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Adrenoreceptor Antagonistsin Essential Tremor J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.10.904 on 1 October 1979. Downloaded from Journal ofNeurology, Neurosurgery, andPsychiatry, 1979, 42, 904-909 -Adrenoreceptor antagonists in essential tremor D. JEFFERSON, P. JENNER, AND C. D. MARSDEN From the University Department of Neurology, Institute of Psychiatry and King's College Hospital Medical School, London S U M M A R Y Three different 8-adrenoreceptor antagonists-propranolol, sotalol, and atenolol- were compared in a double-blind study with placebo in nine patients with essential tremor. All three drugs produced an equal reduction in standing pulse rate but atenolol was less effective in reducing tremor than propranolol and sotalol. These results suggest that the reduction in tremor produced by fi-adrenoreceptor antagonists is mediated by an effect on peripheral 9,-adrenoreceptors. Several studies have shown that the I8- Patients and methods adrenoreceptor antagonist propranolol reduces the amplitude of essential tremor (Winkler and Nine patients with essential tremor were studied. Young, 1971; Dupont et al., 1973; Morgan et al., The diagnosis of essential tremor was made on the 1973; Tolosa and Loewenson, 1975; Young et al., basis of a characteristic postural tremor of the Protected by copyright. 1975; Jefferson et al., 1979). The mechanism of this upper limbs without other neurological abnor- pharmacological effect is unknown, since pro- malities. All patients had normal thyroid, cardiac, pranolol may act on peripheral (Marsden et al., renal, and hepatic function. The main clinical 1967) or central nervous system 8-adrenoreceptors features of the nine patients are presented in (Myers et al., 1975; Day et al., 1977; Taylor et al., Table 1. 1978) blocking both 8I and P32 sites. Furthermore, Propranolol (Inderal), sotalol (Sotacor), atenolol propranolol possesses a membrane stabilising (Tenormin), and placebo were given orally in a ("quinidine-like") effect (Morales-Aguilera and randomised double-blind trial, each drug or Vaughan Williams, 1965) which may contribute placebo being taken for two weeks before the to its therapeutic action in essential tremor. degree of tremor was assessed clinically. Optimum The past decade has witnessed the introduction doses of propranolol for each individual were of several 3-adrenoreceptor antagonists which established before the random phase of the trial may be useful in investigating the precise site and and ranged from 60-160 mg per day, in divided mode of action of propranolol in essential tremor. doses. Equivalent doses of sotalol and atenolol These alternative /8-adrenoreceptor antagonists were used according to the ratios propranolol= differ from propranolol in various ways and may, 1, sotalol= I, and atenolol=2. Individual daily for example, be devoid of membrane stabilising doses of sotalol ranged from 80-240 mg and of http://jnnp.bmj.com/ activity or may be cardioselective, blocking pre- atenolol from 50-100 mg. Propranolol was ad- dominantly 131-receptors. Some of these drugs also show poor penetration of the blood-brain barrier, Table 1 Clinical details of nine patients with essential with little or no central nervous system activity. tremor In the present study, the effect of propranolol in essential tremor has been compared with the effect Patient Age Sex Family Length of (yr) history history of a cardioselective 8-adrenoreceptor antagonist (yr) (atenolol), and with a nonselective P-antagonist on October 6, 2021 by guest. 1 73 F - 10 which possesses no membrane stabilising activity 2 66 M - 16 and which enters the brain with difficulty 3 44 F - 6 (sotalol). 4 45 F + 30 5 31 F + 17 Address for reprint requests: Professor C. D. Marsden, University 6 57 F - 4 Department of Neurology, Institute of Psychiatry and King's College 7 72 F - 6 Hospital, De Crespigny Park, London SE5 8AF. 8 59 M - 34 9 56 F + 30 Accepted 17 April 1979 904 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.10.904 on 1 October 1979. Downloaded from ,8-Adrenoreceptor antagonists in essential tremor 905 ministered three to four times daily, sotalol thrice n =9 daily, and atenolol twice daily. The order of 100 administration of the three drugs was randomised. Clinical assessment was performed within two 90 to four hours of the previous oral dose of drug or of each two weeks of medica- 0 placebo at the end EU5: tion. Measurements were made by the same ._ 80 examiner (DJ) in the same surroundings and at m approximately the same time of day. After a 10 minute period of rest in the supine position, 70t the supine and standing pulse rate and blood lx pressure were measured. Tremor was assessed .10 60 objectively by scoring the degree of tremor of the 0n outstretched hands and by rating tests of hand- C test writing, drawing, and a timed performance IL 50 which involved threading rings onto a peg, as S described elsewhere (Jefferson et al., 1979). The scores obtained in individual tests were added 40 to give a total objective tremor score. Each patient P Pr S A P Pr S A was invited to assess the severity of his or her manual tremor at each visit by marking a linear Supine Standing analogue scale (subjective tremor score) and to Fig. 1. Mean pulse rate (±I SEM) in nine patients comment on the overall subjective effects of the with essential tremor during treatment with placebo previous two weeks of medication. (P), propranolol (Pr), sotalol (S), and atenolol (A). Protected by copyright. Drug compliance was monitored by counting Using Student's t test for paired data, both supine the number of tablets which remained in the con- and standing pulse rates are reduced compared with two week The placebo by propranolol, sotalol, and atenolol tainer at the end of each period. (P<O.OO1). There is no difference (P>O.J) between responses of pulse rate and blood pressure to the the of the different drugs. different treatment schedules were compared using effects the Student's t test for paired data. A non- parametric statistical method (Wilcoxon's test of sotalol (P>0.1). The mean supine diastolic blood paired differences) was used to compare the objec- pressure during treatment with sotalol was reduced tive tremor scores on the different drugs with compared with placebo (P<0.05) but did not those on placebo, which were also subjected to differ significantly from the effect of propranolol analysis of variance with linear contrast. or atenolol (P>0. 1). The mean standing diastolic blood pressure was not reduced significantly by Results any of the three drugs when compared with placebo (P>0. 1). Drug compliance, as judged by tablet counting, was excellent throughout the study, and no patient TREMOR complained of side effects during the different All three 13-adrenoreceptor antagonists produced http://jnnp.bmj.com/ periods of medication. a reduction in the total objective tremor score when compared with placebo (Table 2) (P<0.01- PULSE RATE AND BLOOD PRESSURE (FIGS. 1 AND 2) 0.02). Sotalol and propranolol produced the same All drugs caused a reduction in the supine reduction in objective tremor score but atenolol (P<0.001) and standing (P<0.001) pulse rate reduced the mean tremor score by a smaller when compared with placebo. There was no dif- amount compared with sotalol and propranolol. ference between the effects of the individual drugs, When the patients' subjective tremor scores suggesting that all three were producing a similar (Table 3) were examined using Wilcoxon's test, on October 6, 2021 by guest. degree of blockade of cardiac chronotropic P,- atenolol was no better than placebo in reducing adrenoreceptors. tremor (P>0. 1) whereas sotalol produced a Both sotalol and atenolol reduced the mean definite subjective improvement (P<0.05) and pro- supine and standing systolic blood pressure com- pranolol nearly did (P<0.1). However, analysis of pared with placebo (P<0.05) but there was no variance with linear contrast showed sotalol and difference between the mean systolic pressures propranolol to be more effective than atenolol. during treatment with propranolol, atenolol, and Although none of the patients, when directly J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.10.904 on 1 October 1979. Downloaded from 906 D. Jefferson, P. Jenner, and C. D. Marsden 1501 140 Fig. 2. Mean (I1 SEM) supine and standing systolic and nP9 diastolic blood pressures in nine 130 patients with essential tremor during treatment with placebo (P), propranolol (Pr), sotalol E 120 (S), and atenolol (A). Using E Student's t test for paired data, supine and standing systolic 110 'A blood pressure are reduced compared with placeboi during 100 treatment with sotalol (P<O.05) 0 and atenolol (P<0.05). Mean iCo supine diastolic blood pressure 'U 90 is reduced compared with S1 placebo during treatment with sotalol (P<0.05). Mean blood 80 pressures during treatment with the different drugs do not differ significantly from each other. 70 P rSAPPS SA P Pr SA P Pr SA Supine Standing Supine Standing Protected by copyright. systolic systolic diastolic diastolic Table 2 Changes in objective tremor score during Table 3 Changes in patients' subjective tremor scores treatment with placebo, propranotol, sotalol, and during treatment with placebo, propranolol, sotalol, atenolol and atenolol Patient Placebo Propranolol Sotalol Atenolol Patient Placebo Propranolol Sotalol Atenolol 1 17 11 11 14 1 7 8.5 7 10 2 17 10 12 12 2 10 9 4 9.5 3 1 0 2 1 3 0 0 0 0 4 9 7 6 4 4 2.5 3.5 3.5 3 5 8 4 3 8 5 7 3 3 4.5 6 13 8 6 12 6 9.5 5 7 10 7 18 14 16 15 7 10 6 8.5 9 8 5 3 1 1 8 4 2 0.5 1 9 8 2 4 6 9 6 3 4 6.5 Mean score 10.7 6.6 6.8 8.1 Mean score= 6.2 4.4 4.2 5.9 ±I SEM 1.98 1.55 1.71 1.81 + ISEM 1.17 0.99 0.97 1.32 (Maximum tremor score=25) (Maximum tremor score= 10) Tremor is reduced compared with placebo during treatment with Tremor is subjectively reduced compared with placebo during treat- http://jnnp.bmj.com/ propranolol (P <0.01), sotalol (P <0.01), and atenolol (P <0.02).
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