Beta-blockers, Statins, AF, and the Nocebo Effect

Our brains can easily fool us.

No experienced doctor would deny the power of the placebo effect.

Today I want to discuss the nocebo effect, which occurs when negative expectations of something causes it to have a more negative effect than it otherwise would.

Drugs can exert a strong nocebo effect. If your brain thinks you will have a side effect, you may actually get that effect.

Nocebo brain trickery is relevant to statins. That’s why I used this wording in my last post: (Note the italics)

The actual frequency of muscle symptoms is hotly debated. Randomized controlled trials (in which patients don’t know whether they are taking the statin or placebo) report very small increases in muscle complaints—about a 1-2% increase. Observational studies, however, reveal higher rates of statin muscle complaints–in the range of 10-20%.

The nocebo effect is also relevant to beta-blockers.

Beta-blockers, which are drugs that blunt the effect of adrenaline, carry enormous baggage about side effects. People think they will gain weight, be fatigued, or get short-winded when taking these drugs. Men think they will become impotent.

The evidence, however, does not support these perceptions. Similar to muscle complaints and statins, our brains may be tricking us.

An elegant study from a famous group of British researchers strongly suggests that most side effects from beta-blockers stem from the nocebo effect.

The authors did a systematic review of blinded trials that used beta-blockers in patients with congestive heart failure–a common reason to give beta-blockers. (The linked review is open access.)

They found, sit down for this, 28 of 33 classically described side-effects are not more common on beta-blockers than placebo. Table 3 and Figure 2 of the paper are eye-openers.

Side effects, such as, headache, impotence, weight gain, low blood pressure, shortness of breath were no more common with beta-blockers than placebo.

In fact, the side effect of depression, often attributed to beta-blockers, occurred less often in patients who took the real drug. Read that sentence again.

Some side effects were more common on beta-blockers. Dizziness, for example, occurred 3.7% more often in the beta-blocker arm. But the authors explain that a 3.7% increase actually means that of 100 patients who get dizzy on the beta-blocker, 81 of them would have had it on placebo.

The nocebo effect can also turn asymptomatic people with atrial fibrillation into symptomatic people with atrial fibrillation. I’ve seen the scenario many times. Here’s how it goes:

Mr Smith is in for routine follow-up. I note before going in the exam room that his ECG shows AF. Last year he was in sinus rhythm.

“How are you, Mr Smith?”

“I feel great.” I ask again…”Great? That’s a strong word.”

“Yea, doc, I have never felt better.” His wife confirms that he is active and vigorous.

But then the cheery confident demeanor turns sour when I tell him his ECG shows AF.

I spend the rest of the visit reassuring him that it doesn’t matter; he’s on anticoagulant already, his heart rate is controlled, the previous echo is normal.

No matter, weeks later, Mr. Smith is calling because he is fatigued and short-winded. And so begins the balance of treating AF symptoms without causing harm.

***

The authors of the beta-blocker side-effect paper boldly concluded that “clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect…”

I wonder. We clinicians have immense power with our words. I can’t quantify it, but the human brain surely controls a lot of our health.

JMM

P.S. I’ve written about the possible placebo/nocebo effect of AF ablation. Click on the link: Could Ablation for AF Be an Elaborate Placebo?

11 comments

  1. If someone has a TIA (mini stroke) then this is often dismissed as a ‘funny turn’ in fact the Stroke Association has leaflets advising against the dangers of this. In other words, something serious has happened but we ignore it.

    It is the same with statins, in the case of minor muscle problems.

    You start taking statins and a few weeks later your muscles are a BIT sore, weak, stiff. You dismiss this as the weather, your age, your heart problems (that caused the statin to be given in the first place).

    It takes two weeks to see a doctor so you ignore the slight pains thinking they will go away.

    But they don’t.

  2. From my experience, doctors rarely tell their patients what side effects the medications they’re prescribing have. As well, I wouldn’t be surprised if most people don’t read them unless they start experiencing something. And the TV ads spiel of side effects go in one ear and out the other. I know some drugs have sudden death as a side effect but I can’t tell you which ones. (Speaking of which- how many people have had that as a nocebo effect?)
    That said, I don’t doubt the nocebo effect. I’m just skeptical if it”s as common as the placebo effect, or as high as found in the study. (Besides being skeptical of how the study was actually done and who really funded it.)
    But the biggest thing I find concerning about that study is that more doctors may brush off real and serious side effects as the nocebo effect. My mother was put on amiodarone and became increasingly sick- not to mention required emergency eye surgery. I brought it up to her primary and to the hospitalists during 3 of the last 4 hospitalizations that I believed her illnesses were side effects of amiodarone. None of them would take me seriously. She was eventually sent home on hospice. 3 months off amiodarone and she has recovered enough to be taken off hospice. That’s no placebo effect.
    Otherwise, as far as the patient who said he was great and then complained- I don’t think you can go by that. My mother in law used to do the same thing. She’d be dragging and have many complaints but go to her doctor and tell him she feels great. I’m sure if he told her she had something abnormal in her tests or bloodwork, she would have eventually asked to follow-up.
    Lastly, glad to see you’re on the right track. The human brain does control a lot of our health. We should utilize it first before resorting to costly medications that do have very real side effects.

    1. I will add: And we certainly shouldn’t give doctors more reason to discount our symptoms as all in our head.

  3. John,
    You’re doing a fine job of stirring up statin-haters this week!
    The quote about questioning whether we doctors should be informing patients of possible side effects really resonated with me.
    I know when I mention the possibility of muscle aches I am likely to increase the chances that the patient will experience muscle aches on the statin if the patient was previously unaware of this possibility. However if they have already heard of this possibility or subsequently are told of it and I haven’t educated them on it they are more likely to believe horror stories about statins and either never take or stop taking them.
    So I always give them my spiel on statin associated muscle symptoms (SAMS) . I would say 2/3 of the time the patient already has formed an opinion on statin side effects and it is negative. This is because their acquaintances who had SAMS are much more likely to share their stories than than the ones doing fine on statins.

  4. Also, did you write your post before knowledge of this Lancet publication today (http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)31075-9/fulltext?elsca1=tlpr)
    “Just as the placebo effect can be very strong, so too can the nocebo effect.,” said Peter Sever (Imperial College London), lead author of the study, in a press release. “This is not a case of people making up symptoms, or that the symptoms are ‘all in their heads’. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm. What our study shows is that it’s precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them.”
    If so, remarkably astute timing!

    1. Thanks for adding that link Anthony. It’s compelling data. There was also this one on Medscape from last month. http://www.medscape.com/viewarticle/876404

      Actually, I had been thinking more about the nocebo effect of beta-blockers. Then I thought this fits well with the SAMS issue too.

      I often counsel patients who worry about beta-blocker side effects that, when studied, the drugs don’t cause as many problems as is commonly thought. I went searching for the Frances study because I wanted to make a printout of it–for an exhibit.

      Of course, of all doctors, I am last in line to push drugs on patients. I see myself as an advisor; I strive to be as unbiased and informed as possible.

      1. The new statin “data” are not so compelling when one notes that the single study involved (of a relatively low-potency statin) did have a run-in period.

  5. Hmmm didn’t you forget to mention that this ‘nocebo’ effect is more prevalent in women? That is what I always hear from doctors.

  6. ~ I have previously posted the following comment on Medscape.

    FUNDING: Dr. Mandrola, the text of your story really needs to inform your readers of the fact that the original ASCOT-LLA Lipitor/atorvastatin study, and the current ‘nocebo’ reanalysis of that study in the Lancet, were all funded by a triad of multinational pharmaceutical corporations. Namely, Pfizer Inc (which owns Lipitor/atorvastatin); Servier Laboratories; and Leo Pharma. I trust that you are no stranger to the relevance of undue influence from industry funding and other vested interests within the context of contemporary medical research.

    It is puzzling that you find the observations of this current Lancet study “hard to dispute”. Indeed, a number of expert commentators are questioning its validity for a multitude of reasons, starting with the fact that it is a reanalysis of data from a nearly 20 year old trial which was designed to compare two antihypertensive strategies (inclusive of LOW dose 10mg Lipitor/atorvastatin) for the prevention of CHD. Others have more bluntly asked why researchers have suddenly decided to data dredge a dated study – which was NOT designed to look at adverse effects as a primary end-point – to prove that statins do not have any adverse effects. Of course, others have also noted that the original ASCOT-LLA study, and the current reanalysis, are pharma-funded undertakings. Most notably, funding comes from Pfizer which is currently being sued over adverse effects from its drug Lipitor/atorvastatin — that the new reanalysis now attributes to the nocebo effect. It has been said that he who pays the piper calls the tune.

    By way of additional reading, there was another story about this study a few days ago on Medscape. I’m not a huge fan of Steve Nissen (who has disclosed industry funding from Pfizer and others), but he does have some nifty things to say about the most flagrant flaws of this current study: http://www.medscape.com/viewarticle/879613#vp_1

    Regarding how the side-effects data was collected in the original ASCOT-LLA trial, Nissen said: “These were casually reported symptoms, sort of spontaneous adverse-event reporting. If you want to know whether people have statin-associated muscle symptoms, you have to have a formal process for querying people about their symptoms. The investigators did not do that. There’s no rigor in the way the data were collected…The study was not done with the idea of collecting information on statin-associated symptoms, which means that there may have been lots of people in the study who had symptoms that were never written down”. Nissen doesn’t say ‘garbage in, garbage out’, but that may be one possible interpretation.

    In other reporting, Rita Redberg (Editor-in-Chief, JAMA Internal Medicine,) has repeated her call for the Cholesterol Treatment Trialists (CTT) to release the patient-level data of their trials. “I think if they truly want to contribute to the discussion of the incidence of statin related adverse events in clinical trials, they should make the CTT held trial data publicly available, as Rory Collins said he would do two years ago, but has not happened.” Collins is a leader of the CTT and a co-author of the new paper in the Lancet. “I would just add that I find this publication of the adverse event rate in this 15 year old trial of low dose (10mg) atorvastatin in mostly white, middle aged men, adds little to our knowledge of side effects of statins as used today. The current guidelines recommend high dose statins, which have higher incidence of all side effects”. Moreover, statins are now being far more widely prescribed to a much more demographically varied population, inclusive of all races and ethnicities, people with multiple co-morbidities, women, the elderly, and the frail.

    Meanwhile back at the ranch, Pfizer is gearing up for the next round of legal proceedings with several thousand plaintiffs who are alleging harm from Lipitor/atorvastatin side-effects…. https://www.drugwatch.com/lipitor/litigation/ … As reported by Reuters, this is far more significant than other mass lawsuits of its kind: “For one, Lipitor is the best-selling prescription drug of all time, racking up global sales of more than $130 billion since it went on the market in 1996. More than 29 million patients in the United States have been prescribed the drug, suggesting there is a vast pool of potential plaintiffs”. Suffice to say, Pfizer and all other statin/lipid-lowering stakeholders are still SUPER interested in torturing the research data to disprove evidence of any potentially litigious side effects. In the case at hand, the tool of choice is the ‘nocebo’ effect. Pfizer is currently purveying this defense in the court of public opinion, in preparation for a court of law.

    NOTE: Two thousand lawsuits against Pfizer are presently on appeal after having been dismissed by a federal judge in South Carolina in early 2017. Unfortunately, the current political climate might very well set the stage for a forthcoming ‘nocebo’ legal precedent that vitiates patients rights for a very long time to come. So, we might just want to slow our roll a bit before jumping willy-nilly on the ‘nocebo’ effects bandwagon at this critical time.

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