Not so smart drugs: concerns about modafinil

Modafinil has been in medical use since the late 1980s to improve alertness.

Because of concerns about serious medical risks, medical use has been restricted to treating narcolepsy since 2010 by the European Medicines Agency and the UK's Medicines and Healthcare products Regulatory Agency.

Students and employees, young and old, are being tempted to use 'smart' drugs to try to improve their academic or professional performance. This use of modafinil is not medically licensed - the aim of improving the effectiveness of learning and performance in exams, and other educational assignments.

The drug is reported to be in widespread use by students in Germany, the UK, the US and elsewhere in the hope that it will improve studying, learning and exam performance.
 

How is modafinil thought to act? Its mode of action is unknown. Suggested mechanisms include orexin-mediated enhancement of a range of brain activation neurotransmitters (norepinephrine, dopamine, histamine, serotonin) in brain arousal centres; and increased gap junction communication from brain cell to brain cell.

Does modafinil improve intellectual performance? At best, it is considered no substitute for a healthy sleep pattern. There have been two types of formal study – those in well-slept healthy young or older subject; and studies in sleep deprived subjects. Typically, studies are of a single dose, and medical or psychiatric disorders, and use of other medical drugs, or recreational drugs (including caffeine, alcohol and nicotine) are reasons for exclusion from studies of modafinil.

Studies of possible effects of modafinil on studying and learning are typically based on artificial tests – ie do not test for possible benefits of the drug on what students may be trying to learn, or results of the types of exams students may be sitting. Results are conflicting. In high IQ young subjects, performance of highly complex psychological tests, but not less complex tasks, may be improved. More focused study, with however increased response time has also been reported.

Anecdotally, students have reported that the drug appears to lead to more efficient completion of a deadline but not improvement in content. However these perceptions are vulnerable to placebo responses.

Only a handful of good quality studies have been performed on the possible effects of modafinil on cognition. These have involved psychological model tests, not studies of how well students learn course or professional materials. There remains the need for study of effects and risks of repeated use of modafinil in real world settings using tests relevant to the study activities of students.

Side effects? There are many – from loose bowels, to loss of effectiveness of the oral contraceptive pill, leading to unwanted pregnancy, and rare but life-threatening and fatal skin reactions Stevens-Johnson Syndrome).

Further important side effects include sleep disturbance and neuropsychiatric disorders indirect reasons why performance might be impaired by the drug.

There are also reports by users that in response to modafinil too much focus on details may make it difficult both to complete an assessment and to consider a broad enough range of issues to give a complete answer.

Risks of modafinil may be greater if there are unrecognized problems, in particular if the user has a medical history of cardiovascular or psychiatric problems. Use without clinical advice may mean that important underlying conditions are not identified, for example high blood pressure, disorders of heart rhythm, and psychiatric risk; and potential important interactions with other drugs (including other stimulants) may not be considered.

Modafinil has clinically significant effects on the activity of liver enzymes and drug transporters which are important in the handling and clearance of a wide range of common drugs, including digoxin and warfarin.

Older people are more likely to have medical disorders and to be on treatment which might lead to increased risk from modafinil. A particular concern is that these markers of increased risk may not be considered when off-licence supplies are being sought in the hope that there may be benefit for professional work, or as an aid to studying – for example for revalidation.

  
Is use of modafinil any different from using caffeine? Because of the lack of convincing evidence of real world benefit from modafinil and concerns about serious risks, the drug is not approved for use in the absence of a specified medical condition. There are to date no convincing studies showing a benefit from modafinil in long-term use or for specific types of learning or testing relevant to students.

As for other drugs, the balance between risk and benefit must be considered by prescriber and user. In the event of any benefit for studying from the drug, others not using it are put at a disadvantage. 

In contrast caffeine is widely available for those who chose to use it. Too much caffeine, or sensitivity to caffeine can cause troublesome symptoms, including anxiety, tremor, sleep disturbance and palpitations.

Risks from accessing modafinil  from internet pharmacies? For the above reasons, licensed pharmacies would not supply modafinil in the absence of specified medical conditions. Unlicensed internet pharmacies should be avoided. The quality of medicines is not reliable, with serious risk of being supplied poorly active or counterfeit or contaminated medicines. And medical contra-indications need to be identified and discussed to minimize the risk of preventable serious adverse effects.

Fairness and coercion There are also a number of ethical concerns including: the need to protect students and others from using so-called ‘smart drugs’ in response to pressure to compete, both in exams and in professional life; being fair to other students who do not have access to the drug, or do not wish to use what may be a medically harmful pharmacological aid to improving performance in examinations or to meeting challenges at work.

See also
- June 2009: Opposing opinions in the British Medical Journal from John Harris and Anjan Chatterjee

-  Methylphenidate (Ritalin) – does use by ‘healthy’ students matter?

Mediterranean diet and Cardiovascular Health

Ramon Estruch, a Spanish researcher on benefits of the Mediterranean diet, will speak in London at a Symposium on Cardiovascular Health on 5th December 2013.

Registration and abstract submission is now open for the Symposium.

Professor Estruch's theme will be outcomes of his multi-centre study reporting that, for patients who already are at high cardiovascular risk, a Mediterranean diet without calorie restriction is more effective than a low fat diet in reducing the occurrence of serious cardiovascular events.

His findings were published in the New England Journal of Medicine at the end of February 2013.

This event is one of a series of Symposia on Cardiovascular Health being held by the CVRT at the rooms of the Medical Society of London, one of the oldest continuing medical societies in the world.

Weblink for 5th December Symposium on Cardiovascular Research.

More on the research by Professor Estruch.

The symposium is being organised by  the Cardiovascular Research Trust.

US - European perspectives on potential impact of promoting cycling

As a response to my summer notes on 'city cycling', I was sent a link by @jenicarhee to a graphic (see below) on potential impact of regional schemes to promote cycling. Projected advantages include for health, environment and financial benefit. This approach lends itself to regular update on actual outcomes and imaginative ways to assess impact. See for yourself via: 'How bikes can save us [infographic]'.

Drugs don't work if patients don't take them

@HealthMed A surprisingly common problem: WHO estimates published in 2003 and more recent studies suggest that in the developed world around 50% of patients with chronic medical disorders such as diabetes and asthma do not take their medicines regularly. Indeed, for example, for high blood pressure, around half the patients on drug treatment have stopped taking their tablets within the first year of starting treatment. Despite this evidence that many patients are not benefiting from prescribed medicines, these data may even be underestimates of prevalence of low adherence to medicines, as clinical studies are typically conducted in patients willing to participate, who have less co-morbidity and have fewer prescription medicines than is usual in the general population of patients.
There are multiple potential contributory factors, including costs of paying for medicines, lack of insight into medical conditions or awareness of ways in which medicines may help, perceptions that medicines are not working, and concerns about potential or actual adverse effects of medicines.
Personalising medicines using genetic and other companion diagnostics may help to improve adherence by avoiding drugs more likely to cause adverse effects.
Identifying and improving poor adherence is important to maximise disease control, improve quality of life, and to avoid unnecessary investigation, avoidable treatment escalation and avoidable adverse effects if treatments not normally taken are taken variably by a patient or are dispensed e.g. during acute medical admission.
Poor adherence can be recognized in a number of ways, including direct discussion with the patient, tablet counts, checking timeliness of prescription renewal, and both clinical and laboratory clues from expected biological effects of the medicines.
More studies are needed to identify ways to be more effective in helping patients to be more adherent to their medicines. Meantime the UK'S NICE recommends regular informed discussion with patients to improve adherence to their medicines.

© DRJ Singer

Assessing prescribing skills

@HealthMed Doctors and other prescribers internationally find prescribing challenging. To get this right at times of high pressure, including in the emergency medicine setting, it is vital that basic skills are as well developed as possible. Add to that the need for care in calculation, avoiding the distracting effects of multi-tasking, challenges in medicines reconciliation, and risks inherent in shift-working and other complex work patterns. And electronic prescribing systems alone are not a sufficient safeguard. For example, reporting from the USA indicates that error rates may increase following the move from paper to electronic prescribing. The complex range of skills needed for safe and effective prescribing includes sound core knowledge of basic mechanisms of drug action, drug use in the clinical setting, and the impact of patient genetics, age, gender, lifestyle, the disease to be treated as well as co-existing medical conditions and the impact of other drugs and remedies. Many of these principles are easier to put into practice by adopting a personalized approach to therapeutics, with the aim of prescribing the right drug or drugs at the right dose to the right patient for the right disease and at the right time.

To help to increase focus on early training in essential prescribing principles and practice, in the United Kingdom the British Pharmacological Society and the Medical Schools Council supported by a national team of experts, to develop a Prescribing Skills Assessment that will eventually allow all students to rehearse and demonstrate competencies relevant to safe and effective initiation, monitoring, review and, when needed change in route, dose, duration or type of medicines alone and in combination in clinical practice, along with skills in communicating key points about medicines to patients, their carers and to relevant health professional colleagues.

See related blogs on
- Improving prevention of serious adverse drug reactions 
- Personalized medicine for better drug discovery

Advances in treating acute lung syndromes

@HealthMed Although only described as recently as 1967, a range of important contributory factors have been defined for acute respiratory distress syndrome (ARDS), which is now recognized to be at the severe end of a spectrum of acute lung injury, which imposes high risk for patients and which confers a major burden on health services. Outcome of treating the syndrome has been much improved by developments in devices to treat lung and other organ failure, supported by advances in expertise in intensive care. However, other than treatments for underlying causes, there is still important unmet need with regard to effective specific pharmacological treatments.

A timely review of ARDS by Dushianthan and colleagues is the Editor’s choice article in the September issue of the Postgraduate Medical Journal.  These experts from Southampton provide an update on knowledge of risk factors, including genetic biomarkers, for development of ARDS and other acute lung injury variants, and an up-to-date commentary on general and specific treatment options.

The authors note that ‘sepsis, pneumonia, and trauma with multiple transfusions’ account for most episodes. They highlight the importance for recovery of ‘general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thrombo-embolism and gastrointestinal ulceration’.

They discuss encouraging experimental evidence from trials of corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants, however note that these findings have not as yet being translated into benefits for patients. They note as further treatment targets of interest, new approaches to modulating inflammation, and use of mesenchymal stem cells.

See the free full article for further details.

Networks and personalized medicine for better drugs?

For more on this theme see 
- article with Andrew Marsh in the inaugural March 2012 issue of Health Policy and Technology
- article in the October 2011 issue of Public Service Review: Science and Technology Review.  

For many individual patients treatments may not exist, may not be very effective, or may result in unpleasant adverse effects. How can prescribers improve drug selection andreduce the harmful effects of medicines? Are there better ways to develop drugs for patients who are difficult to treat?  And what can we do to improve poor adherence to medicines? These elements underpin ‘personalized medicine’, in current use the concept that by considering differences among patients in genetics, disease burden and other factors, more effective and safer drugs can be developed. Personalizing medicine is a path to better disease prevention and control where limited treatment options exist, such as for many cancers, resistant infections and dementia syndromes, and better drug development for new medical challenges. These concepts have in recent years attracted interest from the Royal Society, the Nuffield Council on Bioethics and cognate international institutions.

It is clear that there needs to be consistent investment and support from policy makers and regulators to develop and sustain the academic and industry pharmacology expertise and activity needed for the long-term success of a personalized medicine strategy, so that we can continue to be able to improve the health of the public and individual patients.

NICE is an international leader in developing evidence-based treatment guidelines. Its reports increasingly recognize the need to refine drug choice based on patient characteristics. For example, updated national hypertension guidelines released in August 2011 advise drug selection guided by age, gender, ethnicity, and monitoring, with treatment modified depending on clinical response. NICE also recognizes the need for research on ways, tailored to patient preference, to improve long-term adherence to drug treatment.

Pharmacologists are developing two complementary approaches aimed at achieving “precision medicine” in as many patients as possible: better drug discovery combined with high definition biomarkers for drug selection and monitoring. Network pharmacology brings together sophisticated databases of genetic mechanisms for disease, pharmacological pathways, candidate drugs, and population data describing important variants among individuals in drug handling and responsiveness.  These methods also allow ways to find previously unexpected “off-target” actions of existing or new drugs, which may accelerate discovery of new treatments for serious diseases.

Diagnostic methods are increasingly being used to improve drug selection for individual patients. For example growth tyrosine kinase receptors can be blocked using the biological agent imatinib to treat particular patterns of Philadelphia chromosome-positive chronic myeloid leukaemia, and rare gastro-intestinal tumours. Understanding genes and drugs that influence enzymes that modify drugs in the body, improves accuracy in defining patients who will not respond to a given medicine, or may develop adverse effects.  For example, to minimize risk of serious harm, pharmacogenetic testing is recommended for variability in a specific liver enzyme before deciding whether or not to prescribe the anti-HIV drug abacavir. This knowledge also allows better prediction of a patient’s risk of harm from interactions between treatments, based on recognition of medicines and other remedies that interfere with how drugs are cleared by the body. 

See my previous blogs on 
- preventing adverse drug reactions
- new UK guidelines on managing high blood pressure

City cycling: beyond the obvious benefits

Cycling sounds an attractive approach to better personal health, reduced carbon footprint and therefore a generally healthier urban environment. Rojas-Rueda and colleagues in a British Medical Journal paper have recently modeled the health risks and benefits of the Barcelona bike sharing scheme (Bicing), based on the over 180,000 Barcelona residents using the Bicing scheme.  They conclude there are greater health benefits than risks in Barcelona, and a large reduction in annual carbon dioxide emissions.
For Barcelona and elsewhere, bike-sharing appears to offer the opportunity to introduce regular cycling as a way for many in the population to return to, or increase exercise, on a sufficient scale for both public health and environmental benefits.
After Milan's earlier efforts to provide affordable and enjoyable city centre cycling - yellow bikes disappearing around Europe to Geneva and beyond - Paris (launched 2007) and London (launched July 2010) are also addressing the challenge of encouraging exercise and reducing car travel on city centre streets - with some extra effects on healthy mind and body. This includes 'water-cooler' bonding as initiates explain how to use the cycle pay columns or how to free a tricky bike. And more than intended exercise in several forms. Cyclists often need to return for a fresh hire after realising too late that their chosen cycle is faulty - punctured, chain off, saddle collapse syndrome, sticky wheels and so on (a Paris code is to reverse the saddle and or collapse the saddle support on a faulty bike); or moving from full cycle rack to next cycle station looking for a post at which to return a cycle at busier city locations. For the less pressed, this is another opportunity to meet fellow cyclists while waiting, and to compare notes on nearby velib station options. A peak time problem at busier sites is of course there being no bike available; more exercise, locating then walking to the next available station. Paris is trying hard - from the velib website at the end of August, 1233 locations were declared - enough hire and return capacity for this to be more than a tourist or freetime gimmick. The Paris website includes a colour-coded webmap: green for stations with available spaces, red for full cycle stations. The Paris Velib system leads the way globally in number of sites and available cycles. Paris also has the advantage of many wide pavements, and, in some areas, proper cycle lanes - although partnering these with buses and taxis is a source of recurrent adrenaline surge.
A reporting option on the booking terminal at cycle stations would be a good addition, so that the next hirer does not have the same problem; also helpful would be a less sticky webmap for locating alternative Velib stations: not a very mobile phone friendly website. And a review in Paris is planned of the economics of the scheme, with 80-90% of cycles reported in need of repair or replacement due to damage or theft; much less respected than the earlier  Lyon scheme (established May 2005, now with around 340 bike stations, and as for Paris, run as a partnership with advertising company JCDecaux).

© DRJ Singer

Improving prevention of serious adverse drug reactions

Around 1 in 20  admissions to hospital are due to adverse drug reactions in the UK and other countries with well-developed health services. There are multiple causes for this surprisingly high rate of adverse reactions to medicines: the patient might not have followed established guidelines, such as avoiding alcohol; the wrong drug or dose might have been prescribed; an interaction between two drugs might have been overlooked; the patient's genetic makeup might cause an anomalous reaction; the patient might be taking contaminated drugs bought from unregulated sources on the internet; an unknown adverse reaction to a new drug might have been missed in the development and safety testing of that drug.
Many of the adverse drug reactions are preventable. We need to make sure medical students and prescribers are aware of how to prescribe safely, know common and high risk drugs well and, importantly, to make sure adverse reactions are recorded on patients' records so that they don't happen again. Now that people are able to obtain  prescription drugs on the internet, systems also need to be improved in order to better regulate drugs that are accessed in this way. 
Today's national and international regulations on medicine safety have evolved over than a century. In 1906 came a major focus on medicine safety in the USA, with the Food and Drugs Act signed by President Theodore Roosevelt. The UK went on in 1941 with the Pharmacy and Medicines Act to force manufacturers to list active ingredients on drug packaging, and restrict manufacturers from general advertising about medical claims of their products. The thalidomide disaster of the late 1950s and early 1960s brought about further major improvements: previously drug testing was very limited. Now great care is taken in assessing possible risks of medicines during pregnancy.
Many serious adverse drug reactions happen in people with genetic reasons for reduced ability to handle drugs in the body. Drug leaflets now specify if there is any known 'pharmacogenetic’ information on a medicine. The potential seriousness of these differences between people is shown by the example that the Japanese regulatory authorities are unwilling to license drugs for use in their country unless they have been tested on Japanese people.
New pharmacogenetic provide the opportunity to reduce exposure of patients to potentially harmful medicines based on recognizing an increased genetic risk. And new chemical genomics methods allow ways to identify safer and more effective use of current and new medicines.
For further details on these themes, see my interview with Amy McLeod from Warwick's Knowledge Centre.

New ideas on diet and cardiovascular health?

What foods may actively help to promote the health of the heart, brain and circulation? And for people who have cardiovascular risk factors, heart disease or stroke syndromes, are there dietary factors that can reduce disease severity or prevent recurrent disease?

To address these and related questions outlined below, the CVRT organised an afternoon symposium on the 'Cardiovascular effects of ‘Healthy’ foods in London on Thursday 8th December, at the Medical Society of London rooms - 11 Chandos Street - 5 minutes walk from Oxford Circus. The symposium considered evidence and mechanisms for cardiovascular benefits (or not) of ‘healthy’ foods. A key message from KT Khaw was that healthy lifestyle actions are cumulative in protecting against serious disorders of the heart and circulation.

See weblink for the programme.

Too many calories, and high intake of saturated and transfats, are well recognised to increase risk of obesity, diabetes mellitus and accelerated vascular disease (atheroma) and low salt (sodium chloride) and potassium rich foods to confer cardiovascular protection.

Outstanding questions include whether particular types of macro-nutrient (protein, carbohydrate and fats) or micronutrients (vitamins, flavenoids, trace minerals) are protective. An association between dietary factor(s) and apparent cardiovascular benefit may be causative, due to 'reverse causation' [e.g. because healthier people believe in the link or are more likely to be able to afford particular dietary constituents]; or may be a coincidental association.

Speakers at the Symposium included Professor Roger Corder from the William Harvey Institute in London, Professor KT Khaw from the University of Cambridge and Associate Professor Naila Rabbani from the University of Warwick. KT Khaw  discussed current controversies, Naila Rabbani  bioactives in fruit and vegetables, and Roger Corder dietary polyphenols and potential vascular benefits of red wine and chocolate. And Jinit Masania outlined a new EU research programme, applying nutrigenomics to assess health claims made for foods.

This Symposium followed the July 2011 event on Exercise and Cardiovascular Health, also organized by the Cardiovascular Research Trust.

Further Symposia planned by the Cardiovascular Research Trust:
- 2nd Symposia on Cardiovascular Health, Diet and Exercise: Thursday 6th December 2012 

- 3rd Symposia on Cardiovascular Health, Diet and Exercise: Thursday 5th December 2013 

 

See blog on the French healthy heart 'paradox' 20 years on.

See also Dr Carolyn Staton’s excellent blog on 'Food and microcirculation' on the British Microcirculation Society site. 


© DRJ Singer

Painkillers and risk of heart rhythm disorders

This week the British Medical Journal published a report by Schmidt and colleagues from Denmark, North Carolina and Boston, USA on "Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter ..." This has lead to alarming print media and web headlines on risks of heart disease from these commonly used medicines. How worried should we be? On one level this is a general reminder that powerful medicines may have powerful harmful effects. Indeed previous studies have reported an increased risk of atrial fibrillation from NSAIDs and these medicines and the related COX-2 inhibitors have been implicated in increased risk of other types of heart disease. With that in mind, patients on these medicines who develop palpitations or other features of heart problems, including shortness of breath or ankle swelling, should consult their GP for advice. However there are some interesting aspects of the study showing the importance of looking critically behind headlines at the details of research reports. This includes considering potential sources of bias which may lead to undersestimation or exaggeration of effects; and being clear on the difference between absolute effect on risk (e.g. 17 vs. 10 per 1000) and relative risk (e.g. 70% increase). Here is a link to Donald talking about the study on BBC Radio