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Hypnotic Sales Letters: 92 Hypnotic Sales Lette...

A Cornell study has identified four strategies that restaurants use to reap higher wine sales: including the wine list on the food menu; listing prices without a dollar sign; listing wines from certain wineries known for their quality; and including "reserve" wines or another special section.

Hypnotic Sales Letters: 92 Hypnotic Sales Lette...

"We've seen dozens of suggestions for how restaurateurs should present their wines," said Michael Lynn, professor of consumer behavior and marketing at the Cornell School of Hotel Administration, who conducted the study with doctoral student Sybil Yang, "but we haven't seen any research evidence of how presentations are connected with higher sales."

The researchers tested 46 different attributes of the wine lists in 270 restaurants and found that only four attributes were linked with higher sales across all the restaurants. One tactic was connected with lower sales -- using wine style (e.g., sweet, bold, dry) as an organizational category on the list.

The researchers also found that wine sales tend to decline as price increases at casual dining restaurants, but price seemed to have no relationship with sales at fine dining restaurants. They also found that having a longer wine list reaped more sales only at casual dining restaurants, where wine sales increased with the length of the list, up to about 150 wines.

Only that one of the 46 epidemiologic studies of hypnotic drugs reported any association with improved patient survival, and that one only by relying on questionable statistical adjustments20. None of the other 45 studies found hypnotic drug risk ratios significantly less than 1.0. That is, in 45 studies there was no evidence that hypnotics ever benefit patient survival. To find 44 of 46 studies showing a positive risk ratio was very highly significant, P

Of the 46 epidemiologic studies, 35 individual studies reported statistically significant mortality odds ratios, risk ratios, or hazard ratios for hypnotics exceeding 1.0. All 22 studies reporting on samples of >14,000 people found significant mortality risks, but nine of 22 smaller studies found positive trends that were not significant. Most of the non-significant reports were among the earliest 15 published before 2006. Of studies analyzing follow-ups of 8 years or less, 23 of 27 studies reported a significant association, but of studies with longer follow-ups, only 13 of 17 studies observed significant mortality risks. This may suggest that during long prospective follow-ups, many patients initially taking hypnotics will discontinue hypnotic usage, whereas many controls not using hypnotics at prospective baseline may have begun using hypnotics during a long follow-up, so that the longer the follow-up, the more mixing of hypnotic-consuming and control groups becomes likely. Mixing weakens the risk-ratio contrasts observed. In long follow-ups, one is also studying the selected survivors of the more marked short-term risks that have been recently described24,25.

The controlled-trials compilations described above did not include indiplon, an unlicensed zaleplon-like benzodiazepine agonist and hypnotic, for which studies published subsequently indicated three incident cancers in the indiplon groups and none in the randomized control groups60,61. The compilations did include cancers associated with the marketed hypnotic ramelteon that admittedly has a very different molecular mode of action from the benzodiazepine agonists.

The FDA was not persuaded that these human controlled-trials data required regulatory action, because most of the definite cancers were only minor skin cancers, because of heterogeneities in the data, and because the cancers were recognized after such short randomization periods. Nevertheless, the controlled trials data suggested more than skin cancer. There were cancers of organs apart from skin noted among those treated with hypnotics but none among those randomized to placebo. Reconsideration of FDA's deferral of action is now encouraged by new animal testing and new epidemiologic findings: over half of the research referenced in this manuscript appeared after that FDA deferral of action.

Some studies have appeared designed to show that a hypnotic reduced depression scores among patients given an antidepressant known to cause insomnia92,93. In the first of these studies, the benefit of the hypnotic for depression was not significant at week 4 after the investigators removed the rating scale items related to insomnia, whereas the week 8 benefit was nominally significant only at the P=0.04 level not correcting for multiple comparisons. In other words, using rigorous Bonferroni correction for multiple comparisons, the alleged benefit of hypnotic for depression symptoms was not significant. In a second study the authors more readily conceded that the hypnotic had no significant benefit for depression. These studies failed to rebut the evidence that hypnotics cause new depressions.

Some crashes result in deaths of passengers and other-vehicle occupants not themselves using hypnotics, but non-driver deaths are not attributed to the hypnotics on death certificates. One study found that use of benzodiazepines and "Z" hypnotics was increased among victims of homicide as well as among the homicide perpetrators130. Thus, both through bad driving and homicides, hypnotics result in deaths that have not been accounted directly as deaths from these hypnotic drugs.

A new Comparative Effectiveness Review sponsored by the U.S. AHRQ has recently examined theManagement of Insomnia Disorder, largely referring to chronic insomnia177. As a prepublication Peer Reviewer of this report, I was and still remain very critical of its limitation to mainly-subjective data that are known to give a rosier evaluation of hypnotic effects than objective evaluations, its focus on published reports that are known to be commonly biased towards reporting favorable drug results178,179, and the AHRQ report's incomplete attention to adverse effects. Nevertheless, it was striking that the AHRQ study found that the strongest evidence for treatment efficacy was with the cognitive-behavioral treatment of insomnia. The evidence for short-term efficacy of zolpidem and eszopiclone in high doses was considered less sufficient, and evidence for efficacy of other hypnotics was judged to be almost entirely insufficient. Moreover, by its clinical trial selection criteria, this Review found essentially no evidence for efficacy of the very low doses of zolpidem and eszopiclone currently recommended by the FDA for most patients, because higher doses appeared unsafe to FDA. In short, the AHRQ study presented no reason why hypnotics are needed, since cognitive-behavioral treatment of insomnia is better. The AHRQ Review found evidence for increased adverse effects with hypnotics compared to placebo, including hypnotic adverse effects of concern (their selection of studies highlighted fractures and dementia)180. This means that patients randomly treated with hypnotics tended to develop more illness and symptoms, quite the opposite of promoting health. The Review found mention of adverse effects virtually absent for the cognitive-behavioral treatment studies177. Although the Comparative Effectiveness Review found insufficient studies to estimate the comparative effectiveness of hypnotics versus cognitive-behavioral treatments, when it reviewed potential harms, there was no contest. Moreover, controlled trials reviewed above prove that hypnotics cause comorbidities such as infection and depression and driving impairments, whereas cognitive-behavioral treatment has been found to decrease medical comorbidities such as depression89.

Whatever weak evidence for benefits of hypnotics there has been came mainly from carefully selected groups of patients with diagnosed insomnia and few if any comorbidities or contraindications, and who generally did not use opiates or other sedatives or excess alcohol181. There are no clinical trials data demonstrating benefit among patients with multiple comorbidities and contraindications while lacking diagnosed insomnia, but such vulnerable patients are the majority of patients receiving hypnotics.

A new randomized trial of CBT for insomnia showed that whereas zolpidem 10 mg. taken during the first few weeks added somewhat to benefits of CBT, those continuing on zolpidem slept worse on follow-ups of 6 months, 1 year, and 2 years183. This is one of the first randomized trials with long-enough follow-up to show that in the long run, a hypnotic made sleep subjectively worse.

Contrasting with the dubious benefits, the popular benzodiazepine agonists in the U.S. are associated with increased mortality hazards, comparable to the hazards of barbiturates. Medical examiner data document that over 10,000 deaths every year are directly caused by and attributed to hypnotic drugs, and there is substantial evidence that hypnotics cause additional covert respiratory depression, suicides, infection, cancer, accidents, and other disorders that lead to a far larger number of deaths as well as to non-fatal morbidities and suffering. The exact number of deaths caused by hypnotics cannot be estimated from medical examiner data alone147, because most of the deaths produced by hypnotics are covert or indirect due to hypnotic-induced or hypnotic-exacerbated morbidities.

This presentation has focused primarily on zolpidem, temazepam, eszopiclone, zaleplon, triazolam, flurazepam, quazepam, and barbiturates used for sleep (such as pentobarbital, amobarbital, and secobarbital). These drugs were the focus because each had been shown epidemiologically to be associated with high mortality hazards26. This presentation has not focused on other drugs used as hypnotics, either because the epidemiologic and controlled-trials data have not been sufficient to assess their risks as hypnotics or because these drugs are approved and may be effective for indications other than insomnia. Alternative hypnotics approved for treating insomnia in the U.S. include diphenhydramine, ramelteon, doxepin, and suvorexant. Moreover, other drugs commonly available for sleep include trazodone (off label) and melatonin (unregulated). The advantage of alternative drugs is that their risk-benefits ratios are less clearly known to be unfavorable, but the alternative drugs certainly have serious risks140. 041b061a72


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