Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Very Low Dosage (VLD) Bedtime Cyclobenzaprine (CBP) Reduces Cyclic Alternating Pattern (CAP) Rate Indices of EEG Sleep Instability and Improves Pre-Sleep Fatigue in Fibromyalgia Syndrome (FMS).

Moldofsky1,  Harvey, Harris2,  Herbert W., Archambault4,  Tad, Kwong1,  Terence, Lederman3,  Seth

Centre for Sleep & Chronobiology, Toronto, ON, Canada
Krele Pharmaceuticals, Saddle Brook, NJ
Krele Pharmaceuticals, New York, NY
VirtuStat Ltd, North Wales, PA


The importance of nonrestorative sleep in the pathophysiology of FMS suggests new treatments that improve sleep quality may improve daytime symptoms of fibromyalgia (FMS). We previously reported a randomized double-blind placebo-controlled 8 week study of very low dose (VLD) (<=4 mg) cyclobenzaprine (CBP) h.s. in 36 patients with FMS, which showed that bedtime CBP treatment (Tx) was associated with significant improvements in pre-sleep/p.m. fatigue, pain, and pain sensitivity (dolorimetry) with increased Stage 2 non-REM sleep (ref 1). Previous EEG sleep studies in FMS identified increased Cyclic Alternating Patterns (CAP) A2 & A3 in non-REM sleep, measures of sleep instability related to the symptoms of FMS (ref 2 & 3). We now report the effect of CBP Tx on nocturnal sleep EEG CAP and daytime fatigue in FMS.


CAP A2 & A3 rates are objective EEG sleep measures of sleep instability whereas CAP A1 rate is associated with sleep stability. To investigate whether the CAP A2 & A3 rates are decreased by Tx that target unrefreshing sleep in FMS patients, we retrospectively analyzed the polysomnography (PSG) data from a study in which bedtime CBP improved fatigue, pain and subjective sleep in a 8 week dose-escalating, double-blind, placebo-controlled randomized trial involving 36 FMS subjects. Each subject had screening and baseline PSGs (combined 2 pre-Tx PSGs) and 3 single nights of PSG during Tx after 2, 4 and 8 weeks. We analyzed whether subjects had an increased number of nights with decreased CAP(A2+A3) after the initiation of Tx by classifying the subjects nightly into responders and non-responders based on a CAP(A2+A3) rates normalized for the total CAP rate (A1+A2 +A3). Three placebo-Tx subjects, but no CBP-Tx subjects, withdrew from the study after initiation of Tx and without any nights of PSG. Consequently, the LOCF analysis imputed no improvement for these subjects.


Initially we analyzed the study data for CAP(A2+A3)/(A1+A2+A3) over a range (10–50%) to identify cut-offs for responders by LOCF and OC (for >= 1 night improvement) and found that defining responders as <=30% or <=33% had the greatest difference between CBP and placebo-Tx and the smallest p-value (p<0.05). CAP response of >=1 night of sleep EEG analyses that compared 2 pre-Tx drug free nights to 3 post-Tx PSG nights (defined by CAP(A2+A3)/(A1+A2+A3) <=33% was analyzed for correlations with clinical improvement measures of patient-reported fatigue (pre-sleep/p.m. and post-sleep/a.m.); pain (p.m. and a.m.) and dolorimetry. Reduction in p.m. fatigue in CBP-Tx subjects is significantly correlated with CAP response (p = 0.0064), whereas p.m. fatigue was neither decreased nor correlated with responder status in placebo-Tx subjects.


1. Normalized CAP A2 & A3 rates are novel physiological sleep EEG indices of nonrestorative sleep in FMS.

2. Very low dose CBP at bedtime decreases CAP A2 & A3 sleep EEG measures of nonrestorative sleep which correlates strongly with improvement in p.m. fatigue in FMS patients.


1.MoldofskyReynolds WJ, HC. A. (2002) Arth. Rheum. 46(suppl 9): S614.

2.Rizzi, M J Rheum. 2004; 31: 1193–199.

3.Moldofsky, H et al J Rheumatol 2010 in press.

To cite this abstract, please use the following information:
Moldofsky, Harvey, Harris, Herbert W., Archambault, Tad, Kwong, Terence, Lederman, Seth; Very Low Dosage (VLD) Bedtime Cyclobenzaprine (CBP) Reduces Cyclic Alternating Pattern (CAP) Rate Indices of EEG Sleep Instability and Improves Pre-Sleep Fatigue in Fibromyalgia Syndrome (FMS). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :820
DOI: 10.1002/art.28588

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