Novel Fibromyalgia Sleep/Pain Drug Moves Forward

[Cort]

A report earlier this year suggested that four drugs are likely to be approved for fibromyalgia in the coming years. Recent reports suggest that one of those drugs - a very low dose, sublingual form of flexeril called Tonmya - is definitely on track.

• The Future Fibromyalgia Drugs? Pharmaceutical Source Predicts Four Drug Approvals in Coming Years

Both Sleep and Pain Improved

“Our new analyses of the BESTFIT data show that those patients who reported the greatest improvement in sleep quality were the most likely to experience pain relief,” Seth Lederman, MD, Tonix CEO​

Tonix - the developer of the drug - is moving fast. They reported that their Phase II clinical trial for Tonmya was filled in June of this year and reported results on the trial last month.They've already begun final (Phase III) trials.

[fright]

[/fright]A former study using EEG indicated the drug was increasing restorative sleep, which in turn was associated with reductions in pain, fatigue and depression. In a good sign for those in really severe pain, the most recent studies tied together pain levels and sleep quality; those FM patients in the most pain received the most improvements in sleep quality.

Dr. Lederman, Tonix CEO, emphasized that the drug is not a sleeping pill; it doesn't just knock you out - it improves sleep quality.

The drug fared quite well relative to the placebo - another sign that this drug may ultimately get approved.

“We also observed that the group treated with Tonmya was approximately twice as likely as placebo-treated patients to be in the top third of reported sleep quality improvement. Among all patients in BESTFIT who ranked highest in reported sleep quality improvement, twice as many Tonmya-treated patients experienced at least a 30% improvement in their pain as compared to those treated with placebo.” Dr. Lederman​

Novel Approach

"The efficacy and tolerability profile of TNX-102 SL as demonstrated in prior clinical evaluations supports this candidate as a promising treatment for fibromyalgia." Daniel Clauw - FM researcher and Tonix consultant​

The drug's novelty involves the very low dose used and it's sublingual form. The drug is absorbed 10 times more effectively when delivered sublingually than when delivered orally.

[fleft]

[/fleft]Flexeril, the drug Tonmya is derived from, is only effective for a few weeks in reducing muscle spasms. Tonix discovered that cyclobenzaprine - the active ingredient in Flexeril - is converted into a metabolite called norcyclobenzaprine, which builds up in the body when the drug is taken orally. This problem is greatly reduced when the drug is taken sublingually.

The drug appears to be working by affecting down regulating activity in three different systems (serotonin (2A receptor), the sympathetic nervous system (alpha-1 adrenergic receptor) and histamine (histamine-1 receptor.)) The drug's unique approach suggests it's operating differently than any other FM drugs on the market - a good bit of news for FM patients looking for relief.

Tonix believes the drug is reducing both sympathetic nervous system and glutamate (a neuro-excitatory substance) activity. Because SNS functioning and glutamate activity may be increased in chronic fatigue syndrome (ME/CFS), the drug, if approved, will may present new options for ME/CFS patients as well. The drug is also currently being tested in PTSD and episodic tension type headaches.

CEO Lederman emphasized that Tomnya is not a sleeping pill; it's not designed to knock you out - it's designed to improve quality of sleep.

Final Trials Underway

Phase III trials are the last step before drug approval and they have already started. Tonix began a 500 person trials at 36 centers across the U.S. earlier this year. They expect to have the results back in the second half of 2016 and to get FDA approval in 2017.

If you're interested in being in the trial contact Jennifer Underwood at 267 536 3560 or jennifer.underwood@premier-research.com

_________________________________________________

The outcomes were presented via three posters at the 2015 Annual Meeting of the American College of Rheumatology / Association of Rheumatology Health Professionals.

• “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 no. 2307);
• “Responder Compared to Mean Change Analyses in a Fibromyalgia Phase 2b Clinical Study of Bedtime Rapidly Absorbed Sublingual Cyclobenzaprine (TNX-102 SL).” (abstract no. 2308); and
• “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 no. 2309).

 

[Katie]

Good news. I sometimes take cyclobenzaprine (Flexeril) at night. Helps me sleep and improves my restless legs. Can't wait for the sublingual to be available.

 

[Lane]

That's interesting. Had no idea Flexeril was only effective for a few weeks...been taking it nightly for years! Wonder what it means about it forming a metabolite and building up in the body? What does that do? Make it ineffective?

 

[VLynx]

If you already have cyclobenzaprine at home, and want to try this way of using the drug, try this:

The dose of the "new" drug (which will of course be brand name and very expensive) is 2.8 mg in a tablet.

If your cyclobenzaprine tablet is 5 mg, just break it in half, crush or chew it and put it under your tongue at bedtime.
With a 7.5 mg tablet take 1/3, for 10 mg tablet take 1/4.

Warning: people who have tried this (see drug users sites like "bluelight.org") report a numbing or burning sensation in the mouth. Interestingly, the company making the new formulation also reports this side effect: "The most commonly reported side effects were tongue numbness, which occurred in about 41% of patients on active therapy vs 1% of placebo control patients, and abnormal taste, which occurred in 7.8% of patients receiving TNX-102 SL vs none in the placebo group." (Bad News, Good News for Fibromyalgia Drug)

What was the "Bad News" in the above story: "A new sublingual drug that specifically targets nonrestorative sleep, a key feature of fibromyalgia, failed to change average daily pain scores at week 12, the primary endpoint of the study, compared with placebo, a phase 2b trial shows."

Note: if you are using extended release capsules (15 and 30 mg), don't try this, as I don't know how the extended release mechanism works for these.

P.S. if you were interested in the sleep drug Silenor, you can do a similar test with the old and cheap formulation of this drug, doxepin. Silenor comes as 3 mg or 6 mg of doxepin while regular doxepin comes in a 10 mg capsule. So you can ask your doctor for a prescription for the cheap 10 mg capsules and take out a third or a half to try as a sleep aid, for literally 1/100th the cost or less.

 

[Lane]

If you already have cyclobenzaprine at home, and want to try this way of using the drug, try this:

The dose of the "new" drug (which will of course be brand name and very expensive) is 2.8 mg in a tablet.

If your cyclobenzaprine tablet is 5 mg, just break it in half, crush or chew it and put it under your tongue at bedtime.
With a 7.5 mg tablet take 1/3, for 10 mg tablet take 1/4.

Warning: people who have tried this (see drug users sites like "bluelight.org") report a numbing or burning sensation in the mouth. Interestingly, the company making the new formulation also reports this side effect: "The most commonly reported side effects were tongue numbness, which occurred in about 41% of patients on active therapy vs 1% of placebo control patients, and abnormal taste, which occurred in 7.8% of patients receiving TNX-102 SL vs none in the placebo group." (Bad News, Good News for Fibromyalgia Drug)

What was the "Bad News" in the above story: "A new sublingual drug that specifically targets nonrestorative sleep, a key feature of fibromyalgia, failed to change average daily pain scores at week 12, the primary endpoint of the study, compared with placebo, a phase 2b trial shows."

Note: if you are using extended release capsules (15 and 30 mg), don't try this, as I don't know how the extended release mechanism works for these.

P.S. if you were interested in the sleep drug Silenor, you can do a similar test with the old and cheap formulation of this drug, doxepin. Silenor comes as 3 mg or 6 mg of doxepin while regular doxepin comes in a 10 mg capsule. So you can ask your doctor for a prescription for the cheap 10 mg capsules and take out a third or a half to try as a sleep aid, for literally 1/100th the cost or less.

Thanks for that information, VLynx. I have forgotten before and let a Flexeril partially dissolve in my mouth. Not a very pleasant taste and yes, it does cause numbness. I may try your suggestion. Thanks again!

 

[VLynx]

Thanks for that information, VLynx. I have forgotten before and let a Flexeril partially dissolve in my mouth. Not a very pleasant taste and yes, it does cause numbness. I may try your suggestion. Thanks again!

You're welcome. Good luck, hope it helps.

 

[Paw]

Yes, thanks VLynx. You answered my first question, and I'll give it a try.

My second question has to do with my Cymbalta prescription (the only drug so far that significantly reduced my chronic neuropathic burning). I had always assumed I should take it at night for its serotonin, but the study Cort cites says flexeril down-regulates serotonin receptors, suggesting that that's helpful for sleep quality.

Anyone know why we should down-regulate serotonin at night? No doubt a lot of people here take l-tryptophan before bed, no?

 

[Cort]

Yes, thanks VLynx. You answered my first question, and I'll give it a try.

My second question has to do with my Cymbalta prescription (the only drug so far that significantly reduced my chronic neuropathic burning). I had always assumed I should take it at night for its serotonin, but the study Cort cites says flexeril down-regulates serotonin receptors, suggesting that that's helpful for sleep quality.

Anyone know why we should down-regulate serotonin at night? No doubt a lot of people here take l-tryptophan before bed, no?

That's a puzzle to me. I think I'm doing pretty good on 5-HTP...I looked it up again and it is a serotonin H2a receptor antagonist.

Some others include:

• Cyproheptadine blocks 5-HT2A, H1 and is a mild anticholinergic.
• Methysergide is a 5-HT2A antagonist and nonselective 5-HT1 receptor blocker. It causes retroperitoneal fibrosis and mediastinal fibrosis.[citation needed]
• Quetiapine blocks 5-HT2A, 5-HT1A, dopamine receptors D1 and D2, histamine receptor H1, and A1 adrenoreceptors.

 

[Carollynn]

Before thinking of taking this at even low doses, reading the Major, Moderate, and Minor drug and supplement interactions at http://www.drugs.com/drug-interactions/cyclobenzaprine,flexeril-index.html?filter=3&generic_only=,. Major interactions include drugs and supplements that many of us take. "Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea." Moderate drug interactions include diphenhydramine.

I was just prescribed Flexeril for pain (12 years of ME and I have just now joined the pain club as a symptom), but have not started taking it yet for I'd have to go off St. John's Wort and diphenhydramine which I take for allergies, interstitial cystitis, and sleep. It's the holidays, a good time to just deal with the devil I know. Maybe in the new year I'll tinker with change, when I'm not hoping to have a couple of good days on specific squares of the calendar.

 

[Paw]

Cort, I get confused with differentiating between a receptor down-regulator and a reuptake inhibitor, but maybe they amount to the same thing? The flexeril is described as a down-regulator, while the others you list are described as reuptake inhibitors. I've always assumed inhibition builds up the amount of serotonin in the system, while down-regulation would gradually reduce it. But I'm probably totally wrong.

Carollyn, I've experience serotonin syndrome, and indeed it is no fun. I would tend to think that low-dose flexeril would be a minor addition of serotonin, but it's always good to be cautious.

 

[Carollynn]

I talked about the low-dose aspect with my pharmacist and she said it was still better to go off of things that may interact, which I share to give caution to others. Plus the symptoms of serotonin syndrome echo so many symptoms and concomitant conditions of ME that it may be hard for us all to tell that we're descending into that and not "just" a flare of ME.

 

[myoldmill]

Before thinking of taking this at even low doses, reading the Major, Moderate, and Minor drug and supplement interactions at http://www.drugs.com/drug-interactions/cyclobenzaprine,flexeril-index.html?filter=3&generic_only=,. Major interactions include drugs and supplements that many of us take. "Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea." Moderate drug interactions include diphenhydramine.

I was just prescribed Flexeril for pain (12 years of ME and I have just now joined the pain club as a symptom), but have not started taking it yet for I'd have to go off St. John's Wort and diphenhydramine which I take for allergies, interstitial cystitis, and sleep. It's the holidays, a good time to just deal with the devil I know. Maybe in the new year I'll tinker with change, when I'm not hoping to have a couple of good days on specific squares of the calendar.

I have been taking Flexeril off and on for about 15 years. I have used diphenhydramine, for sleep, regularly also during that time. I have not found any problem with them together. Hope you can find a solution. Not being able to sleep is misery.

 

[Cort]

Cort, I get confused with differentiating between a receptor down-regulator and a reuptake inhibitor, but maybe they amount to the same thing? The flexeril is described as a down-regulator, while the others you list are described as reuptake inhibitors. I've always assumed inhibition builds up the amount of serotonin in the system, while down-regulation would gradually reduce it. But I'm probably totally wrong.

Carollyn, I've experience serotonin syndrome, and indeed it is no fun. I would tend to think that low-dose flexeril would be a minor addition of serotonin, but it's always good to be cautious.

It's confusing I agree and maybe I have it backwards. It is described as a serotonin receptor antagonist. To me that sounds as if it's turning down the cells production or use of serotonin but this stuff is so complex that I could be wrong.

 

[Dee4dogs]

Yes, thanks VLynx. You answered my first question, and I'll give it a try.

My second question has to do with my Cymbalta prescription (the only drug so far that significantly reduced my chronic neuropathic burning). I had always assumed I should take it at night for its serotonin, but the study Cort cites says flexeril down-regulates serotonin receptors, suggesting that that's helpful for sleep quality.

Anyone know why we should down-regulate serotonin at night? No doubt a lot of people here take l-tryptophan before bed, no?

I take Cymbalta and my doctor suggested that I take it in the morning. I've been on it so long that I can't remember if he had said that it had a stimulant in it or if it could have a stimulant effect. Probably the later because I've never noticed a stimulant effect while taking it.