Are Chronic Pain Syndromes the Reason for Statin-Associated Muscle Symptoms?

Research Article

J Fam Med. 2022; 9(4): 1300.

Are Chronic Pain Syndromes the Reason for Statin-Associated Muscle Symptoms?

Sheinin R1,2#, Nogueira AR1#, Bragazzi NL3, Watad A1,2, Tiosano S1,2, Gonen T1,2, Yavne Y1,2, Sharif K1,2, Kameri Y2,4, Amital D2,5, Amital H1,2# and Cohen H2,4#*

1Department of Medicine 'B' & The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel

2Sackler Faculty of Medicine, Tel-Aviv University, Israel

3Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy. Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON, Canada

4The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel

5Division of Psychiatry, Barzilai Medical Center, Ashkelon, Israel #Contributed Equally to this Work

*Corresponding author: Cohen H, The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-HaShomer, 5265601 Israel

Received: February 08, 2022; Accepted: April 15, 2022; Published: April 22, 2022


Background: Statin induced myalgia is defined as muscle pain without elevation of serum creatine phosphokinase levels, and is a well-known complaint among statin users. Chronic pain syndromes affect a high percentage of the population; and it may be possible that these pain syndromes confound the reports of statin induced myalgia. We sought to compare the occurrence of chronic pain among patients on statin therapy who developed myalgia with those who did not.

Methods: This study included 112 statin-treated patients, followed up at the clinic of the Lipid Center in Sheba Medical Center. Fifty-six of the subjects had a diagnosis of statin associated muscle symptoms (SAMS) and 56 did not. Verified questionnaires were used to assess the diagnoses of fibromyalgia, pain intensity, functional impairment, anxiety and depression in the study population.

Results: Patients with statin myalgia were more likely to fulfil the diagnostic criteria for fibromyalgia than patients without statin myalgia (11 (19.6%) vs. zero, respectively). Patients in the SAMS group also exhibited higher levels of anxiety and depression in comparison with the control group. Female sex, higher scores on the Brief Pain Inventory pain intensity scale, and a Hamilton rating scale level indicative of an anxiety disorder were found to be significant predictors for fibromyalgia in patients suffering from statin myalgia.

Conclusion: A significant percentage of patients, diagnosed with statin myalgia actually fulfilled the diagnostic criteria for fibromyalgia, depression or anxiety disorder. Detection of these patients and treatment of their primary pain disorder or psychiatric illness has the potential to prevent unnecessary cessation of effective statin therapy.

Keywords: Statin; Myalgia; Pain; Adherence; Fibromyalgia; Anxiety; Depression


CPK: Creatine Phosphokinase; CK: Creatine Kinase; SAMS: Statin Associated Muscle Symptoms; ACR: American College of Rheumatology; WPI: Wide-Spread Index; SS: Symptom Severity; BPI: Brief Pain Inventory; MINI: Mini-International Neuropsychiatric Interview; BMI: Body Mass Index; SD: Standard Deviation; OR: Odds Ratio; ASCVD: Atherosclerotic Cardiovascular Disease.


Statins (3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) are a highly effective medications class, currently used for treating hypercholesterolemia and for primary and secondary prevention of atherosclerotic cardiovascular disease. Statins are commonly prescribed in clinical practice, and are usually well-tolerated [1]. However, overall statin intolerance is observed in 10-15% of patients treated with statins, limiting treatment adherence and affecting potential outcomes [2,3]. Most adverse effects associated with statin therapy is muscle-related [2], defined as SAMS - Statin Associated Muscle Symptoms. The most common symptom of SAMS is myalgia, described as unexplained muscle discomfort, including muscle aches or pains, in the absence of creatine kinase (CK) elevation [4]. Other types of SAMS include myopathy, myositis, and muscle injuryrhabdomyolysis; all are much rarer muscle disorders than myalgia [3,5]. The incidence of myalgia complaints as an adverse effect of statins greatly varies between controlled clinical trials (1-5%) and observational cohorts (11-29%) [6].

In several blinded clinical trials, comparing statin therapy with placebo, there were no significant differences in the fraction of patients with myalgia following both treatments. In other studies, a significant difference was reported, yet high rates of myalgia were also observed in the placebo groups [7-11]. These studies demonstrated the significant role of the nocebo effect, suggesting that the underlying mechanism behind statin myalgia may include a psychosomatic component. In a cross-sectional study of 1,924 subjects, Korhonen et al., [12] reported that statin non-adherence rate was increased by 33% in patients with somatic symptoms of anxiety (rapid pulse, sweating, flushing, etc.) on a daily or weekly basis, in comparison with patients without these symptoms. In a systematic review and meta-analysis assessing factors associated with non-adherence to statin therapy, in individuals older than 65 years, it was found that depression was significantly related with increased rates of nonadherence [13]. The symptoms of muscle pain in SAMS, share common features with the symptoms of fibromyalgia. Fibromyalgia is a chronic pain syndrome, which more commonly affects women (ratio of 5:1). The dominant feature of fibromyalgia is diffuse musculoskeletal pain, and in the past two decades, the definition of fibromyalgia has broadened to additionally include fatigue, cognitive impairment and sleep disorders [14]. The analogous characteristics of both statin myalgia and fibromyalgia, expressed as typical muscle pain led us to hypothesize that a certain portion of patients presenting with SAMS are actually suffering from undiagnosed fibromyalgia. To the best of our knowledge, this is the first study to examine the presence of fibromyalgia or other affective disorders among patients suffering from SAMS.

Materials and Methods

Study population

The study population was comprised of patients with a diagnosis of hypercholesterolemia, from the outpatient lipid clinic at Sheba Medical Center, Tel-HaShomer in Israel. Inclusion criteria included past or current statin therapy, age over 18 and under 65 years, and normal thyroid function. Exclusion criteria included women who were pregnant or breastfeeding, previous or current diagnosis of malignancy (excluding cutaneous basal cell carcinoma), substance abuse (current or past), major psychiatric illness, diagnosis of rheumatic or inflammatory conditions, previously documented fibromyalgia, or any underlying disease-causing significant disability.

Study design

This study was designed as a cross-sectional study. Subjects were divided into two groups: patients with a diagnosis of SAM and patients without myalgia under statin therapy (i.e. the control group). Statin associated myalgia, was defined as muscle pain occurring while a subject was on statin therapy that resulted in the discontinuation of treatment or in a change of the therapy regimen to another statin. The patients were recruited between September 1st 2016 and September 1st 2018 .The local ethical committee of the Sheba Medical Center, Tel-HaShomer, Israel, approved the study. Informed consent was obtained from each patient.

Clinical assessment

Each subject enrolled in the study, underwent an initial assessment, which included the collection of demographic and medical data, past medical history (including any current or past psychiatric disorder), smoking status, and alcohol or substance abuse. Additionally, information regarding history of statin therapy was obtained. The type of hypercholesterolemia (familial or primary), type of prevention provided by therapy (primary or secondary), age at diagnosis, age in which statin therapy was initiated, number of previously statins tried as well as statin dose and type. Duration of treatment prior to the onset of myalgia was not always available as continuous, accurate values, and, as such, was categorized in days, weeks, months or years. CPK and vitamin D serum levels were also obtained for all subjects at the time of enrolment in the study.

Each patient completed a well-validated questionnaire, which included a functional and mental evaluation:

• Diagnosis of fibromyalgia according to the 2010 American College of Rheumatology (ACR) [14]. These classification criteria included calculations of the widespread index (WPI) and the symptom severity (SS) scores.

• Pain assessment using the Brief Pain Inventory (BPI) questionnaire [15].

• Evaluation of depression and anxiety was done by using the Hamilton rating scale for Depression and Anxiety [16,17].

• Severity of depression was categorized as following: 10-13 mild; 14-17 mild to moderate; >17 moderate to severe; severity of anxiety was categorized as a score of 17 or less - mild anxiety severity, 18 to 24 - mild to moderate anxiety, 25 to 30 - moderate to severe anxiety.

• Evaluation of patients’ daily disability using the Sheehan questionnaire [18].

• Evaluation of the existence of psychiatric disorders through the implementation of the Mini-International Neuropsychiatric Interview (MINI) abbreviated questionnaire [19].

Statistical analysis

Prior to proceeding with data manipulation, figures were visually inspected for potential outliers. Normality of data distribution was assessed by the D’Agostino-Pearson omnibus test. Unordered chisquared or exact Fisher Test was used for categorical variables. If these were ordered (i.e., ordinal parameters, such as vitamin D status, statin dose, anxiety and depression levels), the Cochran- Armitage test for trend (known also as the ordered chi-squared test for trend) was applied, besides the classical (and less powerful) unordered test. More specifically, this test enables to capture the potential effects of the ordering of the n categories of a given ordinal variable. For continuous parameters, Student’s t-test and analysis of variance (ANOVA) or their non-parametrical versions (Wilcoxon rank-sum test, also known as Mann-Whitney U test, and Kruskal- Wallis) were carried out at the univariate analysis in order to reveal statistical differences between statin users with and without myalgia and fibromyalgia cases, respectively. The Bonferroni test was used as a post-hoc test for adjusting for multiple pairwise comparisons. Multivariable logistic regression analysis was conducted to analyze the predictors of myalgia among statin users. In more detail, deferent models were run, with various predictors and the best model was chosen based on the findings of the univariate analysis, the Hosmer– Lemeshow test and the highest predictive power in terms of the value of the “area under the curve” (AUC) and Cox and Snell’s R-squared. All statistical analyses were carried out using the commercial software “Statistical Package for the Social Sciences” (SPSS v24, IBM, USA), while graphs were generated by the MedCalc Statistical Software version 17.9.7 (MedCalc Software bvba, Ostend, Belgium; http://; 2017). Figures with p-values of less than 0.05 were considered statistically significant.


Study population baseline characteristics

The study population included 112 patients (56 subjects with SAMS and 56 controls without myalgia). The mean age of the study population was 51.9±11.8 years; 60.7% of the subjects were male. The mean body mass index (BMI) was 26.4±4.1 kg/m². Thirtyseven subjects (33.0%) consumed alcohol and 17 (15.2%) were current smokers. Most of the patients had co-morbidities (103 patients, 92.0%): 10 (8.9%) subjects had an established diagnosis of psychiatric disorders and 11 (9.8%) reported having a familial history of psychiatric diseases. Vitamin D deficiency (25 hydroxy-vitamin D <10ng/ml) was found in one subject (0.9%), whereas twelve patients (10.7%) had vitamin D insufficiency (levels of 10ng/ml <25 hydroxy-vitamin D <30ng/ml). Forty-three subjects (38.4%) were using vitamin D supplementation, and five (4.5%) had a diagnosis of osteoporosis.

Seventy-eight subjects (69.6%) were being treated with statins as primary prevention for atherosclerotic cardiovascular disease (ASCVD). The most prescribed statins were rosuvastatin and atorvastatin (46.6% and 44.3%, respectively). Prior to enrollment in the study, patients had been treated on average with statins for 9.9±7.4 years, while the mean duration of hypercholesterolemia was 12.2±8.4 years. The mean number of different statins previously used by the subjects was 3.0±1.5. Most patients’ depression scores were within the defined normal range (77.7%), whilst 13.4%, 6.3% and 2.7% had scores compatible with mild, moderate and severe depression, respectively. The mean Hamilton depression score was 5.2±4.7, whilst the mean Hamilton anxiety score was 7.6±6.0 (Table 1).