New Approach to Fibromyalgia Tackles Poor-Quality Sleep

Pam Harrison

November 17, 2015

For patients with fibromyalgia, directing treatment toward nonrestorative sleep, a key feature of the syndrome, leads to improvements in other symptoms of the disease, including pain, according to two analyses of data from the phase 2b placebo-controlled BESTFIT study.

"It's been known for a long time that poor-quality sleep correlates with disease severity in patients with fibromyalgia," said Seth Lederman, MD, chief executive officer of Tonix Pharmaceuticals in New York City, who was involved in both analyses.

"We recognized that sleep wasn't only a symptom; poor sleep exacerbates the pain of fibromyalgia. It's probably a vicious cycle of poor sleep, more pain, more pain, and worse sleep," he told Medscape Medical News.

"Bedtime sublingual cyclobenzaprine hydrochloride, which targets several key receptors involved in sleep regulation, doesn't work right away, but after about 4 weeks, we are seeing an improvement in sleep quality, and after that, pain and other symptoms also improve," Dr Lederman said.

The results of the analyses were presented at the American College of Rheumatology (ACR) 2015 Annual Meeting in San Francisco.

BESTFIT Study

In the BESTFIT study, patients who met the 2010 ACR criteria for fibromyalgia were randomized to sublingual cyclobenzaprine 2.8 mg taken at bedtime for 12 weeks or to placebo. Outcome measures included daily diary assessments of pain and sleep rated on a 10-point scale, the Revised Fibromyalgia Impact Questionnaire (FIQR), the Patient Global Impression of Change (PGIC) scale, and the PROMIS Sleep Disturbance scale.

Preliminary results from the study, as reported by Medscape Medical News, showed that bedtime sublingual cyclobenzaprine failed to change average daily pain scores at week 12; however, it did lead to an improvement in a number of secondary end points, including measures of sleep, effect on pain, and the overall burden of symptoms.

In contrast, the final analysis of 172 evaluable patients, presented at the meeting by Harvey Moldofsky, MD, from the Centre for Sleep and Chronobiology in Toronto, demonstrated that sublingual cyclobenzaprine has a favorable effect on both sleep and pain.

All measures of sleep quality improved with cyclobenzaprine over the 12-week study period, as did measures of pain.

The reduction in the PROMIS Sleep Disturbance score was significantly greater in the cyclobenzaprine group than in the placebo group by week 4, and this was sustained out to week 12 (8.96 vs 5.13 points; P = .005).

Reductions in the daily sleep diary score were significantly greater in the cyclobenzaprine group than in the placebo group at week 1. Significance was lost but then regained by week 6, which was sustained out to week 12 (1.85 vs 0.88 points; P < .001).

Reductions in FIQR score, an indication of improved sleep quality, were significantly greater in the cyclobenzaprine group than in the placebo group by week 2, which was sustained out to week 12 (2.9 vs 1.2 points; P < .001).

"Improvements in sleep quality preceded other changes in fibromyalgia," the investigators report.

This was confirmed by results from the second analysis, which were presented by Dr Lederman. A repeated-measures mixed-effects model revealed improvements in multiple domains of fibromyalgia over the 12-week study period.

The pain response rate on the daily diary pain scale, defined as an improvement of at least 30% from baseline to week 12, was better in the cyclobenzaprine group than in the placebo group (34% vs 20.6%; P = .033).

There were also significant improvements in pain scores reported during clinical visits (P = .033) and on the pain item of the FIQR scale (P = .004).

Transient tongue or sublingual numbness occurred in 42% of treated patients, but systemic adverse events were infrequent and weight gain was negligible.

"Our new analyses of the BESTFIT data show that patients who reported the greatest improvement in sleep quality were the most likely to experience pain relief," Dr Lederman said.

"One core difference between cyclobenzaprine and pain medications is that we are attacking fibromyalgia by improving sleep quality instead of treating it with a pain medicine, which is putting on a bandage."

The AFFIRM trial, which is currently underway, is evaluating the effect of bedtime sublingual cyclobenzaprine on sleep quality and pain in 500 patients with fibromyalgia.

Related to Tricyclic Antidepressants

The chemical structure of cyclobenzaprine is related to tricyclic antidepressants and it has the potential to cause the same adverse effects as tricyclics, including dry mouth, drowsiness, and fatigue, said Robert Bennett, MD, from the Oregon Health & Science University in Portland.

"In most cyclobenzaprine in fibromyalgia studies, the initial dosage was 10 mg, with upward titration to 40 mg as needed," Dr Bennett told Medscape Medical News.

He pointed out that in one study, "average overall improvement with cyclobenzaprine was threefold that seen with placebo" (Arthritis Rheum. 2004;51:9-13). However, he explained, "fatigue and tender points did not improve."

Furthermore, higher doses of cyclobenzaprine resulted in a high prevalence of undesirable effects, he added.

But Dr Bennett said he agrees that nonrestorative sleep adversely influences central pain pathways and that drugs that improve sleep quality might improve daytime symptoms of fibromyalgia.

"The current 12-week study of low-dose cyclobenzaprine taken sublingually in the evening confirms its clinical efficacy more rigorously than have previous reports," Dr Bennett said. "And apart from transient tongue and sublingual numbness, side effects were minimal."

Future studies still need to establish whether there is improvement with cyclobenzaprine beyond 12 weeks, and whether the 2.8 mg dose used in this study is the optimal dose, he added. And studies need to establish whether there are any adverse consequences related to the longer-term use of cyclobenzaprine, and whether this drug interacts in a negative way with other drugs commonly used to treat fibromyalgia.

Dr Lederman is the CEO of Tonix Pharmaceuticals. Dr Moldofsky reports receiving honoraria from Tonix Pharmaceuticals. Dr Bennett has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2015 Annual Meeting. Abstracts 2307 and 2308. Presented November 10, 2015.

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