3 March 2021

GPs use n-of-1 trials to bust statin pain myth

Clinical Drugs General Practice Pain Research

The evidence is building that muscle pain is more of a nocebo effect than an inherent side effect of statins, and now researchers have developed a tool to help patients navigate the symptoms.

A study of 151 primary care patients, published in the BMJ, tested whether a GP-led, individual trial affected how patients perceived the drug’s side effects.

While high quality research now suggests that these symptoms are driven more by patient expectations, unblinded observational studies and case studies amplified by the media have spread the idea that statins can cause muscle pain.

“For a patient in routine clinical care, reliably determining whether muscle symptoms are caused by statins is not easy for the clinician or patient,” epidemiologist Professor Liam Smeeth, a member of the StatinWISE Trial Group, wrote. “One way to deal with this uncertainty is to conduct blinded n-of-1 trials in individual patients with symptoms during treatment with statins.”

Participants were recruited from 50 sites across the UK, and were eligible if they complained of statin symptoms during a consultation and expressed interest in quitting the medication, or had stopped taking a statin due to muscle symptoms in the three years prior.

“In an n-of-1 trial, our patient would undergo treatment periods of statin and placebo, in a random order, but – crucially – would be blind to what they were taking,” Professor Smeeth and colleagues explained in an accompanying editorial. “Muscle symptoms would be monitored throughout and, after several periods of statin and placebo, our GP and patient would look at the unblinded results to determine whether symptoms were worse during statin use.”

Their study found that patients were no more likely to report muscle pain when they were taking 20mg of daily atorvastatin compared to when they were taking a placebo over six two-month periods.

Nor were participants in the statin phase more likely to report these symptoms affecting their mood, ability to walk, work, relationships, sleep or enjoyment of life.

Nearly two in three study participants said they intended to begin statin treatment again after learning the results of their study. 

“Given the benefits of statins in cardiovascular disease prevention, and the high frequency of muscle symptom complaints among patients, it is time to incorporate research into routine practice,” wrote Professor Smeeth and colleagues.

The researchers call for the development of n-of-1 trial packets for statins to enable GPs and other clinicians to more easily use this technique in their practice.

“The n-of-1 design would be useful beyond the context of statins and muscle symptoms, and could be used for many reversible short-term drug effects – both beneficial and harmful – where uncertainty exists.”

The study did not include anyone who had a history of serum alanine aminotransferase levels that were three or more times higher than normal, or those with persistent, generalised, unexplained muscle pain (associated with statins or not), or those with levels of creatine kinase at least five times high than the upper limit of normal.

Participants were not eligible if they had contraindications to atorvastatin 20mg or if the GP otherwise believed they were unsuitable for the trial.

BMJ 2021, 24 February

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