Most aches blamed on a cholesterol pill also came with fake pills, trial finds

Many people start a new pill and soon feel achy or tired. It seems obvious to blame the pill. A small trial in London asked a harder question: how much of that feeling comes from the drug, and how much from simply taking a pill and expecting trouble [1][2]?

For one common cholesterol pill, much of it was the expectation. In months when people took fake pills with no medicine in them, their symptoms were nearly as bad as in months on the real drug. The researchers worked out that about nine tenths of the extra trouble on the real pill also showed up on the fake one [2].

One caveat belongs up front. The trial had just 60 people, and all of them had already decided the pills made them ill, so it cannot speak for everyone who takes these pills [2].

The pills were statins, common drugs that lower cholesterol, a fatty substance in the blood. The trial, called SAMSON, was run by doctors at Imperial College London. A short first report came out in the New England Journal of Medicine in 2020 [1]. The full report, led by James Howard of Imperial College London, followed in the Journal of the American College of Cardiology in 2021. Its record lists grants from the British Heart Foundation, the Medical Research Council and the Wellcome Trust [2].

How can a fake pill cause aches?

A placebo is a fake pill that looks just like the real one. When people feel better on one, that is the placebo effect. The reverse can happen too. When people feel worse because they expect side effects, it is called the nocebo effect, from a Latin word meaning I will harm. The aches are real. What brings them on is the expectation, not a drug.

To catch this, the trial ran each person as a trial of their own. All 60 adults had stopped a statin because of side effects that began within two weeks of starting it. Each got 12 bottles, one for each month of a year. Four held the statin, four held a placebo that looked the same, and four were empty [2].

A computer set the order by chance. Neither the person nor the staff knew which full bottles were real. Every day, each person scored their symptoms on a phone app, on a scale up to 100 [2].

What did the trial find?

Of the 60, 49 finished the whole year. In empty months, the average symptom score was 8.0. In statin months it was 16.3, and in placebo months it was 15.4. Both pill months were worse than no pills, but the gap between the real and fake pills was small enough to be luck [2]. The researchers concluded:

The majority of symptoms caused by statin tablets were nocebo.

In plain words, most of the trouble came from taking a pill, not from the drug inside it. The empty months were the key, because they showed what a normal month felt like. People stopped 46 of 213 statin months early and 38 of 221 placebo months early, a gap small enough to be luck. And how fast symptoms came on, or eased after stopping, did not reveal which bottle was which [2].

Six months after the trial, 30 of the 60 people were taking a statin again. The trial was not set up to say whether that was good or bad for them [2].

A bigger trial agrees on the main point. Called StatinWISE, it was led by Emily Herrett of the London School of Hygiene and Tropical Medicine and published in the BMJ in 2021. It ran at 50 family doctor offices in the United Kingdom with 200 people who had stopped, or were thinking of stopping, a statin because of muscle aches. Each had six two month periods of statin or placebo in a random order [3].

Among the 151 people who gave enough scores, muscle symptoms were about the same in statin and placebo periods. That trial had no empty months, though, so it could not measure the nocebo effect the way SAMSON did [3].

SAMSON still has limits. It tested one statin at one strength and looked only at symptoms people could feel, not rare harms that need a blood test to find. Eight people stopped a statin month early but never a placebo month, so some people may react to the drug itself [2].

This trial does not show that no one ever gets side effects from a statin, and it cannot tell any one person where their own aches come from. What it does show is that, for this group, a fake pill brought on most of the same trouble as the real one [2][3].