PUBBLICAZIONE PERIODICA BIMESTRALE - POSTE ITALIANE SPED. IN A. P. 45% ART. 2 COMMA 20/B LEGGE 662/96 AUT. 584/DC/DCI/CN - ISSN 0026-4806 TAXE PERÇUE
Efficacy of wrists overnight compression (HT7 point) on insomniacs: possible role of melatonin? Aim. Insomnia is a major problem which Department of Medical Physiopathologydecreases life quality. Many causes are involved University of Rome “Sapienza”, Rome, Italywith it and anxiety is often associated. The underlying mechanism is not completely understood, even though different factors seem to be associated. Among them melatonin and its circadian rhythm is thought to have an impor- insomniacs, at a higher extent than in the pla- tant role. In addition, acupressure and acu- cebo group. In addition, the 24 hours urinary puncture are known to ameliorate insomnia melatonin metabolite rhythm, obtained at the and anxiety, when a specific wrist point is sti- end of treatment, was considered as being nor- mulated (HT7 Shenmen). With these bases, the mal in a higher percentage of H7-treated aim of the present study has been to evaluate patients, with respect to the placebo group. the efficacy of an acupressure device, “H7- Conclusion. It is plausible to hypothesize that insomnia control”, positioned on HT7 points, the wrist acupressure device might be consi- during the night, in terms of general health dered a valid tool, without adverse effects sin- and anxiety levels, together with the evalua- ce it does not contain pharmaceutical products, tion of sleep quality and the urinary melato- that is able to naturally ameliorate sleep quality nin metabolite 6-hydroxymelatonin sulphate in insomniacs, acting through a not jet com- determination, in a number of insomniacs. pletely clarified mechanism, that may involve Methods. Forty patients with insomnia were melatonin. divided into two groups and randomly received
Key words: Acupressure - Sleep Initiation and either the H7 or placebo treatments, in a dou- Maintenance Disorders - Anxiety - Melatonin - ble-blind protocol, for 20 nights. Before and after treatments every subject answered a series of questionnaires (General Health Question- naire 28 items; State-Trait Anxiety Inventory; Pittsburgh Sleep Quality Index) and collected 24
Acute or chronic lack of sufficient sleep
h urines, divided into two samples of 12 h each.
quality and quantity is defined as insom-
Urinary melatonin metabolite was then deter-
nia and may induce loss of well being asso-
mined using a RIA method.
ciated with a decreased quality of life.1 Many
Results. Data obtained indicate that the device H7-insomnia control is efficacious to ameliorate
aging, stress, chronic illnesses, with anxiety
quality of sleep and reduce anxiety levels in
being associated most of the times, resultingin a more evident problem.2 Results from
Received on September 25, 2008. Accepted for publication on October 13, 2008.
the literature indicate a high frequency rateof insomnia in the older population, how-ever recent data indicate an increased insom-
Corresponding author: M. Nordio, via Flaminia 29, 00196
Rome, Italy. E-mail: [email protected]
nia rate in almost every age, and in fact
pharmaceutical products for insomnia seem
generally, acupressure) efficacy as a thera-
to be the most used therapeutic agents. Data
py for insomnia in general, and particularly
from Italy indicate that roughly 34% of total
when associated to anxiety.14, 15 In fact, elec-
population has chronic insomnia problems,
increased sleep quality, both subjective and
sional insomnia.3 Mean age is usually around
objective, and the decrease of anxiety levels,
55 years or older; however, it seems that it
with the stimulation of a particular acupunc-
is progressively decreasing, possibly due to
ture point called HT7 Shenmen (the gate of
an increased anxiety level in younger sub-
the spirit), located on the outer side of the
jects. From this point of view, most authors
wrist, on the radial side of the flexor carpiulnaris tendon, between the ulna and the
strate a reduced ability to maintain sleep,
pisiform bones.16-18 Acupuncture is used in
the treatment of a variety of mental disor-
ders, such as absent mindedness, insomnia,
disturbing dreams, hysteria, depression, agi-
mented, with respect to normal sleepers.
tation, and mental illness. It is also used in
Biochemical modifications include the rela-
the treatment of heart disease and fatigue.
ergic systems, and melatonin rhythm alter-
through acupuncture nails or, more easily,
ations.4, 5 As far as the latter is concerned, it
is well known that the secretion of this mol-
pointed device (i.e. pen, pencil), for a suf-
ecule, produced by the pineal gland main-
ly during night-time, follows a circadian
which the beneficial effects are obtained is
rhythm and has also the strong ability to
the external environment.6 Therefore, it is
ever, recently insomniacs treated with clas-
possible to state that any condition that may
sic acupuncture demonstrated a significant
increase in sleep quality, in association with
secretion rhythm, is then capable to modi-
the increase of nocturnal melatonin levels.17
In addition, it has been hypothesized that the
included.7 Data obtained to date indicate
effects of HT7 stimulation may be mediated
through opioid peptides production, rein-
pathological factors may be able to deter-
forcing, once more, the known interaction
which has a protective role during stressful
process (melatonin levels physiologically
On the basis of these considerations, the
decrease), stress, jet-lag syndrome, light
aim of the present study was to evaluate the
exposure at night, shift workers, electro-
efficacy, tolerability and “easy-to-use” level of
an experimental acupressure device called
drugs use (i.e. non-steroidal anti-inflamma-
“H7-insomnia control” (roughly, a soft rubber
tory drugs [NSAIDs], and beta-blockers).8-10
pin, kept in place by an adhesive plaque),
Melatonin administration to these subjects is
positioned on HT7 point, in insomniacs, using
self-administered well-known questionnaires.
In addition, the urine melatonin metabolite 6-
rate global subjective sleep quality, while
hydroxymelatonin sulphate (aMT6s) has been
reducing the number and length of noctur-
measured in the same patients, at the end of
the treatment period, in order to ascertain
More recently, increasing data of the lit-
the presence (or absence) of a definite mela-
Materials and methods
position of the true HT7 point, and 20 indi-cating another site, different from HT7, for
wrist application. The sequence of the 20+20(true HT7 and placebo) sites was random-
ized and the randomization key was unknown
to the principles stated by the “Helsinki de-
to the study crew and to the patients.
claration” and the “Good Clinical Practice”,
patients collected two urine samples: the first
defined by the International Conference of
between 08:00 h and 20:00 h of the last day
of treatment, immediately before the last
night; the second between 20:00 h and 08:00
mental design, H7 acupressure device vs
h of the last night, till the next morning. The
insomnia. In particular, the patients enrolled
stored (-20° C) until the aMT6s melatonin
wrist acupressure device “H7-insomnia con-
munoassay method, as described further. In
trol” (briefly, H7; Consulteam s.a.s., Como,
addition, all patients were asked to give their
Italy) which was positioned either on HT7
written impressions and personal evaluation
point of both wrists (treated group), or on a
concerning the use of the device (easiness of
“non-HT7” point located in a different posi-
use, clearness of written instructions, etc.).
tion of both wrists (placebo group), known
Furthermore, they were submitted to the final
as not to interfere with insomnia and/or anx-
physical examination and fulfilled again the
iety. Accordingly to previous data of the lit-
three questionnaires described earlier. Data
erature, which indicate in one to two weeks
(aMT6s, day [D] and night [N] concentrations)
improvement of sleep quality and melatonin
and as night to day levels ratio (N/D) in order
rhythm following acupressure of the appro-
to identify patients with a conserved (N/D
priate point, the treatment was prolonged
ratio higher than 3) or altered melatonin
rhythm (N/D lower than 3). Data, expressed
At enrolment (T=0), after being informed of
as mean ± SD, have been finally processed to
the scope of the study and their role in it, and
ascertain whether statistical differences among
the “Informed Consent” being signed, each
patient underwent physical examination in
priate methods (Student’s t test).
order to ascertain inclusion and exclusion cri-teria, as described in the next paragraph of this
paper, and were administered three interna-
tionally used questionnaires to evaluate thelevel of global life quality of the individual
A patient was included in the study accord-
(General Health Questionnaire, GHQ28), the
level of sleep quality (Pittsburgh Sleep Quality
Index, PSQI), and the level of anxiety (State
— absence of important pathologies, par-
numbered (1 to 40) envelope containing the
ticularly renal and/or liver failure. In parti-
cular, creatinine levels should be within the
wrists, sufficient for the entire 20 nights peri-
od, and was instructed to apply the device
on both wrists at exactly 22:00 h each night.
the study, together with availability and
Moreover, each envelope also contained writ-
ten instructions on how to assemble and apply
the device in the correct way: 20 indicating the
ing to the method described by Arendt et al.21Briefly, each urine sample (or standard) was
It was impossible to enroll a patient in the
prepared by diluting the appropriate amount
presence of only one of the following fac-
in order to obtain a final dilution of 1:250. An
amount of 500 μL was then added to assay
— lack of any of the “inclusion criteria”;
tubes, in duplicate. Then, 200 μL of a specific
— subjects working as “shift workers”.
antiserum were added to the samples (or stan-
— intercontinental flights flown less than
dards, except total counts and non-specific
binding tubes), vortexed and incubated at
room temperature for 30 min. The sheep anti-
serum used in the assay AB/S/06 was suffi-
— psychiatric illnesses, seasonal affective
ciently specific for clinical application, with-
out pre-assay sample preparation. The coef-
ficients of variation intra- and inter-assay were
6.8% and 10.2%, respectively, and the limit
of sensitivity of the assay was 0.5 ng/mL. After
incubation, all the tubes received 100 μL 131I-
Patients treated with benzodiazepines for
aMT6s, then vortexed and incubated for 18
insomnia were permitted to continue their
hours at 4° C. The separation between the
usual therapy, possibly reducing it, depend-
antibody-bound aMT6s and the free fraction
ing on doctor’s decision. Moreover, if a
was obtained by incubation for 15 min at 4°
patient resulted on therapy for a chronic ill-
C on ice, with 500 μL activated dextran-coated
ness, the relative drugs, when not interfering
charcoal, stirred continuously on ice 30 min
with the protocols, were also permitted.
before and during addition. After quick vor-tex, in order to reduce intra-assay variation,
the tubes were centrifuged at 3 000 rpm for 15
min at 4° C. The supernatant was finally
tions of the aMT6s melatonin metabolite in
removed and each tube counted for 1 minute.
urines derives from three considerations.
The aMT6s concentration in the samples was
Firstly, urine collection is far more easier for
determined from the standard curve and the
the patients than day and night (at 03:00 h)
blood collection, therefore a higher compli-ance was expected. Secondly, data of the lit-erature indicate that urine melatonin metabo-
lite excretion parallels melatonin bloodrhythm, and responds to pineal melatonin
Total number of patients included into the
production blockade.21 Thirdly, the aim of
study was 40 individuals, aged 49-77 years
the present study was not an accurate descrip-
(mean 64.05 years), 24 females and 16 males.
tion of melatonin rhythm phases, but simply
In addition, 7 subjects (2 females and 5 males)
the evaluation of its presence (or absence)
decided to abandon the study; therefore, by
after treatment, in each subject. For this rea-
the end the effective number of patients used
son it was also decided to present the results
for the final evaluation was 33, 22 females and
also as night/day ratio and to identify the
11 males. The group treated with H7 was ini-
value of “3” as a cut-off point to divide indi-
tially of 20 patients (11 females and 9 males), as
viduals with a sufficient melatonin rhythm
it was the placebo group (20 patients: 13
from those with a lower value that, there-
females and 7 males). In the same groups, after
fore, may have an altered melatonin rhythm,
dropouts, the numbers were respectively 11
females and 7 males (H7), and 11 females and
4 males (placebo). Taken together, the data
indicate that it has been possible to evaluate a
kit (Stockgrand Ltd., Guildford, UK), accord-
group of 33 individuals, 18 treated with H7 (11
Figure 1.—Mean ± SD scores (arbitrary scale, see the text
Figure 2.—Mean ± SD scores (arbitrary scale, see the text
for values) from the STAI (“trait” arm) questionnaires,
for values) from the STAI (“state” arm) questionnaires,
before and after H7 or placebo treatments, in insomnia
before and after H7 or placebo treatments, in insomnia
patients. *: P=0.0005 (H7 before vs H7 after); NS: not sig-
patients. *: P=0.0004 (H7 before vs. H7 after); **: P=0.0005
(placebo before vs placebo after).
females and 7 males) and 15 treated with place-
bo (11 females and 4 males). It is interesting tounderline that most of the patients which decid-ed to abandon the study, were in the placebo
group (5 out of 7), with respect to the H7-treat-
ed group (2 out of 7) (Figure not shown).
As stated in the protocol, at the beginning
and the end of the study, the patients wereasked to answer a series of internationally val-
idated questionnaires, in order to evaluatetheir subjective response to both treatments
(H7 and placebo). The use of the GHQ28 indi-
Figure 3.—Mean ± SD scores (arbitrary scale, see the text
cates that the patients treated with the H7
for values) from the STAI (“trait” arm) questionnaires,
device, after 20 days obtained a statistically
before and after H7 or placebo treatments, in insomniapatients. *: P=0.001 (H7 before vs H7 after); **: P=0.003
significant better score, with respect to the
(placebo before vs placebo after).
placebo group, indicating a more evident gen-eral well being sensation (H7: from 7.72±2.97to 4.72±2.74, P=0.0005; placebo: from
from the “State” arm of the questionnaire
7.00±2.47 to 6.13±2.13, P=0.07 NS) (Figure 1).
indicate a reduction of anxiety level in both
As far as the second questionnaire is con-
considered groups. In particular, the reduc-
cerned, the STAI, its purpose was to evaluate
tion was highly significant in H7-treated
the anxiety level of each subject, before and
patients (before: 49.27±8.00; after: 40.11±7.06;
after treatment. In addition, it has been possi-
P=0.0004). Nonetheless, a significant reduc-
ble to identify either the level of the so called
tion, whilst of a lesser degree, was also pre-
“State anxiety” (defined as non-habitual emo-
sent in the placebo-treated group (before:
tional stress), and the “Trait anxiety” (intend-
46.80±9.83; after: 42.80±10.19; P=0.0005). The
ed as a more “fixed” characteristic of the per-
results from the “Trait” arm indicate a similar
son, or anxious character). Results obtained
response in terms of anxiety level reduction
Figure 4.—Mean ± SD scores (arbitrary scale, see the text
Figure 5.—Day and night mean ± SD urinary melatonin
for values) from the PSQI questionnaires, before and after
metabolite aMT6s concentrations (ng/mL) in the H7 and
H7 or placebo treatments, in insomnia patients. *:
placebo groups. *: P=0.004 H7 day vs H7 night; **: P=0.01
P=0.00003 (H7 before vs H7 after); **: P=0.0006 (placebo
before vs placebo after); ***: P=0.016 (H7 after vs placeboafter).
in both groups, however of a lesser extent
(H7; before: 53.39±10.16; after: 50.72±10.75;
bo group subjects. The difference was sta-tistically significant (H7: 3.83±1.29, placebo:
P=0.001) (Placebo; before: 48.40±10.39; after:
2.53±1.64; P=0.008) (Figure not shown).
46.40±10.77; P=0.003) (Figures 2, 3).
xiety level scores, after treatment, was more
Urinary sulphate-melatonin evaluation
evident in patients treated with the H7 device,
with respect to those treated with placebo,
but the difference was not statistically signi-
above, using a radioimmunoassay procedure
on the 24 hours urine samples (divided into
questionnaire demonstrated that sleep qual-
Therefore, aMT6s concentrations have been
ity was significantly higher at the end of the
measured in 33 patients, with a total of 66
study, both in H7 and placebo patients (the
samples. Results are expressed as mean ±
lower the score, the highest the quality of
SD of ng/mL urines. In addition, due to the
sleep) (H7: from 11.44±2.57 to 6.61±2.97,
wide physiological interindividual variability
of aMT6s concentrations, and in the effort to
8.86±2.82, P=0.0006). However, the score
reduce these differences, results are also
reduction in H7 patients was significantly
expressed as a ratio between night (N) and
more evident than the reduction obtained in
day (D) values. This N/D ratio has been con-
the placebo group (P=0.016) (Figure 4).
Finally, at completion of the treatment peri-
the contrary, a result lower than 3 indicated
od, all subjects were asked to fill a specific
an alteration of the normal melatonin rhythm.
questionnaire designed to give a global sub-
Similarly to the questionnaires processing,
jective evaluation of the wrist acupressure
results obtained have been statistically ana-
device they used in the study. A score accord-
lyzed using the Student’s t test, when appro-
ing to an arbitrary scale (0=insufficient;
priate. Therefore, the evaluation of data
obtained first of all confirmed the physiologi-
cal difference between nocturnal and diurnal
aMT6s in most subjects. In particular, patients
Figure 6.—Night and day mean ± SD urinary melatonin
Figure 7.—Percentage of subjects treated either with H7 or
metabolite aMT6s ratio in the H7 and placebo groups. *:
placebo having an aMT6s N/D higher than 3. Numbers in
parentheses express the amount of patients with N/D ratiohigher than 3, with respect to the total number of indi-viduals in each group.
treated with the H7 device demonstrated aday/night melatonin rhythm that seems to be
centrations were determined only at the end
more pronounced, with respect to the place-
of the treatment period, therefore impeding a
bo group, and this difference was statistically
significant (H7: day 5.25±5.79 ng/mL, night
after treatment. However, it is authors’ opi-
20.50±16.18 ng/mL; placebo: day 4.52±2.56
nion that having only one melatonin metabo-
ng/mL, night 9.68±5.62 ng/mL; P=0.01) (Figure
lite rhythm (D and N values) determination at
5). Data evaluation as N/D ratio confirms and
the end of the study, the comparison between
amplifies these differences (H7: N/D 5.24±3.32,
the number of patients with a correct mela-
placebo: N/D 2.56±1.42; P=0.004) (Figure 6).
tonin rhythm in the H7 and placebo groups
Data from the questionnaires indicate that
melatonin rhythm is concerned (aMT6s equal
most parameters were positively modified by H7
of higher than 3), the results indicate a per-
treatment, and, in particular, a higher general
centage of 54.5 (18/33). However, when the
wellness level, a reduction of the anxiety level,
an increase of the subjective sleep quality, with
patients showing a normal melatonin rhythm
respect to the placebo group. However, in con-
was significantly higher, with respect to those
junction with the ameliorating action of H7, a
similar positive effect, on a smaller number of
parameters, was also noted in the placebo-treat-
ed patients. In particular, data obtained using the
adverse reactions that could be associated to
STAI and the PSQI questionnaires indicate that,
besides the significant reduction of the anxietylevels and increase in sleep quality in the H7group, a similar reduction and increase, whilst
Discussion
of a lesser extent, were documented also in the
The overall efficacy evaluation of the wrist
placebo group. Therefore the H7 effects on
acupressure device “H7-insomnia control” on
these parameters could be interpreted as “place-
insomnia seems to be positive, even though
bo effects”. However, this seems not the case,
some limitations apply. The first concerning
due to the fact that, first of all, the device was
the small number of patients, and the second
identical for all patients of the two groups and
derived from the design of the study itself. In
they were instructed in the same way on how
fact, due to organizing, timing, and compli-
the device should be correctly assembled before
ance reasons, the melatonin metabolite con-
positioning it on both wrists for the night. The
great importance given to the preparation and
insomnia control demonstrated to be able to
the correct positioning of the device was cho-
sen to contribute to the creation of a sort of effi-
cacy expectation in both groups. Therefore, in
increased subjective well being, sleep quality,
this view it is possible to explain the signifi-
cantly positive effect of the placebo treatment in
— the fact that the same device, diffe-
ameliorating the score of some aspects of STAI
and PSQI questionnaires. However, it is impor-
demonstrated an effect on some subjective
tant to underline that the positive effect of H7
parameters, similar to the HT7 location (even
treatment, especially when sleep quality is con-
though to a lesser extent), indicates that pre-
cerned, was significantly amplified, with respect
liminary activities to its use, as assembling
to the results obtained in the placebo-treated
and attention to its placement may have a
subjects. In this view, the subjective global eva-
luation of easiness of use and efficacy of the
device was considered significantly higher in
increase of sleep quality after treatment was
significantly more evident in H7 patients,
As far as melatonin metabolite results are
concerned, data obtained indicate that a phy-
— the use of H7-insomnia control device
siological day-night difference in melatonin
is associated to a higher possibility to obtain
concentrations was present in a significantly
higher percentage of H7 patients, with respect
with our data it is impossible to adscertain a
to the placebo group. In addition, the mean val-
ue of N/D ratios in the H7 patients reached a
— the acupressure device, its assembling
higher level, therefore indicating the presence
and the instructions included were positively
of a normal melatonin rhythm in this group. On
evaluated by the majority of patients, mostly
the contrary, when the placebo group is con-
from the H7 group, with respect to the placebo;
sidered, the mean value of night/day ratios
was significantly lower than in the H7 group
treatment to be stopped, nor adverse local
and did not reach the cut-off point of 3, indi-
reactions connected to the use of the device
cating an insufficient melatonin rhythm.
Therefore, it is plausible to hypothesize that
nary data obtained in the present study it is
the wrist acupressure device H7-insomnia con-
impossible to state that the wrist acupressure
trol, although not a pharmaceutical product,
might be considered an efficacious tool, with-
out adverse effects, that is able to naturally
(melatonin metabolite determination before
ameliorate sleep quality in insomniacs, at least
treatment is lacking), presumably altered in
those in which “traditional” pharmacological
insomniacs, nevertheless it is possible to
therapies (i.e. benzodiazepines) are con-
hypothesize that the amelioration of well
traindicated. In addition, the hypothesis that
being, anxiety level and sleep quality in these
the positive effects on insomnia might be medi-
ated through an action on melatonin rhythm is
nected, at least in part, to the presence of a
not jet completely confirmed and therefore
Conclusions Riassunto Efficacia dell’acupressione esercitata sui polsi duran-te la notte (sul punto HT7) su soggetti con insonnia:
obtained in the present study it is possible to
Obiettivo. L’insonnia è un problema di vastissima
rilevanza che riduce la qualità della vita. Nella sua
genesi sono coinvolti molti fattori, associati frequen-
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N904-00 Marlyn Neutrac. Take before entering crowded environments or as soon as you start to feel under the weather. DIRECTIONS: Drop one effervescent tablet in 8 ounces of water, let fully dissolve Boost Your and drink. Enjoy in hot or cold water. Take up to 2 times a day as needed. Immunity* INSTRUCCIONES: Deposite una tableta efervescente en 8 onzas de agua, una vezdisuelta c
Chapter 15 1. a. What are the three sources of the barriers to entry that allow a monopoly to remain the sole seller of a product? Answer: A key resource is owned by a single firm (monopoly resource), the government gives a single firm the exclusive right to produce a good (government created monopoly), the costs of production make a single producer more efficient (natural monopoly). b.