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New study finds big risk for sleeping pills
 
 
  New study finds big risk for sleeping pills

"Patients with prescriptions for hypnotics had approximately 4.6 times the hazard of dying over an average observation period of 2.5 years as compared to non-users. These findings were robust with adjustment for multiple potential confounders and consistent using multiple strategies to address confounding by health status. A dose-response effect was seen. Among users in the highest tertiles of annualised dosages, the HRs for death were 5.3, 5.7 and 6.6, respectively, for all hypnotics, zolpidem alone and temazepam alone. This top third of users were prescribed 92.8% of all the prescription doses of hypnotics (supplemental figure 2). Those in the top third were also 35% more likely to develop a new major cancer........Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using <18 hypnotic pills per year. Several strategies to discover biases that could account for this hazard, even at low levels of use, revealed none. Nonetheless, some residual confounding is inevitable in our results as a consequence of factors that were inadequately assessed. However, considering the minimal impact of the major confounders for which we did control upon the HRs, we think it unlikely that confounding explains the high mortality that we found associated with hypnotics........The meagre benefits of hypnotics, as critically reviewed by groups without financial interest,21 30 39 would not justify substantial risks. A consensus is developing that cognitive-behavioural therapy of chronic insomnia may be more successful than hypnotics.40 41 Against meagre benefits, it is prudent to weigh the evidence of mortality risks from the current study and 24 previous reports, in order to reconsider whether even short-term use of hypnotics, as given qualified approval in National Institute for Clinical Excellence guidance,39 is sufficiently safe."

(CBS News) A controversial new study suggests that taking Ambien, Lunesta or other prescription sleep aids may actually dramatically increase your risk of death. The study is alarming, but scientists don't really know what is going on, Dr. Carl Bazil, a neurologist and director of Columbia University's Comprehensive Epilepsy and Sleep Center, said on "CBS This Morning." "There's no question that sleeping pills are over-prescribed," Bazil said. "I think that's one thing that will come out of this. But why the association is there, we don't know. Bazil explained the study simply shows that if you get a prescription for sleeping pills, for whatever reason, you have an increased risk of death. However, other factors, such as a patient's symptoms, may contribute to the higher risk. "There are a lot of unknowns, " Bazil said. "But it is a little bit frightening." "It's not necessarily the pill that's causing the problem," he said. "I think there is an association that they saw with higher doses, and you can certainly see that. If you're overusing sleeping pills, you're going to be drowsy. You might be driving with it, you have other kinds of accidents. That's clearly a problem that needs to be dealt with."

Do people who are currently taking sleeping pills need to be worried?

"I think you always need to weigh the risks versus the benefits," Bazil said. "If there are other ways to help with your sleep, other than taking pills, that's often a better solution."

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Even Low Doses of Sleeping Pills Triple Death Risk

theatlantic.com By Hans Villarica

Feb 28 2012, 7:00 AM ET

Common hypnotic drugs like Ambien, Sonata, and Lunesta may significantly increase mortality and cancer risk, new research suggests.

PROBLEM: In 2010, nearly one in 10 adults in the U.S. took sleeping pills. But how safe are they?

METHODOLOGY: Researchers at the Scripps Clinic Sleep Center tracked the survival of 10,529 people who were prescribed sleeping pills for an average of 2.5 years. They compared these subjects, whose average age was 54, to 23,676 people who had not been prescribed sleeping pills over the same period. They also adjusted the data to account for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use, and previously diagnosed cancer.

Some of the drugs tested in the trial were temazepam (Restoril), zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata).

RESULTS: Those prescribed fewer than 18 doses of sleeping pills a year were more than 3.5 times as likely to die as those in the control group. Moreover, the risk of death of moderate (18 to 132 doses) and heavy users (132+ doses) were four and five times greater than that of non-users, indicating that the risk level rose in tandem with increasing doses. Heavy users were also at higher risk of developing several types of cancer.

CONCLUSION: Sleeping pills are associated with a more than threefold increase in mortality risk, even if seldom used.

IMPLICATION: Alternatives to hypnotic drugs for the treatment of insomnia may be warranted, the authors say in a statement. Their journal editor, Trish Groves, agrees: "Although the authors have not been able to prove that sleeping pills cause premature death, their analyses ... raise important concerns and questions about the safety of sedatives and sleeping pills."

SOURCE: The full study, "Hypnotics' Association With Mortality or Cancer: A Matched Cohort Study," is published in the journal BMJ Open.

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Sleeping pills 'linked to increased death risk'

By Michelle Roberts Health reporter, BBC News

Many sleeping tablets are only available on prescription

Sleeping pills used by thousands of people in the UK appear to be linked with a higher death risk, doctors warn.

The American study in BMJ Open compared more than 10,000 patients on tablets like temazepam with 23,000 similar patients not taking these drugs.

Death risk among users was about four times higher, although the absolute risk was still relatively low.

Experts say while the findings highlight a potential risk, proof of harm is still lacking.

They say patients should not be alarmed nor stop their medication, but if they are concerned they should discuss this with their doctor or pharmacist.

UK guidelines for NHS staff say hypnotic drugs should only be used for short periods of time because of tolerance to the drug and the risk of dependency. But they make no mention of an associated death risk, despite other studies having already reported this potential risk.

The Medicines and Healthcare products Regulatory Agency said it would consider the results of this latest study and whether it has any implications for current prescribing guidance.

"The study needs to be replicated in a different sample and I think we need to hold judgement until we have further studies"

Malcolm Lader Professor of clinical psychopharmacology at the Institute of Psychiatry at King's College London

Millions prescribed

In 2010 in England, there were 2.8 million prescriptions dispensed for temazepam and almost 5.3 million for another common sleeping pill called zopiclone.

There were also more than 725,000 prescriptions dispensed for zolpidem and more than 9,400 for zaleplon, two other drugs in this same family.

The latest study looked at a wide range of sleeping pills, including drugs used in the UK, such as benzodiazepines (temazepam and diazepam), non-benzodiazepines (zolpidem, zopiclone and zaleplon), barbiturates and sedative antihistamines.

The investigators, from the Jackson Hole Centre for Preventive Medicine in Wyoming and the Scripps Clinic Viterbi Family Sleep Centre in California, found that people prescribed these pills were 4.6 times more likely to die during a 2.5-year period compared to those not on the drugs.

Overall, one in every 16 patients in the sleeping pill group died (638 out of 10,531 in total) compared to one in every 80 of the non-users (295 deaths out of 23,674 patients).

This increased risk was irrespective of other underlying health conditions, such as heart and lung diseases, and other factors like smoking and alcohol use, which the researchers say they did their best to rule out.

The researchers say it is not yet clear why people taking sleeping tablets may be at greater risk.

The drugs are sedating and this may make users more prone to falls and other accidents. The tablets can also alter a person's breathing pattern as they sleep and they have been linked to increased suicide risk.

'Meagre benefits'

In this latest study, those taking the highest doses of sleeping tablets also appeared to be at greater risk of developing cancer.

The researchers say: "The meagre benefits of hypnotics, as critically reviewed by groups without financial interest, would not justify substantial risks."

They say even short-term use may not be justifiable.

But Malcolm Lader, professor of clinical psychopharmacology at the Institute of Psychiatry at King's College London, said people should not panic as a result of the findings.

"The study needs to be replicated in a different sample and I think we need to hold judgement until we have further studies.

"What we don't want is people stopping sleeping tablets and then going through a very disturbing period of insomnia.

"People should discuss this with their GP but should not under any circumstances stop taking their medication."

Nina Barnett, of the Royal Pharmaceutical Society, said: "This is an important study and although it is unlikely to radically change prescribing in the immediate term, it should raise awareness and remind both patients and prescribers to the potential risks of sedative use for insomnia.

"The association between mortality and sedation is not new and this research tells us that people who took these medicines were more likely to die than people who didn't take them.

"However it does not mean that the deaths were caused by the medicine."

A spokesman for the Association of the British Pharmaceutical Industry said the safety of medicines was closely monitored and continued even after regulatory approval.

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BMJ

Hypnotics' association with mortality or cancer: a matched cohort study

Abstract


Objectives An estimated 6%-10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.

Setting A large integrated health system in the USA.

Design Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.

Subjects Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.

Main outcome measures Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.

Results As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4-18, 18-132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose-response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.

Conclusions Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

Article summary

Article focus


· Estimate the mortality risks associated with specific currently popular hypnotics in a matched cohort design, using proportional hazards regression models.

· Estimate the cancer risks associated with specific currently popular hypnotics.

· Explore what risk associated with hypnotics can be attributed to confounders and comorbidity.

Key messages

· Patients receiving prescriptions for zolpidem, temazepam and other hypnotics suffered over four times the mortality as the matched hypnotic-free control patients.

· Even patients prescribed fewer than 18 hypnotic doses per year experienced increased mortality, with greater mortality associated with greater dosage prescribed.

· Among patients prescribed hypnotics, cancer incidence was increased for several specific types of cancer, with an overall cancer increase of 35% among those prescribed high doses.

Strengths and limitations of this study

· Design strengths included matching patient and control cohorts by age, gender and smoking. Through stratified statistical analyses, patients using hypnotics were matched with controls diagnosed with the exactly the same combination of 12 categories of comorbidity in up to 116 strata.

· The major limitation was that residual confounding could not be fully excluded, due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance.

· Cohort studies demonstrating association do not necessarily imply causality, but the preferable randomised controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations.

Introduction

Hypnotic drugs are among the most widely used treatments in adult medicine. We estimate that approximately 6%-10% of US adults used these drugs in 2010, and the percentages may be higher in parts of Europe.1 2 By 1979, the Cancer Prevention Study I of the American Cancer Society had found that both cigarette smoking and hypnotic consumption were associated with excessive deaths,3 4 but the hypnotic findings were discounted since the Cancer Prevention Study I was not designed primarily to study these drugs.

At least 24 published studies have now examined mortality associated with hypnotic consumption (supplemental table 1). Of the 24 cited, 18 reported significant (p<0.05) associations of hypnotic usage with increased mortality. Lack of uniformity of measured elements makes it impossible to incorporate the majority of these studies into a meta-analysis. Nevertheless, of 22 reports from which a risk or hazard ratio (HR) for hypnotic-associated deaths could be estimated, 21 observed a risk exceeding 1.0 (p<0.001). One study observed a RR of 1.0 associating total mortality with hypnotics but found hypnotic use significantly associated with cancer mortality.5 Three other studies have reported an association of hypnotics with cancer deaths.6-8 These studies generally failed to report the specific hypnotic drugs used by the participants, often confounded hypnotics with tranquilisers not marketed for treatment of insomnia, and usually omitted monitoring of the quantities of hypnotic drugs provided participants during the follow-up intervals. Moreover, previous studies had insufficient data on the short-acting benzodiazepine agonists such as zolpidem, zaleplon, and eszopiclone that now dominate the US market because their shorter duration of action is believed to provide improved safety.

Using data from longitudinal electronic medical records maintained by a large integrated US health system, the authors planned a matched cohort study to contrast mortality and cancer associations of zolpidem and other new short-acting hypnotics with controls and with older hypnotics.

Results

Zolpidem was the most frequently prescribed hypnotic drug during the study interval from 2002 to 2006, and temazepam was the next most common. Table 1 describes the characteristics of the study sample, including details by categories of hypnotic used. The hypnotic user and control cohorts were well matched in age, gender, period of observation and BMI, and did not differ importantly in ethnicity, marital status or smoking status.

Table 2 presents the rates of comorbidities, including incident diagnoses. These data indicated greater comorbidity among hypnotic users for each class of diagnoses, except for dementias. For most diagnoses, there was greater comorbidity among hypnotic users before the period of observation, and greater new comorbidity incidence during the period of observation (supplemental tables 4-6.)

Associations between hypnotic use and death

Associations between hypnotic prescriptions and deaths from Cox proportional hazards models stratified by comorbidity classes are presented in table 3. Patients prescribed any hypnotic had substantially elevated hazards of dying compared to those with equivalent comorbidity who took no hypnotics. Importantly, the death hazard was evident even in the lowest tertile of use. Compared with non-users, patients prescribed 1-18 pills of any hypnotic per year had a HR for death of 3.60 (95% CI 2.92 to 4.44). HRs increased further in the second and third tertiles of estimated pills consumed at 4.43 (95% CI 3.67 to 5.36) and 5.32 (95% CI 4.50 to 6.30). For use of zolpidem, the HR in the lowest tertile (5-130 mg/year) was similar, 3.93 (95% CI 2.98 to 5.17), and not significantly different from the HR for the lowest tertile of temazepam, 3.71 (95% CI 2.55 to 5.38), with exposure to 10-240 mg/year. For any hypnotic, or for zolpidem or temazepam specifically, the hazards of death in the middle tertiles of use were four to five times higher in users compared to non-users, and the hazards in the highest tertiles were five- or sixfold greater than those in non-users, indicating dose-response relationships for zolpidem and temazepam specifically and for any hypnotic.

The death HR associated with prescriptions for less commonly prescribed hypnotic drugs were likewise elevated, and the confidence limits of death hazards for each other hypnotic overlapped that for zolpidem, with the exception of eszopiclone, which was associated with higher mortality (see supplemental files).

Figure 1 shows that the hazards of hypnotics were seen in every age group. Whereas the absolute magnitude of the added hazards associated with hypnotics increased with age, as did the survival risks of hypnotic-free controls, the ratio of death hazards of hypnotic users compared to non-users was greater in users aged 18-55 years than in older groups (supplemental files).

hypo.gif

Figure 1

Survival curves for patients prescribed no hypnotic are compared with survival curves for patients prescribed hypnotics, divided into four age groups (age at commencement of period of observation). These curves were derived from a special Cox proportional hazards model in which those taking and not taking hypnotics in the four age groups were coded as eight categories of an independent predictor variable. The curves represent the fraction of patients surviving over the increasing years of observation until censored (died, lost to follow-up or end of observation). Those censored <0.23 year of observation were excluded. The red curves represent the fact that a higher percentage of hypnotic users died during the observation periods and fewer survived. Each curve was adjusted for covariates except age (which shared excessive colinearity with the age-based categories) and was adjusted for comorbidity strata.

Models addressing potential confounding of mortality association by health status

To further address the possibility that hypnotic-associated hazards were due to use of hypnotic drugs by patients with a greater burden of disease, so that elevated risks of death might be attributable to comorbidities rather than to hypnotic medications, we conducted analyses within subgroups of hypnotic non-users and users defined by diagnoses in specific disease classes (supplemental table 7). Allowing for differences in sample size, hazards in subgroups restricted to patients with specific diseases were generally consistent with the overall findings. We also observed no statistically reliable differences in death HR in subgroups constructed to assess the overall burden of disease by stratifying on the total number of comorbidities diagnosed for each patient, and no reliable differences in death HR comparing groups diagnosed with different numbers of comorbidity classes. Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls (table 1), adjustment for all covariates (eg, age, gender, BMI, smoking) with stratification by comorbidities only reduced the overall HR to 4.56 (95% CI 3.95 to 5.26).

Associations between hypnotic use and incident major cancer

Since prior studies suggested an association between hypnotics and deaths from major cancers, we constructed Cox models for major cancer incidence (ie, excluding non-melanoma skin cancer incidence) and excluding all patients who had major cancers diagnosed before the period of observation. As shown in table 3, there were modestly increased statistically significant cancer HRs for those prescribed any hypnotic compared to non-users, with the middle and highest tertiles having cancer HRs of 1.20 (95% CI 1.03 to 1.40) and 1.35 (95% CI 1.18 to 1.55), respectively. The association with zolpidem was significant for the highest tertile. The HRs for temazepam were significant for the middle tertile and the highest tertile. The cancer HR of 1.99 (95% CI 1.75 to 2.52) for the highest tertile of temazepam was significantly greater than the corresponding HRs for zolpidem or for all hypnotics combined.

Discussion

Patients with prescriptions for hypnotics had approximately 4.6 times the hazard of dying over an average observation period of 2.5 years as compared to non-users. These findings were robust with adjustment for multiple potential confounders and consistent using multiple strategies to address confounding by health status. A dose-response effect was seen. Among users in the highest tertiles of annualised dosages, the HRs for death were 5.3, 5.7 and 6.6, respectively, for all hypnotics, zolpidem alone and temazepam alone. This top third of users were prescribed 92.8% of all the prescription doses of hypnotics (supplemental figure 2). Those in the top third were also 35% more likely to develop a new major cancer.

Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using <18 hypnotic pills per year. Several strategies to discover biases that could account for this hazard, even at low levels of use, revealed none. Nonetheless, some residual confounding is inevitable in our results as a consequence of factors that were inadequately assessed. However, considering the minimal impact of the major confounders for which we did control upon the HRs, we think it unlikely that confounding explains the high mortality that we found associated with hypnotics.

Multiple causal pathways by which hypnotics might lead to mortality have been demonstrated. Though the acute lethality of benzodiazepine agonists seems less than that of barbiturates, it has been demonstrated in animals given high doses of benzodiazepine agonists, especially in combination with alcohol. Moreover, benzodiazepines and agonists are often present in mixed-drug overdoses.10 11 Compilation of randomised controlled trials has shown that hypnotics increase incident depression.12 Several non-randomised studies have reported an increase in suicide associated with hypnotics use,8 13-15 and depression may increase mortality through other mechanisms besides suicide.16 17

Controlled trials show that hypnotics impair motor and cognitive skills, such as driving.18 Hypnotics have been associated with increased automobile crashes and an increase in falls, due to hangover sedation.19-22 In some patients, hypnotics increase sleep apnoea, prolong apnoeas or suppress respiratory drive, though among other patients, there may be mild improvement.23-25 Sleep apnoeas, in turn, may lead to motor vehicle crashes, hypertension, heart failure, arrhythmias, cardiovascular diseases and death.26 Hypnotics may cause somnambulistic night-eating syndromes resulting in poor diet and obesity27 as well as other automaton-like behaviours, which can be dangerous.28 29 Indeed, in controlled trials, participants randomised to hypnotics experience more adverse medical events overall than those randomised to placebo.21 30

Zolpidem has been shown to increase gastroesophageal regurgitation.31 In our sample, hypnotic prescriptions were associated with increased diagnoses of oesophageal regurgitation and peptic ulcer disease (supplemental files). Increased regurgitation could cause oesophageal damage and cancer. In randomised controlled trials, patients receiving hypnotics reported significantly more infections.32 Joya et al32 inferred that increased upper respiratory irritation and infection might result from the increased gastroesophageal regurgitation caused by hypnotics. Infections, in turn, are major causes of mortality and cancer.33

Sparse data from randomised controlled trials of hypnotics suggested increased rates of cancer,34 and those findings are supported by studies demonstrating carcinogenic effects of hypnotics in laboratory rodents and by evidence that hypnotics can cause chromosomal damage.34 Our finding that for lymphomas, lung, colon and prostate cancers, the HR for hypnotic usage was even greater than the HR for current smoking (supplemental table 11) argues for specific biologic mechanisms. It is possible that patients receiving hypnotics experienced more medical care than non-users, providing greater surveillance and potential cancer detection as contrasted to non-users, even though the Cox models matched users and non-users by numbers of comorbidities. However, it would be hard to imagine how greater surveillance of hypnotic users could explain two- to threefold higher HR for some cancers with no excess mortality for other cancers (see supplemental table 11), whereas specific biological effects of hypnotics would more plausibly explain the differences in HR between cancers.

In addition to the residual confounding discussed above, the data available for this study had further limitations, which should be noted. Importantly, the EHR provided information on medication orders but not on dispensing. Accordingly, we were unable to verify that the medications ordered were dispensed by a pharmacy, and, if dispensed, whether the patient ingested the prescribed hypnotic. Moreover, controls not receiving hypnotic prescriptions might have taken hypnotics prescribed for others or over-the-counter antihistamine sleep drugs equivalent to prescribed antihistamines. Such errors of overestimation of hypnotic consumption among users or underestimation among controls would lead to underestimation of the true hypnotic hazards.

We were unable to control for depression, anxiety and other emotional factors because of Pennsylvania laws protecting the confidentiality of these diagnoses. However, several previous studies reporting hypnotic risks have controlled for these confounders.7 35 Mallon et al found that when depression, hypnotic use and other risk factors were entered into a multivariate model for all-cause mortality, hypnotic use was the strongest risk factor among men (stronger than cigarette smoking). In that analysis, depression was not an independent risk factor for death in either men or women.7 Moreover, one might expect an emotional confounder to cause insomnia, leading, in turn, to use of hypnotics, but several large studies have reported that insomnia is not a significant mortality risk factor, especially when hypnotic usage is controlled.7 35-37 Nevertheless, to the extent that social and psychological problems lead patients to receive hypnotics, and to the extent that these problems cause death through pathways independent of hypnotics, our findings might reflect some confounding by those conditions.

Conclusions

Rough order-of-magnitude estimates at the end of the supplemental files suggest that in 2010, hypnotics may have been associated with 320 000 to 507 000 excess deaths in the USA alone. From this non-randomised study, we cannot be certain what portion of the mortality associated with hypnotics may have been attributable to these drugs, but the consistency of our estimates across a spectrum of health and disease suggests that the mortality effect of hypnotics was substantial. Even 10 000 yearly excess deaths caused by hypnotics would be too many.

A randomised clinical trial of sufficient duration and size could provide definitive evidence for or against the disturbing mortality hazards suggested by our study. Some American NIH reviewers have opined that a randomised trial of hypnotic lethality would be unethical. No such trial has ever been mounted, perhaps for reasons similar to the absence of randomised trials of cigarettes and of skydiving without parachutes.38 Absent randomised trials of sufficient dimensions, we must be guided by observational data for hypnotics, as we have been guided by similar data for cigarettes.

Excess mortality is associated with hypnotic use. Hypnotic users had more prevalent disease of many sorts than non-users before hypnotics were ordered. However, the consistent results across varying levels of comorbidity and the persistent elevated hazards within strata of users and non-users matched for comorbid diagnoses strongly suggest that neither the level of individual health nor the presence of particular categories of comorbidity explains the bulk of the hazard associated with the use of hypnotic medications.

The meagre benefits of hypnotics, as critically reviewed by groups without financial interest,21 30 39 would not justify substantial risks. A consensus is developing that cognitive-behavioural therapy of chronic insomnia may be more successful than hypnotics.40 41 Against meagre benefits, it is prudent to weigh the evidence of mortality risks from the current study and 24 previous reports, in order to reconsider whether even short-term use of hypnotics, as given qualified approval in National Institute for Clinical Excellence guidance,39 is sufficiently safe.

 
 
 
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