Are muscle aches from statins really due to the nocebo effect?
By Maryanne Demasi, PhD and Paula Byrne, PhD.
Doctors report that over 20% of their patients complain of muscle symptoms after statin therapy. However, in blinded randomised trials, people taking statins do not report more muscle pain than people taking a placebo.
Researchers have tried to explain why real world data are at odds with what happens in clinical trials.
Muscle aches from statins are often blamed on the ‘nocebo’ effect, that is, when people experience adverse symptoms because of their negative expectations or perceptions of a treatment.
So, two studies specifically designed to test the ‘nocebo’ effect [known as individual n-of-1 trials] were carried out by recruiting people who’d stopped taking their statins because of perceived muscle pain.
The first study involving 60 people was published in the New England Journal of Medicine in 2020.
The patients received four bottles containing atorvastatin (20 mg), four bottles containing placebo, and four empty bottles; each bottle was to be used for a 1-month period according to a random sequence.
Subjects would record the intensity of their muscle symptoms on a smart phone app. Depending on whether they were taking the statin, the placebo or nothing at all, the primary goal was to measure the ratio of muscle pain induced by placebo vs the statin.
They concluded that 90% of the muscle symptoms elicited by a statin was also elicited by the placebo – meaning, the majority muscle symptoms had nothing to do with the statin.
Half of the patients were able to recommence statin therapy six months after completion of the trial, the rest did not recommence their statins, mainly because of side effects.
The second study involving 200 people was published in The BMJ in 2021.
Subjects were randomly assigned to a sequence of six 2-month treatment periods during which they received either atorvastatin (20 mg) or a matched placebo. At the end of each treatment period, patients were asked to report any muscle symptoms.
Again, the key result of the study was that patients on average, reported no difference in their muscle symptoms between periods of taking a statin or a placebo and the majority of patients who finished the trial decided to continue using statins once the trial ended.
Notably however, 86 out of the 200 randomised participants (43%) withdrew before the end of the 12-month trial.
Media coverage
Mainstream media reported on the studies uncritically, attracting headlines in widely circulated publications such as The Guardian and The New York Times.
The flaws
After analysing both studies, we determined that a fatal design flaw in both studies should have invalidated the authors’ conclusions.
The researchers assumed that muscle symptoms would stop immediately after the statin was discontinued and that there would be no “carry-over” effects into the periods when participants were taking the placebo.
It is well-known however, that muscle pains can take months to appear and to subside after statin therapy.
A study by Hansen et al, found that the mean duration of symptom onset was 6.3 months and that resolution of muscle pain occurred on average 2.3 months after discontinuation of statin therapy.
Another study by Cham et al, found that in some patients, the resolution of muscle symptoms after discontinuation of statin therapy could take as long as 48 months.
Therefore, limiting the study to 1 month or 2 months before switching the person to a new treatment, would likely obfuscate the true observation of muscle symptoms.
Further, 43% of participants dropped out before the end of the second study, and 40% of them, withdrew after reporting “intolerable muscle symptoms.”
Finally, the studies excluded key people from the trial, which would have resulted in an under-estimate of muscle problems.
For example, people likely to report muscle problems were excluded from the trial, such as those with a previous history of rhabdomyolysis (a potentially fatal condition of muscle breakdown that can lead to kidney failure), or those with a previous history of raised blood levels of creatinine kinase (an enzyme elevated when muscle is damaged).
Also, selection bias of participants in the trial could have resulted in the under-estimation of muscle problems because anyone with a strong cause to believe their muscle pains were induced by statin therapy in the past, would be very unlikely to volunteer in the first place.
Our conclusion
Two major studies have concluded that muscle aches from statins are due to the "nocebo" effect, but these conclusions are seriously challenged by the flawed study design.
The high rate of dropouts in the second trial due to “intolerable muscle symptoms” casts further doubt, and the dose of atorvastatin (20 mg) used may not be applicable to people on high intensity statin therapy.
It is possible that the nocebo effect exists, but the authors have not provided robust evidence to conclude that statins are not the major culprit in the cause of muscle pain.
Dr Paula Byrne is a postdoctoral researcher with Evidence Synthesis Ireland & HRB-Trials Methodology Research Network at the University of Galway, Ireland. Follow @pbyrne82
Whilst reading through the article, I very early on considered the time to onset of symptoms, and time to symptom resolution essentially invalidated the studies.
I always measure CK on patients with myalgia who take statins.
My experience is that even when CK levels drop to normal after cessation of the statins, myalgia often persists, sometimes indefinitely.
Then there are the questions as to the doubtful efficacy of statins on primary prevention of heart attacks, especially in those whom a lipid subfractions analysis suggests no increased risk of coronary artery disease.
These 2 studies appear designed to appeal to the ill-informed media class.
I first started statins in 1995 after an early age heart attack. Within a month or two my leg muscles would ache in the morning. This was a year or two before I started to read about the side effects. To this day, depending on the dose level, I will still get the statin muscle ache. No study will ever convince me otherwise that for me statins result in my muscle pain!