Benzodiazepines, OTCs Are As Effective As Newer Rx Sleep Agents - Article

Newer insomnia treatments are no more effective than benzodiazepines and OTC antihistamines, Consumer Reports' August 2006 "Best Buy Drugs" report says.

"There have been very few studies that have directly compared the newer drugs to the older ones and many researchers and doctors believe the case has never been made that the newer drugs are any better or safer," the report says.

"While effective, these medicines are not necessarily better than older, less expensive drugs for many people who need a sleep aid for a night or two."

"For example, non-prescription drugs containing certain antihistamines (such as Benadryl , Nytol , Sominex , Tylenol PM and Unisom ) and older sedatives called benzodiazepines may work just as well," the report says.

The report reviewed five newer prescription insomnia therapies: Sanofi-Aventis' Ambien (zolpidem) and Ambien CR (extended-release zolpidem), Sepracor's Lunesta (eszopiclone), Takeda's Rozerem (ramelteon) and King's Sonata (zaleplon). Consumer Reports selected Ambien as its "Best Buy."

The Best Buy Drugs report is part of a series of studies funded by a grant from the Engelberg Foundation and the National Library of Medicine.

While Consumer Reports states that the newer insomnia agents are "generally as effective" as benzodiazepines, it says "there is ongoing debate about whether they are more effective."

"Older benzodiazepines remain very useful in some circumstances, specifically in treating people who have an anxiety disorder that is also making sleep difficult."

"If you have been diagnosed with anxiety and suffer from insomnia, talk with your doctor about trying a benzodiazepine first, before trying one of the newer and more expensive sleeping pills," the report advises.

While the report says that the newer agents have not been shown to be more efficacious than older therapies, it suggests they may have more favorable side effect profiles.

"Several studies indicate that the older medicines cause more day-after sleepiness and grogginess, and are associated with a higher risk of dependency and what doctors call rebound insomnia."

"All four of the medicines are somewhat less likely to cause dependence than the older insomnia medicines...and that might be their biggest advantage." The report notes, however, that there have been cases of abuse with Ambien.

Consumer Reports cautions that "while the newer drugs may produce fewer side effects than older sleeping pills, they still have side effects and safety issues" including daytime sleepiness, cognitive impairment, dizziness, unsteadiness and loss of coordination.

In addition, the newer products have also been associated with rare instances of "sleep-walking (or sleep driving), temporary amnesia or memory lapses and hallucinations." Sanofi is the subject of a class action lawsuit alleging that the firm failed to warn Ambien patients of the risk of sleep walking and sleep eating (¹ (Also see "Ambien Class Action Suit May Serve As Wake-Up Call For Competitors" - Pink Sheet, 20 Mar, 2006.), p. 18).

"Health authorities have not yet fully studied the potential for these problems," the report notes. While these side effects are rare, the reports "should serve as a caution that some people respond idiosyncratically to drugs that affect the brain."

In an accompanying article in the September 2006 issue of Consumer Reports Magazine, the consumer group notes that a review of FDA's Adverse Event Reporting System found Ambien and Lunesta were cited as the "as the primary drug" in 150 adverse event reports coded as "confusion, aggression, hallucination and injury," resulting in 70 hospitalizations and nine deaths.

With respect to how the newer prescription therapies stack up to OTC antihistamines, the report says that the OTC agents are as effective as the prescription products for minor insomnia conditions.

"People with very mild transient insomnia may do just as well to take an older (sedating) non-prescription antihistamine for a night or two," the report says.

However, the article says that patients should not use OTC agents for the management of chronic insomnia. For chronic insomnia, behavioral therapy works 70%-80% of the time and is "absolutely an alternative to sleeping pills for people with intermittent to chronic insomnia."

For patients 55 years or older, avoidance of sleeping medications is recommended altogether except when absolutely necessary. In addition, the new insomnia agents cause more side effects in the older population and, therefore, patients should use a lower starting dose, the report says.

Consumer Reports' choice of Ambien as its Best Buy was primarily based on zolpidem's upcoming loss of patent exclusivity in October.

"When that happens, generic zolpidem will be substantially less expensive than Ambien and the other three medicines. The cost will either drop right away or in about six months," the report notes.

"We would urge you to talk to your doctor about the impending availability of generic zolpidem. There's no reason to switch now, but you may want to try Ambien instead in the coming months to see if it works for you," the report says.

The choice was also "driven, in part, by evidence showing that Ambien is as effective - or in some studies more effective - than the others."

The report notes that "the evidence is weak that Ambien CR is all that much better than Ambien. And for people whose main problem is getting to sleep, Ambien CR probably offers no advantage at all."

Of the five newer sleeping agents, the report says that Ambien and Sonata act more quickly and are more effective at inducing sleep, with Sonata bringing about sleep 17 minutes faster than Ambien on average. Other studies found that Ambien is better for extending sleep duration, the report adds.

Lunesta, on the other hand, "acts a bit more slowly in the body and thus is slightly less effective at helping you get to sleep." This, in theory, could help patients stay asleep for longer, the report notes.

Rozerem - which targets the receptor for melatonin in the brain instead of targeting the GABA-receptor as the other agents do - appears "to be somewhat less effective than the others in helping people fall asleep" despite a lack of data, the report notes.

With regard to side-effect profiles, Ambien CR and Lunesta were found to cause more next day drowsiness relative to the other drugs. Rebound insomnia occurred in patients receiving Ambien CR, Ambien and Lunesta, but not in patients receiving Sonata and Rozerem.

Rozerem faired better on dependency profile, with the report noting that it "could be an advantage for use in treating people who have dependency problems or a history of drug abuse." Ramelteon is the only one of the four compounds that is not a controlled substance (² (Also see "Takeda To Highlight Rozerem Melatonin Receptor Mechanism Of Action" - Pink Sheet, 1 Aug, 2005.), p. 16).

In the article accompanying the report, "Sleeping pills: Are they worth the risks?" the consumer group suggests that Americans may be overusing sleep therapies, primarily as a result of a recent increase in direct-to-consumer advertising in the category.

"Americans may be jumping to sleeping pills too soon when safer remedies are available," the article says. "Most sleeping pills have side effects ranging from dependency to rebound insomnia....Yet, drug ads imply that medication is the best remedy for sleep problems."

The articles notes that Lunesta was the most frequently advertised drug in 2005, which prompted Sanofi to increase consumer advertising for its Ambien franchise. "The ad blitz may be working. Pharmacists filled 43 mil. prescriptions for sleep drugs in 2005; that's a 32% increase from 2001."

The article includes a critical review of a Lunesta TV commercial, implying that it violates the Pharmaceutical Research & Manufacturers of America's DTC principles by failing to inform patients of other treatment options that exist. The spot also understates Lunesta's safety issues and overplays its benefits, the article maintains.

The PhRMA guidelines went into effect in January (³ (Also see "DTC Guideline Implementation: Does “Ask Your Doctor” Spark A Dialogue?" - Pink Sheet, 22 May, 2006.), p. 27). Sepracor adopted the DTC principles in August 2005 and has recently said that it would increase Lunesta promotion spend following Pfizer's decision to pull out of a partnership with Neurocrine to develop an insomnia agent after a "not approvable" action from FDA (⁴ (Also see "Pfizer Drops Out Of Indiplon Development; Neurocrine To Seek New Partner" - Pink Sheet, 26 Jun, 2006.), p. 10).

Physician advertising and marketing efforts and sampling programs may also be contributing to the jump in script growth, the article ads.