Moruritw 1 (1978) 21-25 8 ElsevierlNorth-HollandBiomedicalPress
21
FAILURE OF RESPONSE 0F MENOPAUSAL VASOMOTOR SYMPTOIUS TO CLONIDINE ’
2 it. LINDSAYand 3 D.M.HART ’ Dcpnrtmenr ofMedicine, WesternInjh~a~, GlasgowCl I 6NT. UK and
a Department of Obstetricsand Gynnecology,StobhillHospital,GlasgowG213UW. UK
(Received 17 November 1977, accepted 19 January 1978)
A double-blind crw.wer trial of clnnidine failed to show any effect of the drug on menopausal vasemotor symptoms. A significant placebo effect was observed, the effect being greater in those with long-stsnding symptoms and a high neurotic index. (Key words: Mcnopausdl,Clonidine)
INTRODUCTION Recent publications [ 1,2] have suggested that clonidin? (Dixarit) may be of use in relieving the vasomotor symptoms of the menopause. For tnose patients in whom oestrogen therapy may be contraindicated., and for those practitioners whose circumstances do not allow regular and vigorous investigation of their patients, which prescription of longterm oestrogen replacement still demands, this could have a considerable advantage. In view of this we have carried out a preliminary double-blind crossover trial of clonidine within the conflles of a mencpausal clinic, to which general practitioners had referred patients with severe menopausal symptoms. Patients were also referred from Bynaecologists when symptoms developed after hysterectomy and bikberal oopborectomy. PATIENTSAND METHODS Patients were selected from referrals on a random basis. Referred patients were assIgned to the trial by a secretary before they had beeu seen In the clinic. In addition, patients who had specific contraindications to oestrogen therapy but had severe menopausal symptoms were Included. Informed consent was obtained from all patients prior to entry, although we omitted to tell the patients that the two sets of tablets would be different, i.e. one secta placebo. Instead we merely suggested that they might receive dummy tablets as part of the t&l. All patients were screened by history and clhJcal examination ’ ma tablets used in this study were kindly supplied by Boehrieger IngelheimLtd. * To whom connpendena should be addrewed.
22
for any intercurrent illness, and routine haematoZogical and biochemical investigations performed as though the patients were being included in a trial of an oestrogen containing compound. All previous treatment for menopausal symptoms was stopped for a minimum of 4 weeks before entry to the trial. After initial assessment the patients were interviewed by a clinical psychologist to obtain personality assessments and to familiar& them with the questionnaire involved. The trial period lasted 13 weeks, 2 courses of treatment of 6 weeks each, randomised according to active drug or placebo as first medication, with a tablet-free week interposed. Diaries were not used, the patients being interviewed at 4 weeks, 7 weeks and 12 weeks and their symptoms assessed both by questionnaire and by direct questioning. “Leading” questions were avoided wherever possible. Tablets were diipensed in plain white boxes contahting 0.025 mg clonidine tablets or an identical placebo. Treatment was commenced with 2 tablets twice daily increasing to 2 tablets thrice daily after one week, if required. Symptoms were assessed using the Blatt Menopausal Index [3) which is a standard rating scale which, according to the orightal authors, contains most of the symptoms tra. ditionally thought to be associated with the climacterium. This allowed a global assess. ment of the well-being of the patients. Items were worded to facilitate understanding, and subjects were reauired to rate the extent to which they were bothered by each symptom on a 4-point scale labelled: not at all, a little, quite a bit,extremely;could not be worse. Certain questions within the scale were loaded according to the original Blatt scheme. In addition to assessing the total scores in this way, flushing attacks, the supposed vasomotor symptom specitic for the climacteric, were assessed using the same 4point scale but separately. Psychological symptoms were assessed using the self-administered symptom rating scale of Kelhter and SheftTeld (41. Initially 100 patients were to have been included. hi fact only 4 1 patients completed treatment in this trial. At that stage the trial was discontinued because of complaints by the patients that the tablets were ineffective. The mean age of the patients included was 46.4 yr (range 35-60) and the mean duration of symptoms I.6 yr (range I mth-5 yr). All patients had undergone a natural “menopause”, the mean thne from last menstrual period being 1’. mth (range 4-30 mth). Twenty-two patients received clonidine first. One patient did not return after her initial assessment and 2 patients failed to take the treatment in the prescribed manner, both cornplaiting of nausea, dry mouth and insomnia whiie taking the active preparation. Two patients complained that the therapy induced marked nocturia; both were taking clot&line. One patient developed nausea on the placebo. These 3 patients all completed the trial. No other side-effects were noted. The results quoted are from the remaining 38 patients.
statistics AUresults are presented as mean scores. Significance between mean scores was tested using a paired t-test for comparisons with initial values, and 2 test for comparisons between groups.
23
133456789
10
II
12
WEEKS
Fis. 1. Pattern of ~mnges in vrromator symptoms during CIOSSOVC~ trial of clonidine. Stippled wea indicates tablet-fret week. Mesa percentage clr~~gesare shown. There b no significant differcncc between group at nny time interval.
RESULT5 During the first treatment period a marked reduction in the symptoms was noted in both groups of patients (Fig. I), using the Blatt Menopausal Il~dex. The placebo response was s!ightly greater than thrc obtained by clonidine but the difference was not significant. The mean reduction in both flushes and the Blatt score was sigdficant in both groups (Table I). During the treatment-free week a slight return of symptoms occurred and this was not affected by subseqJcnt therapy whether this was active clonirbne or the placebo preparation (Fig. I ,Tablc I). Eleven patients preferred their initial therapy (4 placebo: 7 clonidine). Seven patients preferred the second course of tablets (4 placebo: 3 clonidine). Twenty of the 38 patitnts stated no preference and these patients showed only minimal response to both preparations. Those who preferled their initial therapy showed a marked response during this treatment period (43% overall improvemem in flushes} irrespective of which therapy they
I Mensymptom
TABLE
I
wxcs
of patlnts in the trirl (man * S.E.M.).
lnltlal
Wwk 4
P
Week 7
Week 12
P
2.36 t 0.20 22.2 t. 2.6
1.67 t 0.31 19.5 * 3.1
?3, 1167-1170.
]7]
Zaimls, E. and
Haain&m.
E. (1969)
A possible pharmacological approach to migraine. Lance: 2,
298-300. ]B] Utian. W.H. 1.1.579-581.
(1973) Comparative
trinl of P1496, a new non-steroidal ocstmgen andogue. 91. Med.
[91 Wilkinson.R. (1969) Cl&dine in mia&~. Lancet 2,430.
21
FAILURE OF RESPONSE 0F MENOPAUSAL VASOMOTOR SYMPTOIUS TO CLONIDINE ’
2 it. LINDSAYand 3 D.M.HART ’ Dcpnrtmenr ofMedicine, WesternInjh~a~, GlasgowCl I 6NT. UK and
a Department of Obstetricsand Gynnecology,StobhillHospital,GlasgowG213UW. UK
(Received 17 November 1977, accepted 19 January 1978)
A double-blind crw.wer trial of clnnidine failed to show any effect of the drug on menopausal vasemotor symptoms. A significant placebo effect was observed, the effect being greater in those with long-stsnding symptoms and a high neurotic index. (Key words: Mcnopausdl,Clonidine)
INTRODUCTION Recent publications [ 1,2] have suggested that clonidin? (Dixarit) may be of use in relieving the vasomotor symptoms of the menopause. For tnose patients in whom oestrogen therapy may be contraindicated., and for those practitioners whose circumstances do not allow regular and vigorous investigation of their patients, which prescription of longterm oestrogen replacement still demands, this could have a considerable advantage. In view of this we have carried out a preliminary double-blind crossover trial of clonidine within the conflles of a mencpausal clinic, to which general practitioners had referred patients with severe menopausal symptoms. Patients were also referred from Bynaecologists when symptoms developed after hysterectomy and bikberal oopborectomy. PATIENTSAND METHODS Patients were selected from referrals on a random basis. Referred patients were assIgned to the trial by a secretary before they had beeu seen In the clinic. In addition, patients who had specific contraindications to oestrogen therapy but had severe menopausal symptoms were Included. Informed consent was obtained from all patients prior to entry, although we omitted to tell the patients that the two sets of tablets would be different, i.e. one secta placebo. Instead we merely suggested that they might receive dummy tablets as part of the t&l. All patients were screened by history and clhJcal examination ’ ma tablets used in this study were kindly supplied by Boehrieger IngelheimLtd. * To whom connpendena should be addrewed.
22
for any intercurrent illness, and routine haematoZogical and biochemical investigations performed as though the patients were being included in a trial of an oestrogen containing compound. All previous treatment for menopausal symptoms was stopped for a minimum of 4 weeks before entry to the trial. After initial assessment the patients were interviewed by a clinical psychologist to obtain personality assessments and to familiar& them with the questionnaire involved. The trial period lasted 13 weeks, 2 courses of treatment of 6 weeks each, randomised according to active drug or placebo as first medication, with a tablet-free week interposed. Diaries were not used, the patients being interviewed at 4 weeks, 7 weeks and 12 weeks and their symptoms assessed both by questionnaire and by direct questioning. “Leading” questions were avoided wherever possible. Tablets were diipensed in plain white boxes contahting 0.025 mg clonidine tablets or an identical placebo. Treatment was commenced with 2 tablets twice daily increasing to 2 tablets thrice daily after one week, if required. Symptoms were assessed using the Blatt Menopausal Index [3) which is a standard rating scale which, according to the orightal authors, contains most of the symptoms tra. ditionally thought to be associated with the climacterium. This allowed a global assess. ment of the well-being of the patients. Items were worded to facilitate understanding, and subjects were reauired to rate the extent to which they were bothered by each symptom on a 4-point scale labelled: not at all, a little, quite a bit,extremely;could not be worse. Certain questions within the scale were loaded according to the original Blatt scheme. In addition to assessing the total scores in this way, flushing attacks, the supposed vasomotor symptom specitic for the climacteric, were assessed using the same 4point scale but separately. Psychological symptoms were assessed using the self-administered symptom rating scale of Kelhter and SheftTeld (41. Initially 100 patients were to have been included. hi fact only 4 1 patients completed treatment in this trial. At that stage the trial was discontinued because of complaints by the patients that the tablets were ineffective. The mean age of the patients included was 46.4 yr (range 35-60) and the mean duration of symptoms I.6 yr (range I mth-5 yr). All patients had undergone a natural “menopause”, the mean thne from last menstrual period being 1’. mth (range 4-30 mth). Twenty-two patients received clonidine first. One patient did not return after her initial assessment and 2 patients failed to take the treatment in the prescribed manner, both cornplaiting of nausea, dry mouth and insomnia whiie taking the active preparation. Two patients complained that the therapy induced marked nocturia; both were taking clot&line. One patient developed nausea on the placebo. These 3 patients all completed the trial. No other side-effects were noted. The results quoted are from the remaining 38 patients.
statistics AUresults are presented as mean scores. Significance between mean scores was tested using a paired t-test for comparisons with initial values, and 2 test for comparisons between groups.
23
133456789
10
II
12
WEEKS
Fis. 1. Pattern of ~mnges in vrromator symptoms during CIOSSOVC~ trial of clonidine. Stippled wea indicates tablet-fret week. Mesa percentage clr~~gesare shown. There b no significant differcncc between group at nny time interval.
RESULT5 During the first treatment period a marked reduction in the symptoms was noted in both groups of patients (Fig. I), using the Blatt Menopausal Il~dex. The placebo response was s!ightly greater than thrc obtained by clonidine but the difference was not significant. The mean reduction in both flushes and the Blatt score was sigdficant in both groups (Table I). During the treatment-free week a slight return of symptoms occurred and this was not affected by subseqJcnt therapy whether this was active clonirbne or the placebo preparation (Fig. I ,Tablc I). Eleven patients preferred their initial therapy (4 placebo: 7 clonidine). Seven patients preferred the second course of tablets (4 placebo: 3 clonidine). Twenty of the 38 patitnts stated no preference and these patients showed only minimal response to both preparations. Those who preferled their initial therapy showed a marked response during this treatment period (43% overall improvemem in flushes} irrespective of which therapy they
I Mensymptom
TABLE
I
wxcs
of patlnts in the trirl (man * S.E.M.).
lnltlal
Wwk 4
P
Week 7
Week 12
P
2.36 t 0.20 22.2 t. 2.6
1.67 t 0.31 19.5 * 3.1
?3, 1167-1170.
]7]
Zaimls, E. and
Haain&m.
E. (1969)
A possible pharmacological approach to migraine. Lance: 2,
298-300. ]B] Utian. W.H. 1.1.579-581.
(1973) Comparative
trinl of P1496, a new non-steroidal ocstmgen andogue. 91. Med.
[91 Wilkinson.R. (1969) Cl&dine in mia&~. Lancet 2,430.
