Current Medical Research and Opinion
Vol. 3, No. 2, 1975
Pizotifen (BC 105)
J.D. Carroll,* M.D., M.R.C.P.,
in migraine prophylaxis
F.R.C.P.E., and
W. P.Maclay,** M.B.,Ch.B.,
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
D.T.M. and H. Regional Neurological Unit, Royal Surrey County Hospital, Guildford, England
Received: 17th January 1975
Curr. med. Res. Opin., (1975), 3,68.
Summary Pizotifen, an antaminic, was investigated in a double-blindplacebo controlled trial to evaluate its eficacy in migraine prophylaxis. It was found to be an efective prophylactic in a proportion of migraine patients, reducing the frequency as well as the severity of headaches. Some patients showed weight gain. Several patients have continued treatment for up to 2 years with good control of their migraine and a reduction in the amount of medicament required for the acute attack. Key words: Pizotifen - migraine -prophylaxis
Introduction Pizotifen (BC 105) belongs to a group of compounds known as ‘antamines’ and is a benzocycloheptathiophene derivative having a structural formula as shown in Figure 1. This compound possesses a powerful antagonistic action against certain biogenic amines. Basic pharmacological and toxicological studies of pizotifen have shown very strong antiserotonin properties and it also ranks highly in activity as an antihistamine. It protects guinea pigs against tryptamine and it has, to a lesser extent, peripheral anticholinergic properties. Previous studies have shown pizotifen to be effective in the prophylaxis of migraine.3,4-6,9,10Hughes and Foster5 showed it to be of great benefit in certain Figure 1. Structural formula of pizotifen
CH,
*Consultant Neurologist; **Deputy Medical Director, Sandoz Products Ltd., Feltham 68
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
J. D. Carroll and W. P. Maclay
patients, with no major side-effects, and with the interesting observation that a number of patients become depressed on withdrawal of the drug. DalsgaardNielsen and UlrichZ carried out a long-term investigation into the efficacy and tolerance of pizotifen in 76 patients treated for an average of 28.8 months: they showed that the clinical therapeutic effect was independent of the period of treatment. Nelson7 found pizotifen to be an effective medication against vascular headache with an effectiveness range similar to or only slightly less than methysergide. Olgiati and Calobrisis found pizotifen as effective as amitriptyline in patients with psychoneurotic depression. It was considered, therefore, that further evaluation should be done to ascertain the effectiveness of pizotifen (‘Sanomigran’)? as a migraine prophylactic and its effect on depression.
Patients and methods The population included patients who were suffering from either classical migraine or common migraine according to the criteria and classification of the Ad Hoc Committee on Classification of Headache,’ and patients had been suffering from at least 3 attacks of migraine a month during the previous 6 months to the trial. Patients with hepatic and renal disorders were excluded, as were those who had any disease state which might have interfered with absorption, metabolism or excretion of pizotifen. Pregnant patients were also excluded. The form of the trial was a double-blind randomised crossover comparing pizotifen against placebo. Prior to this standard double-blind trial, each patient had received pizotifen for 1 month in order to assess the dose level effectivefor each patient. Thus each patient had 1 month on pizotifen with a 2-month period on both placebo and pizotifen during the double-blind phase, with 2-week washout between periods. Total duration of the trial was 5 months 2 weeks. Pizotifen (0.5 mg.) and placebo were supplied in identical tablet form and on commencing the trial the tablets were introduced slowly, i.e. Days 1 and 2, 1 tablet in the evening; Days 3 and 4, 1 tablet at midday and 1 tablet in the evening; Day 5 , 1 tablet in the morning, 1 at midday and 1 in the evening; and from thereon, 1 tablet t.i.d. Patients returned after 2 weeks and, if required, the dose was adjusted to 2 tablets t.i.d. but no more than 6 tablets a day (3 mg.) Laboratory investigationswere done at the beginning of the trial, after 3 months, and at the end of the trial. These included liver function tests (serum alkaline phosphatase, SGPT), urinary examination included sugar and protein, blood examination (WBC and differential, RBC and Hb) and glucose tolerance tests. The headaches were graded as severe, moderate or mild and the frequency was also recorded. The headache index was calculated by multiplying the number of headache attacks by their intensity using the following scale: severe = 3, moderate = 2, and mild = 1. Thus, if the patient had 1 severe and 2 mild headaches, the index would equal 5. The last 15 patients were given the Beck self-rating scale for depression. ttrade mark, Sandoz
69
Pizotifen (BC 105) in migraine prophylaxis
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Results Twenty-seven patients were accepted into the trial. Of these, 14 had complete records over the 5 months 2 weeks period, 8 patients had incomplete records, 3 patients failed to return, 1 patient became pregnant, and 1 patient stopped the active preparation after 5 days. Table I shows the Headache Index for the 14 patients who completed the trial and details of whether severity and/or frequency were lessened. The results are shown in two groups depending on whether the active dose-finding month was followed by active treatment or by placebo. The dose most commonly given was 3 mg. daily. Four out of the 6 patients in Group 1 (Active-placebo-active)improved and 2 showed no change. Five out of the 8 patients in Group 2 (Active-activeplacebo) improved, 2 became worse, and there was no change in 1 patient. Table I. Headache index in 14 patients with complete records Patient no.
Treatment period scores Month 1
Month 2
Month 3
Group I 1 2 3
4
Active 8 42 17 18
Placebo 27 63 32 10
Active 15 50 41 17
5 6
42 9
46 17
20 14
Active 23 36 29 5 28 7 93 45
Active
Placebo 46 39 62 20 13
Group 2 7
8 9 10 11 12 13 14
17
18 57 13
64 2 100 36
Response
15
52 29
Frequency and severity less Frequency less No change Worse index for active, but clinically better Frequency and severity less No change Frequency and severity less Frequency and severity less Frequency less Frequency and severity less Worse on active Frequency and severity less Worse on active No change
Ten of the 15 patients who were given the Beck self-rating depression scale completed the trial and of these 4 showed a slight increase and 6 a decrease in the rating. There were no abnormalities in the laboratory tests.
Side-effects Three patients put on weight and in 1 patient an increase of 10 Ibs. was sufficient for her to withdraw from the trial. One other also withdrew. The patient who stopped the active preparation after 5 days complained of being 'drugged', dazed, hungry and depressed. Another became depressed after 20 days and withdrew from the trial. Two patients showed side-effects on placebo including hemiparaesthesia and apprehension. In the 8 patients with incomplete records, I withdrew from the trial because of worsening headache and 1 with weight gain.
J. D. Carroll and W. P. Maciay
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Discussion The results of this study indicate that pizotifen is an effective prophylactic in a proportion of migraine patients and that it reduces the frequency as well as the severity of the headaches. The main drawback to the use of the compound in this series of patients was the weight gain in some women in the 20 to 40 age group. It would appear that when a certain weight is reached, it is then maintained. However, when pizotifen is stopped, the patient’s weight reverts to her normal. It has been suggested that pizotifen acts at a metabolic level rather than by direct stimulation of the appetite centre’ l, but it can be postulated that because migraine is concerned in some patients with the hypothalamus, the feeling of well-being and subsequent weight gain may be due to a hypothalamic effect. It is interesting that this trial did not show a clear cut effect on mood as rated on the Beck scale. There certainly were no cases who became depressed on withdrawal of the drug, as noted by Hughes and F ~ s t e rThese . ~ investigators considered that this was due to the tricyclic configuration of pizotifen. Several patients have continued tieatment for up to 2 years with good control of their migraine and a reduction in the amount of medicament required for the acute attack. As time goes on, it will be interesting to see if there is any permanent remission in their migraine. In conclusion, pizotifen appears to be a useful compound for the treatment of certain cases of migraine. References 1. Ad HOCCommittee on Classification of Headache, (1962).Classificationof headache. J. Amer. med. Ass., 179,717. 2. Dalsgaard-Nielsen, T., and Ulrick, J., (1973). Long-term effect and tolerance during prophylactic treatment of migraine with a benzo-cycloheptathiophenederivative, pizotifen. Headache, 13,12-18. 3. Ekbom, K., (1969). Prophylactic treatment of cluster headache with a new serotonin antagonist, BC 105. Acta. neurol. Scand., 45,601-610. 4. Forssman, B., Henriksson, K. G., and Kihlstrand, S., (1972). A comparison between BC 105 and methysergide in the prophylaxis of migraine. Acta. neurol. Scand,, 48,204-212. 5. Hughes, R. C., and Foster, J. B., (1971). BC 105 in the prophylaxis of migraine. Curr. fher. Res., 13,63-68. 6. Lance, J . W., Anthony, M., and Somerville, B., (1970). Comparative trial of serotonin antagonists in the management of migraine. Brit. med. J., 2, 327-330. 7. Nelson, R. F., (1973). BC 105 - a new prophylactic agent for migraine -four years’ experience in seventy-five patients. Headache, 13,96-103. 8. Olgiati, S., and Calobrisi, A., (1974). Clinical results with pizotyline in depression. Dis. nerv. Syst., 35, 35-38. 9. Sicuteri, F., Franchi, G., and Del Bianco, P. L., (1967). An antaminic drug, BC 105, in the prophylaxis of migraine. Znt. Arch. Allergy, 31,78-93. 10. Sjaastad, O., and Stensrud, P., (1969). Appraisal of BC 105 in migraine prophylaxis. Acta. neurol. Scand., 45,594-600. 11. Tsougranis, A., (1972). Clinical study of orexigenic action of a new antiserotonin agent, BC 105 in patients with pulmonary tuberculosis. Curr. ther. Res., 14,372-375.
71
Vol. 3, No. 2, 1975
Pizotifen (BC 105)
J.D. Carroll,* M.D., M.R.C.P.,
in migraine prophylaxis
F.R.C.P.E., and
W. P.Maclay,** M.B.,Ch.B.,
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
D.T.M. and H. Regional Neurological Unit, Royal Surrey County Hospital, Guildford, England
Received: 17th January 1975
Curr. med. Res. Opin., (1975), 3,68.
Summary Pizotifen, an antaminic, was investigated in a double-blindplacebo controlled trial to evaluate its eficacy in migraine prophylaxis. It was found to be an efective prophylactic in a proportion of migraine patients, reducing the frequency as well as the severity of headaches. Some patients showed weight gain. Several patients have continued treatment for up to 2 years with good control of their migraine and a reduction in the amount of medicament required for the acute attack. Key words: Pizotifen - migraine -prophylaxis
Introduction Pizotifen (BC 105) belongs to a group of compounds known as ‘antamines’ and is a benzocycloheptathiophene derivative having a structural formula as shown in Figure 1. This compound possesses a powerful antagonistic action against certain biogenic amines. Basic pharmacological and toxicological studies of pizotifen have shown very strong antiserotonin properties and it also ranks highly in activity as an antihistamine. It protects guinea pigs against tryptamine and it has, to a lesser extent, peripheral anticholinergic properties. Previous studies have shown pizotifen to be effective in the prophylaxis of migraine.3,4-6,9,10Hughes and Foster5 showed it to be of great benefit in certain Figure 1. Structural formula of pizotifen
CH,
*Consultant Neurologist; **Deputy Medical Director, Sandoz Products Ltd., Feltham 68
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
J. D. Carroll and W. P. Maclay
patients, with no major side-effects, and with the interesting observation that a number of patients become depressed on withdrawal of the drug. DalsgaardNielsen and UlrichZ carried out a long-term investigation into the efficacy and tolerance of pizotifen in 76 patients treated for an average of 28.8 months: they showed that the clinical therapeutic effect was independent of the period of treatment. Nelson7 found pizotifen to be an effective medication against vascular headache with an effectiveness range similar to or only slightly less than methysergide. Olgiati and Calobrisis found pizotifen as effective as amitriptyline in patients with psychoneurotic depression. It was considered, therefore, that further evaluation should be done to ascertain the effectiveness of pizotifen (‘Sanomigran’)? as a migraine prophylactic and its effect on depression.
Patients and methods The population included patients who were suffering from either classical migraine or common migraine according to the criteria and classification of the Ad Hoc Committee on Classification of Headache,’ and patients had been suffering from at least 3 attacks of migraine a month during the previous 6 months to the trial. Patients with hepatic and renal disorders were excluded, as were those who had any disease state which might have interfered with absorption, metabolism or excretion of pizotifen. Pregnant patients were also excluded. The form of the trial was a double-blind randomised crossover comparing pizotifen against placebo. Prior to this standard double-blind trial, each patient had received pizotifen for 1 month in order to assess the dose level effectivefor each patient. Thus each patient had 1 month on pizotifen with a 2-month period on both placebo and pizotifen during the double-blind phase, with 2-week washout between periods. Total duration of the trial was 5 months 2 weeks. Pizotifen (0.5 mg.) and placebo were supplied in identical tablet form and on commencing the trial the tablets were introduced slowly, i.e. Days 1 and 2, 1 tablet in the evening; Days 3 and 4, 1 tablet at midday and 1 tablet in the evening; Day 5 , 1 tablet in the morning, 1 at midday and 1 in the evening; and from thereon, 1 tablet t.i.d. Patients returned after 2 weeks and, if required, the dose was adjusted to 2 tablets t.i.d. but no more than 6 tablets a day (3 mg.) Laboratory investigationswere done at the beginning of the trial, after 3 months, and at the end of the trial. These included liver function tests (serum alkaline phosphatase, SGPT), urinary examination included sugar and protein, blood examination (WBC and differential, RBC and Hb) and glucose tolerance tests. The headaches were graded as severe, moderate or mild and the frequency was also recorded. The headache index was calculated by multiplying the number of headache attacks by their intensity using the following scale: severe = 3, moderate = 2, and mild = 1. Thus, if the patient had 1 severe and 2 mild headaches, the index would equal 5. The last 15 patients were given the Beck self-rating scale for depression. ttrade mark, Sandoz
69
Pizotifen (BC 105) in migraine prophylaxis
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Results Twenty-seven patients were accepted into the trial. Of these, 14 had complete records over the 5 months 2 weeks period, 8 patients had incomplete records, 3 patients failed to return, 1 patient became pregnant, and 1 patient stopped the active preparation after 5 days. Table I shows the Headache Index for the 14 patients who completed the trial and details of whether severity and/or frequency were lessened. The results are shown in two groups depending on whether the active dose-finding month was followed by active treatment or by placebo. The dose most commonly given was 3 mg. daily. Four out of the 6 patients in Group 1 (Active-placebo-active)improved and 2 showed no change. Five out of the 8 patients in Group 2 (Active-activeplacebo) improved, 2 became worse, and there was no change in 1 patient. Table I. Headache index in 14 patients with complete records Patient no.
Treatment period scores Month 1
Month 2
Month 3
Group I 1 2 3
4
Active 8 42 17 18
Placebo 27 63 32 10
Active 15 50 41 17
5 6
42 9
46 17
20 14
Active 23 36 29 5 28 7 93 45
Active
Placebo 46 39 62 20 13
Group 2 7
8 9 10 11 12 13 14
17
18 57 13
64 2 100 36
Response
15
52 29
Frequency and severity less Frequency less No change Worse index for active, but clinically better Frequency and severity less No change Frequency and severity less Frequency and severity less Frequency less Frequency and severity less Worse on active Frequency and severity less Worse on active No change
Ten of the 15 patients who were given the Beck self-rating depression scale completed the trial and of these 4 showed a slight increase and 6 a decrease in the rating. There were no abnormalities in the laboratory tests.
Side-effects Three patients put on weight and in 1 patient an increase of 10 Ibs. was sufficient for her to withdraw from the trial. One other also withdrew. The patient who stopped the active preparation after 5 days complained of being 'drugged', dazed, hungry and depressed. Another became depressed after 20 days and withdrew from the trial. Two patients showed side-effects on placebo including hemiparaesthesia and apprehension. In the 8 patients with incomplete records, I withdrew from the trial because of worsening headache and 1 with weight gain.
J. D. Carroll and W. P. Maciay
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Discussion The results of this study indicate that pizotifen is an effective prophylactic in a proportion of migraine patients and that it reduces the frequency as well as the severity of the headaches. The main drawback to the use of the compound in this series of patients was the weight gain in some women in the 20 to 40 age group. It would appear that when a certain weight is reached, it is then maintained. However, when pizotifen is stopped, the patient’s weight reverts to her normal. It has been suggested that pizotifen acts at a metabolic level rather than by direct stimulation of the appetite centre’ l, but it can be postulated that because migraine is concerned in some patients with the hypothalamus, the feeling of well-being and subsequent weight gain may be due to a hypothalamic effect. It is interesting that this trial did not show a clear cut effect on mood as rated on the Beck scale. There certainly were no cases who became depressed on withdrawal of the drug, as noted by Hughes and F ~ s t e rThese . ~ investigators considered that this was due to the tricyclic configuration of pizotifen. Several patients have continued tieatment for up to 2 years with good control of their migraine and a reduction in the amount of medicament required for the acute attack. As time goes on, it will be interesting to see if there is any permanent remission in their migraine. In conclusion, pizotifen appears to be a useful compound for the treatment of certain cases of migraine. References 1. Ad HOCCommittee on Classification of Headache, (1962).Classificationof headache. J. Amer. med. Ass., 179,717. 2. Dalsgaard-Nielsen, T., and Ulrick, J., (1973). Long-term effect and tolerance during prophylactic treatment of migraine with a benzo-cycloheptathiophenederivative, pizotifen. Headache, 13,12-18. 3. Ekbom, K., (1969). Prophylactic treatment of cluster headache with a new serotonin antagonist, BC 105. Acta. neurol. Scand., 45,601-610. 4. Forssman, B., Henriksson, K. G., and Kihlstrand, S., (1972). A comparison between BC 105 and methysergide in the prophylaxis of migraine. Acta. neurol. Scand,, 48,204-212. 5. Hughes, R. C., and Foster, J. B., (1971). BC 105 in the prophylaxis of migraine. Curr. fher. Res., 13,63-68. 6. Lance, J . W., Anthony, M., and Somerville, B., (1970). Comparative trial of serotonin antagonists in the management of migraine. Brit. med. J., 2, 327-330. 7. Nelson, R. F., (1973). BC 105 - a new prophylactic agent for migraine -four years’ experience in seventy-five patients. Headache, 13,96-103. 8. Olgiati, S., and Calobrisi, A., (1974). Clinical results with pizotyline in depression. Dis. nerv. Syst., 35, 35-38. 9. Sicuteri, F., Franchi, G., and Del Bianco, P. L., (1967). An antaminic drug, BC 105, in the prophylaxis of migraine. Znt. Arch. Allergy, 31,78-93. 10. Sjaastad, O., and Stensrud, P., (1969). Appraisal of BC 105 in migraine prophylaxis. Acta. neurol. Scand., 45,594-600. 11. Tsougranis, A., (1972). Clinical study of orexigenic action of a new antiserotonin agent, BC 105 in patients with pulmonary tuberculosis. Curr. ther. Res., 14,372-375.
71
