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

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

References:

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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