HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus.

Many persons infected with HIV-1 (PWH) and opioid-dependent individuals experience deficits in sociability that interfere with daily living. Sociability is regulated by the prefrontal cortico-hippocampal-amygdalar circuit. Within this circuit HIV-1 trans-activator of transcription (HIV-1 Tat) and opioids can increase dendritic pathology and alter neuronal firing. Changes in sociability are also associated with dysregulation of hypothalamic neuropeptides such as oxytocin or corticotropin releasing factor (CRF) in the prefrontal cortico-hippocampal-amygdalar circuit. Accordingly, we hypothesized that the interaction of HIV-1 Tat and morphine would impair inter-male social interactions and disrupt oxytocin and CRF within the PFC and associated circuitry. Male mice were exposed to HIV-1 Tat for 8 weeks and administered saline or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of HIV-1 Tat exposure. Tat attenuated aggressive interactions with an unknown intruder, whereas morphine decreased both non-aggressive and aggressive social interactions in the resident-intruder test. However, there was no effect of Tat or morphine on non-reciprocal interactions in the social interaction and novelty tests. Tat, but not morphine, decreased oxytocin levels in the PFC and amygdala, whereas both Tat and morphine decreased the percentage of oxytocin-immunoreactive neurons in the hypothalamic paraventricular nucleus (PVN). In Tat(+) or morphine-exposed mice, regional levels of CRF and oxytocin correlated with alterations in behavior in the social interaction and novelty tests. Overall, decreased expression of oxytocin in the prefrontal cortico-hippocampal-amygdalar circuit is associated with morphine- and HIV-Tat-induced deficits in social behavior.

Effect of Severity of Opiate Use on Cardiometabolic Profile of Chronic Opiate Dependents of Western Rajasthan.

Lack of cardiometabolic profile data based on severity of opiate dependence for opiate abusers. The study aimed to evaluate the effect severity of opiate abuse on the cardiometabolic profile of male opiate abusers without co-morbidities. The study included 30 healthy controls (HCs), 90 prospective chronic opiate (opium and heroin) abusers, with and without co-dependence of smoking and tobacco-chewing. The subjects were categorized based on severity of opiate dependence questionnaire (SODQ) and metabolic syndrome (MS) based on NCEP ATP-III criteria and fasting blood samples analyzed for sugar, insulin, insulin resistance (IR), lipid profile, Hs-CRP and total antioxidant capacity (TAC). There was higher prevalence of MS in opiate abusers as compared to HCs. Majority of the patients fell in grade 2 and 3 of severity. There was significant difference across groups for WHR (p < 0.001), SBP (p < 0.03), FBS (p < 0.001), insulin (p < 0.02), IR (p < 0.03) and TAC (p < 0.01). Multiple regression analysis of SODQ grades 2 and 3 independently predicted TAC by Hs-CRP (p = 0.032 and 0.042). There was a significant correlation of TAC with serum insulin, IR and Hs-CRP in SODQ grade 2 and serum insulin and Hs-CRP in SODQ grade 3. Chronic opiate abuse is not benign and predisposes abusers to cardiometabolic risk with increasing severity of dependence, owing to oxidative stress and chronic low-grade inflammation.

Immunomodulatory Role of Complement Proteins in the Neuropathology Associated with Opiate Abuse and HIV-1 Co-Morbidity.

The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.

Treatment Strategies for the Opioid-Dependent Patient.

PURPOSE OF REVIEW: This review is intended to help the headache physician think through and plan for management issues concerning the use of opioids. We ask the headache physician to consider if there are instances where prescribing or continuing prescriptions of opiates is plausible, and if so, how can the physician proceed as safely as possible. Our goal is to start a conversation regarding the inevitable encounter with a patient on opiates or requesting opiates. RECENT FINDINGS: The use of opiates in our society has reached a crisis in staggering death and addiction rates. Recent guideline published by the CDC can assist us in developing an algorithmic approach towards opiate use. Recent advances in addiction medicine can also assist us in protecting our patients. Every headache physician will undoubtedly encounter patients on opiates. There still are appropriate reasons to treat patients with opiates. Every headache physician may need to prescribe opiates and they may be indicated. It is important to learn the correct way to approach, manage, and treat patients on opiates.

Management of Patients on Abuse-Deterrent Opioids in the Ambulatory Surgery Setting.

PURPOSE OF REVIEW: The use of prescription opioids for acute and chronic pain has become more prevalent than ever, and concurrent with the increased prescribing of opioids, there has been a steady increase in opioid abuse. Abuse is commonly associated with physical or chemical manipulation of the original opiate to provide more rapid onset of the active ingredient. RECENT FINDINGS: This growing national public health concern has led to the development of various abuse-deterring opioids with the intent of decreasing the diversion of opioids from their prescribed use. Given the ever-increasing percentage of surgeries performed in the ambulatory surgery setting, anesthesia providers will inevitably encounter more and more patients taking these new opioid formulations with abuse-deterring properties. Consequently, a thorough understanding of these medications is vital for optimal anesthetic management. This article reviews the scope of the problem of prescription opiate abuse, summarizes the currently available abuse-deterring opioids, and discusses the anesthetic management of patients who are taking these new medications in the outpatient setting.

Should Excess Topical Decongestant Use Raise a Red Flag? Rhinitis Medicamentosa and Opioid Use Disorder.

OBJECTIVE: The objective of this study was to determine whether patients with rhinitis medicamentosa (RM) have an increased odds of having an opioid use disorder (OUD) and which characteristics may predict this association. METHODS: The authors conducted a retrospective case control study of patients 18 years and older who presented to the otolaryngology clinic at an academic medical center from January 2013 through December 2017. Cases, defined as patients who presented with excessive decongestant nasal spray usage based on history, were matched to control patients who presented with chronic rhinitis and did not report regular nasal decongestant usage. The charts were reviewed for patients that carried a problem of opioid abuse, identified using ICD-9 codes 304.XX or ICD-10 codes F11.XX. The primary outcome of this study was the odds of having an OUD. Secondary outcomes were assessed by summary statistics. RESULTS: One hundred and thirty-one cases of RM were matched to 1871 controls of chronic rhinitis. Seven cases (5.3%) and 24 (1.3%) controls had a diagnosis of OUD, consistent with an odds ratio of 3.98 for opioid abuse in patients with RM (95% CI: 1.47-9.71). Oxymetazoline was used by 85.5% (n = 112) of patients with RM. Thirty-six patients (27.1%) with RM underwent nasal surgery following a diagnosis of RM, of which twenty patients (55.6%) were prescribed opioids following the procedure. CONCLUSIONS: RM is associated with increased odds of having an OUD.

The Impact of Medical Cannabis on Intermittent and Chronic Opioid Users with Back Pain: How Cannabis Diminished Prescription Opioid Usage.

Objective: To determine if cannabis may be used as an alternative or adjunct treatment for intermittent and chronic prescription opioid users. Design: Retrospective cohort study. Setting: A single-center cannabis medical practice site in California. Patients: A total of 180 patients who had a chief complaint of low back pain were identified (International Classification of Diseases, 10th Revision, code M54.5). Sixty-one patients who used prescription opioids were analyzed. Interventions: Cannabis recommendations were provided to patients as a way to mitigate their low back pain. Outcome Measures: Number of patients who stopped opioids and change in morphine equivalents. Results: There were no between-group differences based on demographic, experiential, or attitudinal variables. We found that 50.8% were able to stop all opioid usage, which took a median of 6.4 years (IQR=1.75-11 years) after excluding two patients who transitioned off opioids by utilizing opioid agonists. For those 29 patients (47.5%) who did not stop opioids, 9 (31%) were able to reduce opioid use, 3 (10%) held the same baseline, and 17 (59%) increased their usage. Forty-eight percent of patients subjectively felt like cannabis helped them mitigate their opioid intake but this sentiment did not predict who actually stopped opioid usage. There were no variables that predicted who stopped opioids, except that those who used higher doses of cannabis were more likely to stop, which suggests that some patients might be able to stop opioids by using cannabis, particularly those who are dosed at higher levels. Conclusions: In this long-term observational study, cannabis use worked as an alternative to prescription opioids in just over half of patients with low back pain and as an adjunct to diminish use in some chronic opioid users.

Administration of Naloxone by Prehospital Personnel: A Retrospective Analysis.

Introduction Patient-specific discrepancies in prehospital naloxone administration have been documented. As the opioid epidemic continues to evolve, further evaluation of prehospital naloxone administration practices is needed. The objective of this study was to compare patients who received prehospital naloxone and received an emergency department (ED) diagnosis of opioid overdose with patients who received prehospital naloxone and received an alternative ED diagnosis.  Methods This was a retrospective, multicenter chart review of patients who received naloxone by prehospital personnel for suspected opioid overdose between October 1, 2016, and October 31, 2017. Patients were excluded if age was less than 18 years, naloxone was administered by non-emergency medical service (EMS) personnel, not transported, or if prehospital records could not be linked with ED records. Demographic information and several prehospital clinical findings, including unresponsiveness, apnea, and miosis, were compared between patients diagnosed with opioid overdoses versus an alternative ED diagnosis. Descriptive statistics were utilized. Results A total of 837 patients had complete data available and were included in the analysis. Overall, 402 (48%) of patients received an ED diagnosis of opioid overdose, and 435 (52%) of patients received an alternative ED diagnosis. Patients in the alternative diagnosis group were older, had less known drug use, were more likely to be admitted, and had lower incidences of apnea, unresponsiveness, and miosis. In the opioid overdose group, there was a higher proportion of previous drug use, apnea, unresponsiveness, and miosis in the EMS setting, whereas there was a higher proportion of previous overdose, previous suicide attempts, and neurological deficits in the ED setting. Conclusions In this retrospective review evaluating patients who received prehospital naloxone, several demographic and clinical differences were noted between the two groups. Further elucidation of the safety and efficacy of prehospital naloxone in alternative diagnoses is needed.

Similarities and changes between 15- and 24-year survival and retention rates of patients in a large medical-affiliated methadone maintenance treatment (MMT) center.

BACKGROUND: Environmental and social trends and patients' characteristics may affect predictors for methadone maintenance treatment (MMT) outcome. METHODS: We have expanded our previous study of predictors for MMT outcome (from 619 to 890 patients) and the study period (from 15 to 24 years). Survival and retention in MMT since admission to the MMT clinic (6/1993-6/2016) and until death or study closure (6/2017) were compiled and analyzed. RESULTS: Of 890 patients ever admitted (10,146.9 person-years (py)), 237 passed away (116 while in MMT). The mortality rate did not differ between those who stayed or left (2.6 vs. 2.1 per 100 py, p = 0.1), but it was lower among those who stayed ≥1 year during any admission (2.1 vs. 3.3 per 100 py, respectively, p = 0.004). Age <40 years, no hepatitis C or B, no HIV, and no benzodiazepine abuse after one year predicted longer survival (multivariate analyses). No opiate or benzodiazepine abuse after one year, methadone dose ≥100 mg/d, no DSM-IV-TR Axis II diagnosis only, and no direct hospital referral predicted longer retention. Cocaine abuse predicted poor retention and survival among 271 patients admitted during the extended part of the study period. CONCLUSIONS: Predictors for retention (associated with MMT outcome) and mortality (associated with pre-treatment comorbidity) after 24 years were similar to those after 15 years. Cocaine abuse as a predictor of both poor retention and poor survival in the later period may reflect the escalating trend for cocaine abuse and should be studied if related to other unmonitored substances.

The case for implementing the levels of prevention model: Opiate abuse on American college campuses.

Opiate abuse in the United States is on the rise among the college student population. This public health crisis requires immediate action from professionals and stakeholders who are committed to addressing the needs of prospective, current, and recovering opiate users using comprehensive prevention methods. Such approaches have been used to deliver primary, secondary, and tertiary intervention to alcohol and other drug users but are underutilized in the case of opiate abuse among college students in the United States. There is a definite need for involving college campus faculty, staff, students, and others in efforts to prevent opiate abuse at all levels. Our recommendations include specific strategies to address this imminent issue using an innovative application of the traditional Levels of Prevention Model.

"Tampering to Death": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.

Many homemade tamper processes of medical codeine formulations are available on selected "forums" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called "cold water extraction." Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event.

Alpha2C-adrenoceptor Del322-325 polymorphism and risk of psychiatric disorders: significant association with opiate abuse and dependence.

Objectives α2C-adrenoceptors (α2C-AR) are involved in behavioural responses relevant to psychiatric disorders and suicide completion. The genetic polymorphism α2CDel322-325-AR confers a loss-of-function phenotype. Functional human studies have associated α2CDel322-325-AR polymorphism with major depression pathophysiology. The aim of this study was to analyse, for the first time, the association of α2CDel322-325-AR polymorphism with suicide completion and with related psychiatric disorders: major depression, schizophrenia, opiate and alcohol abuse and dependence. Methods Post-mortem brain DNA was extracted (n = 516) and genotyping performed by HaeIII restriction endonuclease digestion of PCR products and DNA fragment analysis on capillary sequencer. Amplified products were sequenced to confirm the presence of the polymorphism. Results The frequency of α2CDel322-325-AR in suicide (9%, n = 236) and non-suicide victims (11%, n = 280) was similar. Genotype frequencies for the α2CDel322-325-AR polymorphism in depressed (15%, n = 39) and schizophrenic subjects (18%, n = 39) were higher than in controls (7%, n = 187), but these differences did not reach statistical significance (P = 0.125 and P = 0.063, respectively). A selective and significant association of α2CDel322-325-AR polymorphism with opiate abuse and dependence was found (23%, n = 35, P = 0.011). Conclusions Our results indicate that α2CDel322-325-AR may play a role in the pathophysiology of opiate abuse and dependence and raise the interest for larger genetic associative studies.

Hemolytic Disease of the Fetus and Newborn due to Intravenous Drug Use.

Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn. Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy. Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse.

PhytobezoarInduced Small Bowel Obstruction in a Young Male with Virgin Abdomen.

Phytobezoars are a rare cause of small bowel obstruction. Such cases are most commonly associated with previous abdominal surgery or poor dentition or psychiatric conditions. A 40 year old man with a virgin abdomen and excellent dentition and no underlying psychiatric condition presented with an acute abdomen. CT scan revealed a transition point between dilated proximal loops of small bowel and collapsed distal loops. Exploratory laparotomy revealed a phytobezoar unable to be milked into the cecum and an enterectomy with primary anastamosis was performed without complication. A detailed history revealing several less common predisposing factors for phytobezoars should increase clinical suspicion of a phytobezoarinduced small bowel obstruction in the setting of an acute abdomen. Vigilance in presentations of an acute abdomen improves the usefulness of medical imaging, such as a CT, to detect phytobezoars. Understanding mechanisms of phytobezoar formation helps guide management and may prevent surgery.

Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model.

Chronic opiate abuse accelerates the development of cognitive deficits in human immunodeficiency virus (HIV)-1 patients. To investigate morphine's effects on viral infection of the central nervous system, we applied chronic morphine treatment to the LP-BM5 murine acquired immunodeficiency syndrome (MAIDS) model. LP-BM5 infection induces proinflammatory cytokine/chemokine production, correlating to increased blood-brain barrier permeability. Morphine treatment significantly increased LP-BM5 viral load in the hippocampus, but not in the frontal lobe. Morphine reduced the chemokine CCL5 to non-infected levels in the frontal lobe, but not in the hippocampus. These data indicate a region-specific mechanism for morphine's effects on virally-induced neurocognitive deficits.

Retention of participants in medication-assisted programs in low- and middle-income countries: an international systematic review.

BACKGROUND AND AIMS: Medication-assisted treatment (MAT) is a key component in overdose prevention, reducing illicit opiate use and risk of blood-borne virus infection. By retaining participants in MAT programs for longer periods of time, more noticeable and permanent changes in drug use, risk behavior and quality of life can be achieved. Many studies have documented retention in MAT programs in high-income countries, using a 50% average 12-month follow-up retention rate as a marker for a successful MAT program. This study contributes to a systematic understanding of how successful programs have been in retaining participants in low- and middle-income countries (LMIC) over time. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search to identify MAT program studies that documented changes in retention over time for participants in buprenorphine and methadone programs in LMIC. Retention was measured for participants by length of follow-up, type of MAT and treatment dosage. RESULTS: There were 58 MAT program studies, with 27 047 participants eligible for inclusion in the review. Overall average retention after 12 months was 54.3% [95% confidence interval (CI) = 46.2, 63.7%]. Overall average retention was moderately good for both buprenorphine (48.3%, 95% CI = 22.1, 74.6%) and methadone (56.6%, 95% CI = 45.9%, 67.3%) after 12 months of treatment. Among programs using methadone there was no statistically significant difference in average retention by dosage level, and the 10 highest and lowest dosage programs obtained similar average retention levels after 12 months. CONCLUSION: Medication-assisted treatment programs in low- and middle-income countries achieve an average 50% retention rate after 12 months, with wide variation across programs but little difference between those using buprenorphine versus methadone.

Comparing the Effectiveness of Behavioral Recognition and Group Stress Surmounting Techniques Instructions on Changing University Students' Positive Attitudes towards Opiate Abuse.

BACKGROUND: One of the most important strategies in preventing addiction is changing positive attitudes and stabilizing negative attitudes towards opiate abuse. Current research has been comparing the effectiveness of behavioral recognition and stress surmounting techniques instructions on changing students' positive attitudes towards opiate abuse. METHODS: To determine the effectiveness of behavioral-recognition and group stress surmounting instructions on changing student's positive attitudes towards opiate abuse, 90 students (45 boys and 45 girls) who had got good grades in attitude measuring questionnaire were chosen and were randomly assigned in 3 groups (two test groups and the control group) and then, were randomly replaced in 15 person groups with sex distinction. The research data were analyzed using multivariate statistical analysis method. FINDINGS: The results of pot-test analyses showed significant improvement compared with pretest analysis in both training methods and in both genders (P < 0.05). Then, the surmounting methods group training and recognition-behavioral group training both significantly improved positive attitudes towards opiate abuse in male and female students. CONCLUSION: Behavioral-recognition and stress surmounting techniques instructions brought about changes in students attitudes towards opiate abuse and these changes were more prominent in female students than in males.