CYCLOBENZAPRINE: Effects of Bedtime Very Low Dose (VLD) Cyclobenzaprine (CBP) on Symptoms and Sleep Physiology in Patients with Fibromyalgia Syndrome

Jun. 16, 2011

TONIX Pharmaceuticals, a specialty pharmaceutical company developing therapies for challenging disorders of the central nervous system, including Fibromyalgia Syndrome (FM) and Post-traumatic Stress Disorder (PTSD), presented sleep EEG (electroencephalogram) findings from a clinical study in which patients with FM were treated with very low dosage (VLD) cyclobenzaprine (CBP) at bedtime. The VLD CBP treated patients showed a decrease in pain, fatigue, tenderness and depressive symptoms and reported fewer of the side effects often associated with daytime CBP at higher doses. In the new findings, VLD CBP treatment improved sleep efficiency and increased the number of nights with reduced rates of EEG Cyclic Alternating Pattern (CAP) sleep types CAP_A2 + CAP_A3, which are associated with sleep instability and previously were shown to be elevated in FM patients. The findings were the subject of a poster presentation at the Associated Professional Sleep Societies 2011 Anniversary Meeting in Minneapolis, MN.
Dr. Harvey Moldofsky, President and Medical Director, Centre for Sleep and Chronobiology, Toronto, Canada, and lead author of the study, commented, “This study showed that a low dose of cyclobenzaprine taken at bedtime improves the widespread pain and tenderness in patients with fibromyalgia. It also provides a novel algorithm that identifies reductions in a specific EEG pattern of sleep instability that correlate with improvements in the nonrestorative sleep symptoms of fatigue and disturbed mood.”
“These new findings suggest that our technology for bedtime treatment of fibromyalgia with very low dose cyclobenzaprine confers benefits that have been associated with restful or restorative sleep,” stated President Seth Lederman, M.D., Chairman and President of TONIX.
About the Study

The study was a randomized, double-blind, placebo-controlled, dose-escalating parallel-design study in 36 patients with FM conducted at two Canadian sites. The study was analyzed with regard to efficacy, safety and tolerability as well as EEG and other parameters assessed during sleep. VLD CBP treated subjects showed significant improvements over eight weeks in pain, fatigue, tenderness, the Hospital Anxiety and Depression Scale (HAD), and sleep efficiency. In addition, VLD CBP was well tolerated, with no adverse events or discontinuations due to adverse events. The sleep EEG data were analyzed for the types of CAP: CAP_A1 (associated with sleep stability) and CAP_A2 + CAP_A3 (usually associated with sleep instability). VLD CBP treatment increased EEG sleep nights with normalized CAP_A2+A3, or CAP_A2+A3(Norm) ≤ 33%. Increased nights of CAP_A2+A3(Norm) ≤ 33% correlated with improvement in fatigue, total HAD score, HAD depression subscore, and self-rated and clinician-rated change in fatigue. In VLD CBP treated subjects, the correlation of increased nights of CAP_A2+A3(Norm) ≤ 33% with improvement with FM symptoms is consistent with the hypothesized effects of restorative sleep. The symptomatic benefit may relate to VLD CBP decreasing arousal or alarm signals during sleep. CAP_A2+A3(Norm) rate may provide a novel biomarker for assessing treatment effects on nonrestorative sleep and associated subjective somatic and mood symptoms in FM. The full abstract can be found at www.sleepmeeting.org (# 0690).

About TONIX Pharmaceuticals

TONIX Pharmaceuticals is developing new treatments for challenging disorders of the central nervous system. The Company’s most advanced program targets fibromyalgia syndrome based on bedtime treatment with very low dosage cyclobenzaprine. Cyclobenzaprine in higher doses is the active ingredient of U.S. FDA approved muscle relaxants. Based on this foundation, the Company is building a deep and diverse pipeline of high-value medications for other syndromes, disorders and diseases, including post-traumatic stress disorder. For more information, please visit www.tonixpharma.com.

http://www.financialpost.com/markets/news/TONIX+Pharmaceuticals+Presents+Findings+Effects+Bedtime+Very+Dose/4957181/story.html

Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study

14 March 2011.
This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a 30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of “much” or “very much” better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

 http://www.painjournalonline.com/article/PIIS0304395910007724/abstract?rss=yes

Sodium oxybate -- a GABA derivative

Abstract 

This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a 30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of “much” or “very much” better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

 http://www.painjournalonline.com/article/PIIS0304395910007724/abstract?rss=yes