COMMENTARY

The Power of Suggestion: Statin and Beta-blocker Side Effects

John Mandrola, MD

May 10, 2017

Our brains can easily fool us. Reality may be an illusion created by cerebral neurons.[1]

No experienced doctor denies the power of the placebo effect.

The opposite of the placebo effect is the nocebo effect, which occurs when a negative expectation of something is realized more strongly than it otherwise would.

Drug prescriptions can come with a powerful nocebo effect. If your brain thinks you will have a side effect, that may be enough to trigger the effect.[2] Nocebo brain trickery is relevant to both statins and beta-blockers.

First the Statins

The frequency of muscle symptoms with statins is hotly debated. Randomized controlled trials (RCTs) in which patients don't know whether they are taking the statin or a placebo report nearly identical rates of muscle-related adverse events.[3-5] Observational studies, however, report higher rates of statin muscle complaints.[6,7]

As a practicing doctor, I have always felt the truth lies closer to the observational data.

A study published recently in the Lancet suggests I may be wrong. This new study, which has impeccable methods, suggests statin muscle complaints stem not from human muscles but from the human brain.

In the Lancet paper, researchers took advantage of two distinct parts of the primary prevention ASCOT-LLA trial.[8] In the first part of ASCOT-LLA, more than 10,000 people were randomized to either atorvastatin 10 mg daily or placebo in a double-blinded fashion. After completion of the blinded phase of ASCOT-LLA, study participants were invited to take part in a nonblinded and nonrandomized extension study in which they could take atorvastatin open label.

The results turned on whether people knew they were on the statin. In the double-blinded phase of the trial, muscle symptoms occurred at the same rate—2.0% per year in both the statin and placebo groups. In the second phase of the trial, when people knew they were on the statin, side effects occurred at a higher rate (1.3% per year) in the statin group vs the placebo group (1.0% per year). This difference reached statistical significance (hazard ratio 1.41, CI 1.10–1.79; P=0.006).

These are remarkable observations, which are hard to dispute. In an accompanying editorial, two Spanish authors emphasized the obvious strengths of this paper: these were the same patients in both phases, and there was no run-in period in which patients intolerant to statins were excluded.[9]

An even stronger reason to believe this study is that it is not an outlier. The GAUSS-3 trial, also a two-staged randomized trial, included a blinded atorvastatin rechallenge phase in a group of patients with documented statin intolerance. In this RCT, slightly more than one in four patients reported muscle complaints while taking placebo.[10]

Beta-blocker Nocebo Effects

The nocebo effect is also relevant to beta-blockers. People think they will gain weight, develop fatigue, or get short-winded when taking beta-blockers. Men think they will become impotent.

But the evidence, the reality, does not support these commonly held perceptions. Many side effects from beta-blockers may be due to brain trickery.

In 2013, British researchers published a systematic review of 13 blinded randomized controlled clinical trials of beta-blocker vs placebo in more than 15,000 patients with heart failure.[11]

Their results mirror the statin observations: 28 of 33 classically described side effects were not more common with beta-blockers than placebo. For instance, headache, impotence, weight gain, low blood pressure, and shortness of breath were no more common with beta-blockers than placebo. Depression, a symptom often attributed to beta-blockers occurred less frequently in the beta-blocker group (by 35%, P<0.01).

Some side effects—dizziness, for example—occurred more often in the beta-blocker arm. But the authors explain that of 100 patients who report dizziness on beta-blockers, 81 of them would have had it on placebo.

These findings, too, are not an outlier. A 2002 meta-analysis of 15 beta-blocker trials reporting fatigue, sexual dysfunction, or depression side effects had similar results.[12]

Nocebo Effects May Not Involve Drugs

The nocebo effect can also turn asymptomatic people with atrial fibrillation into symptomatic people with atrial fibrillation (AF). 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."

"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—to no avail. Weeks later, Mr. Smith is calling because he is fatigued and short-winded.

I see two possible explanations for Mr Smith's new symptoms: either he developed AF shortly before our visit and his symptoms took weeks to develop, or telling him the ECG results created a new reality in his brain. Having seen this scenario many times, I favor the latter.

Conclusions

The British authors of the beta-blocker systematic review 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 when randomized controlled trials show no significant increase, or indeed a significant reduction."

That view seems extreme. But the nocebo effect surely has relevance to clinicians, whose ultimate role is help people. These striking observations reveal how much of health is controlled by the brain. We clinicians would be wise to know this—and to choose our words carefully.

Finally, nocebo and placebo effects beautifully confirm the correctness of Osler's observation that "the good physician treats the disease; the great physician treats the patient who has the disease."

References

  1. Mark JT, Marion BB, Hoffman DD. Natural selection and veridical perceptions. J Theor Biol. 2010; 266:504-515. Abstract

  2. Olshansky B. Placebo and nocebo in cardiovascular health: Implications for healthcare, research, and the doctor-patient relationship. J Am Coll Cardiol 2007;49:415-421. Article

  3. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2017; 388:2532-2561. Article

  4. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy. A systematic overview of randomized clinical trials. Circuation 2006;114:2788-2797. Article

  5. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014;168:6-15. Abstract

  6. Buettner C, Davis RB, Leveille SG, Mittleman MA, Mukamal KJ. Prevalence of musculoskeletal pain and statin use. J Gen Intern Med 2008;23:1182-1186. Article

  7. Mansi I, Frei CR, Pugh M, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med 2013; 173:1-10. Article

  8. Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): A randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017; DOI:10.1016/S0140-6736(17)31075-9. Abstract

  9. Pedro-Botet J, Rubiés-Prat J. Statin-associated muscle symptoms: Beware of the nocebo effect. Lancet 2017; DOI:10.1016/S0140-6736(17)31163-7. Editorial

  10. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-1590. Article

  11. Barron AJ, Zaman N, Cole GD, et al. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: Recommendations for patient information. Int J Cardiol 2013;168:3572-3579. Article

  12. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002; 288:351-357. Article