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N-of-1 (Single-Patient) Trials for Statin-Related Myalgia

Tisha R. Joy, MD; Alaa Monjed, MD; Guang Yong Zou, PhD; Robert A. Hegele, MD; Charlotte G. McDonald, MD, MSc; and Jeffrey L. Mahon, MD, MSc
[+] Article, Author, and Disclosure Information

From Schulich School of Medicine and Dentistry, Robarts Clinical Trials, and Robarts Research Institute, Western University, London, Ontario, Canada.

Note: All authors had access to the data and take responsibility for the analysis and reported findings.

Acknowledgment: The authors thank Leanne Vanderhaeghe and Christopher Reynaert of the Pharmacy Department at St. Joseph's Hospital for their help with the conduct of this trial, especially the generation of randomization schemes, purchase and compounding of active and placebo capsules, and dispensing of study medications. The authors also thank research assistants Lynda Bere and Patricia Rosas-Arellanos and the patients who participated.

Grant Support: In part by the Program of Experimental Medicine (Dr. Joy) and the Department of Medicine (Drs. Joy and McDonald) from Western University, London, Ontario, Canada.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1921.

Reproducible Research Statement:Study protocol: Available from Dr. Joy (e-mail, tisjoy@hotmail.com). Statistical code: Available from Dr. Zou (e-mail, gy.zou@robartsinc.com). Data set: Not available.

Requests for Single Reprints: Tisha R. Joy, MD, Western University, Schulich School of Medicine and Dentistry, B5-107, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada; e-mail, tisjoy@hotmail.com.

Current Author Addresses: Drs. Joy, McDonald, and Mahon: Western University, Schulich School of Medicine and Dentistry, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.

Dr. Monjed: Al-hejra Street, PO Box 463, Makkah, Saudi Arabia.

Dr. Zou: Robarts Clinical Trials, PO Box 5015, 100 Perth Drive, London, Ontario N6A 5K8, Canada.

Dr. Hegele: Vascular Biology, Robarts Research Institute, 1511 Richmond Street North, London, Ontario N6A 5B7, Canada.

Author Contributions: Conception and design: T.R. Joy, C.G. McDonald, J.L. Mahon.

Analysis and interpretation of the data: T.R. Joy, A. Monjed, G.Y. Zou, J.L. Mahon.

Drafting of the article: T.R. Joy, J.L. Mahon.

Critical revision of the article for important intellectual content: T.R. Joy, R.A. Hegele, C.G. McDonald, J.L. Mahon.

Final approval of the article: T.R. Joy, A. Monjed, G.Y. Zou, R.A. Hegele, C.G. McDonald, J.L. Mahon.

Provision of study materials or patients: T.R. Joy, R.A. Hegele, C.G. McDonald.

Statistical expertise: G.Y. Zou.

Obtaining of funding: T.R. Joy, C.G. McDonald.

Collection and assembly of data: T.R. Joy, A. Monjed, R.A. Hegele.

Ann Intern Med. 2014;160(5):301-310. doi:10.7326/M13-1921
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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-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months.

Limitation: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation.

Conclusion: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability.

Primary Funding Source: Western University, London, Ontario, Canada.


statins ; myalgia


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Figure 1.

Study design.

The study duration was 33 wk. After the baseline assessment at time 0, patients had 3 pairs of active drug (3 wk) and placebo (3 wk) exposures. Randomly assigned treatment pairs comprised 2 treatment periods (active therapy or placebo) separated by a 3-wk washout period. Treatment pairs were also separated by washout periods. A complete n-of-1 trial comprised 3 treatment pairs. Clinic visits occurred at baseline and at the end of each treatment period (solid arrows). Baseline scores for the visual analogue scales and Brief Pain Inventories were collected at time 0. Patients then completed these questionnaires at days 7, 14, and 21 in each treatment period.

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Figure 3.

VAS myalgia scores for each n-of-1 trial, based on treatment period.

The VAS myalgia scores for patients 1 to 8 are presented according to each treatment period (active [solid circle, solid line] and placebo [solid square, dotted line]). A full n-of-1 trial consisted of 6 treatment periods (3 active and 3 placebo). Treatment periods were 3 wk in duration. The VAS myalgia scores were completed at the end of each week in the treatment periods. Higher VAS myalgia scores signify greater muscle pain. Patient 6 crossed over early during treatment period 1, resulting in only 2 VAS myalgia scores for that period. Patient 7 forgot to complete 1 of 3 VASs for myalgia in treatment period 6, and patient 8 discontinued the n-of-1 trial after completing 5 treatment periods. VAS = visual analogue scale.

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Summary for Patients

Treatment Trials to Determine Whether Statins Are the Cause of a Patient's Discomfort

The full report is titled “N-of-1 (Single-Patient) Trials for Statin-Related Myalgia.” It is in the 4 March 2014 issue of Annals of Internal Medicine (volume 160, pages 301-310). The authors are T.R. Joy, A. Monjed, G.Y. Zou, R.A. Hegele, C.G. McDonald, and J.L. Mahon.


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