Treatment blockade of resting tremor by beta-adrenergic The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting tremor was examined in eight patients with idiopathic Parkinson’s disease. With the use of a double-blind, placebo-controlled study of crossover design, patients received 60 to 320 mg of nadoioi for 6 weeks while continuing their previous treatment regimen. Accelerometer readings showed a progressive reduction in tremor amplitude, but no change in tremor frequency, with increasing nadoioi dosage. Maximum benefit was achieved at 240 mg, when resting tremor improved 50% (p < 0.01). Physician ratings confirmed these findings. The results suggest that response to beta-adrenergic blockade may not be limited to postural or intention tremor and that such agents may not reliably differentiate between the tremor of Parkinson’s disease and essential tremor. (AM HEART J 106:1173, 1964.) Norman Marjorie L. Foster, M.D., Richard P. Newman, M.D., Peter A. LeWitt, M.D., M. Gillespie, R.N., and Thomas N. Chase, M.D. Bethesda, Md. Tremor, the most common involuntary movement,’ is a repetitive oscillation about a position of equilibrium. It can be differentiated from other disorders of movement by its bodily distribution, its amplitude and frequency characteristics, and its disappearance during sleep. Despite much study, the mechanism of tremor generation remains poorly understood, and the classification of tremor still rests on its clinical characteristics. Usually tremor is categorized by the conditions when it becomes maximal and the presence, if any, of associated neurologic deficits. Tremor can occur at’rest (resting tremor) or with voluntary activity such as maintenance of a sustained antigravity posture (postural tremor), isometric contraction (contraction tremor), a goal-directed movement (intention tremor). Such a classification scheme is difficult to apply because symptoms are variable and often are detectable under several of these conditions. Following the serendipitous observation of marked improvement of tremor in a patient with cardiac arrhythmia who was taking propranolol,2 attempts have been made to classify tremor on the basis of response to medication. Numerous trials have shown that beta-adrenergic blockers can effectively diminish essential tremor,3-5 which characteristically causes postural and intention tremor unas- sociated with other neurologic signs and is often inherited.‘j Such a response, however, does not appear specific for this condition. It soon became apparent that other causes of postural tremor without associated neurologic deficits also improved with beta-adrenergic blockade: accentuated physiologic tremor such as that associated with anxiety,7’8 tremor seen in thyrotoxicosis,7 and tremor associated with lithium therapf all improved with use of beta-adrenergic receptor antagonists. Further studies have extended the beneficial effects of beta blockers to disorders in which associated neurologic deficits and known neuropathologic features exist. For example, patients with the tremor of Parkinson’s disease appear to benefit from propranolo110-12 and pronethalol,13 and improvement in patients with cerebellar tremor has also been reported recently.14 Since individual components of parkinsonian tremor have not been closely examined, it remains uncertain whether response to beta blockade could be explained by an effect on action tremor resulting from the concurrence of essential tremor12 or the presence of an enhanced physiologic tremor15 or whether resting tremor also improves with betaadrenergic blockade. To examine this question, we have used nadolol, a nonselective hydrophilic betaadrenergic blocker, to treat resting tremor in patients with Parkinson’s disease. From the Experimental Therapeutics rological and Communicative Disorders METHODS Reprint requests: NIH, Bethesda, Thomas N. Chase, MD 20205. Bra@, and M.D., National Stroke. Bldg. Institute 10, Rm. 5C103, of NeuNINCDS/ Tremor was examined in eight patients (five men and three women, ages39 to 74 years, with a mean of 62 years) 1173 October, Foster et al. 1174 American Heart 1984 Journal 1.Effect of nadolol on resting tremor Table Tremor Patient NO. Placebo 2 3 4 5 106 180 125 1682 2410 6 1389 7 942 1 8 73 863 k 315 distance* Drug Clinician (mm) [ib Reduction 73 31 49 91 61 2115 1351 851 519 34 637 + 269 Placebo 36 1.9 0.9 53 1.2 3.3 2.5 5.1 3.4 2.4 1.7 37 5.9 39 2.2 45 53 2.4 3.5 2.9 2.9 *Tremor distance was measured by an acceierometer and is the average of 20-second recordings 4 (very severe) in both hands (maximum score, 8). Values represent the mean of observations placebo periods. tp < 0.01 by Student’s t test. with idiopathic Parkinson’s diseasewhose motor symptoms, other than tremor, were well controlled with conventional antiparkinsonism medications. These drugs, whosedosageremained unchangedthroughout this study, were carbidopa with levodopa (eight patients), bromocriptine or lisuride (four patients), anticholinergics (six patients), and diazepam(three patients). Each subject manifested typical features of Parkinson’sdisease,with rigidity and bradykinesia, as well as tremor, when untreated. Tremor wasmost evident with armsrelaxed and hands at rest. Six of the eight subjectshad tremor more prominently on one side; in these casesthis correspondedto the side in which other parkinsonian features were most pronounced. None of the patients had a family history of tremor. An additional patient who did not take the medication as directed voluntarily withdrew before completing the study and is not included in the analysis. In our double-blind, placebo-controlled, crossover study, patients took nadolol or placebo each morning. Beginning with one tablet (80 mg nadolol), we increased the dosageeach week unlessbradycardia (pulse rate <60 bpm) or hypotension supervened, to a maximum of four tablets daily (320 mg nadolol). The dosewasthen halved each of the following 2 weeks;thus the administration of nadolol and placebo each averaged 6 weeks. Informed consent was obtained following a full explanation of the proceduresto be undertaken. Tremor was assessed weekly, just prior to dose adjustment. Tremor frequency and amplitude were measured with a triaxial piezoelectric linear accelerometer(Wilcoxon Research,Bethesda, Md.) with a sensitivity of 50 to 60 mV/g (g = acceleration of gravity) in all axes.lfi The responsewas linear over the measuredfrequency rangeof 1.5 to 25 Hz. The accelerometer,weighing 22.5 gm, was taped on eachhand while the subject wasseated,and data were recorded for 20 seconds.Resting tumor wasassessed with the forearm supported to the wrist and the hand relaxed. Computer analysisprovided frequency, as well as a calculation of total distance traveled by movements in 2.9 5 Reduction 1.8 51 -26 44 2 9.2t Drug rating + 0.5 2.6 + 0.5 6 14 14 -55 17 29 14 t 11 from each hand. Clinical scores are on a scale of 0 (absent) on all drug doses (80 to 320 mg) and an equal number to of the x, y, and z planes independent of hand orientation. Tremor distance was obtained by double integration of the filtered, digitized accelerometersignal.” In addition, resting tremor wasrated weekly by two clinicians on a 0 to 4 scalefor each hand (maximum scoreof 8). RESULTS Mean resting tremor distance recorded by accelerometer in the right and left hands decreased 36% (p < 0.01) during nadolol therapy (Table I). Since the average tremor frequency did not change (5.4 f 0.2 Hz, mean + SE, with placebo vs 5.4 4 0.4 with drug), this improvement was due to a reduction in tremor amplitude. A dose-response relationship was seen with maximum benefit at 240 mg daily (Fig. 1). At this dose resting tremor improved 50 % Cp < 0.01) over the response to placebo. Clinical scoring showed improvement in all but one patient (2.9 + 0.5, mean f SE, vs 2.6 f 0.5) (Table I). With the elimination of the one patient whose tremor appeared to worsen 55% by clinician ratings but improved 39% as measured by accelerometer, overall reduction in tremor severity in the remaining seven pati&ts was 24% (JJ < 0.01). On the basis of these ratings, benefit was seen only at 240 mg or 360 mg (Fig. 2). Intermittent nonpostural light-headedness in one patient and bradycardia, which limited the maximum nadolol dose in two patients, were the only adverse effects encountered. DISCUSSION Our results are consistent with earlier reports that beta-adrenergic blockers diminish tremor in Parkinson’s diseaselO* ‘L l3 and that these drugs are effective adjuncts to conventional antiparkinsonism agents.12 Volume Number 108 4, Part 2 Beta-blocker therapy of resting tremor I 175 100 r- 01 I Baseline I Placebo Drug 0 80 160 Drug Treatment 240 320 (mg/d) 1. Effect of nadolol dose on resting tremor as measuredby accelerometer.In eight patients with Parkinson’s disease,tremor severity was determined by triaxial accelerometer, which measuresdistancemoved by limb over 20 seconds.For each patient, distancesmoved during resting tremor in right and left hands were averaged. Values are mean percent improvement over placebo for group of patients. Bars indicate range of one standard error. *p < 0.01, **p < 0.005 by Student’s t test. Fig. In contrast to previous studies, however, resting tremor has been examined specifically. This particular component of tremor was suppressed by nadolol treatment, suggesting that response to beta-adrenergic blockade is not limited to postural or intention tremor. Such agents, therefore, may not reliably differentiate between the tremor of Parkinson’s disease and essential tremor. Parkinson’s disease is probably the sole cause of tremor in our subjects. Tremor frequency was in the range typical of Parkinson’s disease but slower than that usually observed in essential tremor.’ In addition, when parkinsonian features were asymmetric, this same asymmetry was seen in the tremor. No family history suggestive of essential tremor was elicited. It is of note that nadolol, a hydrophilic drug with limited access to the central nervous system,18 has been found effective. Its actions can be assumed to be largely peripherally mediated. This is especially important for parkinsonism patients who are more susceptible to central nervous system side effects because of their age and the not infrequent occurrence of dementia. No central side effects such as depression, hallucinations, or change in state of I 80 Treatment I 180 I 240 I 320 (mg/d) 2. Effect of nadolol doseon resting tremor as measured by clinical scoring. In eight patients with Parkinson’s disease, tremor severity was estimated by two observerson a scale of 0 to 4 in each, with 4 being most severe (maximum score of 8). For each patient, all scores while taking placebo or a particular dose of nadolol were averaged. Values are mean score for group of patients. Bars indicate range of one standard error. Fig. alertness, which can be seen with lipophilic betaadrenergic blockers such as propranolol, were noted in our patients being given nadolol. In addition, the long half-life of nadoloPg permits a once-a-day dosage. The precise peripheral site of antitremor action of beta-adrenergic blockers remains uncertain. It has previously been recognized that both periphera120e2’ and central factors22 can modify parkinsonian tremor. It is possible that these drugs merely block the peripheral manifestations of anxiety, which is known to exacerbate parkinsonian resting tremor. On the other hand, some patients included in this study were already taking anxiolytic drugs and had a beneficial response to nadolol similar to the response of those not taking the drugs. Beta blockers may also act on adrenergic receptors found in the muscle spindle23 or extrafusal muscle fibers.24 It is of interest that the response to beta-adrenergic blockade in essential tremor appears to be greatest in subjects with the lowest tremor frequency.4 Such a relationship could not be demonstrated in this study, although the range of frequencies observed was relatively narrow. In this previous study the patients who responded best had tremor of 4.5 to 6 Hz, which is very similar to the average tremor frequency in our patients. The degree of antitremor response occurring when October, 1176 Foster et al. nadolol was added to the therapeutic regimen of our patients was clinically significant. Since no significant adverse effects were associated with nadolol therapy, its use deserves consideration in all patients with Parkinson’s disease in whom tremor resists other forms of dopaminergic and anticholinergic therapy. REFERENCES 1. Jankovic J, Fahn S: Physiologic and pathologic tremors: Diagnosis, mechanism, and management. Ann Intern Med 93:460, 1980. Winkler GF, Young RR: The control of essential tremor by propranolol. Trans Am Neurol Assoc 96:66, 1971. Editorial: Beta-adrenoreceptor antagonists in essential tremor. Lancet 2:1234, 1983. Calzetti S, Findley LJ, Gresty MA, Perucca E, Richens A: Effect of a single oral dose of propranolol on essential tremor: A double-blind controlled study. Ann Neurol 13:165, 1983. Koller WC: Nadolol in the treatment of essential tremor. Neurology (Cleveland) 33:1076, 1983. Critchley E: Clinical manifestations of essential tremor. J Nemo1 Neurosurg Psychiatry 45:393, 1983. Marsden CD, Gimlette TD, McAllister RG, Owen DAL, Miller TN: Effect of beta-adrenergic blockade on finger tremor and Achilles reflex time in anxious and thyrotoxic patients. Acta Endocrinol (Copenh) 7:(suppl):353, 1968. 8. James IM. Griffith DNW. Pearson RM. Newburv P: Effect of oxprenolol on stage-fright in musicians. Lancet”2:952, 1977. 9. Kirk L, Baastrup PC, Schou M: Propranolol and lithiuminduced tremor. Lancet 1:839, 1972. 10. Owen DAL, Marsden CD: Effect of adrenergic P-blockade on parkinsonian tremor. Lancet 2:1259, 1965. 11. Schwab RS, Young RR: Non-resting tremor in Parkinson’s disease. Trans Am Neurol Assoc 96:305, 1971. 12. Kissel P, Tridon P, Andre JM: Levodopa-propranolol therapy in parkinsonian tremor. Lancet 1:403, 1974. 13. Herring AB: Action of pronethalol on parkinsonian tremor. Lancet 2:892, 1964. 14. Edwards RV: Nadolol use for cerebellar tremor. Am J Psychiary 13QA1, 1982. 15. Winkler GF, Young RR: Efficacy of chronic propranolol therapy in action tremors of the familial, senile, or essential varieties. N Engl J Med 290:984, 1974. 16. Frost JD: Triaxial vector accelerometry: A method for quantifying tremor and ataxia. IEEE Trans Biomed Eng 25:17, 1978. 17. Dietrichson P, Engebretsen 0, Fonstelien E, Horland J: Quantitation of tremor in man. In Desmedt JE, editor: Physiological tremor, pathological tremors and colonus. Prog Clin Neurophysiol 5:90, 1978. 18. Woods PB, Robinson ML: An investigation of the comparative liposolubilities of /3-adrenoceptor blocking agents. J Pharm Pharmacol 33:172, 1981. 19. Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS: Nadolol: A review of its pharmacological properties and therapeutic efficacy in hypertension and angina pectoris. Drugs 20:1, 1980. 20. Rondot P, Bathien N: Peripheral factors modulating parkinsonian tremor. In Birkmayer W, Hornykiewicz 0, editors: Advances in parkinsonism. Basel, Switzerland, 1976, Hoffman-LaRoche, pp 269-276. 21. Teravainen H, Evarts EV, Calne DB: Effects of kinesthetic inputs on parkinsonian tremor. In Poirier LJ, Sourkes TL, Bedard PJ, editors: Adv Neurol 24:161, 1979. 22. Evarts E: Pathologic physiology of parkinsonism. In Came DB, moderator: Advances in the neuropharmacology of parkinsonism. Ann Intern Med QOz219, 1979. American Heart 1984 Journal 23. Smith CM: Neuromuscular pharmacology, drugs and muscle spindles. Ann Rev Pharmacol 3:223, 1963. 24. Marsden CD, Meadows JC: The effect of adrenaline on the contraction of human muscle. J Physiol 207:950, 1970. DISCUSSION Dr. Camp: What about the use of nadolol-and presumably also other beta blockers-in lithium-induced tremor? Dr. Foster: Propranolol has been shown to be effective. No studies, to my knowledge, have been done with nadolol. Presumably sincethe two seemto be very similar in their effect, it might also work. Dr. Kaplan: Can we assumethat anything that has been shown with another beta blocker that also is nonselective-that has beta-2 effects-would be true with nadolol? I assumethat the beta-2 selectivity or the nonselectivity is important as far as tremor is concerned. Dr. Foster: As far as we know, the nonselective drugs are all similarly effective. One of the reasonsthat we chose nadolol is that patients with Parkinson’s disease are particularly susceptible to central nervous system side effects becauseof,their age and the frequent concurrence of dementia, and they may therefore benefit more from a drug that acts only peripherally. Dr. Mata: In those resistant cases,would it be possible to use L-dopa and beta blockers together? Dr. Foster: We recommend the use of conventional therapy first. These patients all showed response to conventional therapy, particularly with regard to their rigidity but lessso with regard to their tremor. Certainly many patients with tremor respond to conventional therapy, particularly the combination of L-dopa and carbidopa, sothat should be the first step, and then beta blockers should be considerednext. Dr. Radebaugh: Did any of the patients, particularly the older ones, show psychologic symptoms when they were given the rather high dosesof beta blockers? Dr. Foster: There was one patient who had nonpostural lightheadedness. Two patients who developed bradycardia of <60 bpm we did not allow to go to full dose. There were no other psychologic side effects, and this is further evidence that there is probably a periphral action of the drug. Dr. Scully: Throughout these discussionswe have heard reports of the useof dosagesof nadolol far in excess of what the common clinician uses. Would Dr. Foster comment on giving 240 mg to an older patient who may not be hypertensive? Would thosewho spokeon thyrotoxicosis,migraine, and headachecomment? I am concerned about the dosageof drug being discussedrelevant to my own clinical practice. Dr. Foster: We have not performed a specific doseresponsestudy; we were hoping to find the effective dose. This needsto be done in a more formal way. There is a possibility, since two of the eight patients were unable to reach 320 mg becauseof bradycardia of <60 bpm and a pulserate of <60 bpm, that in fact greater benefit may be seenat 320mg than at 240mg. Our concept is that the dose should be begun at a low level and Volume 108 Number 4, Part 2 Beta-blocker increased as much as possible without side effects until a benefit is seen. The patients whom we selected did not have significant heart disease, and this was important for us when we went on to using higher doses of drug. Most of these patients have returned to using nadolol since this study and have had no problem, despite bradycardia, with the larger doses of drug. These doses, although slowly increased, can be continued, and we have found increasing benefit at higher doses of drug. Dr. Kaplan: In hypertension, at least, the majority of patients really do respond to smaller doses and do not need larger ones. There may be some exceptions, and I certainly will defer to the finding of a study such as Dr. Foster has just presented that for some of the indications, larger doses may be advantageous. I think we shall come back to the issue of thyrotoxicosis, therapy of resting tremor because it may reflect the fact that there is increased hepatic blood flow in patients with thyrotoxicosis, and therefore the plasma levels of a drug, such as propranolol, that is metabolized in the liver could be altered. In most of the studies I have been relating doses to either effects or side effects, there tends to be a fairly flat dose-response curve, and one does not continue to obtain either good or bad effects in a straight-line relationship with higher doses. The point is well taken. The least amount that is effective is what we should be using. However, I think that we need not fear that increasing the dosage will produce many additional problems in patients whose therapeutic response was not as good as we thought it should have been from a smaller dose. The use of higher doses under these circumstances is perfectly rational medicine. Peripheral hemodynamic effects of short-term nadolol administration in essential hypertension A study of forearm arterial and venous hemodynamics by pulsed Doppler velocimetry and plethysmography was performed in 21 patients with essential hypertension, aged 16 to 54 years, before and after short-term nadolol administration at a dose of 0.05 mg/kg. Because of a large intersubject variability in the responses of the hemodynamic parameters to nadolol, an unconventional statistic approach was used to divide the overall population of patients into two homogeneous groups. The first included nine patients (group 1) and the second 12 patients (group 2). In patients of group 1, nadolol significantly decreased the systolic blood pressure (p < O.OOl), venous tone (g < O.Ol), and brachial artery flow (p < 0.05). in patients of group 2, nadolol did not affect any forearm parameters. Each group of patients was compared to an ageand pressure-matched group of patients receiving propranolol at equiblocking doses. Contrary to nadoloi, propranolol was found to increase significantly the forearm vascular resistance in patients of groups 1 and 2 (SO ? 19%, p < 0.001; 63 + lo%, p < 0.001, respectively). Thus the hemodynamic beta-blocking effects of nadolol in the forearm were less marked than those of propranolol, suggesting that the effects of acute beta blockade by nadolol could be offset by other effects, such as a peripheral partial-agonist effect. (AM HEART J 106:1177, 1964.) Jaime Levenson, M.D., Alain C. Simon, M.D., Dominique Moyse, M.D., Jean Bouthier, M.D., and Michel E. !&far, M.D. Paris, France From the Hypertension Supported Recherche Artificiel Travailleurs Diagnostic Research Center and the Hemodynamic Center, Broussais Hospital. Laboratory of the by a grant from the Institut National de la Sante et de la Mkdicale (INSERM), the Association pour 1’Utilisation du Rein (AURA), and the Caisse Nationale de 1’Assurance Maladies des Salari& (CNAMTS), Paris. Reprint requests: rue Didot, 75674 Prof. Paris War. Cedex Centre de Diagnostic, 14, France. HBpital Broussais, 96 Nadolol is a noncardioselective beta-blocking agent that increases renal blood flow,‘r2 in contrast with the effect of other beta blockers.3s4 However, no information exists about the effect of nadolol on other regional circulations such as skeletal muscle and skin blood flow, information that should be 1177