378
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1979), 8 &
ROTH, J.A. & GILLIS, C.N. (1974). Deamination of II-
LACHAPELLE, R. (1962). Nutritional and microbial effects on liver monoamine oxidase and serotonin in the chick. J. Nutr., 76, 119-123.
phenylethylamine by monoamine oxidase-inhibition by imipramine. Biochem. Pharmac., 23, 2537-2545.
PHILLIPS,
A.W.,
NEWCOMB,
H.R.,
RUPP,
F.A.
ROBINSON, D.S., NIES, A., RAVARIS, C.L. IVES, J.O. &
BARTLETT, D. (1978). Clinical pharmacology of phenelzine. Arch. gen. Psychiat. 35, 629-635.
SULLIVAN, J.L., DACKIS, C. & STANFIELD, C. (1977). In
vivo inhibition of platelet MAO activity by tricyclic antidepressants. Am. J. Psychiat., 134, 188-190.
ESSENTIAL HYPERTENSION Drs Geyskes, Boer & Mees (1979) report that fourteen hypertensive patients were admitted to the hospital and given 'informed consent', i.e., presumably telling them all the possible withdrawal symptoms that might occur following abrupt cessation of clonidine. All 14 of the patients developed increased heart rates and blood pressures. Seven of the fourteen developed subjective symptoms such as nervousness, headaches, palpitations, anxiety, etc. I find serious fault in their clinical methodology. It should have been done double-blind v. identical placebo. If the authors wish to attribute subjective symptoms to drug withdrawal, they must minimize bias, both the patients' and the observers'. I am certain that at least 50% of my hypertensive patients would develop the same symptoms as Dr Geyskes' if they had received similar infonned consent after receiving placebo and then having it abruptly withdrawn. Along with anxiety, most of them would also have tachycardia and hypertension. I do not deny that acute withdrawal of an adrenergic blocking agent may result in phaeochromocytoma-like symptoms together with an increase in heart rate and blood pressure. However, I do deny that these symptoms occur in anything like 50% of patients and that hypertension and tachycardia would occur in 100% of patients. Unfortunately, the authors neglected to tell us
what the pre-treatment blood pressures were in the 14 patients. Without this information it is simply not possible to state whether the withdrawal hypertension is a return to the patient's original hypertension level or indeed an exacerbation of pre-existing hypertension. Incidentally, the identical 'acute posttreatment syndrome' has been reported following abrupt cessation of bethanidine and methyldopa (McMahon, 1978). With several million patients having been treated with these adrenergic blockers, including clonidine, I feel that the frequency of this syndrome is extremely rare. F. GILBERT McMAHON Department of Medicine, Tulane University, New Orleans, Louisiana 70112, USA
Received March 28, 1979 References GEYSKES, G.G., BOER, P. & DORHOUT MEES, E.J.
(1979). Clonidine withdrawal. Mechanism and frequency of rebound hypertension. Br. J. clin. Pharmac. 7, 55-62. McMAHON, F.G. (1978). Management of essential hypertension, p. 163. Future Publishing Company.
CLONIDINE WITHDRAWAL We read with interest the article in the British Journal of Clinical Pharmacology entitled 'Clonidine withdrawal: mechanism and frequency of rebound hypertension' (Geyskes, Boer & Dorhout Mees, 1979). While a clonidine withdrawal syndrome can occur, we are concerned that the results of this study
could be interpreted as representing a true frequency of the clonidine discontinuation syndrome. It seems there are several important matters which are not mentioned by the authors. One concerns the mechanism of patients selection and what portion of the hypertensive population these patients represent.
Br. J. clin. Pharmac. (1979), 8
Regarding the patient selection process, it was stated that the patients were not selected on the basis of previous withdrawal reactions. However, it was not stated how they were selected, and why all of the volunteers were receiving 0.9 mg/day of clonidine. It is possible that the selection process introduced a bias, such that the patients were only representative of the individuals who require a large dose of clonidine. Also, the authors did not use placebo during the withdrawal phase of their study, and this could have caused anxiety and apprehension to their patients with accentuation of the withdrawal response to clonidine. More importantly, the study does not represent the majority of patients, who receive clonidine for hypertension. In our experience, most patients with hypertension do not require more than 0.2 to 0.6 mg of clonidine per day. In our study of 20 patients (Whitsett, Chrysant, Dillard & Anton, 1978), the majority were taking less than 0.6 mg/day and none of the individuals had a discontinuation syndrome. Also, for the mean arterial blood pressure to be 110 mmHg on 0.9 mg of clonidine per day, these were most likely not patients with mild to moderate hypertension, but rather individuals with a moderate to severe elevation in blood pressure. Again, the question is raised regarding whether these subjects were representative of the majority of individuals
LETTERS TO THE EDITORS
379
with hypertension, and it would appear to us they were not. While research designed to discern the frequency of a particular condition is important, it is crucial that the study design does not introduce bias. Further, the segment of the population the study sample represents should be stated. Otherwise, it is quite possible that invalid conclusions may be drawn by the authors and the readers. THOMAS L. WHITSETT & STEVEN G. CHRYSANT Department of Medicine, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA
Received May 2, 1979 References GEYSKES, G.G., BOER, P. & DORHOUT MEES, E.J. (1979).
Clondine withdrawal: mechanism and frequency of rebound hypertension. Br. J. clin. Pharmac., 7, 55-62. WHITSETT, T.L., CHRYSANT, S.G., DILLARD, B. & ANTON,
A.H. (1978). Abrupt cessation of clonidine: A prospective study. Am. J. Cardiol., 41, 1285-1290.
CLONIDINE WITHDRAWAL MECHANISM AND FREQUENCY OF REBOUND HYPERTENSION A reply to the letters of Dr McMahon (1979) and Drs Whitsett E Chrysant (1979) We agree that the study of any drug should preferably be done double-blind with identical placebo. In our study, not using placebo, the results are a combination of real pharmacological effects and the psychological effect of withdrawing the clonidine tablets. However, we did not, as Dr McMahon (1979) presumed, tell our patients all the possible symptoms, but, as described under methods, informed them that they might feel uncomfortable, without specification. It is therefore unlikely that these subjective and objective symptoms, which started only 12-24 h after cessation of the medication and were progressive, were the results of the previous interview. Indeed, as the symptoms of our patients were consistent with exaggerated sympathetic tone and identical to those reported by many authors after clonidine withdrawal
(as well as by other patients seen by us who were not aware that withdrawal might cause symptoms) the possibility they were induced by our information seems less probable. The provocation of such a specific syndrome by suggestion has to our knowledge not been documented. Although the question of rebound or overshoot of the blood pressure remains open to discussion, there is no doubt about an overshoot of urinary noradrenaline excretions, which after clonidine withdrawal increased to abnormally high levels in all but one of our patients. In their recent prospective study using placebo, Whitsett, Chrysant, Dillard & Anton (1978), also found an overshoot of urinary noradrenaline excretion in the post clonidine period. In their, as in our study, urinary noradrenaline excretion did
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1979), 8 &
ROTH, J.A. & GILLIS, C.N. (1974). Deamination of II-
LACHAPELLE, R. (1962). Nutritional and microbial effects on liver monoamine oxidase and serotonin in the chick. J. Nutr., 76, 119-123.
phenylethylamine by monoamine oxidase-inhibition by imipramine. Biochem. Pharmac., 23, 2537-2545.
PHILLIPS,
A.W.,
NEWCOMB,
H.R.,
RUPP,
F.A.
ROBINSON, D.S., NIES, A., RAVARIS, C.L. IVES, J.O. &
BARTLETT, D. (1978). Clinical pharmacology of phenelzine. Arch. gen. Psychiat. 35, 629-635.
SULLIVAN, J.L., DACKIS, C. & STANFIELD, C. (1977). In
vivo inhibition of platelet MAO activity by tricyclic antidepressants. Am. J. Psychiat., 134, 188-190.
ESSENTIAL HYPERTENSION Drs Geyskes, Boer & Mees (1979) report that fourteen hypertensive patients were admitted to the hospital and given 'informed consent', i.e., presumably telling them all the possible withdrawal symptoms that might occur following abrupt cessation of clonidine. All 14 of the patients developed increased heart rates and blood pressures. Seven of the fourteen developed subjective symptoms such as nervousness, headaches, palpitations, anxiety, etc. I find serious fault in their clinical methodology. It should have been done double-blind v. identical placebo. If the authors wish to attribute subjective symptoms to drug withdrawal, they must minimize bias, both the patients' and the observers'. I am certain that at least 50% of my hypertensive patients would develop the same symptoms as Dr Geyskes' if they had received similar infonned consent after receiving placebo and then having it abruptly withdrawn. Along with anxiety, most of them would also have tachycardia and hypertension. I do not deny that acute withdrawal of an adrenergic blocking agent may result in phaeochromocytoma-like symptoms together with an increase in heart rate and blood pressure. However, I do deny that these symptoms occur in anything like 50% of patients and that hypertension and tachycardia would occur in 100% of patients. Unfortunately, the authors neglected to tell us
what the pre-treatment blood pressures were in the 14 patients. Without this information it is simply not possible to state whether the withdrawal hypertension is a return to the patient's original hypertension level or indeed an exacerbation of pre-existing hypertension. Incidentally, the identical 'acute posttreatment syndrome' has been reported following abrupt cessation of bethanidine and methyldopa (McMahon, 1978). With several million patients having been treated with these adrenergic blockers, including clonidine, I feel that the frequency of this syndrome is extremely rare. F. GILBERT McMAHON Department of Medicine, Tulane University, New Orleans, Louisiana 70112, USA
Received March 28, 1979 References GEYSKES, G.G., BOER, P. & DORHOUT MEES, E.J.
(1979). Clonidine withdrawal. Mechanism and frequency of rebound hypertension. Br. J. clin. Pharmac. 7, 55-62. McMAHON, F.G. (1978). Management of essential hypertension, p. 163. Future Publishing Company.
CLONIDINE WITHDRAWAL We read with interest the article in the British Journal of Clinical Pharmacology entitled 'Clonidine withdrawal: mechanism and frequency of rebound hypertension' (Geyskes, Boer & Dorhout Mees, 1979). While a clonidine withdrawal syndrome can occur, we are concerned that the results of this study
could be interpreted as representing a true frequency of the clonidine discontinuation syndrome. It seems there are several important matters which are not mentioned by the authors. One concerns the mechanism of patients selection and what portion of the hypertensive population these patients represent.
Br. J. clin. Pharmac. (1979), 8
Regarding the patient selection process, it was stated that the patients were not selected on the basis of previous withdrawal reactions. However, it was not stated how they were selected, and why all of the volunteers were receiving 0.9 mg/day of clonidine. It is possible that the selection process introduced a bias, such that the patients were only representative of the individuals who require a large dose of clonidine. Also, the authors did not use placebo during the withdrawal phase of their study, and this could have caused anxiety and apprehension to their patients with accentuation of the withdrawal response to clonidine. More importantly, the study does not represent the majority of patients, who receive clonidine for hypertension. In our experience, most patients with hypertension do not require more than 0.2 to 0.6 mg of clonidine per day. In our study of 20 patients (Whitsett, Chrysant, Dillard & Anton, 1978), the majority were taking less than 0.6 mg/day and none of the individuals had a discontinuation syndrome. Also, for the mean arterial blood pressure to be 110 mmHg on 0.9 mg of clonidine per day, these were most likely not patients with mild to moderate hypertension, but rather individuals with a moderate to severe elevation in blood pressure. Again, the question is raised regarding whether these subjects were representative of the majority of individuals
LETTERS TO THE EDITORS
379
with hypertension, and it would appear to us they were not. While research designed to discern the frequency of a particular condition is important, it is crucial that the study design does not introduce bias. Further, the segment of the population the study sample represents should be stated. Otherwise, it is quite possible that invalid conclusions may be drawn by the authors and the readers. THOMAS L. WHITSETT & STEVEN G. CHRYSANT Department of Medicine, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA
Received May 2, 1979 References GEYSKES, G.G., BOER, P. & DORHOUT MEES, E.J. (1979).
Clondine withdrawal: mechanism and frequency of rebound hypertension. Br. J. clin. Pharmac., 7, 55-62. WHITSETT, T.L., CHRYSANT, S.G., DILLARD, B. & ANTON,
A.H. (1978). Abrupt cessation of clonidine: A prospective study. Am. J. Cardiol., 41, 1285-1290.
CLONIDINE WITHDRAWAL MECHANISM AND FREQUENCY OF REBOUND HYPERTENSION A reply to the letters of Dr McMahon (1979) and Drs Whitsett E Chrysant (1979) We agree that the study of any drug should preferably be done double-blind with identical placebo. In our study, not using placebo, the results are a combination of real pharmacological effects and the psychological effect of withdrawing the clonidine tablets. However, we did not, as Dr McMahon (1979) presumed, tell our patients all the possible symptoms, but, as described under methods, informed them that they might feel uncomfortable, without specification. It is therefore unlikely that these subjective and objective symptoms, which started only 12-24 h after cessation of the medication and were progressive, were the results of the previous interview. Indeed, as the symptoms of our patients were consistent with exaggerated sympathetic tone and identical to those reported by many authors after clonidine withdrawal
(as well as by other patients seen by us who were not aware that withdrawal might cause symptoms) the possibility they were induced by our information seems less probable. The provocation of such a specific syndrome by suggestion has to our knowledge not been documented. Although the question of rebound or overshoot of the blood pressure remains open to discussion, there is no doubt about an overshoot of urinary noradrenaline excretions, which after clonidine withdrawal increased to abnormally high levels in all but one of our patients. In their recent prospective study using placebo, Whitsett, Chrysant, Dillard & Anton (1978), also found an overshoot of urinary noradrenaline excretion in the post clonidine period. In their, as in our study, urinary noradrenaline excretion did
