Movement Disorders Vol. 6 , No. 1, 1991, pp. 65-68 0 1991 Movement Disorder Society
Quantitative Comparison of Barbiturates in Essential Hand and Head Tremor Enrico Sasso, "Emilio Perucca, ?Roberto Fava, and Stefano Calzetti Institute of Neurology, University of Parma, Parma; *Department of Internal Medicine and Therapeutics, Vniversiiy of Pavia, Pavia; and ?Computer Data Center, USL 4 , Parma, Italy
Summary: The tremorolytic effects of primidone and phenobarbital in essential tremor of hands and head were compared in a double-blind, placebo-controlled trial. Quantitative measurements of tremor were obtained in 15 patients by means of an accelerometric method. Only primidone proved to be superior to placebo in reducing hand tremor, suggesting that its tremorolytic effectiveness is largely dependent on the parent drug rather than its metabolite phenobarbital. Head tremor tended to improve only in three out of six patients with both primidone and phenobarbital, but, likely due to the small number of affected patients, the effect failed to reach statistical significance. Key Words: Essential tremor-Primidone-Phenobarbital-Accelerometry .
The efficacy of the anticonvulsant agent primidone (PMD) in the treatment of essential tremor (ET) was first reported by O'Brien and co-workers (1) and subsequently confirmed in a number of controlled trials (2-5). It is still debated whether the tremorolytic effect of the drug is mainly mediated by the parent drug compound or by its metabolite phenobarbital (PB), as proposed by some authors (6). In a previous article (7), we showed that PMD is superior to PB in controlling ET as assessed by clinical scores and performance tests. However, a comparison based on quantitative measurement of tremor is still lacking. We now report the results of a double-blind, placebo-controlled study in which PMD and PB were compared by using a quantitative evaluation method. The study was also designed t o assess the effect of these on ET of the head, which to our knowledge has not been investigated previously.
PATIENTS AND METHODS Eighteen outpatients (12 men and six women; median age of 72 years; median duration of tremor of 14.5 years) with a diagnosis of ET (monosymptomatic postural hand and/or head tremor without other neurological disorders or biochemical abnormalities) gave their informed consent to participate in the double-blind, placebo-controlled, cross-over study. Quantitative recordings concerning 13 out of 18 patients were obtained during a previous trial comparing the effect of barbiturates by means of clinical assessment, patient's self-rating, and tests of performance (7). In most patients (Table l), tremor was confined to the hands, with a significant head tremor being observed in eight cases. Seventeen patients were not taking any tremorolytic medication, whereas the remaining subject was asked to discontinue propranolol2 weeks prior to the study. Patients received, in randomized order, three consecutive 35-day treatments with PMD (250 mg, tablets), PB (50 mg, tablets), and placebo, respectively. Each treatment was started with %I tablet
Address correspondence and reprint requests to Prof. Stefano Calzetti at Istituto di Neurologia, Universith di Parma, Strada del Quartiere, 4, 43100 Parma, Italy.
65
E. SASS0 ET AL.
66
TABLE 1. Details of the patients included in the study
Patient
Gender
Age (years)
1 2 3 4
M M M F M M M M M F M F M M F F M F
72 60 72 69 78 68 68 77 62 74 75 75 74 67 74 71 67 79
5 6 7 8 9 10 11 12 13 14 15 16 17 18
Duration of tremor (years) 10 6
2 20 14 6 40 18 3 20 3 10 15 32 30 28 27 11
once daily, and the dosage was increased stepwise according to tolerability up to a maximum of 1 tablet three times daily on day 14. The slow run-in schedule was chosen to minimize the risk of early acute intolerance to PMD. After day 14, drug dosage was maintained unchanged for 21 days before crossing over to the next treatment. Patients were assessed on the last day of each treatment period, -2 h after the last dose. Hand tremor was recorded by using piezoresistive monoaxial linear accelerometers (Egax 5 ; Entran Device Inc., Fairfield, NJ, U.S.A.) taped on the dorsal surface of the hands, maintained in a pronated antigravity posture, in the second interspace proximal to the metacarpophalangeal joint. Only tremorograms from the more affected hand were used for assessment of efficacy. In patients with head tremor, a single accelerometer was taped on the forehead with its sensitive axis oriented in the direction of the prevailing tremor component (i.e., horizontal or vertical). The assessment sessions took place in a quiet environment away from noise sources. The bioelectric signals were analyzed on an IBM PC XT using a software package including three separate programs. The acquisition program (Fortran) carried out data sampling at a fixed speed of 128 samples/s on two channels simultaneously over a period of 30 s by means of an IBM analogdigital converter. Computerized power spectrum of the data was then performed by a fast Fourier transform (FFT) program (Fortran) that averaged 30
Movement Disorders, Vol. 6, No. I , 1991
Family history of tremor
More involved side
Seventy of hand tremor
+ + + + + + + + + + + + + + + +
R L L R R = L L R R R R L R L R = L L R = L R L
Moderate Moderate Mild Moderate Severe Moderate Moderate Moderate Mild Severe Mild Moderate Moderate Moderate Severe Severe Moderate Severe
Other parts involved Head Head
Head, legs -
Chin, legs
-
Head Head, voice Head Head Head, legs
tremor samples, each of overlapping 8-s duration, with a resolution in the frequency domain of 0.125 Hz. Before FFT processing, smoothing by means of a Hanning window was performed on each sample in order to insure a filtering effect on artifactual contamination. In the printout program (C), the data obtained by spectrum analysis were displayed on two orthogonal axes in which the root-meansquare magnitude of the frequency components 0, axis) were plotted as a function of their frequency (x axis). Measurements were taken of the dominant peak frequency (Hz) and of its magnitude expressed as acceleration of gravity (1 g = 981 cm/s2). Blood samples were collected at the end of each treatment for the determination of serum levels of PMD and PB by fluorescence polarization immunoassay (TDx; Abbott, Chicago, IL, U.S.A.). Mean changes in tremor magnitude are expressed as means ? SEM. Evaluation of drug effects was based on the comparison with the placebo period. Statistical comparisons were performed by using the Wilcoxon’s rank test. RESULTS
Complete data sets were available for 15 patients because of three drop-outs: two patients discontinued the treatment prematurely because they felt that sedative effect during the PMD period (subject 7) and asthenia during the PB period (subject 16) outweighed any potential benefit; a third patient (subject 5 ) was excluded because of poor compliance .
BARBITURATES IN HAND A N D HEAD TREMOR The mean dosage of the drugs (+SEM) during the maintenance period was 734 2 9.8 mg/day for PMD and 128 2 8.2 mg/day for PB. On accelerometric evaluation, the dominant peak frequency of hand tremor at baseline (pretreatment) ranged from 4.0 to 8.25 Hz (median of 5.8 Hz) and did not vary significantly during the study. Peak hand tremor magnitude at baseline ranged from 4.5 to 595 g x (median 132.9 g x Placebo administration was associated with a small, notstatistically significant reduction in hand tremor (mean percent reduction vs baseline: 8.5% 12.2%) (Fig. 1). As compared to baseline, PMD significantly reduced hand tremor (42.3% f. 9.1%; p < O.Ol), whereas the reduction of hand tremor magnitude produced by PB (22.8% 2 15.2%) was not statistically significant (Fig. 1). The magnitude of postural hand tremor was reduced by >20% of the baseline value in 12 patients during PMD treatment and in eight patients during PB treatment. In the six patients available for head tremor recording, the baseline peak magnitude of head tremor, whose main component was on the horizontal plane for all patients, ranged between 1.9 and 14.8 g x lop3(median of 6.4g x whereas the dominant peak frequency ranged between 2.8 and 3.8 Hz (median 3.0 Hz) and did not change significantly following each treatment. In these patients, no significant changes in baseline head tremor magnitude were found following administration of PMD, PB, and placebo when the data were calculated as percentage values (by 31.8% 19.7%, 30.2% 2 20%, and -7.4% 2 23.6%, respectively). As compared to placebo, no significant difference was found between the percent and absolute reduction in head tremor magnitude produced by both
*
*
1 **
I PLAC
e23 PB
0 PMD
FIG. 1. Percent change in magnitude of hand tremor (vs. baseline) obtained during treatment with PMD, PB, and placebo. Bars, mean ? SEM. **p < 0.01.
67
T C W
.100
o n L
0 C
0 .u
$
50
v
E
n 0 l iPLAC eza PB n PMD FIG. 2. Percent change in magnitude of head tremor (vs. baseline) obtained during treatment with PMD, PB, and placebo. Bars. mean 5 SEM.
PMD and PB (Fig. 2). The magnitude of head tremor was reduced by >20% of the baseline value in three patients during both PMD and PB treatments and in two patients during placebo. Serum PMD levels at time of assessment were 12.6 1.3 pg/ml. Serum PB levels were 15.7 & 1.8 pg/ml during the PMD period and 20.8 4 1.8 pg/ml during the PB period. No significant correlation was found between serum PMD or PB concentrations and changes in tremor magnitude. Side effects were reported by 11 patients during PMD treatment, by nine patients during PB treatment and by five patients during intake of placebo (Table 2).
*
DISCUSSION PMD is generally regarded as the best available treatment for patients with ET who do not respond to P-adrenoceptor antagonists or in whom these drugs are contraindicated. Although a dramatic suppression of tremor can occur more frequently with PMD than with propranolol(4,8), the tolerability of the drug is less than satisfactory because of possible occurrence of early transient intolerance (1,4)and/ or other manifestations of barbiturate toxicity, which could be, at least in part, prevented by using a slow drug run-in schedule. Tolerance to tremorolytic effect of PMD may also occur over time (5,9) in some patients, reducing the benefit of a long-term sustained treatment. The mechanism responsible for the tremorolytic effect of PMD is still largely unknown. Of the main metabolites of PMD, phenylethylmalonamide (PEMA) has been found to be ineffective on tremor (10). Although metabolically derived PB contributes to tremorolytic activity (6,ll), the clinical improvement achieved with PB is generally consid-
Movement Disorders, Vol. 6, No. I , 1991
E . SASS0 ET AL.
68
TABLE 2. Side effects reported by 15 patients w h o c o m p l e t e d the study PMD Sedatioddrowsiness Weakness Dizziness Nausedvomiting Ataxia Depression Dry mouth Headache Constipation Memory loss Digestive problems Total number of patients with side effects
PB
Placebo
8 2 5 2 I
1 1 I
2 11
ered to be less impressive than that obtained with PMD (11). Moreover, PMD has been found to reduce ET shortly after initial administration, at a time when PB is not yet detectable in the serum (9). Clear-cut demonstration for an independent tremorolytic activity of PMD has also been provided in a recent placebo-controlled clinical trial based on clinical, subjective evaluation and performance tests (7). The present study, based on a quantitative measurement of tremor, reinforces the evidence that PMD is superior to PB in relieving essential tremor in the hands. PB may be of some benefit, at least in some instances, in patients who are intolerant to PMD and unresponsive to p-blockers. The lack of correlation between serum barbiturate levels and tremorolytic activity is consistent with previous reports (3,5,9). The results concerning head tremor require a separate comment. To date, ET of the head has been little investigated, drug efficacy data being confined to few anecdotal clinical observations. It is known though that common tremorolytic drugs are generally less effective on head than on hand tremor (12). However, in a recent controlled clinical trial (13), ET of the head was found to be as responsive as hand tremor to propranolol treatment in the same patients. As far as the effect of PMD on head tremor is concerned, there are reports of favorable responses (14,15), even though in a placebo-controlled trial head tremor did not appear to respond as well as the tremor of the hands (3). In the present study, although the average reduction in head tremor was comparable to that observed for hand tremor, only three out of six patients had a definite improvement
Movement Disorders,
Vol. 6 , N o , 1, 1991
on PMD and PB treatments, indicating that head tremor responds less predictably than hand tremor to barbiturates. Results of head tremor could be, at least in part, biased by the evidence that none of the patients included in the present study was exclusively or prominently affected by head ET. Indeed, it could be not excluded that some positive response of head tremor to treatment results from the relief of passive backward transmission of tremor from hands to neck-head system in patients with tremor involving both hands and head. Further, more extensive studies specifically targeted at the population with exclusive or prevailing head ET are indicated to establish the actual value of PMD and PB in the treatment of this disordered head movement. REFERENCES 1 . O’Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 1981;282:178-80. 2. Findley LJ, Calzetti S . Double-blind controlled study of primidone in essential tremor: preliminary results. Br Med J 1982;285:608. 3. Findley LJ, Cleeves L, Calzetti S. Primidone in essential tremor of hands and head: a double-blind controlled study. J Neurol Neurosurg Psychiatry 1985;48:911-5. 4. Gorman WP, Cooper R, Pocock P, Campbell MJ. A comparison of primidone propranolol and placebo in essential tremor using quantitative analysis. J Neurol Neurosurg Psychiatry 1986;49:64-8. 5. Dietrichson P, Espen E. Primidone and propranolol in essential tremor: a study based on quantitative tremor recording and plasma anticonvulsant levels. Acta Neurol Scand 1987;75:33240. 6. Baruzzi A, Procaccianti G , Martinelli P, et al. Phenobarbital and propranolol in essential tremor: a double-blind controlled clinical trial. Neurology 1983;33:296-300. 7. Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and phenobarbital in essential tremor. Neurology 1988;38:808-10. 8. Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology 1986;36:1 2 1 4 . 9. Sasso E, Perucca E, Fava R, Calzetti S. Primidone in the long-term treatment of essential tremor: a prospective study with computerized quantitative analysis. Clin Neuropharmacol 1990;13:67-76. 10. Calzetti S , Findley LJ, Pisani F, Richens A. Phenylethylmalonamide in essential tremor: a double-blind, controlled study. J Neurol Neurosurg Psychiatry 1982;44:9324. 1 1 . Findley LJ, Cleeves L. Phenobarbitone in essential tremor. Neurology 1985;35:1784-7. 12. Young RR. Essential familial tremor and other action tremors. In: Joynt RJ, ed. Seminars in neurology, vol. 2, no. 4 . New York: Thieme-Stratton, 1982:389-91. 13. Koller WC. Propranolol therapy for essential tremor of the head. Neurology 1984;34:1077-9. 14. Chakrabarti A, Pearce JMS. Essential tremor: response to primidone [Letter]. J Neurol Neurosurg Psychiatry 1981;44: 650. 15. Crystal HA. Duration of effectiveness of primidone in essential tremor [Letter]. Neurology 1986;36:1543.
Quantitative Comparison of Barbiturates in Essential Hand and Head Tremor Enrico Sasso, "Emilio Perucca, ?Roberto Fava, and Stefano Calzetti Institute of Neurology, University of Parma, Parma; *Department of Internal Medicine and Therapeutics, Vniversiiy of Pavia, Pavia; and ?Computer Data Center, USL 4 , Parma, Italy
Summary: The tremorolytic effects of primidone and phenobarbital in essential tremor of hands and head were compared in a double-blind, placebo-controlled trial. Quantitative measurements of tremor were obtained in 15 patients by means of an accelerometric method. Only primidone proved to be superior to placebo in reducing hand tremor, suggesting that its tremorolytic effectiveness is largely dependent on the parent drug rather than its metabolite phenobarbital. Head tremor tended to improve only in three out of six patients with both primidone and phenobarbital, but, likely due to the small number of affected patients, the effect failed to reach statistical significance. Key Words: Essential tremor-Primidone-Phenobarbital-Accelerometry .
The efficacy of the anticonvulsant agent primidone (PMD) in the treatment of essential tremor (ET) was first reported by O'Brien and co-workers (1) and subsequently confirmed in a number of controlled trials (2-5). It is still debated whether the tremorolytic effect of the drug is mainly mediated by the parent drug compound or by its metabolite phenobarbital (PB), as proposed by some authors (6). In a previous article (7), we showed that PMD is superior to PB in controlling ET as assessed by clinical scores and performance tests. However, a comparison based on quantitative measurement of tremor is still lacking. We now report the results of a double-blind, placebo-controlled study in which PMD and PB were compared by using a quantitative evaluation method. The study was also designed t o assess the effect of these on ET of the head, which to our knowledge has not been investigated previously.
PATIENTS AND METHODS Eighteen outpatients (12 men and six women; median age of 72 years; median duration of tremor of 14.5 years) with a diagnosis of ET (monosymptomatic postural hand and/or head tremor without other neurological disorders or biochemical abnormalities) gave their informed consent to participate in the double-blind, placebo-controlled, cross-over study. Quantitative recordings concerning 13 out of 18 patients were obtained during a previous trial comparing the effect of barbiturates by means of clinical assessment, patient's self-rating, and tests of performance (7). In most patients (Table l), tremor was confined to the hands, with a significant head tremor being observed in eight cases. Seventeen patients were not taking any tremorolytic medication, whereas the remaining subject was asked to discontinue propranolol2 weeks prior to the study. Patients received, in randomized order, three consecutive 35-day treatments with PMD (250 mg, tablets), PB (50 mg, tablets), and placebo, respectively. Each treatment was started with %I tablet
Address correspondence and reprint requests to Prof. Stefano Calzetti at Istituto di Neurologia, Universith di Parma, Strada del Quartiere, 4, 43100 Parma, Italy.
65
E. SASS0 ET AL.
66
TABLE 1. Details of the patients included in the study
Patient
Gender
Age (years)
1 2 3 4
M M M F M M M M M F M F M M F F M F
72 60 72 69 78 68 68 77 62 74 75 75 74 67 74 71 67 79
5 6 7 8 9 10 11 12 13 14 15 16 17 18
Duration of tremor (years) 10 6
2 20 14 6 40 18 3 20 3 10 15 32 30 28 27 11
once daily, and the dosage was increased stepwise according to tolerability up to a maximum of 1 tablet three times daily on day 14. The slow run-in schedule was chosen to minimize the risk of early acute intolerance to PMD. After day 14, drug dosage was maintained unchanged for 21 days before crossing over to the next treatment. Patients were assessed on the last day of each treatment period, -2 h after the last dose. Hand tremor was recorded by using piezoresistive monoaxial linear accelerometers (Egax 5 ; Entran Device Inc., Fairfield, NJ, U.S.A.) taped on the dorsal surface of the hands, maintained in a pronated antigravity posture, in the second interspace proximal to the metacarpophalangeal joint. Only tremorograms from the more affected hand were used for assessment of efficacy. In patients with head tremor, a single accelerometer was taped on the forehead with its sensitive axis oriented in the direction of the prevailing tremor component (i.e., horizontal or vertical). The assessment sessions took place in a quiet environment away from noise sources. The bioelectric signals were analyzed on an IBM PC XT using a software package including three separate programs. The acquisition program (Fortran) carried out data sampling at a fixed speed of 128 samples/s on two channels simultaneously over a period of 30 s by means of an IBM analogdigital converter. Computerized power spectrum of the data was then performed by a fast Fourier transform (FFT) program (Fortran) that averaged 30
Movement Disorders, Vol. 6, No. I , 1991
Family history of tremor
More involved side
Seventy of hand tremor
+ + + + + + + + + + + + + + + +
R L L R R = L L R R R R L R L R = L L R = L R L
Moderate Moderate Mild Moderate Severe Moderate Moderate Moderate Mild Severe Mild Moderate Moderate Moderate Severe Severe Moderate Severe
Other parts involved Head Head
Head, legs -
Chin, legs
-
Head Head, voice Head Head Head, legs
tremor samples, each of overlapping 8-s duration, with a resolution in the frequency domain of 0.125 Hz. Before FFT processing, smoothing by means of a Hanning window was performed on each sample in order to insure a filtering effect on artifactual contamination. In the printout program (C), the data obtained by spectrum analysis were displayed on two orthogonal axes in which the root-meansquare magnitude of the frequency components 0, axis) were plotted as a function of their frequency (x axis). Measurements were taken of the dominant peak frequency (Hz) and of its magnitude expressed as acceleration of gravity (1 g = 981 cm/s2). Blood samples were collected at the end of each treatment for the determination of serum levels of PMD and PB by fluorescence polarization immunoassay (TDx; Abbott, Chicago, IL, U.S.A.). Mean changes in tremor magnitude are expressed as means ? SEM. Evaluation of drug effects was based on the comparison with the placebo period. Statistical comparisons were performed by using the Wilcoxon’s rank test. RESULTS
Complete data sets were available for 15 patients because of three drop-outs: two patients discontinued the treatment prematurely because they felt that sedative effect during the PMD period (subject 7) and asthenia during the PB period (subject 16) outweighed any potential benefit; a third patient (subject 5 ) was excluded because of poor compliance .
BARBITURATES IN HAND A N D HEAD TREMOR The mean dosage of the drugs (+SEM) during the maintenance period was 734 2 9.8 mg/day for PMD and 128 2 8.2 mg/day for PB. On accelerometric evaluation, the dominant peak frequency of hand tremor at baseline (pretreatment) ranged from 4.0 to 8.25 Hz (median of 5.8 Hz) and did not vary significantly during the study. Peak hand tremor magnitude at baseline ranged from 4.5 to 595 g x (median 132.9 g x Placebo administration was associated with a small, notstatistically significant reduction in hand tremor (mean percent reduction vs baseline: 8.5% 12.2%) (Fig. 1). As compared to baseline, PMD significantly reduced hand tremor (42.3% f. 9.1%; p < O.Ol), whereas the reduction of hand tremor magnitude produced by PB (22.8% 2 15.2%) was not statistically significant (Fig. 1). The magnitude of postural hand tremor was reduced by >20% of the baseline value in 12 patients during PMD treatment and in eight patients during PB treatment. In the six patients available for head tremor recording, the baseline peak magnitude of head tremor, whose main component was on the horizontal plane for all patients, ranged between 1.9 and 14.8 g x lop3(median of 6.4g x whereas the dominant peak frequency ranged between 2.8 and 3.8 Hz (median 3.0 Hz) and did not change significantly following each treatment. In these patients, no significant changes in baseline head tremor magnitude were found following administration of PMD, PB, and placebo when the data were calculated as percentage values (by 31.8% 19.7%, 30.2% 2 20%, and -7.4% 2 23.6%, respectively). As compared to placebo, no significant difference was found between the percent and absolute reduction in head tremor magnitude produced by both
*
*
1 **
I PLAC
e23 PB
0 PMD
FIG. 1. Percent change in magnitude of hand tremor (vs. baseline) obtained during treatment with PMD, PB, and placebo. Bars, mean ? SEM. **p < 0.01.
67
T C W
.100
o n L
0 C
0 .u
$
50
v
E
n 0 l iPLAC eza PB n PMD FIG. 2. Percent change in magnitude of head tremor (vs. baseline) obtained during treatment with PMD, PB, and placebo. Bars. mean 5 SEM.
PMD and PB (Fig. 2). The magnitude of head tremor was reduced by >20% of the baseline value in three patients during both PMD and PB treatments and in two patients during placebo. Serum PMD levels at time of assessment were 12.6 1.3 pg/ml. Serum PB levels were 15.7 & 1.8 pg/ml during the PMD period and 20.8 4 1.8 pg/ml during the PB period. No significant correlation was found between serum PMD or PB concentrations and changes in tremor magnitude. Side effects were reported by 11 patients during PMD treatment, by nine patients during PB treatment and by five patients during intake of placebo (Table 2).
*
DISCUSSION PMD is generally regarded as the best available treatment for patients with ET who do not respond to P-adrenoceptor antagonists or in whom these drugs are contraindicated. Although a dramatic suppression of tremor can occur more frequently with PMD than with propranolol(4,8), the tolerability of the drug is less than satisfactory because of possible occurrence of early transient intolerance (1,4)and/ or other manifestations of barbiturate toxicity, which could be, at least in part, prevented by using a slow drug run-in schedule. Tolerance to tremorolytic effect of PMD may also occur over time (5,9) in some patients, reducing the benefit of a long-term sustained treatment. The mechanism responsible for the tremorolytic effect of PMD is still largely unknown. Of the main metabolites of PMD, phenylethylmalonamide (PEMA) has been found to be ineffective on tremor (10). Although metabolically derived PB contributes to tremorolytic activity (6,ll), the clinical improvement achieved with PB is generally consid-
Movement Disorders, Vol. 6, No. I , 1991
E . SASS0 ET AL.
68
TABLE 2. Side effects reported by 15 patients w h o c o m p l e t e d the study PMD Sedatioddrowsiness Weakness Dizziness Nausedvomiting Ataxia Depression Dry mouth Headache Constipation Memory loss Digestive problems Total number of patients with side effects
PB
Placebo
8 2 5 2 I
1 1 I
2 11
ered to be less impressive than that obtained with PMD (11). Moreover, PMD has been found to reduce ET shortly after initial administration, at a time when PB is not yet detectable in the serum (9). Clear-cut demonstration for an independent tremorolytic activity of PMD has also been provided in a recent placebo-controlled clinical trial based on clinical, subjective evaluation and performance tests (7). The present study, based on a quantitative measurement of tremor, reinforces the evidence that PMD is superior to PB in relieving essential tremor in the hands. PB may be of some benefit, at least in some instances, in patients who are intolerant to PMD and unresponsive to p-blockers. The lack of correlation between serum barbiturate levels and tremorolytic activity is consistent with previous reports (3,5,9). The results concerning head tremor require a separate comment. To date, ET of the head has been little investigated, drug efficacy data being confined to few anecdotal clinical observations. It is known though that common tremorolytic drugs are generally less effective on head than on hand tremor (12). However, in a recent controlled clinical trial (13), ET of the head was found to be as responsive as hand tremor to propranolol treatment in the same patients. As far as the effect of PMD on head tremor is concerned, there are reports of favorable responses (14,15), even though in a placebo-controlled trial head tremor did not appear to respond as well as the tremor of the hands (3). In the present study, although the average reduction in head tremor was comparable to that observed for hand tremor, only three out of six patients had a definite improvement
Movement Disorders,
Vol. 6 , N o , 1, 1991
on PMD and PB treatments, indicating that head tremor responds less predictably than hand tremor to barbiturates. Results of head tremor could be, at least in part, biased by the evidence that none of the patients included in the present study was exclusively or prominently affected by head ET. Indeed, it could be not excluded that some positive response of head tremor to treatment results from the relief of passive backward transmission of tremor from hands to neck-head system in patients with tremor involving both hands and head. Further, more extensive studies specifically targeted at the population with exclusive or prevailing head ET are indicated to establish the actual value of PMD and PB in the treatment of this disordered head movement. REFERENCES 1 . O’Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J 1981;282:178-80. 2. Findley LJ, Calzetti S . Double-blind controlled study of primidone in essential tremor: preliminary results. Br Med J 1982;285:608. 3. Findley LJ, Cleeves L, Calzetti S. Primidone in essential tremor of hands and head: a double-blind controlled study. J Neurol Neurosurg Psychiatry 1985;48:911-5. 4. Gorman WP, Cooper R, Pocock P, Campbell MJ. A comparison of primidone propranolol and placebo in essential tremor using quantitative analysis. J Neurol Neurosurg Psychiatry 1986;49:64-8. 5. Dietrichson P, Espen E. Primidone and propranolol in essential tremor: a study based on quantitative tremor recording and plasma anticonvulsant levels. Acta Neurol Scand 1987;75:33240. 6. Baruzzi A, Procaccianti G , Martinelli P, et al. Phenobarbital and propranolol in essential tremor: a double-blind controlled clinical trial. Neurology 1983;33:296-300. 7. Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and phenobarbital in essential tremor. Neurology 1988;38:808-10. 8. Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology 1986;36:1 2 1 4 . 9. Sasso E, Perucca E, Fava R, Calzetti S. Primidone in the long-term treatment of essential tremor: a prospective study with computerized quantitative analysis. Clin Neuropharmacol 1990;13:67-76. 10. Calzetti S , Findley LJ, Pisani F, Richens A. Phenylethylmalonamide in essential tremor: a double-blind, controlled study. J Neurol Neurosurg Psychiatry 1982;44:9324. 1 1 . Findley LJ, Cleeves L. Phenobarbitone in essential tremor. Neurology 1985;35:1784-7. 12. Young RR. Essential familial tremor and other action tremors. In: Joynt RJ, ed. Seminars in neurology, vol. 2, no. 4 . New York: Thieme-Stratton, 1982:389-91. 13. Koller WC. Propranolol therapy for essential tremor of the head. Neurology 1984;34:1077-9. 14. Chakrabarti A, Pearce JMS. Essential tremor: response to primidone [Letter]. J Neurol Neurosurg Psychiatry 1981;44: 650. 15. Crystal HA. Duration of effectiveness of primidone in essential tremor [Letter]. Neurology 1986;36:1543.
