Treating insomnia
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.329.7476.1198 (Published 18 November 2004) Cite this as: BMJ 2004;329:1198
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EDITOR - Anne Holbrook is to be congratulated on her editorial(1),
for highlighting the lamentable lack of controlled trials on the long-term
effects of sleeping tablets, and for bolstering the courage of the doctor
who wants to resist the seductive request of the patient for a
prescription. It is one thing not to harm the patient, but more difficult
to refrain from harm when the patient is pressing for it. We have an
injunction not to harm our patients – primum non nocere – and perhaps we
should have a supplementary injunction not to harm them even, and perhaps
especially, when they request it – primum non nocere, et volens patiens –
some scholar might hopefully improve on my schoolboy Latin.
1 Holbrook A. Treating insomnia: use of drugs is rising despite
evidence of harm and little meaningful benefit. BMJ 2004;329:1198-1199.
Competing interests:
None declared
Competing interests: No competing interests
Holbrook's editorial although presumably prompted by the NICE report was immediately reminiscent of one written in the BMJ 110 years ago:
"The subject of sleeplessness is once more under public discussion. The hurry and excitement of modern life is quite correctly held to be responsible for much of the insomnia of which we hear: and most of the articles and letters are full of good advice to live more quietly and of platitudes concerning the harmfulness of rush and worry. The pity of it is that so many people are unable to follow this good advice and are obliged to lead a life of anxiety and high tension. Hence the search for some sovereign panacea ... "
Whilst that editorial predated barbiturates it does seem to resonate a little with the notion that a panacea like 'cognitive behaviour therapy' might not be? The older editorial continues: "There can, however, be no doubt that different remedies suit different cases." And that's an important problem - insomnia is not a single entity and unless one bludgeons the brain into submission there are no panaceas nor simple outcome measures and sadly nor are there likely to be with the current economic and regulatory controls of medicines. What may be needed is: 1) a better classification of 'insomnia,' and 2) why do patients who do not become tolerant find sleeping pills nice?
Whilst the NICE review did its best the fundamental problem is that imperfect outcome variables are used to measure a heterogenous condition, which probably leads to lack of discrimination between treatments.
One pernickety point: surely it should be 'z' drugs not 'Z' drugs. Isn't the convention to have generic names lower case and trade names to be capitalised?
- SEPT. 29, 1894 Page 719 The British Medical Journal - Sleeplessness
Competing interests:
Hard to know which: have worked for most organisations involved, written books on insomnia, contributed to NICE evaluation, etc.
Competing interests: No competing interests
Dear Sir,
Holbrook’s editorial (1) assigned to the newer and older hypnotics
the status of “prime examples of iatrogenesis imperfecta” based on results
from the recently released NICE guidance about newer hypnotic drugs for
the short-term management of insomnia (2). That guidance used as the main
source of evidence a preliminary version of the Health Technology
Assessment (HTA) report with a similar title, and dated on June 2004 (3).
Unfortunately, that editorial misused the opportunity to introduce the
questioning or discussing about the tools used to assess efficacy of
hypnotics during pivotal studies. Accordingly with current European
guidance for the development of new hypnotics (4) there are two kinds of
study approaches, out-patients studies and sleep laboratory studies, both
of them equally suitable for pivotal purposes.
From the first-one, the main efficacy outcomes are the subjective
variables: the time to sleep onset, the total sleep time, and the number
of awakenings directly reported by patients in the diary the morning-
after.
On the opposite, the sleep laboratory studies are focused in the computing
of the main objective variables: the latency to persistent sleep, the
sleep continuity or number of awakenings, and the actual total sleep time,
all measured by polysomnography or other objective methods (MSLT,
actigraphy, TV cameras, etc).
A number of publications have pointed concerning the discrepancy between
subjective and objective sleep measurements (5-7). At this time, it is
desirable to remark that the aforementioned HTA report was found almost
exclusively on results from out-patients studies. One significant reason
of that issue maybe that sponsors have focused Phase III in out-patient
studies, where subjective measures are used as primary outcomes. That
choice is clearly reasoned: costs, number of patients, and regulatory
requirements. However, the final cost for sponsor seems to be higher as
can be suggested by the Holbrook’s conclusion.
One desirable strategy could be that systematic review included also
results from sleep laboratory studies, and that analysis was performed
separately of the out-patients studies (iatrogenesis imperfecta vs. review
imperfecta). However, the most desirable would be that Authorities, as the
EMEA or the FDA, requested proof of efficacy from the sleep laboratory
short-term studies (of course, in a fashion cost-effective for sponsors),
and rested the quality of life and the safety and tolerability outcomes in
the out-patients long-term studies.
References:
1.Holbrook AM. Treating insomnia. BMJ 2004; 329: 1198-9
2.National Institute for Clinical Excellence. Guidance on the use of
zaleplon, zolpidem and zopiclone for the short-term management of
insomnia. London: NICE, 2004. (Technology Appraisal 77.) www.nice.org.uk/
TA077guidance (accessed 13 Oct 04).
3.Dundar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al. Newer
hypnotic drugs
for the short-term management of insomnia: a systematic review and
economic
evaluation. Health Technol Assess 2004;8(24). http://www.ncchta.org
(accessed 17 Aug 04).
4.CPMP Note for Guidance on the Clinical Investigation of Hypnotic
Medicinal Products (Adopted on September 1991).
5.Kryger MH, Steljes D, Pouliot Z, Neufeld H, Odynski T. Subjective versus
objective evaluation of hypnotic efficacy: experience with zolpidem. Sleep
1991; 14:399-407
6.Vanable PA, Aikens JE, Tadimeti L, Caruana-Montaldo B, Mendelson WB.
Sleep latency and duration estimates among sleep disorder patients:
variability as a function of sleep disorder diagnosis, sleep history, and
psychological characteristics. Sleep 2000; 23:71-9
7.Means MK, Edinger JD, Glenn DM, Fins AI. Accuracy of sleep perceptions
among insomnia sufferers and normal sleepers. Sleep Med 2003; 4:285-96
Competing interests:
Working in a local pharmaceutical company, within Clinical Research Department
Competing interests: No competing interests
Possible alternative treatments for treating insomnia
In the article “Treating insomnia: use of drugs is rising despite
evidence of harm and little meaningful benefit,”1 the author discusses the
risk/benefit disadvantages of prescription sleeping pills. In emphasizing
her point that the harm outweighs the benefits she concludes with the
following comment:
”No drug has yet been shown to be more effective
and safer than placebo in primary insomnia for
the type of outcomes that matter, such as quality
of life, daytime function, cognition, falls
and fractures, or dependency.”
Sleep loss initiates a number of catabolic processes. These can
include metabolic and immune changes, hyperphagia, weight loss,
hyperthermia, skin lesions and eventual death.2 While not disputing the
author’s conclusion with respect to prescription sleeping pills;
nevertheless, the seriousness of the above-mentioned disease conditions
would seem to warrant a more thorough consideration of alternative
therapeutic options other than prescription sleeping pills.
Though not normally considered a treatment for insomnia, drugs whose
mechanism of action directly affects the underlying causes of insomnia
should also be considered as a treatment for insomnia. Included in this
category are drugs that can treat the catabolic effects of the age-related
rise in cortisol levels. Increased evening cortisol levels are associated
with increased fragmented sleep and reduced REM sleep. 3 With respect to
insomnia in aging patients, drugs are available that can improve sleep
function by suppressing cortisol secretion. 4 At least one of the drugs
mentioned in the above-referenced article (DHEA) has been shown to have a
positive effect on sleep in human subjects.5
1. Holbrook A. Treating insomnia: use of drugs is rising despite
evidence of harm and little meaningful benefit. BMJ 2004; 329: 1198 1199.
2. Prinz PN. Age Impairments in sleep, metabolic and immune
functions.
Experimental Gerontology 2004; 39:1739-43.
3. Van Cauter E, LeProult R and Plat L. Age-related changes in slow
wave sleep and REM sleep and relationship with growth hormone and cortisol
levels in healthy men. JAMA. 2000; 284(7):861-868.
4. Sapse AT. Cortisol, high cortisol diseases and anti-cortisol
therapy. Psychoneuroendocrinology. 1997; 22 Suppl 1:S3-10.
5. Friess E, Trachsel L, Guldner J, Schier T, Steiger A, Holsboer F.
DHEA administration increases rapid eye movement sleep and EEG power in
the sigma frequency range. Am J Physiol. 1995 Jan; 268(1 Pt 1):E107-13.
Competing interests:
None declared
Competing interests: No competing interests