British Journal of Obstetrics and Gynaecology June 1978. Vol85. pp 472-475
A STUDY OF THE EFFECTIVENESS OF PROPRANOLOL IN MENOPAUSAL HOT FLUSHES BY
JEANCOOPE,General Practitioner SUSANWILLIAMS, Student Bollington Group Practice, Bollington, Cheshire AND
J. S . PATTERSON, Medical Adviser Clinical Research Department, ICI Pharmaceuticals Division, Mereside Alderley Park, Macclesjeld, Cheshire Summary A prospective, double-blind, randomized comparison of propranolol, 40 mg three times daily, and matching placebo showed propranolol to be no more effective than placebo in controlling hot flushes in a group of 25 perimenopausal women. Other menopausal symptoms, such as insomnia and palpitations, were equally unaffected. However, a very close correlation was found between the daily atmospheric temperature and the number of flushes occurring in the group.
PATIENTS AND METHODS The study was undertaken between May and September 1976 in a group practice of 7000 patients in East Cheshire; 31 menopausal patients aged 40 to 67 (mean age 53) were recruited and all had menopausal symptoms of flushing with or without palpitations and insomnia. A history of hypertension (a blood pressure of 170 mm Hg or more systolic and 105 or more diastolic), congestive cardiac failure, asthma and ischaemic heart disease disqualified a patient from entry. No hormones or tranquillizers were given during the study and any patients who had been receiving hormone therapy had their treatment discontinued at least two months before entry. Patients were allocated consecutive trial numbers at entry, given a hot flush diary card ‘and scored for severity of flushes, palpitations, insomnia and hot and cold sensations on a 0 to 4 rating, by direct questioning. Supine resting pulse and blood pressure were recorded. After a four-week period of familiarization with the flush card, the study commenced and
OESTROGENIC agents are effective in controlling menopausal symptoms (Wilson and Wilson, 1963). However, they are associated with an alteration of clotting factors (Coope et al, 1975; Poller et al, 1977) and a possible increased risk of gynaecological tumours (Smith et al, 1975). One of us (J.C.) had used propranolol for menopausal symptoms on an open basis, with some success. A formal study was organized to test this observation. As many menopausal patients are known to be placebo responders (Utian, 1972), the study was run in a prospective, controlled fashion. Propranolol was chosen as the study drug because it causes both peripheral and central beta-blockade, is of proven safety and efficacy and has been shown by several authors (Turner et al, 1965; Rowlands et al, 1965) to be an effective agent for palpitations and tachycardias-both of which are commonly associated with menopausal hot flushes. We are not aware of any previous studies comparing propranolol and placebo in this area, or of attempts to correlate hot flush rates with atmospheric temperature. 472
PROPRANOLOL AND HOT FLUSHES
the above readings were repeated at four-week intervals. All patients received a placebo tablet three times daily for four weeks. They were then issued with a second supply of identical tablets containing either propranolol, 40 mg, or placebo for the following month. All patients had a final assessment at the end of the treatment period. The results were analyzed by taking the differences of the means for the placebo and active treatment groups and comparing them in the Wilcoxon Rank Sum Test. The maximum and minimum temperature was recorded each day throughout the trial period by an independent observer (S.W.) at premises within the practice area. RESULTS Six patients failed to complete the study due to spontaneous disappearance of symptoms in the pre-treatment phase, holidays and adverse effects. These adverse effects (diarrhoea, epigastric pain, palpitations, tiredness, headache and dizziness) all occurred in the placebo group. All patients who received propranolol tolerated therapy well. There was no significant difference between the propranolol and placebo groups in hot flush rates (Table I), resting pulse and blood pressure or in the various symptom scores. All hot flush counts were then assimilated to produce a daily mean flush score which was found to correlate significantly with both the
473
minimum and maximum daily temperature recordings (Fig. 1 and Fig. 2). DISCUSSION All patients showed some improvement during the initial placebo run-in and this was maintained during the comparative phase of the study. No statistically significant difference could be detected between the propranolol and placebo groups and so it was concluded from this study that propranolol, 40 mg, three times daily was unlikely to be of value in the treatment of menopausal flushes. These findings are consistent with those of Erkkola et al (1973) who found that, in 30 castrated women, hot flushes were slightly improved by propranolol, 20 mg three times daily, but not as much as by treatment with oxazepam 15 mg three times daily. The improvement they found in both groups was similar to that produced by placebo in our study. Elsdon-Dew (1975) examined the records of 56 menopausal patients from 13 different general practices and compared the improvement in flushes on oxprenolol, 80 mg, three times daily with that produced on other regimes (oestrogens, tranquillizers or a mixture of these). Significant improvement occurred in all patients, but those on other regimes did better than those taking beta-blockers. Owing to the diversity of practices and therapeutic regimes, it is difficult to draw valid conclusions from this report. Neither of these studies was placebo-controlled.
TABLE I Mean daily hot flush counts Mean daily hot flush count Baseline -
Placebo run-in (PI
Treatment
(T)
Difference (P-T)
3.9 (27)
0.1 (1)
~~
Propranolol group
5.3 (37)
4.0 (28) ~
Placebo group
5.5 (38)
4.0
1.5
(40)
(28)
(10)
0.4
1.5
0.1
1.4
NS
NS
NS
NS
5.7
-
Difference in means _
_
_
Significance
_
~
~
Figures in brackets represent the mean weekly flush count per patient in each treatment group. NS = Not statistically significant (P>O.O5).
-
474
COOPE, WILLIAMS AND PATTERSON Number of Flushes v. Maximum Temperature
Number of Flushes v. Minimum Temperature
7
lo0l
90
. . 0.
...
x .m
n
5
60-
.-E c ._ 50-
40 2.0
3.0
5.0
4.0
40 2.0
6.0
3.0
4.0
5.0
6.0
Mean Number of Flushes Per Day
Mean Number of Flushes Per Day
Correlation Coefficient,/= 0.425 ( P~0.01)
Correlation Coefficient,J= 0.700 ( Pc0.001)
FIG.1 Relationship between number of flushes and temperature. 100
- _-__-__-= Maximum ,
/
90
i
:
.
=Mean number of Flushes =Minimum
---
---7
,I\
n
I
/", ,, ,:--..,
,\
,/
\
,,
1',
L-,
0 C c 0
.-c 0
rn
.-C 70 t 3 I
m
L
5
60
c
50
40 .
14 lune
21
28
I
8
,
7 July
I
I
I
I
I
I
I
14
I
l
l
I
I
8
1
21
,
1 I
1
1
I
I
1
28
l
1
1
PROPRANOLOL AND HOT FLUSHES
We decided to look at mean daily flush counts in the whole group of women under observation on each day to determine whether the mean daily flush count correlated with the ambient temperature. The correlation obtained confirms the observation often made by patients that hot weather coincides with more frequent flushes. These findings have importance for those planning menopausal research projects as major atmospheric temperature changes may affect the results of such studies. Similarly, clinical decisions which may precipitate a flushing attack-such as withdrawal of oestrogen therapy-would be best made during the winter months.
ACKNOWLEDGEMENTS The authors are indebted to Miss Elaine Laws for the statistical analyses.
475
REFERENCES Coope, J., Thomson, J. M., and Poller, L. (1975): Brirish Medical Journal, 4 , 139. Elsdon-Dew, R. W. (1975): Journal of International Medical Research, 3, 53. Erkkola, R., halo, E., and Punnonen, R. (1973): Annals of Clinical Research, 5, 208. Poller, L., Thomson, J. M., and Coope, J. (1977): British Medical Journal, 1, 935. Rowlands, D. J., Howitt, G., and Markman, P. (1965): British Medical Journal, 1, 891. Smith, D. C., Prentice, R., Thompson, P. J., and Herrmann, W. L. (1975): New England Journal of Medicine, 293, 1164. Turner, P., Granville-Grossman, W. L., and Smart, J. V. (1965): Lancet, 2, 1316. Utian, W. H. (1972): South African Medical Journal, 46, 732.
Wilson, R. A., and Wilson, T. A. (1963): Journal of American Geriatrics Society, 11, 347,
A STUDY OF THE EFFECTIVENESS OF PROPRANOLOL IN MENOPAUSAL HOT FLUSHES BY
JEANCOOPE,General Practitioner SUSANWILLIAMS, Student Bollington Group Practice, Bollington, Cheshire AND
J. S . PATTERSON, Medical Adviser Clinical Research Department, ICI Pharmaceuticals Division, Mereside Alderley Park, Macclesjeld, Cheshire Summary A prospective, double-blind, randomized comparison of propranolol, 40 mg three times daily, and matching placebo showed propranolol to be no more effective than placebo in controlling hot flushes in a group of 25 perimenopausal women. Other menopausal symptoms, such as insomnia and palpitations, were equally unaffected. However, a very close correlation was found between the daily atmospheric temperature and the number of flushes occurring in the group.
PATIENTS AND METHODS The study was undertaken between May and September 1976 in a group practice of 7000 patients in East Cheshire; 31 menopausal patients aged 40 to 67 (mean age 53) were recruited and all had menopausal symptoms of flushing with or without palpitations and insomnia. A history of hypertension (a blood pressure of 170 mm Hg or more systolic and 105 or more diastolic), congestive cardiac failure, asthma and ischaemic heart disease disqualified a patient from entry. No hormones or tranquillizers were given during the study and any patients who had been receiving hormone therapy had their treatment discontinued at least two months before entry. Patients were allocated consecutive trial numbers at entry, given a hot flush diary card ‘and scored for severity of flushes, palpitations, insomnia and hot and cold sensations on a 0 to 4 rating, by direct questioning. Supine resting pulse and blood pressure were recorded. After a four-week period of familiarization with the flush card, the study commenced and
OESTROGENIC agents are effective in controlling menopausal symptoms (Wilson and Wilson, 1963). However, they are associated with an alteration of clotting factors (Coope et al, 1975; Poller et al, 1977) and a possible increased risk of gynaecological tumours (Smith et al, 1975). One of us (J.C.) had used propranolol for menopausal symptoms on an open basis, with some success. A formal study was organized to test this observation. As many menopausal patients are known to be placebo responders (Utian, 1972), the study was run in a prospective, controlled fashion. Propranolol was chosen as the study drug because it causes both peripheral and central beta-blockade, is of proven safety and efficacy and has been shown by several authors (Turner et al, 1965; Rowlands et al, 1965) to be an effective agent for palpitations and tachycardias-both of which are commonly associated with menopausal hot flushes. We are not aware of any previous studies comparing propranolol and placebo in this area, or of attempts to correlate hot flush rates with atmospheric temperature. 472
PROPRANOLOL AND HOT FLUSHES
the above readings were repeated at four-week intervals. All patients received a placebo tablet three times daily for four weeks. They were then issued with a second supply of identical tablets containing either propranolol, 40 mg, or placebo for the following month. All patients had a final assessment at the end of the treatment period. The results were analyzed by taking the differences of the means for the placebo and active treatment groups and comparing them in the Wilcoxon Rank Sum Test. The maximum and minimum temperature was recorded each day throughout the trial period by an independent observer (S.W.) at premises within the practice area. RESULTS Six patients failed to complete the study due to spontaneous disappearance of symptoms in the pre-treatment phase, holidays and adverse effects. These adverse effects (diarrhoea, epigastric pain, palpitations, tiredness, headache and dizziness) all occurred in the placebo group. All patients who received propranolol tolerated therapy well. There was no significant difference between the propranolol and placebo groups in hot flush rates (Table I), resting pulse and blood pressure or in the various symptom scores. All hot flush counts were then assimilated to produce a daily mean flush score which was found to correlate significantly with both the
473
minimum and maximum daily temperature recordings (Fig. 1 and Fig. 2). DISCUSSION All patients showed some improvement during the initial placebo run-in and this was maintained during the comparative phase of the study. No statistically significant difference could be detected between the propranolol and placebo groups and so it was concluded from this study that propranolol, 40 mg, three times daily was unlikely to be of value in the treatment of menopausal flushes. These findings are consistent with those of Erkkola et al (1973) who found that, in 30 castrated women, hot flushes were slightly improved by propranolol, 20 mg three times daily, but not as much as by treatment with oxazepam 15 mg three times daily. The improvement they found in both groups was similar to that produced by placebo in our study. Elsdon-Dew (1975) examined the records of 56 menopausal patients from 13 different general practices and compared the improvement in flushes on oxprenolol, 80 mg, three times daily with that produced on other regimes (oestrogens, tranquillizers or a mixture of these). Significant improvement occurred in all patients, but those on other regimes did better than those taking beta-blockers. Owing to the diversity of practices and therapeutic regimes, it is difficult to draw valid conclusions from this report. Neither of these studies was placebo-controlled.
TABLE I Mean daily hot flush counts Mean daily hot flush count Baseline -
Placebo run-in (PI
Treatment
(T)
Difference (P-T)
3.9 (27)
0.1 (1)
~~
Propranolol group
5.3 (37)
4.0 (28) ~
Placebo group
5.5 (38)
4.0
1.5
(40)
(28)
(10)
0.4
1.5
0.1
1.4
NS
NS
NS
NS
5.7
-
Difference in means _
_
_
Significance
_
~
~
Figures in brackets represent the mean weekly flush count per patient in each treatment group. NS = Not statistically significant (P>O.O5).
-
474
COOPE, WILLIAMS AND PATTERSON Number of Flushes v. Maximum Temperature
Number of Flushes v. Minimum Temperature
7
lo0l
90
. . 0.
...
x .m
n
5
60-
.-E c ._ 50-
40 2.0
3.0
5.0
4.0
40 2.0
6.0
3.0
4.0
5.0
6.0
Mean Number of Flushes Per Day
Mean Number of Flushes Per Day
Correlation Coefficient,/= 0.425 ( P~0.01)
Correlation Coefficient,J= 0.700 ( Pc0.001)
FIG.1 Relationship between number of flushes and temperature. 100
- _-__-__-= Maximum ,
/
90
i
:
.
=Mean number of Flushes =Minimum
---
---7
,I\
n
I
/", ,, ,:--..,
,\
,/
\
,,
1',
L-,
0 C c 0
.-c 0
rn
.-C 70 t 3 I
m
L
5
60
c
50
40 .
14 lune
21
28
I
8
,
7 July
I
I
I
I
I
I
I
14
I
l
l
I
I
8
1
21
,
1 I
1
1
I
I
1
28
l
1
1
PROPRANOLOL AND HOT FLUSHES
We decided to look at mean daily flush counts in the whole group of women under observation on each day to determine whether the mean daily flush count correlated with the ambient temperature. The correlation obtained confirms the observation often made by patients that hot weather coincides with more frequent flushes. These findings have importance for those planning menopausal research projects as major atmospheric temperature changes may affect the results of such studies. Similarly, clinical decisions which may precipitate a flushing attack-such as withdrawal of oestrogen therapy-would be best made during the winter months.
ACKNOWLEDGEMENTS The authors are indebted to Miss Elaine Laws for the statistical analyses.
475
REFERENCES Coope, J., Thomson, J. M., and Poller, L. (1975): Brirish Medical Journal, 4 , 139. Elsdon-Dew, R. W. (1975): Journal of International Medical Research, 3, 53. Erkkola, R., halo, E., and Punnonen, R. (1973): Annals of Clinical Research, 5, 208. Poller, L., Thomson, J. M., and Coope, J. (1977): British Medical Journal, 1, 935. Rowlands, D. J., Howitt, G., and Markman, P. (1965): British Medical Journal, 1, 891. Smith, D. C., Prentice, R., Thompson, P. J., and Herrmann, W. L. (1975): New England Journal of Medicine, 293, 1164. Turner, P., Granville-Grossman, W. L., and Smart, J. V. (1965): Lancet, 2, 1316. Utian, W. H. (1972): South African Medical Journal, 46, 732.
Wilson, R. A., and Wilson, T. A. (1963): Journal of American Geriatrics Society, 11, 347,
