Do statins cause joint or muscle pain?

Musculoskeletal symptoms, including joint and muscle pain, are the most frequently reported statin-associated side effects. Although the incidence rate of muscle problems in statin randomized controlled trials (RCTs) is fairly low, and is similar between statin-treated patients and untreated controls, the reported frequency of muscle problems overall among people taking statins varies considerably. Muscle pain is reported in 5% to 29% of patients in clinical trials, registries, and observational studies.¹ Levels of creatine kinase, an indicator of muscle damage, were elevated in some statin users compared to controls.² In addition, a possible biological basis of muscle toxicity is supported by evidence that statins in some studies decrease mitochondrial function and affect muscle protein degradation in the laboratory.³ Further study is needed to quantify the actual frequency of statin-associated muscle symptoms (SAMS), as well as their biological basis and clinical significance.

The rates of muscle or joint pain that were reported in pre-market trials according to statin package inserts vary considerably from statin to statin and when compared to placebo (Table 1).^4–10 While rates of musculoskeletal symptoms in these trials were consistently higher in treated individuals compared to placebo, it is not evident from this data if the differences were clinically or statistically significant. Also, more recent guidelines focus on muscle-specific problems associated with statins and exclude joint symptoms that are more likely attributable to arthritis and other pain syndromes.^11,12

Diagnosing SAMS can be challenging because it is difficult to distinguish between self-reported symptoms that are truly caused by the use of a statin and symptoms that are caused by other common sources of musculoskeletal pain such as overuse and chronic pain disorders. The reported incidence of muscle symptoms is often similar among patients taking statins and those taking placebo, as several crossover studies have illustrated. For example, Taylor et al. conducted a double-blind, placebo-controlled crossover study of 120 patients with a history of SAMS. Among the study participants, 35.8% reported muscle symptoms only when taking simvastatin, 17.5% had no symptoms on simvastatin or placebo, 29.2% reported muscle pain when taking placebo but not when they were taking simvastatin, and 17.5% reported pain when taking both simvastatin and placebo.¹³  

The variation in reported muscle adverse events may also be explained by differences in definition used by different study authors.² The 2014 National Lipid Association’s Muscle Safety Expert Panel examined the definitions used for muscle problems associated with statin use.¹² In an attempt to lessen the ambiguity of terminology in clinical trials, they described the spectrum of muscle toxicity as including myalgia (muscle discomfort), myopathy (muscle weakness), myositis (tenderness to palpation or muscle inflammation determined by biopsy or imaging), myonecrosis (mild to severe muscle enzyme elevations), and clinical rhabdomyolysis (myonecrosis with myoglobinuria or acute renal failure). After a review of the relevant literature, they reported the incidence of myalgia to be from 1% to 5% in clinical trials and between 11% and 29% in observational cohorts.

Another estimate of potential statin-associated muscle toxicity is a patient’s decision to discontinue a statin because of patient-perceived muscle problems.^1,14 In one survey of 1220 people who had discontinued a statin prescription, 62% gave the main reason for discontinuation to be side effects, predominantly muscle-related symptoms.¹⁵ Discontinuation of a statin can increase the risk of cardiovascular events and should be avoided whenever possible.¹⁶

Many patients who have side effects respond to a statin re-challenge with an alternate statin or revised dosing of the same statin.^12,14,17,18 In the Reasons for Geographic and Racial Differences in Stroke study, 1081 (15%) discontinued treatment, and of those, 593 cited muscle problems from the statins as the cause.¹⁹ Of note, 28% of those who discontinued their statin due to SAMS were willing to re-initiate use of a statin, with guidance by their physician.

Two other possible measures of muscle-related effects of statin use are the level of creatine kinase in the blood and exercise performance. Creatine kinase is elevated in the blood after exercise but can also be a measure of muscle damage in the absence of exercise. Parker et al. assessed the effect of atorvastatin 80 mg on 420 statin-naive healthy patients’ muscle function and performance.²⁰ Objective measures of strength and exercise performance did not differ between those on atorvastatin and controls, but muscle complaints and average creatine kinase levels differed significantly between the two groups. Average creatine kinase increased 20.8 ± 14.1 U/L (p<0.0001) with atorvastatin, suggesting that further study is needed to evaluate prolonged use of high-dose statin therapy on muscle function.

Severe muscle damage, necrosis, and rhabdomyolysis can occur in patients taking statins, but this is rare.²¹ Graham et al. identified a cohort of statin users (n=252,460) from a large health insurance data base from 11 managed care plans in the US to estimate the risk of rhabdomyolysis. The number needed to treat to observe one case of rhabdomyolysis was 22,727 people per year of statin monotherapy.

^References

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