Today’s guest post is from a pharmacist who blogs under the pseudonym Avicenna, who looks at the evidence supporting the use of Coenzyme Q10 to treat statin-related muscle pain.
My pharmacy stocks plenty of natural health products (NHPs) and ensuring they can be used safely is challenging, given the limited information available on safety, quality, purity, and efficacy. Answering patient questions is always interesting and often very challenging, as they can often be non-specific. A typical question like “Is product ‘X’ good for treating condition ‘Y’?” can be difficult to answer without gathering some further information. My usual response is, “Let’s talk about this. I want to make sure I give you an answer that is right for you, given your medical conditions.”
I recently spoke with a patient taking atorvastatin (Lipitor), a cholesterol-lowering medication from the “statin” family, who was complaining about muscle pain, and asking about Coenzyme Q10 (CoQ10) for treating that pain. Treating or preventing statin-related muscle pain is a common question, given the popularity of statins and the frequency of the complaint: About 1 in 15 develop this symptom. Before diving into the efficacy of CoQ10, let’s review statins.
If you have high blood pressure, are overweight, diabetic, or sedentary, you should know your cholesterol levels: Keeping them in the normal range will lower your death risk in the short and long term. If you need drug therapy to reduce your cholesterol levels, you’re probably on a statin. Statins are a class of highly effective cholesterol-lowering drugs that work to inhibit HMG-CoA [3-hydroxy-3-methyl-glutaryl-CoA] reductase. Statins work by lowering cholesterol points (e.g., low-density lipoprotein (LDL), triglycerides) and/or moderately increasing good cholesterol (i.e., high density lipoprotein (HDL)). High levels of “bad” cholesterol is a contributor to heart disease and other negative cardivascular outcomes. It clogs the arteries that feed oxygen to the heart, and is involved in the process of blood clot formation.
Statins have been extensively studied and are very effective at improving cholesterol measures, and overall cardiovascular outcomes. For example, taking statins for 5 years will prevent 1 heart attack for each 28 patients treated (compared to placebo) and will prevent 1 heart-related death in 69 patients. Statin therapy is even effective at preventing a first heart attack (though the effects are less impressive than in those who have already had cardiac events.
In addition to the effects on cholesterol, statins also lower C-Reactive Protein (CRP), an inflammation marker, which appears to also offer additional benefits to one’s risk of heart disease.
In general, statins are well tolerated. Muscle pain (myalgia) is the only common side-effect (rate of more than 1%), but surprisingly, the frequency is no different than a placebo. Risk factors for muscle pain include age (65 years or older), acute or chronic renal failure, liver disease or dysfunction, hypothyroidism, genetics, the statin dose, and other medications.
Some side effects have been established as clearly linked to statins: Increased liver enzymes (aminotransferase enzymes); as well as muscle pain with elevated muscle breakdown enzyme (Creatine protein kinase, CPK). 
Uncommon side effects reported with statin therapy include more severe forms of muscle pain, including the rare but serious rhabdomyolysis, which has been associated with kidney failure.  The evidence that statins cause this side-effect is contradictory: randomized controlled trials show no association, but some lesser quality trials (observatory or cohort trials) have linked statins to some of these rare side-effects.
The safety profile of statins results in a scenario where muscle pain complaints are frequent, but rarely serious. All require investigation, but in the vast majority of patients, discontinuing the drug is not medically necessary.
Management of Statin-Associated Muscle Pain
Statin-associated muscle pain (myopathy) typically appears as aching muscle pain, muscle weakness (but not joint pain), usually affecting both sides of the body, and more than one muscle group. Red flags for medical referral include flu-like symptoms, low back and/or proximal muscle pain, and brownish coloured urine, which could signal rhabdomyolysis.
Muscle symptoms typically appear after a few weeks to months of treatment, though they can appear anytime after the first week. Symptoms typically disappear within days to weeks of discontinuing treatment.
When statin muscle pain develops (without evidence of more serious complications) options for management can include: decreasing the dose, stopping therapy for a few weeks, switching to other statins (some data suggests pravastatin and fluvastatin may be better tolerated ), alternate day treatment, or completely stopping statin therapy and switching to another type of cholesterol-lowering drug. Given the demonstrated benefits of statin therapy, this is usually the least-desirable option.
Here’s where Coenzyme Q10 comes in.
It’s been proposed that statins may reduce the amount of Coenzyme Q10 in the body, since it shares a metabolic pathway with cholesterol. Give the supplement, reduce the pain, goes the hypothesis. So, let’s look at the evidence.
Developing a Focused Clinical Question
Before I could answer my patient’s question, I needed to focus it enough to be answerable. Using the PICO format, I developed a question that could be answered in a science-based way:
P – Patient (or Population) – What are the characteristics of the patient? In this case, a 67-year-old male with familial hypercholesterolemia, on atorvastatin, and no other medications. Let’s look at the data for any statin, as in general, the drugs are therapeutically alike.
I – Intervention – What intervention or treatment were we interested in? For this case, we’re interested in giving CoQ10 orally, adding it to existing drug therapy.
C – Comparison – CoQ10 compared to what? In this case, compared to no treatment (watchful waiting) or placebo.
O – Outcome – What is the intervention supposed to do? We want to know if it reduces patient-reported complaints of muscle pain.
So my focused clinical question was the following: In a 67 year old patient with familial hypercholesterolemia, on a statin, is CoQ10 superior to a placebo for the reduction of muscle pain symptoms?
What is CoQ10?
Also named ubiquinone, Coenzyme Q10 is an oil-soluble, vitamin-like substance that is obtained through food (meats, seafood) and also produced in the body. It is present in most cells of our body, but mostly in mitochondria (energy producing part of cells) of heart and liver cells Coenzyme Q10 levels are highest in the first 20 years of life. It declines with age to the point that at 80 years of age, the levels are lower than at birth. It has many functions in the body, ranging from antioxidant to biochemical cofactor.
CoQ10 is, in Canadian regulatory terminology, a “natural health product”. It’s available without a prescription and is sold in pharmacies and health food stores. Taking CoQ10 supplements does lead to increased blood levels. In the blood, it’s transported in cholesterol particles (mostly in LDL). Dosage usually ranges from 50 to 250 mg divided in two or three daily doses.
Purported uses for CoQ10 include hypertension, angina, congestive heart failure, Huntington’s disease, migraines, muscular dystrophy, breast cancer, infertility and many, many other conditions. Most of these uses have little to no evidence to support their use, and little research exists to demonstrate the natural product is factor in any of these conditions. The only FDA approved condition is for the rare genetic disorder of mitochondrial encephalomyopathy. The relevance of CoQ10 to statin myopathy is thought to come from its involvement in cell energy production, where preliminary data emerged to suggest that muscle mitochondrial dysfunction due to low levels of CoQ10 in the body might explain the muscle pain and/or weakness. 
Limited data means it’s not clear that low levels of CoQ10 cause myalgia, or if myalgia can occur without low levels of CoQ10. In fact, at least four other equally valid hypotheses for statin-induced mylagia exist. Consequently, the measurement of CoQ10 levels is not clinically relevant.
Safety and Interactions
CoQ10 is well tolerated. Reported side effects seem to be minor and include nausea, vomiting, diarrhoea, appetite suppression, heartburn, stomach discomfort in less than 1% of patients. Allergic reactions have also been reported. CoQ10 oral supplements at recommended doses in most adults seems safe in studies lasting up to 30 months. There is little data in children, pregnancy and in breastfeeding women. However, it is generally very well tolerated in most people.
CoQ10 interferes with some drug therapy. It can magnify the effects of blood pressure medications. Tt can also interfere with warfarin (Coumadin) therapy, possibly increasing the risk of clotting. CoQ10 may also interfere with cancer chemotherapy, reducing its effectiveness.
A 2007 systematic review by Marcoff looked at laboratory and clinical evidence for CoQ10 and its potential role in statin myopathy. It found that statins do not conclusively decrease blood levels of CoEQ10; low dose statins do not decrease CoQ10 levels in muscles, (but this may be drug and dose dependant); and no consistent mechanism of cellular damage or effects can explain myopathy.
The review identified two relevant trials and found contradictory results. In the first trial, 44 patients with high cholesterol and a history of statin-induced muscle pain who were off statins for at least 2 weeks, re-treatment with statin therapy (escalating doses of simvastatin 10 – 40mg daily), while taking CoQ10 supplements for 3 months did not affect pain scores or how patients could tolerate therapy. This suggests that CoQ10 does not seem to prevent muscle pain in people who have had a history of statin-induced muscle pain.
The only positive evidence mentioned in the systematic review comes from another small study done by Case et al. This second trial evaluated if CoQ10 supplements could treat or improve muscle pain in patients currently taking statins. They enrolled 32 patients (15 women, 17 men) who had myopathy symptoms defined as pain alone or accompanied by other symptoms, such as weakness and fatigue. Authors measured pain at the start of the trial and after 30 days using the subjective Brief Pain Inventory questionnaire (BPI) and Pain Interference Score (PIS), the latter being a test of how pain affects their daily living and well-being. Eighteen patients were randomized to receive either 100 mg of CoEQ10 per day, while the remaining (N=14) received 400 IU of vitamin E. Patients and investigators were blinded to which treatment was given.
Results were encouraging. The investigators found a significant decrease in pain scores by about 40% -+11% (Pain severity score, PSS=2.97-+0.48, p0.001) and a reduced interference of pain on daily living of about 38% -+14% (PIS 2.82 -+0.61, p0.02) in the Coenzyme Q10 group compared to placebo group (vitamin E). Sixteen of the 18 patients taking CoQ10 improved while only 3 of the 14 improved with vitamin E. This suggest that CoQ10 may provide moderate, short-term relief of statin-induced muscle pain.
Limitations to the trial included its small size, randomization process (not detailed), and little evidence the two groups were matched with respect to other medical conditions or other medications. Importantly, the use of other prescription or non-prescription medications was not detailed. The short trial duration (30 days) limits the relevance of the findings: Statin pain tends to last much longer than 30 days. Also, it is questionable if 30 days of CoQ10 could even have affected muscle levels at all. Longer studies with tissue sample would be required to demonstrate this. Finally, the control group used (vitamin E) may not be a true placebo group (sugar pill), only one dose of CoQ10 was used, and the trial did not have the size to evaluate if patients on high doses of statins had better relief of pain.
Muscle pain during statin treatment is a common problem encountered by patients, and a frequent question posted to pharmacists. The documented benefits of statins on morbidity and mortality suggest that all evidence-based efforts should be made to keep patients on therapy.
Consider this: in moderate to high risk heart patients, for every 1 million patients treated with a statin, 15 cases of the severe adverse effect rhabdomyolysis might occur. However, 30,000 cardiovascular deaths or non-fatal myocardial infarctions would be avoided. That is one case of rhabdomyolysis for every 2000 severe cardiovascular events avoided. In light of this risk- benefit relationship, it’s critical that muscle pain be evaluated by a physicians before statin therapy is discontinued, because the benefits outweigh the risks of treatment.
Unfortunately, there’s little high-quality, persuasive evidence to support the use of CoQ10. This initial data is promising, but larger, better trials are required before using this supplement can be considered to be supported by good science. In light of the risk-benefit ratio, however, in cases where discontinuation of statin therapy is being contemplated, a trial of CoQ10 may be reasonable.
For Additional Information
 Hulten E et al. The Effect of Early, Intensive Statin Therapy on Acute Coronary Syndrome A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2006;166, 1814-1821.
 Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005. 366(9493): 1267–78.
 Larosa et al. Effect of Statins on Risk of Coronary Disease: A Meta-analysis of Randomized Controlled Trials J American Medical Association. 1999 Dec 22-29;282(24):2340-6.
 Thavendiranathan P et al. Primary Prevention of Cardiovascular Diseases with Statins:A Meta-analysis of Randomized Controlled Trials,Arch Intern Med. 2006;166:2307-2313.
 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002: 360(9326): 7–22.
 Kashani A, Phillips CO et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006 Dec 19;114(25):2788-97.
 Josan K, Majumdar SR et al. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. Can Med Assoc Journal. February 26, 2008; 178 (5).
 Miller ML, et al., Muscle injury associated with lipid lowering drugs. In: UpToDate, Basow, DS (Ed), UpToDate,
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 P.D. Thompson, P. Clarkson and R.H. Karas, Statin-associated myopathy, JAMA 289 (2003), pp. 1681–1690.
 P.S. Phillips, R.H. Haas and S. Bannykh et al., Statin-associated myopathy with normal creatine kinase levels, Ann Intern Med 137 (2002), pp. 581–585.
 MARCOFF, L., & THOMPSON, P. (2007). The Role of Coenzyme Q10 in Statin-Associated MyopathyA Systematic Review Journal of the American College of Cardiology, 49 (23), 2231-2237 DOI: 10.1016/j.jacc.2007.02.049
 Young JM et al., CoEnzyme Q10 does not improve simvastatin tolerability in dyslipidemic patients with prior statin-induced myalgia, AHA 2006 (abstract). Circulation 2007;114:II41.
 CASO, G., KELLY, P., MCNURLAN, M., & LAWSON, W. (2007). Effect of Coenzyme Q10 on Myopathic Symptoms in Patients Treated With Statins The American Journal of Cardiology, 99 (10), 1409-1412 DOI: 10.1016/j.amjcard.2006.12.063
 Tsuyuki RT et al., Assessment of muscle pain associated with statins — A tool for pharmacists, Canadian Pharmacists Journal, Volume 142, Issue 6 (November-December 2009), pp. 280–283.