NEUROENDOCRINOLOGY
LETTERS including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology
and
Human Ethology
ISSN 0172–780X
A DOUBLE BLIND - PLACEBO CONTROLLED STUDY ON Melatonin
Efficacy to Reduce Anxiolytic Benzodiazepine Use in The Elderly
Daniel P. Cardinali MD PhD,1
Elisa Gvozdenovich MD,2
Marcos R. Kaplan MD,3
Isidoro Fainstein MD,4
Hugo A. Shifis MD,5
Santiago Pérez Lloret,1
Liliana Albornoz Ph D,1 and
Armando Negri MD.6
1. Department of Physiology, Faculty of Medicine, University
of Buenos Aires,
2. Geriatric Clinic, Hospital Durand, Buenos Aires,
3. Geriatric Clinic, Hospital Italiano, Buenos Aires,
4. Centro Médico Ing. A. Roca, Hospital Italiano, San
Justo, Provincia de Buenos Aires,
5. Geriatric Clinic, Hospital Militar Central, Buenos Aires,
6. Elisium, SA, Buenos Aires, Argentina.
Submitted:
January 11, 2002
Accepted: January 14, 2002
Key
words: melatonin,
aging, benzodiazepines
Abstract
OBJECTIVE.
The present double blind-placebo controlled study was carried
out to assess whether melatonin (3 mg p.o., fast release form)
could be useful to reduce benzodiazepine dosage in old patients
with minor sleep disturbance. The possible correlation of
urinary excretion of 6-sulphatoxymelatonin (aMT6s) before
starting treatment and outcome of treatment was also examined.
METHODS.
Forty-five patients (36 females, 70.5 ± 13.1 years
old) regularly taking anxiolytic benzodiazepines in low doses
were studied. Overall quality of morning freshness, daily
alertness, sleep quality, and sleep onset and offset time
were assessed from structured clinical interviews and from
logs completed by the patients. Patients were randomized to
receive either melatonin or placebo for 6 weeks. On day 14
of treatment, benzodiazepine dose was reduced by half and
on day 28, it was halted. No significant modifications of
sleep or wakefulness were detected after benzodiazepine withdrawal.
As compared to basal, there was a general lack of changes
in quality of wakefulness or sleep in patients taking melatonin
or placebo. Sleep quality of patients taking melatonin during
the first two weeks of treatment was significantly lower than
that of placebo. Melatonin advanced sleep onset by 27.9 ±
11.9 min and decreased significantly the variability of sleep
onset time (p= 0.03). The urinary concentration of aMT6s prior
to the study did not correlate with any parameter examined.
CONCLUSION.
The present study does not support melatonin efficacy to reduce
the use of benzodiazepines in low doses. This contrasted with
the demonstrable effectiveness of melatonin to reduce benzodiazepine
consumption in insomniac patients when used in hypnotic amounts.
Introduction
Several
studies have indicated that in aged patients with primary
insomnia taking benzodiazepines, melatonin is effective to
halt or reduce benzodiazepine consumption [1-6]. For example,
we reported that 13 out of 20 insomniac patients taking benzodiazepines
together with melatonin, benzodiazepine use could be stopped
and in other 4 patients benzodiazepine dose could be decreased
to 25-66 % of initial doses [6]. The data agreed with the
efficacy of melatonin treatment to increase sleep efficiency
and total sleep time and to decrease wake after sleep onset,
sleep latency and number of awakenings in elderly subjects
who have been taking benzodiazepines and had low melatonin
output [5]. Moreover, a rapid reversal of tolerance to benzodiazepine
hypnotics by treatment with oral melatonin has been observed
[3].
In a study including 34 insomniacs kept on benzodiazepine
therapy and who received melatonin (2 mg in a controlled-release
formulation) or placebo for 6 weeks, the patients were encouraged
to reduce their benzodiazepine dosage 50% during week 2, 75%
during weeks 3 and 4, and to discontinue benzodiazepine therapy
completely during weeks 5 and 6 [4]. Fourteen of 18 subjects
who had received melatonin therapy, but only 4 of 16 in the
placebo group, discontinued benzodiazepine therapy, sleep-quality
scores being significantly higher in the melatonin therapy
group.
Since many old patients with minor sleep disturbance received
benzodiazepines in anxiolytic doses, we carried out the present
study to assess whether melatonin could be useful to reduce
low benzodiazepine dosage as it is in insomniac patients treated
with hypnotic benzodiazepines. A double blind-placebo controlled
study on the efficacy of a 3 mg-melatonin dose p.o. (fast
release form) was carried out. A possible correlation of urinary
excretion of 6-sulphatoxymelatonin (aMT6s) before starting
treatment and outcome of treatment was also examined.
