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Insomnia: Too Much Alpha Wave Activity at Night

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The brains of people with insomnia are active at night, even during quiet sleep. This activity isn’t often noted in sleep studies, where the point is to identify dominant wave forms. But looking closer, scientists are discovering slight but crucial differences in insomniacs’ brain waves at night, which may explain our trouble falling and staying asleep.

“Alpha wave intrusion” is a term used to describe the wake-like brain activity observed during the deep sleep of people with fibromyalgia and major depression. Now a new study in the Journal of Sleep Research presents evidence of abnormal alpha wave activity in insomniacs’ brains at night. Here are the two main findings:

Picture the brain at night. It’s mostly quiet except during rapid eye movement (REM) sleep. Then clusters of neurons in the brain stem start firing away like mad. These bursts of activity are perfectly normal during REM sleep, alternating with periods of quiet non-REM sleep through most of the night.

The brains of people with insomnia are more active at night—even during non-REM sleep. This activity isn’t often noted in sleep studies, where the point is to identify dominant wave forms. But looking closer, scientists are discovering slight but crucial differences in insomniacs’ brain waves at night, which may explain our trouble falling and staying asleep.

Alpha wave intrusion is a term used to describe the wake-like brain activity observed during the deep sleep of people with fibromyalgia and major depression. Now a new study in the Journal of Sleep Research presents evidence of abnormal alpha wave activity in insomniacs’ brains at night. Here are the two main findings:

TROUBLE FALLING ASLEEP

The descent from wakefulness into deep sleep occurs fairly quickly in healthy sleepers. The pressure to pay off the day’s sleep debt is strong, compelling a rapid descent into deep (slow-wave) sleep.

But in people with sleep onset insomnia, who typically take more than 30 minutes to fall asleep at night, the descent takes quite a bit longer, research shows. Insomniacs—for unknown reasons—seem to have reduced sleep pressure. Not only does it take us longer to fall asleep. It also takes us longer to descend into deep sleep, the really restorative stuff.

WHY THE SLOW DESCENT?

The research team investigating alpha wave activity looked at the sleep studies of 18 good sleepers and 10 insomniacs and found one difference that occurred before sleep began. Alpha waves—associated with a relaxed, meditative state of consciousness that occurs when the eyes are closed—are predominant in the period leading up to sleep. They’re generated by neurons firing at frequencies of 7.5 to 12.5 cycles per second.

As the healthy sleepers in the study were falling asleep, the alpha rhythms in their brains began to fluctuate and decay. But the alpha wave activity in insomniacs’ brains continued going strong.

Sleep onset insomnia may have something to do with decreased alpha variability, the researchers concluded. Insomniacs are relaxed and ready for sleep—yet (again for unknown reasons) we remain stuck in alpha mode.

WAKING UP AT NIGHT

Alpha waves may also play a role in sleep maintenance insomnia. Polysomnogram studies show that normal sleepers awaken at least a few times a night but are mostly unaware of these awakenings.

People with sleep maintenance insomnia, in contrast, are conscious of waking up at night. These awakenings make our sleep feel fitful and less restorative. (And some sleep maintenance insomniacs are told their problem involves alpha wave intrusion following a sleep study.)

Adults spend up to 80% of the night in non-REM sleep, and in the alpha wave study, different kinds of alpha activity occurred in the brains of healthy sleepers and insomniacs throughout non-REM sleep. Brief arousals in the healthy sleepers were characterized by alpha waves that stayed well below the frequency of alpha waves during conscious wakefulness.

But the alpha frequencies in participants with insomnia rebounded to wake levels. In this situation, a sleeper might be easily awakened by noise or movement and memories could be formed. It might account for why so many insomniacs complain of light and/or broken sleep.

THE TAKE-AWAY

Higher alpha frequencies during brief arousals and lower alpha variability at the approach of sleep fit with the hyperarousal theory of insomnia, which suggests that people prone to insomnia experience higher levels of arousal around the clock. As for how to correct these alpha abnormalities, we’ll have to wait and see.

Sedating Antidepressants for Insomnia?

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Antidepressants have been prescribed as de facto sleeping pills for over 3 decades now. This used to bother me. Most antidepressants have not been tested on people with simple insomnia and shown to improve sleep.

In contrast, sleeping pills approved for the treatment of insomnia have been tested on insomniacs in clinical trials and shown to work. Why would a doctor prescribe a drug that hasn’t been held to the same standard? It looked like a cop-out to me.

These days I see things differently. Not because the pharmaceutical companies have suddenly come forward with proof that sedating antidepressants improve the sleep of people with insomnia in the absence of depression. (One such drug, low-dose doxepin, a tricyclic antidepressant, has been tested and approved for insomnia. Details are below.)

I’ve changed my mind for a personal reason: about 9 months ago, I was persuaded to start taking a low dose of a tricyclic antidepressant for a stomach problem I have. As a result, I can now eat small portions of many foods that were off-limits to me for 5 or 6 years.

Do I care that nortriptyline has never been tested and approved for the treatment of functional dyspepsia? No. Eating is believing. And now I’m willing to accept the idea that low-dose antidepressants might be a reasonable solution to the sleep problems of insomniacs who say they need medication to get a decent night’s sleep. Here’s some general information about sedating antidepressants and details about those frequently prescribed for people with insomnia.

Sedating Antidepressants

Doctors like antidepressants in part because of what they’re not. Most sleeping pills on the market today—zolpidem (Ambien), eszopiclone (Lunesta), and suvorexant (Belsomra), for example—are Schedule IV drugs, meaning that they’re believed to have some potential for abuse and dependence. Nightly users of these drugs may also develop tolerance to them and find they no longer work.

In contrast, antidepressants are unscheduled drugs not known to foster dependency or abuse. They’re considered relatively safe for long-term use. If you find one that helps you manage your insomnia, your doctor will probably be happy to prescribe it indefinitely.

The downside of many sedating antidepressants is that they have side effects at the high doses typically prescribed for people with depression. Drowsiness, increased susceptibility to falls, cognitive impairment, weight gain, dry mouth, constipation, difficulty with urination, and fine tremor are adverse effects noted by significant numbers of users. In the absence of formal testing, it’s hard to predict how frequently these adverse effects would occur at the low doses prescribed for people with insomnia.

Doxepin (Silenor)

As mentioned above, this is the only antidepressant approved for the treatment of insomnia. Doxepin at doses prescribed for depression (over 75 mg) acts on several neurotransmitter systems. At the low dose typically prescribed for insomnia (less than 10 mg), its sole appreciable effect is to block secretion of histamine, a neurotransmitter associated with wakefulness.

Strengths and weaknesses, per a review of randomized placebo-controlled trials:

  • Doxepin is better than placebo at keeping people sleeping through the night, extending sleep time, and improving sleep efficiency. The higher the dose, the more marked are the effects.
  • Doxepin does not help with sleep initiation. Headache and grogginess are possible side effects.

Trazodone (Desyrel)

Trazodone is the sedating antidepressant most commonly prescribed for people diagnosed with insomnia in the United States. At the low dose typically prescribed for sleep (50 mg), its blockade of histamine, serotonin, and alpha-1 receptors likely gives this drug its sedative effects. Trazodone’s popularity as a hypnotic is based on little hard evidence. No long-term studies of the drug’s efficacy as a hypnotic exist. This is unfortunate because it’s generally used as a maintenance treatment for people with insomnia.

Short-term trials obtained the following results:

  • In a large, 2-week trial comparing 50 mg trazodone with 10 mg zolpidem and placebo, trazodone in the first week reduced wakefulness at night and improved total sleep time and sleep quality. The drug performed no better than placebo in the second week.
  • In a small week-long trial of 50 mg of trazodone conducted to assess the drug’s side effects, investigators found that compared with placebo, trazodone cut down on nighttime awakenings and stage 1 sleep (the lightest stage). On day 7 only, subjects got more deep sleep and experienced less sleepiness the following day. However, taking the drug also led to “small but significant impairments of short-term memory, verbal learning, equilibrium, and arm muscle endurance across time points.” How likely these side effects would be to occur with long-term use is unknown.

Mirtazapine (Remeron)

Mirtazapine is a tetracyclic antidepressant also used for insomnia. This drug has never been tested on people with simple insomnia. But in 15 to 45-mg doses, it’s been found to have sedative effects in people with depression and insomnia. This is likely due to the drug’s blockade of histamine and serotonin receptors.

Strengths and weaknesses, per short- and long-term trials conducted on people with depression and insomnia (most of these trials did not have a placebo or FDA-approved control) :

  • Mirtazapine helps with falling asleep and staying asleep and may improve sleep quality.
  • Mirtazapine may potentially cause weight gain. Other common side effects include daytime drowsiness or dizziness and dry mouth.

According to a review article in the Journal of the American Pharmacists Association, “Lower doses (e.g., 7.5–15 mg) of mirtazapine may actually provide more sedation when compared with higher doses, as higher doses . . . [may blunt] the drug’s sedative effect.”

Amitriptyline (Elavil)

Amitriptyline is a tricyclic antidepressant that is sometimes prescribed in low doses (5–25 mg) for people with insomnia and other chronic health conditions. No clinical trials of the drug’s efficacy as a treatment for insomnia have ever been conducted. But studies conducted on people with depression and healthy individuals have found that amitriptyline has sedative effects.

Common side effects are daytime drowsiness, dry mouth, and urinary problems.

The Take-Away

The point of this blog is not to suggest that sedating antidepressants are a good solution to the sleep problems of everyone with persistent insomnia. My point is that these drugs may be a viable option for people who haven’t found relief through other means.

If you’ve tried an antidepressant for sleep, what was your experience like?

Will Ambien Go the Way of Halcion?

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In the early 1990s, word was spreading that Halcion, a popular short-acting sleeping pill prescribed for insomnia, was a dangerous drug. Not only did it make users anxious, depressed, and suicidal.

It was also implicated in a series of murders. Sales of Halcion plunged. Today the drug is still on the market but is rarely prescribed.

Now zolpidem (Ambien) is receiving intensive post-marketing scrutiny, raising questions about the drug’s safety.

In the early 1990s, word was spreading that Halcion, a popular short-acting sleeping pill prescribed for the treatment of insomnia, was a dangerous drug. Not only did it make users anxious, depressed, and suicidal.

It was also implicated in a series of murders. (The murderers were absolved of their crimes based on the argument that Halcion rendered people incapable of understanding their actions). Sales of Halcion plunged. Today the drug is still on the market but is rarely prescribed.

Now zolpidem (Ambien) is receiving intensive post-marketing scrutiny, raising questions about the drug’s safety. In January 2013 the Food and Drug Administration lowered the recommended dose for women and older adults from 10 mg to 5 mg following reports of zolpidem-related car crashes and an analysis linking the drug to drowsiness in the morning. Studies and reports published in the past 2 years cast more doubt on the drug’s safety. So is zolpidem now set to go the way of Halcion?

A POPULAR SLEEPING PILL

About 5 million Americans now use medications containing zolpidem (generic zolpidem, Ambien, Ambien CR, Intermezzo, Edluar, and Zolpimist), according to the Institute for Safe Medication Practices. Like several other sleeping pills, zolpidem acts on GABA-producing neurons, helping tranquilize the brain.

Benzodiazepine drugs like Halcion bind to several kinds of GABA receptor complexes and consequently produce a range of adverse effects. Zolpidem binds more selectively. Early tests showed that it facilitated sleep and produced fewer adverse effects.

So the FDA in 1992 approved zolpidem for “short-term treatment of insomnia characterized by difficulties with sleep initiation.” FDA approval of the extended-release version came in October 2005—notably without the short-term restriction. Zolpidem in its many formulations dominated the hypnotics market for years despite occasional reports of people sleepwalking, sleep eating, and sleep driving under its influence.

A TROUBLING CDC REPORT

People with zolpidem-related problems and injuries were also showing up in hospital emergency departments. The Centers for Disease Control and Prevention recently reported on a survey of psychiatric medications identified as the reason for emergency department visits.

The results were surprising: of all psychiatric medications prescribed, zolpidem ranked first in adverse drug event cases. About 11.5 percent of all emergency department visits among adults were attributable to zolpidem, as were 21 percent of the visits in adults 65 and older. Authors of the report estimated that zolpidem accounted for 10,212 annual visits to hospital emergency departments, 25 percent of which required hospital admission.

REGULAR USERS AT RISK

Two new cohort studies suggest that it’s the regular users of zolpidem who are prone to serious accidents:

  1. In a study in Mayo Clinic Proceedings (May 2014), Taiwanese investigators found that long-term zolpidem use significantly increased the risk of major injuries requiring hospitalization. Depending on the dosage, users young and old were 2 to nearly 5 times as susceptible as nonusers to head injuries and fractures.
  2. In a large study in the American Journal of Public Health (August 2015), University of Washington researchers used new prescription and collision records to determine the relationship between the use of sleeping pills and motor vehicle crashes. Regular users of zolpidem were over twice as likely to have crashes as nonusers.

SOME PERSPECTIVE ON THE PROBLEM

Why is a medication approved as safe and effective by the FDA causing so many problems? The Institute for Safe Medication Practices analyzed a 2012 health care survey to find out if zolpidem was being prescribed and used in a manner consistent with safe use guidelines. Here’s a summary of the report, which appeared in the May 6, 2015, issue of QuarterWatch:

  • Zolpidem was originally approved for short-term use only, yet 68 percent of the users with drug-related injuries or problems were long-term users of zolpidem, on average taking a pill about 2 nights out of 3.
  • Despite the FDA’s recent recommendation that women and older adults be prescribed the lowest approved dose of the drug (5 mg zolpidem or 6.25 mg extended release), in 2012 (before the recommendation came out), few people were taking the lower dose.
  • Drug-drug interactions were common among regular users of zolpidem. Prescribing information warns against taking other drugs that depress the central nervous system while taking zolpidem. Yet about 22 percent of regular zolpidem users were also using opioids on a sustained-use basis. About 23 percent were taking another drug (a benzodiazepine, pregabalin, or gabapentin) that, like zolpidem, acts on the GABA system, producing complex effects.
  • Finally, the prescribing information for zolpidem says the drug may worsen depression and suicidal thoughts in patients with depression. Yet 34 percent of the regular users of zolpidem were also using an antidepressant.

Many regular users of zolpidem may never experience drug-related complications. (This may also have been the case for the majority of Halcion users.) But with so much data now showing that zolpidem is causing harm to significant numbers of users, prescribing patterns will likely change. Don’t be surprised if the next time you ask for a renewal of your zolpidem prescription, you’re prescribed something else instead.

If you use zolpidem for insomnia, how do you feel about the possibility of losing access to this sleeping pill?

Ebb Insomnia Therapy: The Silver Bullet We’ve Been Waiting For?

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The company name has changed. So has the wearable part of this sleep-promoting medical device.

But the product launch at selected sleep centers is still set for the final months of 2017, with full production capacity expected next year. Here’s an update on a device that will add to research-based treatment options for people with insomnia.

What It Is

The Ebb Insomnia Therapy device was developed by Ebb Therapeutics (formerly Cerêve, Inc.). Worn at night, it consists of a soft headband (rather than the plastic cap envisioned last year) attached by a tube to a temperature regulator that sits on a bedside table. Fluid is continuously pumped through the part of the headband that rests against the forehead, cooling it down. Research has shown that by cooling the forehead, the device reduces metabolic activity in the front part of the brain and hastens the onset of sleep.

Excessive Brain Activity at Night

The bane of many insomnia sufferers at night is a mind that keeps going and going and doesn’t want to stop. Such thinking and other executive activities (planning, decision-making) are functions of the frontal cortex, or the front part of the brain, involving the metabolizing of glucose.

Functional brain imaging studies—movies of processes occurring in the brain—have shown that the brains of normal sleepers are mainly quiet at night. No activity is detected in the frontal areas. In contrast, imaging studies conducted by Ebb Therapeutics founder Eric Nofzinger have revealed a great deal of metabolic activity occurring at night in the brains of insomniacs, including activity in the frontal cortex. Published images show that at night, the brains of people with insomnia are “lit up like Christmas trees.”

Cooling the Brain

Why might cooling the brain help? For starters, our core body temperature tends to rise in the daytime and fall at night. Previous research has shown that we tend to fall asleep more readily when our core body temperature is on the downward part of the cycle.

Two early studies conducted on people with insomnia showed that cooling the forehead at night

  • reduced participants’ core body temperature, and
  • reduced metabolic activity in the brain, particularly in the frontal cortex.

When Nofzinger and colleagues conducted a third, larger study (randomized and placebo controlled), they found that wearing the device significantly reduced the amount of time it took insomnia sufferers to fall asleep.

Compared With Current Insomnia Treatments

Many medications for insomnia have unwanted side effects. Ebb Insomnia Therapy is reported to have no appreciable side effects and classified as low risk by the FDA. As for its effectiveness, only time will tell how well it stacks up against insomnia drugs such as Ambien and Belsomra. New insomnia treatments like Ebb are only required to perform significantly better than sham treatment or placebo pill to gain FDA approval.

Cognitive behavioral therapy for insomnia (CBT-I), currently the gold standard in insomnia treatments, requires effort and commitment to a rigorous, weeks-long therapeutic process. Ebb Insomnia Therapy is relatively effortless. All it involves is wearing a headband at night. Some insomnia sufferers may begin to benefit right away, according to the company website. Others may take time to adjust to the device and need to use it anywhere from 2 to 4 weeks before seeing sleep improvements.

Limitations

The device will not be sold over the counter. It requires a prescription from a licensed physician or a licensed nurse practitioner. Nor has Ebb Therapeutics said how much it will cost. The company has taken out several patents, though, so the device will not be cheap. In addition, a new fluid cartridge will need to be purchased every three months. The device and cartridges are not expected to be reimbursable by health insurance companies anytime in the near future.

It’s doubtful the device will solve the sleep problems of every insomniac. The studies show that Ebb Insomnia Therapy reduces the time it takes to fall asleep and users report, after 30 days, that it improves sleep quality. Nowhere is the company claiming the device cuts down on night-time wake-ups or increases total sleep time, two items on the wish list of many insomnia sufferers.

Even so, it may be the silver bullet that at least some insomniacs have been waiting for. Particularly if you feel your sleep problem is driven by a yammering brain that just won’t stop, Ebb Insomnia Therapy is certainly worth checking out.