Cyclobenzaprine has been commonly compounded by pharmacists into topically applied dosage forms for the treatment of pain disorders. However, the efficacy and transdermal penetration of topically applied compounded cyclobenzaprine is currently unknown. In this study, the transdermal penetration of cyclobenzaprine was studied in Franz diffusion cells using porcine skin. Cyclobenzaprine was compounded in two commercially available bases; Lipobase, Lipoderm, and a standard poloxamer lecithin organogel. In addition, cyclobenzaprine was tested in an in vivo formalin pain model. Cyclobenzaprine 5% compounded into all three bases yielded significant transdermal penetration and results in modest levels of cyclobenzaprine being retained in the skin tissue. Systemically administered cyclobenzaprine (10 mcg/kg), but not topically administered cyclobenzaprine (1% and 5%), attenuated nociception in a rodent formalin pain model.