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Clomipramine and Metoprolol in Migraine Prophylaxis -- A Double-blind Crossover Study
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Design
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Randomized, double-blind, crossover study
N= 36
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Objective
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To compare the efficacy of clomipramine, a serotonin-reuptake inhibitor, as an anti-migraine drug, with that of metoprolol, a beta-blocking agent |
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Study Groups
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Study patients (N= 36)
Group 1 (n= 8)
Group 2 (n= 5)
Group 3 (n= 5
Group 4 (n= 9)
Group 5 (n= 7)
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Inclusion Criteria
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Receives at least 1 migraine attack per week |
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Exclusion Criteria
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Cardiac insufficiency, neurologic deficits, chronic drug abuse, experienced undesirable adverse events |
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Methods
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Patients were initially selected randomly from a group of 300. After the exclusion criteria, the remaining patients underwent double-blind crossover into 5 groups.
Group 1: Clomipramine for 4 weeks, followed by a 4-week washout period, then placebo.
Group 2: Placebo, followed by a washout period, then clomipramine.
Group 3: Metoprolol, followed by a 4-week drug-free period, then placebo.
Group 4: Placebo, followed by a washout period, then metoprolol.
Group 5: Clomipramine, followed by a 4-week drug-free period, then metoprolol.
Clomipramine and metoprolol were gradually increased to 100 mg per day. Patients were required to fill a headache diary to rank the daily course of migraine attack, headache intensity and duration, mood, and medication according to a 9-pole scale.
Autoregressive-moving-average models (ARIMA) was used for their time series analysis by comparing baseline and therapy periods, as well as the follow-up data for each patient. To detect both positive (improvement) and negative (deterioration) changes in clinical values, the researchers used a simple discontinuity model and calculated z-values. They converted probability values into z-values using a method called z-conversion.
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Duration
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~24 weeks |
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Outcome Measures
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Clinical effect: defined by summing the z-values for each patient, obtained through time series analysis, then divided by the square root of the number of patients |
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Baseline Characteristics
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Study patients (N= 36)
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Age, years (range)
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44.3 (24-60) |
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Female
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24 (66.7%) |
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Migraine diagnosis
Common
Classical
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23 (63.9%)
13 (36.1%)
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Migraine duration, years (range)
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20.8 (5-41)
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Pretherapy
Acupuncture
Medication
Psychotherapy
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14 (38.9%)
36 (100%)
5 (13.9%)
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Results
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Endpoint
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Group 1 (n= 8)
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Group 2 (n= 5)
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Group 3 (n= 5)
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Group 4 (n= 9)
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Group 5 (n= 7)
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Z-value for reduction in migraine attacks
Therapy 1
Washout
Therapy 2
Follow-up
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-2.13
-1.90
-3.60
-5.38
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+0.3
+5.30
-1.19
-1.33
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-4.03
-8.36
-3.95
-2.63
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-0.86
-1.94
-2.47
-3.41
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+1.33
+0.45
-2.21
-0.38
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Z-value for reduction in headache duration
Therapy 1
Washout
Therapy 2
Follow-up
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+1.64
+0.61
+0.28
-0.67
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+0.98
+0.42
-2.21
-2.24
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-2.38
-2.84
-2.21
-0.54
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+0.34
-2.16
-2.10
-2.70
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+0.28
-0.08
-3.35
-3.16
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Z-value for reduction in ergotamine medication
Therapy 1
Washout
Therapy 2
Follow-up
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-0.49
+1.60
+1.06
+0.37
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-0.64
-2.86
-2.73
-5.99
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-4.28
-5.54
-4.90
-3.36
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-0.13
-1.47
-3.77
-2.69
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-0.90
+1.30
-1.57
-0.49
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Adverse Events
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The main reason for discontinuation was severe adverse reactions to clomipramine (67%). Overall, there were 79 different adverse reactions reported for clomipramine, 30 for metoprolol, and 16 for the placebo. The most commonly reported reactions include insomnia, sweating, tiredness, constipation, and nausea.
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Study Author Conclusions
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Only metoprolol significantly reduced attack frequency and headache duration. Adverse reactions to clomipramine were severe. |
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InpharmD Researcher Critique
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Patients who experienced undesirable adverse events were excluded from the study, with limited details regarding the events. The analysis of results was unorthodox and typically not reflective of current clinical trial protocols. |