THE EFFECTS OF CLONIDINE IN THE PROPHYLACTIC TREATMENT OF MIGRAINE ROBERT E. RYAN, SR., M.D., M.S., B.S.* ROBERT E. RYAN, JR., M.D. B.S.** *Professor
of Otolaryngology, St. Louis University School of Medicine. Director, Department of Otolaryngology, St. John's Mercy Medical Center. **Dept.
Otolaryngology, Mayo Clinic, Rochester, Minn.
PROBABLY ONE OF the most common and perplexing problems encountered by physicians is the treatment of the headache patient. It is certainly safe to say that every physician, regardless of his specialty, is frequently confronted by the headache patient. To complicate the situation, radio, television and the press daily remind our American public of this or that "cure all" preparation for the headache, thus creating a "headache conscious" audience. As a result, headache ranks as a high source of revenue for the manufacturers of patent and of proprietary remedies. Headache in itself is not a disease but merely a symptom of a disease which may accompany many different organic or functional conditions. Successful handling of the chronic headache problem is dependent upon the establishment of a correct diagnosis and upon effective treatment, which may be in the nature of pharmaceutical therapy, psychotherapy or, at times, surgical therapy. A headache patient, like any other patient, desires that the physician give him something which will stop his headache if it does occur (symptomatic treatment). He also wants the physician to give him something which will prevent him from having headaches in the future (prophylactic treatment). It is the prophylactic form of the treatment of migraine that we are concerned with in this paper. At the present time there are several reports in the medical literature on the use of Clonidine. However, all of these reports came from England or the European continent. Wilkinson found Clonidine to be a useful drug in the prophylactic treatment of migraine in some 30% of the patients she observed.1 She further stated that the success rate may be significantly improved by prior selection with tyramine. In her study she found drowsyness and depression to be the most common side effects and she points out that these are the result of the central action of Clonidine. In previous studies of Clonidine there are many cases of migraine which are much more severe when this drug is used. This is a difficult factor to explain but it may be a dose-dependent effect. Clonidine hydrochloride a unique anti-hypertensive agent, was synthesized in the laboratories of Boehringer Ingelheim G.m.b.H., Republic of West Germany. Minute oral discs of Clonidine (fraction of a milligram) were found to lower the blood pressure in man. While its mode of action has not been completely defined, it is distinctive from other anti-hypertensive agents in that Clonidine apparently acts centrally to inhibit or diminish the discharge of sympathetic impulses to the periphery. Clonidine is now commercially available in West Germany, and investigations are underway in England, Australia, Sweden, Switzerland and Mexico, as well as in the United States. The most frequently observed side effects have been sedation, dry mouth and constipation, which sometimes lessen or disappear with continued treatment.
Clonidine is an imidazoline with the following chemical name and structure:
It is odorless, bitter-tasting white crystalline powder with good solubility in water (1: 7) and alcohol (1:10), and practically insoluble in chloroform or ether. A l0% aqueious solution has a pH of 4.5-5.5. Clonidine hydrochloride is an imidazoline derivative chemically related to tologaline and phentalamine. Grabner and Wolff found it to reduce blood pressure and that it caused sedation, dry mouth and bradycardia.2 Extensive pharmacological investigations have shown that its actions differ from other antihypertensive drugs. It has no direct vasodilator action, it does not deplete catecholamine stores and there is no block of ganglionic, post ganglionic, or A/B adrenergic transmission. It has vasoconstrictors and central depressant effects. Zaimis and Hannington found that in concentrations of 1-2 mg/kg body weight, clonidine decreases the responsiveness of peripheral blood vessels to circulating vasoactive amines and the blood vessels neither constrict nor dilate as much as normal.3 It was this that lead to the belief that possibly clonidine might be of some use in the treatment of migraine. The use of this drug in migraine in clinical trails in England gave encouraging results.4,5 More recently in Europe, a statistically significant superiority of Clonidine over placebo has been shown in a double-blind clinical trial.6 In all of these studies the effective dose level in the prophylactic treatment of migraine cases was considerably lower than these used to lower the blood pressure. Therefore, there were no hypotensive effects. More recently Clonidine was investigated in England in a study using a double-blind crossover comparison with placebo in the prophylactic aspect of migraine therapy.7 In this study 59% of the patients with migraine benefited from the prophylactic administration of Clonidine, whereas only 17% benefited from placebo. These results with Clonidine maintained their improvement for a period up to one year with continued administration of the drug. The dose range in this study was 1-2 mg/kg day. Clonidine is remarkably free from serious side effects, and is therefore relatively a safe drug to use. No contraindications have been identified as yet for Clonidine, however it should not be used in pregnant women regardless of the fact that reproduction studies in animals have revealed no teratogenicity with the oral use of Clonidine. Studies have continued to show that sedation and dry mouth are the primary side effects of Clonidine, being variously reported in 30%-70% of the patients. In most but not all instances, these symptoms abated with prolonged therapy. Constipation and orthostatic complaints were less frequently reported. Mild bradykardia often accompanied Clonidine therapy, and any EKG changes have been consistent with this finding. Impotence was noted infrequently. Interestingly, one patient with impotence and another with gynecomastia associated with a previous antihypertensive regimen improved when Clonidine was substituted.8 Depression or anxiety were reported in a few patients.9,10 In most cases there was a previous history of these symptoms, so that a causal role of the drug was not apparent.
Adverse reactions associated with Clonidine have been; for the most part, mild and often transient. Sedation and dry mouth predominated, and were usually dose-related. In most instances they subsided during treatment, but occasionally were poorly tolerated and dose-limiting. Constipation was reported less frequently but tended to be associated more often with long-term therapy. Bradycardia has consistently been observed in single-dose studies with Clonidine, and was often present to a mild degree during continuous therapy. However, extreme slowing of the pulse has been rare. Although the standing blood pressure is usually somewhat lower than the supine during Clonidine treatment, orthostatic complaints such as dizziness and headache are not often encountered, and rarely are severe. Facial pallor is rarely seen during oral administration of Clonodine, but it may be seen more often when the drug is given intravenously, as may be chills and piloerection. Weight gain responsive to an oral diuretic has been reported occasionally, but congestive heart failure and edema have rarely resulted. Associated with Clonidine have been rare instances of the following: burning of the tongue; itching, dryness or burning of the eyes; dryness of nasal mucosa; nasal stuffiness; urinary retention; muscle aching; thinning of the hair; gynecomastia. Paralytic ileus and periorbital swelling with itching have occurred in one patient each. Isolated (transient) elevations in the following values have been observed; creatine phosphokinase; alkaline phosphatase; serum bilibrubin; serum transaminase; BUN; BSP retention; uric acid. No adverse effect on the hemogram has been evident. The circulatory effects of Clonidine was studied in hypertensive patients at rest and when exercising. 11 The results showed a lowering of the blood pressure was achieved by a variable reduction of cardiac output and systemic vascular resistance. The circulatory responses to blood in the supine and the erect position were unimpaired. In 1971, Wilkinson reported on a study dealing with Clonidine in which she observed the success rate of the drug in patients who were tyramine-positive and in patients who were tyramine-negative. This study srowed that in the tyramine-positive patients improvement of 73.5% was obtained. In the migraine patients who were tyramine-negative the improvement rate was 43.5%. In a third group which was composed of unselected migraine patients the improvement rate was found to be 46%. These results indicated that Clonidine was far more effective in the prophylactic treatment of migraine when it is used by tyramine-positive patients. In this study which we are reporting on in this paper, seventy-five patients were selected who gave a history of having three or more migraine attacks per month. These patients either had common or classical migraine. Both male and female patients were included in the study between the ages of 21 and 60. None of the female patients were pregnant. None of the patients had liver disease, kidney disease, cardiovascular disease or depressive illness. No other prophylactic medication was administered to these patients, but they were all instructed to use various medications for the symptomatic treatment of their headache attacks when they did occur. The name of the drug and the dosage used for each attack were all recorded in a medical diary which the patient used daily. The amount of the trial medication taken each day was also recorded in this diary. This diary is shown in Figure 1. The object of this study was to evaluate the efficacy and safety of Clonidine in the prophylactic treatment of migraine headache in comparison with placebo treatment. It was a double blind, cross-over type of study. Each patient received Clonidine for a period of 8 week's and
then was crossed over to the placebo, or from the placebo to Clonidine. If the patient received poor results after a period of 6 weeks and did not seem to respond to the treatment, they were crossed over at that time. The order of treatment was randomized. At the time of the crossover, each patient was instructed not to take any of the test medication for a period of 2 days. After 2 days without medication had elapsed the patients returned for their second medication. On the initial visit a brief history of the patient was recorded with certain leading questions being asked such as relation of headache attacks to emotional stress, menses, foods, seasons of the year, etc. This is shown in Figure 2. Figure 3 shows further history of the patient with regards to other medication being used by the patient. It also outlines the procedure to take with appointments and the actual taking of the medication. This is filled out on the first visit. Also on the first visit each patient received an examination, which included blood pressure, pulse and electrocardiogram. This is shown in Figure 4. These tests were rechecked at the crossover time and at the end of the test. Finally, on the first visit certain laboratory tests were done. Both the blood and the urine were examined as shown in Figure 5. These tests were also rechecked at the cross over period and at the end of the procedure. The vital signs were recorded every 2 weeks on each patient during the study and also 48 hours after the patient had completed each course of drug treatment. At this time interval (2 weeks) each patient was seen. At this time the patients diary was examined and a global evaluation was made concerning the frequency, duration and severity of the headache attacks during the 2 week period. Side effects were also recorded at this time. This is shown in Figure 6 and Figure 7.
At the beginning of the trial, each patient was instructed to take one tablet twice a day, one in the morning and one in the evening. After a period of 2 weeks if there was no remission of the symptoms, the dosage was increased to two tablets in the morning and two tablets in the evening (4 tablets per day). This was the dosage level for another two weeks and if the desired degree of response was not achieved the dosage was increased to three tablets twice a day. This was the maximum dosage used. These patients who failed to receive the desired results with the 6 tablets per day dosage schedule were then crossed over to the second drug. In these cases, therefore, the crossover took place in 6 weeks. In the cases in which satisfactory results were obtained, the cross over took place 8 weeks after the investigation began. Between the trial with drug #1 and that of drug #2, there was a 48 hour period in which no prophylactic medication was taken. After the 48 hours the patient returned for a re-check of the vital signs and the patients evaluation. This data sheet is shown in Figure 8. This paper is merely a preliminary report. It includes the statistical analysis of the first one half of the total study; in other words, up to the crossover point of the study. The final report of the entire study will be reported at a later date. In this report, of the 75 patients, seventeen (17) were found to be tyramine positive and fifty-eight (58) were tyramine negative non-tyramine sensitive. This work was done by Robert E. Ryan, Jr., M.D.12 The patients ranged in age from twenty (20) to sixty (60) and both male and female patients were used. Fifteen males and sixty females were selected. The weights varied from ninety pounds to two hundred and twenty-nine pounds. Both common and classical migraine patients were studied. Each patient received one tablet (25 mg.) of Clonidine twice a day, or the exact appearing placebo twice a day. If good results were obtained the dosage was not changed for weeks three and four. If unsatisfactory results were reported, the dosage was elevated to two tablets (50 mg.) twice a day, or two placebos twice a day. If after week four, the results were still not satisfactory the dosage was increased to two tablets three times a day (either 150 mg. per day of Clonidine or 2 placebos three times a day ), for weeks five and six. No higher dosage was given any patient regardless of the results. One of the outstanding features of this preliminary report, is the lack of side effects reported. This is shown in Figure 9. The overall mean global response index of the tyramine positive patients receiving Clonidine was significantly better (higher) than those patients receiving a placebo. No significant difference was found for tyramine negative group between the overall mean global response index for those patients receiving Clonidine and those patients receiving a placebo. This is shown in Figure 10. A significantly fewer mean number of ergotamine pills were taken for symptomatic relief of their headache attack by the tyramine positive patients receiving Clonidine than those patients receiving a placebo. On the other hand, no difference was found between the mean number of ergotamine pills taken by the tyramine negative group of patients receiving Clonidine and the patients receiving a placebo. This is also shown in Figure 10. As far as analgesic pills taken for the symptomatic relief of their headache attacks, no significant difference was found for either the tyramine positive group or the tyramine negative group. This was true regardless if the patient was receiving Clonidine or the placebo. This is shown in Figure 10. This was also true in the case of ergotamine plus analgesic
SIDE EFFECTS Tyramine Positive
Tyramine Negative Placebo Clonidine 11 33 1 3 0 3 0 0 1 3 2 9
Clonidine 6 0 0 0 1 1
Number of patients (75) 2 weeks 4 weeks 6 weeks 8 weeks
Placebo 25 2 2 0 3 7
FIGURE 9 Tyramine Positive Mean Index Number of patients (75) Global response Number Ergotamine pills Number Analgesic pills Number Analgesic and Ergotamine pills
Clonidine 6 2.8 6.5 11.8 6.4
Tyramine Negative Placebo CIonidine Placebo 11 33 25 1.7 2.5 2.4 17.8 11.9 7.1 6.4 10.0 6.8 6.1 4.6 2.9
FIGURE 10
Severe Moderate Mild Overall
MEAN NUMBER OF HEADACHES Tyramine Positive Tyramine Negative Clonidine Placebo Clonidine Placebo 0.8 0.8 0.8 1.0 1.7 2.9 1.5 1.2 2.0 2.8 2.2 1.6 1.5 2.1 1.5 1.2
FIGURE 11 drugs for the symptomatic relief of the headache attacks. In regards to the overall mean number of headaches, for those patients receiving Clonidine and those patients receiving a placebo, there was no statistical significant difference for either the tyramine positive group or the tyramine negative group. This is shown in Figure 1. A headache index was computed for each patient. This index was calculated by multiplying the number of severe, moderate, and mild headaches by 3, 2, and 1 respectively and summing to yield the index value. No statistical significant difference was found between the overall means for those patients receiving Clonidine and those patients receiving a placebo for the tyramine positive group or the tyramine negative group. This is shown in Figure 12. Another factor with consideration is the headache frequency. Here it was found that there also was no statistical significant difference between the overall mean for those patients receiving Clonidine and those patients receiving a placebo for both the tyramine positive group of patients and the tyramine negative group. This is shown in Figures 13 and 14. This report is actually a preliminary one and takes us up to the cross over point in the total study. The most pertinent findings have been illustrated. It will be interesting to see what these same patients response will be after the second half of the study is completed. They will be reported at a later date when the figures are available.
HEADACHE Index Tyramine Positive Clonidine 10.2 11.0 3.8 14.5 10.4
2 weeks 4 weeks 6 weeks 8 weeks Overall
Tyramine Negative Clonidine Placebo 11.3 11.7 10.7 8.7 3.8 3.2 11.4 8.2 10.0 8.5
Placebo 14.4 16.8 5.8 15.8 14.6
FIGURE 12 HEADACHE FREQUENCY Tyramine Positive Week Severe Moderate Mild Overall
Clonidine 4 6 1.2 0.0 1.7 0.5 2.7 0.0
2 1.2 1.7 3.3
Placebo 8
2
1.2 3.0 2.0 1.5
0.5 3.1 2.9
4 1.3 3.6 2.9
6 0.2 1.5 2.5 2.1
8 1.1 3.3 2.7
FIGURE 13 HEADACHE FREQUENCY Tyramine Negative Clonidine Week Severe Moderate Mild
2 0.9 2.3 2.5 Overall
4 0.8 1.6 2.2 1.5
6 0.3 0.7 1.4
8 1.1 1.5 2.6
Placebo 2 4 1.3 1.1 1.4 1.4 2.4 1.6
6 0.5 0.7 0.9 1.2
8 1.0 1.2 1.4
FIGURE 14 REFERENCES l. Wilkinson, M. et al.: Clonidine in the Treatment of Migraine at the City Migraine Clinic in Patients Selected with Tyramine. Proceedings International Headache Symposium, Elsinore, Denmark May 16-18, 1971, pp 219-221. 2.
Grabner, W. and Wolf, M.: Arzmeimithal-Forchung, 16:1055, 1966.
3.
Zaimis, E. and Hannington, E.: A Possible Pharmacological Approach to Migraine. Lancet 2:298-300, 1969.
4.
Wilkinson, M.: Lancet 2:430, 1969.
5. Wilkinson, M.: Proceedings of the International Migraine Headache Symposium, Florence, Italy, 26-28 May 1970. pp 117-118, 6.
Sjaastad, O. and Stensrud, P.: Acta Neurol. Scand. 47:120-122, 1971.
7. Barrie, M.A. et al.: The Use of Clonidine (ST-155) in Migraine and the Problems Encountered in a Multicenter Trial. Proceedings International Headache Symposium, Elsinore, Denmark, May 16-18, 1971, pp 23-26. 8.
Horwitz, D. et al.: Presented at the Second Catapres Symposium, September 18-19, 1968.
9.
Fairbairn, J.F. II, et al.: Presented at the Second Catapres Symposium, September 18-19, 1968.
10.
Gifford, R.W., Jr.: Presented at the Second Catapres Symposium, September 18-19, 1968.
11.
Muir, A.L., et al.: Circulatory Effects at Rest and Exercise of Clonidine, Lancet July 26, 1969, pp 181-185.
12. Ryan, Robert E., Jr.: A Clinical Study of Tyramine as an Etiological Factor in Migraine, Headache 14:43-49 (Apr.) 1974. Address reprint requests to: Robert E. Ryan, M.D., M.S., B.S. 621 South New Ballas Road St. Louis, Mo. 63141
of Otolaryngology, St. Louis University School of Medicine. Director, Department of Otolaryngology, St. John's Mercy Medical Center. **Dept.
Otolaryngology, Mayo Clinic, Rochester, Minn.
PROBABLY ONE OF the most common and perplexing problems encountered by physicians is the treatment of the headache patient. It is certainly safe to say that every physician, regardless of his specialty, is frequently confronted by the headache patient. To complicate the situation, radio, television and the press daily remind our American public of this or that "cure all" preparation for the headache, thus creating a "headache conscious" audience. As a result, headache ranks as a high source of revenue for the manufacturers of patent and of proprietary remedies. Headache in itself is not a disease but merely a symptom of a disease which may accompany many different organic or functional conditions. Successful handling of the chronic headache problem is dependent upon the establishment of a correct diagnosis and upon effective treatment, which may be in the nature of pharmaceutical therapy, psychotherapy or, at times, surgical therapy. A headache patient, like any other patient, desires that the physician give him something which will stop his headache if it does occur (symptomatic treatment). He also wants the physician to give him something which will prevent him from having headaches in the future (prophylactic treatment). It is the prophylactic form of the treatment of migraine that we are concerned with in this paper. At the present time there are several reports in the medical literature on the use of Clonidine. However, all of these reports came from England or the European continent. Wilkinson found Clonidine to be a useful drug in the prophylactic treatment of migraine in some 30% of the patients she observed.1 She further stated that the success rate may be significantly improved by prior selection with tyramine. In her study she found drowsyness and depression to be the most common side effects and she points out that these are the result of the central action of Clonidine. In previous studies of Clonidine there are many cases of migraine which are much more severe when this drug is used. This is a difficult factor to explain but it may be a dose-dependent effect. Clonidine hydrochloride a unique anti-hypertensive agent, was synthesized in the laboratories of Boehringer Ingelheim G.m.b.H., Republic of West Germany. Minute oral discs of Clonidine (fraction of a milligram) were found to lower the blood pressure in man. While its mode of action has not been completely defined, it is distinctive from other anti-hypertensive agents in that Clonidine apparently acts centrally to inhibit or diminish the discharge of sympathetic impulses to the periphery. Clonidine is now commercially available in West Germany, and investigations are underway in England, Australia, Sweden, Switzerland and Mexico, as well as in the United States. The most frequently observed side effects have been sedation, dry mouth and constipation, which sometimes lessen or disappear with continued treatment.
Clonidine is an imidazoline with the following chemical name and structure:
It is odorless, bitter-tasting white crystalline powder with good solubility in water (1: 7) and alcohol (1:10), and practically insoluble in chloroform or ether. A l0% aqueious solution has a pH of 4.5-5.5. Clonidine hydrochloride is an imidazoline derivative chemically related to tologaline and phentalamine. Grabner and Wolff found it to reduce blood pressure and that it caused sedation, dry mouth and bradycardia.2 Extensive pharmacological investigations have shown that its actions differ from other antihypertensive drugs. It has no direct vasodilator action, it does not deplete catecholamine stores and there is no block of ganglionic, post ganglionic, or A/B adrenergic transmission. It has vasoconstrictors and central depressant effects. Zaimis and Hannington found that in concentrations of 1-2 mg/kg body weight, clonidine decreases the responsiveness of peripheral blood vessels to circulating vasoactive amines and the blood vessels neither constrict nor dilate as much as normal.3 It was this that lead to the belief that possibly clonidine might be of some use in the treatment of migraine. The use of this drug in migraine in clinical trails in England gave encouraging results.4,5 More recently in Europe, a statistically significant superiority of Clonidine over placebo has been shown in a double-blind clinical trial.6 In all of these studies the effective dose level in the prophylactic treatment of migraine cases was considerably lower than these used to lower the blood pressure. Therefore, there were no hypotensive effects. More recently Clonidine was investigated in England in a study using a double-blind crossover comparison with placebo in the prophylactic aspect of migraine therapy.7 In this study 59% of the patients with migraine benefited from the prophylactic administration of Clonidine, whereas only 17% benefited from placebo. These results with Clonidine maintained their improvement for a period up to one year with continued administration of the drug. The dose range in this study was 1-2 mg/kg day. Clonidine is remarkably free from serious side effects, and is therefore relatively a safe drug to use. No contraindications have been identified as yet for Clonidine, however it should not be used in pregnant women regardless of the fact that reproduction studies in animals have revealed no teratogenicity with the oral use of Clonidine. Studies have continued to show that sedation and dry mouth are the primary side effects of Clonidine, being variously reported in 30%-70% of the patients. In most but not all instances, these symptoms abated with prolonged therapy. Constipation and orthostatic complaints were less frequently reported. Mild bradykardia often accompanied Clonidine therapy, and any EKG changes have been consistent with this finding. Impotence was noted infrequently. Interestingly, one patient with impotence and another with gynecomastia associated with a previous antihypertensive regimen improved when Clonidine was substituted.8 Depression or anxiety were reported in a few patients.9,10 In most cases there was a previous history of these symptoms, so that a causal role of the drug was not apparent.
Adverse reactions associated with Clonidine have been; for the most part, mild and often transient. Sedation and dry mouth predominated, and were usually dose-related. In most instances they subsided during treatment, but occasionally were poorly tolerated and dose-limiting. Constipation was reported less frequently but tended to be associated more often with long-term therapy. Bradycardia has consistently been observed in single-dose studies with Clonidine, and was often present to a mild degree during continuous therapy. However, extreme slowing of the pulse has been rare. Although the standing blood pressure is usually somewhat lower than the supine during Clonidine treatment, orthostatic complaints such as dizziness and headache are not often encountered, and rarely are severe. Facial pallor is rarely seen during oral administration of Clonodine, but it may be seen more often when the drug is given intravenously, as may be chills and piloerection. Weight gain responsive to an oral diuretic has been reported occasionally, but congestive heart failure and edema have rarely resulted. Associated with Clonidine have been rare instances of the following: burning of the tongue; itching, dryness or burning of the eyes; dryness of nasal mucosa; nasal stuffiness; urinary retention; muscle aching; thinning of the hair; gynecomastia. Paralytic ileus and periorbital swelling with itching have occurred in one patient each. Isolated (transient) elevations in the following values have been observed; creatine phosphokinase; alkaline phosphatase; serum bilibrubin; serum transaminase; BUN; BSP retention; uric acid. No adverse effect on the hemogram has been evident. The circulatory effects of Clonidine was studied in hypertensive patients at rest and when exercising. 11 The results showed a lowering of the blood pressure was achieved by a variable reduction of cardiac output and systemic vascular resistance. The circulatory responses to blood in the supine and the erect position were unimpaired. In 1971, Wilkinson reported on a study dealing with Clonidine in which she observed the success rate of the drug in patients who were tyramine-positive and in patients who were tyramine-negative. This study srowed that in the tyramine-positive patients improvement of 73.5% was obtained. In the migraine patients who were tyramine-negative the improvement rate was 43.5%. In a third group which was composed of unselected migraine patients the improvement rate was found to be 46%. These results indicated that Clonidine was far more effective in the prophylactic treatment of migraine when it is used by tyramine-positive patients. In this study which we are reporting on in this paper, seventy-five patients were selected who gave a history of having three or more migraine attacks per month. These patients either had common or classical migraine. Both male and female patients were included in the study between the ages of 21 and 60. None of the female patients were pregnant. None of the patients had liver disease, kidney disease, cardiovascular disease or depressive illness. No other prophylactic medication was administered to these patients, but they were all instructed to use various medications for the symptomatic treatment of their headache attacks when they did occur. The name of the drug and the dosage used for each attack were all recorded in a medical diary which the patient used daily. The amount of the trial medication taken each day was also recorded in this diary. This diary is shown in Figure 1. The object of this study was to evaluate the efficacy and safety of Clonidine in the prophylactic treatment of migraine headache in comparison with placebo treatment. It was a double blind, cross-over type of study. Each patient received Clonidine for a period of 8 week's and
then was crossed over to the placebo, or from the placebo to Clonidine. If the patient received poor results after a period of 6 weeks and did not seem to respond to the treatment, they were crossed over at that time. The order of treatment was randomized. At the time of the crossover, each patient was instructed not to take any of the test medication for a period of 2 days. After 2 days without medication had elapsed the patients returned for their second medication. On the initial visit a brief history of the patient was recorded with certain leading questions being asked such as relation of headache attacks to emotional stress, menses, foods, seasons of the year, etc. This is shown in Figure 2. Figure 3 shows further history of the patient with regards to other medication being used by the patient. It also outlines the procedure to take with appointments and the actual taking of the medication. This is filled out on the first visit. Also on the first visit each patient received an examination, which included blood pressure, pulse and electrocardiogram. This is shown in Figure 4. These tests were rechecked at the crossover time and at the end of the test. Finally, on the first visit certain laboratory tests were done. Both the blood and the urine were examined as shown in Figure 5. These tests were also rechecked at the cross over period and at the end of the procedure. The vital signs were recorded every 2 weeks on each patient during the study and also 48 hours after the patient had completed each course of drug treatment. At this time interval (2 weeks) each patient was seen. At this time the patients diary was examined and a global evaluation was made concerning the frequency, duration and severity of the headache attacks during the 2 week period. Side effects were also recorded at this time. This is shown in Figure 6 and Figure 7.
At the beginning of the trial, each patient was instructed to take one tablet twice a day, one in the morning and one in the evening. After a period of 2 weeks if there was no remission of the symptoms, the dosage was increased to two tablets in the morning and two tablets in the evening (4 tablets per day). This was the dosage level for another two weeks and if the desired degree of response was not achieved the dosage was increased to three tablets twice a day. This was the maximum dosage used. These patients who failed to receive the desired results with the 6 tablets per day dosage schedule were then crossed over to the second drug. In these cases, therefore, the crossover took place in 6 weeks. In the cases in which satisfactory results were obtained, the cross over took place 8 weeks after the investigation began. Between the trial with drug #1 and that of drug #2, there was a 48 hour period in which no prophylactic medication was taken. After the 48 hours the patient returned for a re-check of the vital signs and the patients evaluation. This data sheet is shown in Figure 8. This paper is merely a preliminary report. It includes the statistical analysis of the first one half of the total study; in other words, up to the crossover point of the study. The final report of the entire study will be reported at a later date. In this report, of the 75 patients, seventeen (17) were found to be tyramine positive and fifty-eight (58) were tyramine negative non-tyramine sensitive. This work was done by Robert E. Ryan, Jr., M.D.12 The patients ranged in age from twenty (20) to sixty (60) and both male and female patients were used. Fifteen males and sixty females were selected. The weights varied from ninety pounds to two hundred and twenty-nine pounds. Both common and classical migraine patients were studied. Each patient received one tablet (25 mg.) of Clonidine twice a day, or the exact appearing placebo twice a day. If good results were obtained the dosage was not changed for weeks three and four. If unsatisfactory results were reported, the dosage was elevated to two tablets (50 mg.) twice a day, or two placebos twice a day. If after week four, the results were still not satisfactory the dosage was increased to two tablets three times a day (either 150 mg. per day of Clonidine or 2 placebos three times a day ), for weeks five and six. No higher dosage was given any patient regardless of the results. One of the outstanding features of this preliminary report, is the lack of side effects reported. This is shown in Figure 9. The overall mean global response index of the tyramine positive patients receiving Clonidine was significantly better (higher) than those patients receiving a placebo. No significant difference was found for tyramine negative group between the overall mean global response index for those patients receiving Clonidine and those patients receiving a placebo. This is shown in Figure 10. A significantly fewer mean number of ergotamine pills were taken for symptomatic relief of their headache attack by the tyramine positive patients receiving Clonidine than those patients receiving a placebo. On the other hand, no difference was found between the mean number of ergotamine pills taken by the tyramine negative group of patients receiving Clonidine and the patients receiving a placebo. This is also shown in Figure 10. As far as analgesic pills taken for the symptomatic relief of their headache attacks, no significant difference was found for either the tyramine positive group or the tyramine negative group. This was true regardless if the patient was receiving Clonidine or the placebo. This is shown in Figure 10. This was also true in the case of ergotamine plus analgesic
SIDE EFFECTS Tyramine Positive
Tyramine Negative Placebo Clonidine 11 33 1 3 0 3 0 0 1 3 2 9
Clonidine 6 0 0 0 1 1
Number of patients (75) 2 weeks 4 weeks 6 weeks 8 weeks
Placebo 25 2 2 0 3 7
FIGURE 9 Tyramine Positive Mean Index Number of patients (75) Global response Number Ergotamine pills Number Analgesic pills Number Analgesic and Ergotamine pills
Clonidine 6 2.8 6.5 11.8 6.4
Tyramine Negative Placebo CIonidine Placebo 11 33 25 1.7 2.5 2.4 17.8 11.9 7.1 6.4 10.0 6.8 6.1 4.6 2.9
FIGURE 10
Severe Moderate Mild Overall
MEAN NUMBER OF HEADACHES Tyramine Positive Tyramine Negative Clonidine Placebo Clonidine Placebo 0.8 0.8 0.8 1.0 1.7 2.9 1.5 1.2 2.0 2.8 2.2 1.6 1.5 2.1 1.5 1.2
FIGURE 11 drugs for the symptomatic relief of the headache attacks. In regards to the overall mean number of headaches, for those patients receiving Clonidine and those patients receiving a placebo, there was no statistical significant difference for either the tyramine positive group or the tyramine negative group. This is shown in Figure 1. A headache index was computed for each patient. This index was calculated by multiplying the number of severe, moderate, and mild headaches by 3, 2, and 1 respectively and summing to yield the index value. No statistical significant difference was found between the overall means for those patients receiving Clonidine and those patients receiving a placebo for the tyramine positive group or the tyramine negative group. This is shown in Figure 12. Another factor with consideration is the headache frequency. Here it was found that there also was no statistical significant difference between the overall mean for those patients receiving Clonidine and those patients receiving a placebo for both the tyramine positive group of patients and the tyramine negative group. This is shown in Figures 13 and 14. This report is actually a preliminary one and takes us up to the cross over point in the total study. The most pertinent findings have been illustrated. It will be interesting to see what these same patients response will be after the second half of the study is completed. They will be reported at a later date when the figures are available.
HEADACHE Index Tyramine Positive Clonidine 10.2 11.0 3.8 14.5 10.4
2 weeks 4 weeks 6 weeks 8 weeks Overall
Tyramine Negative Clonidine Placebo 11.3 11.7 10.7 8.7 3.8 3.2 11.4 8.2 10.0 8.5
Placebo 14.4 16.8 5.8 15.8 14.6
FIGURE 12 HEADACHE FREQUENCY Tyramine Positive Week Severe Moderate Mild Overall
Clonidine 4 6 1.2 0.0 1.7 0.5 2.7 0.0
2 1.2 1.7 3.3
Placebo 8
2
1.2 3.0 2.0 1.5
0.5 3.1 2.9
4 1.3 3.6 2.9
6 0.2 1.5 2.5 2.1
8 1.1 3.3 2.7
FIGURE 13 HEADACHE FREQUENCY Tyramine Negative Clonidine Week Severe Moderate Mild
2 0.9 2.3 2.5 Overall
4 0.8 1.6 2.2 1.5
6 0.3 0.7 1.4
8 1.1 1.5 2.6
Placebo 2 4 1.3 1.1 1.4 1.4 2.4 1.6
6 0.5 0.7 0.9 1.2
8 1.0 1.2 1.4
FIGURE 14 REFERENCES l. Wilkinson, M. et al.: Clonidine in the Treatment of Migraine at the City Migraine Clinic in Patients Selected with Tyramine. Proceedings International Headache Symposium, Elsinore, Denmark May 16-18, 1971, pp 219-221. 2.
Grabner, W. and Wolf, M.: Arzmeimithal-Forchung, 16:1055, 1966.
3.
Zaimis, E. and Hannington, E.: A Possible Pharmacological Approach to Migraine. Lancet 2:298-300, 1969.
4.
Wilkinson, M.: Lancet 2:430, 1969.
5. Wilkinson, M.: Proceedings of the International Migraine Headache Symposium, Florence, Italy, 26-28 May 1970. pp 117-118, 6.
Sjaastad, O. and Stensrud, P.: Acta Neurol. Scand. 47:120-122, 1971.
7. Barrie, M.A. et al.: The Use of Clonidine (ST-155) in Migraine and the Problems Encountered in a Multicenter Trial. Proceedings International Headache Symposium, Elsinore, Denmark, May 16-18, 1971, pp 23-26. 8.
Horwitz, D. et al.: Presented at the Second Catapres Symposium, September 18-19, 1968.
9.
Fairbairn, J.F. II, et al.: Presented at the Second Catapres Symposium, September 18-19, 1968.
10.
Gifford, R.W., Jr.: Presented at the Second Catapres Symposium, September 18-19, 1968.
11.
Muir, A.L., et al.: Circulatory Effects at Rest and Exercise of Clonidine, Lancet July 26, 1969, pp 181-185.
12. Ryan, Robert E., Jr.: A Clinical Study of Tyramine as an Etiological Factor in Migraine, Headache 14:43-49 (Apr.) 1974. Address reprint requests to: Robert E. Ryan, M.D., M.S., B.S. 621 South New Ballas Road St. Louis, Mo. 63141
