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New Sleeping Pills

The Latest Information From A to Zzzzz (PDF Format)

By Lisa Lorden Myers

[Reprinted from Fibromyalgia Frontiers, 2005 (Volume 13, Number 1)]

For 126 million people in the U.S. who experience occasional or chronic insomnia, the development of a new generation of sleeping pills is big news. According to the National Sleep Foundation’s 2002 Sleep in America poll, 58% of the adult population has difficulty falling or staying asleep at least a few nights a week. Sleep problems are even more prevalent in women and the elderly.

Insomnia is often a secondary problem associated with other health conditions such as heart disease, depression, or sleep disorders like sleep apnea. Sometimes treating the primary disorder improves or eliminates the sleep problem. Unfortunately, this is not usually the case with fibromyalgia (FM). For people with FM, difficulty falling or staying asleep is one of the most common complaints, to which there is no easy solution. Most FM patients have tried a wide variety of both prescription and non-prescription remedies, and the effectiveness of existing treatments has been disappointing for many.

Enter a new kid on the block in the two-billion-dollar sleep drug market: Lunesta™. In December 2004, the U.S. Food and Drug Administration (FDA) approved Lunesta (eszopiclone) for the treatment of insomnia, and it is likely to be available to consumers within the first quarter of 2005. Like its new-generation predecessors—the widely used Ambien and Sonata—Lunesta helps people fall asleep without the next day "hangover" characteristic of older-generation sleep drugs.

So how is Lunesta different from Ambien, currently the most commonly prescribed sleeping pill? Clinical trials have shown that in addition to helping people fall asleep, Lunesta helps people stay asleep. With a longer half-life (which determines how long a drug remains active in the body) than Ambien, Lunesta may be more effective for those who have difficulty sleeping through the night. Even more notable is that Lunesta is the first and only sleep drug specifically approved for long-term use. In approving other sleep medications, the FDA has always warned that the drugs should be used for no more than 7-10 days, since long-term studies of their safety and effectiveness have not been conducted.

However, as part of the FDA approval process, Sepracor, Inc., the manufacturer of Lunesta, not only sponsored short-term clinical trials demonstrating the drug’s effectiveness but also initiated several studies analyzing prolonged use of the drug for patients with chronic insomnia. Some studies lasted six months, and one study was extended for a full year of continuous use. The results led to the FDA’s approval of Lunesta for long-term, nightly use. The longer-term studies are in contrast with the 12-week trials conducted before the approval of Ambien and Sonata.

The studies of Lunesta found that people taking it over a long period of time did not build up tolerance to the drug, thus avoiding a common concern for those who take sleep medications for an extended period and find themselves needing higher and higher doses to achieve the same effect. Moreover, when the use of Lunesta was stopped abruptly, there were few if any of the withdrawal symptoms that often occur with other prescription sleep aids.

All prescription medications that help induce or maintain sleep are referred to as hypnotics, but these drugs differ based on their chemical structure and on their half-life. In the 1960s, a group of hypnotics called benzodiazepine agonists was developed, which work by acting on areas of the brain believed to be involved in sleep promotion.

Until recent years, benzodiazepines (such as Valium, Halcion, and Xanax) were the mainstays of short-term treatment for insomnia. They work by increasing the gamma-aminobutyric acid (GABA) activity in the brain, helping to induce sleep. These drugs are less dangerous than the narcotics that preceded them; however, they still have several disadvantages. The half-life of these medications tends to be longer than that of the newer sleep medications, and consequently can cause next-day drowsiness or impairment. People who use one of these drugs frequently may develop tolerance, causing the drug to work less well than before. Benzodiazepines can also be addicting, and they typically cause withdrawal symptoms when discontinuing the medication after long-term use.

In addition, while benzodiazepines can help people sleep, they have the undesirable effect of changing the quality of sleep by altering "sleep architecture," according to Donna Arand, Ph.D., Clinical Director of the Kettering Sleep Disorders Center in Kettering, Ohio. "They tend to decrease the amount of time spent in certain stages of sleep, particularly stages three and four—the deepest, most restful stages of sleep," Arand told WebMD in a recent interview. This is a particular problem for FM patients, who already suffer from "non-restorative" sleep, which might be related to a reduction of stage three and four sleep.

In the last decade, a new generation of sleep medications has come of age, promising a good night’s sleep without the perils of traditional sleep aids. Ambien, Sonata, and Lunesta are all non-benzodiazepine hypnotics. They work only on specific receptors in the brain, while older classes of drugs have a more generalized effect on multiple receptors. This allows the newer prescription sleep aids to have a much more precise effect, says Timothy Roehrs, M.D., Director of Research at the Sleep Disorders and Research Center, Henry Ford Hospital in Detroit. Roehrs offers, "It’s not very scientific, but you can think of the new sleep medications this way: Instead of whacking people with a big hammer and knocking them out, you use a little ball peen hammer and gently tap, tap, tap them to sleep." The non-benzodiazepines do not tend to have an effect on sleep architecture and are purported to be less likely to cause addiction, although all people taking sleep medicines for an extended period of time have some risk of becoming dependent on the medicine.

While drugs like Ambien, Sonata, and Lunesta represent breakthroughs in the science of sleep medicine, they will not be alone for long. Also in the pipeline is indiplon, a prescription sleep aid from Neurocrine Biosciences in partnership with pharmaceutical giant Pfizer. Indiplon (which has not yet received a brand-name) is a non-benzodizaepine like the other modern sleep drugs, and it will likely gain FDA approval for long-term use, reaching the market in about a year. Like Sonata, it works to induce sleep very quickly and wears off very fast. However, indipolon will be marketed in two formulations, one that is fast-acting (like Sonata), and another "modified release" formula, which essentially provides one dose at bedtime and another dose in the middle of the night to help patients stay asleep. Clinical trials have shown positive results with no next-day residual effects.

Another sleep drug, gaboxadol, developed by Danish pharmaceutical firm Lundbeck, is currently undergoing Phase III clinical trials and could be approved in 2006 or 2007. U.S. drug giant Merck recently agreed to a licensing deal with Lundbeck to develop and market the drug. Gaboxadol works differently from the other new-generation sleep drugs in that it directly activates GABA receptors, while the other modern sleep aids indirectly enhance GABA activity. Phase II studies have found the drug effective not only in inducing and maintaining sleep, but also in increasing "slow wave sleep," which is believed to enhance the restorative effects of sleep.

Another investigational drug for insomnia currently undergoing late-stage clinical trials is ramelteon, developed by Japanese drug company Takeda Pharmaceuticals. Ramelteon is known as a "melatonin agonist" and works completely differently from other sleep drugs, which directly or indirectly target GABA receptors. The drug specifically affects the MT1 and MT2 receptors in the brain, which are believed to be critical in the regulation of the body’s sleep-wake cycle. Takeda has completed several Phase III trials and is currently conducting a year-long safety study. Ramelteon could reach the U.S. market in 2008.

In addition to these new medications, you can expect to see the results of pharmaceutical companies’ efforts to make their sleep drugs work better. A controlled-release form of Ambien is expected later in 2005, which might help those who struggle with nighttime awakenings. Given Lunesta’s FDA approval for long-term use, other drug firms—like the makers of Ambien and Sonata—may follow suit and pursue that approval as well.

Some physicians and sleep specialists question the wisdom of using a sleeping pill for weeks or months at a time, especially a new drug approved after six months of testing with 2,700 patients. It’s easy to find an example of "approved" medicines with dangerous side effects. Perhaps most notable is the recent news of Vioxx, Celebrex, and Bextra and the increased risk of heart attack and stroke that emerged after millions of patients began taking the drugs. According to Gregg D. Jacobs, Ph.D., a sleep specialist at Beth Israel Deaconess Medical Center in Boston, "Lunesta is like every drug approved by the FDA. We don’t know what the long-term side effects are…The message is: Buyer beware."

Others worry that patients looking for a quick fix will opt to simply "pop a pill" rather than explore potential underlying problems and/or use behavioral techniques to combat insomnia. Thomas Roth, M.D., Director of the Sleep Disorders and Research Center at Henry Ford Health System in Detroit, points out that sleep medications should not be used in isolation. "You want to use them in conjunction with good sleep practices, good behavioral therapies, and treating accompanying conditions."

The good news is that insomnia is a problem that is receiving serious attention. According to Martin B. Scharf, Ph.D., Director of the Tri-State Sleep Disorders Center in Cincinnati, there is a growing recognition that few health needs are more important than sleep. Scharf, who helped conduct the clinical trials that led to the approval of Ambien, believes that the new sleep medications are extremely safe; in fact, he tells his own mother to take Ambien on a nightly basis. "I feel it’s safer for her to get a good night’s sleep," said Scharf, according to Forbes.com. The drug firms’ increasing efforts to provide a variety of treatments with differing characteristics reflects an acknowledgment that not all insomniacs are alike. Some patients have trouble falling asleep; others struggle to stay asleep. Some need a short-term solution for an occasional difficulty sleeping, while others need treatment for a chronic condition. With more and more choices available, FM sufferers are likely to find their doctors more willing and able to determine a solution that works for them.

Xyrem

Can A Controversial Drug Bring New Hope To FM Patients?

By Lisa Lorden Myers

[Reprinted from Fibromyalgia Frontiers, 2004 (Volume 12, Number 3)]

By some estimates, 70 million people in the United States suffer from some type of sleep disorder. Sleep aids are big business in this country, as evidenced by the huge success of the prescription drug Ambien (which brought in $1.5 billion in 2003 alone) and at least two new sleep medications scheduled to come on the market in 2005. But for fibromyalgia (FM) patients, the most promising development may be medicines that help people get the right kind of sleep.

Fibromyalgia patients frequently complain that they awaken in the morning feeling exhausted, even after spending eight or more hours in bed. It turns out that this complaint can actually be documented in the sleep lab. Research using electroencephalograms (EEGs) has shown that FM is associated with "alpha intrusion" during deep sleep; that is, during the stages of deep sleep (Stages 3 and 4)—normally characterized by thousands of delta waves in the brain—EEGs reveal the occurrence of alpha waves, which normally appear during periods of relaxed wakefulness. When these alpha waves intrude into deep sleep, patients complain that they awaken feeling unrefreshed. According to one noteworthy study, 50-70% of patients with FM have sleep patterns characterized by alpha intrusion.

Why is refreshing sleep so important? If you’ve ever seen a television commercial for an over-the-counter or prescription sleep aid, you’ve seen the smile on the face of the actor getting out of bed as the morning sunlight streams in the bedroom window—the smile that says, "I just slept through the night and I feel great." However, in reality, a good night’s sleep is a much more complicated event. There are a number of biological processes that take place during deep sleep. Growth hormone, which is released almost exclusively during the deep stages of sleep, plays an important role in adults by maintaining bone density and muscle mass and restoring muscle tissue which breaks down as a result of the rigors of the day. Eighty percent of the growth hormone released in the body over a 24-hour period occurs during the deep stages of sleep. Fibromyalgia patients have a documented decrease in deep sleep and in growth hormone secretion, which may explain why people with FM have so much pain and fatigue in reaction to a small amount of physical activity.

Unfortunately, no medication has been shown to reduce alpha intrusions in patients with non-restorative sleep. Until now. A recent study published in the Journal of Rheumatology reports the effects of a compound called sodium oxybate on sleep patterns and symptoms in patients with fibromyalgia. The study, conducted by Dr. Martin Scharf, Ph.D., Director of the Tri-State Sleep Disorders Center in Cincinnati, Ohio, and his colleagues, found that sodium oxybate effectively reduced symptoms of pain and fatigue and dramatically reduced the sleep abnormalities associated with nonrestorative sleep (alpha intrusion and decreased deep sleep).

Sodium oxybate is currently manufactured and marketed by Orphan Medical, Inc., under the name Xyrem. Approved in 2002 by the U.S. Food and Drug Administration (FDA) for the treatment of cataplexy, the sudden loss of muscle tone and strength that is frequently associated with narcolepsy, it is the first and only approved medication for the disorder. Because of the drug’s unique properties and its potential to enhance deep sleep, it is being studied for fibromyalgia, and some doctors are already prescribing it "off-label" to FM patients. "There is no currently approved treatment for fibromyalgia syndrome," says John Bullion, Orphan Medical Chief Executive Officer, "and we believe that Xyrem could play an important role in the treatment of this substantial patient population."

To date, no other drug has been reported to reduce the alpha sleep abnormality. Scharf’s research has shown that sodium oxybate increases the deep stages of sleep, increases growth hormone in patients who are deficient in it, and actually decreases the alpha-intrusion. Although the alpha sleep abnormality is not necessarily specific to fibromyalgia—and it is not clear whether it is a cause or effect of FM—reducing alpha intrusion appears to correlate with clinical improvement in FM patients. Says Scharf, "The bottom line is their pain gets better, their fatigue gets better, their cognitive function gets better, and overall they function much better."

Yet the buzz about Xyrem is not all good. Gamma-hydroxybutyrate (GHB), the active ingredient in Xyrem, has a rather notorious history and remains controversial because of the potential for abuse. In the early 1990s, GHB was marketed as a dietary supplement purporting to enhance athletic performance and sexual activity, relieve depression, and aid sleep. However, it was abused as a recreational drug for its sedative and euphoric effects. When mixed with alcohol, the sedative effects are profound. Since GHB is odorless and tasteless, it was easily "slipped into drinks" in social settings and thus, it became known in the popular press as "the date rape drug." As a result of a number of serious adverse events—including deaths—associated with the use and misuse of GHB, the FDA intervened and banned the marketing of the substance. When Orphan Medical conducted studies that revealed the usefulness of GHB in treating cataplexy, the FDA approved the medication for treating this small population of patients, under strict distribution guidelines.

GHB is a natural substance that we all have in our bodies. At very high doses, it is an anesthetic; at lower doses it is sedating. Xyrem comes in liquid form and must be mixed with water. The drug works quickly and therefore should be taken while one is in bed and ready for sleep. Because it only remains in the body a short time, patients must take the medication two times each night, the first dose right at bedtime and the second dose 2.5 to 4 hours later. Patients are instructed to set an alarm to make sure they wake up to take the second dose.

While this may seem counterintuitive to FM patients trying to sleep through the night, it is important to remember that the goal is not just to sleep, but to improve the kind of sleep. Traditional hypnotic agents, which may help patients fall asleep or stay asleep, do not provide restorative sleep or reduce pain. Orphan Medical has begun development of a new formulation of Xyrem that could extend the activity of a single dose from the current two- to four-hour range to one that would last six to eight hours.

"So far our numbers are too good to believe," said Scharf in an August 2003 interview for The People’s Pharmacy, a syndicated radio program. "We’re getting a very dramatic response in probably 90 percent of our patients." Scharf points out that his studies have been very selective in enrolling patients to participate, choosing those with a documented history of fibromyalgia who have been found in the sleep lab to have alpha intrusion. The goal, says Scharf, is to "have something objective to work with in terms of what to treat for this condition."

Dr. Scharf’s initial studies have been extremely small, and more research is needed before the FDA will consider the approval of Xyrem specifically for FM patients. Orphan Medical has begun patient enrollment in a Phase II clinical trial designed to evaluate the use of Xyrem in the treatment of FM. The protocol calls for 150 patients to complete a three-month trial that will assess the impact of Xyrem on the symptoms of fibromyalgia, including the sleep disturbance that typically accompanies FM. Trial sites will be located throughout the United States and Canada with approximately 20 participating centers.

Because of the safety concerns associated with the use of the drug, Xyrem is considered a Schedule III controlled substance and is distributed only in accordance with strict FDA regulations. GHB is also now considered a controlled drug in Britain though not yet in some other European countries.

Orphan Medical has worked with the FDA to design a comprehensive risk management program, creating a central pharmacy where the company can monitor prescriptions and provide education for physicians and patients to make sure they understand the safety issues. The product can be obtained only through this single centralized pharmacy, and medication is mailed directly to patients after they have received educational information about the drug. Patients taking Xyrem also have round-the-clock access to a team of pharmacists who provide needed assistance, and doctors are expected to report all serious adverse events.

According to Orphan Medical’s Patient Medication Guide, the most common side effects of Xyrem are nausea, dizziness, headache, sleep problems, confusion, vomiting, and bed-wetting. Less common side effects may include sleepwalking, increased sleepiness during the day, sleep apnea, breathing problems, depression, and abnormal thinking.

The abuse of GHB has been associated with a number of serious problems, including seizure, respiratory depression, and loss of consciousness, even coma and death. Abuse of Xyrem could also lead to dependence, craving for the medicine, and severe withdrawal symptoms. When used as recommended, however, Xyrem does not appear to be addictive. In clinical trials, no overt withdrawal symptoms were observed after two weeks of withdrawal following an average twenty-one months of therapy.

Dr. Richard Podell, M.D., Clinical Professor at the UMDNJ-Robert Wood Johnson Medical School and a specialist in chronic fatigue syndrome and fibromyalgia, believes that Xyrem could have significant benefits for fibromyalgia, despite the potential for side effects. Says Podell, "I believe that the benefit/risk ratio should be favorable—for well-selected individuals."

Yet many physicians are reluctant to prescribe Xyrem for FM patients because of the drug’s controversial history and the fact that it is so tightly controlled. Orphan Medical Chief Scientific and Medical Officer, William Houghton, M.D., acknowledges these concerns. Said Dr. Houghton in a recent interview, "Obviously it is a medication that comes with baggage, both in terms of drug abuse and drug-related sexual abuse." He points out, however, that GHB’s problems are not necessarily related to the pharmaceutical product. "They are related to drugs that are made in a garage or [obtained] through the suppliers of illicit drugs." To date, there have been no reports of Xyrem being misappropriated in those ways since the drug was commercialized.

Other factors may also affect the use of Xyrem among FM patients. Xyrem is expensive; some insurers may not cover off-label use, and others may require a sleep study prior to prescribing the drug. Some patients may be put off by the patient information materials or the process of obtaining the drug. Said one FM patient who recently began taking Xyrem, "You get the impression that Xyrem is serious stuff. It’s a little scary."

Houghton is not surprised by such reactions. He admits that the prescription procedure is complex, and this was done to make any inappropriate use of the drug as difficult as possible. Says Dr. Houghton, "It’s a very cautious, restrictive distribution process that makes it unique in pharmaceutical terms…some people will be very put off by that, thinking it’s uniquely dangerous, rather than us being uniquely careful."

Further research should go far to address the concerns of both doctors and patients about Xyrem. The company expects that initial data from the upcoming clincial trial will be available in mid-2005; if the results are positive, a full development program and extensive additional clinical testing will then be undertaken. It would likely take several more years before the FDA regulatory process is completed.

If the results of future clinical trials are as impressive as the initial research, it seems likely that Xyrem could ultimately gain FDA approval as a treatment for fibromyalgia. Orphan Medical’s hopes are high and their goals specific. The company is looking for evidence that the drug can treat not just disturbed sleep, but the entire symptom complex of FM, including pain.

According to Houghton, "We’re not looking to Xyrem just as a sleep aid in fibromyalgia but as a true symptom treatment for the full disease." This is surely music to the ears of many FM sufferers. But it remains to be seen whether or not this unique medication proves to be a new ray of hope for millions of people with fibromyalgia.