Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial

Fabio Frediani, Licia Grazzi, Annalisa Zanotti, Federico Mailland, Boris Maurizio Zappacosta, Gennaro Bussone

Cephalalgia Frediani F, Grazzi L, Zanotti A, Mailland F, Zappacosta BM, Bussone G. Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial. Cephalalgia 1991;11:117-21. Oslo. ISSN 0333-1024 Dihydroergokryptine has been evaluated in the prophylaxis of headache attacks in patients with migraine without aura. The study was controlled vs dihydroergotamine with a double-blind crossover design. After a 1-month run-in period, 30 patients were randomized into two groups and submitted to 4 months treatment with dihydroergokryptine 10 mg b.i.d. or dihydroergotamine (controlled release) 5 mg b.i.d. The treatment was repeated in crossover after 2 months washout. The clinical patients' evaluation was determined by monthly Pain Total Index recording, headache days/month and analgesic consumption. The patients were considered responsible when Pain Total Index decreased by 50% or more in 1 or more months of each treatment period; otherwise the patients were considered unresponsive. The response rate to dihydroergokryptine was 66% while 48% of cases were responsive to dihydroergotamine. The response rate to both treatments was 41%, while 26 % did not respond to either treatment. Seven cases unresponsive to dihydroergotamine responded positively to dihydroergokryptine while two cases only, resistant to dihydroergokryptine, responded positively to dihydroergotamine. Three cases dropped out during treatment with dihydroergotamine due to gastric pain and nausea, while they did not show any side effects during dihydroergokryptine therapy. During treatment with dihydroergokryptine there was one case of skin rash which disappeared after drug withdrawal. In conclusion, dihydroergokryptine appears to be an effective drug for the prophylaxis of migraine attacks. € Dihydroergokryptine, dihydroergotamine, migraine, migraine prophylaxis, migraine without aura Fabio Frediani, Licia Grazzi, Boris Maurizio Zappacosta, Gennaro Bussone, Centro Cefalee, Istituto Neurologico "C. Besta", via Celoria 11, 20133 Milano, Italy; Annalisa Zanotti, Federico Mailland, Development and Clinical Research Department, Poli Industria Chimica S.P.A. P.zza Agrippa 1, 20141 Milano, Italy; Correspondence to Gennaro Bussone; Accepted 19 April 1991 Alpha-dihydroergokryptine is a hydrogenated ergot alkaloid derivative endowed with dopaminergic activity. The dopaminergic activity of dihydroergokryptine has already been demonstrated with various methods, both in experimental animals and humans (1-3). The use of ergot alkaloids with a prevalent serotonin-agonist activity such as ergotamine and di-hydroergotamine in both the prophylaxis and treatment of migraine attacks is well documented (4-7). Recently, another ergot derivative, lisuride, having a prevalent dopamine agonist activity, has proved to be active as a preventive treatment for headaches (8). The presence of an altered tone of the dopaminergic system in migraine subjects not only during the painful crisis but even under basal conditions has been confirmed by a series of data from the literature (9, 10). According to some studies (11) there is a supersensitivity of dopaminergic receptors in the central nervous system of patients suffering from migraine: the long-term administration of dopamine agonists causes a down regulation of the receptors. In fact the decrease in frequency and severity of attacks is evident after at least 2 months of treatment, while the effect lasts several weeks or months after drug withdrawal. In a previous controlled study vs placebo (12) the preventive activity of dihydroergokryptine in migraine has been demonstrated. The purpose of our study was to evaluate the therapeutic efficacy of dihydroergokryptine in the prevention and treatment of migraine without aura in a controlled trial vs a well known and well tested drug, i.e. di-hydroergotamine. Materials and methods

Seven males and 23 females were admitted to the trial, aged 20 to 47 years (mean 33.93 ± 9.07 years), suffering from migraine without aura according to the International Headache Society (IHS) criteria (13). Age of onset of headache ranged between 8 and 39 years (mean 15.97 ± 7.73 years). Onset was acute in three cases, progressive in 26 and not specified in one. Occurrence was spontaneous in 28 cases, secondary to stress in one case and caused by alcohol intake in one case. The initial site of pain was quite

variable but in most patients the frontal region was involved. In a minority of cases (six patients) lateral pain was observed while in the other cases pain was bilateral or alternated. Headache was continuous in nine cases, pulsating in 14, continuous and pulsating in six, continuous and heavy in one case. According to patients' complaints, pain occurred upon waking up in six cases, during the morning in seven, in the afternoon in four, in the evening in one and varied in 12 cases. The frequency was 5-6 monthly attacks in most of the patients; the attacks were reported to be usually severe (22 patients), while they were moderate in seven and extremely severe in one. The mean duration of each attack was less than 5 h in two patients, between 5 and 8 h in 10, between 9 and 24 h in nine, and more than 24 h in nine cases. During the first phase, patients were checked for 1 month while receiving no treatment; only non-ergot analgesics were allowed. Subsequently, the double-blind crossover controlled totally randomized study vs dihydroergotamine was started. The patients were divided into two groups: group 1 was treated with dihydroergokryptine 20mg b.i.d. (except for the first 15 days when the daily dose was 10mg); group 2 was treated with di-hydroergotamine retard 5 mg b.i.d. In the dihydroergokryptine group the dose was gradually increased from 10 to 20 mg/day, while dihydroergotamine was always given at a dose of 10 mg/day. The packages of the two drugs were indistinguishable. The treatments were administered for 4 months; subsequently the patients underwent a 2-month washout period when analgesics only were allowed. The treatments were then crossed-over at the end of the washout period (in sequence A the first treatment was dihydroergotamine, while in sequence B it was dihydroergokryptine). Before being admitted to the study, each patient was submitted to a clinical and neurological examination, and gave informed consent to the study. Each patient received 11 monthly time charts which were used to make a daily record of the frequency, length and severity of headache during the month preceding treatment, during the two treatment courses and during the washout period. Any side effects occurring during the treatment courses were reported in the patient's case report form. The efficacy of treatment was evaluated as follows: (a) Pain Total Index (14), as calculated at the beginning of treatment and then every month. The Pain Total Index values were calculated according to the following formula: (D1.1) + (D2.2) + (D3.3) Where D1 = total number of hours/month with headache as under (1); D2 = total number of hours/ month with headache as under (2), etc.; (b) days with headache/month; (c) analgesic consumption/ month; (d) tolerability. All data were processed by statistical analysis. The patients' personal data and medical history were codified into categories or classes and for each the numerical frequencies and the percent values were calculated. The central trend and variability indexes were also calculated for each variable. The analysis of the two-period repeated measurements crossover design was performed by univariate split-plot analysis of variance according to the Wallenstein model (15). The Fisher exact test and the chi-square test were employed to evaluate responder and non-responder patients in the two groups. Results

One patient discontinued dihydroergotamine administration at the end of the fourth month on her physician's advice, since he suspected renal insufficiency (this failed to be substantiated by the laboratory tests carried out at the Besta Hospital). In spite of efforts, the patient refused to continue the trial and to be submitted to the second treatment period. Another patient did not begin dihydroergokryptine treatment because he moved away. Similarly, another patient discontinued dihydroergokryptine during the third month because of skin rash and did not start the second treatment. As a consequence, 28 patients received dihydroergokryptine and 29 received dihydroergotamine. Twenty-seven patients were treated with both drugs. Five other cases discontinued dihydroergotamine before the end of the study, two because it was ineffective and three because of side effects (gastric pain and nausea); of these five patients only one interrupted treatment with dihydroergokryptine for inefficacy. As shown in Fig. 1 the patients of both sequences showed a gradual but steady reduction of Pain Total Index, which was especially evident from the second to the third month of therapy and lasted for 2 months after drug withdrawal. A residual effect of the previous treatment was demonstrated by the fact that Pain Total Indexes were usually lower at the beginning of the second treatment period, irrespective of the sequence. As shown in Fig. 2, the patients of both sequences presented a gradual and steady reduction of the number of headache days/month during the first treatment period: a residual effect of the previous treatment was demonstrated also for this parameter as the baseline values before the second treatment period were lower than baseline values before the

study. In Fig. 3 it can be seen that the consumption of analgesics did not increase for the dihydroergokryptine group during the washout period, while for dihydroergotamine an increase in analgesic intake was seen in the same period. The statistical analysis performed on both these target variables, according to Wallenstein design

(15), showed a significant difference (p

Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial.

Dihydroergokryptine has been evaluated in the prophylaxis of headache attacks in patients with migraine without aura. The study was controlled vs dihy...
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