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.

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.

5-HT2A receptor- and M1 muscarinic acetylcholine receptor-mediated activation of Gαq/11 in postmortem dorsolateral prefrontal cortex of opiate addicts.

BACKGROUND: Chronic exposure to opiates causes the development of tolerance and physical dependence as well as persistent brain neuroplasticity. Despite a wealth of postmortem human studies for opiate addicts, little direct information regarding the functional status of serotonergic and cholinergic receptor-mediated signaling pathways in the human brain of opiate addicts is yet available. METHODS: Functional activation of Gαq/11 proteins coupled to 5-HT2A and M1 type muscarinic acetylcholine receptor (mAChR) was assessed by using the method named [35S]GTPγS binding/immunoprecipitation in frontal cortical membrane preparations from postmortem human brains obtained from opiate addicts and matched controls. RESULTS: Concentration-response curves for 5-HT and carbachol in individual subjects were analyzed according to a nonlinear regression model, which generated the values of maximum percent increase (%Emax), negative logarithm of the half-maximal effect (pEC50) and slope factor. As for 5-HT2A receptor-mediated Gαq/11 activation, the %Emax values were reduced significantly and the pEC50 values were decreased significantly in opiate addicts as compared to the control group. Regarding carbachol-induced Gαq/11 activation, no significant difference in %Emax or pEC50 values was detected between the both groups, whereas the slope factor was increased significantly in opiate addicts as compared to the control group. CONCLUSION: Our data demonstrate that the signaling pathways mediated by Gαq/11 proteins coupled with 5-HT2A receptors and M1 mAChRs in prefrontal cortex are functionally altered in opiate addicts in comparison with control subjects. These alterations may underpin some aspects of addictive behavior to opiate as well as neuropsychological consequences or comorbid mental disorders associated with opioid use.

Deprescribing medications that may increase the risk of hepatic encephalopathy: A qualitative study of patients with cirrhosis and their doctors.

BACKGROUND AND AIMS: Multiple medications are associated with an increased risk of incident hepatic encephalopathy. Despite this known risk, medications such as opioids, benzodiazepines, gabapentin/pregabalin, and/or proton pump inhibitors are increasingly prescribed to persons with cirrhosis. Deprescribing is a promising intervention to reduce the burden of hepatic encephalopathy. Given that deprescribing has not been trialed in cirrhosis, we evaluated the barriers and facilitators to safe and successful deprescribing in cirrhosis. METHODS: We conducted, transcribed, and analyzed semi-structured interviews using qualitative methodology with 22 subjects. This included eight patients with cirrhosis and recent use of opiates, benzodiazepines, gabapentin/Lyrica, and/or proton pump inhibitors as well as 14 providers (primary care, transplant surgery, transplant hepatology). Interviews explored opinions, behaviors, and understanding surrounding the risks and benefits of deprescribing. RESULTS: Major provider-specific barriers included deferred responsibility of the deprescribing process, knowledge gaps regarding the risk of hepatic encephalopathy associated with medications (e.g., proton pump inhibitors) as well as the safe method of deprescription (i.e., benzodiazepines), and time constraints. Patient-specific barriers included knowledge gaps regarding the cirrhosis-specific risks of their medications and anxiety about the recurrence of symptoms after medication discontinuation. Patients uniformly reported trust in their provider's opinions on risks and wished for more comprehensive education during or after visits. Providers uniformly reported support for deprescription resources including pharmacist or nurse outreach. CONCLUSION: Given knowledge of medication risks related to hepatic encephalopathy in patients with cirrhosis, deprescribing is universally seen as important. Knowledge gaps, inaction, and uncertainty regarding feasible alternatives prevent meaningful implementation of deprescription. Trials of protocolized pharmacy-based deprescribing outreach and patient-facing education on risks are warranted.

Reduction of Drug-Drug Interaction Risk; CDC Guidelines Influence on Opiate Benzodiazepine Prescribing.

We examined the results of 1.3 million drug tests performed on patients being monitored for compliance with pain medications and substance abuse rehabilitation to determine if the 2016 CDC prescribing guidelines had any impact on opiate benzodiazepine use. We observed that the combination of the opiate drugs morphine, oxycodone, and hydrocodone with the benzodiazepine metabolites oxazepam, alphahydroxyalprazolam, and 7-aminoclonazepam showed many patients were on a combination of these drugs. This ranged from approximately 9 to 16%. There was considerable variability between opiate drug pairs, but there was a general trend to fewer patients on the combination of opiate-benzodiazepine over the 2016 to 2019 time frame.

The association between use of opiates, cocaine, and amphetamines during pregnancy and maternal postpartum readmission in the United States: A retrospective analysis of the Nationwide Readmissions Database.

BACKGROUND: Substance use during pregnancy has increased in the United States, with adverse consequences for mother and baby. Similarly, postpartum readmission (PPR) imposes physical, emotional, and financial stressors causing disruption to family functioning and childcare. We used national data to estimate the extent to which women who used opiates, cocaine, and amphetamines during pregnancy are at increased risk of PPR. METHODS: We analyzed 2010-2014 data from the Nationwide Readmissions Database (NRD). Our exposure, drug use during pregnancy, was identified using diagnosis codes indicative of opioid, cocaine or amphetamine use, abuse, or dependence. The outcome was all-cause PPR, maternal readmission within 42 days following discharge from the delivery hospitalization. Multivariable logistic regression was used to estimate odds ratios (OR) that represented associations between drug use and PPR. RESULTS: Among 11 million delivery hospitalizations, nearly 1 % had documented use of opiates, cocaine and/or amphetamines. The crude PPR rate was nearly four times higher among users (54.6 per 1000) compared to non-users (14.0 per 1000), and 1 in 10 women who had documented use of more than one drug category experienced postpartum readmission. Even after controlling for sociodemographic and clinical confounders, we observed a two-fold increased odds of PPR among users compared to non-users (OR = 1.95; 95 % CI: 1.82, 2.07). CONCLUSIONS: The national opioid epidemic should encourage a paradigm shift in health care public policy to facilitate the management of all substance use disorders as chronic medical conditions through evidence-based public health initiatives to prevent these disorders, treat them, and promote recovery.

"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.

Acute stressors and clinical characteristics differentiate death by suicide, accident, or natural causes among illicit and prescription opiate users.

BACKGROUND: Opiate misuse has reached epidemic levels. Prevention efforts depend on distinguishing opiate users from abusers. The current study compared opioid users who died by natural cases, accidents, and suicide using psychological autopsy methods. Groups were compared on substance use characteristics, treatment history, experiences of negative life events, and circumstances at the time of death. METHODS: Substance use and suicide risk were evaluated using psychological autopsy methods in 63 decedents with positive toxicology for opiates at death divided into three groups: adults dying by suicide (n = 19), accident (n = 19), and natural causes (n = 25). Groups were compared on several dependent measures, using chi-square analyses to examine categorical variables and one-way analyses of variance (ANOVA) to examine continuous variables. RESULTS: Individuals who died by suicide were similar in many ways to adults who died by an accidental overdose. However, suicide completers were more likely to have struggled with severe depression, and previously attempted suicide, whereas the accidental overdose sample was more likely to display a chronic pattern of severe drug abuse. CONCLUSIONS: The current study helps to distinguish between opiate users who are at risk for death by an accidental or intentional overdose. In the ongoing opiate crisis, clinicians must understand the risk of overdose and the nuances of accidental behaviors compared to purposeful ones. Signs of suicidal planning, relevant psychopathology, and ongoing life stress may be useful points of intervention for stopping the increasing number of deaths among opiate users.

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.

Uso racional de opioides en el medio hospitalario / Rational use of opioids in hospitals

No disponible

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.

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.

[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.

Approaches to managing older people using opiates and their risk of dependence.

There is little doubt that opiates have transformed healthcare, particularly in relation to pain management. However, many patients prescribed this type of drug develop problems such as dependency. Although we do not know how many older people have developed such problems due to opiate use we know that some will. It is important for nurses to understand the context in which opiates are used, as well as the specific needs of older people and how to respond to them.

Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 6: Pharmacodynamic Considerations.

This column is the sixth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. This sixth column in the series discusses some key issues related to pharmacodynamic interactions involving commonly used psychiatric medications. The column first discusses 3 types of pharmacological agents that deserve special mention because of the widespread types of pharmacodynamic DDIs they can have with psychiatric and other medications: ethanol, opioids, and monoamine oxidase inhibitors, with a special focus on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors. The column also discusses DDIs in terms of effects on the cardiovascular system, including QTc prolongation, blood pressure and heart rate regulation, increased risk of bleeding and abnormal bleeding, and valvular heart disease, and on the central nervous system, including increased sedation, respiratory depression, body temperature regulation, and tardive dyskinesia. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use more than 1 drug in combination to optimally treat a patient.

Opiate Use and Escalation of Care in Hospitalized Adults with Acute Heart Failure and Sleep-disordered Breathing (OpiatesHF Study).

Rationale: Sleep-disordered breathing (SDB) is highly prevalent in adults hospitalized with acute heart failure. Data are limited on the implications of inadvertent opiate use in this population.Objectives: To determine the prevalence and impact of in-hospital opiate use in adults hospitalized for acute heart failure.Methods: From a prospective sleep registry, we selected a sequential group of adult participants who were admitted to the hospital for acute heart failure and received a portable sleep study (PSS) after screening for SDB using the STOP-BANG questionnaire. A retrospective review of charts was performed to assess use of opiates, need for escalation of care (defined as transfer to the intensive care unit [ICU]), 30-day readmission, and length of stay. A logistic regression model was used to calculate propensity scores for each participant with a screening apnea-hypopnea index (AHI) greater than or equal to 10/h. Study endpoints, including escalation of care to the ICU and 30-day hospital readmission, were compared using a χ2 test with stabilized inverse probability-weighted propensity scores to control for potential confounding variables.Results: A total of 301 consecutive adults admitted with acute heart failure between November 2016 and October 2017 underwent PSS after SDB screening. Overall, 125 of 301 (41.5%) received opiates in the hospital, and 149 (49.5%) patients had an AHI greater than or equal to 10/h by PSS (high risk of SDB). In this high-risk group, 47 of 149 (32%) received opiates. Among those with an AHI greater than or equal to 10/h, escalation of care occurred in 12 of 47 (26%) of those who received opiates versus 4 of 102 (4%) of those who did not (P < 0.001; weighted estimate of treatment difference, 23.5%; 95% confidence interval [CI], 9.9 to 37.2). Similarly, readmission within 30 days occurred in 7 of 47 (15%) of those who received opiates versus 9 of 102 (9%) of those who did not (P = 0.14; weighted estimate of treatment difference, 8.3%; 95% CI, -4.0 to 20.6). Mean length of stay (days) did not differ between groups (P = 0.61; weighted estimate of treatment difference, -0.3 d; 95% CI, -1.4 to 0.8).Conclusions: In adults admitted with acute heart failure and found to be at high risk of SDB, opiate use in the hospital was highly prevalent and was associated with a greater likelihood of escalation of care.

Assessment of Changes in the Geographical Distribution of Opioid-Related Mortality Across the United States by Opioid Type, 1999-2016.

Importance: As the opioid epidemic evolves, it is vital to identify changes in the geographical distribution of opioid-related deaths, and the specific opioids to which those deaths are attributed, to ensure that federal and state public health interventions remain appropriately targeted. Objective: To identify changes in the geographical distribution of opioid-related mortality across the United States by opioid type. Design, Setting, and Participants: Cross-sectional study using joinpoint modeling and life table analysis of individual-level data from the National Center for Health Statistics on 351 630 US residents who died from opioid-related causes from January 1, 1999, to December 31, 2016, for all of the United States and the District of Columbia. The analysis was conducted from September 6 to November 23, 2018. Exposures: Deaths involving any opioid, heroin, synthetic opioids, and natural and semisynthetic opioids. Main Outcomes and Measures: Opioid-related mortality rate, annual percent change in the opioid-related mortality rate, and life expectancy lost at age 15 years by state and opioid type. Results: From 1999 to 2016, a total of 231 264 men and 120 366 women died from opioid-related causes across the whole United States. Sixty-six observations were removed owing to missing data on age; therefore, 351 564 US residents were included in this study. The mean (SD) age at death was 39.8 (12.5) years for men and was 43.5 (12.9) years from women. Opioid-related mortality rates, especially from synthetic opioids, rapidly increased in all of the eastern United States. In most states, mortality associated with natural and semisynthetic opioids (ie, prescription painkillers) remained stable. In contrast, 28 states had mortality rates from synthetic opioids that more than doubled every 2 years (ie, annual percent change, ≥41%), including 12 with high mortality rates from synthetic opioids (>10 per 100 000 people). Among these 28 states, the mortality rate from natural and semisynthetic opioids ranged from 2.0 to 18.7 per 100 000 people (with a mean mortality rate of 6.0 per 100 000 people). The District of Columbia had the fastest rate of increase in mortality from opioids, more than tripling every year since 2013 (annual percent change, 228.3%; 95% CI, 169.7%-299.6%; P < .001), and a high mortality rate from synthetic opioids in 2016 (18.8 per 100 000 people); the mortality rate from natural and semisynthetic opioids was 6.9 per 100 000 people. Nationally, overall opioid-related mortality resulted in 0.36 years of life expectancy lost in 2016, which was 14% higher than deaths due to firearms and 18% higher than deaths due to motor vehicle crashes; 0.17 years of the life expectancy lost was due specifically to synthetic opioids. In 2016, New Hampshire and West Virginia lost more than 1 year of life expectancy due to opioid-related mortality. Conclusions and Relevance: Opioid-related mortality, particularly mortality associated with synthetic opioids, has increased in the eastern United States. These findings indicate that policies focused on reducing opioid-related deaths may need to prioritize synthetic opioids and rapidly expanding epidemics in northeastern states and consider the potential for synthetic opioid epidemics outside of the heroin supply.