N-of-1 (Single-Patient) Trials for Statin-Related Myalgia
Abstract
Background Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. Objective To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. Design N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. Patients Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. Intervention Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. Measurements Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). Results Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-…
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23 studies were included for data extraction, with 9 RCTs analyzed quantitatively.
“23 studies were included for data extraction [20–26,35–50], with 9 RCTs analyzed quantitatively.”
New evidence on the management of SAMS has become available from randomized controlled trials and observational data.
“New evidence on the management of SAMS have since become available both from randomized control trials (RCTs) and from observational data [20–26].”
8 out of 13 RCTs were judged at low risk of bias.
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
Nine trials assessed statin against placebo.
“nine trials assessed statin against placebo [20–26,43]”
Nine trials provided data for treatment discontinuation due to muscle symptoms.
“Nine trials [22,25,26,40,43,46–48] provided data for treatment discontinuation due to muscle symptoms”
Most trials used a mean difference in pain intensity between statin and comparator group.
“most trials [22,23,25,40,49] used a mean difference in pain intensity between statin and comparator group”
In earlier studies, SAMS were assessed through incidence of SAMS and later quantified with the VAS.
“In earlier studies, SAMS were assessed through incidence of SAMS [17,43,46–48] and later quantified with the VAS (visual analogue scale) [22,23,25,40,49].”
N-of-1 trials demand long-term investment of each individual, which can lead to high rates of missing data.
“On the contrary, n-of-1 trials demand long-term investment of each individual, which can lead to high rates of missing data [22,25].”
Many studies implemented wash-out periods or a threshold time for SAMS occurrence, which presents a difficulty for cross-over designs and particularly n-of-1 trials.
“Although many studies implemented wash-out periods [23] or a threshold time for SAMS occurrence [22,49], this presents a difficulty for cross-over designs and particularly n-of-1 trials.”
Cites
Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J., Gotto, A. M., Kastelein, J. J. P., Koenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0807646 · Cited by 6,674 · see citing works
Dworkin, R. H., Turk, D. C., Wyrwich, K. W., Beaton, D., Cleeland, C. S., Farrar, J. T., Haythornthwaite, J. A., Jensen, M. P., Kerns, R. D., Ader, D. N., et al. (2008) · The Journal of Pain · doi:10.1016/j.jpain.2007.09.005 · Cited by 3,471 · see citing works
Breivik, H., Borchgrevink, P. C., Allen, S. M., Rosseland, L. A., Romundstad, L., Breivik Hals, E. K., Kvarstein, G., & Stubhaug, A. (2008) · British Journal of Anaesthesia · doi:10.1093/bja/aen103 · Cited by 2,108 · see citing works
Statin Safety: A Systematic Review
Law, M., & Rudnicka, A. R. (2006) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2005.12.010 · Cited by 808 · see citing works
Narrative review: statin-related myopathy
Joy, T. R., & Hegele, R. A. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-12-200906160-00009 · Cited by 453 · see citing works
Self-citationStatin Safety: An Overview and Assessment of the Data—2005
Bays, H. (2006) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2005.12.006 · Cited by 264 · see citing works
Muscle coenzyme Q10 level in statin-related myopathy
Lamperti, C., Naini, A. B., Lucchini, V., Prelle, A., Bresolin, N., Moggio, M., Sciacco, M., Kaufmann, P., & DiMauro, S. (2005) · Archives of Neurology · doi:10.1001/archneur.62.11.1709 · Cited by 178 · see citing works
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Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., Braun, L. T., de Ferranti, S., Faiella-Tommasino, J., Forman, D. E., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000625 · Cited by 6,185 · see citing works
Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., Braun, L. T., de Ferranti, S., Faiella-Tommasino, J., Forman, D. E., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.003 · Cited by 2,691 · see citing works
Interpretation of the evidence for the efficacy and safety of statin therapy
Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., Blumenthal, R., Danesh, J., Smith, G. D., DeMets, D., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31357-5 · Cited by 1,857 · see citing works
Kazi, D. S., Moran, A. E., Coxson, P. G., Penko, J., Ollendorf, D. A., Pearson, S. D., Tice, J. A., Guzman, D., & Bibbins-Domingo, K. (2016) · JAMA · doi:10.1001/jama.2016.11004 · Cited by 382 · see citing works
2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia
Blumenthal, R. S., Morris, P. B., Gaudino, M., Johnson, H. M., Anderson, T. S., Bittner, V. A., Blankstein, R., Brewer, L. C., Cho, L., de Ferranti, S. D., et al. (2026) · JACC · doi:10.1016/j.jacc.2025.11.016 · Cited by 304 · see citing works
McDonald, S., Quinn, F., Vieira, R., O’Brien, N., White, M., Johnston, D. W., & Sniehotta, F. F. (2017) · Health Psychology Review · doi:10.1080/17437199.2017.1316672 · Cited by 200 · see citing works
A randomized trial of Coenzyme Q10 in patients with confirmed statin myopathy
Taylor, B. A., Lorson, L., White, C. M., & Thompson, P. D. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.12.016 · Cited by 200 · see citing works
Optimizing cholesterol treatment in patients with muscle complaints
Rosenson, R. S., Baker, S., Banach, M., Borow, K. M., Braun, L. T., Bruckert, E., Brunham, L. R., Catapano, A. L., Elam, M. B., Mancini, G. B. J., et al. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.07.752 · Cited by 193 · see citing works
Writing Committee Members, Blumenthal, R. S., Morris, P. B., Gaudino, M., Johnson, H. M., Anderson, T. S., Bittner, V. A., Blankstein, R., Brewer, L. C., Cho, L., et al. (2026) · Circulation · doi:10.1161/cir.0000000000001423 · Cited by 122 · see citing works
Penson, P. E., Mancini, G. B. J., Toth, P. P., Martin, S. S., Watts, G. F., Sahebkar, A., Mikhailidis, D. P., Banach, M., & on behalf of Lipid and Blood Pressure Meta‐Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP) (2018) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12344 · Cited by 110 · see citing works
Kristiansen, O., Vethe, N. T., Peersen, K., Wang Fagerland, M., Sverre, E., Prunés Jensen, E., Lindberg, M., Gjertsen, E., Gullestad, L., Perk, J., et al. (2021) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvaa076 · Cited by 27 · see citing works
Kraut, R., Wierenga, F., Molstad, E., Korownyk, C., Perry, D., Dennett, L., & Garrison, S. (2023) · PLOS ONE · doi:10.1371/journal.pone.0295857 · Cited by 7 · see citing works
Aebi, P. S., Villoz, F., Bührer, J., Lyko, C., Abolhassani, N., Del Giovane, C., Gencer, B., Rodondi, N., & Blum, M. R. (2025) · PLOS One · doi:10.1371/journal.pone.0338575
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
Influential
- Authors
- Joy, T. R., Monjed, A., Zou, G. Y., Hegele, R. A., McDonald, C. G., & Mahon, J. L.
- Affiliations
- Western University (CA)
- From Schulich School of Medicine and Dentistry, Robarts Clinical Trials, and Robarts Research Institute, Western University, London, Ontario, Canada.
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 2014-03-04
- Volume
- 160
- Issue
- 5
- Pages
- 301-310
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W2058451295
- Cited by
- 130
- References
- 7
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 11 · 2021: 6 · 2020: 13 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 17 · 2015: 15 · 2014: 17
- FWCI
- 20.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- statin rechallenge, N-of-1 trials, statin tolerability, statin discontinuation, creatine kinase elevation, pain interference, lipid-lowering therapy
- MeSH terms
- Rosuvastatin Calcium, Atorvastatin, Aged, Aged, 80 and over, Double-Blind Method, Female, Fluorobenzenes, Heptanoic Acids, Humans, Hypercholesterolemia, Male, Pyrimidines, Pyrroles, Research Design, Sulfonamides, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myalgia
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