Zolpidem had more impact on sleep than on amnesia, muscle relaxation, and the other effects associated with drugs that bind to gaba receptors. In theory, at least, this selectivity meant that the drug would have fewer undesirable outcomes. Zolpidem was launched in France in Pelus-Kaplan once attended a conference, incognito, to confirm that her husband was being overlooked. It was George who built the molecule, but Kaplan argues that the initial collaboration created the blueprint for all that followed.
George agrees. Ambien had the good fortune to reach the market just as the reputation of Halcion, which had been promoted as safer than barbiturates, collapsed. It remains available in the U. And a fatal overdose would be very hard, if not impossible, to engineer. Nevertheless, Ambien was accepted as a better drug. Then I show them the data. Ambien quickly became the national best-seller in its category.
By the turn of the century, there were more U. In , Kaplan negotiated a payment—about thirty thousand dollars—from his former employers. George, who stayed at the company, happily, until his retirement, in , received a little less.
After Kaplan retired from his career in law, he formed an organization that lobbies on behalf of people who invent things while working as a salaried employee. Therefore, I call it a comfort drug. Ambien can be disinhibiting and depersonalizing. When the neurotransmitter sticks to its target, negatively charged chloride ions flow into cells, making the inside of the cells more negative, and less likely to fire.
Many people experience this as a contented swoon that silences inner chatter while giving a half glimpse of childhood; they are overtaken by sleep, like a three-year-old in a car seat. But others resist sleep and embrace the woozy, out-of-body license. After taking the drug, they larked around and knocked on the doors of other athletes. But for many Ambien users, like the eBay shopper, their activities on the border of wakefulness and sleep are less purposeful.
He had Ambien and an anti-nausea medication in his body. By the following spring, the F. This kind of behavior can occur during dreamless, slow-wave sleep—the state of an unmedicated sleepwalker—or, more commonly, Jed Black suspects, while someone is awake but disinhibited, by Ambien alone or by Ambien and alcohol.
Black noted that this altered state can be mischaracterized as sleep by people who have forgotten their adventures. A recent study, described in European Neuropsychopharmacology, suggests that these phenomena affect five per cent of users. Other studies have reported lower numbers. Thomas Roth, the director of the sleep center at Henry Ford Hospital, in Detroit, who has consulted for Merck and other pharmaceutical companies, told me he has not yet seen persuasive evidence that there is more of this behavior among Ambien users than among the rest of the population which includes drinkers.
There may be other risks associated with zolpidem. In a recent paper in the online edition of the British Medical Journal , Daniel Kripke, a professor emeritus at the University of California San Diego School of Medicine, examined five years of electronic medical records collected by a health system in Pennsylvania.
He compared more than ten thousand patients who had been prescribed a sleep medicine—most commonly Ambien—and more than twenty thousand patients who had not. After adjusting for age, gender, smoking habits, obesity, ethnicity, alcohol use, and a history of cancer, and after controlling, as much as possible, for other diseases and disorders, Kripke found that people who had taken sleeping pills were more than three times as likely to have died during the study period as those who had not.
Those on higher doses of the drugs were more than five times as likely to have died. That is, more than four hundred thousand Americans a year. Kripke acknowledges that his study did not identify the cause of any death; ill people take more sleeping pills than others, and some users might have had illnesses that were undiagnosed, and therefore not controlled for in the study.
And insomnia itself could present a significant health risk, although Kripke resists that idea. Jed Black finds the data interesting but too inconclusive.
Other research has linked zolpidem and similar drugs to depression, suicide, and car accidents; there are also data connecting zolpidem to cancer. Such numbers do not establish causation. The U. If the public has largely overlooked such data, even as it pays attention to Patrick Kennedy—or to his cousin Kerry Kennedy, who was arrested last year with zolpidem in her body, having driven for several miles on a shredded tire after colliding with a tractor-trailer—it may be because Ambien deaths are disguised by circumstances.
John Renger, the Merck neuroscientist, has a homemade, mocked-up advertisement for suvorexant pinned to the wall outside his ground-floor office, on a Merck campus in West Point, Pennsylvania. A woman in a darkened room looks unhappily at an alarm clock. Renger showed me one. Two years later, MK became suvorexant. If suvorexant reaches pharmacies, it will have been renamed again—perhaps with three soothing syllables Valium, Halcion, Ambien.
How many get to develop a drug that goes all the way? Probably fewer than ten per cent. In , when Renger was in Japan, finishing his postdoctoral work, two groups of scientists announced almost simultaneously that they had identified, in rodents, a previously unknown neurotransmitter.
One group, in San Diego, called it hypocretin, after the hypothalamus, the area of the brain where it is produced. Orexin-abundant mice gained more weight than others on the same diet. The orexin papers were widely noticed, in part because of the connection to feeding. Several pharmaceutical companies, including Merck, began investigating possible obesity treatments.
A year later, a remarkable paper from Stanford sent everyone in another direction. Since the seventies, Stanford sleep scientists, led first by William Dement, had bred narcoleptic dogs. This was an achievement in itself. The animals suffered from extreme daytime sleepiness and had a propensity for mid-coital collapse: at moments of high emotion, the dogs, like narcoleptic humans, experienced sudden muscle weakness, or cataplexy.
The first Stanford dog was a poodle named Monique. Later, there were other breeds; the Stanford colony, mostly Dobermans, had eighty dogs at its peak. Narcoleptic dogs gave birth to narcoleptic puppies; the disorder in canines has a single genetic cause. In , after a decade-long search, a team led by Emmanuel Mignot, a researcher at Stanford, located the damaged gene, and reported that it encoded a receptor: the same one that had just been identified by the work done in California and Texas.
Narcoleptic dogs lacked orexin receptors. Mignot recently recalled a videoconference that he had with Merck scientists in , a day or two before he published a paper on narcoleptic dogs. He has never worked for Merck, but at that point he was contemplating a commercial partnership.
In narcoleptic humans, the cells that produce orexin have been destroyed, probably because of an autoimmune response. Orexin seemed to be essential for fending off sleep, and this changed how one might think of sleep. We know why we eat, drink, and breathe—to keep the internal state of the body adjusted. But sleep is a scientific puzzle. Orexin seemed to turn notions of sleep and arousal upside down. Mignot had done something very unusual: he had discovered the genetic cause of a condition, helped to reframe thinking about a fundamental human behavior, and revealed clear pharmaceutical opportunities.
An orexin receptor is the kind of place that many existing drugs are designed to reach. A drug that activated orexin receptors might help treat narcoleptics, and a drug that blocked orexin receptors, if introduced to a brain producing orexin at unwelcome times, might help insomniacs, perhaps without intoxicating them.
Pharmaceutical companies were reluctant to give up their obesity-drug ambitions, but it seemed that the orexin mice described in were fat because they stayed up late and had more time to eat. Insomnia was not one of them. Should Merck invest in a market dominated by a drug that, within a few years, would become a cheap generic? Indeed, one detects a little professional defensiveness from the suvorexant team. But orexin-related work promised pharmaceutical novelty, which is extraordinarily uncommon.
Most new drugs are remixes of old drugs—clever circumventions of patent protections. The last truly original medicines in neuroscience were triptans, for the treatment of migraines, introduced in the early nineteen-nineties.
The work was also feasible. Renger, upon his arrival at Merck, had set up a sleep laboratory that could make very fast, semiautomated measurements of the sleep patterns of rodents and monkeys. The lab was designed to identify sleep-related side effects of Merck compounds, but was well suited for testing insomnia treatments.
Merck has a library of three million compounds—a collection of plausible chemical starting points, many of them the by-products of past drug developments. I saw a copy of this library, kept in a room with a heavy door. Rectangular plastic plates, five inches long and three inches wide, were indented with hundreds of miniature test tubes, or wells, in a grid. Each well contained a splash of chemical, and each plate had fifteen hundred and thirty-six wells.
There were twenty-four hundred plates; stacked on shelves, they occupied no more space than a filing cabinet. In , Merck conducted a computerized, robotized examination of almost every compound in the library. Plate by plate, each of the three million chemicals in the library was introduced into this soup, along with an agent that would cause the mixture to glow a little if orexin receptors were activated.
Finally, orexin was added, and a camera recorded the result. Renger and his colleagues, hoping to find a chemical that sabotaged the orexin system, were looking for the absence of a glow. I visited the room in which this work had been done. Yellow robotic arms, on the same scale as car-assembly robots, were moving the trays from here to there, making bursts of sound like a nut being loosened in a tire shop. A computer monitor showed enhanced images of reactions on the plates: a fuzzy grid of light and dark dots, like a blurry telescope image of distant stars.
The molecules that best blocked orexin receptors were re-screened, in various ways. Renger took me to see the rats and monkeys. The lab has soundproofed walls built out of the kind of air-infused blocks used in bomb shelters. The rats were transmitting live EEG data, wirelessly, from brain implants. So were the monkeys; they also had touch-responsive screens in their cages, on which they sometimes played games, for rewards of juice.
A red square might appear on the screen and then disappear; after a pause, a red square might appear alongside a yellow square, and the monkey would be rewarded for touching the red one. With these games, Renger could simultaneously measure wakefulness and cognition. The work went back and forth between the chemists and the biologists: compounds were improved and tested.
At the monthly meeting of the pre-clinical-development review committee, they pitched their best bet to the company. But Renger wanted the drug to extend sleep. Merck approved the compound.
The company was now likely to fund at least a year or two of work. To bring a drug to market now costs an average of about two billion dollars, Hargreaves said. Despite years of sleep problems, Samar Chatterjee, a seventy-year-old environmental engineer, had until recently never taken a sleep aid. Chatterjee, who lives in Washington, D. He thought that the study might benefit society, and he hoped to learn if he had sleep apnea: people with the condition would not be allowed to participate.
After being monitored over two nights of imperfect sleep, at the Chevy Chase center, Chatterjee learned that he did not have sleep apnea, or other complicating conditions, and that he was sufficiently insomniac to join the trial.
The center, one of many contracted by Merck, heard from five hundred applicants, but found only seventeen who met all the criteria. When Chatterjee slept at home, he delivered an account of his night to the center, through an automated telephone questionnaire.
He suspected, correctly, that he was taking a drug rather than a placebo. He fell asleep faster than usual, and stayed asleep. This seems to have pleased him, but left him ambivalent about insomnia medication. I asked him about side effects.
Maybe some dizziness or pain. Headache, that type of thing. Drug trials usually have three phases, and Chatterjee had taken part in the final phase of the suvorexant trials.
The Phase I trials, begun in , tested for safety. In , results from Phase I studies of suvorexant showed that it was safe enough to go forward. In late , suvorexant began a Phase II trial, involving two hundred and fifty-four insomniacs in the U. The results would establish the doses for much larger, and more expensive, Phase III trials, whose results are at the center of any submission to the F.
In Phase II, Merck tested the drug at ten, twenty, forty, and eighty milligrams. Sleep measurements were taken by observing patients in the lab, and by collecting sleep diaries.
Daniel Kripke, of U. But the pharmaceutical companies, and the F. That impact is assessed objectively, with electronic monitoring, and subjectively, using patient reports.
Objective data show that insomnia medications, on average, provide a gain of only ten or twenty minutes in total sleep time.
In this framework, insomnia is a condition not just of losing sleep but of being disturbed by sleeplessness. Indeed, most people with prescriptions for insomnia never visit a sleep lab, trusting their own assessment of a sleep deficit.
This emphasis on the subjective also makes the amnesiac effect of sleep drugs oddly advantageous to those who manufacture them: the drugs inhibit people from creating memories of waking during the night.
The Phase II results were strong: suvorexant worked on insomniacs. By then, the company had begun considering which of the four doses of suvorexant it should take into Phase III. The placebo effect of sleep drugs is powerful. A recent paper in the British Medical Journal suggested that it accounts for half the effect of z-drugs.
So insomnia medications need to be quite potent to distinguish themselves from a placebo in clinical trials. Merck then made an important decision. For Phase III, starting in late , it would drop ten and eighty milligrams in favor of twenty and forty milligrams, with forty regarded as the likely standard dose.
In Phase III, Merck would also test fifteen- and thirty-milligram doses on patients sixty-five and older, who were more sensitive to the drug.
The Chevy Chase sleep center, along with more than a hundred other facilities around the world, was contracted to test the four doses. Eighteen hundred patients participated in the trial. At the time, Jed Black, the Stanford sleep specialist, was on a two-year leave of absence, working full time on almorexant, the rival drug made by Actelion.
Phase III trials of the drug were under way. Black, who is back at Stanford, suspects that almorexant will be launched, and is certain that such drugs will eventually become dominant. Merck used zolpidem in two tiny studies, but not in larger ones. This omission might seem surprising. Merck scientists sometimes seemed evasive in their responses to this question, but an answer eventually came into focus. On the core issues that interest the F.
These include medical guidelines for taking an Ambien generic, its proper dosage, and side effects. Zolpidem is a prescription medication that produces a calming chemical in the brain, which helps in falling asleep faster and staying asleep longer.
Generally, zolpidem is prescribed for weeks. If you have been prescribed zolpidem, we here at Minded can answer any questions you may have. We provide information as well as assist with refills. Common side effects include drowsiness and dizziness. Other side effects may include stuffy nose and nasal irritation, dry mouth and sore throat, or gastrointestinal problems such as nausea, constipation, diarrhea, and upset stomach. You also may experience headaches, changes in your vision, muscle pain, and heart palpitations.
More serious side effects of Zolpidem include allergic reactions manifesting with a swelling of your face or tongue and breathing problems. You also may experience memory loss or become unexpectedly aggressive. Thought, mood, and behavior changes are also possible, including thoughts of harming yourself or wanting to die, agitation, loss of interest in the activities you normally enjoy, feelings of worthlessness and guilt, irrational thoughts, sleepwalking, even sleep driving , hallucinations, and having no recollection of these or other events.
As mentioned earlier, certain medications may interfere with the desired actions of zolpidem, as well as increase the risk of side effects. Anticonvulsant drugs and antibiotics, such as rifampin, rifabutin, and rifapentine, can diminish the effectiveness of zolpidem.
The medication guide that comes with your prescription provides this and other important information.
Zolpidem dosage is different for women and men. The dose may depend on the severity of your condition, your age, and any medical conditions you might have noted above. In most cases, your doctor will start you off with a lower dosage and gradually increase it, as needed.
The recommended dose for women is generic Ambien 5 mg and is 10 mg for men. Take the tablet right before bedtime and only if you have at least hours before you need to awaken. If the 5 mg dosage is not sufficient, let your doctor know so that changes might be considered.
Keep in mind that immediate release tablets generally are prescribed if a person has trouble falling asleep. If you have problems staying asleep, speak to your doctor, because there are extended-release ER tablets. Generic Ambien or zolpidem is not recommended for those younger than Research, to date, is insufficient to endorse prescribing this medication to those less than 18 years of age.
Similarly, adults over the age of 65 are prescribed lower doses because the breakdown of this and other medication s is longer than that of younger people, resulting in higher blood levels or duration in the body. Generic Ambien or zolpidem is as effective as brand Ambien for the treatment of insomnia. However, an Ambien generic is less costly than the brand name, if cost is a consideration. Consult your doctor before taking generic Ambien; provide information about medical conditions you may have as well as other medications you might be taking.
If you are currently taking zolpidem and have questions , please feel free to reach out to the professionals at Minded. We are standing by to help you navigate considering a medication as well as the prescription refill process —for zolpidem and many other mental health prescription medications. Get mental health and wellness resources delivered right in your inbox every month.
If you're having a medical or mental health emergency, call or go to your local ER.
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