeries with the most postoperatively prescribed opioids were for tonsillectomy (varied by patient age), neck dissection (13.4 pills), open reduction of facial trauma (10.5 pills), parotidectomy (10.0 pills), and thyroid/parathyroidectomy (9.0 pills). The largest volume of postoperative opioids for both groups was prescribed following tonsillectomy. Attendings prescribed significantly more opioids after facelift and brow lift than did residents (p = 0.01 and p = 0.003, respectively). CONCLUSION: There was good concordance between resident and attending prescribers. Improvement in opioid prescribing and pain management should be an essential component of otolaryngology residency education and attending continuing medical education. LEVEL OF EVIDENCE: 4.

Exposure to Hurricane Sandy and Risk of Opioid Abuse.

BACKGROUND: Given both the increased prevalence of natural disasters in recent years and the crippling opioid epidemic, identifying at-risk groups for substance abuse post-disaster is imperative to survivor mental health. The objective of this study was to examine the association between exposure to Hurricane Sandy and risk of opioid abusive behavior. METHODS: We conducted a retrospective analysis using data from two cross-sectional studies that examined the impact of Hurricane Sandy on mental health from October 2013- August 2016. Patient demographics, hurricane exposure and mental health history were obtained via self-report questionnaires. Opioid abuse risk was determined and categorized using adaptations from the Opioid Risk Tool (ORT). Multinomial logistic regression was used to examine the relationship between hurricane exposure and opioid abuse risk. RESULTS: Data was available on 1,687 Hurricane Sandy survivors, the majority being female (59.3%), white (52.0%) and an average age of 46.1 years (std. 19.2). Approximately 9.0% of survivors were classified as being 'High' risk for opioid abuse. For every increase in total exposure reported, the odds of being classified as high risk was 1.09 greater (95% CI 1.05, 1.14) compared to low risk, after adjusting for covariates. Among personal exposures only (i.e. injury to self or family member), for every increase in reported exposure the adjusted odds of being classified as high risk was 1.25 times greater (95% CI 1.15, 1.37) compared to low risk. CONCLUSIONS: These findings suggest that exposure to a natural disaster, specifically personal exposures, are associated with increased risk for opioid abusive behavior.

A Case Report of Torsade de Pointes and Brugada Pattern Associated with Loperamide Misuse and Supratherapeutic Loperamide Concentrations.

BACKGROUND: Loperamide, commonly sold under the brand name Imodium® (Johnson & Johnson, Fort Washington, PA), is a widely available, over-the-counter antidiarrheal medication that possesses µ-opioid agonist properties and can have catastrophic cardiac events when misused or abused. Since the start of the opioid epidemic in the United States, there has been an increasing number of case reports and deaths linking loperamide abuse with cardiac events such as torsades de pointes (TdP) and Brugada syndrome. CASE REPORT: This case report presents a 22-year-old man who presented in cardiac arrest from polymorphic ventricular tachycardia consistent with TdP and a Type 1 Brugada pattern after intentional loperamide abuse. We discuss this patient's management and the proposed pathophysiology of these two cardiotoxicities, of which, to our knowledge, no previously published case report has displayed both in the same patient after a supratherapeutic loperamide ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As the prevalence of opioid dependency and misuse has increased, so, too, has the misuse of un-scheduled medications such as loperamide to achieve central nervous system opioid effects. It is important for the emergency physician to know about and understand loperamide-associated cardiotoxicities such as prolongation of the QRS, unmasking of Brugada patterns, QT prolongation, or ventricular dysrhythmias such as TdP to be able to recognize and treat it.

Mental health and substance use affect perioperative opioid demand in upper extremity trauma surgery.

BACKGROUND: Patients undergoing upper extremity fracture surgery often have postoperative pain that can be mitigated with opioid pain medications. Opioid misuse and abuse are growing concerns regarding the liberal use of opioids in the perioperative setting. The impact of mental health disorders and substance abuse on perioperative opioid demand is largely unknown. The purpose of this study is to describe perioperative opioid filling and risk factors for increased filling after upper extremity fractures. The study hypothesis is that poor mental health and substance abuse will be associated with increased opioid demand. METHODS: This is a retrospective, cohort study of 26,283 patients undergoing operative fixation of upper extremity fractures involving the proximal humerus through distal radius using a commercially available insurance database. Opioid prescription filling in oxycodone 5-mg equivalents and refills were tabulated from 1 month preoperation to 1 year postoperation. Multivariable linear and logistic regression models were constructed in R (Statistical Analysis Software) to evaluate associations between mental health and substance use disorders and opioid-related outcomes with adjustment for baseline patient and treatment factors such as age, sex, comorbidities, and fracture location. RESULTS: Of the 26,283 patients in the cohort, 79.9%, 32.6%, and 83.1% filled at least 1 opioid prescription in the 1-month preoperative to 90-day postoperative, 3-month postoperative to 1-year postoperative, and 1-month preoperative to 1-year postoperative time frames, respectively. Mean opioid volume prescribed during those time frames was 103.7, 53.5, and 156.9 oxycodone 5-mg equivalents, respectively. Drug abuse, psychoses, and preoperative opioid filling were significant mental health-related drivers of increased postoperative opioid demand. DISCUSSION: This study reports the rate and volume of opioid prescription filling in patients undergoing upper extremity fracture surgery. Mental health and substance use disorders were significant drivers of perioperative opioid demand. These study findings can guide surgeons to anticipate expected perioperative opioid demand and identify patients who may benefit from collaboration with pain management specialists during the perioperative period.

HIV and opiates dysregulate K+- Cl- cotransporter 2 (KCC2) to cause GABAergic dysfunction in primary human neurons and Tat-transgenic mice.

Approximately half of people infected with HIV (PWH) exhibit HIV-associated neuropathology (neuroHIV), even when receiving combined antiretroviral therapy. Opiate use is widespread in PWH and exacerbates neuroHIV. While neurons themselves are not infected, they incur sublethal damage and GABAergic disruption is selectively vulnerable to viral and inflammatory factors released by infected/affected glia. Here, we demonstrate diminished K+-Cl- cotransporter 2 (KCC2) levels in primary human neurons after exposure to HIV-1 or HIV-1 proteins ± morphine. Resulting disruption of GABAAR-mediated hyperpolarization/inhibition was shown using genetically-encoded voltage (Archon1) and calcium (GCaMP6f) indicators. The HIV proteins Tat (acting through NMDA receptors) and R5-gp120 (acting via CCR5) but not X4-tropic gp120 (acting via CXCR4), and morphine (acting through µ-opioid receptors) all induced KCC2 loss. We demonstrate that modifying KCC2 levels or function, or antagonizing NMDAR, CCR5 or MOR rescues KCC2 and GABAAR-mediated hyperpolarization/inhibition in HIV, Tat, or gp120 ± morphine-exposed neurons. Using an inducible, Tat-transgenic mouse neuroHIV model, we found that chronic exposure to Tat also reduces KCC2. Our results identify KCC2 as a novel therapeutic target for ameliorating the pathobiology of neuroHIV, including PWH exposed to opiates.

Prevention of Opioid Abuse and Treatment of Opioid Addiction: Current Status and Future Possibilities.

Prescription opioid medications have seen a dramatic rise in misuse and abuse, leading regulators and scientists to develop policies and abuse-deterrent technologies to combat the current opioid epidemic. These abuse-deterrent formulations (ADFs) are intended to deter physical and chemical tampering of opioid-based products, while still providing safe and effective delivery for therapeutic purposes. Even though formulations with varying abuse-deterrent technologies have been approved, questions remain about their effectiveness. While these formulations provide a single means to combat the epidemic, a greater emphasis should be placed on formulations for treatment of addiction and overdose to help those struggling with opioid dependence. This article analyzes various ADFs currently in clinical use and explores potential novel systems for treatment of addiction and prevention of overdose.