Statin Related Muscle Pain - Is It All In Your Head?
Why deciphering statin side effects is harder than it seems.
Statin therapies are one of the most commonly prescribed medications on the planet.
For some reason, there are also often the most controversial.
Side effects from statin therapies are a major barrier in getting patients to their target cholesterol level and getting people to agree to take them in the first place.
Any medication has a range of potential side effects.
Statins are no different.
But there is one statin-specific side effect that comes up again and again:
Muscle Pain.
But do statins cause most of this muscle pain, or are they innocent bystanders?
Let’s get into one of the most controversial areas of cardiology.
SAMS - Statin Associated Muscle Symptoms
Let’s start with some basic facts.
Statin-induced muscle pain is real1.
Some patients may even experience serious muscle damage with the breakdown of muscle tissue and elevated blood levels of CK, a marker of muscle damage at high levels.
This type of serious muscle damage, however, is rare;
Occurring in between 1:1000 and 1:10,000 people.
The majority of patients with muscle symptoms have mild symptoms and rarely have significant elevations in the blood marker CK.
How frequent the milder variation of this is, is hard to say. For reasons, I will explain shortly.
The literature says mild symptoms occur in approximately 7 - 29% of patients, depending on the type of study2.
Any side effect with a range as wide as ~20% tells you there is more to this story than meets the eye.
Nocebo Effect - The Placebo Effects Evil Twin
The placebo effect is a well-recognised phenomenon where a benefit is accrued because of an input that is not likely to have caused it.
The effect is very real, but the reason for the improvement is down to how we perceive its benefit rather than any active ingredients in the placebo medication.
The nocebo effect is the same thing, but instead of a beneficial change, there is a perceived harm or negative change.
Enter statins and muscle pain.
But how do we tell the difference between real or nocebo-induced statin muscle pain?
Answer: With great difficulty.
“It’s All In Your Head”
Patients with muscle aches while on statin therapy often feel they are told that their symptoms are ‘In Their Head’.
This is 100% true.
Why?
Because EVERYTHING is in your head.
Every memory, encounter, relationship, dinner, holiday etc., has been experienced in your head.
There is nothing you can experience in life that is NOT in your head.
And if you EXPERIENCE muscle aches on statin therapy, then they are real.
It might be the result of the nocebo effect, but they are still real for the patient.
A common strategy we take with patients who have suspected statin-induced muscle pain is to take them off the medication for a week or two, see if their symptoms improve and then restart the medication to see if they return.
This sounds like a reasonable plan, but the issue is the patient KNOWS when they are on and off the medication.
How do we get around this issue?
Answer: Blinded Placebo-Controlled Trials.
ENTER SAMPSON
The SAMPSON trial evaluated patients already identified as ‘Statin Intolerant’ due to muscle pains34.
These patients were then randomly assigned to rotating 1-month periods of either no medication (No Pill), placebo (Pill) or low-dose statin (Pill).
Over 12 months, they recorded daily symptom scores on a scale of 1-100.
For the periods on a low-dose statin (Pill), the average symptom score was 16.3.
When on no medications (No Pill), the average symptom score was 8.0.
Case closed. Statins cause way more symptoms.
Or do they?
For the periods on the placebo (Pill), the average symptom score was 15.4. With no difference between the low-dose statin (Pill) group and the placebo (Pill) group.
The real difference was between those taking ‘No Pill’ versus any ‘Pill’, whether it was a placebo or statin.
It was the taking of a ‘Pill’ that was driving the difference, not the active ingredients of the statin.
It seems like the nocebo effect was hard at work.
When individual participant data are examined from 19 placebo-controlled randomised trials, we can see that statin side effects are real but rare.
In almost 100,000 people included in these blinded trials, those on statin therapy experienced muscle aches with a frequency of 27.1%.
Not insignificant.
But those on a placebo experienced muscle aches with a frequency of 26.6%5
This means that in more than 90% of cases, the muscle aches experienced by patients on statin therapy are unrelated to statin therapy.
They are real.
They just aren’t being caused by the statin medication.
So What Now?
The challenge in clinical practice, however, is that we do not have access to placebos to experiment with our patients.
We are left with known trials on and off therapy, re challenges at different doses and statin types.
For some patients, even with all the above attempts, we have no choice but to use an alternative therapy.
Thankfully we have lots of other options lately.
But what is most interesting is that in the SAMPSON trial, in those who had been defined as ‘Statin Intolerant’ who were taken through the blinded placebo process and had their results explained to them, 50% were able to restart and continue their statin medication6.
Statin-related muscle aches are real.
The problem is they are a result of the nocebo effect in the vast majority of cases.
But without a placebo substitute, we have limited options to troubleshoot this very challenging problem with our patients.
It is a problem that is mostly ‘All In Our Heads’.
But so is every problem in life.
Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, European Heart Journal, Volume 36, Issue 17, 1 May 2015, Pages 1012–1022,
European Atherosclerosis Society Consensus Panel, Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, European Heart Journal, Volume 36, Issue 17, 1 May 2015, Pages 1012–1022,
Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. J Am Coll Cardiol. 2021 Sep, 78 (12) 1210–1222.
N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. NEJM Nov 15 2020
Cholesterol Treatment Trialists' Collaboration. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials. Lancet. 2022 Sep 10;400(10355):832-845.
Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. J Am Coll Cardiol. 2021 Sep, 78 (12) 1210–1222.
Excellent article, thank you.
So, if one was somehow able to run a trial enrolling only people who had never heard of statin muscle-ache side effects, any guess as to what their average symptom score would be on a statin?