1660 T.A. ZESIEWICZ ET AL.
pects of the disease, or by the simple measurement of
nigrostriatal dopaminergic terminal integrity. Third, be-
cause there are many “silent” areas/cells in the brain that
provide functional resilience (compensatory mecha-
nisms) after insult, a fundamental understanding of the
PD process, in terms of cell death, needs to account for
the loss of silent cells, both within and outside the
dopaminergic system. For these reasons, future ventric-
ular volumetric studies involving more discordant PD-
twin pairs, larger case– control studies with genetically
unmatched subjects, and/or longitudinal cohort studies of
PD subjects (all with correlation to PD-specific func-
tional measurements) may appear warranted.
Acknowledgments: This work was supported in part by
NIH grants AG21491 (XH), RR00046 (GCRC). We are thank-
ful to the discordant PD-twin pair who participated in the
studies. We also thank Dr. Douglas W. Jones for providing
MRI data on the nine pairs of healthy twins and Drs. Ken
Marek and Danna Jennings for performing the SPECT studies.
REFERENCES
1. Lee CS, Schulzer M, Mak E, Hammerstad JP, Calne S, Calne
DB. Patterns of asymmetry do not change over the course of
idiopathic parkinsonism: implications for pathogenesis. Neurol-
ogy 1995;45(3, Part 1):435-439.
2. Kumar A, Mann S, Sossi V, et al. [11C]DTBZ-PET correlates of
levodopa responses in asymmetric Parkinson’s disease. Brain
2003;126 (Part 12):2648-2655.
3. Huber SJ, Miller H, Bohaska L, Christy JA, Bornstein RA. Asym-
metrical cognitive differences associated with hemiparkinsonism.
Arch Clin Neuropsychol 1992;7:471-480.
4. Tomer R, Sharon-Peretz J, Tsitrinbaum Z. Dopamine asymmetry
interacts with medication to affect cognition in Parkinson’s dis-
ease. Neuropsychologia 2007;45:357–367.
5. Marie RM, Barre L, Rioux P, Allain P, Lechevalier B, Baron JC.
PET imaging of neocortical monoaminergic terminals in Parkin-
son’s disease. J Neural Transm Park Dis Dement Sect 1995;9:55-
71.
6. Hu MT, White SJ, Chaudhuri KR, Morris RG, Bydder GM, Brooks
DJ. Correlating rates of cerebral atrophy in Parkinson’s disease
with measures of cognitive decline. J Neural Transm 2001;108:
571-580.
7. Styner M, Lieberman JA, McClure RK, Weinberger DR, Jones
DW, Gerig G. Morphometric analysis of lateral ventricles in
schizophrenia and healthy controls regarding genetic and disease-
specific factors. Proc Natl Acad Sci USA 2005;102:4872-4877.
8. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive
ability of an incident cohort of Parkinson’s patients in the UK. The
CamPaIGN study. Brain 2004;127 (Part 3):550-560.
9. Muslimovic D, Post B, Speelman JD, Schmand B. Cognitive
profile of patients with newly diagnosed Parkinson disease. Neu-
rology 2005;65:1239-1245.
10. Van LK, Maes F, Vandermeulen D, Suetens P. Automated model-
based bias field correction of MR images of the brain. IEEE Trans
Med Imaging 1999;18:885-896.
11. Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active
contour segmentation of anatomical structures: significantly im-
proved efficiency and reliability. Neuroimage 2006;31:1116-1128.
12. Paviour DC, Price SL, Jahanshahi M, Lees AJ, Fox NC. Longitu-
dinal MRI in progressive supranuclear palsy and multiple system
atrophy: rates and regions of atrophy. Brain 2006;129 (Part 4):
1040-1049.
Movement Disorders, Vol. 22, No. 11, 2007
A Pilot, Double-Blind, Placebo-
Controlled Trial of Pregabalin
(Lyrica) in the Treatment of
Essential Tremor
Theresa A. Zesiewicz, MD,1,2,3,4,5*
Christopher L. Ward, LMT,1,2,4
Robert A. Hauser, MD,1,2,3,4 Jason L. Salemi, MPH,6
Shaila Siraj, BS,1,2,4 Maria-Carmen Wilson, MD,2 and
Kelly L. Sullivan, MSPH1,2,4
1
Parkinson’s Disease and Movement Disorders Center,
University of South Florida, Tampa, Florida, USA;
2
Department of Neurology, University of South Florida,
Tampa, Florida, USA; 3Department of Pharmacology and
Experimental Therapeutics, University of South Florida,
Tampa, Florida, USA; 4National Parkinson Foundation
Center of Excellence, University of South Florida, Tampa,
Florida, USA; 5James A. Haley Veterans Administration
Hospital, University of South Florida, Tampa, Florida, USA;
6
Birth Defects Surveillance Program, Department of
Pediatrics, University of South Florida, Tampa, Florida, USA
Abstract: We performed a pilot, double-blind, placebo-
controlled, randomized trial to evaluate the efficacy and
tolerability of pregabalin (PGB, Lyrica), an antiepileptic
agent, in treating essential tremor (ET). Twenty two pa-
tients with ET were randomly assigned to receive PGB or
placebo. PGB was initiated at 50 mg/day and was escalated
by 75 mg/day every 4 days to a maximum dose of 600
mg/day. Patients were evaluated by accelerometry and the
Fahn–Tolosa–Marin (FTM) rating scale. There was a sig-
nificant reduction in tremor amplitude in the PGB group
compared with the placebo group, as measured by acceler-
ometry, at a mean dose of 286.76 ⴞ 100.05 mg/day. Action
tremor limb scores on the FTM also improved in the PGB
group compared with the placebo group (P-value for mul-
tilevel modeling ⴝ 0.04). PGB was fairly well tolerated, with
about one-third of patients dropping out of the study be-
cause of adverse events. PGB provided significant improve-
ments in accelerometry and in action tremor limb scores on
the FTM. However, larger studies are needed to further
The authors have confirmed with the Editor that their work complies
with the Journal’s Editorial policy on ghost writing [Mov Disord
2005;20(12):1536].
This article includes supplementary video clips, available online at
http://www.interscience.wiley.com/jpages/0885-3185/suppmat.
*Correspondence to: Dr. Theresa A. Zesiewicz, University of South
Florida, 12901 Bruce B. Downs Blvd, MDC Box 55, Tampa, Florida
33612. E-mail: tzesiewi@hsc.usf.edu
Received 16 February 2007; Revised 26 March 2007; Accepted 18
May 2007
Published online 19 June 2007 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.21629
 PREGABALIN IN THE TREATMENT OF ESSENTIAL TREMOR
evaluate the potential effect of PGB on ET. © 2007 Move-
ment Disorder Society
Key words: pregabalin; Lyrica; essential tremor.
Essential tremor (ET) is a tremor disorder that is
characterized by postural and kinetic tremor that usually
affects the hands, head, or voice. Only one drug, pro-
pranolol (Inderal), is approved by the Food and Drug
Administration (FDA) to treat ET, and it is estimated that
⬃30% of ET patients will not respond to it.1 Pregabalin
(PGB, Lyrica) is an antiepileptic agent that is approved
as adjunctive therapy for adult patients with partial onset
seizures.2 It is an isomer of ␥-amino-butyric acid
(GABA), and there is some evidence that PGB can
reduce tremor. In a recent case report, 2 ET patients
experienced marked improvement in upper extremity
action tremor with the use of PGB 200 mg/day as mea-
sured by accelerometry and the Fahn–Tolosa–Marin
(FTM) rating scale.3
We evaluated the tolerability and efficacy of PGB in
reducing tremor in ET patients in a double-blind pilot
study.
DESIGN/METHODS
Patients diagnosed with ET and followed at a univer-
sity movement disorders center were invited to partici-
pate in the study during a 3-month recruitment period.
Eligibility criteria included age 18 to 80 years, and a
diagnosis of definite ET as defined by the Tremor Inves-
tigator Group that affected the upper extremities,4 stable
antitremor medications for at least 14 days prior to base-
line, independent ambulation, and the ability to take oral
medication. Exclusion criteria included a Mini-Mental
Status Exam5 score less than 24, botulinum toxin treat-
ment for upper limb tremor in the prior 6 months, deep
brain stimulation for ET or any other brain surgery,
isolated physiological or psychogenical tremor, use of
PGB 30 days prior to study entry, alcohol or drug ad-
diction, the use of benzodiazepines other than in fixed
doses for treatment of ET, and any major neurological,
psychiatric, or medical disorders that were judged by the
principle investigator (PI) to disqualify a patient from
entering the study, including Parkinson’s disease.
Women of child-bearing age were required to have a
negative pregnancy test in the 7 days prior to study entry
and were using birth control that was judged adequate by
the PI. Patients who met inclusion and exclusion criteria
provided written informed consent to enter the study.
Institutional review board approval for the study was
granted through the University of South Florida.
1661
At baseline, patients were randomly assigned to re-
ceive either PGB or placebo according to a computer-
generated randomization schedule. It was determined
that 11 patients per group would be required to detect a
50% improvement in accelerometry measures at a sig-
nificance level of 0.05 (two-sided) and 80% power. Both
patients and raters were blinded to randomization. PGB
and placebo were supplied in identical containers that
were marked with code numbers. PGB was initiated at 50
mg/day and the dose was escalated by 75 mg/day every
4 days in the active study group to a maximum dose of
600 mg/day. Titration was stopped if patients experi-
enced resolution of tremor or if side-effects prevented an
increase in dose. Patients were evaluated by accelerom-
etry, the FTM rating scale,6 and the Clinical Global
Impression (CGI) scale7 at baseline, and days 7, 14, 21,
28, and 42 (study endpoint). Because PGB is a schedule
V drug that is approved for the management of posther-
petic neuralgia and for diabetic peripheral neuropathy,
patients also were rated on the 11-point Verbal Numeric
Rating Scale.8 The primary outcome measure was the
change in tremor amplitude from baseline to endpoint as
measured by accelerometry.
The accelerometry device utilized in this study was a
component of a portable-PC based test system (Catsys
System) that measures coordination reaction time,
tremor, and postural sway or stability (Danish Product
Development, Ltd).9 A comprehensive gender-and-age
separated normal material has been published using this
apparatus and method of analysis.9 Neurological exami-
nations were conducted by a movement disorders spe-
cialist (TAZ), and tremor measurements were conducted
by a blinded rater (KLS). To measure postural tremor,
patients were asked to hold the pen in a writing posture
with the arms extended level with the shoulders. The pen
was held with the long axis parallel to the ground, and
hand vibrations were recorded and displayed in real-time
against a time axis plot on the computer screen.
Data were analyzed using independent samples t-tests
and growth curve modeling. The mean ⫾ standard de-
viation is reported. Last observation carried forward
(LOCF) was used for analyses for patients who prema-
turely withdrew from the study. Unconditional growth
curve models were used to compare the treatment groups
on their change in outcomes over time.
RESULTS
Twenty-two patients (mean age ⫽ 57 ⫾ 14 years)
were randomly assigned to either PGB (n ⫽ 11) or
placebo (n ⫽ 11). Baseline characteristics are shown in
Table 1. LOCF was used for 7 patients who withdrew
prior to endpoint (total study dropout rate ⫽ 32%). Three
Movement Disorders, Vol. 22, No. 11, 2007
1662
TABLE 1. Baseline characteristics
Age (yr)
Gender
Duration of tremor (yr)
Adjunct tremor medications
Values shown are mean ⫾ SD.
patients (27%) in the PGB group dropped out of the
study (1 patient due to dizziness on day 9 while taking
100 mg/day, 1 patient due to flu on day 13 while taking
100 mg/day, and 1 patient had malaise on day 18 while
taking 150 mg/day). Four dropouts (36%) in the placebo
group were due to fatigue and palpitations in 1 patient
(day 2), and withdrawal of consent for personal reasons
in 3 patients (relocation in 2 patients and family issues in
1 patient). No adverse events were noted in any of the
remaining patients.
There was a greater reduction in tremor amplitude in
the PGB group compared with the placebo group
(⫺0.99 ⫾ 1.27 m/s2 vs. 0.80 ⫾ 3.02 m/s2, P-value for
multilevel modeling ⫽ 0.05) at a mean dose of 286.76 ⫾
100.05 mg/day (Fig. 1). Action tremor limb scores on the
FTM part A were improved in the PGB group compared
with the placebo group (⫺2.40 ⫾ 2.22 m/s2 vs. ⫺1.38 ⫾
1.06 m/s2, P-value for multilevel modeling ⫽ 0.04).
However, there were no significant differences in the
FTM total scores between the 2 groups, nor in the FTM
parts A, B, or C subsections (Table 2).
FIG. 1. Growth curve modeling: tremor amplitude change over time.
Movement Disorders, Vol. 22, No. 11, 2007
T.A. ZESIEWICZ ET AL.
Lyrica (n ⫽ 11) Placebo (n ⫽ 11) P-value
53.91 ⫾ 13.01 60.4 ⫾ 14.83 0.2907
5 male, 6 female 6 male, 5 female 0.6698
17.58 ⫾ 19.86 18.33 ⫾ 14.07 0.9413
Alprazolam (n ⫽ 1) Clonazepam (n ⫽ 1) n/a
Clonazepam (n ⫽ 1) Metoprolol (n ⫽ 1)
Propranolol (n ⫽ 1) Primidone (n ⫽ 2)
Propranolol LA (n ⫽ 1) Propranolol (n ⫽ 1)
Sotalol (n ⫽ 1) Propranolol LA (n ⫽ 1)
Topiramate (n ⫽ 2)
At the study endpoint, 67% of patients in the PGB
group reported improvement in tremor on the CGI (1
patient very much improvement, 2 patients much im-
proved, 3 “a little improved”) (Video 1). No patient in
the PGB group reported an increase in tremor. In the
placebo group, 20% (n ⫽ 10) of patients thought that
their tremor was a “little improved”. There were no
changes in the pain scale in either the PGB or placebo
groups. Fifty percent of patients who took PGB re-
quested to remain on the drug at the conclusion of the
study for treatment of tremor.
DISCUSSION
In this randomized double-blind placebo-controlled
pilot study, PGB significantly improved tremor ampli-
tude scores as measured by accelerometry and action
tremor scores on the FTM rating scale compared to
placebo. Two-thirds of the patients who took PGB felt
that their tremor improved, as measured by the CGI.
Despite these findings, the FTM total and part A, B,
and C subsection scores did not improve significantly in
the PGB group compared with the placebo group, pos-
sibly because of the small number of patients in the study
(n ⫽ 22) or the large placebo effect. For example, there
was a 45% improvement in the FTM part A in the
placebo group compared with a 55% improvement in the
PGB group. Recent clinical trials of other neurological
diseases, such as restless leg syndrome, have similarly
demonstrated placebo effects as high as 50%.10 Larger
studies may be necessary to evaluate the clinical effect as
assessed by clinical rating scales. In the current study,
accelerometry was a more sensitive measure of the effect
of PGB on tremor amplitude than the tremor rating scale.
There is evidence that the neurotransmitter GABA
may be involved in the pathophysiology of ET,11-13 and
it is logical that PGB and gabapentin, isomers of GABA,
may have antitremor efficacy. There is also evidence that
the efficacy of both PGB and gabapentin as antiepilep-
tics, pain management medications, or anxiolytics, may
 PREGABALIN IN THE TREATMENT OF ESSENTIAL TREMOR 1663

TABLE 2. Results
P-value for
Outcome Group Baseline* LOCF* Change* multilevel modeling
Amplitude (m/s2) Lyrica 2.16 ⫾ 1.80 1.23 ⫾ 1.85 ⫺0.99 ⫾ 1.27 0.0504
Placebo 1.47 ⫾ 2.71 2.48 ⫾ 5.92 0.80 ⫾ 3.02
FTM action tremor (limbs) Lyrica 5.73 ⫾ 2.41 3.70 ⫾ 3.43 ⫺2.40 ⫾ 2.22 0.0408
Placebo 4.00 ⫾ 2.24 3.38 ⫾ 2.26 ⫺1.38 ⫾ 1.06
FTM total Lyrica 43.18 ⫾ 22.04 28.67 ⫾ 27.69 ⫺14.89 ⫾ 16.25 0.2204
Placebo 35.91 ⫾ 20.50 32.63 ⫾ 20.59 ⫺7.38 ⫾ 12.65
FTM part A Lyrica 15.45 ⫾ 9.96 7.22 ⫾ 8.01 ⫺8.89 ⫾ 11.29 0.1420
Placebo 11.00 ⫾ 10.09 8.38 ⫾ 7.33 ⫺5.25 ⫾ 10.08
FTM part B Lyrica 17.64 ⫾ 8.61 13.56 ⫾ 13.21 ⫺3.78 ⫾ 9.62 0.5708
Placebo 15.18 ⫾ 9.34 14.88 ⫾ 9.19 ⫺1.63 ⫾ 6.96
FTM part C Lyrica 9.73 ⫾ 9.73 8.11 ⫾ 6.60 ⫺1.56 ⫾ 3.68 0.5994
Placebo 9.73 ⫾ 4.22 9.38 ⫾ 4.81 ⫺0.50 ⫾ 0.93

*Values shown are mean ⫾ SD.

be due to their binding to the auxiliary ␣2␦ subunit of
voltage-sensitive Ca 2⫹ channels (VSCC), which may
modulate neurotransmission,14 rather than to GABAer-
gical effects. Whether VSCC modulate neurotransmis-
sion related to ET is unclear. One study performed in-
tracellular recordings in guinea-pig brainstem slices and
found that high molecular weight alcohols, which have
been used to treat ET, block at least low threshold
calcium channels (LTCC) in the inferior olive.15
Additional basic and clinical research is needed to
address the efficacy and pathophysiology of PGB as a
potential treatment for ET. Future research should focus
on the long-term effects of PGB on ET.
LEGENDS TO VIDEO
Segment 1. It shows a 59-year-old woman with es-
sential tremor before treatment with PGB.
Segment 2. It shows the patient’s tremor treated with
PGB 300 mg/day. In the study, accelerometry scores
significantly improved, as did action rating scale scores
on the Fahn–Tolosa–Marin rating scale.
REFERENCES
1. Koller WC, Vetere-Overfield B. Acute and chronic effects of
propranolol and primidone in essential tremor. Neurology 1989;
39:1587-1588.
2. French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA.
Dose-response trial of pregabalin adjunctive therapy in patients
with partial seizures. Neurology 2003;60:1631-1637.
3. Zesiewicz TA, Ward CL, Hauser RA, Pease Campbell JA, Sullivan
KL. Pregabalin (Lyrica) in the treatment of essential tremor. Mov
Disord 2007;22:139-141.
4. Findley LJ, Koller WC. Definitions and behavioral classifications.
In: Findley JL, Koller WC, editors. Handbook of tremor disorders.
New York: Marcel Dekker; 1995. p 1–5.
5. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a prac-
tical method for grading the state of patients for the clinician.
J Psychiatr Res 1975;12:189-198.
6. Fahn SE, Tolosa E, Marin C. Clinical rating scale for tremor. In:
Jankovic J, Tolosa E, editors. Parkinson’s disease and movement
disorders, 2nd ed. Baltimore, MD: Williams & Wilkins;1988. p
225–234.
7. Guy W. ECDEU assessment manual for psychopharmacology—
revised. US Department of Health, Education, and Welfare, Public
Health Service, Alcohol, Drug Abuse, and Mental Health Admin-
istration, NIMH Psychopharmacology Research Branch, Division
of Extramural Research Programs, Rockville, MD; 1976. p 218 –
222. DHEW Publ No ADM 76-338.
8. Jensen MP, Karoly P. Self-report scales and procedures for assess-
ing pain in adults. In: Turk DC, Melzack R, editors. Handbook of
pain assessment. New York: Guilford Press; 1992.
9. Despres C, Lamoureux D, Beuter A. Standardization of a neuro-
motor test battery: the CATSYS system Neurotoxicology 2000;21:
725-735.
10. Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety
of pramipexole in restless legs syndrome. Neurology 2006;67:
1034-1039.
11. Kralic JE, Criswell HE, Osterman JL, et al. Genetic essential
tremor in gamma-aminobutyric acidA receptor alpha1 subunit
knockout mice. J Clin Invest 2005;115:774-779.
12. Mally J, Baranyi M, Vizi ES. Change in the concentrations of
amino acids in CSF and serum of patients with essential tremor.
J Neural Transm Gen 1996;103:555-560.
13. Pahapill PA, Levy R, Dostrovsky JO. Tremor arrest with thalamic
microinjections of muscimol in patients with essential tremor. Ann
Neurol 1999;46:249-252.
14. Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca(2⫹) channel
alpha(2)delta ligands: novel modulators of neurotransmission.
Trends Pharmacol Sci 2007;28:75-82.
15. Sinton CM, Krosser BI, Walton KD, Llinas RR. The effectiveness
of different isomers of octanol as blockers of harmaline-induced
tremor. Pflugers Arch 1989;414:31-36.

Movement Disorders, Vol. 22, No. 11, 2007