Please could you give a brief introduction to sleep disorders and who they affect?
Sleep disorders are a large area. We are focused on one particular type of sleep disturbance called “non-restorative” sleep. People with this problem do sleep, but they don’t wake up feeling refreshed or feeling that their sleep has had the restorative effects of healthy sleep.
To put this into context with all of the different sleep disorders, it is important to note that most sleep disorders are classified as insomnia. Most insomnia is a problem with the quantity of sleep. Non restorative sleep is a problem with the quality of sleep. Sleep quantity and sleep quality are different. We are focused on improving the quality of sleep for people with non-restorative sleep.
People suffer from non-restorative sleep for a number of reasons. We are particularly focused on patients with fibromyalgia syndrome. Fibromyalgia is a chronic pain syndrome. Patients with fibromyalgia hurt all over their bodies. They also can’t get restorative sleep. There is a vicious cycle of chronic pain and non-restorative sleep. Pain disturbs sleep and people with non-restorative pain have a greater sensitivity to pain and more trouble extinguishing pain.
While sleep quality and sleep quantity are different, no one can get good quality sleep if they don’t get enough sleep. One reason that non-restorative sleep is so prevalent in our modern society is that people did not evolve to function on so little sleep. Less than a hundred years ago, the vast majority of humans were awake when it was light outside, and slept when it was dark. In areas away from the equator, in winter people slept more than 12 hours a night.
It is challenging for people to adapt to sleeping less and less. A good night’s sleep for most people is around 8 hours; but many people have to get by on 6 hours or less. One of the reasons that people sleep so little is because there is so much artificial light and so much nighttime stimulation keeping them awake, like television and the Internet. For people with non-restorative sleep, the first thing I like to advise them is, ‘Give sleep a chance’. Many people in the field refer to this as “sleep hygiene”. In the same way that people should wash their hands to remove germs, they should pay attention to get enough good quality sleep to avoid the consequences of poor sleep.
Another modern problem with sleep quality, that is just about 30 or 40 years old, is the jet lag people suffer as a consequence of the widespread use of airplanes and the challenges that people face in trying to adjust to time-zone changes. Most people can recover from jet lag if they take care to give sleep a chance. However, some people can’t easily recover from jet leg and in these people jet lag can trigger a series of events that can become a downward spiral into worse and worse sleep problems. These people are not able to recover from jet lag, because they can’t get restorative sleep even if they spend time in bed staring at the ceiling. When someone can get sleep and recover from jet lag, then I call it compensation. When someone is unable to back on track, I think of their problem as decompensation. Once someone has decompsenated, their inability to get restorative sleep can lead to other problems.
One of the most important challenges to getting good quality sleep is the fact that the body changes over time and people can’t always adjust their sleep hygiene to the changes in their bodies as they grow older. Young people can get away with much less sleep than older people. Women find menopause challenging, because sweating and hot flashes lead to sleepless nights.
When people begin to experience chronic problems sleeping, the body is able initially to compensate and maintain health despite poor sleep. However, if the sleep problem continues for a long time, at some point the body becomes unable to compensate. This progression leads to a vicious cycle where non-restorative sleep leads to pain and pain leads to further difficulty sleeping.
Why is a good night’s sleep so important?
Sleep is an active process. It is not a time when the brain is inactive. It is a time when the brain is actively processing information from the day – storing certain experiences into memory, but also editing other experiences, so that they will be excluded from the repertoire of frequently recalled memories.
It is during restorative sleep that painful memories are edited. For healthy people with restorative sleep, this means that they won’t get fixated on reliving painful memories. For people with non-restorative sleep, these painful memories can be recalled and they can become psychological fixations that become nightmares during sleep and resurface during awake hours and can be troubling for days, weeks, months or years.
Another very important aspect of restorative sleep is that it refreshes the body’s system for perceiving and processing pain. Healthy people who experience an athletic injury, or some other sort of painful event, can wake up from a night of restorative sleep, with the pain significantly diminished. Healthy people also find that a good night’s sleep restores the body’s ability to perceive and process pain. Even before the injury is repaired, their bodies have a mechanism that operates during restorative sleep to adapt to pain and to work around it.
However, people who are unable to get restorative sleep, frequently cannot reset the body’s processes that perceive and process pain. Their pain can accumulate from day to day. Over time, their pain swamps the system. They become unable to adapt to pain or to work around it.
The mechanism by which the body can turn off or extinguish pain is called, “central inhibition”. Extreme examples of central inhibition’s capabilities have been described when a rock has pinned the arm of a mountain climber or a when soldier’s limb is severely damaged by a blast or shell. Central inhibition is the process that allows the brain to turn off perception of pain from such injured limbs. Central inhibition in such extreme cases kicks in when there’s no hope for the body to avoid further pain and when continuing to perceive pain is counter-productive.
Fibromyalgia seems to be connected with a problem in central pain, because fibromyalgia patients experience pain all over their bodies despite the fact that it’s counter-productive. In healthy people, central inhibition can extinguish local pain perception connected with severe, local injuries. In fibromyalgia, central inhibition seems to fail at a higher level, because their pain is widespread.
Almost the opposite of central inhibition is called “phantom limb” syndrome, when people experience pain from limbs that have been amputated. Some cases of phantom limb or physical pain result in a spreading of the pain to other parts of the body that were not part of the original injury. These cases seem to illustrate the processes that cause fibromyalgia. In fact, some fibromyalgia cases begin with a physical injury. For example, Rheumatologists believe that the artist Frida Kahlo suffered from fibromyalgia and that her problems began with a back injury.
One of the our company’s important long term goals is to provide a medicine that helps people get back the ability to get a restful night’s sleep on their own. We don’t know if our existing medicine TNX-102 SL will have this capability or if it will require better understanding of sleep and the development of second or even third generation sleep quality products. It might be helpful to regard such a medicine using the metaphor of a crutch. If someone can’t walk because of a temporary injury, a crutch can help until they can walk again on their own. We hope that our efforts will lead to a bedtime medicine can help improve the quality of sleep in patients who can’t get restorative sleep, until the time when these patients can sleep normally again on their own.
Whatever processes are going on in the brains and bodies of fibromyalgia patients, all we can hope to do with TNX-102 SL is get them back to the point of being able to get restorative sleep and allowing sleep’s natural restorative processes to work on reducing pain. We hope that it will refresh their ability to process pain.
What do patients currently use to try to get to sleep?
People who have trouble getting restorative sleep often learn from their life experiences that, they feel better all over, if they are able to get a night of restful sleep. Since people who have trouble getting restorative sleep frequently suffer with chronic pain from fibromyalgia or PTSD, they often learn that their pain improves if they are able to get a night of restful sleep.
For people who experience this kind of relief, getting a night of restorative sleep can become an all-consuming quest. It may even take over their lives. They may risk other consequences in order to achieve it. For this reason many chronic pain patients turn to prescription sleep drugs in the hopes of getting restorative sleep. These medicines may work once, twice or for a short period. But unfortunately, prescription sleep drugs increase only the quantity of sleep. They do not increase the quality of sleep.
People who turn to prescription sleep drugs may become dependent upon them, and not get the benefit that they are really seeking in a reliable way. In fact, dependence on prescription sleep drugs is one of the reasons why people cannot get restorative sleep.
Our program is heading in a completely different direction, as we’re trying to help people get increased sleep quality, not necessarily increasing sleep quantity.
Alcohol is probably the most common non-prescription chemical that people use to help them sleep. Men typically use alcohol more frequently than women and men seem to have a higher predisposition for self-medicating using alcohol.
Alcohol has some ability to work as a sedative. Unfortunately, alcohol fragments sleep and does not help to improve sleep quality. Another feature of alcohol is that it exerts an effect that is fairly short-acting and not long-lasting. If someone uses alcohol to help them go to sleep at 10pm at night, it is not uncommon for them to wake up at 2am or 3am more activated than if they had not taken alcohol.
From a drug-designer’s perspective, alcohol does not have the right pharmacokinetic profile to be an effective sleep medicine since people wake up activated in the middle of the night. Obviously, alcohol also has other issues. For example, only small amounts of alcohol have any beneficial effects. If someone drinks too much alcohol then there are other consequences. Drinking more alcohol to try to extend the time that it acts as a sedative is a dangerous and unhealthy proposition. Tonix Pharmaceuticals have recently announced that they have a promising new drug under development for treating fibromyalgia and the sleep problems that come with this condition. Please could you tell us a little bit about this drug and what are its benefits over traditional sleep drugs?
We’re working on a new type of sleep quality medicine that is a sublingual tablet, which patients will take at bedtime under their tongue. It is designed to improve the quality of sleep. We are focusing on two indications: fibromyalgia and PTSD.
Our lead indication is for patients with fibromyalgia. Fibromyalgia is a pain syndrome that affects mostly women. Approximately, 90% of fibromyalgia patients are women and only approximately 10% are men. Our second indication is for people with PTSD. PTSD affects a significant number of the soldiers returning from deployments in Afghanistan and before that, from Iraq.
In the United States, fibromyalgia affects approximately 5 million people. It is a chronic pain syndrome that is characterized by chronic widespread pain and it can frequently take over the life of the patient. The patient may have
· trouble working
· trouble with normal daily activities
· trouble maintaining social relationships
This is because the pain caused by fibromyalgia becomes so pervasive.
We have evidence from our Phase IIa study, which is a study on 36 patients with fibromyalgia, that bedtime treatment with a primitive version of our product resulted in improved sleep quality and decreased pain from fibromyalgia.
We’re excited to move forward with the development of our product and we will be starting a Phase III efficacy study in the first quarter of 2013.
Our PTSD program is not as advanced as our fibromyalgia program, so we anticipate that we will start enrolling into a proof-of-concept study early in 2013. In PTSD, we are testing a similar hypothesis to FM. People with PTSD have difficulty sleeping and many of them experience chronic widespread pain. We believe that by improving the quality of sleep they will experience less pain.
Please could you tell us how this drug has been developed?
The discovery of the effects of our drug all began with Dr Iredell Iglehart, who is a rheumatologist in Baltimore in private practice. Dr Iglehart started experimenting with patients in his practice, using low doses of a prescription drug that is already available called Flexeril®, which is the Merck brand name for cyclobenzaprine.