Coenzyme Q10 (CoQ10) deficiency has been proposed to be causal in 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor (statin)-induced myopathies. However, the clinical benefit of supplementation is unproved. The purpose of the present study was to assess the effect of CoQ10 supplementation on myalgias presumed to be caused by statins. Patients currently receiving a statin who developed new-onset myalgias in ≥2 extremities within 60 days of initiation or a dosage increase were eligible. Patients continued statin therapy and were randomized using a matched design to either CoQ10 60 mg twice daily or matching placebo. Double-blind treatment continued for 3 months, and patients completed a 10-cm visual analog scale (VAS) and the Short-Form McGill Pain Questionnaire at baseline and at each monthly visit. The primary end point was the comparison of the VAS score at 1 month. A total of 76 patients were enrolled (40 in the CoQ10 arm and 36 in the placebo arm). The mean VAS score was 6 cm at baseline in both groups. At 1 month, no difference was seen in the mean VAS score between the 2 groups (3.9 cm in the CoQ10 group and 4 cm in the placebo group; p = 0.97). However, 5 patients in the CoQ10 group and 3 in the placebo group discontinued therapy during the first month because of myalgias. The baseline median score on the Sensory Pain Rating Index subscale was 10 in the CoQ10 group and 11.5 in the placebo group. At 1 month, these scores had decreased to 6.5 and 7.5, respectively, with no statistically significant difference (p = 0.34). In conclusion, CoQ10 did not produce a greater response than placebo in the treatment of presumed statin-induced myalgias.
It has been proposed that myalgias in patients receiving 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) result from the depletion of coenzyme Q10 (CoQ10) in muscle cells. A congenital deficiency in CoQ10 has been linked to myopathy related to mitochondrial dysfunction. CoQ10 is a cofactor in the mitochondrial electron transport system, and evidence for mitochondrial dysfunction has been reported in patients receiving statin therapy with and without myalgias. CoQ10 is a product of the mevalonate pathway that is blocked by statins. Patients receiving statin therapy have been shown in most studies to have decreased serum concentrations of CoQ10 (from 16% to 49%). Furthermore, CoQ10 supplementation has been shown to prevent or reverse this decrease. One study exploring statin-induced myalgias detected a portion of patients with decreased myocyte levels of CoQ10. However, the muscle concentrations have not been consistently shown to be decreased in patients receiving statins. Two small trials evaluating supplementation have been published but yielded discrepant results. The present study evaluated the benefit of CoQ10 supplementation in patients with presumed statin-induced myalgias.
Methods
The present study was conducted at a single United States Army hospital. The hospital’s institutional review board approved the present study, and all patients provided written informed consent before enrollment.
The patients were eligible for inclusion if they were currently receiving statin therapy and experiencing myalgias that were generalized or present in ≥2 extremities. The pain had to have begun within 60 days of initiation of the drug or a dosage increase. This period was chosen in an attempt to increase the likelihood that the myalgias were induced by the statin. Presumably, it would have been short enough to support a temporal relationship but long enough to allow for depletion of CoQ10 to occur. Additionally, it must have been present for ≥2 weeks, with no other cause determined. The exclusion criteria included a serum creatine kinase level >300 U/L, a diagnosis of fibromyalgia, and a recent traumatic injury to the affected areas.
The patients were randomized to either CoQ10 60 mg twice daily (Miller Pharmacal Group, Carol Stream, Illinois) or a matching placebo using a matched design. The patients and investigators were both unaware of the treatment allocation. Initial randomization was performed using a random number table, and the patients were paired according to the results of a baseline visual analog scale (VAS) score. This process was performed by a pharmacist who also dispensed the study medications but was not otherwise involved in the conduction of the trial. The matched design was chosen to yield a similar mean baseline pain score between the groups to avoid the potential for confounding owing to regression to the mean. Patients were instructed not to take open-label CoQ10, but vitamin supplementation was allowed.
At baseline, the patients indicated the average intensity of the pain using a 10-cm VAS. The Short-Form McGill Pain Questionnaire was also administered. This scale measures both sensory and affective domains, which are combined into a total score. The maximum score for the sensory subscale is 33 and is 12 for the affective subscale. Patients returned for follow-up visits monthly for 3 months, and statin therapy was continued at the current dosage. The VAS and pain questionnaire were repeated at each visit. Adherence to the study drug was assessed using pill counts.
The primary end point was the difference between the results of the 1-month VAS score. A sample size calculation revealed that 60 patients were required to detect a 15-mm difference between the groups in the VAS at the 1-month evaluation, with a power of 90%. The sample size was increased to 76, assuming a 20% withdrawal rate. The Student t test was used to compare the mean scores of the VAS between the 2 groups. The Wilcoxon rank sum test was used to compare the median values obtained from the pain questionnaire. The chi-square test was used to compare the frequencies. All analyses were based on the intention to treat principle.
Results
A total of 111 patients were screened, and 76 were enrolled. The reasons for exclusion included pain in only 1 extremity (n = 17), the onset of myalgia >60 days after drug initiation or dose increase (n = 11), and elevated creatine kinase levels (n = 2). Additionally, 5 patients declined entry into the study. The baseline characteristics of the groups are listed in Table 1 . The mean age was approximately 62 years in both groups. Approximately 53% of the CoQ10 group were men compared to 31% of the placebo group (p = 0.07). Most of the subjects in both groups were white, and simvastatin was the most common statin prescribed. The calves and thighs were the 2 most common pain locations. For 57% of the participants, the myalgias were defined as recurrent. These patients reported a previous episode of myalgia that had resolved completely when statin treatment was stopped but recurred with a rechallenge. A trend was seen toward a greater rate of patients meeting this definition in the CoQ10 group (68% vs 44%; p = 0.06).
| Variable | CoQ10 (n = 40) | Placebo (n = 36) | p Value |
|---|---|---|---|
| Mean age (years) | 61.6 | 61.8 | 0.96 |
| Gender | 0.07 | ||
| Male | 21 | 11 | |
| Female | 19 | 25 | |
| Race | 0.42 ⁎ | ||
| White | 31 | 24 | |
| Black | 8 | 10 | |
| Other | 1 | 2 | |
| Recurrence | 0.06 | ||
| Yes | 27 | 16 | |
| No | 13 | 20 | |
| Statin | |||
| Simvastatin | 22 | 22 | 0.64 |
| Pravastatin | 10 | 5 | 0.26 |
| Atorvastatin | 7 | 7 | 1.0 |
| Rosuvastatin | 1 | 2 | 0.60 |
| Myalgia location | |||
| Calves | 33 | 31 | 0.76 |
| Thighs | 25 | 18 | 0.35 |
| Arms | 13 | 16 | 0.35 |
| Shins | 17 | 11 | 0.34 |
| Concomitant drugs | |||
| Nonsteroidal anti-inflammatory drug | 9 | 5 | 0.39 |
| Acetaminophen | 5 | 5 | 1.0 |
| Opiate | 4 | 4 | 1.0 |
| Vitamin D | 8 | 11 | 0.30 |
| Previous hypertension | 31 | 31 | 0.39 |
| Previous osteoarthritis | 20 | 23 | 0.25 |
| Previous gastroesophageal reflux disease | 19 | 15 | 0.65 |
| Previous diabetes mellitus | 16 | 18 | 0.49 |
| Previous coronary artery disease | 11 | 11 | 0.80 |
| Previous depression | 7 | 10 | 0.41 |
| Previous obesity | 5 | 9 | 0.24 |
Of the 76 patients, 10 withdrew from the study before the 1-month follow-up visit, 6 in the CoQ10 group and 4 in the placebo group. Continued myalgia was the most common reason in both groups (5 and 3 patients, respectively). One patient in each group was lost to follow-up during the first month. During the second and third months of the study, the withdrawal rates were similar between the 2 groups. During the 3-month period, 9 patients in the CoQ10 group and 6 patients in the placebo group withdrew because of myalgia (p = 0.58).
The results of the VAS are listed in Table 2 . The mean score was approximately 6 cm in both groups at baseline. At 1 month, both the CoQ10- and placebo-treated patients had a significant decrease to a mean score of approximately 4 cm (p <0.01). However, no significant difference was found between the 2 groups (p = 0.94). Also, no significant change was seen in the VAS score at the 2- or 3-month evaluation compared to the 1-month value in either group. Two patients were pain free in each group at the 1-month visit. At 3 months, 4 patients in the CoQ10 group and 6 patients in the placebo group were pain free.
| Measurement Period | CoQ10 | Placebo | p Value | ||
|---|---|---|---|---|---|
| Patients (n) | Mean Score (cm) | Patients (n) | Mean Score (cm) | ||
| Baseline | 40 | 6.0 ± 2.2 | 36 | 5.9 ± 2.0 | 0.94 |
| 1 month | 34 | 3.9 ± 2.2 | 32 | 4.0 ± 2.2 | 0.97 |
| 2 month | 31 | 3.8 ± 2.2 | 30 | 3.8 ± 2.7 | 0.96 |
| 3 month | 27 | 3.2 ± 2.3 | 26 | 3.1 ± 2.2 | 0.94 |
The results of the Short-Form McGill Pain Questionnaire are listed in Table 3 . At baseline, no significant differences were seen between the 2 groups in the median total score, sensory subscale, or affective subscale. All 3 scores had decreased significantly (p <0.05) at the 1-month visit; however, no significant differences were seen between the CoQ10 and placebo groups. The median score on the sensory subscale showed an additional decrease at the 2-month visit, but no difference was seen between the 2 groups.
| Measurement | CoQ10 | Placebo | p value |
|---|---|---|---|
| Total pain rating index | |||
| Baseline | 12 | 14 | |
| 1 month | 7.5 | 9 | 0.39 |
| 2 month | 4 | 7 | 0.27 |
| 3 month | 5 | 4 | 0.57 |
| Sensory pain rating index | |||
| Baseline | 10 | 11.5 | |
| 1 month | 6.5 | 7.5 | 0.34 |
| 2 month | 4 | 4.5 | 0.52 |
| 3 month | 3 | 4 | 0.24 |
| Affective pain rating index | |||
| Baseline | 2.5 | 2 | |
| 1 month | 1 | 1 | 0.81 |
| 2 month | 0 | 1 | 0.06 |
| 3 month | 0 | 0 | 0.37 |
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