Clinical Evaluation of Diphenhydramine Hydrochloride for the Treatment Insomnia in Psychiatric Patients: A Double-Blind Study Yoshio
Kudo,
MD,
and
Masanao
Kurihara,
of
MD
The usefulness of the antihistaminic agent diphenhydramine hydrochloride was evaluated using a double-blind procedure at sleeping doses of 12.5, 25, and 50 mg in 144 psychiatric patients with insomnia. The general condition of the patients with insomnia was at least “slightly improved” in 62.5% (12.5-mg group), 60% (25-mg group), and 67.4% (50-mg group) after treatment with the test drug for 2 weeks. Side effects were observed in a total of 11 patients (7.6%) but were not severe. No symptoms suggestive of drug dependence were evident. Global improvement was not influenced by patient background factors except for the presence or absence of previous treatment for insomnia. The hypnotic effect of diphenhydramine hydrochloride was significantly greater in patients who had not been treated previously. A dose-dependent increase in the hypnotic effect was also seen in patients who had not received any previous treatment. Diphenhydramine hydrochloride thus appears to be effective in the treatment of insomnia, but the appropriate dosage will depend on previous medical treatment of insomnia.
R ecently,
the number of patients complaining of insomnia is increasing in all clinical fields. Also, with the general aging of the population, insomnia is becoming more prevalent in the elderly. Drugs based on specific benzodiazepine derivatives that exhibit a strong hypnotic effect have been used as the primary source of hypnotics in the treatment of insomnia. Their use, however, should be restricted because they produce various side effects and drug dependence. Similar problems are also seen in patients who have complications due to disease and otherwise show a general decline in their physical condition. Consequently, hypnotics with milder adverse effects are essential. The antihistaminic agent, diphenhydramine hydrochloride, has long been known to produce “drowsiness,”1 and this effect has been used empirically for insomnia. The effect of this agent on sleep From the Institute of Clinical Pharmacology (Dr. Yoshio Kudo) Aino Hospital, Osaka, Japan, and the Department of Psychiatry (Dr. Masanao Kurihara, Controller) Toranomon Hospital, Tokyo, Japan. Source of preparations: Rhoto Pharmaceutical Co., Ltd. 1-8-1, Tatsuminishi Ikuno-ku, Osaka 544, Japan. Address for reprints: Yoshio Kudo, MD,
Aino Hospital,
11-18,
J Clin Pharmacol
Takada-cho,
1990;30:1041-1048
Ibaraki, Osaka 567, Japan.
EEGs
has
also
been
widely
studied,
with
previous
reports indicating that it elongates sleeping time2 and decreases sleep latency2 and percentages of REM sleep.2’5 On the basis of these facts, there have been several clinical studies, including double-blind trials fulness
in the United States,61#{176} to determine of diphenhydramine hydrochloride
the
useas a
sleeping aid. Some preparations containing this agent have recently become commercially available as nonprescription night-time sleep aids because of the earlier test results. In Japan, however, only the Ookuma study was conducted to determine the optimal dose of the agent. In this study, the sleep-inducing effect of diphenhydramine hydrochloride was tested in some patients.11 We previously evaluated the hypnotic effects and safety of three dose levels (25, 50, and 75 mg) of diphenhydramine hydrochloride by the fixed-flexible method in 142 psychiatric patients complaining of insomnia.12 Clinically sufficient hypnotic effects were observed at all doses with satisfactory safety and little drug dependence, indicating it to be useful. The effects of the drug sharply increased when its dose was increased from 25 to 50 mg but did not appreciably
1041
KUDO
increase
from
appropriate
50 to 75 mg. Thus, as the
maximum
AND
50 mg is considered suitable
dose.
In consideration of the aforementioned, the current study was carried out to determine the relationship among dosage, efficacy, and safety of diphenhydramine hydrochloride administered in doses of 12.5, 25, or 50 mg to psychiatric patients with insomnia. This was a double-blind placebocontrolled those
in
our
procedure previous
involving study.12
patients
similar
to
Subjects Subjects for the study were selected from inpatients and outpatients who reported insomnia to the psychiatric departments of the 24 institutions participating in the study. Initially, 147 patients diagnosed with insomnia, neurosis, or depression were chosen. The study protocol was approved by each institutional review board, and all patients were fully informed as to the nature of the experiment. All gave their consent for participation in this study.
Three test
patients preparation
who
were previously were excluded
administered from the study,
and analysis was carried out on data from the remaining 144 patients. Table I shows the background data of these patients. There were no significant differences in these data among the three dose groups.
Test
Preparations
The subjects regimen by
and
Procedure
were randomly the controller
assigned to each of the study (M.K.), 25, and 50 mg of the
separately received 12.5, once a day for 2 weeks before sleeping. record form was kept for each volunteer observations on the state of the patient’s following four preparations were used:
dose and
drug A patient to record sleep. The (1) 12.5-mg
diphenyhydramine hydrochloride tablet (white) (2) 25-mg diphenyhydramine hydrochloride tablet (white) (3) 25-mg diphenyhydramine hydrochloride tablet (blue) (4) placebo (blue). These preparations the combinations
were listed.
administered
for 2 weeks
There was not a washout period for patients who had received other hypnotic agents before this study. 12.5-mg group: 12.5mg tablet (white) + placebo (blue) 25-mg group: 25-mg tablet (white) + placebo (blue) 50-mg group: 25-mg tablet (white) + 25-mg tablet (blue). Patients were instructed to take one white and one blue tablet once a day before sleeping. Other hypnotic agents or antihistaminic preparations were prohibited during administration of the in
1042
#{149} J Clin Pharmacol
1990;30:1041-1048
test drug. Consumption of alcoholic beverages, fee, or tea before bedtime was also forbidden. necessary for the treatment of primary diseases permitted on the condition that they and their would not be altered during this study.
Observation Sleep
and
cofDrugs were doses
Evaluation
and
Quality
sician assessed by patient daily
METHODS
the
KURIHABA
Side
Effects.
Each
the quality of sleep records and patient
attending
phy-
and side inquiries.
effects
The patients were examined for the onset of sleep, state of sleep, interruption of sleep, dreams, duration of sleep, duration of interruptions of sleep, mental and physical conditions on awakening, and presence or absence of factors disturbing sleep. Routine blood biochemical studies and urinalysis were conducted before and after drug administration. Drug
Dependence.
sheet
developed
Based
by
on
Kurihara
the
dependence
et al,13
the
check
following
signs of drug dependence were examined: previous medications, drug resistance, increase in dosage, requests for continued use of drugs, symptoms after discontinuation of administration, and lessening of insomnia after discontinuation of administration. Drug dependence was comprehensively graded as
(+): positive;
(±): questionable;
General Evaluation. Global on change in the features tient inquiry as follows: (2) improved; (3) slightly (5)
(-):
negative.
improvement was based of sleep and results of pa(1) markedly improved; improved; (4) no change;
aggravated.
The safety of the test drug was evaluated using the following scale based on side effects: (1) none; (2) mild (side effects requiring no particular treatment); (3) moderate (side effects requiring treatment but administration continued); (4) severe (administration discontinued due to side effects). Usefulness safety; of usefulness:
the
useful;
not
and
Statistical
(4)
was based on general improvement lower of the two determined the level (1) very useful; (2) useful; (3) slightly
useful;
(5) undesirable.
Analysis
The Kruskal-Wallis h-test was used to analyze the difference of two background factors (age of patients, severity of sleep disorders) and to compare three general evaluation parameters (global improvement, safety, usefulness) among the three dose groups. This test was also used for analyzing the influence of five background factors (age of patients, sleep dis-
EFFICACY
OF
DIPHENHYDRAMINE
TABLE
(Analysis
FOR
INSOMNIA
I
Background Factors by Patient Classification According
to Dose)
Dose (mg) Background
Factors
12.525
Total Sex Male Female Inpatient/outpatient Inpatient Outpatient Age (years)
Total
46
144
48
50
17 31
24
19
26
27
60 84
11 37
10 40
14 32
35 109
7 5 6
3 1 13 9
4 14 25 25
16 4 4
20
7
43
6 6
7 6
17 16
35 13
35 15
30 16
100 44
26
20
19
21
30
24 3
65 75 4
ns
94 36 9 2 4
ns
-
34 6 2 2 1
15-19
1
20-29 30-39 40-49 50-59 60-65 66-82
6 7
Concomitant
50
Results of H-test or X2-test
-
10
ns ns
ns
medication
Yes
No
ns
Severity Mild
Moderate Severe Sleep Disorders Cause Psychogenic Depression Organic changes of brain Physicalsymptoms Others Type
1
-
30
30
13 3
17 4
-
-
3 33
35
31
99
Unsound sleep
25
25
26
76
Interruption of sleep
20 11 2
17 13 1
14 10 2 -
51 34 5 1
Difficulty
in falling
asleep
Early awakening Dreamingtoo
much
Others Treatments within 1 month before administration
1
-
Yes
25
31
24
80
No
23
19
22
64
16 15 15 2
23 14 12 1
20 5 18 3
59 34 45 6
Primary disease Neurosis Depression Sleep disorders Others Values in the table are the numbers ns: not significant
MISCELLANEOUS
ns
of patients.
1043
KUDO
AND
KURIHARA
TABLE Sleep
II
Quality Dosage
Parameter State of Interruption Feelings Duration Severity ns *
sleep* of sleep* on awakening* of sleept of insomnia*
= not significant. Wilcoxon signed
rank
P
Groups
12.5
25.0
ns
ns
ns ns ns
ns ns ns
=
.042
(mg) 50.0
P
=
Overall
.0036
P = P = P = P = P =
ns ns
P
=
ns
.0099 ns
.0012 .0130
.0 168 .0008 .0002
test.
t I-test.
orders
the
[severity,
cause,
type],
effects of the drug. Additionally, the h-test
three
general
dose ground
regimens factor.
evaluation
in Each
primary
was
used
diseases)
to compare of the
parameters
subgroups dose regimen
on
classified was
square
test:
sex,
orders (cause, tant medication,
the three
by backevaluated in
inpatient/outpatient,
sleep
type),
treatment
within
Ordinal compared
scale before
presence/absence presence/absence I month, and primary
parameters and after
the
dis-
of concomiof previous diseases.
of sleep quality administration
were of the
nine subgroups, one subgroup for each background factor: age, sex, inpatient/outpatient, sleep disorders (type, severity, cause), presence/absence of concomitant medication, presence/absence of previous treatment for insomnia within 1 month, and primary diseases. The Mann-Whitney u-test was used to analyze the influence of four background factors (sex, inpatient/outpatient, presence/absence of concomitant
RESULTS Each feature of sleep and severity of insomnia was compared before and after administration. Overall, the state of sleep, its interruption, feelings on
medication, ment within
awakening, duration of sleep, nia significantly improved
presence/absence I month) on
drug with Wilcoxon’s signed rank test, and intervalscaled parameters were compared with the paired test. Differences were regarded as significant at a probability of less than 5%.
of previous treatof the drug.
the effects
Distribution of the following seven background factors and the frequency of side effects were cornpared among the three dose groups using the chi-
(Table II). However, nificant improvement Global improvements
TABLE Global Markedly Improved
Improved
8 (16.7)
12 (41.7)
and after
severity of insomadministration
specific dose groups showed sigfor only some parameters. are shown in Table III. The
ill
Improvement
Slightly Improved
No Change
Aggravated
Unknown
Total
15 (93.8) 16
2 (97.9)
1 (100)
48
2 (96.0) 4 (95.7) 8 (96.5)
2 (100) 2 (100) 5 (100)
50
H-test
Dose (mg) 12.5 25
9
8
50
(18.0) 4 (8.7)
(34.0) 15 (41.3)
21 (14.6)
35 (38.9)
Total Values in the tables
1044
are the numbers
#{149} .i CIln Pharmacol
of patients;
1990;30:1O41-1048
10 (62.5) 13 (60.0) 12 (67.4) 35 (63.2) cumulative
% in parentheses.
(92.0) 9 (87.0) 40 (91.0) ns: not significant.
46 144
ns
EFFICACY
OF
DIPHENHYDRAMINE
general condition of the patients was at least “slightly improved” in 62.5% of the 12.5-mg group, 60% of the 25-mg group, and 67.4% of the 50-mg group. Concerning safety, side effects were “none” in 95.8% of the 12.5-mg group, 88% of the 25-mg group, and 82.6% of the 50-mg group. No significant differences in safety were observed among subgroups classified
according
to different
background
factors:
age, sex, inpatient/outpatient, sleep disorders (type, severity, cause), presence/absence of concomitant medication, presence/absence of previous treatment for insomnia within I month, and primary diseases. evaluated
the
The usefulness as “slightly
12.5-mg
60.9%
of the
of the useful”
group,
58%
50-mg
test preparations was or better, in 62.5% of
of the
group.
No
25-mg
group,
significant
and
differences
were noted in global improvement, safety, or usefulness among the three dose groups. As shown in Table IV, 15 instances of side effects were observed in II patients (7.6%): malaise (7 instances), stuffiness of the ear (2 instances), and I instance
each
of
dry
mouth,
heaviness
the head,
of
perspiration,
dysarthria, increased GOT, and increased GPT. The frequency of side effects increased with dose, although not significantly. These effects were “mild” in nine and “moderate” in two patients (malaise and heaviness of head, perspiration and increase in GPT). The latter belonged to the 50-mg group.
FOR
Because values for
of the overall low rate usefulness were similar
improvement =
in all three
groups
effects, the of general
(i.e.,usefulness
Global improvement was statistically analyzed. Patients were classified according to the severity, cause, and type of insomnia; concomitant medication; 66-85 years); and presence
presence age (15-19, or absence
or absence of 20-65, and of hypnotic
medication within I month before the beginning of the study. No significant differences were observed among the patients except between and not previously treated. There nificant differences (other than treated) seen among the patients
groups
evaluated
factors orders
(age, [type,
concomitant vious mary As
according
medication,
treatment diseases). noted above,
to specific background
for
there
within
each
I month,
significant had not
pri-
differences been treated
before beginning hydrochloride.
ad-
64 untreated patients were global improvement was better in the untreated
group (Table V). Global improvement group
of pre-
within
were
When 80 treated versus evaluated separately, found to be significantly
in each
disof
presence/absence insomnia
between subjects who had and for insomnia within I month ministration of diphenhydramine
groups
those previously were also no sigtreated vs. nonin the three dose
sex, inpatient/outpatient, sleep severity, cause], presence/absence
had no significant treated or untreated
IV
of side to those
safety + global improvement).
pared
TABLE
INSOMNIA
according (Table
VI).
influence patients of the
two
Treated
(N
to dose was Patient
com-
background
on the previously or among the dose classifications.
Side Effects Side Effects Dose (mg) No. of Patients
12.5
25
50
48
50
46
1
Malaise of mouth Heaviness of head Perspiration Stuffiness of ear Dysarthria Increase in GOT Increase in GPT side
effects
Frequency (No. of patients with side effects/No. of allpatients)
2.1%
group,
25.8%
were
80). Insomnia was at at least “slightly imin the 12.5-mg group. at least
“improved”
1
1
thus, no evidence
1
were “none” in 96% of the 12.5 mg group, 83.8% of the 25-mg group, and 83.4% of the 50-mg group in a dose-dependent manner, but this dose dependency
5 4
9 6
8.0%
13.0%
4 1
Symptoms and abnormal laboratory findings considered related to the test drug, or the relationship of which to the test drug was unknown. Differences in the frequency of side effects according to dose were not significant (X2-test).
MISCELLANEOUS
25-mg
=
1 1 1
2
1
1 1
In the
in 40% and of the patients
and 48.4% were at least “slightly improved.” For the 50-mg group, 20.8% were at least “improved,” and 58.3% were at least “slightly improved.” There was no significant difference between the groups, and
Dryness
No. of side effects No. of patients with
Patients Previously least “improved” proved” in 56%
was
not
statistically
for dose
dependency.
significant.
Neither
significant differences in the evaluation ness according to dose. Patients
Not
Previously
Treated
(N
=
64).
condition of these patients was at least in 43.5% and at least “slightly improved” the 12.5-mg group. In the 25-mg group,
Side
effects
were
there
of useful-
The
general
“improved”
in 69.6% 47.4%
of
were
1045
KUDO
AND
KURIHARA
TABLE
(Analyses Global Patient
General Evaluations
Background
Markedly Improved
Total Previous
Yes
treatment for sleep disorders
No
Values in the tables
are the numbers
at least
“improved”
and
Improved
21
35
(15)
(39)
of patients;
78.9%
were
No Change
35 (63)
40 (91)
16
(29)
20 (54)
27 (87)
19 (52)
15 (75)
13
1
(95)
(97)
Treated
“slightly
at least
25 50 Total
Not Treated
12.5
4 (56.0) 7
8 (88.0)
(25.8)
(48.4)
(4.2)
4 (20.8)
9 (58.3)
7 (87.6)
7 (8.8)
16 (28.8)
20 (53.8)
27 (87.4)
6 (69.6) 6 (78.9) 3
4
(43.5)
50
Total
(13.6) 14
(63.6) 19
(21.9) 21 (14.6)
(51.6) 35 (38.9)
4 (47.4) 11
Analyses by patient classification according to whether treatment made for sleep disorders within 1 month before the administration drug.
1046
#{149} J CIln Pharmacol
1990:30:1041-1048
0011
(100)
Improvement
8 (40.0) 4
6
Total
=
VI
Slightly improved
(26.1) 5 (26.3) 3
25
i
2
12.5-mg group, 94.7% of the 25-mg group, and 81.8% of the 50-mg group in a dose-dependent manner, but the dose dependency was not statistically significant. No significant differences could be found in usefulness according to dose. In the drug-dependency test items, requests to continue drug administration were made by nine patients (6.7%) on day 14 of administration. This
improved
2 (8.0) 4 (12.9) 1
5
(100) 3 (100)
Improvement Global
12.5
U-test
5% in parentheses.
cumulative
Global
Markedly Improved
Unknown
8
7
TABLE
Dose (mg)
Aggravated
(9)
improved.” For the 50-mg group, 63.6% were at least “improved” and 77.3% were at least “slightly improved.” The percentages were higher than those in previously treated patients at each dose and showed a dose-dependent increase, although the differences in percentages according to dose were not significant. The side effects were “none” in 95.7% of the
Treated for Sleep Disorder
General Classification
Improvement
Slightly Improved
(97) 7 (96)
14 (22)
by Patient
No Change
Aggravated
Unknown
12
2 (96.0) 2
1 (100) 2
(87.0)
(93.5)
(100)
7
3 (100) 7 (96.2)
3
31
80
-
-
23
-
-
19
(100) 4 (100) 2
1
2
(90.9)
(100)
15 (75.0)
13 (95.3) 40 (91.0)
1 (96.9) 8 (96.5)
2 (100) 5 (100)
had been of the test
25
(100)
(86.4)
35
H-test
24
-
(77.3)
(63.2)
Total
Values in the tables are the numbers ns: not significant.
of patients;
22
cumulative
ns
64 144
% in parentheses.
EFFICACY
OF
FOR
DIPHENHYDRAMINE
INSOMNIA
V Evaluations According
to Patient
Background) Usefulness
Safety None
Mild
Safety Moderate
128
9
2
(89)
(95)
(97) 2 (96)
705 (87) 58
(94) 4 (97)
(91)
Severe
-
-
Drug
one
patient
with
the
because
-
2 (100)
(8) 13
ns
(20)
graded
(3.2%)
drug.
as (+) in only
of his
Before
DISCUSSION Since chloride
the
antihistaminic has been shown
diphenhydramine
hydro-
to induce drowsiness, the clinical value of the drug is seen as a hypnotic agent in Japan. In our previous study on patients with insomnia using the test drug administered by the fixed-flexible method in 25- to 75-mg doses, diphenhydramine hydrochloride was found to have sufficient hypnotic effect and safety.12 However, this effect was not enhanced at doses above 50 mg, and the optimal dose could not be determined. The current study was
done blind No
found
to determine the optimal regimen of 3 doses of 12.5, statistically
significant
in global improvement
dose by a double25,
differences
and
50
mg. could
7
5
(97) 7 (96)
21
14
(53)
(75)
(92) 31 (88) 14 (97)
(100) 3 (100) 2 (100)
Unknown
group
(Table
II). Dose
.000
P
effects. the agent
adequately safe and it may find clinical as a safe and useful night-time sleep aid. Global improvement was influenced by patient had received previous treatment. the 144 patients in the study had been treated for insomnia, and 64 had not. provement was significantly higher only
treated
U-test
dependence
to be
application whether Eighty
a of
previously Global in the
imun-
was
ob-
served of the have pared
in the untreated group after further analysis results (Table V). Essentially the same findings been reported by Sunshine et al,9 who comthe results of the same three doses of diphenhydramine hydrochloride (each administered to about 180 patients) with those of a placebo in patients having mild insomnia (75% of whom had not been previously treated). They found each dose of diphenhydramine hydrochloride to be more effective than the placebo and its effect to be enhanced dose dependently from 12.5 to 50 mg. This indicates that diphenhydramine hydrochloride has dose-dependent hypnotic effects at doses of 50 mg or below in patients who were not previously treated for insomnia. The hypnotic effects of this agent were not dose dependent in patients who had received previous hypnotic treatments. Additional studies must be conducted to determine the proper diphenhydramine hydrochloride dose levels that should be administered clinically to these patients.
be
for these three doses,
and even at 12.5 mg the hypnotic effect was unexpectedly high. Thus, there was no evidence to indicate a dose-dependent difference in efficacy (Table II). Side effects were not severe in any patient (Table
MISCELLANEOUS
45
(60) 12 (49)
Undesirable
III),and there were no “hang-over” Overall, these findings indicate
after
of adminis-
strong desire to continue the start of the study this patient had “itching” as a side effect of benzodiazepine therapy, but this disappeared with diphenhydramine hydrochloride. The hypnotic effect of the test drug was sufficient after the change in therapy. The patient strongly desired to continue the test drug and was thus graded as (+); however, considering the lack of other signs of drug dependence as discussed earlier, this preference by the patient was consequently not considered a sign of habituation. test
26
(42) 21 (34)
19
(13) 6
(100)
was
42
5
(100) 3
-
dependence
Not Useful
Useful
U-test
number had decreased to four patients the second week following completion
tration.
Slightly Useful
Very Useful
Unknown
The authors thank T. Sakai, MD; Y. Kawakita, MD; T. Nishimura, MD; M. Saito, MD; T. Nakajima, MD; M. Hanada, MD; K. Nishinuma, MD; C. Igawa, MD; Y. Higashi, MD, and the participation of N. Motomura, MD; 0. lnoue, MD; M. Hayashi, MD; H. Onishi, MD; T. Chikami, MD; E. Hirayama. MD; D. Furutsuka,
1047
AND
KUDO
MD: K. Tada, MD; H. Suzuki. MD; M. Takeda, MD; MD; H. Yamane, MD; E. Kitamura, MD; K. Akashi, zaki, MD; S. Uruha, MD; N. Nakamukae, MD; T. Kagano, MD; A. Murata, MD; T. Kinoshita, MD; Y. K. Nobuhara, Inoue, MD;
Taniguchi,
MD; R. Yura, Kasa, MD;
MD; N. Iwase, H. Kawamura,
MD; N. Imaoka,
T. Kususe, Fujimoto, Rhoto
and
M.
MD; S. Yamashita,
MD; H. Osawa, MD; H. Okamoto, Pharmaceutical
assisted
MD; MD:
Y. Nakamura, MD; K. MiyaOno, MD; Y. Okajima, MD;
K. Fukui, M. lida,
MD; MD;
MD; S. Oomi,
K. K.
MD;
MD; H. Oribe, MD; S. Kitajima, MD; Y. MD; S. Tsutsumi, MD; M. Shiba, MD. Co. provided samples of the test drug
in the statistical
analysis.
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1984;7:137-141.
5. Kales A, Malmstrom logical and biochemical
1048
FJ, Roth
Sleep, physiology and pathology. J. B. Lippincott, 1970:331-343.
11.
3. Noell WK, Chinn HI, Haberer CE: Electroencephalographic evaluation of the sedative effects of antihistaminic drugs. States Air Force 1955: Report No. 55-35. 4. Roehrs antihistamines.
hypnotics: delphia,
9. Sunshine A, Zighelboim phenhydramine, methapyrilene, I 978;1 8:425-431.
REFERENCES
GW, Schultz of diphenhydramine 050041.
KURIHARA
H,
pa-
H: Hypnotic Medical
Y: A clinical dipherihydramine
Med
H, Schiller
family practice 1983;23:235-242.
1989;5:1047-1074
evaluation
effect of resConsultation of hyphydrochlo(Japanese).
Hirose T: Double-blind comparison of (fludiazepam) diazepam and placebo on and a tentative draft of dependency Evaluation 1977;5:341-368 (Japa-
Kudo,
MD,
and
Masanao
Kurihara,
of
MD
The usefulness of the antihistaminic agent diphenhydramine hydrochloride was evaluated using a double-blind procedure at sleeping doses of 12.5, 25, and 50 mg in 144 psychiatric patients with insomnia. The general condition of the patients with insomnia was at least “slightly improved” in 62.5% (12.5-mg group), 60% (25-mg group), and 67.4% (50-mg group) after treatment with the test drug for 2 weeks. Side effects were observed in a total of 11 patients (7.6%) but were not severe. No symptoms suggestive of drug dependence were evident. Global improvement was not influenced by patient background factors except for the presence or absence of previous treatment for insomnia. The hypnotic effect of diphenhydramine hydrochloride was significantly greater in patients who had not been treated previously. A dose-dependent increase in the hypnotic effect was also seen in patients who had not received any previous treatment. Diphenhydramine hydrochloride thus appears to be effective in the treatment of insomnia, but the appropriate dosage will depend on previous medical treatment of insomnia.
R ecently,
the number of patients complaining of insomnia is increasing in all clinical fields. Also, with the general aging of the population, insomnia is becoming more prevalent in the elderly. Drugs based on specific benzodiazepine derivatives that exhibit a strong hypnotic effect have been used as the primary source of hypnotics in the treatment of insomnia. Their use, however, should be restricted because they produce various side effects and drug dependence. Similar problems are also seen in patients who have complications due to disease and otherwise show a general decline in their physical condition. Consequently, hypnotics with milder adverse effects are essential. The antihistaminic agent, diphenhydramine hydrochloride, has long been known to produce “drowsiness,”1 and this effect has been used empirically for insomnia. The effect of this agent on sleep From the Institute of Clinical Pharmacology (Dr. Yoshio Kudo) Aino Hospital, Osaka, Japan, and the Department of Psychiatry (Dr. Masanao Kurihara, Controller) Toranomon Hospital, Tokyo, Japan. Source of preparations: Rhoto Pharmaceutical Co., Ltd. 1-8-1, Tatsuminishi Ikuno-ku, Osaka 544, Japan. Address for reprints: Yoshio Kudo, MD,
Aino Hospital,
11-18,
J Clin Pharmacol
Takada-cho,
1990;30:1041-1048
Ibaraki, Osaka 567, Japan.
EEGs
has
also
been
widely
studied,
with
previous
reports indicating that it elongates sleeping time2 and decreases sleep latency2 and percentages of REM sleep.2’5 On the basis of these facts, there have been several clinical studies, including double-blind trials fulness
in the United States,61#{176} to determine of diphenhydramine hydrochloride
the
useas a
sleeping aid. Some preparations containing this agent have recently become commercially available as nonprescription night-time sleep aids because of the earlier test results. In Japan, however, only the Ookuma study was conducted to determine the optimal dose of the agent. In this study, the sleep-inducing effect of diphenhydramine hydrochloride was tested in some patients.11 We previously evaluated the hypnotic effects and safety of three dose levels (25, 50, and 75 mg) of diphenhydramine hydrochloride by the fixed-flexible method in 142 psychiatric patients complaining of insomnia.12 Clinically sufficient hypnotic effects were observed at all doses with satisfactory safety and little drug dependence, indicating it to be useful. The effects of the drug sharply increased when its dose was increased from 25 to 50 mg but did not appreciably
1041
KUDO
increase
from
appropriate
50 to 75 mg. Thus, as the
maximum
AND
50 mg is considered suitable
dose.
In consideration of the aforementioned, the current study was carried out to determine the relationship among dosage, efficacy, and safety of diphenhydramine hydrochloride administered in doses of 12.5, 25, or 50 mg to psychiatric patients with insomnia. This was a double-blind placebocontrolled those
in
our
procedure previous
involving study.12
patients
similar
to
Subjects Subjects for the study were selected from inpatients and outpatients who reported insomnia to the psychiatric departments of the 24 institutions participating in the study. Initially, 147 patients diagnosed with insomnia, neurosis, or depression were chosen. The study protocol was approved by each institutional review board, and all patients were fully informed as to the nature of the experiment. All gave their consent for participation in this study.
Three test
patients preparation
who
were previously were excluded
administered from the study,
and analysis was carried out on data from the remaining 144 patients. Table I shows the background data of these patients. There were no significant differences in these data among the three dose groups.
Test
Preparations
The subjects regimen by
and
Procedure
were randomly the controller
assigned to each of the study (M.K.), 25, and 50 mg of the
separately received 12.5, once a day for 2 weeks before sleeping. record form was kept for each volunteer observations on the state of the patient’s following four preparations were used:
dose and
drug A patient to record sleep. The (1) 12.5-mg
diphenyhydramine hydrochloride tablet (white) (2) 25-mg diphenyhydramine hydrochloride tablet (white) (3) 25-mg diphenyhydramine hydrochloride tablet (blue) (4) placebo (blue). These preparations the combinations
were listed.
administered
for 2 weeks
There was not a washout period for patients who had received other hypnotic agents before this study. 12.5-mg group: 12.5mg tablet (white) + placebo (blue) 25-mg group: 25-mg tablet (white) + placebo (blue) 50-mg group: 25-mg tablet (white) + 25-mg tablet (blue). Patients were instructed to take one white and one blue tablet once a day before sleeping. Other hypnotic agents or antihistaminic preparations were prohibited during administration of the in
1042
#{149} J Clin Pharmacol
1990;30:1041-1048
test drug. Consumption of alcoholic beverages, fee, or tea before bedtime was also forbidden. necessary for the treatment of primary diseases permitted on the condition that they and their would not be altered during this study.
Observation Sleep
and
cofDrugs were doses
Evaluation
and
Quality
sician assessed by patient daily
METHODS
the
KURIHABA
Side
Effects.
Each
the quality of sleep records and patient
attending
phy-
and side inquiries.
effects
The patients were examined for the onset of sleep, state of sleep, interruption of sleep, dreams, duration of sleep, duration of interruptions of sleep, mental and physical conditions on awakening, and presence or absence of factors disturbing sleep. Routine blood biochemical studies and urinalysis were conducted before and after drug administration. Drug
Dependence.
sheet
developed
Based
by
on
Kurihara
the
dependence
et al,13
the
check
following
signs of drug dependence were examined: previous medications, drug resistance, increase in dosage, requests for continued use of drugs, symptoms after discontinuation of administration, and lessening of insomnia after discontinuation of administration. Drug dependence was comprehensively graded as
(+): positive;
(±): questionable;
General Evaluation. Global on change in the features tient inquiry as follows: (2) improved; (3) slightly (5)
(-):
negative.
improvement was based of sleep and results of pa(1) markedly improved; improved; (4) no change;
aggravated.
The safety of the test drug was evaluated using the following scale based on side effects: (1) none; (2) mild (side effects requiring no particular treatment); (3) moderate (side effects requiring treatment but administration continued); (4) severe (administration discontinued due to side effects). Usefulness safety; of usefulness:
the
useful;
not
and
Statistical
(4)
was based on general improvement lower of the two determined the level (1) very useful; (2) useful; (3) slightly
useful;
(5) undesirable.
Analysis
The Kruskal-Wallis h-test was used to analyze the difference of two background factors (age of patients, severity of sleep disorders) and to compare three general evaluation parameters (global improvement, safety, usefulness) among the three dose groups. This test was also used for analyzing the influence of five background factors (age of patients, sleep dis-
EFFICACY
OF
DIPHENHYDRAMINE
TABLE
(Analysis
FOR
INSOMNIA
I
Background Factors by Patient Classification According
to Dose)
Dose (mg) Background
Factors
12.525
Total Sex Male Female Inpatient/outpatient Inpatient Outpatient Age (years)
Total
46
144
48
50
17 31
24
19
26
27
60 84
11 37
10 40
14 32
35 109
7 5 6
3 1 13 9
4 14 25 25
16 4 4
20
7
43
6 6
7 6
17 16
35 13
35 15
30 16
100 44
26
20
19
21
30
24 3
65 75 4
ns
94 36 9 2 4
ns
-
34 6 2 2 1
15-19
1
20-29 30-39 40-49 50-59 60-65 66-82
6 7
Concomitant
50
Results of H-test or X2-test
-
10
ns ns
ns
medication
Yes
No
ns
Severity Mild
Moderate Severe Sleep Disorders Cause Psychogenic Depression Organic changes of brain Physicalsymptoms Others Type
1
-
30
30
13 3
17 4
-
-
3 33
35
31
99
Unsound sleep
25
25
26
76
Interruption of sleep
20 11 2
17 13 1
14 10 2 -
51 34 5 1
Difficulty
in falling
asleep
Early awakening Dreamingtoo
much
Others Treatments within 1 month before administration
1
-
Yes
25
31
24
80
No
23
19
22
64
16 15 15 2
23 14 12 1
20 5 18 3
59 34 45 6
Primary disease Neurosis Depression Sleep disorders Others Values in the table are the numbers ns: not significant
MISCELLANEOUS
ns
of patients.
1043
KUDO
AND
KURIHARA
TABLE Sleep
II
Quality Dosage
Parameter State of Interruption Feelings Duration Severity ns *
sleep* of sleep* on awakening* of sleept of insomnia*
= not significant. Wilcoxon signed
rank
P
Groups
12.5
25.0
ns
ns
ns ns ns
ns ns ns
=
.042
(mg) 50.0
P
=
Overall
.0036
P = P = P = P = P =
ns ns
P
=
ns
.0099 ns
.0012 .0130
.0 168 .0008 .0002
test.
t I-test.
orders
the
[severity,
cause,
type],
effects of the drug. Additionally, the h-test
three
general
dose ground
regimens factor.
evaluation
in Each
primary
was
used
diseases)
to compare of the
parameters
subgroups dose regimen
on
classified was
square
test:
sex,
orders (cause, tant medication,
the three
by backevaluated in
inpatient/outpatient,
sleep
type),
treatment
within
Ordinal compared
scale before
presence/absence presence/absence I month, and primary
parameters and after
the
dis-
of concomiof previous diseases.
of sleep quality administration
were of the
nine subgroups, one subgroup for each background factor: age, sex, inpatient/outpatient, sleep disorders (type, severity, cause), presence/absence of concomitant medication, presence/absence of previous treatment for insomnia within 1 month, and primary diseases. The Mann-Whitney u-test was used to analyze the influence of four background factors (sex, inpatient/outpatient, presence/absence of concomitant
RESULTS Each feature of sleep and severity of insomnia was compared before and after administration. Overall, the state of sleep, its interruption, feelings on
medication, ment within
awakening, duration of sleep, nia significantly improved
presence/absence I month) on
drug with Wilcoxon’s signed rank test, and intervalscaled parameters were compared with the paired test. Differences were regarded as significant at a probability of less than 5%.
of previous treatof the drug.
the effects
Distribution of the following seven background factors and the frequency of side effects were cornpared among the three dose groups using the chi-
(Table II). However, nificant improvement Global improvements
TABLE Global Markedly Improved
Improved
8 (16.7)
12 (41.7)
and after
severity of insomadministration
specific dose groups showed sigfor only some parameters. are shown in Table III. The
ill
Improvement
Slightly Improved
No Change
Aggravated
Unknown
Total
15 (93.8) 16
2 (97.9)
1 (100)
48
2 (96.0) 4 (95.7) 8 (96.5)
2 (100) 2 (100) 5 (100)
50
H-test
Dose (mg) 12.5 25
9
8
50
(18.0) 4 (8.7)
(34.0) 15 (41.3)
21 (14.6)
35 (38.9)
Total Values in the tables
1044
are the numbers
#{149} .i CIln Pharmacol
of patients;
1990;30:1O41-1048
10 (62.5) 13 (60.0) 12 (67.4) 35 (63.2) cumulative
% in parentheses.
(92.0) 9 (87.0) 40 (91.0) ns: not significant.
46 144
ns
EFFICACY
OF
DIPHENHYDRAMINE
general condition of the patients was at least “slightly improved” in 62.5% of the 12.5-mg group, 60% of the 25-mg group, and 67.4% of the 50-mg group. Concerning safety, side effects were “none” in 95.8% of the 12.5-mg group, 88% of the 25-mg group, and 82.6% of the 50-mg group. No significant differences in safety were observed among subgroups classified
according
to different
background
factors:
age, sex, inpatient/outpatient, sleep disorders (type, severity, cause), presence/absence of concomitant medication, presence/absence of previous treatment for insomnia within I month, and primary diseases. evaluated
the
The usefulness as “slightly
12.5-mg
60.9%
of the
of the useful”
group,
58%
50-mg
test preparations was or better, in 62.5% of
of the
group.
No
25-mg
group,
significant
and
differences
were noted in global improvement, safety, or usefulness among the three dose groups. As shown in Table IV, 15 instances of side effects were observed in II patients (7.6%): malaise (7 instances), stuffiness of the ear (2 instances), and I instance
each
of
dry
mouth,
heaviness
the head,
of
perspiration,
dysarthria, increased GOT, and increased GPT. The frequency of side effects increased with dose, although not significantly. These effects were “mild” in nine and “moderate” in two patients (malaise and heaviness of head, perspiration and increase in GPT). The latter belonged to the 50-mg group.
FOR
Because values for
of the overall low rate usefulness were similar
improvement =
in all three
groups
effects, the of general
(i.e.,usefulness
Global improvement was statistically analyzed. Patients were classified according to the severity, cause, and type of insomnia; concomitant medication; 66-85 years); and presence
presence age (15-19, or absence
or absence of 20-65, and of hypnotic
medication within I month before the beginning of the study. No significant differences were observed among the patients except between and not previously treated. There nificant differences (other than treated) seen among the patients
groups
evaluated
factors orders
(age, [type,
concomitant vious mary As
according
medication,
treatment diseases). noted above,
to specific background
for
there
within
each
I month,
significant had not
pri-
differences been treated
before beginning hydrochloride.
ad-
64 untreated patients were global improvement was better in the untreated
group (Table V). Global improvement group
of pre-
within
were
When 80 treated versus evaluated separately, found to be significantly
in each
disof
presence/absence insomnia
between subjects who had and for insomnia within I month ministration of diphenhydramine
groups
those previously were also no sigtreated vs. nonin the three dose
sex, inpatient/outpatient, sleep severity, cause], presence/absence
had no significant treated or untreated
IV
of side to those
safety + global improvement).
pared
TABLE
INSOMNIA
according (Table
VI).
influence patients of the
two
Treated
(N
to dose was Patient
com-
background
on the previously or among the dose classifications.
Side Effects Side Effects Dose (mg) No. of Patients
12.5
25
50
48
50
46
1
Malaise of mouth Heaviness of head Perspiration Stuffiness of ear Dysarthria Increase in GOT Increase in GPT side
effects
Frequency (No. of patients with side effects/No. of allpatients)
2.1%
group,
25.8%
were
80). Insomnia was at at least “slightly imin the 12.5-mg group. at least
“improved”
1
1
thus, no evidence
1
were “none” in 96% of the 12.5 mg group, 83.8% of the 25-mg group, and 83.4% of the 50-mg group in a dose-dependent manner, but this dose dependency
5 4
9 6
8.0%
13.0%
4 1
Symptoms and abnormal laboratory findings considered related to the test drug, or the relationship of which to the test drug was unknown. Differences in the frequency of side effects according to dose were not significant (X2-test).
MISCELLANEOUS
25-mg
=
1 1 1
2
1
1 1
In the
in 40% and of the patients
and 48.4% were at least “slightly improved.” For the 50-mg group, 20.8% were at least “improved,” and 58.3% were at least “slightly improved.” There was no significant difference between the groups, and
Dryness
No. of side effects No. of patients with
Patients Previously least “improved” proved” in 56%
was
not
statistically
for dose
dependency.
significant.
Neither
significant differences in the evaluation ness according to dose. Patients
Not
Previously
Treated
(N
=
64).
condition of these patients was at least in 43.5% and at least “slightly improved” the 12.5-mg group. In the 25-mg group,
Side
effects
were
there
of useful-
The
general
“improved”
in 69.6% 47.4%
of
were
1045
KUDO
AND
KURIHARA
TABLE
(Analyses Global Patient
General Evaluations
Background
Markedly Improved
Total Previous
Yes
treatment for sleep disorders
No
Values in the tables
are the numbers
at least
“improved”
and
Improved
21
35
(15)
(39)
of patients;
78.9%
were
No Change
35 (63)
40 (91)
16
(29)
20 (54)
27 (87)
19 (52)
15 (75)
13
1
(95)
(97)
Treated
“slightly
at least
25 50 Total
Not Treated
12.5
4 (56.0) 7
8 (88.0)
(25.8)
(48.4)
(4.2)
4 (20.8)
9 (58.3)
7 (87.6)
7 (8.8)
16 (28.8)
20 (53.8)
27 (87.4)
6 (69.6) 6 (78.9) 3
4
(43.5)
50
Total
(13.6) 14
(63.6) 19
(21.9) 21 (14.6)
(51.6) 35 (38.9)
4 (47.4) 11
Analyses by patient classification according to whether treatment made for sleep disorders within 1 month before the administration drug.
1046
#{149} J CIln Pharmacol
1990:30:1041-1048
0011
(100)
Improvement
8 (40.0) 4
6
Total
=
VI
Slightly improved
(26.1) 5 (26.3) 3
25
i
2
12.5-mg group, 94.7% of the 25-mg group, and 81.8% of the 50-mg group in a dose-dependent manner, but the dose dependency was not statistically significant. No significant differences could be found in usefulness according to dose. In the drug-dependency test items, requests to continue drug administration were made by nine patients (6.7%) on day 14 of administration. This
improved
2 (8.0) 4 (12.9) 1
5
(100) 3 (100)
Improvement Global
12.5
U-test
5% in parentheses.
cumulative
Global
Markedly Improved
Unknown
8
7
TABLE
Dose (mg)
Aggravated
(9)
improved.” For the 50-mg group, 63.6% were at least “improved” and 77.3% were at least “slightly improved.” The percentages were higher than those in previously treated patients at each dose and showed a dose-dependent increase, although the differences in percentages according to dose were not significant. The side effects were “none” in 95.7% of the
Treated for Sleep Disorder
General Classification
Improvement
Slightly Improved
(97) 7 (96)
14 (22)
by Patient
No Change
Aggravated
Unknown
12
2 (96.0) 2
1 (100) 2
(87.0)
(93.5)
(100)
7
3 (100) 7 (96.2)
3
31
80
-
-
23
-
-
19
(100) 4 (100) 2
1
2
(90.9)
(100)
15 (75.0)
13 (95.3) 40 (91.0)
1 (96.9) 8 (96.5)
2 (100) 5 (100)
had been of the test
25
(100)
(86.4)
35
H-test
24
-
(77.3)
(63.2)
Total
Values in the tables are the numbers ns: not significant.
of patients;
22
cumulative
ns
64 144
% in parentheses.
EFFICACY
OF
FOR
DIPHENHYDRAMINE
INSOMNIA
V Evaluations According
to Patient
Background) Usefulness
Safety None
Mild
Safety Moderate
128
9
2
(89)
(95)
(97) 2 (96)
705 (87) 58
(94) 4 (97)
(91)
Severe
-
-
Drug
one
patient
with
the
because
-
2 (100)
(8) 13
ns
(20)
graded
(3.2%)
drug.
as (+) in only
of his
Before
DISCUSSION Since chloride
the
antihistaminic has been shown
diphenhydramine
hydro-
to induce drowsiness, the clinical value of the drug is seen as a hypnotic agent in Japan. In our previous study on patients with insomnia using the test drug administered by the fixed-flexible method in 25- to 75-mg doses, diphenhydramine hydrochloride was found to have sufficient hypnotic effect and safety.12 However, this effect was not enhanced at doses above 50 mg, and the optimal dose could not be determined. The current study was
done blind No
found
to determine the optimal regimen of 3 doses of 12.5, statistically
significant
in global improvement
dose by a double25,
differences
and
50
mg. could
7
5
(97) 7 (96)
21
14
(53)
(75)
(92) 31 (88) 14 (97)
(100) 3 (100) 2 (100)
Unknown
group
(Table
II). Dose
.000
P
effects. the agent
adequately safe and it may find clinical as a safe and useful night-time sleep aid. Global improvement was influenced by patient had received previous treatment. the 144 patients in the study had been treated for insomnia, and 64 had not. provement was significantly higher only
treated
U-test
dependence
to be
application whether Eighty
a of
previously Global in the
imun-
was
ob-
served of the have pared
in the untreated group after further analysis results (Table V). Essentially the same findings been reported by Sunshine et al,9 who comthe results of the same three doses of diphenhydramine hydrochloride (each administered to about 180 patients) with those of a placebo in patients having mild insomnia (75% of whom had not been previously treated). They found each dose of diphenhydramine hydrochloride to be more effective than the placebo and its effect to be enhanced dose dependently from 12.5 to 50 mg. This indicates that diphenhydramine hydrochloride has dose-dependent hypnotic effects at doses of 50 mg or below in patients who were not previously treated for insomnia. The hypnotic effects of this agent were not dose dependent in patients who had received previous hypnotic treatments. Additional studies must be conducted to determine the proper diphenhydramine hydrochloride dose levels that should be administered clinically to these patients.
be
for these three doses,
and even at 12.5 mg the hypnotic effect was unexpectedly high. Thus, there was no evidence to indicate a dose-dependent difference in efficacy (Table II). Side effects were not severe in any patient (Table
MISCELLANEOUS
45
(60) 12 (49)
Undesirable
III),and there were no “hang-over” Overall, these findings indicate
after
of adminis-
strong desire to continue the start of the study this patient had “itching” as a side effect of benzodiazepine therapy, but this disappeared with diphenhydramine hydrochloride. The hypnotic effect of the test drug was sufficient after the change in therapy. The patient strongly desired to continue the test drug and was thus graded as (+); however, considering the lack of other signs of drug dependence as discussed earlier, this preference by the patient was consequently not considered a sign of habituation. test
26
(42) 21 (34)
19
(13) 6
(100)
was
42
5
(100) 3
-
dependence
Not Useful
Useful
U-test
number had decreased to four patients the second week following completion
tration.
Slightly Useful
Very Useful
Unknown
The authors thank T. Sakai, MD; Y. Kawakita, MD; T. Nishimura, MD; M. Saito, MD; T. Nakajima, MD; M. Hanada, MD; K. Nishinuma, MD; C. Igawa, MD; Y. Higashi, MD, and the participation of N. Motomura, MD; 0. lnoue, MD; M. Hayashi, MD; H. Onishi, MD; T. Chikami, MD; E. Hirayama. MD; D. Furutsuka,
1047
AND
KUDO
MD: K. Tada, MD; H. Suzuki. MD; M. Takeda, MD; MD; H. Yamane, MD; E. Kitamura, MD; K. Akashi, zaki, MD; S. Uruha, MD; N. Nakamukae, MD; T. Kagano, MD; A. Murata, MD; T. Kinoshita, MD; Y. K. Nobuhara, Inoue, MD;
Taniguchi,
MD; R. Yura, Kasa, MD;
MD; N. Iwase, H. Kawamura,
MD; N. Imaoka,
T. Kususe, Fujimoto, Rhoto
and
M.
MD; S. Yamashita,
MD; H. Osawa, MD; H. Okamoto, Pharmaceutical
assisted
MD; MD:
Y. Nakamura, MD; K. MiyaOno, MD; Y. Okajima, MD;
K. Fukui, M. lida,
MD; MD;
MD; S. Oomi,
K. K.
MD;
MD; H. Oribe, MD; S. Kitajima, MD; Y. MD; S. Tsutsumi, MD; M. Shiba, MD. Co. provided samples of the test drug
in the statistical
analysis.
1. Goodman LS, Gilman A: The Pharmacological Basis peutics. (Seventh edition), Macmillan Publishing 1985:741-752.
of TheraCo., Inc.
2. Vogel tiveness Volume
the effecaid. OTC
EN,
TA,
Tietz
Sleep
Swenson GW: hydrochloride
El, Zorick
#{149} J Clin Pharmacol
6. Jick
H. Slonc
notics:
A controlled
D, Shapiro
Concerning as a sleep
T: Daytime
sleepiness
8. Teutsch C, Mahler Brown BW: Hypnotic lene. and pentobarbital.
EJ, Scharf MB, Rubin RT: Psychophysiochanges following use and withdrawal
1990;30:1041-1048
10. Rickels Wemstock tients:
ride,
and
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