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Critical Care (London, England) Nov 2017Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric... (Review)
Review
BACKGROUND
Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions.
METHODS
A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting.
RESULTS
Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis.
CONCLUSIONS
Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.
Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Consciousness Disorders; Drug-Related Side Effects and Adverse Reactions; Humans; Neurotoxicity Syndromes; Seizures
PubMed: 29137682
DOI: 10.1186/s13054-017-1856-1 -
American Journal of Preventive Medicine Nov 2021Supervised injection facilities are harm reduction interventions that allow people who inject drugs to use previously obtained substances under the supervision of health... (Review)
Review
CONTEXT
Supervised injection facilities are harm reduction interventions that allow people who inject drugs to use previously obtained substances under the supervision of health professionals. Although currently considered illegal under U.S. federal law, several U.S. cities are considering implementing supervised injection facilities anyway as a response to the escalating overdose crisis. The objective of this review is to determine the effectiveness of supervised injection facilities, compared with that of control conditions, for harm reduction and community outcomes.
EVIDENCE ACQUISITION
Studies were identified from 2 sources: a high-quality, broader review examining supervised injection facility-induced benefits and harms (from database inception to January 2014) and an updated search using the same search strategy (January 2014‒September 2019). Systematic review methods developed by the Guide to Community Preventive Services were used (screening and analysis, September 2019‒December 2020).
EVIDENCE SYNTHESIS
A total of 22 studies were included in this review: 16 focused on 1 supervised injection facility in Vancouver, Canada. Quantitative synthesis was not conducted given inconsistent outcome measurement across the studies. Supervised injection facilities in the included studies (n=number of studies per outcome category) were mostly associated with significant reductions in opioid overdose morbidity and mortality (n=5), significant improvements in injection behaviors and harm reduction (n=7), significant improvements in access to addiction treatment programs (n=7), and no increase or reductions in crime and public nuisance (n=7).
CONCLUSIONS
For people who inject drugs, supervised injection facilities may reduce the risk of overdose morbidity and mortality and improve access to care while not increasing crime or public nuisance to the surrounding community.
Topics: Canada; Drug Overdose; Harm Reduction; Humans; Needle-Exchange Programs; Substance Abuse, Intravenous
PubMed: 34218964
DOI: 10.1016/j.amepre.2021.04.017 -
JAMA Apr 2016Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with... (Review)
Review
IMPORTANCE
Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose.
OBJECTIVE
To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care.
PROCESS
The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category.
EVIDENCE SYNTHESIS
Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects.
RECOMMENDATIONS
There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.
CONCLUSIONS AND RELEVANCE
The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.
Topics: Acute Pain; Adult; Analgesics, Opioid; Benzodiazepines; Centers for Disease Control and Prevention, U.S.; Chronic Pain; Communication; Contraindications; Drug Prescriptions; Drug Therapy, Combination; Goals; Humans; Observational Studies as Topic; Prescription Drug Misuse; Primary Health Care; Randomized Controlled Trials as Topic; Treatment Outcome; United States; Withholding Treatment
PubMed: 26977696
DOI: 10.1001/jama.2016.1464 -
Neuroscience and Biobehavioral Reviews Aug 2015N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC... (Review)
Review
N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
Topics: Acetylcysteine; Adolescent; Adult; Clinical Trials as Topic; Female; Humans; Male; Mental Disorders; Nervous System Diseases; Neurology; Psychiatry; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult
PubMed: 25957927
DOI: 10.1016/j.neubiorev.2015.04.015 -
The Cochrane Database of Systematic... Feb 2018Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites.
OBJECTIVES
To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews.
SELECTION CRITERIA
Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software.
MAIN RESULTS
We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults.
AUTHORS' CONCLUSIONS
These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.
Topics: Acetaminophen; Acetylcysteine; Analgesics, Non-Narcotic; Antidotes; Charcoal; Cysteamine; Dimercaprol; Drug Overdose; Gastric Lavage; Humans; Intestinal Absorption; Liver Failure, Acute; Liver Transplantation; Methionine; Randomized Controlled Trials as Topic
PubMed: 29473717
DOI: 10.1002/14651858.CD003328.pub3 -
Drug and Alcohol Dependence Jul 2019Benzodiazepine misuse is a growing public health problem, with increases in benzodiazepine-related overdose deaths and emergency room visits in recent years. However,...
BACKGROUND
Benzodiazepine misuse is a growing public health problem, with increases in benzodiazepine-related overdose deaths and emergency room visits in recent years. However, relatively little attention has been paid to this emergent problem. We systematically reviewed epidemiological studies on benzodiazepine misuse to identify key findings, limitations, and future directions for research.
METHODS
PubMed and PsychINFO databases were searched through February 2019 for peer-reviewed publications on benzodiazepine misuse (e.g., use without a prescription; at a higher frequency or dose than prescribed). Eligibility criteria included human studies that focused on the prevalence, trends, correlates, motives, patterns, sources, and consequences of benzodiazepine misuse.
RESULTS
The search identified 1970 publications, and 351 articles were eligible for data extraction and inclusion. In 2017, benzodiazepines and other tranquilizers were the third most commonly misused illicit or prescription drug in the U.S. (approximately 2.2% of the population). Worldwide rates of misuse appear to be similar to those reported in the U.S. Factors associated with misuse include other substance use, receipt of a benzodiazepine prescription, and psychiatric symptoms and disorders. Benzodiazepine misuse encompasses heterogeneous presentations of motives, patterns, and sources. Moreover, misuse is associated with myriad poor outcomes, including mortality, HIV/HCV risk behaviors, poor self-reported quality of life, criminality, and continued substance use during treatment.
CONCLUSIONS
Benzodiazepine misuse is a worldwide public health concern that is associated with a number of concerning consequences. Findings from the present review have implications for identifying subgroups who could benefit from prevention and treatment efforts, critical points for intervention, and treatment targets.
Topics: Benzodiazepines; Drug Overdose; Humans; Prescription Drug Misuse; Prescription Drugs; Prevalence; Public Health; Quality of Life; Substance-Related Disorders
PubMed: 31121495
DOI: 10.1016/j.drugalcdep.2019.02.033 -
BMJ (Clinical Research Ed.) Apr 2017To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and... (Meta-Analysis)
Meta-Analysis Review
To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment. Systematic review and meta-analysis. Medline, Embase, PsycINFO, and LILACS to September 2016. Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine. Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis. There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment. Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.
Topics: Buprenorphine; Drug Overdose; Humans; Methadone; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Risk
PubMed: 28446428
DOI: 10.1136/bmj.j1550 -
Medicine May 2019The administration of opioids has been used for centuries as a viable option for pain management. When administered at appropriate doses, opioids prove effective not... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The administration of opioids has been used for centuries as a viable option for pain management. When administered at appropriate doses, opioids prove effective not only at eliminating pain but further preventing its recurrence in long-term recovery scenarios. Physicians have complied with the appropriate management of acute and chronic pain; however, this short or long-term opioid exposure provides opportunities for long-term opioid misuse and abuse, leading to addiction of patients who receive an opioid prescription and/or diversion of this pain medication to other people without prescription. Several reviews attempted to summarize the epidemiology and management of opioid misuse, this integrative review seeks to summarize the current literature related with responsible parties of this opioid abuse crisis and discuss potential associations between demographics (ethnicity, culture, gender, religion) and opioid accessibility, abuse and overdose.
METHODS
We performed an extensive literature search in Google Scholar and Pub Med databases that were published between December 7, 1999 and January 9, 2018 in accordance with the Preferred Reporting Items for Systematic Reviews and meta-Analysis (PRISMA) guidelines. Searches were referenced using medical subject headings (MeSH) that included "opioids", "over-prescription", "opioid consumption", or "opioid epidemic". The final review of all data bases was conducted on July 24, 2018.
RESULTS
A total of 7160 articles were originally identified. After 3340 duplicate articles were removed, 3820 manuscripts were removed after title and abstract screening. Following this, 120 manuscripts underwent eligibility selection with only 70 publications being selected as reliable full-texts addressing related factors surrounding the opioid crisis.
CONCLUSION
With approximately 100 million people suffering from both chronic and acute pain in the United States (US) in 2016, opiates will continue to remain a prominent class of medication in healthcare facilities and homes across the US. Over 66% of total overdose episodes in 2016 were opioid-related, a figure that attests to the severity and wide-spread nature of this issue. A three-point approach accentuating the prevention, treatment, and rehabilitation of both those currently affected and at-risk in the future may be the comprehensive solution.
Topics: Acute Pain; Adolescent; Adult; Analgesics, Opioid; Behavior, Addictive; Chronic Pain; Delivery of Health Care; Drug Overdose; Epidemics; Female; Humans; Inappropriate Prescribing; Male; Middle Aged; Opioid-Related Disorders; Pain Management; United States; Young Adult
PubMed: 31096439
DOI: 10.1097/MD.0000000000015425 -
Cureus Mar 2023The opioid overdose epidemic is exacerbated by the emergence of Xylazine as an illicit drug adulterant. Xylazine, a veterinary sedative, can potentiate opioid effects... (Review)
Review
INTRODUCTION AND OBJECTIVES
The opioid overdose epidemic is exacerbated by the emergence of Xylazine as an illicit drug adulterant. Xylazine, a veterinary sedative, can potentiate opioid effects while also causing toxic and potentially fatal side effects. This systematic review aims to assess the impact of Xylazine use and overdoses within the opioid epidemic context.
METHOD
A systematic search was conducted following PRISMA guidelines to identify relevant case reports, and case series related to Xylazine use. A comprehensive literature search included databases like Web of Science, PubMed, Embase, and Google Scholar, utilizing keywords and Medical Subject Headings (MeSH) terms related to Xylazine. Thirty-four articles met the inclusion criteria for this review.
RESULTS
Intravenous (IV) administration was a common route for Xylazine use among various methods, including subcutaneous (SC), intramuscular (IM), and inhalation, with overall doses ranging from 40 mg to 4300 mg. The average dose in fatal cases was 1,200 mg, compared to 525 mg in non-fatal cases. Concurrent administration of other drugs, primarily opioids, occurred in 28 cases (47.5%). Intoxication was identified as a notable concern in 32 out of 34 studies, and treatments varied, with the majority experiencing positive outcomes. Withdrawal symptoms were documented in one case study, but the low number of cases with withdrawal symptoms may be attributed to factors such as a limited number of cases or individual variation. Naloxone was administered in eight cases (13.6%), and all patients recovered, although it should not be misconstrued as an antidote for Xylazine intoxication. Of the 59 cases, 21 (35.6%) resulted in fatal outcomes, with 17 involving Xylazine use in conjunction with other drugs. The IV route was a common factor in six out of the 21 fatal cases (28.6%).
CONCLUSION
This review highlights the clinical challenges associated with Xylazine use and its co-administration with other substances, particularly opioids. Intoxication was identified as a major concern, and treatments varied across the studies, including supportive care, naloxone, and other medications. Further research is needed to explore the epidemiology and clinical implications of Xylazine use. Understanding the motivations and circumstances leading to Xylazine use, as well as its effects on users, is essential for developing effective psychosocial support and treatment interventions to address this public health crisis.
PubMed: 37009344
DOI: 10.7759/cureus.36864