Abstract
Background and objective: The clinical utility of cyclobenzaprine for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions is limited by cholinergic adverse effects associated with its use. As expected, these effects may be pronounced in the elderly in whom altered renal and hepatic function may change drug pharmacokinetics. The goal of this study was to characterize the pharmacokinetics of the extended-release formulation of cyclobenzaprine (CER) in elderly volunteers.
Methods: This randomized, open-label, two-period crossover study compared the pharmacokinetics, safety and tolerability of a single oral 30-mg dose of CER with those of 10 mg of cyclobenzaprine immediate-release (CIR) administered every 8 hours for a total of three doses in 18 healthy volunteers aged 65–75 years. Volunteers were assigned to either CER or CIR on days 1 and 15 (separated by a 14-day washout). Outcome measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours (AUC168) and infinity (AUC∞), peak plasma cyclobenzaprine concentration (Cmax), time to observed Cmax (tmax) and terminal elimination half-life of cyclobenzaprine. Adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug.
Results: Eighteen subjects were randomized and completed the first treatment period; 17 completed both periods of the study. The pharmacokinetics of CER 30 mg were characterized by an absorption phase with a median tmax of 8 hours compared with an initial peak for CIR (following the first dose) at about 5 hours. Plasma cyclobenzaprine concentrations at 5 hours were 13.6 ng/mL for CER and 11.0 ng/mL for CIR. Systemic cyclobenzaprine exposure (AUC168, AUC∞ and Cmax) was similar for a single dose of CER and three doses of CIR and met bioequivalence criteria. Most AEs were mild in intensity; the most common AE was somnolence. No serious AEs or discontinuations as a result of AEs were reported during the study.
Conclusion: Once-daily CER 30 mg exhibited controlled release of cyclobenzaprine and resulted in systemic exposure similar to that of CIR in subjects aged 65–75 years.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev 2003; 4(2): CD004252
Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage 2004; 28(2): 140–75
Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther 2003; 25(4): 1056–73
Browning R, Jackson JL, O’Malley PG. Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med 2001; 161(13): 1613–20
Nibbelink DW, Strickland SC, McLean LF, et al. Cyclobenzaprine, diazepam and placebo in the treatment of skeletal muscle spasm of local origin. Clin Ther 1978; 1(6): 409–24
Katz WA, Dube J. Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience. Clin Ther 1988; 10(2): 216–28
Nibbelink DW, Strickland SC. Cyclobenzaprine (Flexeril™): report of a postniarketing surveillance program. Curr Ther Res 1980; 28(6): 894–903
Darwish M, Hellriegel ET, Xie F. Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults: a randomized, open-label, two-period crossover, single-centre study. Clin Drug Investig 2008; 28(12): 793–801
Weil A, Narayana A, Chang SCK, et al. Efficacy of cyclobenzaprine hydrochloride extended-release 15 mg and 30 mg once-daily for low back and neck pain associated with muscle spasms: a pooled analysis of two randomized, double-blind, parallel-group, placebo-controlled, multicenter studies [abstract no. 206]. Pain Med 2008; 9(1): 134–5
Weil AJ, Altman C, Chang SCK, et al. Efficacy of cyclobenzaprine hydrochloride extended-release 15 and 30 mg once daily for low back and neck pain associated with muscle spasm: a pooled analysis of two randomized, double-blind, parallel-group, placebo-controlled, multicenter studies [poster no. 206]. 24th Annual Meeting of the American Academy of Pain Medicine; 2008 Feb 12–16; Orlando (FL)
Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003; 38(8): 843–53
Sadean MR, Glass PS. Pharmacokinetics in the elderly. Best Pract Res Clin Anaesthesiol 2003; 17(2): 191–205
Cyclobenzaprine hydrochloride tablets [package insert]. Corona (CA): Watson Laboratories, Inc., 2006
World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects [online]. Available from URL: http://www.wma.net/e/policy/pdf/17c.pdf [Accessed 2008 Oct 10]
Acknowledgements
ECR Pharmaceuticals (Richmond, VA, USA) sponsored this study. Cephalon, Inc. (Frazer, PA, USA), acquired the North American rights to CER (Amrix®) in August 2007. Editorial support for the preparation of this manuscript was provided by Peloton Advantage, LLC; funding was provided by Cephalon, Inc. The authors acknowledge the contributions of Islah Ahmed, MD (former Medical Director and Study Monitor, Omnicare Clinical Research, Inc., Troy, NY, USA), and the medical review by Charles Altman, MD, MBA (Cephalon, Inc., Frazer, PA, USA). Both authors are employees of Cephalon, Inc., Frazer, PA, USA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Darwish, M., Xie, F. Comparison of the Single-Dose Pharmacokinetics of Once-Daily Cyclobenzaprine Extended-Release 30 mg and Cyclobenzaprine Immediate-Release 10 mg Three Times Daily in the Elderly. Drugs Aging 26, 95–101 (2009). https://doi.org/10.2165/0002512-200926020-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/0002512-200926020-00001