Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids.

Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild μ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia

Use of analgesics in intentional drug overdose presentations to hospital before and after the withdrawal of distalgesic from the Irish market

BACKGROUND: Distalgesic, the prescription-only analgesic compound of paracetamol (325 mg) and dextropropoxyphene (32.5 mg) known as co-proxamol in the UK, was withdrawn from the Irish market as of January 2006. This study aimed to evaluate the impact of the withdrawal of distalgesic in terms of intentional drug overdose (IDO) presentations to hospital emergency departments (EDs) nationally. METHODS: A total of 42,849 IDO presentations to 37 of the 40 hospitals EDs operating in Ireland in 2003-2008 were recorded according to standardised procedures. Data on sales of paracetamol-containing drugs to retail pharmacies for the period 1998-2008 were obtained from IMS Health. RESULTS: The withdrawal of distalgesic from the Irish market resulted in an immediate reduction in sales to retail pharmacies from 40 million tablets in 2005 to 500,000 tablets in 2006 while there was a 48% increase in sales of other prescription compound analgesics. The rate of IDO presentations to hospital involving distalgesic in 2006- 2008 was 84% lower than in the three years before it was withdrawn (10.0 per 100,000). There was a 44% increase in the rate of IDO presentations involving other prescription compound analgesics but the magnitude of this rate increase was five times smaller than the magnitude of the decrease in distalgesic-related IDO presentations. There was a decreasing trend in the rate of presentations involving any paracetamol-containing drug that began in the years before the distalgesic withdrawal. CONCLUSIONS: The withdrawal of distalgesic has had positive benefits in terms of IDO presentations to hospital in Ireland and provides evidence supporting the restriction of availability of means as a prevention strategy for suicidal behaviour

Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database

The fatal toxicity index (FTI) is the absolute number of fatal poisonings caused by a particular drug divided by its consumption figure. Consequently, it is a useful measure in evaluating toxicity of the drug and its relevance in fatal poisonings. In this study, we assessed the FTI of medicinal drugs in 3 years (2005, 2009, and 2013) in Finland. As the measure of drug consumption, we used the number of defined daily doses (DDD) per population in each year. There were 70 medicinal drugs in Finland for which the mean FTI expressed as the number of deaths per million DDD over the three study years was higher or equal to 0.1. The Anatomical Therapeutic Chemical (ATC) classification system was used for the classification of the active ingredients of medicinal drugs according to the organ or system which they act on. Of these 70 drugs, 55 drugs (78.6 %) acted on the nervous system (denoted by ATC code N), 11 (15.7 %) on the cardiovascular system (C), three (4.3 %) on the alimentary tract and metabolism (A), and one (1.4 %) on the musculoskeletal system (M). The nervous system drugs consisted of 20 psycholeptics, (ATC code N05), 20 psychoanaleptics (N06), eight analgesics (N02), six antiepileptics (N03), and one other nervous system drug (N07). The highest individual FTIs were associated with the opioids methadone, dextropropoxyphene, oxycodone, tramadol, and morphine; the antipsychotics levomepromazine and chlorprothixene; and the antidepressants doxepin, amitriptyline, trimipramine, and bupropion. Buprenorphine was not included in the study, because most of the fatal buprenorphine poisonings were due to smuggled tablets. A clearly increasing trend in FTI was observed with pregabalin and possibly with bupropion, both drugs emerging as abused substances.Peer reviewe

Recent developments concerning the DRD Key Indicator in United Kingdom

Final Published versio

ACMD consideration of tramadol.

Briefing from the Chair of the ACMD to the UK Home Secretary and Secretary of State for Health on Tramadol. Tramadol is a synthetic analogue of the phenanthrene alkaloid codeine and is an analgesic of significant medical use for treating moderate to severe pain. Tramadol has wide ranging applications, including the treatment of fibromyalgia (chronic widespread pain), cancer pain and moderate to severe musculoskeletal pain. In a similar way to other psychoactive agents of the opioid class, it can be liable to misuse. Tramadol has a unique dual-action pharmacological profile that increases the risk of adverse effects seen in overdose. Opioids such as tramadol exhibit weak agonist activity at opiate receptors in the brain and may contribute towards euphoria and respiratory depression. In addition, tramadol enhances serotoninergic and noradrenergic systems in the brain by inhibiting their reuptake mechanisms. Prescribing data from the UK NHS Business Services Authority (NHSBSA) indicate an increase in prescribing, with the number of Daily Defined Doses (England)1 increasing from approximately 5.9 million in September 2005 to 11.1 million in September 2012. This may be associated with Co-Proxamol‟s phased withdrawal from 2005. Data from the UK Office of National Statistics (ONS) for 2011 shows 154 deaths where tramadol had been mentioned on the death certificates; in 2009 there were 87 such mentions and in 2008 this figure was 83. The majority of tramadol related deaths are where it has been obtained through non–prescribed means

Clinical review: Aggressive management and extracorporeal support for drug-induced cardiotoxicity

Poisoning may induce failure in multiple organs, leading to death. Supportive treatments and supplementation of failing organs are usually efficient. In contrast, the usefulness of cardiopulmonary bypass in drug-induced shock remains a matter of debate. The majority of deaths results from poisoning with membrane stabilising agents and calcium channel blockers. There is a need for more aggressive treatment in patients not responding to conventional treatments. The development of new antidotes is limited. In contrast, experimental studies support the hypothesis that cardiopulmonary bypass is life-saving. A review of the literature shows that cardiopulmonary bypass of the poisoned heart is feasible. The largest experience has resulted from the use of peripheral cardiopulmonary bypass. However, a literature review does not allow any conclusions regarding the efficiency and indications for this invasive method. Indeed, the majority of reports are single cases, with only one series of seven patients. Appealing results suggest that further studies are needed. Determination of prognostic factors predictive of refractoriness to conventional treatment for cardiotoxic poisonings is mandatory. These prognostic factors are specific for a toxicant or a class of toxicants. Knowledge of them will result in clarification of the indications for cardiopulmonary bypass in poisonings

Importance of pesticides for lethal poisoning in India during 1999 to 2018: a systematic review

BACKGROUND: Poisoning is a major problem in India. However, there is little systematic information on the key poisons responsible for most deaths by geographical area and over time. We aimed to review the literature to identify the poison classes causing the greatest number of deaths in India over the last 20 years. METHODS: We performed a systematic literature review in Medline, Embase and Google Scholar (1999–2018), and Indian online medical journals, to find papers that reported deaths from all forms of poisoning in India, with last search 20 April 2020. We included epidemiological studies, observational studies, randomised trials, interventional studies, and case series published from 1999 to 2018 that showed the number of deaths and autopsy studies indicating the specific poisons or poison classes. Studies providing the case fatality for specific poisons or classes, which enabled calculation of the number of deaths, were also included. We excluded deaths due to animal bites and stings, ethanol or methanol poisoning, and gas inhalation as well as papers reporting a single death (case study of single patient). We grouped the papers into 5-year intervals and identified the two most common poison classes in each paper. We used descriptive statistics to summarise the findings over time based on the causative poison and the location of the study. RESULTS: We identified 186 papers reporting 16,659 poisoning deaths between 1999 and 2018. The number of publications per 5-year interval showed no clear trend over the period (48, 38, 67, and 36 for consecutive periods). Half of the deaths (n = 8338, 50.0%) were reported during the first 5 years of the study (1999–2003), the number of deaths declining thereafter (to n = 1714 in 2014–2018). Deaths due to pesticide poisoning (94.5%) were dominant across the study period compared to other classes of poison [hair dye paraphenylenediamine poisoning (2.6%), medicine overdose (1.4%) or plant poisoning (1.0%)]. Among the pesticides, aluminium phosphide was the most important lethal poison during the first 10 years before declining markedly; organophosphorus insecticides were important throughout the period, becoming dominant in the last decade as aluminium phosphide cases declined. Unfortunately, few papers identified the specific organophosphorus insecticide responsible for deaths. CONCLUSION: Use of the published literature to better understand the epidemiology of lethal poisoning in India has clear limitations, including secular variation in publishing practices and interest in poisoning. Unfortunately, there are no long-term detailed, combination hospital and community studies from India to provide this information. In their absence, our review indicates that pesticides are the most important poison in India, with organophosphorus insecticides replacing aluminium phosphide as the key lethal poison after government regulatory changes in 2001 reduced the latter’s lethality. Plant and hair dye poisoning and medicines overdose caused few deaths. Aluminium phosphide deaths mostly occurred in northern Indian states, whereas deaths from organophosphorus insecticide poisoning occurred throughout India. Paraquat poisoning has become a clinical problem in the last 10 years. Lethal pesticide poisoning remains alarmingly common, emphasising the need for additional regulatory interventions to curtail the burden of pesticide poisoning deaths in India. More detailed reporting about the specific pesticide involved in lethal poisoning will be helpful to guide regulatory decisions

Increase in self-injury as a method of self-harm in Ghent, Belgium : 1987-2013

Background : Self-harm is a major health care problem and changes in its prevalence and characteristics can have important implications for suicide prevention. The objective was to describe trends in the epidemiology of self-harm based on emergency department (A&E departments) visits over a 26-year period in Ghent, Belgium. Methods : We analyzed data on all self-harm presentations from the three large general hospitals in Ghent between 1987 and 2013. We investigated trends in prevalence (events by year per 100.000), methods and alcohol use. Results : Rates of self-harm steadily decreased during the 26-year study period. In general female rates of self-harm were higher than male rates. The mean patient age was 35 years. The most commonly used method of self-harm was self-poisoning by means of an overdose of medication (80.8%), followed by cutting (10.2%) and hanging (4.2%). Psychotropics (including antidepressants, benzodiazepines, barbiturates and other tranquilizers) were the most frequently used drugs (74.5%). A proportional increase in the use of self-injurious methods in self-harm was highly significant, more specifically in the use of hanging, jumping from heights and the use of other violent methods such as the use of firearms, jumping before a moving object or other traffic related injury. Conclusion : This epidemiological study showed an increase in the use of high-lethality methods in self-harm which has important implications for suicide prevention. As restrictions in the availability of these methods are difficult or impossible to achieve, prevention programmes will have to emphasize the role of thorough psychosocial assessment and adequate follow-up care of self-harm patients

Chronic non-cancer pain: Focus on once-daily tramadol formulations

Despite progress in pain management, chronic non-cancer pain (CNCP) represents still a clinical challenge. The efficacy and safety profile of tramadol make it suitable as a long-term treatment in a variety of CNCP conditions. New once-daily (OD) formulations of tramadol have been marketed in various countries, in order to offer the advantage of a reduced dosing regimen and to improve patients’ compliance. This review focuses on the technology, pharmacology, clinical efficacy, and safety of different once-daily tramadol formulations. Hydrophilic vs hydrophobic matrix systems and newer technologies used in once-daily formulations to control drug delivery are discussed. Three randomized controlled trials (RCTs) established OD tramadol analgesic efficacy to be superior to that of placebo for pain management and functional improvement in patients with osteoarthritis. Three RCTs demonstrated similar rates of efficacy between OD tramadol and immediate-release (IR) or sustained-release (SR) formulations, with a better adverse events profile. An open trial on long term tolerability showed that OD tramadol is generally safe in rheumatological pain treatment

Medication used in intentional drug overdose in Flanders 2008-2013

Background : Intentional drug overdose is the most common method of self-harm. As psychiatric disorders are very common in self-harm patients, the medication used to treat these disorders can become the means for the self-harm act. The present study aimed at investigating an association between the use of prescribed medication (analgesics and antipyretics, anti-epileptics, antipsychotics, antidepressants and psychostimulants) as a method of self-harm and prescription rates of this medication in Flanders. We investigated the possible effect of gender, alcohol use during the self-harm act and a history of self-harm. Methods : Data from the multicenter study of self-harm in Flanders between 2008 and 2013 were used. The significance of differences in percentages was calculated by GEE and the strength by odds ratios (OR). Results : There was an increase in the odds of using antidepressants (0.8%) and antipsychotics (2%) among females when the rate of prescription increases. Analgesics and antipyretics (39.3/1,000) and antidepressants (124.9/1,000) were the most commonly prescribed drugs among females. Antidepressants (63.9/1,000) and antipsychotics (26.5/1,000) were the most commonly prescribed drugs among males. Antidepressants and analgesics and antipyretics were the most frequently used medications for self-harm. Analgesics and antipyretics during the self-harm act were more common among first-timers, while repeaters more commonly overdosed using antipsychotics and antidepressants. Conclusion : These findings suggest that the availability of medication via prescriptions plays an important role in the choice of the medication ingested during the self-harm act. Precautions are necessary when prescribing medication, including restrictions on the number of prescriptions and the return of unused medication to pharmacies after cessation of treatment. These issues should be a focus of attention in the education and training of physicians and pharmacists