Fibromyalgia at the ACR 2015 Meeting in San Francisco / Cyclobenzaprine

I was quite surprised to see cyclobenzaprine on the agenda. I’ve found an abstract from 1986, when fibromyalgia still was called fibrositis, which is a good read: RA Gatter: “Pharmacotherapeutics in fibrositis” (see link below). The abstract reveals: “Double-blind, placebo-controlled studies show cyclobenzaprine to be an effective medication in the treatment of fibrositis (fibromyalgia).” If you are a regular reader of my blog, you know, how alerted I am now. A drug that has already been studied, now comes back in sublingual form. JK Tofferi et al. published a meta-analysis in 2004. Results of this meta-analysis: „Five randomized, placebo-controlled trials were identified. The odds ratio for global improvement with therapy was 3.0 (95% confidence interval [95% CI] 1.6-5.6) with a pooled risk difference of 0.21 (95% CI 0.09-0.34), which calculates to 4.8 (95% CI 3.0-11) individuals needing treatment for 1 patient to experience symptom improvement. Pain improved early on, but there was no improvement in fatigue or tender points at any time.“

The first study on cyclobenzaprine at the ACR 2015 Annual Meeting in San Francisco is by Harvey Moldofsky and colleagues. They studied TNX-102 SL (sublingual tablet formulation of low dose cyclobenzaprine HCl) for its safety and efficacy in a phase 2b study of fibromyalgia (the BESTFIT study). In conclusions we find: “Together, these data suggest TNX-102 SL targets non-restorative sleep and provides a novel approach to treating FM [fibromyalgia].“

There’s nothing new under the sun!

Interestingly H. Moldofsky and colleagues published the following study in 2011: “Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study.” The starting dosage has ben 1 mg and could be increased up to 4 mg. Conclusion: „Bedtime VLD CBP [very low dose cyclobenzaprine] treatment improved core FM [fibromyalgia] symptoms.“

The other two studies took data from the study of Moldofsky et al for a responder analysis: 1. Abstract No. 2308 by R Michael Gendreau and colleagues (“Results from this Phase 2b trial support the finding that responder analyses for analgesia and other patient-reported outcomes may reveal significant and meaningful effects that are missed by group mean changes.”), and 2. Abstract No. 2309 by Seth Lederman and colleagues (“Together these findings suggest that sleep quality is a target of therapy in FM and TNX-102 SL improvement in sleep quality was well tolerated was associated with broad symptomatic improvement.”).

I don’t like responder analysis. You loose the advantage of a double-blind, placebo-controlled study. I won’t question the results of this Phase 2b study, which has been presented in a trinity. There are known effects of cyclobenzaprine in fibromyalgia patients and a study to know more about these effects might be useful. But I see in this study an effort to revive an old drug.

BTW: cyclobenzaprine isn't approved for fibromyalgia (off-label) and isn't approved at all in Germany; TNX-102 SL is an investigational drug.

Addendum (27.11.2015):
The pain response rate was defined as an improvement of at least 30% from baseline to week 12, which is weird as the pregabalin study (L.J. Crofford) looked at an improvement of 50% from baseline, was better in the cyclobenzaprine group than in the placebo group (34% vs 20.6%; P = .033). That isn't very convincing. The effect size would be estimated as being very low. And what of the 66% not improving? NNT (number needed to treat) hasn't been estimated.

References:

RA Gatter: Pharmacotherapeutics in fibrositis. Am J Med. 1986 Sep 29;81(3A):63-6. PMID: 3464210. http://www.ncbi.nlm.nih.gov/pubmed/3464210

JK Tofferi et al.: Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis Rheum. 2004 Feb 15;51(1):9-13. PMID: 14872449. http://www.ncbi.nlm.nih.gov/pubmed/14872449

H Moldofsky et al: Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study. J Rheumatol. 2011 Dec;38(12):2653-63. doi: 10.3899/jrheum.110194. Epub 2011 Sep 1. http://www.ncbi.nlm.nih.gov/pubmed/21885490

Moldofsky H, Gendreau RM, Clauw DJ, Gendreau J, Vaughn B, Daugherty B, Forst A, Sullivan G, Lederman S. Relationship of Sleep Quality and Fibromyalgia Outcomes in a Phase 2b Randomized, Double-Blind, Placebo-Controlled Study of Bedtime, Rapidly Absorbed, Sublingual Cyclobenzaprine (TNX-102 SL) [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/relationship-of-sleep-quality-and-fibromyalgia-outcomes-in-a-phase-2b-randomized-double-blind-placebo-controlled-study-of-bedtime-rapidly-absorbed-sublingual-cyclobenzaprine-tnx-102-sl/. Accessed November 12, 2015.

Gendreau RM, Clauw DJ, Gendreau J, Daugherty B, Lederman S. Responder Compared to Mean Change Analyses in a Fibromyalgia Phase 2b Clinical Study of Bedtime Rapidly Absorbed Sublingual Cyclobenzaprine (TNX-102 SL) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/responder-compared-to-mean-change-analyses-in-a-fibromyalgia-phase-2b-clinical-study-of-bedtime-rapidly-absorbed-sublingual-cyclobenzaprine-tnx-102-sl/. Accessed November 12, 2015.

Lederman S, Gendreau RM, Clauw DJ, Arnold LM, Gendreau J, Daugherty B, Forst A. Bedtime, Rapidly Absorbed Sublingual Cyclobenzaprine (TNX-102 SL) for the Treatment of Fibromyalgia: Results of a Phase 2b Randomized, Double-Blind, Placebo-Controlled Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/bedtime-rapidly-absorbed-sublingual-cyclobenzaprine-tnx-102-sl-for-the-treatment-of-fibromyalgia-results-of-a-phase-2b-randomized-double-blind-placebo-controlled-study/. Accessed November 12, 2015.