Analgesic Drug Use Associated with Statin Prescription – a Cross- Sectional Study in Primary Care Settings D

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16 Current Drug Safety, 2012, 7, 16-20 Analgesic Drug Use Associated with Statin Prescription – A Cross- Sectional Study in Primary Care Settings D. Moßhammer*,1, J. Schwarz1, S. Meznaric1, R. Muche2, G. Lorenz1 and K. Mörike3

1Division of General Practice, University Hospital Tübingen, Germany 2Institute of Biometrics, University of Ulm, Germany 3University Hospital Tübingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology, Germany

Abstract: Background: To investigate whether features of muscular complaints (MC) differ between receivers of a statin prescription and non-receivers. To analyze the relationship between analgesics prescription, statin prescription and/or musculoskeletal disorders. Methods: Cross-sectional study. Consecutive patients in offices of family practitioners were interviewed using a standardized questionnaire. Target variables: Rates of features of MC in patients with or without a statin prescription and rates of analgesic drug prescription in patients with or without statin prescription and/or musculoskeletal disorders. Odds ratios (adjusted for age, sex, and socio-economic status) were calculated using logistic regression analysis. Results: 1135 patients in 26 general practitioners’ offices were asked to participate, and 1031 patients agreed. Features of MC did not differ between the two groups of patients. Analgesic prescription was found to be associated with statin prescription in patients without musculoskeletal disorders (OR 2.2, CI 1.1-4.7 without statin, OR 2.5, CI 0.9-6.9 with statin) and particularly in those with musculoskeletal disorders (OR 5.2, CI 2.9-9.3 without statin, OR 9.3, CI 4.5-19.1 with statin). Conclusions: Analgesic prescriptions are probably positively associated with statin prescription. Assuming that analgesics attenuate MC, an even stronger association between MC and statin use seems likely. The results generate the hypothesis that statin use contributes to analgesic use in primary care patients. Keywords: Lipid-lowering drugs, statins, musculoskeletal disorders, general practice, analgesics, primary health care.

INTRODUCTION In a retrospective analysis of large community-practice data (N=32,225 patients), statin initiation was found to be Data on the features of muscular adverse side effects of associated with an approximate doubling of the risk for statins mainly derive from clinical trials and are sparse in myopathic events (myalgia, mild myositis) [6]. primary care. Newer data has revealed a ten percent rate of mild to moderate muscular complaints (MC) under high dose In our recent analysis of this cross-sectional study in statin therapy in unselected primary care patients [1]. Since primary care settings among 1031 patients ( 50 years), a in primary care MC might be due to a variety of underlying similar positive association (OR 1.5; 95%-CI 1.1-2.0) causes, it has been supposed that primary-care physicians between statin prescription and the reporting of MC was may easily miss statin-associated muscular side effects [2, found. In the complete patient cohort (n=1031), the rate of 3]. It is unknown whether the features of statin-associated reporting muscular complaints in the previous 4 weeks was MC differ from MC of other origin. Commonly, muscular 40% (n=411), and 23% (n=239) of patients were found to adverse effects of statins are collectively termed as have a prescription of a statin. Furthermore, the use of myopathy which includes muscular pain, tenderness, cramps, analgesic drugs was detected in the multivariate logistic heaviness, stiffness or weakness [4]. regression model to be positively associated with MC (odds ratio 1.8; 95% confidence interval 1.3-2.5) [7]. It is The U.S. National Health and Nutrition Examination Survey unknown, however, whether statin use is associated with (from 1999-2002), in a representative cross-sectional study analgesic drugs use. This is particularly important because among 3580 adults without arthritis (40 years), found an analgesics may attenuate MC. association between musculoskeletal pain and statin use (Odds Ratio [OR] 1.5; 95% confidence interval [95%-CI] 1.07-2.11). This report includes the analysis of (1.) the MC features Also, a significant association with lower back pain (OR 1.59; of patients with and without a statin prescription and (2.) the 95%-CI 1.04-2.44) and lower extremity pain (OR 1.50; 95%-CI relationships between analgesics prescription, statin 1.02-2.22), respectively, was observed [5]. prescription and/or musculoskeletal disorders.

METHODS

*Address correspondence to this author at the Division of General Practice, Eberhard Karls University of Tübingen, University Hospital Tübingen, The approach and methodology have been described in a Österbergstrasse 15, D-72074 Tübingen, Germany; previous report [7]. In brief, a cross-sectional study was Tel: +49 7071 29-80255; Fax: +49 7071 29-5896; performed in 26 general practitioners´ offices from March, E-mail: [email protected] 2006, to March, 2007. It was an exploratory approach.

The ethical committee of the Medical Faculty of the Features of Musculoskeletal Symptoms Eberhard Karls University of Tübingen approved the study Table 2 shows the results of the univariate analysis of protocol. muscular symptoms in patients with and without statin Patients: Patients at the age of 50 years entering the offices prescription. Among MC patients (n=411), those with a statin were asked for participation after informed consent. Upon prescription reported amelioration of MC while recumbent (OR completion of an interview, the investigator asked the next 2.1, CI 1.2-3.5, adjusted OR 1.9, CI 1.1-3.3) (26%, n=28), as patient entering the office for participation. compared with statin non-prescription (15%, n=45). No Materials: A questionnaire was developed along established significant associations were found in other items, i.e., questionnaires for musculoskeletal complaints and pain [8, 9] localization, character, physical activity, and frequency. and covered information on the severity, frequency, time course, location, amelioration, deterioration, and character of muscular Analgesic Drug Prescription Associated with Statin Use complaints. To minimize recall bias in this cross-sectional and/or Musculoskeletal Disorders study, a period of 4 weeks preceding the interview was Recipients of analgesic prescriptions among MC patients considered to be appropriate for the reporting of MC. increased from those without underlying musculoskeletal With a standardized procedure, the interviewers (J.S. and disorder (OR 2.2, CI 1.1-4.7 without statin, OR 2.5, CI 0.9-6.9 S.M.) used this pseudonymized questionnaire to collect the with statin) to those with musculoskeletal disorder (OR 5.2, CI information from the patient during a personal interview and, 2.9-9.3 without statin, OR 9.3, CI 4.5-19.1 with statin). The subsequently, office documentation database (office files). From reference group were 251 patients without muscular symptoms the office files, the interviewers extracted information on and without preexisting musculoskeletal disorders (see Table 3). medication prescription and diseases of organ systems as th categorized by the International Classification of Diseases, 10 DISCUSSION revision (ICD 10). Prescriptions were grouped into drug classes and analyzed on a yes/no basis. The interviewers checked the Main Findings of this Study quality and completeness of the data at the end of the interview. Basically, no differences of MC between users and non- Data analysis: Data of patients with muscular symptoms users of statins were found. The only exception is that more (n=411, i.e. 40% of 1031 participating patients) were extracted users than non users of statins report amelioration of MC by from the complete data set of 1031 patients. To analyse for any recumbency. Buettner et al., however, in their large U.S. associations between features of muscular symptoms of patients National Health and Nutrition Examination Survey, observed (such as character, frequency, intensity, duration, amelioration, even further characteristics and localization of musculoskeletal deterioration) and statin prescription, odds ratios with 95%- pain in users as compared to non-users of statins. The most confidence intervals were calculated and chi-square tests were likely explanation is that our study did not exclude patients with performed. Univariate analysis was used to screen for factors arthritis. An underestimation of the true association may result. potentially associated with MC in statin users and non-users. An To strengthen these possible associations, the effects of alpha error of 0.05 was considered to be significant. If, in this termination or discontinuation of statin therapy on MC and univariate analysis, variables were found to be significant they creatine kinase serum activities should be included in the were included into a multivariate logistic regression analysis analysis in subsequent prospective studies. adjusting for age, sex, and socio-economic status (Wald-Odds Our second observation was that rates of analgesic ratios with 95%-confidence intervals). prescription receivers tended to increase among patients with To describe the relationships between analgesics statin prescription taking musculoskeletal disorders into account. prescription, statin prescription, and muscular complaints Even upon controlling for the classical confounding variables /musculoskeletal disorders, we calculated age, sex, and socio- (i.e., age, sex, and socio-economic status), the OR for analgesic economic status adjusted Wald-Odds ratios (with 95%- prescription remained stable. This suggests an underlying causal confidence intervals) using logistic regression analysis. For the relationship. Our office-based prescription records may latter analysis, the reference group consisted of 251 patients underestimate the true consumption of analgesics, e.g. by over- (24% of the 1031 participating patients) without muscular the-counter purchase. The true consumption of analgesics may symptoms and without preexisting musculoskeletal disorders. be higher than documented prescriptions in the office files. If so, this would strengthen, rather than weaken, the association. All analyses were done in an exploratory fashion. To account for clustering, we calculated the proportion of muscular symptoms of each office [7]. This proportion ranges from 25 to What is Already Known on this Topic 66 percent, with a p-value of the chi-square test of 0.2. Due to Statin use appeared to be independently associated with this result, we assumed independency between the practices. MC, so did analgesic drugs use in primary care patients [7]. The The significance level for the tests was set at 0.05. Data analyses latter finding is not surprising because analgesic drug use may were performed with the SAS software version 9.1. be a marker of MC. Until recently, it has been unknown whether statin use is an independent factor associated with RESULTS musculoskeletal complaints. Data on this topic are lacking because reports on muscular side effects of lipid-lowering drugs Table 1 shows the comparison of the extracted data set of mainly derive from large trials of lipid-lowering and clinical patients having muscular complaints (n=411) with and without endpoint effects. Clinical trials frequently exclude patients at statin prescription (n=106 and n=305, respectively) and of the risk for myopathy (e.g. elderly patients, or patients with elevated complete data set (n=1031). 18 Current Drug Safety, 2012, Vol. 7, No. 1 Moßhammer et al.

Table 1. Patients Subgroups with Muscular Complaints (n=411) with and without Statin Prescription and the Total Patient Cohort (n=1031)

Variable Specification n/%, SP (n=106) n/%, wSP (n=305) Total (n=1031)

Sex Female 59/56 209/69 594/58 Age Years (mean) 69 65 66 Social class/occupation Upper class 4/4 21/7 59/6 Employees and self-employed 6/6 34/11 106/11 Workers with or without qualification 13/12 42/14 133/13 Retirees 80/76 189/62 683/66 At home or unemployed 3/3 19/6 55/5 BMI kg/m2 (mean) 28 27 27 Smoking Yes 9/9 35/12 134/13 11/10 24/8 100/10 daily 15/14 33/11 136/13 >once per week 14/13 51/17 175/17 Alcohol consumption Once per week 16/15 49/16 157/15 <2 to 3 times per month

None 50/47 148/49 463/45 8/8 20/7 60/6 daily 22/21 85/28 210/20 >once per week 14/13 40/13 141/14 Depressed mood in the previous 4 weeks Once per week 19/18 56/18 182/18 <2 to 3 times per month

None 43/41 104/34 438/43 Always 44/42 160/53 496/48 often 15/14 43/14 148/14 Reading drug information leaflets seldom 22/21 57/19 206/20 never 25/24 45/15 181/18 Chronic disorders (d) Cardiovascular Yes 84/79 184/61 693/67 Pulmonal Yes 15/14 41/13 162/16 Gastrointestinal Yes 38/36 68/22 259/25 Muskoloskeletal Yes 74/70 213/70 656/64 Endocrinologic/metabolic Yes 91/86 180/59 680/66 Malignant Yes 10/9 28/9 125/12 Neuro-psychiatric Yes 37/35 104/34 327/32 Urogenital Yes 18/17 56/18 210/20 Miscellaneous Yes 76/72 203/67 659/64 N, absolute number; SP, patients with muscular symptoms and statin prescription; wSP, patients with muscular symptoms without statin prescription; BMI, body mass index; d, according to the practice data base documentation. creatine kinase serum activity, history of muscular symptoms) In conclusion, the present findings generate the and may underestimate the frequency of adverse effects. In hypothesis that statin use contributes to analgesic drug use in contrast, our study patients were from an unselected primary primary care patients. The evaluation of MC in primary care care population. patients should include statin use.

Limitations What this Study Adds Our analysis has some limitations. Obviously, due to the Our findings show a trend that analgesic drug use is nature of this cross-sectional study, a statistical association, positively associated with statin use. Assuming that not a causal relationship, between statin prescription, analgesics attenuate MC, the true association between statin muscular symptoms, and analgesic prescription has been use and MC may be even stronger.

Analgesic Drug Use Associated with Statin Prescription Current Drug Safety, 2012, Vol. 7, No. 1 19

Table 2. Characterisation of Muscular Symptoms in Patients with and without Statin Prescription

Variable Specification n/%, SP (n=106) n/%, wSP (n=305) OR (95% CI) P-Value Localisation Arms 58/55 170/56 1.0 (0.6-1.5) 0.83 Legs 67/63 186/61 1.1 (0.7-1.7) 0.71 Trunk 56/53 177/58 0.8 (0.5-1.3) 0.34 Proximal 85/80 228/75 1.3 (0.8-2.3) 0.28 Distal 53/50 173/57 0.8 (0.5-1.2) 0.22 Type Gnawing 2/2 12/4 0.5 (0.1-2.1) 0.31 Twinging 37/35 114/38 0.9 (0.6-1.4) 0.69 Stabbing 27/26 58/19 1.5 (0.9-2.4) 0.16 Cramping 22/21 72/24 0.8 (0.5-1.4) 0.53 undifferentiated 57/54 169/56 0.9 (0.6-1.4) 0.75 Constant 21/20 54/18 1.1 (0.7-2.0) 0.64 fluctuating intensity 58/55 160/53 1.1 (0.7-1.7) 0.71 Sore muscles 48/46 145/48 0.9 (0.6-1.4) 0.68 Muscle cramps 67/63 204/67 0.8 (0.5-1.3) 0.44 Muscle stiffness* 44/44 148/52 0.7 (0.5-1.1) 0.17 Muscle weakness** 53/52 158/53 1.0 (0.6-1.5) 0.93 Intensity very light and light 22/21 67/24 0.9 (0.5-1.5) 1.0 Medium 37/35 130/46 0.7 (0.5-1.1) 0.17 1.5 (1.0-2.4) 0.07 strong and very strong 47/44 105/35 Ameliorated by Rest 30/28 84/28 1.0 (0.6-1.7) 0.89 Movement 31/29 101/33 0.8 (0.5-1.3) 0.45 Sitting 6/6 15/5 1.2 (0.4-3.1) 0.77 Recumbent 28/26 45/15 2.1 (1.2-3.5) <0.01 Upright 3/3 7/2 1.2 (0.3-4.9) 0.76 Cold 5/5 15/5 1.0 (0.3-2.7) 0.93 Warmth 42/40 121/40 1.0 (0.6-1.6) 0.97 “Don’t know” 9/9 27/9 1.0 (0.4-2.1) 0.90 Deteriorated by Rest 6/6 16/5 1.1 (0.4-2.8) 0.88 Movement 18/17 43/14 1.2 (0.7-2.3) 0.48 Sitting 11/10 42/14 0.7 (0.4-1.5) 0.72 Recumbent 11/10 27/9 1.2 (0.6-2.5) 0.65 Upright 14/13 35/12 1.2 (0.6-2.3) 0.64 Cold 14/13 47/16 0.8 (0.4-1.6) 0.58 Warmth 2/2 6/2 1.0 (0.2-4.8) 0.96 “Don’t know” 21/20 64/21 0.9 (0.5-1.6) 0.79 Time course 1 to 4 times 22/21 61/20 1.0 (0.6-1.8) 0.89 Frequency in the previous 4 weeks 4 to 10 times 30/28 81/27 1.1 (0.7-1.8) 0.80 >10 times 54/51 163/53 0.9 (0.5-1.4) 0.73 for days or weeks or months 30/28 86/28 1.0 (0.6-1.6) 1 Duration for years 76/72 218/72 1.0 (0.6-1.6) 1 yearly or monthly or weekly 55/52 147/49 1.1 (0.6-1.4) 0.65 Frequency of occurrence daily or always. 50/48 152/51 0.9 (0.6-1.4) 0.65 seconds or minutes 27/26 79/26 1.0 (0.6-1.6) 1 Duration of episodes hours or days 48/45 137/45 1.0 (0.7-1.6) 0.91 weeks or month or years 31/29 88/29 1.0 (0.6-1.7) 0.90 Due to the exploratory character of this analysis, no adjustment for multiple testing was performed. N, absolute number; SP, patients with muscular symptoms and statin prescription; wSP, patients with muscular symptoms without statin prescription; OR (95% CI), odds ratio (95% confidence interval). Missing values: * n=23; ** n=8. 20 Current Drug Safety, 2012, Vol. 7, No. 1 Moßhammer et al.

Table 3. Odds Ratios (Adjusted for Age, Sex, and Socio-Economic Status) of the Association Between the Reporting of Muscle Complaints and Analgesic Drug Use (d) in 1031 Primary Care Patients Related to Musculoskeletal Disorders (d) and Lipid-Lowering Drug Use (d)

Muscle Complaints in the Previous 4 Weeks (n/%) Yes Musculoskeletal Disorders No Yes No Lipid-Lowering Drug Use Lipid-Lowering Drug Use

analgesics use (n/%) Yes No Yes No No (800/78) 504/81 44/59 148/69 26/81 78/85 Yes (231/22) 116/19 30/41 65/31 6/19 14/15 Total 1031 620/60 (*) 74/7 213/21 32/3 92/9 OR (95%-CI) 9.3 (4.5–19.1)1 5.2 (2.9–9.3)2 2.5 (0.9–6.9)3 2.2 (1.05–4.7)4 Overall OR (95%-CI) 6.0 (3.43–10.3)5 2.4 (1.2–4.7)6 d - according to the office documentation. * - 24 percent of the patients reported no muscular symptoms and no musculoskeletal disorders (n=251); in this patient group, analgesics were used by 7 percent (n=4) with and 8 percent (n=15) without lipid-lowering drug use, respectively. Therefore, this group of patients was considered as reference. Explanation: An analgesic prescription was found in 15% (n=14) and 19% (n=6) in the cohort without musculoskeletal disorders, and in 31% (n=65) and 41% (n=30) in the cohort with musculoskeletal disorders, respectively. Overall p-value <0.01. Ref - reference category. OR - odds ratio with 95%-confidence-interval (CI). 1,2,3,4,5,6 Crude odds ratios (CI) – logistic regression analysis (without adjusting for confounding variables): 1 8.3 (4.3–16.1); 2 5.4 (3.1–9.3); 3 2.8 (1.0–7.7);4 2.2 (1.0–4.6); 5 6.0 (3.5– 10.2); 6 2.3 (1.2–4.6). shown. Types of analgesics, e.g., non-steroidal anti- [2] Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of inflammatory drugs and opioids, were not differentiated in statins. J Cardiovasc Pharmacol 2002; 40(2): 163-71. [3] Corsini A. Statin-related muscle complaints: an underestimated this exploratory study. It should be noted that these drugs risk. Cardiovasc Drugs Ther 2005; 19(6): 379-81. can potentially cause muscular symptoms. According to the [4] Joy TR, Hegele RA. Narrative review: statin-related myopathy. drug information leaflet, muscle pain and myopathy is a Ann Intern Med 2009; 150(12): 858-68. potential adverse side effect of paracetamol. The use of [5] Buettner C, Davis RB, Leveille SG, Mittleman MA, Mukamal KJ. morphine, fentanyl or oxycodone can cause muscle rigidity. Prevalence of musculoskeletal pain and statin use. J Gen Intern Med 2008; 23(8): 1182-6. [6] Nichols GA, Koro CE. Does statin therapy initiation increase the CONFLICT OF INTEREST STATEMENT risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther 2007; 29(8): 1761-70. The authors declare that no conflicts of interest exist. [7] Mosshammer D, Lorenz G, Meznaric S, Schwarz J, Muche R, Morike K. Statin use and its association with musculoskeletal symptoms - a cross-sectional study in primary care settings. Fam REFERENCES Pract 2009; 26(2): 88-95. [8] Parsons S, Carnes D, Pincus T, et al. Measuring troublesomeness [1] Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to of chronic pain by location. BMC Musculoskelet Disord 2006; 7: moderate muscular symptoms with high-dosage statin therapy in 34. hyperlipidemic patients - the PRIMO study. Cardiovasc Drugs Ther [9] Kuorinka I, Jonsson B, Kilbom A, et al. Standardised Nordic 2005; 19(6): 403-4. questionnaires for the analysis of musculoskeletal symptoms. Appl Ergon 1987; 18(3): 233-7.

Received: August 2, 2011 Revised: January 12, 2012 Accepted: January 13, 2012