Hypocretin/Orexin Interactions with Norepinephrine Contribute to the Opiate Withdrawal Syndrome.

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal.SIGNIFICANCE STATEMENT Previously, we have shown that the hypothalamic hypocretin system undergoes profound anatomic changes in human heroin addicts and in mice exposed to morphine, suggesting a role of this system in the development of addictive behaviors. The locus coeruleus plays a key role in opioid addiction. Here we report that the hypothalamic hypocretin innervation of the locus coeruleus increases dramatically with morphine administration to mice. This increase is correlated with a massive increase in tyrosine hydroxylase expression in locus coeruleus. Elimination of hypocretin neurons prevents the tyrosine hydroxylase increase in locus coeruleus and dampens the somatic and affective components of opioid withdrawal.

Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation.

AIMS: Atrial fibrillation (AF) is now regarded as a preventable disease, requiring a search for modifiable risk factors. With legalization of cannabis and more lenient laws regarding the use of other illicit substances, investigation into the potential effects of methamphetamine, cocaine, opiate, and cannabis exposure on incident AF is needed. METHODS AND RESULTS: Using Office of Statewide Health Planning and Development databases, a longitudinal analysis was performed of adult Californians ≥18 years of age who received care in an emergency department, outpatient surgery facility, or hospital from 1 January 2005 to 31 December 2015. Associations between healthcare coding for the use of each substance and a new AF diagnosis were assessed. Among 23,561,884 patients, 98 271 used methamphetamine, 48 701 used cocaine, 10 032 used opiates, and 132 834 used cannabis. Of the total population, 998 747 patients (4.2%) developed incident AF during the study period. After adjusting for potential confounders and mediators, use of methamphetamines, cocaine, opiates, and cannabis was each associated with increased incidence of AF: hazard ratios 1.86 [95% confidence interval (CI) 1.81-1.92], 1.61 (95% CI 1.55-1.68), 1.74 (95% CI 1.62-1.87), and 1.35 (95% CI 1.30-1.40), respectively. Negative control analyses in the same cohort failed to reveal similarly consistent positive relationships. CONCLUSION: Methamphetamine, cocaine, opiate, and cannabis uses were each associated with increased risk of developing incident AF. Efforts to mitigate the use of these substances may represent a novel approach to AF prevention.

Identifying Co-Exposure to Opiates and Gabapentin During Pregnancy.

Neonatal withdrawal can be difficult to treat in infants with co-exposure to opiates and gabapentin. Because maternal self-report can underestimate exposures, we evaluated the effect of universal toxicology screening for gabapentin. Identification of co-exposure to opiates and gabapentin increased after implementation of toxicology screening, with implications for improved neonatal care.

"He Bore it Like a Scarlet Letter": Medical Student Reflections on Substance Use Disorders.

OBJECTIVE: Substance abuse in the context of the opioid crisis presents a major public health concern. Despite some evidence that medical students' attitudes towards substance use disorders worsen during medical school, very few studies have examined how students' early clinical experiences with substance use disorders shape their views of this clinical population. This study uses student reflective essays to explore these formative educational experiences. METHODS: Using content analysis, the authors analyzed a collection of 802 medical student reflective essays written during core clerkships (excluding Psychiatry), coding for ethical and professional themes as well as descriptions of substance use disorders. In addition to the qualitative identification of themes, the authors used chi-square analysis to determine which themes had statistically significant associations with substance use disorders. RESULTS: Fifty-three essays described patients with substance use disorders. The most common substances described were opioids (n = 25), alcohol (n = 18), and cocaine (n = 11). There were five themes statistically associated with substance use disorders (p < 0.05): (1) adequate treatment, (2) pain, (3) difficult patient, (4) jumping to conclusions, and (5) malingering. CONCLUSIONS: In the sample, students found the treatment of pain to be a significant ethical challenge related to substance use disorders. In considering a comprehensive educational plan, medical educators may need to consider educational venues outside of the Psychiatry clerkship to address substance use disorders.

Illicit drugs: Effects on eye.

There is a myriad of changes that can be produced in the eye by toxic drugs ranging from mild/no symptoms to severe loss of vision from endophthalmitis. The routes of administration include oral ingestion, smoking, nasal inhalation, intravenous injection, topical application or application to other mucosal surfaces. It is important to recognize certain clinical signs and symptoms in the eye produced by these toxins. This article describes in brief some of the ocular effects of commonly abused drugs. For identification of a particular poisoning, in addition to the clinical presentation, pulse, blood pressure, respiration and body temperature, pupillary size, pupillary reaction to light, ocular convergence and nystagmus can be useful indicators of the type of drug the patient is exposed to. Unmasking these features help the clinician in an early and accurate diagnosis of the offending drug as well as timely management.

Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) Syndrome.

BACKGROUND: Abnormal restricted diffusion on magnetic resonance imaging is often associated with ischemic stroke or anoxic injury, but other conditions can present similarly. We present six cases of an unusual but consistent pattern of restricted diffusion in bilateral hippocampi and cerebellar cortices. This pattern of injury is distinct from typical imaging findings in ischemic, anoxic, or toxic injury, suggesting it may represent an under-recognized clinicoradiographic syndrome. Despite initial presentation with stupor or coma in the context of obstructive hydrocephalus, patients may have acceptable outcomes if offered early intervention. METHODS: We identified an ad hoc series of patients at our two institutions between years 2014 and 2017 who presented to the neurocritical care unit with severe, otherwise unexplained cerebellar edema and retrospectively identified several commonalities in history, presentation, and imaging. RESULTS: Between two institutions, we identified six patients-ages 33-59 years, four male-with similar presentations of decreased level of consciousness in the context of intoxicant exposure, with acute cytotoxic edema of the cerebellar cortex, hippocampi, and aspects of the basal nuclei. All patients presented with severe cerebellar edema which led to obstructive hydrocephalus requiring aggressive medical and/or surgical management. The five patients who survived to discharge demonstrated variable degrees of physical and memory impairment on discharge and at follow-up. CONCLUSIONS: We present findings of a potentially novel syndrome involving a distinct pattern of cerebellar and hippocampal restricted diffusion, with imaging and clinical characteristics distinct from ischemic stroke, hypoxic injury, and known toxidromes and leukoencephalopathies. Given the potential for favorable outcome despite early obstructive hydrocephalus, early identification and treatment of this syndrome are critical.

[OPIATES IN THE COMPLEX OF ANALGESIA AFTER THORACOTOMY AND ANALYSIS OF THE COMPLICATIONS].

The goal: to study the influence of various methods of analgesia on the state of postoperative anesthesia in patients after thoracotomy; compare the quantity of narcotic analgesics (morphine) used in different types of anesthesia and anesthesia related complications. In 85 patients after thoracotomy, anesthesia was performed by prolonged paravertebral analgesia (PVA) (19 patients), by prolonged epidural analgesia (EDA) (36 patients) with 0.2% solution of rapamycain and by an intravenous patient-controlled analgesia (PCA) with a morphine solution in the control group (30 patients). In all three groups, the nonsteroidal anti-inflammatory drug (NSAIDs) ketorolac tromethamine was used intramuscularly. The evaluation was performed within 3 days after surgery using the visual analog scale (VAS). In the PVA group, the pain level was 29.1 points four hours after surgery to 18.7 points at the end of the third day; in the EDA group - from 24.2 to 20.3 points, respectively; in the control group - from 48.8 to 38.0 points, respectively. The need for morphine administration within the first day after surgery was the highest in the control group and was 42.83±13.23 mg/day. In experimental groups, the need for morphine was 15.0±5.0 mg/day in the EDA group and 16.15±5.38 mg/day in the PVA group. The greatest number of complications was observed in the control group and was associated with the use of morphine. The method of anesthesia associated with the use of PVA was accompanied by the least amount of complications. In terms of the effectiveness of analgesia and the amount of narcotic analgesic used, it was comparable to EDA. Patients of this group least often developed chronic postoperative pain syndrome. PVA may be a priority for postoperative pain management in patients after thoracotomy.

Analgesic and sedative agents used in the intensive care unit: A review.

Pain is a common experience for most patients in the intensive care unit (ICU). In the current study, the advantages and disadvantages of analgesic and sedative drugs used in the ICU are reviewed. An ideal sedative and analgesic agent should have features such as rapid onset of action, rapid recovery after discontinuation, predictability, minimal accumulation of the agent and metabolites in the body, and lack of toxicity. None of the sedative and analgesic agents have all of these desired characteristics; nevertheless, clinicians must be familiar with these classes of drugs to optimize pharmacotherapy and ensure as few side-effects as possible for ICU patients.

Exposure to opiates in male adolescent rats alters pain perception in the male offspring.

During the past decades, the use/misuse of opioids has increased dramatically among adolescent population. It is now well acknowledged that various morphological and physiological changes occur in the brain during adolescence. During this critical period, brain development and maturation could be affected by several factors including stress, drug abuse, nutritional status, etc. Although studies on transgenerational effects of substances such as alcohol, nicotine, and cocaine have focused on both paternal and maternal drug exposure, most reports on transgenerational effects of morphine are restricted to maternal exposure. Thus, in this study, we aimed to investigate the transgenerational effect of paternal morphine exposure during adolescence on pain perception and antinociceptive effect of morphine in rat offspring. Male rats received escalating doses of morphine for 10 days during postnatal days 31-40. Twenty days after the last morphine injection, male rats were mated with intact female rats, and then behavioral tests were conducted on the male offspring on postnatal day 60. Pain perception and morphine antinociception were evaluated using the formalin test. Our results demonstrated that morphine-sired and saline-sired animals differed in the interphase and phase 2 of the formalin test. These findings indicate a significant transgenerational effect of paternal morphine exposure on pain-related behaviors in rat offspring.

Lower prevalence of gastroesophageal reflux disease in patients with noncardiac chest pain on opiates: a cross-sectional study.

Opiates can cause heartburn and spastic esophageal dysmotility but their role in noncardiac chest pain (NCCP) is not known. Our aim was to characterize opiate effects on esophageal function using esophageal pH monitoring and high-resolution manometry (HREM) in these patients.We performed a cross sectional study of opiate users with NCCP who underwent HREM and esophageal pH study from 2010 to 2017 using opiate nonusers as a comparison group. Demographic data, symptoms, opiate use, endoscopic findings, esophageal pH study parameters, and HREM data were abstracted.Thirty three patients with NCCP on opiates were compared to 144 opiate non-users. Compared to opiate nonusers, opiate users had lower total acid exposure (2.3% vs. 3%, P = 0.012), lower upright acid exposure (1.2% vs. 3.1%, P = 0.032) and lower DeMeester score (6.5 vs. 12.7, P = 0.016). Opiate users also had higher lower esophageal sphincter integrated relaxation pressure (LES-IRP) (7.0 mm Hg [2.2, 11.7] vs. 3.7 mm Hg [1.1, 6.2] P = 0.011) and greater mean distal contractile integral (DCI) (2575 mm.Hg.s.cm [1134, 4466] vs. 1409 mm.Hg.s.cm [796, 3003] P = 0.03) than opiate non-users. The prevalence of hypertensive motility disorders (15.2% vs. 11.1%) and achalasia (12.1% vs. 2.1%) was higher in opiate users (P = 0.039) but did not reach significance on multivariate analysis.In patients presenting with NCCP, opiate users had lower esophageal acid exposure compared to opiate nonusers. This might be due to higher LES pressures preventing reflux and higher DCI leading to more rapid acid esophageal clearance.

Detailed Transmission Network Analysis of a Large Opiate-Driven Outbreak of HIV Infection in the United States.

In January 2015, an outbreak of undiagnosed human immunodeficiency virus (HIV) infections among persons who inject drugs (PWID) was recognized in rural Indiana. By September 2016, 205 persons in this community of approximately 4400 had received a diagnosis of HIV infection. We report results of new approaches to analyzing epidemiologic and laboratory data to understand transmission during this outbreak. HIV genetic distances were calculated using the polymerase region. Networks were generated using data about reported high-risk contacts, viral genetic similarity, and their most parsimonious combinations. Sample collection dates and recency assay results were used to infer dates of infection. Epidemiologic and laboratory data each generated large and dense networks. Integration of these data revealed subgroups with epidemiologic and genetic commonalities, one of which appeared to contain the earliest infections. Predicted infection dates suggest that transmission began in 2011, underwent explosive growth in mid-2014, and slowed after the declaration of a public health emergency. Results from this phylodynamic analysis suggest that the majority of infections had likely already occurred when the investigation began and that early transmission may have been associated with sexual activity and injection drug use. Early and sustained efforts are needed to detect infections and prevent or interrupt rapid transmission within networks of uninfected PWID.

Anaesthesia in patients with liver disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent up to date research data and recommendations regarding anaesthetic management of patients with liver disease undergoing surgery. The incidence of chronic liver disease (CLD) continues to rise and perioperative mortality and morbidity remains unacceptably high in this group. Meticulous preoperative assessment and carefully planned anaesthetic management are vital in improving outcomes in patients with liver disease undergoing surgery. RECENT FINDINGS: The presence of cirrhosis is associated with a significantly increased risk of postoperative morbidity and mortality in patients undergoing elective surgery. The Child--Pugh--Turcotte scale and model for end-stage liver disease (MELD) score remain the most commonly applied scoring systems in preoperative risk assessment, but new MELD-based indices and novel scoring systems might offer better prognostic value. Propofol and new inhalational agents (sevoflurane, desflurane) are recommended hypnotic agents. The titration of opiates in the perioperative period is recommended because of their altered metabolism in patients with liver disease. Perioperative management should include close haemodynamic monitoring and admission to a critical care area should be considered. SUMMARY: Patients with liver disease undergoing anaesthesia pose significant challenges and advanced planning and preparation are required in order to improve perioperative outcomes in this group. VIDEO ABSTRACT: http://links.lww.com/COAN/A43.

Lifetime Cocaine and Opiate Use and Chronic Kidney Disease.

BACKGROUND: More than 50% of American adolescents and adults report having used illicit drugs in their lifetime. We examined the association of lifetime opiate and cocaine use with reduced kidney function, albuminuria and rapid kidney function decline among urban-dwelling adults. METHODS: Our prospective cohort included 2,286 Healthy Aging in Neighborhoods of Diversity across the Life Span study participants who were community-dwelling adults residing in Baltimore, MD. The predictive variables were lifetime opiate and cocaine use, defined as use of opiates or crack/cocaine ≥5 times. Outcomes included prevalent reduced estimated glomerular filtration rate (eGFR; <60 ml/min/1.73 m2 by Chronic Kidney Disease (CKD)-Epidemiology Collaboration), albuminuria (albumin-to-creatinine ratio >30 mg/g, n = 1,652) and rapid kidney function decline (>3 ml/min/1.73 m2 per year over a median of 4.7 years, n = 1,660). RESULTS: Participants' mean age was 48 years, 15% reported opiate use, and 22% reported cocaine use. A total of 115 (5.0%) participants had reduced eGFR, 190 (11.5%) had albuminuria and 230 (13.8%) experienced rapid decline in kidney function. In adjusted logistic regression analyses, both substances were associated with greater odds of reduced eGFR (OR 2.71, 95% CI 1.50-4.89 for opiates; OR 1.40, 95% CI 0.87-2.24 for cocaine). Both substances were associated with greater odds of albuminuria (OR 1.20, 95% CI 0.83-1.73 for opiates; OR 1.80, 95% CI 1.29-2.51 for cocaine). Neither substance was associated with the rapid decline of kidney function. CONCLUSIONS: Lifetime opiate and cocaine use was associated with prevalent reduced eGFR and albuminuria, yet not with rapid kidney function decline. The use of opiate and cocaine may be an important risk factor for CKD in urban populations.

Deconstructing the nature of episodic foresight deficits associated with chronic opiate use.

OBJECTIVES: Episodic foresight refers to the capacity to mentally travel forward in time and has been linked to a wide variety of important functional behaviours. Evidence has recently emerged that chronic opiate use is associated with deficits in this critical capacity and that these difficulties are not simply a secondary consequence of broader cognitive dysfunction. The current study aimed to better understand the circumstances in which chronic opiate users might be expected to have problems with episodic foresight, by addressing whether deficits reflect compromised scene construction, self-projection, or narrative ability. METHODS: Thirty-five chronic opiate users and 35 demographically matched controls completed an imagination task in which they were instructed to imagine and provide descriptions of an atemporal event, a plausible, self-relevant future event, as well as complete a narrative task. These three imagination conditions systematically varied in their demands on scene construction, self-projection, and narrative ability. RESULTS: Consistent with prior literature, chronic opiate users exhibited reduced capacity for episodic foresight relative to controls. However, this study was the first to show that these difficulties were independent of capacity for scene construction and narration. Instead, a specific impairment in self-projection into the future appears to contribute to the problems with episodic foresight seen in this clinical group. CONCLUSIONS: Deficits in self-projection into the future may have important implications in therapeutic environments given that many relapse prevention strategies rely heavily on the ability to project oneself into an unfamiliar future, free of problem substance use. PRACTITIONER POINTS: A reduced capacity for episodic foresight highlights the importance of refining current relapse prevention protocols that place significant demands for mental time travel into the future. Psychosocial treatments should focus on the attainment of more immediate or short-term goals. It is difficult to delineate the effects of specific substances given long-standing drug use history common to chronic opiate users. Conclusions relating to neurological functioning are speculative given the absence of neuroimaging data.

Nonallergic drug hypersensitivity reactions.

BACKGROUND: Nonallergic drug hypersensitivities, also referred to as pseudoallergic or anaphylactoid reactions, have clinical manifestations that are often indistinguishable from allergic reactions. METHODS: We performed a PubMed search using the terms 'drug allergy, drug hypersensitivity, pseudoallergies, anaphylaxis and nonallergic drug reactions' and reviewed 511 publications dated between 1970 and 2012. A total of 160 papers that were relevant to the most common nonallergic drug hypersensitivity reactions were selected for discussion. RESULTS: Nonallergic drug hypersensitivities do not involve either IgE-mediated (type 1) or delayed (type 4) hypersensitivity. Nonallergic hypersensitivities are commonly referred to as pseudoallergic or idiosyncratic reactions. The common nonallergic drug hypersensitivities are secondary to chemotherapeutic drugs, radiocontrast agents, vancomycin, nonsteroidal anti-inflammatory agents, local anesthetic reactions and opiates. Protocols for skin testing of radiocontrast, nonsteroidal anti-inflammatory agents, local anesthetics and chemotherapeutic agents have been developed, though most have not been validated or standardized. Other diagnostic tests include in vitro-specific IgE tests, and the current 'gold' standard is usually an oral challenge or bronchoprovocation test. In the case of aspirin, even though it is not believed to be IgE-mediated, a 'desensitization' protocol has been developed and utilized successfully, although the mechanism of this desensitization is unclear. CONCLUSIONS: Diagnostic methods exist to distinguish allergic from nonallergic drug hypersensitivity reactions. The best option in nonallergic drug hypersensitivity is avoidance. If that is not possible, premedication protocols have been developed, although the success of premedication varies amongst drugs and patients.