The Rosetta Stone of Rheumatic Pain


Profiles in Rheumatology: Seth Lederman, M.D., chairman and CEO of Tonix Pharmaceuticals

In 2007, Seth Lederman, M.D., launched Tonix Pharmaceuticals, a New York company that specializes in the development of new therapies for fibromyalgia, post-traumatic stress disorder and episodic tension-type headache.

Dr. Lederman is a Columbia University-trained rheumatologist. He served on the Columbia University Division of Rheumatology faculty for 12 years developing an interest in fibromyalgia, which remains his primary interest today. Fibromyalgia, he says, “has gone from a condition that was unmentionable to a syndrome that is now a Rosetta stone for understanding pain.”

“When I was a rheumatologist at Columbia, most doctors ignored fibromyalgia. It was dismissed by many physicians as nonexistent and there was pressure from some of the senior faculty not to study it or even diagnose it. The history of fibromyalgia shows how scientists and doctors with good intentions can make themselves blind to something standing right in front of them. Fibromyalgia was hidden in plain view,” he said.

In fibromyalgia, patients experience widespread chronic pain, but they also experience heightened sensory perceptions. Bright lights, strong odors, foul tastes and loud noises can be problematic. A new concept in fibromyalgia points to the central nervous system in overdrive in a process called “central sensitization.”

In this Q&A, Dr. Lederman discusses his research, including the development of a new therapeutic agent designed to remediate pain by improving sleep quality.[[{"type":"media","view_mode":"media_crop","fid":"45444","attributes":{"alt":"Seth Lederman M.D.","class":"media-image media-image-right","id":"media_crop_8641891558654","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5210","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Seth Lederman M.D.","typeof":"foaf:Image"}}]]


QUESTION:  In 1998, you founded a company called Vela Pharmaceuticals Inc. (now Pharmos Corp.) to develop a new treatment for fibromyalgia, but the research program was dropped due to lack of evidence. How has research changed since then?


ANSWER:  Ever since 2007, when the FDA approved Pfizer’s Lyrica (pregabalin) for fibromyalgia, fibromyalgia has become enshrined in the medical literature. There were ACR (American College of Rheumatology) criteria for fibromyalgia in 1990, but that was 17 years before the FDA approval. Today, there is a diagnostic code for fibromyalgia in ICD-10 – now that’s progress.

The importance of the approval of Lyrica to the field was really epochal. Fibromyalgia patients had been told by many physicians who were not experts that, “it’s all in your head.” I think that the affirmation and the validation by the FDA’s approval of new therapies certainly gave dignity to patients and it marks an important turning point in academic research in understanding fibromyalgia.


QUESTION:  During ACR/ARHP 2015 you presented data from a 12-week, 205-patient Phase IIb BESTFIT clinical study of Tonmya (TNX-102 SL; cyclobenzaprine HCl sublingual tablets, 2.8 mg) to be taken once daily at bedtime for fibromyalgia. You are currently enrolling patients in phase III trials (AFFIRM) which will include 500 patients. How well did TNX-102 SL perform in phase IIb?


ANSWER:  In the phase IIb, we found that fibromyalgia patients who reported improvements in sleep quality were more likely to experience pain relief by 30 percent or more as compared to the placebo group. Of 88 patients treated with TNX-102 SL, 36, or 41 percent, reported improvements in sleep quality as compared to 18 of the 84 patients, or 21 percent, in the placebo group. The majority of patients with improved sleep quality experienced at least a 30 percent improvement in pain.


QUESTION:  Please describe the mechanism of action for TNX-102 SL.


ANSWER:  Fibromyalgia is closely associated with a particular sleep problem called non-restorative sleep, which has been linked to altered processes in the brain that are thought to be responsible for certain fibromyalgia symptoms. Bedtime TNX-102 SL is designed to treat fibromyalgia by improving sleep quality. In a healthy person, restorative sleep leads to resetting the brain’s pain perception apparatus to control pain.

The active ingredient of TNX-102 SL is called cyclobenzaprine. It works on three receptors in the brain that are associated with sleep quality:  the serotonin type 2A receptor, the alpha-1 adrenergic receptor and the histamine-1 receptor.


QUESTION:  So would TNX-102 SL work in patients suffering from chronic pain that is not related to rheumatic disease?


ANSWER:  We are only studying TNX-102 SL as a bedtime therapy in patients with fibromyalgia. We have not studied it in other pain conditions. Fibromyalgia is closely associated with non-restorative sleep. The deficiency in non-restorative sleep leads to a deficiency in resetting their brain’s pain perception apparatus. Consequently, fibromyalgia patients accumulate pain experiences and have trouble extinguishing them.


QUESTION:  Please explain the physiological connection between sleep and chronic pain.


ANSWER:  In most fibromyalgia patients there is no pathologic finding. Fibromyalgia has been described as a “functional disorder,” which would be the equivalent of saying a computer has a software problem rather than a hardware problem. In fibromyalgia, the system that isn’t working is the sensory processing apparatus in the brain. It may not be broken forever, but it is difficult to reprogram and it takes a long time.

One of the pioneers in the field, Dr. Harvey Moldofsky, made a number of important observations in fibromyalgia including the importance of sleep in exacerbating symptoms. In clinical studies, he found that the effects of sleep loss in healthy individuals was reversible, but not in patients with fibromyalgia.

We know that sleep and pain are highly interrelated, but we don’t know why. We see it in practice and in clinical trials, but we don’t yet know how the lack of quality sleep is connected to the pain of fibromyalgia. We also don’t know which comes first:  poor sleep or widespread pain.

Dr. Daniel Clauw, a rheumatologist at the University of Michigan Health System, is one of the leading thinkers in the connection between osteoarthritis, RA and pain. His work is focused on how the brain interprets pain. His findings have shown that regional pain over a long period of time can lead to widespread pain, which is the hallmark feature of fibromyalgia.

The important thing to remember is that pain is not always textbook. In textbooks, pain is either regional or neuropathic or central. In real life, pain can be a mixture of different types of pain. We are on the verge of understanding how the brain processes pain. And maybe we will find that sleep quality is at the root of the problem for many people. That’s why I believe fibromyalgia is a Rosetta stone - because it is showing us how sleep problems can lead to pain that originates in the pain perception apparatus of the brain.


QUESTION:  Doctors have traditionally prescribed opiates for pain control, but that’s no longer true today due to widespread abuse, but also, due to better, long-term solutions for pain control. Where does your work fall into this quandary?


ANSWER:  Living with chronic pain is not only discouraging, but it is exhausting. It can take a toll on physical and mental health. America is waking up to the crisis of chronic pain. Opiates have some use in acute pain and are used in chronic pain for cancer, but now we have an epidemic with the overuse of opiates for many kinds of chronic pain.

If we can help fibromyalgia patients with chronic pain, then our work could lead to new ways of thinking about pain control for other conditions. The idea that fibromyalgia may be a Rosetta stone for understanding and treating pain is what keeps me and my team motivated. We are building a road map to pain pathways.



S. Lederman, Tonix Pharmaceuticals



Seth Lederman, R Michael Gendreau, et. al.


Bedtime, Rapidly Absorbed Sublingual Cyclobenzaprine (TNX-102 SL) for the Treatment of Fibromyalgia: Results of a Phase 2b Randomized, Double-Blind, Placebo-Controlled Study,"

ACR/ARHP. Tuesday, November 10, 2015 

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