Concomitant Use Of Benzodiazepines Research Articles

Drugs that can cause respiratory depression with concomitant use of opioids

Abstract Aims Respiratory depression is a serious life threatening condition and a known adverse event of opioids. Little is known about the use of the opioid antidote naloxon in Iceland, and the additive effects of other potentially respiratory depressive drugs administered with opioids. The aim of the study was to review the literature on drugs that may cause respiratory depression and to assess medication use in patients receiving parenteral naloxone in Landspítali University Hospital. Methods A review and analysis of drugs that can cause respiratory depression based on information from the scientific literature, medicine databases and clinical guidelines. A retrospective study was performed using data collected from the electronic medical records system of Landspítali University Hospital for all patients, 18 years and older that had parenteral naloxon administered in the years 2010–2014. Information about the type of opioid and other respiratory depressive drugs was collected and the data was further investigated in regards to age, gender, and type of service. Results The most potential drugs and drug classes that can cause respiratory depression when used concomitantly with opioids are benzodiazepines and other anxiolytics, hypnotics and sedatives, antipsychotics, antiepileptics, antihistamins and anesthetics. When use was examined (N=138) morphine was the most frequent opioid given (49%). Concomitant use of opioids and other respiratory depressive drugs was seen in 63% of cases, and benzodiazepines were the most frequent drugs given with opioids (33%). Conclusions The concomitant use of benzodiazepines and other sedative drugs with opioids is frequent, despite the known risk of additive respiratory depression as described in the literature. Other patient risk factors such as medical condition, general health and consciousness should be considered in context with drugs used.

Opioids and Other Central Nervous System-Active Polypharmacy in Older Adults in the United States.

To determine patterns of and trends in contributions to central nervous system (CNS) polypharmacy, defined by the Beers Criteria as three or more CNS-active medications of each medication class, of adults aged 65 and older seen in U.S. outpatient medical practices. National Ambulatory Medical Care Survey (2004-2013). U.S. outpatient medical care. Visits by older adults to outpatient physicians (N = 97,910). Visits including three or more CNS medications including antipsychotics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics (NBRAs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and opioids. The proportion of CNS polypharmacy that each medication class contributed during 2011 to 2013 was determined, and then logistic regression was used to determine trends from 2004 to 2013 in the contribution of individual medication classes to such polypharmacy. Of recent CNS polypharmacy visits, 76.2% included an opioid, and 61.8% included a benzodiazepine; 66.0% of the polypharmacy visits with benzodiazepines included opioids, and 53.3% of the polypharmacy visits with opioids included benzodiazepines. Between 2011 and 2013, opioid and benzodiazepine co-prescribing occurred at approximately 1.50 million visits (95% confidence interval (CI) = 1.23-1.78 million) annually. From 2004 (reference) to 2013, the proportion of polypharmacy visits with opioids rose from 69.6% to 76.2% (adjusted odds ratio = 2.15, 95% CI = 1.19-3.91, P = .01), and the corresponding proportion that included benzodiazepines fell. Of the polypharmacy visits, the odds of SSRI, NBRA, and antipsychotic use were unchanged, and that of TCAs decreased. In older adults, opioid use appears to be largely driving the recent national increase in CNS polypharmacy. Although concomitant use of opioids and benzodiazepines is associated with greater mortality, they are the most common contributors to CNS polypharmacy in older adults.

Zopiclone Use and Risk of Fractures in Older People: Population-Based Study

ObjectivesThe primary objective was to evaluate the risk of fractures associated with use of zopiclone, a new Z-hypnotic, in a population-based cohort of older people in New Zealand (NZ) in a real-world setting. The secondary objective was to examine a nonlinear relationship with age and risk for fractures in zopiclone users. DesignPopulation-based cohort study with a case-crossover design. SettingA nationwide representative sample of New Zealanders aged 65 years and older sourced from the pharmaceutical collections and hospital discharges. Participants74,787 older individuals with a first-time fracture between January 1, 2005, and December 31, 2015, were analyzed using a case-crossover design for fracture risk with zopiclone use. MeasurementsPrescription records (2005–2014) of zopiclone were sourced from NZ Pharmaceutical Collections (Pharms). The first-time coded diagnosis of fracture was extracted from the National Minimal Datasets. Datasets were linked by a unique patient identifier to set up case-crossover designs. Relative risks (RRs) of fracture associated with zopiclone was calculated using conditional logistic regression. A varying-coefficient conditional logistic model was employed to examine the influence of age as a risk factor for fractures. ResultsThe risk of fracture associated with zopiclone is higher [RR = 1.45, 95% confidence interval (CI) = 1.37–1.55], compared to non-use. The increased risk of fracture associated with zopiclone [adjusted relative risk (ARR) = 1.36, 95% CI = 1.28–1.45] remained significant after adjusting for concomitant use of alpha blockers, antipsychotics, beta blockers, benzodiazepines, and tricyclic antidepressants. The varying coefficient model showed that the risk of fracture increases significantly and monotonically with age. ConclusionThe results support that the magnitude of the risk of fracture is higher with use of zopiclone compared to non-use. Prescribers must be aware that the relationship between age and fracture risk is nonlinear, and the oldest old are highly vulnerable to fractures with zopiclone use.

Development of a targeted naloxone coprescribing program in a primary care practice

ObjectivesTo develop a targeted naloxone coprescribing program in a primary care practice. SettingLarge academic family medicine practice in western North Carolina. Practice descriptionA robust pain management program was developed at this institution in 2012 which incorporated many of the recommendations later outlined in the 2016 Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain. The only guideline-recommended initiative that was not addressed involves providing naloxone to patients on chronic opioid therapy at high risk for opioid overdose. Practice innovationPharmacists embedded in this practice developed a targeted naloxone coprescribing program for patients who are on chronic opioid therapy and have doses of 50 mg or more morphine equivalents daily (MED), are taking benzodiazepines, have a history of substance use disorder, or have a history of overdose. EvaluationA retrospective chart review was conducted to determine the number of patients on chronic opioid therapy who meet the CDC guidelines for offering naloxone. ResultsA total of 1297 patients were identified, and 709 met the criteria for chronic opioid use. Nearly one-half (n = 350; 49.4%) of these patients met the criteria for naloxone, although only 3.4% had naloxone on their medication list. Doses of 50 mg or more MED was the primary reason for needing naloxone (n = 216; 61%) with concomitant benzodiazepine use as the second most likely reason (n = 130; 37.1%). For patients taking 50 mg or more MED, 37.5% were also on a benzodiazepine and 4.1% also had a history of substance use disorder. ConclusionPharmacists embedded in a primary care practice are well poised to develop a targeted naloxone coprescribing program to increase patients’ access to naloxone.

Rapid widespread distribution of intranasal naloxone for overdose prevention

BackgroundTake home naloxone programs have been successful internationally in training bystanders to reverse an opioid overdose with naloxone, an opioid antagonist. A multi-site naloxone distribution program began in Norway in 2014 as part of a national overdose prevention strategy. The aim of this study was to a) describe the program, and b) present findings from the government-supported intervention. MethodsFrom July 2014 to December 2015, staff from multiple low-threshold facilities trained clients on how to use intranasal naloxone. Distribution occurred without an individual prescription or physician present. Questionnaires from initial and refill trainings were obtained, and distribution rates were monitored. ResultsThere were 2056 naloxone sprays distributed from one of the 20 participating facilities, with 277 reports of successful reversals. Participants exhibited known risks for overdosing, with injecting (p=0.02, OR=2.4, 95% CI=1.14, 5.00) and concomitant benzodiazepine use (p=0.01, OR=2.6, 95% CI=1.31, 5.23) being significant predictors for having had high rates of previous overdoses. Suggested target coverage for large-scale programs was met, with an annual naloxone distribution rate of 144 per 100,000 population, as well as 12 times the cities mean annual number of opioid-related deaths. ConclusionA government-supported multisite naloxone initiative appears to achieve rapid, high volume distribution of naloxone to an at-risk population.

Ethanol Infusion for Alcohol Withdrawal Prophylaxis Does Not Cause Intoxication

Objective: Alcohol Withdrawal Syndrome (AWS) remains a common problem, especially in trauma and surgical patients. An intravenous ethanol infusion protocol was developed at this institution and previously validated for AWS prophylaxis. One concern with intravenous ethanol has been potential for intoxication and/or side effects. This study was performed on patients receiving AWS prophylaxis with an intravenous ethanol protocol to evaluate for intoxication and the occurrence of any adverse effects. Methods: We did a retrospective review of all patients in our hospital who received AWS prophylaxis by ethanol infusion between 2008 and 2013. Information collected specific to ethanol infusion included rate of administration, serum ethanol levels, serum sodium level, use of benzodiazepines and anti-emetics, and development of AWS. Intoxication was defined using the Texas limit for blood alcohol content in a driver of .08% (80mg/dL). The study period began at admission and lasted 7 days. Results: Ninety-seven patient charts were reviewed. Average serum ethanol level on admission was 137 mg/dL. Serum ethanol levels increased in 12% of patients after administration of ethanol infusion, and levels generally decreased over time. Asymptomatic hyponatremia (serum sodium <135) occurred in 60% of patients. Benzodiazepines were administered to 52 patients (54%); of these, only 15 received increases in infusion rates indicating appropriate protocol use. In addition, 32 of the 52 had the ethanol infusion discontinued prior to scheduled protocol wean. Conclusion: Ethanol infusion for alcohol withdrawal prophylaxis in the hospitalized patient rarely induces alcohol intoxication. However, a majority of patients experience asymptomatic hyponatremia. The high rate of concomitant benzodiazepine use suggests possible low efficacy of the infusion, although low adherence to the protocol could be a contributing factor.

The Pharmacology and Toxicology of the ‘Holy Trinity’

Combining opioids with benzodiazepines and skeletal muscle relaxants ('The Holy Trinity') has been reported to potentiate the 'high'. Through unique interactions with colocalized μ-opioid and GABAA receptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by μ1 -opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAA R to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAA R to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.

Potential drug–drug interaction in Mexican patients with schizophrenia

Objective: The aim of this study was to observe potential drug–drug interactions in the medication of Mexican schizophrenic patients.Methods: We performed a retrospective and cross-sectional study that was carried out in a psychiatric clinic. Only the prescriptions of patients with schizophrenia whose diagnoses were based on the DSM-IV instrument were included in this study. The Drug Interactions Checker software (http://www.drugs.com/drug_interactions.html) was used in this study to analyse potential drug–drug interactions.Results: In total, 86 of 126 patients were at risk of potential drug–drug interactions. Haloperidol and biperiden was the most common drug pair of 232 pairs evaluated. In our study, 13.8% of drug–drug interaction showed a major level of severity, whereas in 83.2%, the interaction was moderate. Finally, central nervous system (CNS) depression and anticholinergic effect were the main possible effects of drug–drug interaction.Conclusions: Our results revealed a high number of patients with schizophrenia receiving two or more drugs. The potential drug–drug interactions observed in the Mexican population are consistent with the concomitant use of antipsychotics, benzodiazepines, and antidepressants prescribed in schizophrenia that could cause central nervous system (CNS) depression and anticholinergic effect. Drug–drug interaction must be considered when the patient with schizophrenia is medicated.

The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month

The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure). Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity. Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.

Concomitant use of benzodiazepine and alcohol in methadone‐maintained patients from the ANRS–Methaville trial: Preventing the risk of opioid overdose in patients who failed with buprenorphine

AbstractIntroduction and AimsConcomitant elevated alcohol consumption and use of benzodiazepines (BZD) during methadone treatment is widespread and particularly worrying because of the increased risk of overdose. Using concomitant binge drinking and use of BZD as a proxy of overdose risk, we aimed to study whether buprenorphine switchers were at higher risk of overdose during methadone treatment.Design and MethodsThe French National Agency for Research for Aids and Viral Hepatitis –Methaville multisite randomised trial enrolled 195 patients to assess the feasibility of initiating methadone in primary care by comparing it with methadone initiation in specialised centres. We selected 174 patients with available data on BZD use and alcohol binge drinking at baseline and 12 months, accounting for 318 visits. The outcome was defined to take into account an overdose risk gradient as follows: no BZD use, BZD use without and with binge drinking during the previous month. To identify factors associated with the outcome, we performed a mixed multinomial logistic regression analysis.ResultsAt baseline, 26% of the sample reported BZD use alone while 16% reported BZD use and binge drinking. Half of the sample (51%) was switching from buprenorphine treatment. After multivariate analysis, employment, depressive symptoms and switching treatment from buprenorphine to methadone [odds ratio (95% confidence interval) 5.38 (1.74–16.62)] remained associated with BZD use and binge drinking.Discussion and ConclusionsAs well as the importance of identifying socially vulnerable and depressed methadone‐maintained patients, clinicians should be aware that patients who fail buprenorphine treatment and switch to methadone require greater clinical monitoring and management to avoid the risk of overdose. [Roux P, Lions C, Michel L, Mora M, Maradan G, Marcellin F, Spire B, Alain M, Patrizia CM, the ANRS Methaville Study Group. Concomitant use of benzodiazepine and alcohol in methadone‐maintained patients from the ANRS Methaville trials: Preventing the risk of opioid overdose in patients who failed with buprenorphine. Drug Alcohol Rev 2015; ●●:●●–●●]

The duration and course of opioid therapy in patients with chronic non-malignant pain.

Prescription databases provide the opportunity for investigating opioid treatment and co-medication within large populations. So far, few studies have investigated the duration of opioid therapy, and large differences in discontinuation rates have been reported. Data from the Norwegian Prescription Database were used to follow the study population of all adult persistent opioid users with non-malignant pain in Norway in 2005 (n = 44,867) for 6 years. Persistent opioid use was defined as being dispensed ≥ 180 defined daily doses (DDD) or 4500 mg oral morphine equivalents (OMEQ) during a 365-day period. The study population was stratified according to previous opioid use into new persistent opioid users, without previous persistent opioid use, and previous low-dose or previous high-dose persistent opioid users, having earlier persistent opioid use and received less or more than 120 mg OMEQ/day in 2005, respectively. Twenty-seven percent of new, 59% of previous low-dose, and 55% of previous high-dose users met the criteria of persistent use of opioids each year. Exactly, 22%, 11%, and 3% increased their cumulative yearly opioid dose by 200% or more during the study period. With 80% still being regular users of either drugs, 6 years later, long-term persistent opioid users were more likely to continue concomitant use of benzodiazepines or z-hypnotics than other users, The findings confirm high discontinuation rates in patients receiving opioids for chronic non-malignant pain. However, a clinically significant number of patients increase their doses over 6 years and many patients combine long-term opioid treatment with benzodiazepines and z-hypnotics.

Former Heroin-Dependent Alcohol Use Disorder Patients. Prevalence, Addiction History and Clinical Features.

To examine the prevalence of former heroin dependence (FHA) in Alcohol Use Disorder (AUD) patients; to compare the clinical characteristics of FHA-AUD patients versus AUD patients without any past use of heroin at alcohol treatment entry; to document the heroin dependence history of FHA-AUD patients, and review treatment strategies for this group. Retrospective case review of 448 consecutive AUD patients. The annual entry of FHA-AUD showed stability over the study period of 3 years overall 60/448 (13.3%). FHA-AUD patients showed higher concomitant use of cocaine, benzodiazepines, cannabis and hallucinogens than other heroin addicts. They consumed higher amounts of alcohol at the beginning of their alcohol dependence history, and reached a high maximum level of alcohol consumption, than other AUD patients, and tended to have more physical disorders. The most important signals of FHA-AUD were polyabuse and older age at the time of presentation. FHA-AUD patients tended to have had a severe pattern of heroin dependence associated with inadequate agonist opiate treatment. The prevalence of FHA-AUD patients is not negligible. This may relate to previous inadequate treatment of heroin addiction contributing to the development of severe AUD. For these patients we propose a reconsideration of 'soft' (low dose) agonist opiate treatment.

386 Use of Quetiapine in the Emergency Department for Acute Agitation and Associated Physiologic Effects

Agitation is commonly encountered in the emergency department (ED) and antipsychotics are frequently used for treatment. Quetiapine is a second generation antipsychotic (SGA) indicated for treatment of schizophrenia and bipolar mania. It is rarely used for acute agitation because of its blockade of alpha-receptors, which can lead to a drop in blood pressure (BP). Decreases in systolic BP, which have been previously reported prospectively in a pilot study of ED patients, are thought to be unrelated to dose. However, it is unknown if other factors such as alcohol or concomitant benzodiazepine use contribute to these observed decreases in BP. This study measured the association of dose, alcohol use, benzodiazepine use, and age on decreases in systolic BP in patients receiving quetiapine in the ED. This is a multicenter structured review of an historical cohort of patient visits over 7 years. Visits were included if quetiapine was administered and vital signs were obtained both before and within 4 hours after administration. Age, dose of quetiapine, use of benzodiazepines, and presence of alcohol (as measured by Breathalyzer) were utilized as predictor variables, with benzodiazepines/alcohol dummy-coded for inclusion into a multivariate linear regression model. Decreases in systolic BP were utilized as the dependent variable, and were measured within a particular patient so as to prevent any pre-dose differences among groups from skewing the results. During the study period quetiapine was administered on 117 patient visits to 109 unique patients at an average dose of 200 mg (72% male, average age 44, range 19-86). Alcohol intoxication was present in 17.1% of patients (average BAL 120 mg/dl). Benzodiazepines were used adjunctively in 12.8% of quetiapine patients with an average dose of 2.8 mg in lorazepam equivalents. Seventy-two patient visits met all inclusion criteria for further analysis. The average decrease in systolic blood pressure was 12.5 mm Hg, but the decrease was not related to age, dose, alcohol use, or benzodiazepine use (all P>.10). Four patients became hypotensive defined as SBP ≤ 95 mm Hg, with one of these patients being 77 years (the others were 40, 45 & 46) with doses of 100 mg, 600 mg, 100 mg and 600 mg, respectively. In these four patients, none were taking alcohol and only one (age 46) received adjunctive benzodiazepines. The drop in SBP was from 110 to 90 mm Hg in the 77-year-old, 118 to 80, 111 to 91, and 137 to 95 in the other three subjects. The rest of the subjects had relative drops in SBP, but not to the level what we defined as hypotensive. Fifteen (20.8%) patients had alcohol use and 0% became hypotensive. Eleven (15.3%) patients received adjunctive benzodiazepines and 9.1% (n=1) became hypotensive. None of the patients studied had an O2 sat drop below 92% after medication administration. Quetiapine is infrequently used in the ED for agitation. Most patients in the ED setting will have at least some decrease in blood pressure after administration of quetiapine, but it remains difficult to predict which patients will become hypotensive. Decreases in blood pressure appear to not be related to dose, alcohol use or adjunctive benzodiazepine use. Additional research is warranted to determine other contributing factors.

A mixed MDPV and benzodiazepine intoxication in a chronic drug abuser: Determination of MDPV metabolites by LC–HRMS and discussion of the case

We report on a case of repeated MDPV consumptions that resulted in severe psychosis and agitation prompting the concomitant abuse of benzodiazepines. A 27-year-old man was found irresponsive in his apartment and was brought to the emergency department (ED) of a local hospital. When in ED, he rapidly recovered and self-reported to have recently injected some doses of MDPV that he had bought in the Internet. He left the hospital without medical cares. 15 days after, he was again admitted to the same ED due to severe agitation, delirium and hallucinations, and reported the use of MDPV and pharmaceutical drugs during the preceding week. He was sedated with diazepam and chlorpromazine.Urine samples collected in both occasions were sent for testing using liquid chromatography–high resolution mass spectrometry (LC–HRMS) and liquid chromatography–high resolution multiple mass spectrometry (LC–HRMS/MS) on an Orbitrap. The LC–HRMS analysis revealed the presence of MDPV and its phase I and phase II metabolites (demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-methyl-oxo-MDPV, demethylenyl-hydroxy-alkyl-MDPV, demethylenyl-methyl-hydroxy alkyl-MDPV, demethylenyl-oxo-MDPV and their corresponding glucuronides), alprazolam and alprazolam metabolite at the first ED admission; at the time of the second ED access, the same MDPV metabolites, alprazolam, temazepam, and chlordiazepoxide were detected together with diazepam and metabolites. LC–HRMS/MS was use to determine the following concentrations, respectively on his first and second admission: MDPV 55ng/mL, alprazolam 114ng/mL, α-hydroxyalprazolam 104ng/mL; MDPV 35ng/mL, alprazolam 10.4ng/mL, α -hydroxyalprazolam 13ng/mL; chlordiazepoxide 13ng/mL, temazepam 170ng/mL, diazepam 1.3ng/mL, nordiazepam 61.5, oxazepam 115ng/mL.The toxicological findings corroborated the referred concomitant use of multiple pharmaceutical drugs and benzodiazepines. Confirmation of previous hypothesis on human metabolism of MDPV could be inferred by the analysis of urine.

Methadone Overdose and Cardiac Arrhythmia Potential: Findings From a Review of the Evidence for an American Pain Society and College on Problems of Drug Dependence Clinical Practice Guideline

The number of deaths associated with methadone use increased dramatically in parallel with marked increases in its use, particularly for treatment of chronic pain. To develop a clinical guideline on methadone prescribing to reduce potential harms, the American Pain Society commissioned a review of various aspects related to methadone safety. This article summarizes evidence related to unintentional overdose due to methadone and harms related to cardiac arrhythmia potential. We searched Ovid MEDLINE, the Cochrane Library, and PsycINFO databases through January 2014 for studies assessing harms associated with methadone use; we judged 70 studies to be relevant and to meet inclusion criteria. The majority of studies on overdose and cardiac arrhythmia risk are observational and provide weak evidence on which to base clinical guidelines. In patients prescribed methadone for treatment of opioid dependence, data suggest that mortality benefits related to reduction in illicit drug use outweigh harms. Despite epidemiologic data showing marked increases in the numbers of methadone-related deaths that have been primarily attributed to increased use of methadone for chronic pain, evidence on methadone and mortality risk in this population has been somewhat contradictory. There is some evidence that recent initiation of methadone, psychiatric admissions, and concomitant use of benzodiazepines are associated with a higher risk for overdose. Evidence on cardiac risks is primarily limited to case reports of torsades de pointes, primarily in patients on high doses of methadone, and to studies showing an association between methadone use and prolongation of QTc intervals. Research is needed to understand the effectiveness of dosing methods, electrocardiogram monitoring, and other risk mitigation strategies in patients prescribed methadone. PerspectiveThis systematic review synthesizes the evidence related to methadone use and risk for overdose and cardiac arrhythmia. Findings regarding the association between methadone use and QTc interval prolongation and risk factors for methadone-associated overdose suggest potential targets for risk mitigation strategies, though research is needed to determine the effectiveness of such strategies at reducing adverse outcomes.

Despite Expert Recommendations, Second-generation Antipsychotics Are Not Often Prescribed in the Emergency Department

BackgroundRecent expert guidelines recommend oral second-generation antipsychotics (SGAs) as first-line therapy for acute agitation in the emergency department (ED), with intramuscular (IM) SGAs as an alternative. However, little is known about how these meds are used in the ED or how often SGAs are prescribed. Objectives1) The measurement of patient characteristics, concomitant benzodiazepine use, and use of SGAs compared to haloperidol or droperidol; 2) the prescribing rates of SGAs over time in ED patients. MethodsThis is a structured analysis of a historical patient cohort from 2004–2011 in two university EDs. The cohort consisted of all patients receiving aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone. Descriptive analysis compared age, gender, use of first-generation antipsychotics (FGAs) such as haloperidol/droperidol, and rates of concomitant benzodiazepine use. Linear regression was used to test whether SGA prescribing increased over time. ResultsThere were 1680 unique patients accounting for 1779 ED visits who received SGAs over the study period, which is a minority of patients receiving any antipsychotic. Of patients receiving any SGA in the ED, most were given orally (93%). Adjunctive benzodiazepines were administered on 21% of visits, and were also administered on 21% of the visits involving alcohol + patients. The rate of SGA use in the ED is not increasing over time. ConclusionDespite expert recommendations, SGAs are administered a minority of the time to ED patients. The rate is not increasing over time. When used, SGAs are most commonly given orally, are often administered with benzodiazepines, and are frequently administered to alcohol-intoxicated patients.

Comparison of toxicity associated with nonmedical use of benzodiazepines with buprenorphine or methadone

BackgroundPolysubstance use is prevalent in individuals using buprenorphine or methadone nonmedically, with benzodiazepines being a common co-ingestant. The objective of this study was to compare the severity of buprenorphine and methadone toxicity with concomitant use of benzodiazepines. MethodsA retrospective analysis of buprenorphine and methadone cases from November 1, 2002 to December 31, 2010 reported to the American Association of Poison Control Centers’ National Poison Data System (NPDS) was conducted. Inclusion criteria: age ≥18 years, nonmedical use of methadone with benzodiazepines (methadone-BZD) or buprenorphine with benzodiazepines (BUP–BZD), and case followed to a documented outcome. Cases with co-ingestants other than benzodiazepines were excluded. Clinical effects, treatments, disposition and final medical outcomes were evaluated. ResultsThere were 692 methadone-BZD cases and 72 BUP-BZD cases. Clinical effects in methadone-BZD and BUP–BZD groups were lethargy (71.1%, 59.7%), respiratory depression (29.0%, 15.3%), coma (22.4%, 5.6%), respiratory arrest (4.5%, 0), hypotension (11.8%, 2.8%) and cardiac arrest (1.9%, 0), respectively. Patients in the methadone-BZD group were four-times more likely to receive naloxone (60.4% vs 15.3%) or be intubated (16.3% vs 4.2%) than in the BUP–BZD group. Hospitalization rates were highest for methadone-BZD patients with 67.3% receiving medical admissions compared to 43.3% of BUP–BZD patients. Outcomes were more serious for methadone-BZD cases (p<0.0001); while there were no BUP–BZD deaths, exposure to methadone-BZD yielded 16 deaths. ConclusionsNonmedical use of benzodiazepines with methadone is associated with higher hospitalization rates, greater ICU utilization rates and considerably worse medical outcomes when compared to nonmedical use of benzodiazepines with buprenorphine.

Methadone‐Related Deaths – Epidemiological, Pathohistological, and Toxicological Traits in 10‐year Retrospective Study in Vojvodina, Serbia

The number of methadone-related deaths (MRDs) during a 10-year period (2002-2011) in the region of Vojvodina, Serbia, was increased. The cases were evaluated according to epidemiological parameters, pathohistological findings, and toxicological screening. The majority of victims were men, aged from 20 to 38. Pathohistologically, the signs of acute focal myocardial damage were present in the heart of victims with drug abuse history shorter than 2years, while both signs of recent and chronic focal myocardial damage were developed among victims with longer drug abuse history (2-5years). In postmortem blood samples of 54.84% of victims, methadone was detected in combination with diazepam, both in therapeutic range. Alcohol was absent in most cases. Other detected drugs were antipsychotics and antidepressants in therapeutic concentrations. These findings raise the attention to the concomitant use of methadone and benzodiazepines with the need for further studies to clarify the mechanism of death in such cases.

Treatment of acute schizophrenia with paliperidone ER: Predictors for treatment response and benzodiazepine use

The Paliperidone ER Treatment in Acute Intervention (PERTAIN) study was designed to explore treatment response, tolerability, and safety of flexible doses of paliperidone ER in patients with schizophrenia admitted for an acute exacerbation. This paper addresses a secondary analysis of PERTAIN data designed to explore predictors for treatment response, flexible dosing, and concomitant benzodiazepine use. This prospective, multicenter, phase 3b, open-label, single-arm, 6-week study used flexible doses of paliperidone ER (3 to 12mg once daily) to treat patients hospitalized for an acute exacerbation of schizophrenia, reflecting more closely daily clinical practice. Predictive models were evaluated for paliperidone ER flexible dosing, treatment response, and concomitant treatment with benzodiazepines as distinct independent variables. For the analysis of explanatory variables, a stepwise logistic regression was used, taking into account patient age, gender, body mass index, diagnosis and duration of schizophrenia, number of prior hospitalizations, psychotic symptoms (PANSS), disease severity (CGI-S), and patient functioning (PSP) at baseline. Early response (defined as response within 2weeks of treatment initiation) was also used as a predictor. Clinical response (defined as ≥30% decrease in PANSS total score and ≥1 point decrease in CGI-S from baseline to endpoint) was predicted by early clinical response (p<0.001) and there was a trend for the diagnosis of paranoid schizophrenia vs. other types of schizophrenia to predict clinical response (p=0.0525). High response (defined as ≥50% decrease in PANSS total score and ≥2 points decrease in CGI-S from baseline to endpoint) was predicted by early high response, higher baseline CGI-S, or female gender. More severely ill patients with a higher baseline CGI-S were twice likely to be treated concomitantly with a benzodiazepine.

Impact of concomitant use of opioids and benzodiazepines in opioid‐dependent pregnant women on the outcome of their newborns

OBJECTIVEThe study objective was to compare neonatal outcome parameters of children born to opioid‐dependent women in opioid maintenance therapy with differing concomitant consumption patterns during the last trimester of pregnancy.METHODSAn observational design and t‐tests were applied to analyze the outcome of 106 neonates born to opioid‐maintained, smoking mothers with (n=27) versus without (n=79) concomitant consumption of opiates and benzodiazepines.RESULTSNewborns of mothers with concomitant opiate and benzodiazepine consumption had significantly higher average withdrawal scores (8.27 vs. 6.15, p=0.007) and significantly longer postnatal hospital stays (26.5 vs. 18.6 days, p=0.011) compared to those of mothers without problematic concomitant consumption. A subgroup analysis confirmed the results for the 62 newborns whose mothers were maintained on methadone throughout pregnancy, but these differences could not be shown in the 44 children of buprenorphine‐maintained mothers.CONCLUSIONSThese findings suggest that the opioid maintenance medication might have a stronger influence on neonatal outcome parameters than concomitant consumption of other substances during the last trimester.