Statins and the nocebo effect

Around 7-8 million adults in the UK are on statins - they’re one of the UK’s most commonly prescribed drugs. They work to lower the amount of “bad” cholesterol, known as low density lipoprotein, in the blood. High levels can be dangerous, and are linked to cardiovascular problems. Like all medicines, statins have side effects. But, this does seem to be a particular problem for some people when it comes to statins, and can lead to patients stopping the tablets all together as a result. Muscle aches and pains are common among the reported problems. In the paper cognitive neuroscientist Duncan Astle looked at this month, by comparing the side effects experienced on statins against those experienced on identical-looking dummy pills, a team from Imperial College London set out to explore whether these side effects were due to the actual drug, or if something else could be going on. What they found was something called the nocebo effect - where being concerned about feeling worse on the tablets means people do actually feel worse. Duncan spoke to Katie Haylor...

Duncan - So in this study, they had 60 participants who had previously stopped taking statins because of the side effects. And they were randomised into different groups and they were actually given different pots of medication. And in some pots they would contain statins. And in some pots they would contain placebo pills. Participants themselves at any one time were blind to what type of pill they were taking. And the people running the study were blind to what type of pill any participant was taking at any one time. And they used a scale to rate from zero, no side effects at all to 100, the worst imaginable side effects.

Katie - So what did they find out then?

Duncan - When you're taking a statin, your average score on the zero to 100 side effect scale is 16.3. When you're taking a placebo it's 15.4. And when you're taking neither it's eight. So whatever pill you're taking relative to taking no pills, you experience significantly more side effects. But the difference between the statins and the actual placebo is very, very small. In fact, 90% of the side effects are present in the placebo condition, which implies that they have little to do with the active ingredients of statins, and more to do with people's expectation of the kinds of side effects you get when you take statins.

Katie - Do you think this is specific to these particular people? Are they particularly vulnerable, or could it be quite a generalised thing?

Duncan - It may well be that these are all people who have tried to taking statins and discontinued because of the side effects. And that could mean that they are a special, but significantly large subpopulation of individuals who experience these kinds of side effects enough that it's easy for them to think that when they're on the statins, these are the results of the medication that they're taking. The other way of thinking about it, is the nature of the drug. When people decide to take statins, it's not as simple as, "this is the cure for A or B", or "this will prevent you from getting condition A or B". in reality, it's about adjusting your risk.

And so when GPs decide that patients should go on to statins, what they're doing is evaluating the potential benefit in terms of reduced risk with the potential cost in terms of any side effects. And so, because everybody is so familiar with what the side effects are,and the fact that people experience the side effects, I think it creates the expectation that there will be side effects. And thus you start to code any headache, any feeling of being a bit sick as a side effect of the medication. Whereas as these data show, actually your expectation can drive those effects also.

Katie - Do you think it could be particularly prevalent in cases where you're taking a drug, you're trying to maintain a status quo. So if it's working, you might not see any sort of outward results.

Duncan - Exactly. So as far as I know, the only way that you would know if the statin was working is when you did your LDL cholesterol count. So you won't spontaneously find out and start feeling differently if the drug is working. And I think that that creates this perfect scenario for experiencing a nocebo effect.

Katie - So did they then tell the participants what had happened?

Duncan - They did. So once the results were revealed to the participants, half of the trial participants were then able to restart statins. And as far as we know so far, they're still on those statins. It demonstrates that when you provide participants, or in this case, patients with information about the likelihood that their side effects are actually being caused by the medication they're taking, people are actually able to readjust the kind of priors and beliefs that presumably have given rise to those symptoms in the first place, such that they're then able to successfully restart the medication.

Katie - So what do you reckon that means for patients and compliance of taking these sorts of medicines?

Duncan - Data like these could be put into an incredibly easy to read, digestible format that could be given to patients when they start taking things like statins. So that they can be primed to realise that actually much of what they consider to be a side effect of the medication might actually have nothing to do with the medication itself. And you may well start to find that you get a reduced rate of dropout through side effects.

Now it’s been well over half a year since the Naked Scientists office was inhabited. But what can the digital interruptions that come with many jobs - chat boxes, emails etc, - do to our stress levels? This month, perceptual psychologist Helen Keyes has looked at a study done before lockdown, in a mocked up open plan office, asking this very question, and Helen told Katie Haylor about it...

Helen - The researchers recruited 90 working age participants. They had to pretend to be employees of a fictitious insurance company. And they did things like typed up some handwritten notes, arranged meetings with clients and some simple computations, some sales computations for this fictitious company. The participants were divided into three groups. In the first group they were just the control group. And somebody pretending to be from HR came in and had a friendly chat with everybody. In the second group, somebody from HR came in and said that "surprise, we're going to evaluate you all to see who's going to get a promotion". And then in the third group, those people also had this HR conversation where they're going to be evaluated, but they were also constantly interrupted, using a chat feature coming from their pretend line manager and required immediate responses each time.

While they were undergoing this workplace environment scenario, the researchers measured their cortisol levels from their spit. So we know that cortisol is a stress hormone and it increases when we're stressed. They also measured all of the participants heart rates continuously, and they measured some subjective measures of stress, mood, nervousness, those types of things, self-report measures from the participants. And they found the idea of "you're about to be evaluated" significantly increased all of your biological measures of stress in both of the evaluation conditions compared to the control.

Katie - That makes sense, right?

Helen - It makes total sense. However, in the stress condition where you're being evaluated and you're being interrupted, your cortisol levels doubled. So you were twice as stressed out physiologically. However, and this is quite surprising, those people who were in that interrupted condition, despite their higher cortisol levels, they reported feeling less stressed and feeling happier than those who were just in the "being evaluated" condition. And a nice explanation for this is down to the cortisol on itself. So we think of cortisol usually and its long-term effects, which can be quite negative. So can lead to fatigue, anxiety, depression, digestive problems, and even is associated with weight gain. But the short term effects of cortisol are quite interesting. Cortisol is an adaptive response of the body to stress. And it's there for a reason. It actually increases your blood sugar, gives you a temporary spike in energy, improves your memory and even increases your pain threshold. So short-term cortisol bursts have a really useful response. And it looks like in this last really stressful condition where you're being evaluated and interrupted, that extra cortisol burst actually makes it easier for you to deal with that stressful scenario. However, in the long-term, if that really was your office environment with the constant interruptions and that long-term cortisol exposure is going to have negative effects on your health.

Katie - Do we know what it does to productivity? Because constant interruptions via emails and other things is a reality for a lot of people in the workplace.

Helen - Oh, without a doubt, it reduces your productivity. And there is a huge amount of work done on this, whether it's to do with working in open plan offices or those general interruptions to your workflow. Absolutely it decreases productivity. It's very difficult for us to maintain focus or get anything done when we're interrupted. But while there have been a lot of studies on that kind of cognitive effect that we perform more poorly when we're interrupted, there hasn't been as much of a focus on stress and wellbeing. And that's a newer aspect of this type of research.

Stress isn't always a bad thing. A lot of situations in our life where we need to progress or change or get to the next level or further ourselves, involve some levels of stress. It's not always a bad thing to be stressed. However, sustained long-term stress is a negative thing for our health.

Katie - Do you think there's anything particularly pertinent about this study as we're in a time where a fair few people are working from home, if their job facilitates that?

Helen - Reading about open plan office was almost, nostalgic. Things have radically changed. Like you say, we're not in that environment where we're in front of other people. So it's a bit less threatening if something is happening, you're not in front of other people when that's happening. However, I would agree that there is much less downtime. Much less off time. Much less time away from your screen or notifications on your computer. And I think there's an awful lot of work still to be done on that. On the general effects of the pandemic on our working behaviours.

Duncan - There are certain tasks you can do alongside each other very happily. There are certain other tasks that you can't, if both tasks draw upon similar resources. So for example, if you're trying to write some texts whilst listening to music that's got lots of lyrics in, it can be very difficult because it's very similar neural systems that you use for sort of sub vocal kind of rehearsal of what you're writing are consumed by processing the lyrics of the songs. Whereas lots of studies have shown that actually certain types of white noise or music that hasn't got lyrical content can actually be quite facilitating. So it's interesting that the type of thing that's going on in the background can actually either kind of hinder or help productivity.