What’s in placebos? No one’s telling…

Placebos – the inert substances taken by control groups in clinical trials – are often assumed to be harmless sugar pills or something along those lines. New research has found that actually it’s impossible to know what’s in placebos because there’s precious little documentation of what exactly is used in clinical trials.

Out of 176 research studies published in four of the biggest international medical journals, only one in five fully disclosed the composition of the placebo treatment. This lack of transparency suggests that all sorts of things could be being used, some of which might be having some sort of physiological effect and compromising the validity of findings on the study drug.

Placebo controlled clinical trials investigate the effects of a particular drug on a disease by comparing people who receive the treatment against patients receiving a placebo, which looks, smells, and tastes the same as the study drug but has no active ingredients. This design accounts for the placebo effect – the possibility that people in a trial may experience a health benefit because they’re taking a drug, not because the study drug they’re taking is effective.

In this study, the authors searched for randomised, placebo controlled trials published from January 2008 to December 2009 in four top medical journals – New England Journal of Medicine, JAMA, The Lancet, and Annals of Internal Medicine. A total of 176 trials were eligible for inclusion in the study – six studies of placebo pills, 65 studies of placebo injections, and 25 studies of other treatment methods (for example, nasal spray).

Only 40 (23%) of the 176 trials studied fully disclosed the composition of the placebo treatment, and 120 (68%) did not disclose any information on the placebo at all. The remainder partially disclosed what was in the placebo treatment.

Less than one in 10 (9.3%) studies that used pills disclosed the placebo, compared with 33.8% of studies that used injections and 40.0% that assessed other treatments. When papers that referred to previous publications for their primary findings or study design were excluded, these figures fell to 8.24%, 26.3%, and 27.8%, respectively.

By not paying attention to what’s in the placebo, researchers could be burying cases where the placebo has some sort of effect that’s similar to the effect of the study drug. The authors cite the example of trials of cholesterol lowering drugs that use olive oil and corn oil as the placebo. The monounsaturated and polyunsaturated fatty acids of these “placebos,” and their antioxidant and anti-inflammatory effects, could potentially reduce lipid levels and heart disease, just like the study drug, causing researchers to underestimate the effect of the cholesterol lowering drug.

“A positive or negative effect of the placebo can lead to the misleading appearance of a negative or positive effect of the drug,” author Beatrice Golomb, associate professor of medicine at the University of California, San Diego School of Medicine, told Science Daily. “And an effect in the same direction as the drug can lead a true effect of the drug to be lost. These concerns aren’t just theoretical. Where the composition has been disclosed, the ingredients of the placebo have in some instances had a likely impact on the result of the study – in either direction (obscuring a real effect, or creating a spurious one). In the cases we know about, this is not because of any willful manipulation, but because it can in fact be difficult to come up with a placebo that does not have some kind of problem.”
This post was chosen as an Editor's Selection for ResearchBlogging.org
The authors highlight what a huge effect this lack of transparency regarding placebos could have on medical research. “Because inferences from clinical trials propagate to clinical practice, failure to report placebo composition compromises the foundation on which medical decisions are based, and on which the fate of lives may rest,” they write.

Golomb BA et al. (2010) What’s in placebos: who knows? Analysis of randomized, controlled trials. Annals of Internal Medicine 153 (8): 532-5 PMID: 20956710

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Schemes that promote cycling seem to have limited benefit

Boris bikesCity wide programmes that promote cycling – such as London’s new bike hire scheme – seem a great way to get the public active and tackle the obesity epidemic. But new research published in the BMJ suggests that interventions to promote cycling don’t have much discernible effect after all.

Public health programmes that specifically aimed to increase cycling in a population found increases the the proportion of trips made by bike or the number of bike trips per person of 3.4 percentage points at the most, whereas there was little evidence that cycling increased physical activity or reduces obesity population wide.

Adults in the UK are supposed to at least 150 minutes of moderate intensity physical activity or 75 minutes of vigorous physical activity a week, but few manage. Cycling can fit relatively easily people’s daily routines as a means of travel from place to place, so people might be more inclined to adopt and maintain this type of physical activity than something like running or swimming. Also, if people cycle rather than take the bus or get in their cars, they’re helping to reduce harmful traffic pollution – so cycling could help the environment as well as provide a double whammy of health benefits.

The authors of this paper looked at 25 controlled or “before and after” studies on the effect of various different cycle schemes, such as free bike programmes, building new cycle routes, and promoting cycling to families. The studies were from seven countries, including the UK and the US.

Six studies assessed programmes that specifically aimed to promote cycling, of which four – an intensive one-to-one scheme for obese women, improvements to a cycle route network, and two multifaceted cycle promotion initiatives at town or city level – were found to be associated with increases in cycling. For example, one study found that improving the connectivity of the cycle route network in the Dutch city of Delft increased the proportion of household trips made by bicycle from 40% to 43% over a three year period compared with a change from 38% to 39% over the same period in an area where no improvements had been made.

A further 16 studies evaluated individualised marketing of “environmentally friendly” modes of transport (walking, cycling, and public transport) via marketing and incentives such as free bus tickets. On average this approach increased the number of cycling trips each individual made by eight a year.

Three other studies examined the effects of efforts to change travel behaviour in general, such as car sharing schemes. Two of these trials found small increases in the proportion of trips made by bicycle or the frequency of cycle trips per person (+1.1 and +0.17 a week, respectively), whereas the third actually found a decrease in the proportion of bike trips of almost 12%.

Only two of the 25 studies assessed looked at the health benefits of schemes to promote cycling, one of which reported a small but positive shift in the amount of overall physical activity in the population studied.

Discussing their less that glowing findings, the authors write that “There is nevertheless a strong case for promoting cycling on health grounds,” pointing to evidence that at an individual level cycling to work or school has been shown to improve cardiorespiratory fitness and reduce mortality. “Promoting cycling is, therefore, a viable approach to improving health,” they conclude.
Yang L et al. (2010) Interventions to promote cycling: systematic review. BMJ 341:c5293. DOI: 10.1136/bmj.c5293

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Sleep starved dieters might be thwarting their fat loss plans

A small study from the United States has suggested that getting too little sleep might prevent dieters from losing as much body fat as they would have had they slept properly.

When individuals slept for five and a half hours a night, they lost half as much body fat as when they were allowed to sleep for eight and a half hours a night and 50% more lean body mass. These results highlight the importance of human sleep for the loss of body fat when dieting.

Many people today are overweight or obese – the prevalence of obesity in England is thought to be 33% and 28% for men and women, respectively. Furthermore, 42% of men and 30% of women are expected to be overweight in 2010.

Losing weight by dieting is one sensible way of addressing this epidemic and thus reducing the poor health associated with being overweight or obese. However, emerging data suggest that insufficient sleep might affect the response of our hormones to reduced food intake and negatively influence the metabolic effects of eating less.

A total of 12 overweight, non-smoking, middle aged (range 35 to 49 years) individuals were enrolled in this study, of whom 10 (three women and seven men) took part. Alarmingly, one woman was withdrawn from the study because the combination of calorie and sleep restriction caused heart palpitations, whereas another woman dropped out for reasons unrelated to the study.

Participants spent two 14 day stints in the University of Chicago sleep laboratory, with three months inbetween to recover. To start with six were allowed 8.5 hours of sleep a night, while the other four were only allowed 5.5 hours. Then the groups switched over so that those who had been enjoying 8.5 hours a sleep a night were only allowed 5.5, and vice versa.

Before and after each study period, fasting body weight, adiposity, fat-free body mass, and the levels of various hormones related to metabolism were measured. Participants ate their normal diet during each 14-day intervention period, but its calorie content was 10% than what they would usually eat.

Interestingly, both the sleep situations – 5.5 hours a night and 8.5 hours a night – were associated with about 3kg of weight loss. However, when people were sleeping 8.5 hours a night, roughly half of the weight loss (1.4kg) was down to reduction in fat, compared with only about a quarter (0.6kg) when people had 5.5 hours of sleep (55% less fat loss in the sleep reduction group). When sleep was restricted to 5.5 hours a night, people lost more fat-free body mass instead, which is largely made up of muscle and water (60% increase in fat-free weight loss).

People were also hungrier and had higher concentrations of the hormone ghrelin when they only got 5.5 hours of sleep a night. Ghrelin has been shown to reduce energy expenditure, stimulate hunger and food intake, and promote retention of fat. People also had a lower resting metabolic rate during the 5.5 hours a night study period – all the better to ensure the finite amount of energy available would stretch to cover the longer waking hours.

The authors suggest that in the sleep deprived state, the body concentrates increasing amounts glucose in fat tissue to support the more prolonged energy needs of the glucose hungry brain. When energy intake is reduced in this situation, the body “holds on” to fat stores to make sure enough energy is available for the drawn out waking hours and instead uses energy stored in muscle – the fat-free body mass.

The authors also suggest that people trying to lose weight who don’t get enough sleep could find it harder to stick to their diet and might be more susceptible to piling on the pounds if they do slack off. “The enhanced metabolic, neuroendocrine, and behavioral compensation in the form of increased hunger and reduced energy expenditure that develop in response to combined caloric and sleep restriction can disrupt adherence to a lower-energy diet and promote efficient weight regain once it is discontinued,” they write.

Writing in an editorial on the topic, Shahrad Taheri of the University of Birmingham, UK, and Emmanuel Mignot from Stanford Sleep Medicine Center in California suggest that sleep should be included as part of the lifestyle package for weight loss, which traditionally has focused on diet and exercise instead.

Nedeltcheva AV et al. (2010) Insufficient sleep undermines dietary efforts to reduce adiposity. Annals of Internal Medicine 153 (7): 435-41. PMID: 20921542

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“Do it yourself” tests for chlamydia could be missing around 80% of cases

Commercially available home tests for chlamydia could be failing to identify between 75% and 83% of people infected when compared with the “gold standard” biochemical lab test, according to new research from the Netherlands.

The study of 772 women found that three “point of care” tests available on the internet and in pharmacies only correctly identified 17-25% of women who had chlamydia according to nucleic acid amplification testing commonly used by GPs and sexual health clinics.

Chlamydia is the most common sexually transmitted infection in the United Kingdom. More than 200,000 people were diagnosed in 2009, the majority of whom were aged 15-24. Around 50% of men and 70-80% of women who get chlamydia will have no symptoms, yet left undiagnosed chlamydia cause infertility.

Point of care tests for chlamydia usually involve the woman taking a vaginal swab herself and sending the sample to a laboratory to be tested, then going for an appointment with her doctor to get the result. Currently testing involves one doctor’s appointment to have a sample taken and a second 1-2 weeks to get the result, which is a much more time consuming approach.

The authors of this study assessed all women over the age of 16 who applied for a consultation at a sexual health clinic in Maastricht between September 2007 and April 2008. A total of 772 women with a median age of 23 were included in the final study.

When nucleic acid amplification testing was used, 11% of these women were found to be infected with Chlamydia trachomatis.

The authors then assessed whether three tests commercially available and certified in Europe – Handilab-C, Biorapid CHLAMYDIA Ag test, and QuickVue Chlamydia test – could identify which women had chlamydia.

The three tests only picked up 17.1-25.0% of women who had chlamydia (sensitivity) and correctly excluded 93.7-99.7% of those who didn’t (specificity). World Health Organization criteria indicate that point of care tests should have a sensitivity of between 43% and 65% and a specificity of 98%.

The sensitivity of two of the tests improved slightly if they were performed within 72 hours of the women taking a vaginal swab. As little as 19.8% of women who tested positive actually had chlamydia, although about 90% of those who tested negative were free from disease.

The results of this study indicate that many infections would have been missed had these point of care tests been used on their own, allowing women to go untreated and potentially spread the infection, and people with false positive results could have been treated unnecessarily.

On this basis the authors state: “In our opinion, the chlamydia point of care tests we have evaluated are not ready for widespread use.”

In an editorial on the topic, Dr Sue Skidmore from the Department of Microbiology at Princess Royal Hospital, Telford, agrees. “It is widely agreed that rapid tests for sexually transmitted infections with high sensitivity and specificity would provide advantages,” she writes, “although the introduction of their use, particularly for home use, needs to be rigorously evaluated and controlled with an assurance that robust quality assurance is in place when appropriate.”

van Dommelen L et al. (2010) Alarmingly poor performance in Chlamydia trachomatis point-of-care testing. Sexually Transmitted Infections 86:355-359. DOI: 10.1136/sti.2010.042598

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