Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.38623.768588.47 (Published 17 November 2005) Cite this as: BMJ 2005;331:1169
All rapid responses
Glass et al sound a note of caution about the risks of hypnotic use
in the elderly 1. In addition to the risks they studied, the problem of
creating drug dependency must be held in mind. This is particularly worth
noting in the elderly, since it is suggested that these patients have
poorer outcomes than younger adults following attempts to discontinue
benzodiazepines 2.
I audited the prescription of hypnotics to patients over the age of
65 on a psychiatry ward at Chase Farm Hospital. In my sample 13% of all
patients were discharged from hospital with hypnotics that they were not
taking on admission. Furthermore, 19% of patients who commenced a hypnotic
continued it for more than three weeks, potentially exposing them to
problems with habituation or dependency. It seemed patients were
frequently prescribed these drugs on an as required basis on admission to
hospital, without a mechanism to ensure that their use was time limited.
Since elderly patients may have long stays in hospital it is prudent to
consider ways of limiting the length of treatment before writing a
prescription.
1.Glass, J., Lanctot, K.L., Herrmann, N., Sproule, B.A. & Busto,
U.E. Sedative hypnotics in older people with insomnia: meta-analysis of
risks and benefits. BMJ 2005 331: 1169-73.
2.Atkinson, R.M. Substance abuse. In Textbook of geriatric
neuropsychiatry (2nd edn) 2000 pp 367-400 ed. C.E.Coffey &
J.L.Cummings Washington D.C.,American Psychiatric press Washingto DC.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR- I read with great interest “Sedative hypnotics in older
people with insomnia: meta-analysis of risks and benefits” by Glass et al.
The study is very relevant to current clinical practice and
demonstrates important problems associated with the use of hypnotics in
the elderly. However, it has some limitations.
In analysing the methodological quality of individual trials used in
the meta-analysis, the authors do not provide information on inter-rater
reliability. This could introduce potential bias in the analysis.
Quality of methodology of randomized trials is influenced by a set of
important factors such as method of randomization, concealment of
treatment allocation, blinding and intention to treat analysis. The
authors evaluated concealment of treatment allocation and method of
randomization for individual trials, did they however assess blinding and
intention to treat analysis? The absence of the latter two factors
certainly has important implications on the overall results of the meta-
analysis.
The authors excluded articles written in other languages apart from
English. This introduces language bias, which is an important factor that
should be addressed in systematic reviews and meta-analysis.
Importantly, the selection criteria used in the abstract of the
article “.. Randomised controlled trials of any pharmacological treatment
for insomnia for at least five consecutive nights in people aged 60 or
over with insomnia and otherwise free of psychiatric or psychological
disorders”, is inconsistent with the inclusion criteria detailed in the
body of the article, where specifically only studies in English are
selected.
The exclusion criteria most probably exclude the very patient
population who need hypnotics for psychiatric disturbances and physical
illness. This would imply that the results of this meta-analysis are most
probably not generalisable to the group of elderly patients who are most
likely to require hypnotics.
Finally, the authors’ conclusion should be interpreted with caution.
They indicate that “..the added risk of an adverse event may not justify
these benefits, particularly in a high risk elderly population..”,
however, the meta-analysis did not include or identify any high risk
group. If anything at all, the potential high risk group was excluded.
I hope this contribution is useful.
Reference Literature:
1) O Ajetunmobi. Making Sense of Critical Appraisal, Oxford
University Press Inc, 2002
2) Altman DG, Bland JM. Treatment allocation in controlled trials:
why randomise? BMJ 1999;318:1209-1209
Competing interests:
None declared
Competing interests: No competing interests
The odds ratio for psychomotor adverse effects is 2.25 (95% CI 0.93-
5.41) as per Fig 2. The Abstract, however, cites the OR as 2.61 (95% CI
1.12-6.09). This (OR 2.61) is also cited in the Discussion (p. 1172).
Which one (Figure or text) is correct?
Further, 10 out of the 24 studies mentioned in the online Table were
conducted on inpatients in various settings. The study protocol excluded
those patients "with psychiatric disorders, concurrent use of drugs
affecting the central nervous system, and severe and acute illnesses that
might disrupt sleep" (as per the online version). It would be interesting
to learn why these patients were kept as inpatients then - was it only for
insomnia? If (presumably) not so, then could the background clinical
characteristics have influenced the results?
Similarly, even if these patients were not on other drugs directly
affecting the central nervous system, could they have been on other drugs
(e,g., for cardiovascular or atherosclerotic disease etc.) that might have
an interaction with sedative-hypnotic drugs, modifying the
pharmacokinetics or dynamics of the latter?
Finallly, the duration of treatment with sedative-hypnotics ranged
from 5 days to 9 weeks. Similarly, doses of drugs varied widely too. These
variables could have influenced the results as well.
Competing interests:
None declared
Competing interests: No competing interests
The recent meta-analysis of sedative hypnotics demonstrates that
their clinical benefits are small, and that these benefits probably do not
outweigh their risks (falls and cognitive impairment)1. These data are
timely, unsurprising and randomised studies fail to show a benefit of
newer agents over more established drugs2, 3.
We have recently studied the incidence of cancer following
prescriptions for zopiclone, in a cohort of individuals with
predisposition to tumours due to infection with the human immunodeficiency
virus (HIV-1)4. While this medication has been available in Europe for
over 15 years, the S-(+)-enantiomer of this drug, eszopiclone, was
approved last year by the United States Food and Drug Administration with
a chronic use label, following clinical trials in less than 3,000
individuals. A large section of this label remarkably concerned a
discussion regarding carcinogenicity and mutagenesis5. For example, rats
fed high doses had an increase in breast adenocarcinomas and chromosomal
aberration assays were positive in vitro.
We have recently described that out of 606 individuals prescribed
zopiclone for at least 2 weeks in our cohort (6.7% of the whole cohort), a
total of 32 individuals have subsequently been diagnosed with cancer,
mainly the types one would expect to observe in the setting of
immunosuppression secondary to HIV (Kaposi’s sarcoma and non Hodgkin’s
lymphoma)4. These patients were diagnosed with cancer at least 3 months
after exposure to zopiclone and of these, 11 were diagnosed during the
highly active antiretroviral therapy era. These proportions are not
statistically higher than the ‘non zopiclone’ patients. However, there was
one case of disseminated non small cell lung cancer with a highly unusual
case of direct pericardial infiltration which led to the patient’s death.
In addition, our data only included those individuals prescribed zopiclone
from the hospital pharmacy and thus the incidence may be higher in
reality.
Zopiclone and its isomer have issues in animals and in vitro
regarding carciginogenicity and mutagenesis. This assumes increased
importance with a condition such as sleep that is not ‘a disease’ itself,
but often a derivative of one and thus drugs in this setting should be
scrutinised to a higher degree. Unusual complications or those that occur
only with long term use may not become apparent until a drug is used in
large populations for an extended length of time. As cancers in
immunocompetent people may take decades to develop, we suggest that the
incidence of cancer following prescriptions for zopiclone and its isomer,
deserves prospective attention4. Absence of evidence, is not evidence of
absence.
1. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative
hypnotics in older people with insomnia: meta-analysis of risks and
benefits. Bmj 2005.
2. Holbrook AM. Treating insomnia. Bmj 2004;329(7476):1198-9.
3. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of
benzodiazepine use in the treatment of insomnia. Cmaj 2000;162(2):225-33.
4. Stebbing J, Waters L, Davies L, Mandalia S, Nelson M, Gazzard B, et al.
Incidence of cancer in individuals receiving chronic zopiclone or
eszopiclone requires prospective study. J Clin Oncol 2005;23(31):8134-6.
5. Label for Lunesta, eszopiclone [www.sepracor.com].
Competing interests:
None declared
Competing interests: No competing interests
The authors of this paper believe that sedative hypnotic medication
in the elderly may be more trouble than its worth. The mean effect size
was small but this of course misses a hugely important clinical point
which is the overall response rate: whether the individual patient derives
a worthwhile response as defined by themselves ('better sleep') and
whether this occurs without any signficant adverse effect. If they do
'respond' then they should continue taking the drug. If they do not
respond then they should stop it. This meta-anlaysis, like many others, is
capable of only measuring generalities and misses the more important
clinical specifics. Most clinicians know that many of their patients
benefit from sedative hypnotics without suffering significant adverse
effects because we ask them.
Competing interests:
None declared
Competing interests: No competing interests
The authors worry about the effects of "sedative hypnotics" in the
elderly: should we conclude that the use of "non-sedative hypnotics" in
this population would be much safer?
Competing interests:
None declared
Competing interests: No competing interests
Neuropsychiatric reactions associated with zolpidem and zopiclone?
Zolpidem (Stilnoct® /Stilnox®/ Ambien®) has been the subject of
worldwide media attention since the publication of the Australian Adverse
Drug Reactions Bulletin 1 describing a range of distressing neurological
and psychiatric reactions associated with this drug.
Over the past three years the consumer helpline for adverse drug
reaction reporting in Australia, known as the Adverse Medicine Event Line,
has increasingly received reports of neuropsychiatric effects associated
with zolpidem including sleep-eating, sleep-driving, with two events (one
of sleep-walking and one motor bike riding) resulting in accidental
death. In 80% of these cases, the patient’s doctor was not notified of
the adverse event because the patient was too embarrassed, did not think
it was medically relevant, or they feared psychiatric assessment. In the
remaining 20%, the consumers stated their doctor did not link the reaction
with zolpidem generally because the product information did not describe
such events as driving or eating in an amnestic dissociated state as a
potential side effect.
A total of 29 reports of neuropsychiatric reactions associated with
zolpidem (n=26) and zopiclone (n=3) have now been reported to our
helpline, all of which have been reported to the Adverse Drug Reactions
Advisory Committee (ADRAC). Thus, we would like to take this opportunity
to outline the salient characteristics of these adverse events so that
prescribers may recognise them and appropriate warnings be provided to
consumers.
1) The time of onset of adverse events can be
• before the person goes to sleep, within 5-30 minutes after taking the
medication (n= 12);
• during sleep, commencing 1-3 hours after medication administration (n=
15); or
• immediately after waking the following day (n=2).
2) Resultant behaviour has fallen into three broad profiles:
• A semi-conscious, dissociated and disinhibited state sometimes referred
to amnestic automatism- The patient may look awake, but they are not
conscious of their actions. They can perform automatic behaviours such as
cooking, eating, ironing, driving; but these activities may have an
element of disinhibition e.g. performed in the nude. The following day the
patient will have fractured memory of their actions.
• A sleep-walking state- Similar to the above, but the patient is
completely amnestic the following day.
• Psychotic-like state- Sensory distortion has been reported whilst under
the influence of zolpidem (but not yet with zopiclone) including visual
and auditory hallucinations, perception of paralysis and violent vivid
nightmares. Symptoms seem to manifest when the drug is reaching peak
concentrations i.e. 1 to 2 hours after administration. The patient usually
remembers the hallucinations, but they may have coincided with
sleepwalking which they don’t remember.
3) Possible pre-disposing factors may be traumatic life stressors
e.g. divorce, psychiatric instability, or financial crisis. Such factors
may also precede hypnotic use and may be common precipitants for sleep
disorders such as somnambulism. It may therefore be prudent, therefore,
for prescribers to avoid zolpidem and zopiclone in patients experiencing
traumatic life events. Consumers with a history of psychoactive drug abuse
appear to be more prone to the hallucinatory effects reported.
4) The normal therapeutic dose, 5 to 12.5mg, was taken in 95% of
cases. This is relevant in that similar neuropsychiatric reactions have
been reported with benzodiazepines and alcohol, but usually in high or
intravenous doses.2
This case series demonstrates the valuable contribution that
consumers make to post-marketing pharmacovigilance. Zolpidem and zopiclone
have been marketed for over 10 years, but the potential for bizarre
neuropsychiatric reactions is only now coming to the attention of health
authorities. It is probably the atypical nature of the adverse events that
has prevented consumers from sharing their experience with their doctor,
whereas a pharmacist-operated telephone helpline can access this
information by providing a non-confronting, confidential channel of
communication. We believe that the neuropsychiatric adverse events
associated with zolpidem and zopiclone represent an emerging public health
problem and it is time that regulatory authorities take action.
1. ADRAC. Zolpidem and bizarre sleep related effects. Aust Adv Drug
React Bull 2007;26:2-3.
2. Ferner RE, Norman E, Rawlins MD.. Forensic pharmacology: medicines,
mayhem and malpractice. 1st ed. Oxford University Press; London, 1996:141-
9.
Acknowledgement: The AME Line is currently funded by the Pharmacy
Guild of Australia.
Competing interests:
None declared
Competing interests: No competing interests