Cambridgeshire Methotrexate Toxicity Report

November 23, 2019


In April of 2000, a patient died following an avoidable presribing mistake. A once weekly dose of methotrexate was prescribed daily. A speaker at the Royal Pharmaceutical Society’s Conference last Sunday reminded me that the excellent Cambridgeshire Health Authority report of this incident used to be kept on my old website, since the original NHS website had disappeared.

For the purposes of keeping this important example in the public domain, I have put the PDF of the report on this site.


Photograph: “error” by strange little woman on stream. Attribution 2.0 Generic (CC BY 2.0)

Shortages and Shifts

November 20, 2019

White pills on blue

Medicines shortages are more than the abscence of medicines for patients. Prescribers will prescribe alternative drugs, which may be less safe. As a brief follow-up to a recent post on drug shortages, I looked at the outcomes following a shortage of naproxen (a non-steroidal anti-inflammatory drug – NSAID) using Open Prescribing Data. It appears that patients have been switched, at least in part, to other NSAIDs that carry a greater risk of cardiovascular, renal, and gastric adverse effects. I have posted this in a BMJ rapid response to Ferner et al’s piece on drug shortages:

From September to December 2018, prescribing of naproxen in English CCGs fell from 581,927 items to 480,171 items (a 17.5% fall). In September 2018, naproxen prescribing cost £1,495,703 – by January 2019 it had risen to £9,206,903, despite reduced prescribing. Apart from these financial costs, there was a regrettable shift in prescribing, as the proportion of NSAIDs with greater risks of cardiovascular, gastrointestinal, and renal adverse effects rose. The “Number of prescription items for all NSAIDs excluding ibuprofen and naproxen as a percentage of the total number of prescription items for all NSAIDs” rose from 20% in September 2018 to 24% in January 2019.

Given the current problems with shortages, care needs to be taken when substituting medicines. Those who write guidelines, or issue prescribing advice, should consider second line therapies in the event that the first line drug is unavailable.

Photograph: “White round pills on blue background” by Marco Verch. Attribution 2.0 Generic (CC BY 2.0)

Medication Safety - Call for Papers

November 07, 2019

Writing a Paper

Pharmacists are involved in all areas of the development, manufacture, supply, and monitoring of medication. They work in pharmacies, hospitals, the pharma industry, medicines regulators, and increasingly, in the UK, in General Practice. They are ideally placed, and trained, to help reduce the major burden of drug-related harm caused by the widespread use of inappropriate medicines.

As part of the need to develop the evidence base for the contribution pharmacists can make in this area, including how pharmacists can work with patients, I am co-editing a special themed issue of the International Journal of Pharmacy Practice.

there will be a special issue of the IJPP in 2020, containing papers relating to the contribution of pharmacists to medication safety. We welcome submission of papers describing innovative approaches to enhancing medication safety, or rigorous evaluation of existing validated medication safety tools. Papers addressing the contribution of pharmacists to communication with patients and carers and multidisciplinary attempts to reduce the harms of medications are also encouraged. Please submit papers by 31st January 2020, using our online system, and use the tick box provided to indicate that you wish the paper to be considered for inclusion in the special issue. Accepted papers are available immediately on our web pages via ‘early view’. The print version of the special issue is scheduled for the second half of 2020.

The rest of the details of the call for papers can be found here.

Photograph by Ivan Radic. Attribution 2.0 Generic (CC BY 2.0)

Brexit and Drug Shortages

October 30, 2019


Here’s a short piece on the potential effects of Brexit on the supply of medicines I wrote for the University of Birmingham. I set these concerns against the underlying problems around drug shortages, and was considering a no deal Brexit. Any deal is likely to further mitigate the problems of any Brexit.

The effects of Brexit, and consequences of attempts to mitigate those effects, are difficult to predict. Any evaluation is complicated by the baseline rates of drug shortages caused by other factors. Media reports of medicine shortages and their causes in the aftermath of Brexit may be influenced by the polarisation seen in the wider Brexit debate. What is clear though, is that even if government attempts to avoid medicine shortages are entirely successful, and supply chains adapt rapidly to post-Brexit changes, the underlying structural causes of medicine shortages will affect the supply of medicines for years to come.

Photograph Banksy does Brexit by Dunk. Attribution 2.0 Generic (CC BY 2.0)

Conformity and Pharmacovigilance

June 28, 2019


In the recent Chernobyl TV series, the dangers of conformity were clearly demonstrated. Multiple times. Shortly after the explosion, the Pripyat Executive Committee meets. A member expresses concern about the dangers facing Pripyat. He is effectively silenced by the social cost of not conforming to the group, the power of a high-ranking Soviet official, and false reassurances of a nuclear expert. Pripyat was not evacuated.

The costs of conformity are apparent these days on social media, where “cancel culture” and “pile ons” are used to enforce norms (often for opinions that might be widely held and are uncontroversial in offline culture) leading to political polarisation. Neither do you have to have lived in the Soviet Union to have been in a meeting where items are not challenged, or useful information not proffered, because of the potential cost of being “wrong”. The net loss of information this causes has its own cost. The emperor will walk without clothes far longer, or in the case of drug safety, unsafe prescribing practice may continue unabated.

At the turn of the century it was a widely accepted view that hormone replacement therapy (HRT) conferred cardiovascular benefits. An expert speaker on an evidence-based medicine course I was running in the very early 2000s berated a paper that suggested that these effects were unlikely, Observational data and mechanisms were provided as to why the cardiovascular benefit was real. Everyone nodded. Later it was found that HRT did not confer a cardiovascular benefit in a randomised clinical trial and, in fact, inflicted a harm instead.1

Confounding was likely the cause in the observational studies. Women seeking HRT may have been unrepresentative of the general population, and less likely to develop cardiovascular disease. Was it the only cause though? The spread of the cardiovascular benefit of HRT amongst prescribers was widespread. Why do ideas become established, even when dissenting voices could challenge them? Cass Sunstein’s book on Conformity gives some clues.

Sunstein is a Professor at Harvard, who worked at the White House Office of Information and Regulatory affairs from 2009 to 2012, and was co-author of Nudge. His book is a concise journey through the psychology of conformity. Two key ideas start the book. The first, is that the actions and words of people around you are used as information to try to discern the truth. Secondly, what people do and say around you informs you how to behave to remain part of the group. Even if you have misgivings, you may suppress your views to remain part of the tribe.

Sunstein uses HRT as a example of how wrong information cascades. Rather than using privately held information, trusting their own judgement, prescribers will look at informational signals from other prescribers. A prescriber deciding whether or not to prescribe HRT for cardiovascular benefit will see other doctors have prescribed HRT, and unless they are extremely confident about their alternative view, they will prescribe it. The informational cascade of wrong information grows. None of the doctors may be confident about the evidence of a cardiovasular benefit of HRT. However, the uncertainity is kept private and the net effect is to show high confidence of benefit by virtue of the informational signals (prescribing) the prescribers send.

Such informational cascades can be broken, the change in views on opiate prescribing may be one recent example, but are still common. Sunstein also cites prostate-specific antigen (PSA) testing as another example. In the field of drug safety and pharmacovigilance, understanding how to break such informational cascades may be key to changing prescribing culture, once a risk has been identified. Certainly, the current track record of influencing prescribing decisions is mixed.2

This is only one aspect of the book; Sunstein provides a lens to view several current challenges in the world. Even at a more parochial level, for those want to make better group decisions with maximal information, and with less group think, the book provides useful information to engender an open culture to enable useful dissent.

Photograph The Corrosion of Conformity by Thomas Hawk. Attribution-NonCommercial 2.0 Generic

  1. Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. _JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321 

  2. Barber C, Gagnon D, Fonda J et al. Assessing the impact of prescribing directives on opioid prescribing practices among Veterans Health Administration providers. Pharmacoepidemiology and Drug Safety. 2017;26(1):40-46