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For any therapeutic intervention in an individual, there is a balance between the potential benefits and the possible harms. The extent to which the benefits are desirable in a given condition depends on the efficacy of the intervention, the chance of obtaining it and the seriousness and intensity of the condition. The extent to which the harms are undesirable depends on the nature of the hazard that can lead to harm, the chance that the harm will occur and its seriousness and intensity. Rational therapeutic decisions require clinicians to consider competing courses of action, with potential benefits of different desirability and potential harms of different undesirability. They also have a duty to explain to the patient, for the contemplated interventions, both the possible benefits and the potential harms that the patient may consider significant. In an individual patient, it is necessary to consider (a) the probabilities of benefit from both intervention and non-intervention and (b) the probabilities of harm from both intervention and non-intervention. However, there are several potential problems. Here, we consider how failure to distinguish maximum benefits from probable benefits, or hazards (potential harms) from probable harms, and failure to consider all the competing probabilities may lead to imperfect therapeutic decisions. We also briefly discuss methods to assess the benefit to harm balance. [ABSTRACT FROM AUTHOR]

Background Opioid deaths have increased in England and Wales. Coroners' Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners' concerns to prevent future deaths. Methods In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK's Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners. Results Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%). Conclusions Opioids could be used more safely if coroners' concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians. [ABSTRACT FROM AUTHOR]

Health systems encourage switching from originators to biosimilars as biosimilars are more cost‐effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re‐establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short‐term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post‐switch if appropriate. [ABSTRACT FROM AUTHOR]

Drug shortages are repeatedly in the news. The earliest drug shortages were reported during the First World War, but the numbers of shortages have increased in recent years. In the first part of this two‐part review, we discuss definitions of drug shortages and so‐called stockouts, which are localized shortages, and the harms that they can cause. Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations, but we lack an adequate definition. The problems are too complicated to be encompassed in a brief intensional dictionary‐style definition, and that is reflected in the many different attempts at definition that have been proposed. We therefore propose an extensional operational definition that incorporates the processes by which products are manufactured, the causes of shortages and the contributory factors. A definition of this sort allows one to identify the main causes of a particular drug shortage and therefore the remedies that might prevent, mitigate or manage it. In the second part of the review we discuss the causes and solutions in more detail. Adverse drug reactions and medication errors attributable to shortages occur but are not often reported. Adverse reactions to substitute medicines are possible, and errors can occur because of unfamiliarity or unnecessary treatment with replacement medicines. Other harmful outcomes include withdrawal reactions, undertreatment, treatment delays and cancellations, failure of alternatives and disruption of clinical trials. [ABSTRACT FROM AUTHOR]

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock‐outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just‐in‐time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off‐label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies. [ABSTRACT FROM AUTHOR]

Background: Coroners, who hold inquests to determine the causes of unnatural deaths in England and Wales, having recognised factors that could cause other deaths, are legally obliged to signal concerns by sending 'Reports to Prevent Future Deaths' (PFDs) to interested persons. We aimed to establish whether Coroners' concerns about medications are widely recognised. Methods: We searched MEDLINE, Embase and Web of Science up to 30 November, 2022 for publications linking PFDs and medications using a combination of search terms "coroner*", "inquest*", "medicine*", "medication*" and "prevent*". We also searched the BMJ, a UK journal that carries news items; and the databases Nexis Advance and News On the Web for reports in national newspapers between 2013 and 2022, using the search terms ("regulation 28" OR "prevent future deaths" OR "prevention of future deaths") AND "coroner". We recorded the number of publications, as well as their citations in Google Scholar at 23 May, 2023. Results: Only 11 published papers on medicines referenced UK PFDs, nine of which were from our group. The BMJ carried 23 articles mentioning PFDs, five related to medicines. Of 139 PFDs (out of over 4000) mentioned in national newspapers, only nine related to medicines. Conclusions: The PFDs related to medicines are not widely referred to in medical journals or UK national newspapers. By contrast, the Australian and New Zealand National Coronial Information System has contributed cases to 206 publications cited in PubMed, of which 139 are related to medicines. Our search suggests that information from English and Welsh Coroners' PFDs is under-recognised, even though it should inform public health. The results of inquiries by Coroners and medical examiners worldwide into potentially preventable deaths involving medicines should be used to strengthen the safety of medicines. [ABSTRACT FROM AUTHOR]

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost‐effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10‐point checklist that is proposed as a tool to aid evidence‐based implementation of pharmacogenomic testing into routine clinical care within the NHS. Conclusion: Our 10‐point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence‐based framework for adoption. Such an approach could also be applied to other health systems. [ABSTRACT FROM AUTHOR]

Background: Insulin poisoning, as opposed to hypoglycaemia induced by therapeutic doses of insulin, is rare, and guidelines on management differ. We have reviewed the evidence on treatment of insulin poisoning. Methods: We searched PubMed, EMBASE and J‐Stage with no restrictions of date or language for controlled studies on treatment of insulin poisoning, collected published cases of insulin poisoning from 1923, and used data from the UK National Poisons Information Service. Results: We identified no controlled trials of treatment in insulin poisoning and few relevant experimental studies. Case reports described 315 admissions (301 patients) with insulin poisoning between 1923 and 2022. The insulin with the longest duration of action was long‐acting in 83 cases, medium‐acting in 116, short‐acting in 36 and a rapid‐acting analogue in 16. Decontamination by surgical excision of the injection site was reported in six cases. To restore and maintain euglycaemia, almost all cases were treated with glucose, infused for a median 51 hours, interquartile range 16–96 h in 179 cases; 14 patients received glucagon and nine octreotide; adrenaline was tried occasionally. Both corticosteroids and mannitol were occasionally given to mitigate hypoglycaemic brain damage. There were 29 deaths reported, 22/156 (86% survival) up to 1999 and 7/159 (96% survival) between 2000 and 2022 (p = 0.003). Conclusions: There is no randomized controlled trial to guide treatment of insulin poisoning. Treatment with glucose infusion, sometimes supplemented with glucagon, is almost always effective in restoring euglycaemia, but optimum treatments to maintain euglycaemia and restore cerebral function remain uncertain. [ABSTRACT FROM AUTHOR]

Introduction: Medicines cause over 1700 preventable deaths annually in England. Coroners' Prevention of Future Death reports (PFDs) are produced in response to preventable deaths to facilitate change. The information in PFDs may help reduce medicine-related preventable deaths. Objectives: We aimed to identify medicine-related deaths in coroners' reports and to explore concerns to prevent future deaths. Methods: We carried out a retrospective case series of PFDs across England and Wales, dated between 1 July, 2013 and 23 February, 2022, collected from the UK's Courts and Tribunals Judiciary website using web scraping, generating an openly available database: https://preventabledeathstracker.net/. We used descriptive techniques and content analysis to assess the main outcome criteria: the proportion of PFDs in which coroners reported that a therapeutic medicine or drug of abuse had caused or contributed to a death; the characteristics of included PFDs; coroners' concerns; the recipients of PFDs; and the timeliness of their responses. Results: There were 704 PFDs (18%; 716 deaths) that involved medicines, representing an estimated 19,740 years of life lost (average of 50 years lost per death). Opioids (22%), antidepressants (9.7%), and hypnotics (9.2%) were the most common drugs involved. Coroners expressed 1249 concerns, primarily around the major themes of patient safety (29%) and communication (26%), including minor themes of failures of monitoring (10%) and poor communication between organizations (7.5%). Most expected responses to PFDs (51%; 630/1245) were not reported on the UK's Courts and Tribunals Judiciary website. Conclusions: One in five coroner-reported preventable deaths involved medicines. Addressing coroners' concerns, including problems with patient safety and communication, should reduce harms from medicines. Despite concerns being raised repeatedly, half of the PFD recipients failed to respond, suggesting that lessons are not generally learned. The rich information in PFDs should be used to foster a learning environment in clinical practice that may help reduce preventable deaths. Clinical Trial Registration: https://doi.org/10.17605/OSF.IO/TX3CS. [ABSTRACT FROM AUTHOR]

The initial purposes of regulation of medicines in England, and latterly in the United Kingdom, were principally to raise government revenue, to discourage murder by poisoning and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to curtail misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics. [ABSTRACT FROM AUTHOR]

Aims: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high‐cost medicines in England. Methods: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high‐cost drug database. Results: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016–18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high‐cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR‐funded treatment, 54% (19/35) who received CCG IFR‐funded treatment and 91% (21/23) who were funded via other routes. Conclusion: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high‐cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes‐based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system. [ABSTRACT FROM AUTHOR]

Direct‐acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non‐valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non‐Europid ethnic backgrounds. [ABSTRACT FROM AUTHOR]

Introduction: Free‐of‐charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company‐FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company‐FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth. Conclusion: Company‐FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co‐ordinate schemes. Motivations for company‐FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence. [ABSTRACT FROM AUTHOR]

In response to the COVID‐19 pandemic, Health Education England (HEE) and the University of Birmingham provided National Health Service (NHS) staff free access to SCRIPT, a national eLearning programme for safer prescribing and therapeutics. The eLearning was particularly for those returning to work or being redeployed. In the year March 2020‐21, 3412 users registered to access portfolios and opened an aggregate of 17 198 modules. Each user completed a median of 2 (range 1‐50, interquartile range [IQR] 1‐7) assessed learning modules. Marks improved from pre‐test to post‐test by a median of 2 (IQR 0‐3) marks out of 10. The most frequently selected modules were Adherence and Concordance (1109 users), Fluids (981 users) and Diabetic Emergencies (818 users). A total of 878 users accessed the unassessed COVID‐19 module. The SCRIPT modules provided standardised education in core principles relating to prescribing and therapeutics, and were used by professionals from many healthcare disciplines. [ABSTRACT FROM AUTHOR]

Introduction: The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published frequent summaries of spontaneous reports of suspected adverse drug reactions (ADRs) (Yellow Cards) to vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The EudraVigilance database has provided similar data for the European Economic Area. Objective: Our objective was to characterize the evolution over time of spontaneous reports of suspected ADRs to coronavirus disease 2019 (COVID-19) vaccines and to observe the effect of a publicized reaction (cerebral venous and sinus thrombosis [CVST]) on reporting rates. Methods: We used publicly available data on reports of suspected ADRs and doses of vaccine administered, published by the MHRA, EudraVigilance, and the European Centre for Disease Prevention and Control to calculate reporting rates. Results: Approximately 4814 Yellow Card reports (23 fatal) per million doses of ChAdOx1 nCoV-19 (AstraZeneca) and 2890 (13 fatal) per million doses of tozinameran (Pfizer/BioNTech) have been lodged. Between 15 March and 31 October 2021, cumulative European reports of CVST rose from 0 to 443 (183 with thrombocytopenia, 72 fatal) with ChAdOx1 nCoV-19 and from 2 to 315 (9 with thrombocytopenia, 28 fatal) with tozinameran. European cases of retinal vein occlusion and thrombosis rose from 0 to 168 with ChAdOx1 nCoV-19 and from 1 to 220 with tozinameran; four of the ChAdOx1 nCoV-19 cases were associated with thrombocytopenia. Conclusion: Reports of fatal adverse reactions to coronavirus vaccines are very rare. Reports of CVST have been made in relation to both vaccines. Most were submitted after the reaction had been publicized. Thrombocytopenia occurred in a minority of cases. Reports linked both vaccines to cases of retinal vein thrombosis, just four cases with thrombocytopenia. This suggests two different mechanisms of thrombosis associated with the vaccines. [ABSTRACT FROM AUTHOR]

The article discusses the successful national Prescribing Safety Assessment (PSA) in United Kingdom (UK) medical education as of 2023. Topics covered include its push for medical schools to ensure students' capability in prescription, the UK Medical Licensing Assessment (MLA), and the dilemma in its relation to the PSA. Also noted is the PSA's possible other purpose that the MLA cannot cover.

Introduction: Harms from medical devices are important, but have been much less well studied than adverse drug reactions. Information provided to device users is of variable quality.Objective: Our aim was to define "medical device fault" and "adverse effect of a medical device"; to establish whether medical device faults arise in design, manufacture, or use; and to consider ways of mitigating the adverse effects of medical devices.Methods: We analysed 100 consecutive faults reported by the US Food and Drug Administration (FDA) and 50 faults reported by the UK Medicines and Healthcare products Regulatory Agency (MHRA), and classified faults according to the point at which they occurred.Results: Nearly 70% of reported faults related to devices that entered the body. Over 70% arose at the design stage, a quarter of the faults were associated with manufacture, and less than 5% were primarily caused by faulty use.Conclusion: We defined a medical device fault as an unintended failure in the design, manufacture, or use of a medical device that leads to, or has the potential to lead to, harm to the patient, and an adverse effect of a medical device as an unintended and appreciably harmful effect, caused by a medical device, which demonstrates a hazard of the device and may warrant preventive measures, or a change in the mode of use, or withdrawal of the device. Most faults that generate warnings arise from problems at the design stage, some arise at the manufacturing stage, and a few in usage. Careful assessment of the design of safety-critical devices in the light of previous problems may help to prevent repetition of errors. It would be helpful if, in addition to user manuals, manufacturers were required to produce Summaries of Device Characteristics (SDCs, "labels") that contained a systematically presented set of information about a product. [ABSTRACT FROM AUTHOR]

We propose the following definition of a medical device: "A contrivance designed and manufactured for use in healthcare, and not solely medicinal or nutritional." Current regulatory classifications of medical devices are complex and designed primarily for regulators. We propose a simpler classification, based on (1) the site of application of the device, (2) the time scale of its use, and (3) whether it has an external power source. The regulation of medical devices is less well developed than the regulation of medicinal products, which it could follow more closely. In particular, devices that incorporate medicines should be required to meet the same regulatory standards as medicinal products. This would remove the anomaly that some delivery systems that incorporate medicines are classified as devices while other similar systems that deliver the same medicines are classified as medicinal products. Some improvements might also result from more widespread use of registries, such as those used for prosthetic joint replacements. Registries would allow both a prospective examination of the performance of high-risk devices and a retrospective analysis when signals from other sources of information suggest problems. Those who apply for a marketing authorization for a new device should have to assure regulators of its quality of manufacture, safety, and efficacy before licensing. Even the most straightforward device should be shown to be useable in practice. Trials on patients, or at least simulations of use in the real world, should be practicable for most devices. [ABSTRACT FROM AUTHOR]

Aims To assess the transfer of patients treated with originator biological therapies to biosimilar products in a large UK tertiary referral hospital reflecting practice within the National Health Service (NHS) using prospectively collected data by a hospital‐based registry administered by the Biologics Steering Group (BSG). Methods: We analysed data collected prospectively in a hospital‐based registry in a large NHS tertiary referral hospital in the UK. The registry was administered by the hospital's BSG, which considered requests for patients to remain on or revert to originator products. The registry contained prospectively collected data on patients switching therapy from an originator to a biosimilar. The data included clinical circumstances or rationale for each request, whether it was granted, and the results of clinical reviews at 3–6 months. Results: In a 12‐month period, we identified 1299 patients who could switch to the respective biosimilar and, of these, 1196 (92%) did so. Of the 260 patients taking infliximab, 250 (96%) switched to infliximab biosimilar; of the 390 patients taking etanercept 50 mg, 298 (76%) switched to etanercept 50 mg biosimilar; and of the 649 patients taking rituximab, 648 (99%) switched to rituximab biosimilar. The BSG received 39 applications: 12 (out of 39) applications were to remain on the originator and 27 (out of 39) were to switch back to the originator. Of the applications to remain on the originator 10 (out of 12) were approved. At 3–6 month review, 2 of these approvals reported continued efficacy, 3 switched to the biosimilar, 3 switched to an alternative therapy and 2 stopped treatment. Two (out of 10) applications were not approved, both applicants reported efficacy with the biosimilar at follow up. Of the 27 applications to switch back to the originator, 16 (out of 27) applications were approved. At 3–6 months, 9 (out of 16) applicants reported regain of efficacy, 6 (out of 16) reported cessation of reported adverse effects and 1 (out of 16) switched to alternative therapy. Eight (out of 27) applications were not approved, and, at point of follow up, 50% reported efficacy with the biosimilar and 50% had switched to an alternative therapy. Three (out of 27) applications were withdrawn by the clinical team as efficacy was achieved with the biosimilar. Conclusion: We have set up a system within a busy NHS clinical practice to successfully switch patients to biosimilars, and established a mechanism to guide decisions on continuing with or reverting back to the originator. Such a system could be of use more broadly within the NHS and other health care systems. [ABSTRACT FROM AUTHOR]

Context of the Article: An important forensic problem is whether the presence of a drug such as morphine caused or contributed to a death or was merely incidental. The reliance that can be based on postmortem drug concentrations remains controversial. To investigate this further we obtained antemortem and postmortem samples of individuals admitted to hospital who were receiving morphine and who died in hospital. Methods: Eleven subjects were recruited. Samples were sent for analysis for free and total morphine concentrations. Results: The median difference (postmortem – antemortem) free morphine concentration was 25.5 (range 0 to +126) µg/L, p <.01; the mean difference between postmortem and antemortem total morphine concentration was 34.5 (range −225 to 342) µg/L (not significant). Discussion: Our study supports previous investigators who note that there is an inconstant and sometimes tenuous relationship between ante- and postmortem morphine concentrations. [ABSTRACT FROM AUTHOR]

Antihypertensive drugs have usually been approved at doses near the top of their respective dose–response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy. [ABSTRACT FROM AUTHOR]

The clinical doses of antithrombotics—antiplatelet and anticoagulant agents—need to balance efficacy and safety. It is not clear from the published literature how the doses currently used in clinical practice have been derived from preclinical and clinical data. There are few large randomised controlled trials (RCTs) that compare outcomes with different doses vs placebo. For newer antithrombotics, RCT doses appear to have been chosen to maximise the probability of demonstrating noninferiority when compared to established agents such as warfarin or clopidogrel. Data from RCTs show that aspirin is an effective antithrombotic at doses below 75 mg daily, and that direct oral anticoagulants reduce the risk of stroke in patients with coronary disease at doses 1/4 of those recommended in atrial fibrillation. Lower doses than those currently recommended are safer and still maintain substantial efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Coroners inquire into sudden, unexpected, or unnatural deaths. We have previously established 99 cases (100 deaths) in England and Wales in which medicines or part of the medication process or both were mentioned in coroners' 'Regulation 28 Reports to Prevent Future Deaths' (coroners' reports).Objective: We wished to see what responses were made by National Health Service (NHS) organizations and others to these 99 coroners' reports.Methods: Where possible, we identified the party or parties to whom these reports were addressed (names were occasionally redacted). We then sought responses, either from the UK judiciary website or by making requests to the addressee directly or, for NHS and government entities, under the Freedom of Information Act 2000. Responses were analysed by theme to indicate the steps taken to prevent future deaths.Results: We were able to analyse one or more responses to 69/99 cases from 106 organizations. We analysed 201 separate actions proposed or taken to address the 160 concerns expressed by coroners. Staff education or training was the most common form of action taken (44/201). Some organisations made changes in process (24/201) or policy (17/201), and some felt existing policies were sufficient to address some concerns (22/201).Conclusions: Coroners' concerns are often of national importance but are not currently shared nationally. Only a minority of responses to coroners' reports concerning medicines are in the public domain. Processes for auditing responses and assessing their effectiveness are opaque. Few of the responses appear to provide robust and generally applicable ways to prevent future deaths. [ABSTRACT FROM AUTHOR]

Context:Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. Aim:To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. Methods:We made a systematic search of EMBASE 1980–2016 using the search terms (“bile/” OR “exp drug bile level/concentration/”) AND “drug blood level/concentration/”, PubMed 1975–2017 for (“bile[tw]” OR “biliary[tw]”) AND (“concentration[tw]” OR “concentrations[tw]” OR “level[tw]” OR “levels[tw]”) AND “post-mortem[tw]” and also MEDLINE 1990–2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios:Median bile:blood concentration ratios varied from 0.18 (range 0.058–0.32) for dextromoramide to 520 (range 0.62–43,000) for buprenorphine. Median bile concentrations exceeded blood concentrations by one order of magnitude for several drugs, including dihydrocodeine, quetiapine and sildenafil; and by two orders of magnitude of for buprenorphine, colchicine and 3,4-methylenedioxy-methamphetamine (MDMA), among others. The minimum and maximum values for the ratio differed by a factor of three or more in three-quarters of the cases where data were available and by a factor of 10 or more for over half of the analytes. Limitations:The data were difficult to find. Medline does not explicitly index the term “drug bile concentration”. It may well be that other reports exist, although they would not alter our major conclusion. Many of the papers that contributed data failed to specify the source of the blood samples or the post-mortem interval, so that no judgment was possible regarding post-mortem redistribution in whole blood or bile. Conclusions:For most drugs, there are wide ranges of bile:blood concentration ratios, which means that bile and blood concentrations are generally poorly correlated. Bile concentration measurements cannot readily be used to establish post-mortem blood concentrations; nor can they be extrapolated to ante-mortem concentrations. However, because drug concentrations in bile often exceed those in blood, bile may allow qualitative identification of drugs present, even when the blood concentration is below the limit of detection. [ABSTRACT FROM PUBLISHER]

Introduction: Since legislation in 2009, coroners in England and Wales must make reports in cases where they believe it is possible to prevent future deaths. We categorised the reports and examined whether they could reveal preventable medication errors or novel adverse drug reactions.Methods: We examined 500 coroners' reports by pre-defined criteria to identify those in which medicines played a part, and to collect information on coroners' concerns.Results: We identified 99 reports (100 deaths) in which medicines or a part of the medication process or both were mentioned. Reports mentioned anticoagulants (22 reports), opioids (17), antidepressants (17), drugs of abuse excluding opioids (12 deaths) and other drugs. The most important concerns related to adverse reactions to prescribed medicines (22), omission of necessary treatment (21), failure to monitor treatment (17) and poor systems (17). These were related to defects in education or training, lack of clear guidelines or protocols and failure to implement existing guidelines, among other reasons. Most reports went either to NHS Hospital Trusts or to local trusts. The responses of addressees were rarely published. We identified four safety warnings from the Medicines and Healthcare Products Regulatory Agency that were based on coroners' warnings.Conclusion: Coroners' reports to prevent future deaths provide some information on medication errors and adverse reactions. They rarely identify new hazards. At present they are often addressed to local bodies, but this could mean that wider lessons are lost. [ABSTRACT FROM AUTHOR]

The terms 'licensed', 'unlicensed', and 'off-label', often used in relation to marketing and prescribing medicinal products, may confuse UK prescribers. To market a medicinal product in the UK requires a Marketing Authorization ('product licence') for specified indications under specified conditions, regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The Marketing Authorization includes the product's agreed terms of use (the 'label'), described in the Summary of Product Characteristics (SmPC). Prescribing a licensed product outside those terms is called 'off-label' prescribing. Products for which no-one holds a UK Marketing Authorization are unlicensed. Prescribers can prescribe authorized products according to the conditions described in the SmPC ('on-label') or outside those conditions ('off-label'). They can also prescribe unauthorized products, even if they are unlicensed in the UK, if they are licensed elsewhere or if they have been manufactured in the UK by a licensed manufacturer as a 'special'. The complexities of this system can be understood by considering the status of the manufacturer of the product, the company that markets it (which may or may not be the same), the product itself, and its modes of use, and by emphasizing the word 'authorized'. If a Marketing Authorization is granted to the supplier of a product, it will specify the authorized modes of use; the product will be prescribable as authorized (i.e. 'on-label') or in other modes of use, which will all be off-label. Unlicensed products with no authorized modes of use can be regarded as 'unauthorized products'. All 'specials' can be regarded as authorized products lacking authorized modes of use. [ABSTRACT FROM AUTHOR]

Objective:To review the evidence for “the Mellanby effect”, that is, whether the response to a given blood alcohol concentration (BAC) is more marked when BAC is rising than at the same concentration when BAC is falling. Methods:We systematically searched the databases EMBASE, Medline, and Scopus up to and including December 2016 using text words “tolerance”, “ascending”, “descending” or “Mellanby” with Medline term “exp *alcohol/” or “exp *drinking behavior/” or equivalent. Articles were identified for further examination by title or abstract; full text articles were retained for analysis if they dealt with acute (within dose) alcohol tolerance in human subjects and provided quantitative data on both the ascending and descending parts of the BAC–time curve. Reference lists of identified works were scanned for other potentially relevant material. We extracted and analyzed data on the subjective and objective assessment of alcohol effects. Results:We identified and screened 386 unique articles, of which 127 full-text articles were assessed; one provided no qualitative results, 62 involved no human study, 25 did not consider acute tolerance within dose, and 13 failed to provide data on both ascending and descending BAC. We extracted data from the 26 remaining articles. The studies were highly heterogeneous. Most were small, examining a total of 770 subjects, of whom 564 received alcohol and were analyzed in groups of median size 10 (range 5–38), sometimes subdivided on the basis of drinking or family history. Subjects were often young white men. Doses of alcohol and rates of administration differed. Performance was assessed by at least 26 different methods, some of which measured many variables. We examined only results of studies which compared results for a given alcohol concentration (C) measured on the ascending limb (Cup) and the descending limb (Cdown) of the BAC-time curve, whether in paired or parallel-group studies. When subjects were given alcohol in more than one session, we considered results from the first session only. Rating at Cdownwas better than at Cupfor some measures, as expected if the Mellanby effect were operating. For example, subjects rated themselves less intoxicated on the descending limb than at the same concentration on the ascending limb in 12/13 trials including 229 subjects that gave statistically significant results. In 9 trials with a total of 139 subjects, mean difference could be calculated; weighted for study size, it was 29% [range 24–74%]. Willingness to drive was significantly greater in 4 of 6 studies including a total of 105 subjects; weighted mean difference increased by 207% [range 79–300%]. By contrast, measure of driving ability in three groups of a total of 200 trials in 57 subjects showed worse performance by a weighted mean of 96% [range 3–566%]. In three trials that tested inhibitory control (cued go or no-go response times), weighted mean performance was 30% [range 14–65%] worse on the descending limb. Conclusions:The “Mellanby effect” has been demonstrated for subjective intoxication and willingness to drive, both of which are more affected at a stated ethanol concentration when BAC is rising than at the same concentration when BAC is falling. By contrast, objective measures of skills necessary for safe driving, such as response to inhibitory cues and skills measured on driving simulators, were generally worse on the descending part of the BAC-time curve for the same BAC. [ABSTRACT FROM PUBLISHER]

Background: Junior doctors in the UK must complete various educational components during their two year Foundation training programme. It is important that mandatory learning is informative and engaging. The aim of this study was to evaluate trainee doctors’ perceptions of a Technology Enhanced Learning (TEL) programme developed to improve prescribing competency. Method: Focus groups and interviews were conducted at three hospital sites in the West Midlands. Codes, sub-themes and themes were determined using deductive and inductive thematic analysis. Results: Data were collected from 38 Foundation trainee doctors. Results revealed major themes relating to prescribing education, the user experience and user engagement. Key findings included the positive impact of preparedness following undergraduate education on the user experience of the TEL programme at the postgraduate level; the impact of content, structure, and individual learning needs and styles on the user experience; and the impact of motivation and time on engagement. Most trainees engaged with the programme owing to its mandatory nature; however, some trainees also used the programme voluntarily, for example, to acquire knowledge prior to starting a new placement. Conclusions: It is important to ensure that learners are willing to engage with mandatory TEL, and that they have the time and motivation to do so. It is also important to ensure that learners have a positive user experience and that in designing TEL individual differences in learning styles and needs are taken into account. These findings have implications for educators and system developers in the construction and design of mandatory eLearning programmes. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacovigilance includes analysis of large databases of information on drugs and events using algorithms that detect disproportional frequencies of associations. In order to test such algorithms, attempts have been made to provide canonical reference lists of so-called 'positive controls' and 'negative controls'. Reference sets with even modest levels of misclassification may result in under- or overstatement of the performance of algorithms.Aim: We sought to determine the extent to which 'negative control' drug-event pairs in the Observational Medical Outcomes Partnership (OMOP) database are misclassifiedMethods: We searched the medical literature for evidence of associations between drugs and events listed by OMOP as negative controls.Results: The criteria used in OMOP to classify positive and negative controls are asymmetric; drug-event associations published only as case series or case reports are classified as positive controls if they are cited in Drug-Induced Diseases by Tisdale and Miller, but as negative controls if case series or case reports exist but are not cited in Tisdale and Miller. Of 233 drug-event pairs classified in the 2013 version of OMOP as negative controls, 21 failed to meet pre-specified OMOP adjudication criteria; in another 19 cases we found case reports, case series, or observational evidence that the drug and event are associated. Overall, OMOP misclassified, or may have misclassified, 40 (17 %) of all 'negative controls.'Conclusions: Results from studies of the performance of signal-detection algorithms based on the OMOP gold standard should be viewed with circumspection, because imperfect gold standards may lead to under/overstatement of absolute and relative signal detection algorithm performance. Improvements to OMOP would include omitting misclassified drug-event pairs, assigning more specific event labels, and using more extensive sources of information. [ABSTRACT FROM AUTHOR]

Background Adverse drug reactions are sometimes described as being 'non-dose-related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. Methods We searched for published adverse drug reactions that have been described as non-dose-related and analysed them. Results We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose-response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. Conclusions and implications If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind. [ABSTRACT FROM AUTHOR]

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions. [ABSTRACT FROM AUTHOR]

Aims Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition. Methods Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken. Results One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m−2. Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) m m and serum potassium of 3.3 (95% CI 3.0, 3.5) m m. Mean urinary sodium concentration was 64 m m (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide. Conclusions Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7-14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required. [ABSTRACT FROM AUTHOR]

Background A computerized physician order entry (CPOE) system with embedded clinical decision support can reduce medication errors in hospitals, but might increase the time taken to generate orders. Aims We aimed to quantify the effects of temporal (month, day of week, hour of shift) and other factors (grade of doctor, prior experience with the system, alert characteristics, and shift type) on the time taken to generate a prescription order. Setting A large university teaching hospital using a locally developed CPOE system with an extensive audit database. Design We retrospectively analyzed prescription orders from the audit database between August 2011 and July 2012. Results The geometric mean time taken to generate a prescription order within the CPOE system was 11.75 s (95% CI 11.72 to 11.78). Time to prescribe was most affected by the display of high-level (24.59 s (24.43 to 24.76); p<0.001) or previously unseen (18.87 s (18.78 to 18.96); p<0.001) alerts. Prescribers took significantly less time at weekends (11.29 s (11.23 to 11.35)) than on weekdays (11.88 s (11.84 to 11.91); p<0.001), in the first (11.25 s (11.16 to 11.34); p<0.001) and final (11.56 s (11.47 to 11.66); p<0.001) hour of their shifts, and after the first month of using the system. Conclusions The display of alerts, prescribing experience, system familiarity, and environment all affect the time taken to generate a prescription order. Our study reinforces the need for appropriate alerts to be presented to individuals at an appropriate place in the workflow, in order to improve prescribing efficiency. [ABSTRACT FROM AUTHOR]

Rational therapeutics requires a balance between benefits and harms. (i) Harm may be inevitable. Some adverse drug reactions cannot be predicted or prevented. (ii) Some harm occurs in error when a medicine is wrongly formulated, prescribed, dispensed or administered. Adverse drug reactions that might have been prevented, for example, by monitoring, fall into this category. (iii) Rarely, harm is inflicted deliberately, for example, in murder by poisoning. Here I consider adverse drug reactions, errors and deliberate drug-induced harm from the perspective of a clinical pharmacologist. [ABSTRACT FROM AUTHOR]

Background: Clinical decision support (CDS) for electronic prescribing systems (computerized physician order entry) should help prescribers in the safe and rational use of medicines. However, the best ways to alert users to unsafe or irrational prescribing are uncertain. Specifically, CDS systems may generate too many alerts, producing unwelcome distractions for prescribers, or too few alerts running the risk of overlooking possible harms. Obtaining the right balance of alerting to adequately improve patient safety should be a priority. Methods: A workshop funded through the European Regional Development Fund was convened by the University Hospitals Birmingham NHS Foundation Trust to assess current knowledge on alerts in CDS and to reach a consensus on a future research agenda on this topic. Leading European researchers in CDS and alerts in electronic prescribing systems were invited to the workshop. Results: We identified important knowledge gaps and suggest research priorities including (1) the need to determine the optimal sensitivity and specificity of alerts; (2) whether adaptation to the environment or characteristics of the user may improve alerts; and (3) whether modifying the timing and number of alerts will lead to improvements. We have also discussed the challenges and benefits of using naturalistic or experimental studies in the evaluation of alerts and suggested appropriate outcome measures. Conclusions: We have identified critical problems in CDS, which should help to guide priorities in research to evaluate alerts. It is hoped that this will spark the next generation of novel research from which practical steps can be taken to implement changes to CDS systems that will ultimately reduce alert fatigue and improve the design of future systems. [ABSTRACT FROM AUTHOR]

Background: The behaviour of doctors and their responses to warnings can inform the effective design of Clinical Decision Support Systems. We used data from a University hospital electronic prescribing and laboratory reporting system with hierarchical warnings and alerts to explore junior doctors' behaviour. The objective of this trial was to establish whether a Junior Doctor Dashboard providing feedback on prescription warning information and laboratory alerting acceptance rates was effective in changing junior doctors' behaviour. Methods: A mixed methods approach was employed which included a parallel group randomised controlled trial, and individual and focus group interviews. Junior doctors below the specialty trainee level 3 grade were recruited and randomised to two groups. Every doctor (N = 42) in the intervention group was e-mailed a link to a personal dashboard every week for 4 months. Nineteen participated in interviews. The 44 control doctors did not receive any automated feedback. The outcome measures were the difference in responses to prescribing warnings (of two severities) and laboratory alerting (of two severities) between the months before and the months during the intervention, analysed as the difference in performance between the intervention and the control groups. Results: No significant differences were observed in the rates of generating prescription warnings, or in the acceptance of laboratory alarms. However, responses to laboratory alerts differed between the pre-intervention and intervention periods. For the doctors of Foundation Year 1 grade, this improvement was significantly (p = 0.002) greater in the group with access to the dashboard (53.6% ignored pre-intervention compared to 29.2% post intervention) than in the control group (47.9% ignored pre-intervention compared to 47.0% post intervention). Qualitative interview data indicated that while junior doctors were positive about the electronic prescribing functions, they were discriminating in the way they responded to other alerts and warnings given that from their perspective these were not always immediately clinically relevant or within the scope of their responsibility. Conclusions: We have only been able to provide weak evidence that a clinical dashboard providing individualized feedback data has the potential to improve safety behaviour and only in one of several domains. The construction of metrics used in clinical dashboards must take account of actual work processes. [ABSTRACT FROM AUTHOR]

Background: Life-threatening adverse drug reactions (ADRs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) continue to affect patients' lives long after the event. Survivors and their relatives rely heavily on Internet sources for support and advice, but narratives of their experiences posted on patient websites have not been explored previously.Objectives: The aim of the study was to illuminate patient experience by analysing Internet narratives of drug-induced SJS and TEN and considering the reasons for postings on patient websites, and the concerns they reflect. We also aimed to compare these experiences with a previous study of survivors of SJS and TEN conducted by face-to-face interview.Methods: We searched for unsolicited personal narratives or descriptions of drug-induced SJS and TEN posted on the Internet between February 2009 and June 2010, and analysed them using a thematic qualitative approach.Results: We analysed 208 Internet descriptions. Motivation for posting on the Internet included a desire to share experiences and to seek advice from others. Patients and their relatives expressed concern that the ADR may be hereditary, worries about effects on fertility and a fear of recurrence. They also wished to increase awareness of the potential harms from medicines and to inform others of the suspected cause of the ADR.Conclusion: Individuals experiencing SJS or TEN had many unanswered questions and concerns long after the event. Our findings could guide health professionals in the management of survivors of the ADR, and in communicating more effectively with patients and their relatives. Internet forum postings of patient experiences of ADRs provide insight into patient concerns and supplement findings from detailed face-to-face interviews. [ABSTRACT FROM AUTHOR]

Background: Life-threatening adverse drug reactions (ADRs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) continue to affect patients' lives long after the event. Survivors and their relatives rely heavily on Internet sources for support and advice, but narratives of their experiences posted on patient websites have not been explored previously. Objectives: The aim of the study was to illuminate patient experience by analysing Internet narratives of drug-induced SJS and TEN and considering the reasons for postings on patient websites, and the concerns they reflect. We also aimed to compare these experiences with a previous study of survivors of SJS and TEN conducted by face-to-face interview. Methods: We searched for unsolicited personal narratives or descriptions of drug-induced SJS and TEN posted on the Internet between February 2009 and June 2010, and analysed them using a thematic qualitative approach. Results: We analysed 208 Internet descriptions. Motivation for posting on the Internet included a desire to share experiences and to seek advice from others. Patients and their relatives expressed concern that the ADR may be hereditary, worries about effects on fertility and a fear of recurrence. They also wished to increase awareness of the potential harms from medicines and to inform others of the suspected cause of the ADR. Conclusion: Individuals experiencing SJS or TEN had many unanswered questions and concerns long after the event. Our findings could guide health professionals in the management of survivors of the ADR, and in communicating more effectively with patients and their relatives. Internet forum postings of patient experiences of ADRs provide insight into patient concerns and supplement findings from detailed face-to-face interviews. [ABSTRACT FROM AUTHOR]