Painkillers: powerful drugs with important adverse effects

A new report in the Lancet from the Oxford Clinical Trials Unit provides an update on potential risks from newer and traditional painkillers of the non-steroidal anti-inflammatory drug type. The report analysed results of a large number of clinical trials comparing these painkillers against placebo or against a comparator different painkiller. Studies were largely of high doses of the drugs, prescribed for relatively short duration - on average for under a year.

Below is a summary of my comments on the Lancet article provided to the Science Media Centre.

"In this pooled assessment (meta-analysis) of a large number of clinical trials against placebo or other pain-killer options, the Oxford Clinical Trials Service Unit confirm previous reports that the newer pain-killer drugs – coxibs - are associated with a clinically important increase in risk of coronary disease.

"Their major new finding is that among traditional non-steroidal anti-inflammatory painkiller drugs [tNSAIDs] – diclofenac, and possibly ibuprofen, but not naproxen appear associated with a similar increase fatal and non-fatal coronary heart events to the coxibs. However all naproxen, like all coxibs and tNSAIDs they studied, was associated with increased risk of heart failure and gastro-intestinal complications such as bleeding.

"The type of vascular risk with these painkillers appeared selective as none of these treatments were associated with an increase in stroke risk.

“Cautions include that we are not told about details of adjustments across treatment groups for degree of different cardiovascular risk factors e.g. from smoking as a source of bias. And the authors themselves acknowledge that their findings are largely for high dose tNSAIDs and for treatment on average for under a year. They note that they therefore cannot be sure whether the reported coronary and other risks would persist in patients on longer term treatment or on lower doses of these medicines.

“The paper underscores a key point for patients and prescribers: powerful drugs may have serious harmful effects. It is therefore important to be cautious when considering use of these medicines and to take into account cardiovascular risk, and risk of stomach or intestinal adverse effects, when tNSAIDs are prescribed or obtained over the counter, and when coxibs are considered.”

Many patients taking these tablets rely on them for relief of symptoms from arthritis and other long-term painful conditions. Patients who are concerned should consult their medical or pharmacist adviser.

See also articles by reporters on BBC Health, Reuters, Agence France Presse, CBS News ...

Spanish researchers provide evidence for primary prevention of cardiovascular disease by a Mediterranean diet

Professor Ramón Estruch from Barcelona and his colleagues have published in the New England Journal of Medicine results of an important study on the greater value of a Mediterranean diet vs. low fat diet in the prevention of cardiovascular risk.  

In their multi-centre, randomised trial in Spain, 7447 high risk patients with no clinical vascular disease (age range 55-80, 57% women)  were asked to follow one of 3 dietary options:

• a Mediterranean diet with 
• extra-virgin olive oil
• or with  mixed nuts

• or a control diet with advice to reduce dietary fat.

The primary end point was rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). The trial was stopped early after median follow-up 4.8 years.

What did they find? After adjusting for obvious bias, both Mediterranean diet groups had significantly better outcomes: hazard ratios compared to the control group  (109 clinical events)

- added oil: 0.70 (95% confidence interval [CI], 0.54 to 0.92) - 96 clinical events

- with nuts: 72 (95% CI, 0.54 to 0.96) - 83 clinical events

In other words, the relative risk of serious cardiovascular disease was reduced by one third by following a calorie unrestricted Mediterranean diet vs. a low fat diet. The absolute risk reduction was 3 fewer clinical events for every 1000 patient years of treatment ie ~3 fewer clinical events for every 200 patients following the Mediterranean diet option for 5 years. There were 2-3 future strokes per 1000 patient years of treatment.

Considering the impact of these preventable strokes alone, using UK data as an example, that decrease of 2-3 strokes per 1000 patient years of treatment would represent ~300-450 fewer strokes per year at a saving in direct and indirect health costs, and further societal annual costs of ~£16–25m  [€18-28m].

Of note, patients were supported during the study by regular educational prompts, as well as some free food supplements.

These were clearly patients at high risk from cardiovasular disease either from:

• type 2 diabetes mellitus or 
• at least three of 
• smoking
• hypertension
• raised bad (LDL) cholesterol 
• low good (HDL) cholesterol
• overweight or obesity
• family history of premature coronary heart disease

The authors themselves raise the obvious questions whether people not living in a Mediterranean and/or at lower cardiovascular risk would receive similar benefit.

Their results at least however 'support the benefits of the Mediterranean diet for the primary prevention of cardiovascular disease' in patients already at high risk: an important message for policy makers, health professionals, and at least those with the above risk factors for serious vascular events.

See the research paper 

Estruch R, Ros E, Salas-Salvadó J et al: the PREDIMED Study Investigators. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med. 2013 Feb 25. [Epub ahead of print]

Shift work and cardiovascular risk

@HealthMed It is well-known that shift workers have increased risk factors for serious heart disease, for example as reported in Knuttson's 1986 Lancet paper on papermill workers. They are more likely to smoke and tend to have higher blood pressure, cholesterol and weight and be more likely to have diabetes than  workers whose work pattern is confined to the daytime. They are also more likely to have insomnia, itself an independent risk factor for cardiovascular disease. Clinical pharmacologist Daniel Hackem from Ontario and his colleagues from Norway, Sweden and the USA had now raised further public and health professional interest in this disease link in a paper published in the British Medical Journal.

They looked at 34 previous studies of over 2 million shiftworkers. Together, there were over 17,000 heart events, over 6000 heart attacks and almost 2000 strokes. They concluded that stroke risk was around 5% higher and coronary event risk 24% higher in the shift-workers. Surprisingly, despite their large dataset, the researchers found no associated increase in mortality.

They take care to point out, as with any other observational study, that this is not necessarily a cause and effect relationship. People who take on shift work may be different in some unconnected way that puts up risk of vascular disease. Lower socio-economic status is an obvious important confounder. The work itself may be more stressful, at the same time as their being fewer other staff members in support 'out of hours'. Shift workers may also take more caffeine to try to stay alert during often long shifts.

Nonetheless there are several key messages reinforced by this report.

Shift-workers are more likely to have an excess of a wide range of cardiovascular risk factors. They  should therefore be encouraged to seek regular medical advice and their employers to raise awareness of these health risks and to support their staff in seeking regular medical advice. Shift-workers should also be supported in ensuring a healthy lifestyle despite the constraints on exercise and diet of unsocial hours of work.

Clinical pharmacologists and other health professionals should make sure to take a good occupational health history, including identifying whether a patient does shift work. They should make sure particular  care is taken to identify and reduce severity of cardiovascular risk factors in shift workers, supported by effective regular advice on healthy lifestyle. And where drug treament is indicated, prescribing treatment targets should be adjusted to take account of the increased cardiovascular risk to be prevented.

Employers should also make sure that patterns of shift work follow international guidance regarding avoiding abrupt shift changes, maximum shift duration and ensuring sufficient staff are working 'out of hours' to ensure that work is done both safely for employers' outcomes as well as their workers' health.

Alcohol and risk: surprising early warning from F Scott Fitzgerald.

F Scott Fitzgerald

@HealthMed More early 20th Century discussion in literary fiction of risks of over-indulgent lifestyle.
F Scott Fitzgerald addresses lifestyle risk twice in his 1922 novel 'The beautiful and damned': smoking as a risk for a young woman's complexion, and later in the book, risks of alcohol.
Usher girlfriend Georgina challenges Harvard man Anthony Patch on his drinking - both for the amount and as a daily habit, predicting serious disease. She comments: 'you and your friends keep on drinking all the time. I should think you'll ruin your health'. She then adds: 'Think what you'll be at 40'.
Anthony is dismissive, replying that 'I only get really tight once a week'. He is neither concerned about weekly binges nor about the long term. For him 40 is beyond his horizon.
Apparent insight, but not for him - for Fitzgerald - take heed of what he says, not as he does.
The book is remarkably prophetic in that the author himself did not live much beyond 40, dying aged ~44 after what was considered a second heart attack, with excessive alcohol considered a major health problem,  oesophageal varices suggested as the cause of a major illness. Retrospective risk factor ascertainment is of course problematic, however it is likely that his smoking contributed to his early demise, assuming the heart attack diagnoses are correct.

Notes on why and how to stop smoking. 

Smoking warnings in literary fiction

Smoking and hip fracture risk

Ideas for losing weight

French paradox

Stopping smoking - why and how?

@HealthMed UK No Smoking day is 14th March 2012: some helpful Q & As.

But no need to wait until then to stop ...

Why bother?
Apart from the obvious: cost, smell on clothes and breathe, and taste impairment and eventual loss of taste? Smoking is the single most preventable cause of disease and death.
For primary prevention, smokers and their advisers need to be well informed of the personally relevant risks of smoking and benefits of stopping. For younger smokers, risks include premature ageing of the skin, increased risk of impotence, risk to the developing baby in the womb, and increased risk in offspring of serious chest disorders. For older smokers, the more pressing risks are increased risk of cancer of the lung, mouth, throat, bladder and many other types of cancer; premature ageing of arteries, leading to heart attacks, strokes and other serious disorders of the heart, brain and circulation; and serious lung disorders including chronic obstructive lung disease and emphysema. And in the long-term, it is estimated that around half the smokers who do not give up smoking will die from one or more of these and other smoking-related diseases.
For non-smokers and confirmed ex-smokers the question has to be - why bother? Give up now to improve your medical and financial health.
For current smokers, the challenges are to beat the psychological, physical (nicotine), and social addiction, including resisting peer pressure. Useful ammunition to help smokers to stop smoking includes being aware that giving up tobacco can help you live longer, and that the risk of getting cancer is less with each year you stay smoke-free.

Help from friends and family
Now is a good time for smokers to be ready to think about stopping, to think about stopping and to prepare to stop. That might mean telling friends and family you are serious about stopping, and to seek whatever help may work - e.g. from pharmacist, family doctor or nurse, or other health professional, and smoking cessation support groups. The US National Institutes of Health recommend:
- 'Try not to view past attempts to quit as failures. See them as learning experiences'.
- 'Make a plan about what you will do instead of smoking at those times when you are most likely to smoke'.
- 'Satisfy your oral habits in other ways'. 
Their website provides excellent advice on other ways to help to smoking including how to plan stopping, setting a stop date, and having alternative strategies for times you associate with smoking. 

Stop smoking apps
There are now several free or low cost 'apps' which may be helpful. For example, the UK NHS mobile 'Quit smoking' app provides links for UK smokers to the NHS Stop Smoking helpline and other UK NHS Stop Smoking Servces. 'My Last Cigarette' - MLC provides a dashboard with daily changing reminders of dangers of smoking, and updating estimates of effects of stopping smoking on risk of heart disease, lung disease and other serious medical problems, money saved since stopping, life expectancy gained, and number of smoking-related deaths since the time a smoker has stopped.

Benefits of training health professionals and funding nicotine replacement treament
A controlled study in Germany reported benefits from extra training for family doctors, and further benefit when costs of anti-smoking treatment are subsidized. However, for these over 10/day cigarette smokers, although very helpful for those who succeed in stopping, outcomes were very modest: by
12 months after intervention, 1 in 30 had stopped with usual support, 1 in 10 when their family doctor had received training and been paid a €130 incentive for each patient who stopped, and 1 in 7 where patients also had costs of treatments subsidized.

Unexpectedly rapid benefits from banning smoking in public places
More recent encouragement for anti-smoking campaigns has come from evidence of the rapid time to benefit from stopping: around 1 in 5 fewer heart attacks within 1 year of stopping in countries which have moved to ban smoking in public places. That provides clear evidence to smokers that their cardiovascular risk reduces very rapidly after stopping smoking.

Avoiding temptation to smoke
A recent review of a large number of trials of ways to help people to stop smoking concluded that the evidence for success was 'strongest for interventions focusing on identifying and resolving tempting situations'.

If you are a smoker you quit, what worked for you? Please add a comment ...

© DRJ Singer