treatment with statins is highly effective in primary and secondary cardiovascular disease prevention , but their use can be associated with a variety of adverse effects , mainly affecting the muscles and liver .
the most frequent symptom is myalgia , which occurs in 1015% of patients treated with statins . in primary prevention ,
up to 25.4% of patients stop taking statins by 6 months after the beginning of treatment . for patients who can not tolerate statin therapy ,
statins inhibit the rate - limiting step in cholesterol synthesis through acting on the key enzyme 3-hydroxy-3-methylglutaryl coenzyme a ( hmgcoa ) reductase .
besides inhibiting the synthesis of cholesterol , biosynthesis of coenzyme q10 is also reduced , since coenzyme q10 is an intermediate in the mevalonate pathway .
statins were shown to reduce serum / plasma levels of coenzyme q10 by 1654% and coenzyme q10 supplementation was reported to increase the levels of coenzyme q10 in plasma .
coenzyme q10 , also known as ubiquinone , is localized in cellular membranes and participates in electron transport , and during oxidative phosphorylation in mitochondria , protects against oxidative stress and regenerates active forms of the antioxidant vitamin e .
deficiency of coenzyme q10 affects oxidative phosphorylation and mitochondrial adenosine triphosphate ( atp ) production , and consequently impairs muscle energy metabolism .
therefore , a deficiency of coenzyme q10 is the most probable mechanism of statin - related myopathy [ 79 ] .
if the proposed mechanism of statin - related muscle pain is at least partially correct , coenzyme q10 supplementation seems a logical step in its reduction .
several previous studies have reported conflicting results regarding decrease of statin - related muscle pain by coenzyme q10 supplementation in different study populations [ 6,1113 ] .
therefore , the aim of the present study was to test whether coenzyme q10 supplementation could decrease mild - to - moderate statin - associated muscle pain .
the specifics of the chosen group represent one of the most frequent clinical scenarios in statin - related adverse effects .
fifty patients of both sexes , aged between 40 and 65 years , with statin - related muscle pain were recruited in this study .
important inclusion criteria were the use of a statin for more than 6 months and the presence of statin - associated muscular symptoms for at least 6 months . in all enrolled patients , before the inclusion to the study , all possible efforts to decrease symptoms and to identify possible association with statin use were made as follows : gradual decreases of statin dose , de - challenge and re - challenge of statin treatment , and switch to another statin .
where other possible identifiable causes of myopathy were suspected , patients were not eligible for enrollment . also , patients with serious medical conditions or any other specific disease ( e.g. , hepatic , vascular , renal , or endocrine ) or coagulopathy were excluded .
a neurologist and an orthopedist also excluded possible neurological and orthopedic reasons for muscle pain before the inclusion to the study .
this was a double - blind , placebo - controlled study with balanced randomization ( 1:1 ) . an independent pharmacist ,
who was not clinically involved in the study , packed containers with either placebo or q10 ( mgc company , japan ) and numbered them according to a simple randomization procedure ( computerized random numbers ) .
the substances , placebo or q10 , were in the form of tablets identical in appearance , packed in the same white , opaque containers .
the key to the content of each numbered container was stored in the safe deposit box of the pharmacist .
each participant was assigned an order number and received the corresponding prepacked container according to the simple randomization procedure .
the allocation sequence obtained was concealed in a sealed envelope from the researchers enrolling and assessing participants .
the control group ( n=25 ) received placebo , and the q10 group ( n=25 ) received coenzyme q10 supplementation over a period of 30 days .
the patients were recruited at the department of vascular diseases , university of ljubljana medical center .
they reported myopathic symptoms consisting of muscle pain per se or accompanied by other symptoms , such as muscle weakness , muscle fatigue , or both .
a definition of mild - to - moderate muscle symptoms was used , representing the pain severity score ( pss ) or pain interference score ( pis ) of 26 .
the study protocol was approved by the national medical ethics committee of slovenia and informed consent was obtained from all the patients .
enrolled patients were assessed in 2 separate visits : at the beginning and at the end of the study ( i.e. , day 0 and day 30 of the study ) . on the first visit , a clinical examination of each subject was performed and each subject completed a brief pain inventory ( bpi ) questionnaire for evaluation of myopathic symptoms before intervention .
the questionnaire consisted of 2 parts : a pain severity score ( pss ) , calculated by averaging scores of the 4 pain intensity categories and a pain interference score ( pis ) , computed by averaging values of the 7 interference items from the questionnaire .
a blood sample was also obtained for the following laboratory analyses : fasting plasma lipid profile ( total cholesterol , low - density lipoprotein ( ldl ) cholesterol , and triglycerides ) , creatine kinase ( ck ) concentration , and liver function enzymes ( transaminases and gamma - glutamyl transpeptidase ) .
patients were then randomly assigned to receive either coenzyme q10 supplementation ( a daily supplement consisting of 50 mg of water - soluble coenzyme q10 twice daily ) or placebo twice daily for 30 days .
their assigned statin therapy was continued during the course of the study . on the second visit after completion of supplementation therapy ,
myopathic symptoms were re - evaluated with the bpi questionnaire and another blood sample was obtained for the above - listed laboratory analyses .
intragroup differences in q10 and placebo groups from the beginning to the end of the supplementation period were assessed by the paired t test .
intergroup comparisons of relative changes ( before / after study ) between q10 and placebo group were assessed by the t test .
power analysis for the difference between the placebo and the q10 groups for the pain severity score ( pss ) and pain interference score ( pis ) was conducted .
parameters needed for the power analysis  the difference between groups and standard deviations  were estimated from the sample .
a power of 99.1% and 98.5% was achieved when pis and pss , respectively , were used as a response .
fifty patients of both sexes , aged between 40 and 65 years , with statin - related muscle pain were recruited in this study .
important inclusion criteria were the use of a statin for more than 6 months and the presence of statin - associated muscular symptoms for at least 6 months . in all enrolled patients , before the inclusion to the study , all possible efforts to decrease symptoms and to identify possible association with statin use were made as follows : gradual decreases of statin dose , de - challenge and re - challenge of statin treatment , and switch to another statin .
where other possible identifiable causes of myopathy were suspected , patients were not eligible for enrollment . also , patients with serious medical conditions or any other specific disease ( e.g. , hepatic , vascular , renal , or endocrine ) or coagulopathy were excluded .
a neurologist and an orthopedist also excluded possible neurological and orthopedic reasons for muscle pain before the inclusion to the study .
this was a double - blind , placebo - controlled study with balanced randomization ( 1:1 ) . an independent pharmacist ,
who was not clinically involved in the study , packed containers with either placebo or q10 ( mgc company , japan ) and numbered them according to a simple randomization procedure ( computerized random numbers ) .
the substances , placebo or q10 , were in the form of tablets identical in appearance , packed in the same white , opaque containers .
the key to the content of each numbered container was stored in the safe deposit box of the pharmacist .
each participant was assigned an order number and received the corresponding prepacked container according to the simple randomization procedure .
the allocation sequence obtained was concealed in a sealed envelope from the researchers enrolling and assessing participants .
the control group ( n=25 ) received placebo , and the q10 group ( n=25 ) received coenzyme q10 supplementation over a period of 30 days .
the patients were recruited at the department of vascular diseases , university of ljubljana medical center .
they reported myopathic symptoms consisting of muscle pain per se or accompanied by other symptoms , such as muscle weakness , muscle fatigue , or both .
a definition of mild - to - moderate muscle symptoms was used , representing the pain severity score ( pss ) or pain interference score ( pis ) of 26 .
the study protocol was approved by the national medical ethics committee of slovenia and informed consent was obtained from all the patients .
enrolled patients were assessed in 2 separate visits : at the beginning and at the end of the study ( i.e. , day 0 and day 30 of the study ) . on the first visit , a clinical examination of each subject was performed and each subject completed a brief pain inventory ( bpi ) questionnaire for evaluation of myopathic symptoms before intervention .
the questionnaire consisted of 2 parts : a pain severity score ( pss ) , calculated by averaging scores of the 4 pain intensity categories and a pain interference score ( pis ) , computed by averaging values of the 7 interference items from the questionnaire .
a blood sample was also obtained for the following laboratory analyses : fasting plasma lipid profile ( total cholesterol , low - density lipoprotein ( ldl ) cholesterol , and triglycerides ) , creatine kinase ( ck ) concentration , and liver function enzymes ( transaminases and gamma - glutamyl transpeptidase ) .
patients were then randomly assigned to receive either coenzyme q10 supplementation ( a daily supplement consisting of 50 mg of water - soluble coenzyme q10 twice daily ) or placebo twice daily for 30 days .
their assigned statin therapy was continued during the course of the study . on the second visit after completion of supplementation therapy ,
myopathic symptoms were re - evaluated with the bpi questionnaire and another blood sample was obtained for the above - listed laboratory analyses .
intragroup differences in q10 and placebo groups from the beginning to the end of the supplementation period were assessed by the paired t test .
intergroup comparisons of relative changes ( before / after study ) between q10 and placebo group were assessed by the t test .
all statistical analyses were performed using graph pad prism 5.0 and spss 15.0 software . power analysis for the difference between the placebo and the q10 groups for the pain severity score ( pss ) and pain interference score ( pis )
parameters needed for the power analysis  the difference between groups and standard deviations  were estimated from the sample .
a power of 99.1% and 98.5% was achieved when pis and pss , respectively , were used as a response .
fifty patients were enrolled in the study , of whom 25 received coenzyme q10 and 25 received placebo .
nineteen patients received statin therapy in secondary prevention and 31 in primary prevention . in patients who received statin in secondary prevention ,
intensive dose reduction was not performed and statin discontinuation lasted for a short time ( not more than for 2 weeks ) .
patient characteristics at inclusion in the study are summarized in table 1 and did not differ between groups .
the distribution of types of statin among the patients was as follows : 22 patients received rosuvastatin 1020 mg daily , 20 patients received atorvastatin ( 10 patients 40 mg daily , and 10 patients 1020 mg daily ) , 4 patients received simvastatin 1020 mg daily , 3 patients received fluvastatin 80 mg daily , and 1 patient received lovastatin 20 mg daily . at inclusion in the study ,
the intensity of myopathic pain , measured as the pain severity score ( pss ) , was similar in both groups ( placebo and q10 group ) .
intragroup comparison showed that after 30 days of intervention , the intensity of myopathic pain in the q10 group was significantly reduced , from 3.90.4 to 2.90.4 ( p<0.001 ) , but there was no significant change in myopathic pain intensity in the placebo group ( figure 1a ) . when comparing the percentage of change between the groups ( intergroup comparison )
, we found that the intensity of myopathic pain was significantly reduced after 30 days of intervention in the q10 group compared to the placebo group ( 33.15.7% and 0.46.3% , respectively ; both p<0.05 ) .
interference of pain with daily activities was measured as the pain interference score ( pis ) . at inclusion in the study ,
intragroup comparison showed that after q10 intervention , pis was significantly reduced , from 4.00.4 to 2.60.4 ( p<0.001 ) . in the placebo group ,
the pis did not change significantly ( figure 1b ) . when comparing the percentage of change between the groups ( intergroup comparison )
, we found that the intensity of myopathic pain was significantly reduced after 30 days of intervention in the q10 group compared to the placebo group ( 40.37.0% and 11.510.2% , respectively ; both p<0.05 ) .
the results of the biochemical analyses made at the beginning and at the end of the study are presented in table 2 .
there were no differences in liver and muscle enzymes or cholesterol levels in the q10 or placebo groups during the course of the study ( intragroup comparison ) ( table 2 ) .
fifty patients were enrolled in the study , of whom 25 received coenzyme q10 and 25 received placebo .
nineteen patients received statin therapy in secondary prevention and 31 in primary prevention . in patients who received statin in secondary prevention ,
intensive dose reduction was not performed and statin discontinuation lasted for a short time ( not more than for 2 weeks ) .
patient characteristics at inclusion in the study are summarized in table 1 and did not differ between groups .
the distribution of types of statin among the patients was as follows : 22 patients received rosuvastatin 1020 mg daily , 20 patients received atorvastatin ( 10 patients 40 mg daily , and 10 patients 1020 mg daily ) , 4 patients received simvastatin 1020 mg daily , 3 patients received fluvastatin 80 mg daily , and 1 patient received lovastatin 20 mg daily .
at inclusion in the study , the intensity of myopathic pain , measured as the pain severity score ( pss ) , was similar in both groups ( placebo and q10 group ) .
intragroup comparison showed that after 30 days of intervention , the intensity of myopathic pain in the q10 group was significantly reduced , from 3.90.4 to 2.90.4 ( p<0.001 ) , but there was no significant change in myopathic pain intensity in the placebo group ( figure 1a ) . when comparing the percentage of change between the groups ( intergroup comparison )
, we found that the intensity of myopathic pain was significantly reduced after 30 days of intervention in the q10 group compared to the placebo group ( 33.15.7% and 0.46.3% , respectively ; both p<0.05 ) .
interference of pain with daily activities was measured as the pain interference score ( pis ) . at inclusion in the study ,
intragroup comparison showed that after q10 intervention , pis was significantly reduced , from 4.00.4 to 2.60.4 ( p<0.001 ) . in the placebo group ,
the pis did not change significantly ( figure 1b ) . when comparing the percentage of change between the groups ( intergroup comparison )
, we found that the intensity of myopathic pain was significantly reduced after 30 days of intervention in the q10 group compared to the placebo group ( 40.37.0% and 11.510.2% , respectively ; both p<0.05 ) .
the results of the biochemical analyses made at the beginning and at the end of the study are presented in table 2 .
there were no differences in liver and muscle enzymes or cholesterol levels in the q10 or placebo groups during the course of the study ( intragroup comparison ) ( table 2 ) .
in the present study , the possible beneficial effects of coenzyme q10 supplementation on mild - to - moderate statin - related muscle symptoms were studied , since this is one of the most frequent reasons for statin therapy withdrawal .
we found that supplementation with coenzyme q10 ( 50 mg twice daily for 30 days ) reduced muscle pain and produced less interference by pain with daily life activities .
overall , coenzyme q10 supplementation decreased statin - related muscle symptoms in 75% of patients .
we observed no significant effects of coenzyme q10 supplementation on liver and muscle enzymes , which were within normal ranges during the course of the study in both treatment groups . also , cholesterol levels did not change significantly from the beginning to the end of the study .
the observed beneficial effects of coenzyme q10 supplementation could lead to better statin treatment compliance .
the present study was designed as a double - blind , randomized , placebo - controlled trial to evaluate the possible beneficial effect of coenzyme q10 supplementation ( 50 mg twice daily for 30 days ) on statin - associated muscle pain .
a 30-day period was chosen because data in the literature indicate that the effect should reveal itself within that period . in its absence ,
extended supplementation is not recommended . using the standardized and simple brief pain inventory ( bpi ) questionnaire , consisting of a pain severity score ( pss ) and a pain interference score ( pis )
, we found that after 30 days with coenzyme q10 supplementation , muscle pain and the interference of pain with daily life activities in the mild - to - moderate symptom group were significantly reduced from the beginning to the end of the study ( from 3.90.4 to 2.90.4 and from 4.00.4 to 2.60.4 , respectively , both p<0.001 ) .
the relative values of pss and pis significantly decreased in the q10 group compared to placebo group ( 33.1 and 40.3% , respectively ; both p<0.05 ) , showing the effectiveness of q10 .
coenzyme q10 supplementation did not affect liver and muscle enzymes , which were in the normal ranges in both groups during the course of the study . according to the guidelines , all patients included in our study had myalgia 
muscle pain per se that could also be accompanied with other muscular symptoms such as muscle weakness , muscle fatigue , or both .
the levels of all cholesterols did not differ significantly before and after intervention in separate groups .
conflicting results of coenzyme q10 supplementation on statin - induced muscle pain were observed in previous studies .
the beneficial effects of coenzyme q10 were confirmed in 2 studies , but not in others .
reported that coenzyme q10 supplementation at a 200-mg daily dose ( twice that used in our study ) for 12 weeks did not improve myalgia in patients receiving simvastatin ( in a dosage of 1040 mg daily ) . in that study ,
the myalgia score was assessed by a visual analogue scale , which is known to be less accurate than the more complex brief pain inventory ( bpi ) questionnaire used in our study , and this could be the reason for the negative result observed .
similar results were observed in a study by bookstaver et al . , in which coenzyme q10 was supplemented in a dosage of 120 mg daily for 3 months .
it is also interesting that the intervals of observation were longer in both of these 2 studies compared to the present study . on the other hand ,
the most similar regimen to ours was in the study by caso et al . ,
in which the same dosage of coenzyme q10 was prescribed ( 100 mg daily ) and the bpi questionnaire was used to assess pain severity and pain interference with daily activities .
also , the duration of supplementation was the same . like our results , a decrease in both parameters was observed after 30 days of coenzyme q10 supplementation , but its major limitation was not being placebo - controlled . from that point of view , the results obtained in the present study have greater value and confirm the beneficial effect of coenzyme q10 supplementation . a recent study by fedacko et al
. showed that coenzyme q10 supplementation decreased symptoms of statin - associated myopathy , intensity of muscle pain , muscle weakness , muscle cramps , and muscle tiredness . considering all data from the above - mentioned studies together , we believe that the conflicting results show a complex relation between statin - related muscle symptoms and coenzyme q10 supplementation , probably due to the many confounding factors that influence the efficacy of coenzyme q10 supplementation .
the limitation of the present study was the relatively small number of patients involved , which consequently limits extensive generalization of the results obtained .
the main reason for the relatively small population group lay in the strict inclusion criteria , which ensured recruiting only patients with  real  statin - related muscular symptoms , who were highly motivated and informed , and consequently an accurate estimate of the intervention efficacy could be obtained .
specifically , over - subjective estimation of statin - associated muscular symptoms is a well - known problem , which could importantly affect the results and conclusions .
undoubtedly , further studies enrolling larger numbers of participants are warranted to address this problem .
importantly , patients with mild - to - moderate muscular symptoms were included , which is probably the most frequent clinical scenario in patients with statin - related symptoms .
furthermore , it is important to note that it was placebo - controlled and used widely accessible , relatively objective standardized questionnaires , allowing for great comparability . on the other hand
, we do not know whether the proposed therapy is effective in all patients with statin - associated symptoms , but according to our data , it should be effective in the mild - to - moderate statin - associated symptoms group .
the present study was patient - oriented and designed to focus on clinical effects of coenzyme q10 supplementation in statin - induced muscle symptoms , and not its mechanistic background .
therefore , the concentration of coenzyme q10 in plasma or muscles and possible mechanistic background ( e.g. , anti - inflammatory and anti - oxidative ) were not addressed in this study .
the present study revealed that by simple coenzyme q10 supplementation of the regular statin treatment , associated muscle pain in the mild - to - moderate symptoms group could be significantly reduced .
consequently , it may lead to lower interference with daily activities and higher compliance with statin treatment .
these observations mean a better quality of life , besides adequate cardiovascular protection , which is the primary goal of statin therapy .
the results of the present study are very promising , but require further testing in larger clinical trials , mainly to allow them to be generalized .
 backgroundstatin use is frequently associated with muscle - related symptoms . 
 coenzyme q10 supplementation has yielded conflicting results in decreasing statin myopathy . herein , we tested whether coenzyme q10 supplementation could decrease statin - associated muscular pain in a specific group of patients with mild - to - moderate muscle symptoms.material/methodsfifty patients treated with statins and reporting muscle pain were recruited . 
 the q10 group ( n=25 ) received coenzyme q10 supplementation over a period of 30 days ( 50 mg twice daily ) , and the control group ( n=25 ) received placebo . 
 the brief pain inventory ( bpi ) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation.resultsthe intensity of muscle pain , measured as the pain severity score ( pss ) , in the q10 group was reduced from 3.90.4 to 2.90.4 ( p<0.001 ) . 
 the pain interference score ( pis ) after q10 supplementation was reduced from 4.00.4 to 2.60.4 ( p<0.001 ) . in the placebo group , pss and pis 
 did not change . 
 coenzyme q10 supplementation decreased statin - related muscle symptoms in 75% of patients . 
 the relative values of pss and pis significantly decreased ( 33.1% and 40.3% , respectively ) in the q10 group compared to placebo group ( both p<0.05 ) . from baseline , no differences in liver and muscle enzymes or cholesterol values were found.conclusionsthe present results show that coenzyme q10 supplementation ( 50 mg twice daily ) effectively reduced statin - related mild - to - moderate muscular symptoms , causing lower interference of statin - related muscular symptoms with daily activities . 
Background
Material and Methods
Patients
Study protocol
Statistical analysis
Results
Patient characteristics
Intensity of myopathic pain
Interference of pain with daily activities
Laboratory serum analyses
Discussion
Conclusions