Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis
WD Gerber, HC Diener, E Scholz, U Niederberger
Cephalalgia Gerber WD Diener HC, Scholz B, Niederberger U, Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 1991;11:37-45. Oslo. ISSN 0333-1024 The aim of the present study was to ascertain, on the basis of single case statistics and time-series analysis, responder and non-responder rates for metoprolol, propranolol and nifedipine in migraine prophylaxis. In addition, an attempt was made to identify the dose relationship for the various drugs on headache parameters. In a double-blind dose-finding study, 58 patients were treated in five consecutive dosage steps each lasting 1-3 months. All patients kept a headache diary before, during and after treatment. Serum drug levels were also determined. The data were assessed by time-series analysis, as well as by multiple regression and analysis of variance. A significant improvement was noted in 54.4% of patients with migraine during treatment with metoprolol. The study did not confirm the high success rates in migraine prophylaxis of nifedipine and propranolol quoted in the literature. Administration of nifedipine led to an increase in migraine attacks in 71% of the patients. Nifedipine was of no value in the prophylaxis of migraine. Only 32% of patients showed a reduction in frequency of migraine attacks during administration of propranolol. The analysis of variance failed to show any significant difference between the responder rates for metoprolol and propranolol. Higher doses of propranolol and metoprolol were more effective. Multiple regression analysis explained a considerable part of variance for propranolol (but not for metoprolol) as a result of reduced intake of ergotamine preparations and analgesics. It can therefore be concluded that part of the prophylactic effect of propranolol is attributable to a reduction in the use of migraine medication. • Beta-blockers, calcium antagonists, migraine prophylaxis WD Gerber, U Niederberger, Department of Medical Psychology, University of Kiel, Germany; HC Diener, Department of Neurology, University of Essen, E Scholz, Department of Neurology, University of Tubingen, Germany; Correspondence to WD Gerber, Center of Nervous Disease, University of Kiel, Niemannsweg 147, 2300 Kiel, Germany; Accepted 6 November 1990 Over the last 10 years, many studies have been performed to investigate the efficacy of substances like beta-adrenergic blockers, calcium antagonists, and serotonin antagonists in the prophylaxis of migraine (1-3). Closer scrutiny of the collected data presented in the various review articles on this question reveals a substantial range of variation between the positive results quoted in the individual studies. For example, the figures for the reduction in frequency of attacks achieved by the non-selective beta-blocker propranolol vary between 55% and 93% (3). The reduction of attacks said to be achieved by the selective beta-blocker metoprolol varied with the method of statistical analysis used and was as little as 19% and as much as 81% (4). Results for the calcium antagonist nifedipine are also very variable (5). On the basis of these results it is very difficult to achieve an overall evaluation of the value of these various substances for clinical use. One important reason for the non-uniformity of results is the lack of methodological comparability between the various studies undertaken. The studies differ not only in terms of experimental design and procedure, but also in terms of the criteria used to assess therapeutic success and in terms of the assessment and statistical analysis of the parameters of success (e.g. frequency of attacks: see (6)). The percentage of responders is often calculated on the basis of a 50% criterion (7). If, for example, a patient suffers 10 attacks per month before treatment and then only five attacks per month as a result of the medication, this reduction by five attacks per month is assumed to represent a rate of improvement of 50%. This same improvement rate of 50% is also assumed for a reduction from two attacks to one attack per month. However, an absolute reduction by one attack is certainly of less significance than an absolute reduction by five attacks. Such a definition of response rates is therefore artificial. Headache studies are generally group experiments designed to find out whether two or more substances differ in terms of their effect on patients' headache symptomatology. This usually involves the use of headache diaries as indices of possible success. The data thus obtained may be arranged graphically and/or numerically. Many studies give percentage figures for the number of responders
which are based in part upon such criteria as "reduction in number of attacks per month by >50%, 1-50%, and negative". For the reasons mentioned above, however, response rates defined in this way are extremely inaccurate. An exact definition of efficacy in an individual patient (not in a group of patients) can, however, be quite easily obtained using statistical single case analysis and time-series analysis. Single case analysis is useful for studies in which the course of treatment is investigated with the help of headache diaries. It is also suitable for substances which, due to possible side effects, have to be given initially in low doses which are then gradually increased. Single case analysis is therefore useful for dose-finding studies. Responders are differentiated from non-responders on the basis of the statistical value of the time-series analysis (e.g. z-values). The differentiation of responders from non-responders allows the possibility of defining specific indications for one or another medication. The calculation of serial data by time-series analysis is based upon pioneering work by Box and Jenkins (8), Glass et al. (9), McLeary & Hay (10), and Gottman (11). In clinical pharmacological studies the effect of a medication is generally investigated over a specific period of time, e.g. three or four months. In studies of this type (e.g. using headache diaries) the data under investigation (time-series data) occur sequentially and the individual pieces of data are therefore not independent events. In research practice. a mere inspection of headache diaries often reveals a not insignificant reduction in headache symptoms shortly after introduction of the diaries, i.e. in the run-in phase before initiation of treatment. Statistical time-series analysis can be used to evaluate such sequential data. Almost all published studies report only positive findings (12), whereas negative results can only be surmised and in many cases are not mentioned. Negative results may also be useful (12). In particular, the distinction between responders and non-responders could help to answer the question as to which particular kind of patient, i.e. under what circumstances, a particular substance is indicated. Finally, the available results are in many cases of little relevance for clinical practice, since the need for a strict experimental design makes dose-finding very difficult. The questions addressed above were investigated in the present study. The aim of this experimental double-blind dose-finding study was to ascertain, on the basis of single case statistics and time-series analysis, the therapeutic efficacy of the beta1-selec-tive blocker metoprolol, the non-selective blocker propranolol and the calcium blocker nifedipine. Particular attention was addressed to the statistical separation and definition of responders (therapeutic success) and non-responders (therapeutic failure). Moreover, conventional group statistics, based on mean values of the treatment trials, were carried out. Methods
Patients The study included 58 migraine patients aged between 18 and 65 years. Following an eight-week baseline period patients were allocated through stratified randomizations to one of the three treatment groups. Table 1 provides a detailed description of the sample in terms of the three substances under investigation. No significant differences were found between the groups for any of the variables examined. The diagnosis was based on the classification criteria of the International Headache Society (IHS) (1988). The criterion for inclusion was the occurrence of at least two attacks per month over the 4 weeks immediately preceding the study. Both patients with and without aura (IHS classifications 1.1, 1.2.1 and 1.2.2) were included. In accordance with the IHS classification, the study included patients who satisfied at least two of the four named headache parameters. Exclusion criteria included pregnancy, abuse of ergotamine or analgesics, use of other agents for the prophylaxis of migraine attacks, and the specific contraindications for the individual substances (e.g. lactation, AV block, heart failure, bradycardia, obstructive pulmonary disease). Treatment The treatment was planned as a double-blind dose-finding study with three parallel groups. The study design is shown in Fig. 1. Following an eight-week baseline period during which a migraine diary was kept, the patients were allocated randomly to one of three treatment groups, metoprolol, propranolol or nifedipine. All the treatment groups commenced with a four-week initial phase of gradually increasing dosage ("run-in", low dosage) followed by a three-month phase of high dosage. This in turn was followed by three time periods of one month each with gradually decreasing dosage. The study ended with an eight-week follow-up period. The dosages given during the various phases are indicated in Fig. 1. For the abortion of migraine attacks, the patients were allowed to use whichever other medication they found helpful. At the beginning and end of the study and during the various treatment phases, the patients underwent a neuro-logical and psychological investigation including
Table 1. Description of the sample. Variable No. of patients Age (years) x s Range Sex Male Female Migraine duration (years) x s Range Migraine frequency/month x s Range Diagnosis Without aura With-aura Localization Hemicrania Holocrania
Metoprolol 22
Treatment group Propranolol 19
17
42.9 12.6 18-64
43.2 11.8 24-65
40.9 11.8 20-63
4 18
3 16
4 13
21.9 14.3 1-55
22.9 31.1 1-47
17.6 12.3 1-47
F = 0.777 n.s.
3.8 1.6 1-7
3.3 1.7 1-6
3.5 1.6 1-6
F = 0.596 n.s.
21 1
18 1
15 2
12 10
7 12
10 6
Nifedipine
Significance F = 0.182 n.s. chi2 = 0.83 n.s.
chi2 = 4.33 n.s.
x = arithmetic mean; s = standard deviation; n.s. = not significant.
EEG, VEP, laboratory parameters, blood pressure, and heart rate. We decided to use nifedipine with respect to the positive results of Meyer and Hardenberg (5). Over the entire duration of treatment, the patients kept a headache diary to record the following parameters: 1. Days on which a migraine attack occurred. 2. Duration of migraine attack in hours. 3. Duration of additional, non-migrainous, headaches in hours. 4. Intensity of headache (three assessment times per day using a visual analogue scale). 5. Site of pain. 6. Dose of all medication taken. 7. Duration of sleep in hours. 8. Daily mood (analogue scale). 9. Weekly evaluation of medication and listing of side effects. Responders/non- responders : definition and statistical analysis of data The method of time-series analysis employs a modified product-moment correlation in order to determine the serial dependency of the sequential data. Autocorrelation permits the correlation of the values at time t with the values at time t + 1, t + 2, ... t + n. Assuming that adjacent values are equally closely correlated with each other, the autocorrelations can be calculated by taking a mean across the various points in time. The various procedures of time-series analysis are designed to eliminate the serial dependency of the data. The ARIMA (Auto-regressive Integrated Moving Average) model developed by Box and co-workers (8) is particularly suitable for clinical serial data, and therefore also for headache studies; an extended ARIMA model can be used to determine periodicity. Although these procedures are not universally accepted, they
nevertheless are the best methods currently available for the analysis of time-series (11). For the practical application of time-series analysis to headache studies, a number of preconditions must be satisfied: at least 50 equidistant measurement time points are required (8), since more sample-dependent parameter estimations must be made with serially correlated data than with serially uncorrelated data. The various phases (baseline, treatment) should be as long as possible. An investigation of the efficacy of a substance should not just provide information on the results in individual cases, but should also answer the question of the applicability of the results to the entire patient group. Recently developed procedures permit the statistical processing of individual case results so as to make them applicable to the entire group. In addition we used the aggregation of individual data (9, 10). For each individual time-series and parameter (e.g. duration of headache), a z-value was calculated by computing the respective percentile of the t distribution in the standard normal distribution. Z-values were available from all patients who could then be classified into different responder groups. These z-values, moreover, could be evaluated as normally distributed values by statistical inference. This method, modified from the Stouffer method, was described by Mosteller & Bush (13) for individual cases, and time-series analysis were used in the present study for the investigation of the comparison of responders versus non-responders. The following statistical definitions of responders and non-responders were adopted. Responder type A:-Significant z-values (z £ -1.96) for the treatment phases Run In (Ri), High Dosage (HD), Reduction 1 (RED 1), RED 2, RED 3, and total reduction phase (RED) in the following headache variables: · · · ·
Reduction of number of days with migraine. Reduction of duration of migraine. Reduction of severity of headaches. Reduced use of analgesics and ergots.
Responder type B:-A tendency to improvement (but no statistically significant improvement) (z £ -1.65 to 1.96) in the parameters described above. Non-responder type C:-No improvement in the parameters (z = 0 to -1.65). Non-responder type D:-Tendency to deterioration, or statistically significant deterioration (positive z-values). The time-series analysis was used to compare the values for each patient in each treatment phase (run in, high dosage, reduction, follow-up) with those of Table 2. Percentages of responders (ARIMA) in the three treatment groups in various variables and treatment trials. Variable Migraine days LD HD RED 1 RED 2 RED 3 CAT Migraine duration LD HD RED I RED 2 RED 3 CAT Severity of headache LD HD RED 1 RED 2 RED 3 CAT Reduction of ergotamine intake LD HD RED 1 RED 2 RED 3 CAT
Metoprolol
Treatment group Propranolol
Nifedipine
40.9% 54.4% 56.3% 37.5% 53.8% 28.6%
21.1% 32.0% 23.5% 26.7% 15.4% 0.0%
0.0% 7.7% 11.1% 11.1% 0.0% 0.0%
40.9% 60.0% 37.5% 25.0% 38.5% 14.3%
15.8% 27.8% 23.5% 20.0% 15.4% 0.0%
11.8% 30.8% 11.1% 0.0% 0.0% 0.0%
54.5% 55.0% 50.5% 37.5% 30.8% 28.6%
21.1% 33.3% 23.5% 26.7% 15.4% 25.0%
0.0% 0.0% 0.0% 11.1% 0.0% 0.0%
18.2% 30.0% 37.5% 31.3% 38.5% 28.6%
21.1% 38.9% 23.5% 13.3% 30.8% 25.0%
17.6% 38.5% 33.3% 22.2% 22.2% 0.0%
Trial: LD = low dosage; HD = high dosage; RED 1-RED 3 = reduction of the dosages; CAT = follow-up. the pretreatment phase (baseline). Percentage values are given for the number of responders and non-responders for each of the assessment criteria. The individual case results were calculated as group statistics using non-parameteric methods (Crosstabs, Wilcoxon test) and by multifactorial analysis of variance with repetition of measurement. Moreover, conventional group statistics, based upon mean values of the treatment trials, were carried out. In order to calculate the variance components of the three substances in their therapeutic effectiveness, multiple regression analyses were performed. For this purpose, a stepwise algorithm was selected, i.e. beginning with the variable with the greatest explained variance (inclusion criterion, p < = 0.05). The following illustration of the data includes single case analyses (ARIMA) as well as conventional group statistics (ANOVA). Results
Responder and non-responder analysis for the three substances Tables 2 and 3 summarize the percentages of
Table 3. Classification of responders and non-responders (ARIMA) in the three treatment groups in various variables during high dosage phase of treatment. Treatment group Variable Migraine days
Migraine duration
Severity of headache
Reduction of Ergotamine intake
Responder classification A B C D A B C D A B C D A B C D
Metoprolol 54.4% 5.0% 35.6% 0.0% 60.0% 5.0% 35.0% 0.0% 55.0% 5.0% 40.0% 0.0% 30.0% 0.0% 65.0% 5.0%
Propranolol 32.0% 0.0% 62.4% 5.6% 27.8% 5.6% 61.1% 5.6% 33.3% 5.6% 61.1% 0.0% 38.9% 0.0% 55.6% 5.6%
Nifedipine 7.7% 15.4% 61.5% 15.4% 30.8% 7.7% 46.2% 15.4% 0.0% 7.7% 69.2% 23.1% 38.5% 0.0% 53.8% 7.7%
Responder-classification A-D (see text). A = sign. improvement; B = tendency to improvement; C = no improvement; D = tendency to deterioration. responder and non-responder rates (ARIMA) in the three treatment groups under various treatment conditions. Responders and non-responders with metoprolol:- Twelve of 22 patients (54.5%) taking metoprolol (100 mg or 200 mg) showed a significant improvement in terms of the number of days with migraine attacks. After the run-in phase, only two patients (9%) dropped out because of lack of response. A further four patients refused to reduce the dosage; in three of these patients this was because of inadequate effect, whereas in the fourth patient it was because of the very good effect experienced. The proportion of responders (Types A and B) and non-responders (Types C and D) for the various treatment phases is shown in Tables 2 and 3. Responders and non-responders with propranolol:-Six of 19 patients taking propranolol, i.e. 32%, experienced a significant reduction in the frequency of attacks (days with migraine). The dropout rate due to side effects or lack of therapeutic effect was low (one patient after the run-in period, and a further patient in the high-dosage phase). Table 2 shows the proportion of responders (Types A and B) and non-responders (Types C and D) for the various treatment phases. It has been shown also that there was a worsening of symptoms during the reduction phase in 41.1% of patients (as compared with 25% for the metoprolol group). Responders and non-responders with nifedipine:-Four patients dropped out after the run-in phase and eight patients dropped out after the high-dosage phase due to lack of effect or side effects. At a dosage of 40 mg, only one patient showed an improvement in terms of frequency of attacks, but this patient refused to continue to take the drug because of side effects. A total of 71% of the patients showed a significant deterioration after as little as 20 mg of nifedipine. The minor increase in the improvement rate during the reduction phase can be unequivocally attributed to the tailing-off of the medication. Differential efficacy of metoprolol, propranolol and nifedipine In order to assess the differential efficacy of the three drugs, the outcome of the statistical time-series analysis (z-values) and also the mean values of the treatment phases were submitted to a bifactorial analysis of variance with repetition of measurements (factors: group (medication), time (treatment phase)). The analysis of variance was calculated for the following variables: 1. Number of days with migraine. 2. Duration of migraine in hours. 3. Intensity (severity) of headache. 4. Number of tablets taken to abort attacks (ergotamine intake). Reduction in the number of days with migraine:-The bifactorial analysis of variance showed significant principal effects for the factors "group" and "time" (medication: F(32,2) = 6.28, p < 0.01; dose: F(128,4) = 3.31, p < 0.05). Individual comparisons using the Scheffé test revealed significant differences at the 5% level between the improvement rates for metoprolol and nifedipine, but not between those for metoprolol and propranolol or for those between propranolol and nifedipine. Fig. 2 shows
the relatively high and stable response rates for metoprolol as compared with the other two substances. Reduction in duration of migraine attacks in hours:-Analysis of variance also revealed significant principal effects for the factors "group" and "time" (medication: F(32,2) = 3.25, p = 0.05; dose: F(128,4) = 2.95, p < 0.05). Again, the Scheffè test showed a significant difference at the 5% level between the metoprolol and nifedipine group, but no significant differences between the other groups. Fig. 3 shows the good improvement rates associated with metoprolol (especially in the high-dosage phase) as compared with the other substances. Improvement in terms of severity of headache :-Again, significant principal effects for the factors "group" and "time" were found (medication: F(32,2) = 5.24, p = 0.01; dose: F(128,4) = 2.54, p < 0.05). Individual comparisons with the Scheffé test at the 5% level revealed that the metoprolol group differed significantly from both the nifedipine group and the propranolol group; there were no other significant differences between groups. Fig. 4 shows that only metoprolol and propranolol reduced the severity of headaches. The slight improvement rates associated with nifedipine in the reduction dosage phase can be explained by a reduction of side effects.
Reduction in intake of medications to abort attacks. Analysis of variance of response rates revealed no significant differences between the group in terms of reduction in intake of medication to abort attacks (F(32,2) = 0.05, p > 0.10), nor was there any significant time/dose difference demonstrated (F(128,4) = 1.65, p > 0.10) (see Fig. 5). Specificity of the treatment effects An important factor in the assessment of the clinical relevance of a substance is its specificity. The statistical parameters of the time-series analysis permitted an investigation of the characteristics of the responders. For this purpose, multiple regressions analyses were calculated, the following variables being considered as possible effect variables (independent variables, predictors): 1. Age of patient. 2. Duration of illness (migraine). 3. Systolic blood pressure. 4. Diastolic blood pressure. 5. Analgesic intake. 6. Ergotamine intake. 7. Ergotamine combined with codeine/caffeine. 8. Ergotamine combined with analgesics/barbiturates. These variables were selected because they showed the highest explained variance in the first multiple regression analysis. The following dependent variables were taken: 1. Days with migraine. 2. Duration of migraine in hours. 3. Duration of non-migrainous headaches. 4. Intensity of migraine.
The calculations were performed only for metoprolol and propranolol, as the number of significant responders was too small with nifedipine. We found significant regression weights principally for propranolol. This means that the improvement in patients who took propranolol could be attributed predominantly to the reduction in the intake of analgesics and ergots. For the variable "reduction in migraine days", 57.6% of the variance was explained in this way. For metoprolol significant predictors in the regression analysis were not found. The effect of metoprolol seems to be more specific. Side effects Fig. 6 summarizes reported side effects of the three drugs investigated. The most commonly reported side effects were tiredness and vertigo. Discussion
On the basis of single case statistical analysis and time-series analysis, the present double-blind dose-finding study was aimed at investigating the clinical efficacy of metoprolol, propranolol, and nifedipine. Particular attention was paid to the statistical differentiation and definition of responders (successful treatment) as compared with non-responders (unsuccessful treatment). Effects of metoprolol The present study confirms the success rates quoted in the literature (7) for metoprolol. We showed that the administration of 100 mg and 200 mg of metoprolol produced "significant" effects in 41% and 54.5% of patients, respectively. Only 13.6% of patients showed a worsening of migraine symptoms. Side effects, principally tiredness, were reported more frequently with metoprolol than with propranolol. Effects of propranolol The response rates for propranolol of 21% at 80 mg and 32% at 120 mg were far below those reported in the literature (3). For example, Diamond et al. (14) reported 72.5% responders to propranolol on the basis of a "headache unit index". Here it can be seen that time-series analysis gives significantly lower, but more realistic, success rates. In the study by Diamond et al. a mere 5.7% of patients dropped out, and this low rate was confirmed in the present study: only one patient stopped taking the medi-cation because of side effects. Nevertheless, the spectrum of activity of propranolol appears to have been overestimated in the various studies performed previously. In the present study, as many as 38.9% of patients on 160 mg of propranolol showed no improvement in the frequency of attacks, and 27.8% even showed a deterioration. Notwithstanding all this, especially in view of its low rate of side effects, propranolol can still be recommended for the prophylaxis of migraine; however, a dosage of 160 mg should be given. Effects of nifedipine The statistical differentiation of a responder and a non-responder group for each medication showed that even low doses (20 mg) of nifedipine led to an increase in migraine attacks in 71% of patients. Jonsdottir et al. (15) and Meyer and Hardenberg (5)
reported an improvement in frequency of attacks in 65% of patients on nifedipine. The present study, by contrast, showed a significant improvement in only one patient. The occurrence of pronounced side effects including non-migrainous headaches led many of the patients to refuse further intake of the medication. It therefore seems incomprehensible that daily doses of between 30 and 120 mg of nifedipine were tolerated in the study by Meyer and Hardenberg (5). It can only be assumed that of the complete sample, results were given only for those patients who showed some sort of effect, no matter what sort of effect this was. On the basis of the results of the present study, we would regard nifedipine as being useless for the prophylaxis of migraine. Analysis of variance revealed a significant time effect during the treatment. Higher doses are significantly more effective than lower doses. The effect of the medication becomes more effective with time. For clinical practice, patients should therefore be treated with high enough doses over a long enough time interval (at least 3 months). Some patients, however, already responded to the treatment when giver the lowest dose. In these it is of no use to prescribe higher dosages. The results of the regression analysis were disappointing. With one exception we were not able to identify factors that would allow a prediction as to whether a certain substance is effective or not. We were, however, able to show a correlation between the reduced intake of ergots and analgesics in the propranolol group and the reduction of migraine days. We possibly induced a positive cycle, where propranolol reduces the number of migraine attacks, this reduction leads to the intake of fewer migraine pills and this again improves migraine. It is a well established fact that the frequent intake of ergot-amine and analgesics can cause headache (16). The mechanism of action for beta-blocking agents is still unknown. They must have central effects, as can be shown by their effect on evoked cortical potentials and contingent negative variation (17, 18, 19). It is interesting to observe a correlation between the serum levels of metoprolol and its effectiveness. This was not the case for propranol, which correlates with the results of other authors (20, 2l, 22). This observation makes it unlikely that increasing the dosages of propranolol to more than 240 mg/day will result in a more effective action. The fact that nifedipine was useless in our study does not imply that all calcium channel blockers are ineffective. The group of calcium channel blockers is very incongruent, and flunarizine has been shown to be effective in migraine prophylaxis. In summary, the differentiation of responders from non-responders on the basis of time-series analysis permits a better clinical assessment of the practical value of drugs for the prophylaxis of migraine. The present dose-finding study shows that a well-shaped treatment programme as used in this study is highly suitable for clinical practice. References
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Cortelli P, Sacquegna T, Albani F, Baldrati A, D'Alessandro R, Buruzzi A, Lugaresi E. Propranolol plasma levels and relief of migraine. Arch Neurol 1985;42:46-8
WD Gerber, HC Diener, E Scholz, U Niederberger
Cephalalgia Gerber WD Diener HC, Scholz B, Niederberger U, Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 1991;11:37-45. Oslo. ISSN 0333-1024 The aim of the present study was to ascertain, on the basis of single case statistics and time-series analysis, responder and non-responder rates for metoprolol, propranolol and nifedipine in migraine prophylaxis. In addition, an attempt was made to identify the dose relationship for the various drugs on headache parameters. In a double-blind dose-finding study, 58 patients were treated in five consecutive dosage steps each lasting 1-3 months. All patients kept a headache diary before, during and after treatment. Serum drug levels were also determined. The data were assessed by time-series analysis, as well as by multiple regression and analysis of variance. A significant improvement was noted in 54.4% of patients with migraine during treatment with metoprolol. The study did not confirm the high success rates in migraine prophylaxis of nifedipine and propranolol quoted in the literature. Administration of nifedipine led to an increase in migraine attacks in 71% of the patients. Nifedipine was of no value in the prophylaxis of migraine. Only 32% of patients showed a reduction in frequency of migraine attacks during administration of propranolol. The analysis of variance failed to show any significant difference between the responder rates for metoprolol and propranolol. Higher doses of propranolol and metoprolol were more effective. Multiple regression analysis explained a considerable part of variance for propranolol (but not for metoprolol) as a result of reduced intake of ergotamine preparations and analgesics. It can therefore be concluded that part of the prophylactic effect of propranolol is attributable to a reduction in the use of migraine medication. • Beta-blockers, calcium antagonists, migraine prophylaxis WD Gerber, U Niederberger, Department of Medical Psychology, University of Kiel, Germany; HC Diener, Department of Neurology, University of Essen, E Scholz, Department of Neurology, University of Tubingen, Germany; Correspondence to WD Gerber, Center of Nervous Disease, University of Kiel, Niemannsweg 147, 2300 Kiel, Germany; Accepted 6 November 1990 Over the last 10 years, many studies have been performed to investigate the efficacy of substances like beta-adrenergic blockers, calcium antagonists, and serotonin antagonists in the prophylaxis of migraine (1-3). Closer scrutiny of the collected data presented in the various review articles on this question reveals a substantial range of variation between the positive results quoted in the individual studies. For example, the figures for the reduction in frequency of attacks achieved by the non-selective beta-blocker propranolol vary between 55% and 93% (3). The reduction of attacks said to be achieved by the selective beta-blocker metoprolol varied with the method of statistical analysis used and was as little as 19% and as much as 81% (4). Results for the calcium antagonist nifedipine are also very variable (5). On the basis of these results it is very difficult to achieve an overall evaluation of the value of these various substances for clinical use. One important reason for the non-uniformity of results is the lack of methodological comparability between the various studies undertaken. The studies differ not only in terms of experimental design and procedure, but also in terms of the criteria used to assess therapeutic success and in terms of the assessment and statistical analysis of the parameters of success (e.g. frequency of attacks: see (6)). The percentage of responders is often calculated on the basis of a 50% criterion (7). If, for example, a patient suffers 10 attacks per month before treatment and then only five attacks per month as a result of the medication, this reduction by five attacks per month is assumed to represent a rate of improvement of 50%. This same improvement rate of 50% is also assumed for a reduction from two attacks to one attack per month. However, an absolute reduction by one attack is certainly of less significance than an absolute reduction by five attacks. Such a definition of response rates is therefore artificial. Headache studies are generally group experiments designed to find out whether two or more substances differ in terms of their effect on patients' headache symptomatology. This usually involves the use of headache diaries as indices of possible success. The data thus obtained may be arranged graphically and/or numerically. Many studies give percentage figures for the number of responders
which are based in part upon such criteria as "reduction in number of attacks per month by >50%, 1-50%, and negative". For the reasons mentioned above, however, response rates defined in this way are extremely inaccurate. An exact definition of efficacy in an individual patient (not in a group of patients) can, however, be quite easily obtained using statistical single case analysis and time-series analysis. Single case analysis is useful for studies in which the course of treatment is investigated with the help of headache diaries. It is also suitable for substances which, due to possible side effects, have to be given initially in low doses which are then gradually increased. Single case analysis is therefore useful for dose-finding studies. Responders are differentiated from non-responders on the basis of the statistical value of the time-series analysis (e.g. z-values). The differentiation of responders from non-responders allows the possibility of defining specific indications for one or another medication. The calculation of serial data by time-series analysis is based upon pioneering work by Box and Jenkins (8), Glass et al. (9), McLeary & Hay (10), and Gottman (11). In clinical pharmacological studies the effect of a medication is generally investigated over a specific period of time, e.g. three or four months. In studies of this type (e.g. using headache diaries) the data under investigation (time-series data) occur sequentially and the individual pieces of data are therefore not independent events. In research practice. a mere inspection of headache diaries often reveals a not insignificant reduction in headache symptoms shortly after introduction of the diaries, i.e. in the run-in phase before initiation of treatment. Statistical time-series analysis can be used to evaluate such sequential data. Almost all published studies report only positive findings (12), whereas negative results can only be surmised and in many cases are not mentioned. Negative results may also be useful (12). In particular, the distinction between responders and non-responders could help to answer the question as to which particular kind of patient, i.e. under what circumstances, a particular substance is indicated. Finally, the available results are in many cases of little relevance for clinical practice, since the need for a strict experimental design makes dose-finding very difficult. The questions addressed above were investigated in the present study. The aim of this experimental double-blind dose-finding study was to ascertain, on the basis of single case statistics and time-series analysis, the therapeutic efficacy of the beta1-selec-tive blocker metoprolol, the non-selective blocker propranolol and the calcium blocker nifedipine. Particular attention was addressed to the statistical separation and definition of responders (therapeutic success) and non-responders (therapeutic failure). Moreover, conventional group statistics, based on mean values of the treatment trials, were carried out. Methods
Patients The study included 58 migraine patients aged between 18 and 65 years. Following an eight-week baseline period patients were allocated through stratified randomizations to one of the three treatment groups. Table 1 provides a detailed description of the sample in terms of the three substances under investigation. No significant differences were found between the groups for any of the variables examined. The diagnosis was based on the classification criteria of the International Headache Society (IHS) (1988). The criterion for inclusion was the occurrence of at least two attacks per month over the 4 weeks immediately preceding the study. Both patients with and without aura (IHS classifications 1.1, 1.2.1 and 1.2.2) were included. In accordance with the IHS classification, the study included patients who satisfied at least two of the four named headache parameters. Exclusion criteria included pregnancy, abuse of ergotamine or analgesics, use of other agents for the prophylaxis of migraine attacks, and the specific contraindications for the individual substances (e.g. lactation, AV block, heart failure, bradycardia, obstructive pulmonary disease). Treatment The treatment was planned as a double-blind dose-finding study with three parallel groups. The study design is shown in Fig. 1. Following an eight-week baseline period during which a migraine diary was kept, the patients were allocated randomly to one of three treatment groups, metoprolol, propranolol or nifedipine. All the treatment groups commenced with a four-week initial phase of gradually increasing dosage ("run-in", low dosage) followed by a three-month phase of high dosage. This in turn was followed by three time periods of one month each with gradually decreasing dosage. The study ended with an eight-week follow-up period. The dosages given during the various phases are indicated in Fig. 1. For the abortion of migraine attacks, the patients were allowed to use whichever other medication they found helpful. At the beginning and end of the study and during the various treatment phases, the patients underwent a neuro-logical and psychological investigation including
Table 1. Description of the sample. Variable No. of patients Age (years) x s Range Sex Male Female Migraine duration (years) x s Range Migraine frequency/month x s Range Diagnosis Without aura With-aura Localization Hemicrania Holocrania
Metoprolol 22
Treatment group Propranolol 19
17
42.9 12.6 18-64
43.2 11.8 24-65
40.9 11.8 20-63
4 18
3 16
4 13
21.9 14.3 1-55
22.9 31.1 1-47
17.6 12.3 1-47
F = 0.777 n.s.
3.8 1.6 1-7
3.3 1.7 1-6
3.5 1.6 1-6
F = 0.596 n.s.
21 1
18 1
15 2
12 10
7 12
10 6
Nifedipine
Significance F = 0.182 n.s. chi2 = 0.83 n.s.
chi2 = 4.33 n.s.
x = arithmetic mean; s = standard deviation; n.s. = not significant.
EEG, VEP, laboratory parameters, blood pressure, and heart rate. We decided to use nifedipine with respect to the positive results of Meyer and Hardenberg (5). Over the entire duration of treatment, the patients kept a headache diary to record the following parameters: 1. Days on which a migraine attack occurred. 2. Duration of migraine attack in hours. 3. Duration of additional, non-migrainous, headaches in hours. 4. Intensity of headache (three assessment times per day using a visual analogue scale). 5. Site of pain. 6. Dose of all medication taken. 7. Duration of sleep in hours. 8. Daily mood (analogue scale). 9. Weekly evaluation of medication and listing of side effects. Responders/non- responders : definition and statistical analysis of data The method of time-series analysis employs a modified product-moment correlation in order to determine the serial dependency of the sequential data. Autocorrelation permits the correlation of the values at time t with the values at time t + 1, t + 2, ... t + n. Assuming that adjacent values are equally closely correlated with each other, the autocorrelations can be calculated by taking a mean across the various points in time. The various procedures of time-series analysis are designed to eliminate the serial dependency of the data. The ARIMA (Auto-regressive Integrated Moving Average) model developed by Box and co-workers (8) is particularly suitable for clinical serial data, and therefore also for headache studies; an extended ARIMA model can be used to determine periodicity. Although these procedures are not universally accepted, they
nevertheless are the best methods currently available for the analysis of time-series (11). For the practical application of time-series analysis to headache studies, a number of preconditions must be satisfied: at least 50 equidistant measurement time points are required (8), since more sample-dependent parameter estimations must be made with serially correlated data than with serially uncorrelated data. The various phases (baseline, treatment) should be as long as possible. An investigation of the efficacy of a substance should not just provide information on the results in individual cases, but should also answer the question of the applicability of the results to the entire patient group. Recently developed procedures permit the statistical processing of individual case results so as to make them applicable to the entire group. In addition we used the aggregation of individual data (9, 10). For each individual time-series and parameter (e.g. duration of headache), a z-value was calculated by computing the respective percentile of the t distribution in the standard normal distribution. Z-values were available from all patients who could then be classified into different responder groups. These z-values, moreover, could be evaluated as normally distributed values by statistical inference. This method, modified from the Stouffer method, was described by Mosteller & Bush (13) for individual cases, and time-series analysis were used in the present study for the investigation of the comparison of responders versus non-responders. The following statistical definitions of responders and non-responders were adopted. Responder type A:-Significant z-values (z £ -1.96) for the treatment phases Run In (Ri), High Dosage (HD), Reduction 1 (RED 1), RED 2, RED 3, and total reduction phase (RED) in the following headache variables: · · · ·
Reduction of number of days with migraine. Reduction of duration of migraine. Reduction of severity of headaches. Reduced use of analgesics and ergots.
Responder type B:-A tendency to improvement (but no statistically significant improvement) (z £ -1.65 to 1.96) in the parameters described above. Non-responder type C:-No improvement in the parameters (z = 0 to -1.65). Non-responder type D:-Tendency to deterioration, or statistically significant deterioration (positive z-values). The time-series analysis was used to compare the values for each patient in each treatment phase (run in, high dosage, reduction, follow-up) with those of Table 2. Percentages of responders (ARIMA) in the three treatment groups in various variables and treatment trials. Variable Migraine days LD HD RED 1 RED 2 RED 3 CAT Migraine duration LD HD RED I RED 2 RED 3 CAT Severity of headache LD HD RED 1 RED 2 RED 3 CAT Reduction of ergotamine intake LD HD RED 1 RED 2 RED 3 CAT
Metoprolol
Treatment group Propranolol
Nifedipine
40.9% 54.4% 56.3% 37.5% 53.8% 28.6%
21.1% 32.0% 23.5% 26.7% 15.4% 0.0%
0.0% 7.7% 11.1% 11.1% 0.0% 0.0%
40.9% 60.0% 37.5% 25.0% 38.5% 14.3%
15.8% 27.8% 23.5% 20.0% 15.4% 0.0%
11.8% 30.8% 11.1% 0.0% 0.0% 0.0%
54.5% 55.0% 50.5% 37.5% 30.8% 28.6%
21.1% 33.3% 23.5% 26.7% 15.4% 25.0%
0.0% 0.0% 0.0% 11.1% 0.0% 0.0%
18.2% 30.0% 37.5% 31.3% 38.5% 28.6%
21.1% 38.9% 23.5% 13.3% 30.8% 25.0%
17.6% 38.5% 33.3% 22.2% 22.2% 0.0%
Trial: LD = low dosage; HD = high dosage; RED 1-RED 3 = reduction of the dosages; CAT = follow-up. the pretreatment phase (baseline). Percentage values are given for the number of responders and non-responders for each of the assessment criteria. The individual case results were calculated as group statistics using non-parameteric methods (Crosstabs, Wilcoxon test) and by multifactorial analysis of variance with repetition of measurement. Moreover, conventional group statistics, based upon mean values of the treatment trials, were carried out. In order to calculate the variance components of the three substances in their therapeutic effectiveness, multiple regression analyses were performed. For this purpose, a stepwise algorithm was selected, i.e. beginning with the variable with the greatest explained variance (inclusion criterion, p < = 0.05). The following illustration of the data includes single case analyses (ARIMA) as well as conventional group statistics (ANOVA). Results
Responder and non-responder analysis for the three substances Tables 2 and 3 summarize the percentages of
Table 3. Classification of responders and non-responders (ARIMA) in the three treatment groups in various variables during high dosage phase of treatment. Treatment group Variable Migraine days
Migraine duration
Severity of headache
Reduction of Ergotamine intake
Responder classification A B C D A B C D A B C D A B C D
Metoprolol 54.4% 5.0% 35.6% 0.0% 60.0% 5.0% 35.0% 0.0% 55.0% 5.0% 40.0% 0.0% 30.0% 0.0% 65.0% 5.0%
Propranolol 32.0% 0.0% 62.4% 5.6% 27.8% 5.6% 61.1% 5.6% 33.3% 5.6% 61.1% 0.0% 38.9% 0.0% 55.6% 5.6%
Nifedipine 7.7% 15.4% 61.5% 15.4% 30.8% 7.7% 46.2% 15.4% 0.0% 7.7% 69.2% 23.1% 38.5% 0.0% 53.8% 7.7%
Responder-classification A-D (see text). A = sign. improvement; B = tendency to improvement; C = no improvement; D = tendency to deterioration. responder and non-responder rates (ARIMA) in the three treatment groups under various treatment conditions. Responders and non-responders with metoprolol:- Twelve of 22 patients (54.5%) taking metoprolol (100 mg or 200 mg) showed a significant improvement in terms of the number of days with migraine attacks. After the run-in phase, only two patients (9%) dropped out because of lack of response. A further four patients refused to reduce the dosage; in three of these patients this was because of inadequate effect, whereas in the fourth patient it was because of the very good effect experienced. The proportion of responders (Types A and B) and non-responders (Types C and D) for the various treatment phases is shown in Tables 2 and 3. Responders and non-responders with propranolol:-Six of 19 patients taking propranolol, i.e. 32%, experienced a significant reduction in the frequency of attacks (days with migraine). The dropout rate due to side effects or lack of therapeutic effect was low (one patient after the run-in period, and a further patient in the high-dosage phase). Table 2 shows the proportion of responders (Types A and B) and non-responders (Types C and D) for the various treatment phases. It has been shown also that there was a worsening of symptoms during the reduction phase in 41.1% of patients (as compared with 25% for the metoprolol group). Responders and non-responders with nifedipine:-Four patients dropped out after the run-in phase and eight patients dropped out after the high-dosage phase due to lack of effect or side effects. At a dosage of 40 mg, only one patient showed an improvement in terms of frequency of attacks, but this patient refused to continue to take the drug because of side effects. A total of 71% of the patients showed a significant deterioration after as little as 20 mg of nifedipine. The minor increase in the improvement rate during the reduction phase can be unequivocally attributed to the tailing-off of the medication. Differential efficacy of metoprolol, propranolol and nifedipine In order to assess the differential efficacy of the three drugs, the outcome of the statistical time-series analysis (z-values) and also the mean values of the treatment phases were submitted to a bifactorial analysis of variance with repetition of measurements (factors: group (medication), time (treatment phase)). The analysis of variance was calculated for the following variables: 1. Number of days with migraine. 2. Duration of migraine in hours. 3. Intensity (severity) of headache. 4. Number of tablets taken to abort attacks (ergotamine intake). Reduction in the number of days with migraine:-The bifactorial analysis of variance showed significant principal effects for the factors "group" and "time" (medication: F(32,2) = 6.28, p < 0.01; dose: F(128,4) = 3.31, p < 0.05). Individual comparisons using the Scheffé test revealed significant differences at the 5% level between the improvement rates for metoprolol and nifedipine, but not between those for metoprolol and propranolol or for those between propranolol and nifedipine. Fig. 2 shows
the relatively high and stable response rates for metoprolol as compared with the other two substances. Reduction in duration of migraine attacks in hours:-Analysis of variance also revealed significant principal effects for the factors "group" and "time" (medication: F(32,2) = 3.25, p = 0.05; dose: F(128,4) = 2.95, p < 0.05). Again, the Scheffè test showed a significant difference at the 5% level between the metoprolol and nifedipine group, but no significant differences between the other groups. Fig. 3 shows the good improvement rates associated with metoprolol (especially in the high-dosage phase) as compared with the other substances. Improvement in terms of severity of headache :-Again, significant principal effects for the factors "group" and "time" were found (medication: F(32,2) = 5.24, p = 0.01; dose: F(128,4) = 2.54, p < 0.05). Individual comparisons with the Scheffé test at the 5% level revealed that the metoprolol group differed significantly from both the nifedipine group and the propranolol group; there were no other significant differences between groups. Fig. 4 shows that only metoprolol and propranolol reduced the severity of headaches. The slight improvement rates associated with nifedipine in the reduction dosage phase can be explained by a reduction of side effects.
Reduction in intake of medications to abort attacks. Analysis of variance of response rates revealed no significant differences between the group in terms of reduction in intake of medication to abort attacks (F(32,2) = 0.05, p > 0.10), nor was there any significant time/dose difference demonstrated (F(128,4) = 1.65, p > 0.10) (see Fig. 5). Specificity of the treatment effects An important factor in the assessment of the clinical relevance of a substance is its specificity. The statistical parameters of the time-series analysis permitted an investigation of the characteristics of the responders. For this purpose, multiple regressions analyses were calculated, the following variables being considered as possible effect variables (independent variables, predictors): 1. Age of patient. 2. Duration of illness (migraine). 3. Systolic blood pressure. 4. Diastolic blood pressure. 5. Analgesic intake. 6. Ergotamine intake. 7. Ergotamine combined with codeine/caffeine. 8. Ergotamine combined with analgesics/barbiturates. These variables were selected because they showed the highest explained variance in the first multiple regression analysis. The following dependent variables were taken: 1. Days with migraine. 2. Duration of migraine in hours. 3. Duration of non-migrainous headaches. 4. Intensity of migraine.
The calculations were performed only for metoprolol and propranolol, as the number of significant responders was too small with nifedipine. We found significant regression weights principally for propranolol. This means that the improvement in patients who took propranolol could be attributed predominantly to the reduction in the intake of analgesics and ergots. For the variable "reduction in migraine days", 57.6% of the variance was explained in this way. For metoprolol significant predictors in the regression analysis were not found. The effect of metoprolol seems to be more specific. Side effects Fig. 6 summarizes reported side effects of the three drugs investigated. The most commonly reported side effects were tiredness and vertigo. Discussion
On the basis of single case statistical analysis and time-series analysis, the present double-blind dose-finding study was aimed at investigating the clinical efficacy of metoprolol, propranolol, and nifedipine. Particular attention was paid to the statistical differentiation and definition of responders (successful treatment) as compared with non-responders (unsuccessful treatment). Effects of metoprolol The present study confirms the success rates quoted in the literature (7) for metoprolol. We showed that the administration of 100 mg and 200 mg of metoprolol produced "significant" effects in 41% and 54.5% of patients, respectively. Only 13.6% of patients showed a worsening of migraine symptoms. Side effects, principally tiredness, were reported more frequently with metoprolol than with propranolol. Effects of propranolol The response rates for propranolol of 21% at 80 mg and 32% at 120 mg were far below those reported in the literature (3). For example, Diamond et al. (14) reported 72.5% responders to propranolol on the basis of a "headache unit index". Here it can be seen that time-series analysis gives significantly lower, but more realistic, success rates. In the study by Diamond et al. a mere 5.7% of patients dropped out, and this low rate was confirmed in the present study: only one patient stopped taking the medi-cation because of side effects. Nevertheless, the spectrum of activity of propranolol appears to have been overestimated in the various studies performed previously. In the present study, as many as 38.9% of patients on 160 mg of propranolol showed no improvement in the frequency of attacks, and 27.8% even showed a deterioration. Notwithstanding all this, especially in view of its low rate of side effects, propranolol can still be recommended for the prophylaxis of migraine; however, a dosage of 160 mg should be given. Effects of nifedipine The statistical differentiation of a responder and a non-responder group for each medication showed that even low doses (20 mg) of nifedipine led to an increase in migraine attacks in 71% of patients. Jonsdottir et al. (15) and Meyer and Hardenberg (5)
reported an improvement in frequency of attacks in 65% of patients on nifedipine. The present study, by contrast, showed a significant improvement in only one patient. The occurrence of pronounced side effects including non-migrainous headaches led many of the patients to refuse further intake of the medication. It therefore seems incomprehensible that daily doses of between 30 and 120 mg of nifedipine were tolerated in the study by Meyer and Hardenberg (5). It can only be assumed that of the complete sample, results were given only for those patients who showed some sort of effect, no matter what sort of effect this was. On the basis of the results of the present study, we would regard nifedipine as being useless for the prophylaxis of migraine. Analysis of variance revealed a significant time effect during the treatment. Higher doses are significantly more effective than lower doses. The effect of the medication becomes more effective with time. For clinical practice, patients should therefore be treated with high enough doses over a long enough time interval (at least 3 months). Some patients, however, already responded to the treatment when giver the lowest dose. In these it is of no use to prescribe higher dosages. The results of the regression analysis were disappointing. With one exception we were not able to identify factors that would allow a prediction as to whether a certain substance is effective or not. We were, however, able to show a correlation between the reduced intake of ergots and analgesics in the propranolol group and the reduction of migraine days. We possibly induced a positive cycle, where propranolol reduces the number of migraine attacks, this reduction leads to the intake of fewer migraine pills and this again improves migraine. It is a well established fact that the frequent intake of ergot-amine and analgesics can cause headache (16). The mechanism of action for beta-blocking agents is still unknown. They must have central effects, as can be shown by their effect on evoked cortical potentials and contingent negative variation (17, 18, 19). It is interesting to observe a correlation between the serum levels of metoprolol and its effectiveness. This was not the case for propranol, which correlates with the results of other authors (20, 2l, 22). This observation makes it unlikely that increasing the dosages of propranolol to more than 240 mg/day will result in a more effective action. The fact that nifedipine was useless in our study does not imply that all calcium channel blockers are ineffective. The group of calcium channel blockers is very incongruent, and flunarizine has been shown to be effective in migraine prophylaxis. In summary, the differentiation of responders from non-responders on the basis of time-series analysis permits a better clinical assessment of the practical value of drugs for the prophylaxis of migraine. The present dose-finding study shows that a well-shaped treatment programme as used in this study is highly suitable for clinical practice. References
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