A Elsevier Scientific Publishers Ireland Ltd. 227 MAT 00436 Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study M.G.M. Bergmans’, J.M.W .M. Merkusl, R.S. Corbey2, L.A. Schellekens3 and J.M.H. Ubachs3 ‘Lkpartment of Obstetrics and Gynaecologv, Mario Ziekenhub, 5#42 AD Tilburg, ‘Department of Obstetrics and Gynaecology, Groot Ziekengasthuis, 5211 NL ‘s Hertogenbosch and 3Department of Obstetrics and Gynaecology, “De Wever” Ziekenhuis, 6419 PC Heerlen, The Netherlands (Received 18 April 1986; revision received 18 February 1987; accepted 1 July 1987) The effect of Belle@ Retard (BR) on climacteric complaints was evaluated versus a placebo in an 8-wk double-blind study, followed by a 4-wk open study in which only BR was used as medication. There was a marked decrease in complaints in both the BR and the placebo groups. Statistically significant differences were observed between the groups after 2 and 4 wk of treatment, indicating superior results with BR. After 8 wk of study however, these differences were no longer apparent. It was concluded that studies on medication for climacteric complaints should not only be placebo- controlled, but also be of at least 8 to 12 wk duration for proper evaluation. (Key words: BelIergal Retard. Climacteric complaints) Introduction Since the beginning of this century, the average life span of women has exceeded the age at menopause and the problems related to cessation of the reproductive function have become clearer [ 1,2]. This century has also seen a significant increase in the socioeconomic status of women. This improved status has been shown to be correlated with a greater readiness to consult a physician about climacteric complaints [3]. Consequently, the past 20 yr, have been a period of growing interest in the climacteric. A range of complaints associated with the climacteric were classified by Bogchelman et al. [4] into 3 groups: a. metabolic changes and changes in the urogenital tract caused by oestrogen deficiency, such as osteoporosis, colpitis, thrombosis and arteriosclerosis, Correspondence to: M.G.M. Bergmans, St. Laurentiusziekenhuis, Mgr. Driessenstraat 6, 6043 CV Roermond, Netherlands. 0378-5122/87/$03.50 0 1987 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
Transcript
AElsevier Scientific Publishers Ireland Ltd.
227
MAT 00436
Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled
‘Lkpartment of Obstetrics and Gynaecologv, Mario Ziekenhub, 5#42 AD Tilburg, ‘Department of Obstetrics and Gynaecology, Groot Ziekengasthuis, 5211 NL ‘s Hertogenbosch and 3Department of
Obstetrics and Gynaecology, “De Wever” Ziekenhuis, 6419 PC Heerlen, The Netherlands
(Received 18 April 1986; revision received 18 February 1987; accepted 1 July 1987)
The effect of Belle@ Retard (BR) on climacteric complaints was evaluated versus a placebo in an 8-wk double-blind study, followed by a 4-wk open study in which only BR was used as medication. There was a marked decrease in complaints in both the BR and the placebo groups. Statistically significant differences were observed between the groups after 2 and 4 wk of treatment, indicating superior results with BR. After 8 wk of study however, these differences were no longer apparent. It was concluded that studies on medication for climacteric complaints should not only be placebo- controlled, but also be of at least 8 to 12 wk duration for proper evaluation.
Since the beginning of this century, the average life span of women has exceeded the age at menopause and the problems related to cessation of the reproductive function have become clearer [ 1,2].
This century has also seen a significant increase in the socioeconomic status of women. This improved status has been shown to be correlated with a greater readiness to consult a physician about climacteric complaints [3]. Consequently, the past 20 yr, have been a period of growing interest in the climacteric.
A range of complaints associated with the climacteric were classified by Bogchelman et al. [4] into 3 groups:
a. metabolic changes and changes in the urogenital tract caused by oestrogen deficiency, such as osteoporosis, colpitis, thrombosis and arteriosclerosis,
Correspondence to: M.G.M. Bergmans, St. Laurentiusziekenhuis, Mgr. Driessenstraat 6, 6043 CV Roermond, Netherlands.
0378-5122/87/$03.50 0 1987 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
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ectropion urethrae, atrophic cystitis and urethritis, stress and urge incontinence and changes in body weight;
b. complaints caused by autonomic dysregulation, such as hot flushes, sweating, dysregulation of the blood flow in the distal extremities, shoulder pain, palpitations, carpal tunnel syndrome and (pseudo) angina pectoris;
c. psychosomatic complaints, often influenced by social and cultural factors, such as headaches, insomnia, hyperirritability, dizziness, depression, loss of libido and vague anxieties.
Most complaints disappear on oestrogen therapy. A cyclic low dose of natural oestrogens is recommended monthly during the last lo-12 days in combination with a progestogen.
However, oestrogen therapy is unacceptable to some women because of adverse reactions such as fluid retention, headaches or mastalgia, even at low doses. For others it is contra-indicated because of the presence or a history of oestrogen-dependent tumours such as breast carcinoma or endometrial carcinoma. Further contra-indications are a history of thrombosis or embolism, hypertension developed during oestrogen treatment, diseases of the liver (cholestatic icterus, hepatitis), cholecystitis, pancreatitis and melanoma [4]. Non- hormonal therapies have consequently been sought for patients with such problems. The majority of complaints can be classified as psychosomatic or arising from autonomic dysregulation. Many autonomic stabilizers have therefore been tried and some placebo-controlled studies have indicated that clonidine [5,6] and methyldopa [7] are useful for non-hormonal treatment.
Bellergal Retard (BR) has been mentioned as one such alternative. Each tablet is composed of 0.6 mg ergomatine tartrate, 0.2 mg levorotatory alcaloids and 40 mg phenobarbital. The first 2 components inhibit adrenergic and cholinergic impulses peripherally, i.e. in the effector organs themselves, while the central action of phenobarbital should potentiate this effect [8].
We performed a double-blind, placebo-controlled study to evaluate the efficacy of BR in treating climacteric complaints.
Subjects and methods
The study was performed between August 1980 and March 1981. It included patients from 3 general teaching hospitals in the Netherlands (de Wever ziekenhuis, Heerlen; Grootziekengasthuis, ‘s Hertogenbosch; Maria-ziekenhuis, Tilburg).
The participants were made up of women reporting hot flushes and sweats as their most serious complaints, together with one or more of the following: insomnia, palpitations, headaches, paresthesia, dizziness, nervousness, hyperirritability, depression, vague anxieties or loss of libido. Ovariectomized patients and women suffering from glaucoma, obliterating vascular disease, severe myocardial lesions, severe coronary insufficiency, relevant disturbances of renal or liver function, or porphyria were excluded.
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There were initially 71 participants in the study, but 5 dropped out for personal reasons. Of the remaining 66 subjects, 33 were treated with BR and 33 with a placebo for 8 wk. During the study, 12 women in the BR group and 16 in the placebo group dropped out, in the BR 2 because of ineffectiveness, 7 because of adverse reactions and 3 owing to a combination of both. In the placebo group, 10 dropped out because of ineffectiveness and 6 because of adverse reactions.
The remaining 38 women who completed the placebo-controlled study also participated in an open study using the same dose of BR for a further 4 wk.
The patients received BR and matched placebo tablets of identical taste and appearance, packed and randomized by the manufacturer. They were instructed to take 1 tablet in the morning and 1 in the evening.
During the first visit, before therapy was started, a general physical examination was performed. At this and subsequent visits (after 2, 4, 8 and 12 wk) body weight and blood pressure were also recorded.
The efficacy of the drug in regard to different symptoms was assessed by rating each symptom as absent, slight, moderate or severe. Overall efficacy was evaluated independently by the patient and the investigator by rating the medication as poor, fair, acceptable, good or excellent at the end of the study.
Intragroup statistical analysis was performed by means of the Sign test (Dixon- Mood), and intergroup analysis, for measured values, by means of the U-test (Mann-Whitney-Wilcoxon). Categorical data were condensed into a 2 x 2 table and then analyzed by means of the Fisher-exact-test. The level of significance was P = 0.05.
Hot flushes
Before starting the study, the mean number of hot flushes per 24 h in the BR group was 14.48 (S.D. = 11.64) and in the placebo group it was 14.55 (S.D. = 11.48). During medication these rates decreased significantly (P 4 0.001): in the BR group to 3.57 (S.D. = 4.11) and in the placebo group to 4.72 (S.D. = 6.33) at the end of the double-blind study. With BR the overall percentage reduction after 8 wk was 75% and with the placebo it was 68%. The difference in the frequency of hot flushes was of statistical significance only at the second visit after 2 weeks of therapy, with P 4 0.001 (Fig. 1).
The severity of the complaints was evaluated on a scale from 0 to 3, signifying ‘absent’, ‘slight’, ‘moderate’, or ‘severe’. Before therapy the mean score for hot flushes in the BR group was 2.93 (87.9% severe, 12.1% moderate). For the placebo patients the mean score was 2.81 (72.2% severe, 24.2% moderate and 3 Qo slight).
During the study, the mean score in the BR group decreased to 0.89 (9.5% severe, 14.3% moderate, 42.9% slight and 33.3% absent). In the placebo group the mean fell to 1.10 (16.7% severe, 22.2Qo moderate, 27.8% slight and 33.3Qo absent).
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flushes/24 h- (n) 28- - Bcl let-gal
: retard 24- i ------ placebo
I 0 I stat. 1
20- 1 T
sign.diff.
I ’
0 I v I 1 (32.4 8 1
weeks -c----(
double open blind study study
Fig. 1. Effect of Jkllergal Retard and a placebo on the number of flushes per 24 hr.
The only intergroup difference of statistical significance was again found at the second visit, when P 6 0.008. Although the majority of patients in both groups had significantly fewer complaints after therapy, it should be stressed that only 33% reportedatotal absence of hot flushes at the end of the double-blind study (Fig. 2).
In the open study, both the number of hot flushes per 24 hr and the severity of the complaints increased slightly in the BR patients, while the patients previously treated with a placebo showed slight decreases (Figs. 1 and 2).
Sweating
In the case of sweats the mean score before therapy was 2.71 in the BR group (63.6% severe, 33.3% moderate and 3.1010 slight). In the placebo group the mean score was 2.83 (75% severe, 15.6% moderate and 9.4% slight).
During the double-blind study, the mean score fell significantly in both groups (P Q 0.001): for BR patients to 0.45 (9.5% moderate, 38.1% slight and 52.4% absent) and for the placebo patients to 0.88 (11.8% severe, 23.5% moderate, 23.5% slight and 41.2% absent).
The only statistically significant difference between the groups was found after
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complaints of flushes severe P/4 100
1
024 8 12
double “open‘ blind study study
without
1 - Bellergal retard
------ placebo
I I , I I 024 8 12
weeks --
double blind
op@n study
study
-I
Fii. 2. Effect of Bdlergal Retard and a placebo on the degree of severity of hot flushes.
2 weeks of treatment (P < 0.04). The number of patients with severe complaints decreased significantly in both groups, but only about 40% of all the patients were free of sweats at the end of the double-blind study (Fig. 3).
In the open study the same tendency was seen as in the case of the hot flushes.
Other complaints
The effect of BR vs. a placebo on insomnia, palpitations, headaches, paresthesia, dizziness, nervousness, hyperirritability, depression, vague anxieties and loss of libido was studied in the same way. The findings are summarized in Table I.
In the patients treated with BR, statistically significant reductions were achieved for insomnia, headache, paresthesia, dizziness, nervousness and hyperirritability.
In the patients treated with the placebo this was achieved for insomnia, nervousness, hyperirritability and loss of libido. Statistically significant intergroup differences were found after 2 wk of study for insomnia and dizziness and after 4 wk for insomnia only, BR being superior in all cases. After 8 wk of treatment, no statistically significant differences could be seen at all.
Overall efficacy
The overall efficacy was assessed independently by the patient and the
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complaints of sweats severe(%)
80
60
~~ without 1
- Bellergai retard
-----. placebo
f I ,
024 8 12 weeks
double blind
open. study
study
double “open’ blind study
Fig. 3. Effect of Belle& Retard and a placebo on the degree of severity of sweating.
TABLE I
EFFECT OF BELLERGAL RETARD AND A PLACEBO ON CLIMACTERIC COMPLAINTS
B. As awssed by the investigator Excellent 10 Good 7 Acceptable 3 Fair 4 Poor 9
5 I5 2 14 6 1 2 2
18 6
investigator after the double-blind and the open studies had been completed (Table II). Their opinions proved to be similar. BR was assessed as excellent or good in 51 Vo of cases and placebo therapy in 21%, the difference being statistically significant in favour of BR.
Adverse reactions
Adverse reactions are obviously important factors to be taken into account in assessing therapy. No relevant changes were seen in body weight or blood pressure. Nineteen (19) patients in the BR group complained of adverse reactions and 9 stopped therapy for this reason. The most important complaints were dry mouth, dizziness and sleepiness.
In the placebo group, 18 patients had adverse reactions and 6 of these stopped therapy for this reason. The most important complaints were dry mouth, dizziness, sleepiness, headache and nausea.
Discussion
This study clearly shows that Bellergal Retard can reduce climacteric complaints significantly, although there is a marked placebo effect. A decrease in symptoms was achieved in more than 50% of the patients using a placebo and this medication was even assessed as good or excellent in 21% of cases. Other investigators have also reported relief of symptoms in 25-40070 of cases with placebo therapy [7,81.
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The efficacy of the drug was significantly better than that of the placebo for the first 4 wk, but after 8 wk of treatment differences were no longer apparent between the BR and placebo groups. However, the level of complaints was significantly lower than before the therapy in both groups. BR acted more rapidly in reducing complaints and the study indicates that a placebo needs more time to achieve about the same effect (Fig. 1). This finding may have important implications for other studies, since it suggests that studies concerning therapy for climacteric complaints should not only be placebo-controlled, but also have a duration of at least 8 to 12 wk for proper evaluation.
References
1 Soules MR, Bremner WJ. The menopause and the climacteric; endocrinologic base and associated symptomatology. J Am Geriatr Sot 1982; 30: 547-560.
2 Zador G. The pathophysiology and methods of treatment of climacteric disorders. Acta Obstet Gynecol Stand Suppl 1977; 65: 19-26.
3 van Duren J. Frijling BW, Leeuw FL. Ziektedrempel bij overgangsklachten. Medisch Contact 1979; 29: 116121.
4 Bogchelman DH, Lappiihn RE, Janssens J. De behandeling van vrouwen met climacterigle klachten met nadruk op de perimenopausale hormoontherapie. Ned Tijdschr Geneeskd 1979; 123: 1072-1075.
5 Claiden JR, Bell JW, Pollard P. Menopausal flushing: Double-blind trial of non-hormonal medication. Br Med J 1974; 1: 409412.
6 Eddington RF. Chagnon JP, Steinberg WM. Clonidine (Dixarit) for menopausal flushing. Can Med Assoc J 1980; 123: 23-26.
7 Nesheim BI. Saetre I. Reduction of menopausal hot flushes by methyldopa. Eur J Clin Pharmacol 1981; 20: 413-416.
8 Lebherz TB, French L. Non-hormonal treatment of the menopausal syndrome. Obstet Gynecol 1969; 33: 795-799.
