PRAMIPEXOLE MAY BE AN EFFECTIVE TREATMENT OPTION IN
Mihály Herceg1, MD; Ferenc Nagy1, MD, PhD; Endre Pál2;, MD, PhD
József Janszky2, MD, DSc, Ildikó Késmárki3, MD; Sámuel Komoly2 , MD, DSc;
Norbert Kovács2*, MD, PhD
1Department of Neurology, Kaposi Mór County Hospital, Kaposvár, Hungary
2Department of Neurology, University of Pécs, Pécs, Hungary
3Department of Neurology, Health Center of City of Pécs, Pécs, Hungary
Dr. Norbert Kovacs
University of Pécs
Department of Neurology
H-7623, Pécs, Rét utca 2,
Tel: +36 70 2221178
Fax: +36 72 535911
Word count for text: 1250
Running title: Pramipexole for essential tremor
Keywords: essential tremor; pramipexole; dopamine agonist; pilot study
Study Funding: Bolyai Scholarship of Hungarian Academy of Sciences (NK and JJ)
Abbreviations: ADL =Activities of Daily Living (Schwab and England Scale), CGI-I = Clinical
Global Impression of Improvement Scale; EQ-5D = The EuroQol instrument for detecting health
outcome; EQ-VAS = visual analogue scale included in EQ-5D; ER= extended release
formulation; FTMTRS = Fahn-Tolosa-Marin Tremor Rating Scale; IR= immediate release
formulation, PD = Parkinson’s disease
This is a preprint form of the article published in Clin Neuropharmacol. 2012 Mar-Apr;35(2):73-6.
doi: 10.1097/WNF.0b013e31824687bf. Link:
Objectives: To perform a pilot study assessing possible efficacy, safety and optimal
dosage of pramipexole in essential tremor.
Methods: Twenty-nine patients with essential tremor were enrolled into this 16 weeks
long study. After recording baseline condition, two different dosages of immediate-release
formulation of pramipexole were evaluated (1.05mg/die and 2.1mg/die in three identical
dosages). Subsequently, immediate- and extended-release (ER) formulations were compared.
Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), Activities of Daily Living, the EuroQol
instrument for detecting health-related outcome (EQ-5D) and Clinical Global Impression of
Improvement Scale (CGI-I) were obtained. After completing the study, a rater blinded to the
treatment reassessed the tremor rating scales based on video recordings.
Results: Twenty-four patients completed the study (82.6%). Causes for discontinuation
were pramipexole side-effects: intolerable nausea (n=3), daytime sleepiness (n=1) and anxiety
(n=1). Twenty-one patients had a score<3 on CGI-I (treatment responders, 72.4%). All the major
outcome values demonstrated significant improvement. The severity of tremor was reduced by
52.0% (43.7 vs. 20.8 points, FTMTRS) and the EQ-5D improved from 0.69 to 0.91 (p<0.01). The
dose of 2.1mg was more effective than that of 1.05mg; however, both the immediate- and
extended-release formulations were equally efficacious. After completion of the study 15 patients
wanted to remain on pramipexole treatment (51.7% of enrolled patients).
Conclusions: This pilot study suggests that pramipexole may be effective in the
treatment of essential tremor. However, further controlled studies are required.
Essential tremor (ET) is one of the most common movement disorders with the
prevalence of 3-5% among the elderly population1. Although its main clinical feature is the
bilateral, predominantly postural-kinetic tremor, newer studies suggest that ET is a spectrum of
clinical features with both motor and nonmotor elements not homogeneously distributed2, 3.
Despite its high occurrence, the pharmacological treatment of ET is limited. Although the
mainline drugs, propranolol and primidone, can provide good clinical benefit in a portion of
cases, >50% of the patients stop the medication due to inefficacy or side-effects4. Hypotension,
dizziness, bradycardia, cognitive impairment, fatigue and erectile dysfunction are the most
common side-effects contributing to medication discontinuation. Although several studies tried to
introduce new drugs for treating ET, only a few of them achieved this goal: Out of the many
evaluated agents, only topiramate5 and zonisamide6 seem to be effective. Other trials showed
either inefficacy (e.g. levetiracetam7-9, pregabalin10) or inconsistent results (e.g. gabapentine)11,
Our aim was to perform an open-label pilot study for evaluating the effectiveness of
pramipexole for ET and finding the optimal dosage and format (e.g. extended release, ER vs.
immediate release, IR) for further controlled trials. Pramipexole, a non-ergot derived dopamine
agonist, is proven to be capable of efficiently controlling tremor in Parkinson’s disease (PD)13, 14.
Previously, we identified some ET patients who were initially considered as tremor dominant PD
patients by non-movement disorder specialists and successfully treated by pramipexole
monotherapy. This experience served as a priori reason to suggest that pramipexole could work
in the treatment of ET and conduct this pilot-study.
Twenty-nine patients (age: 41.2±12.5 years, 14 male, disease duration: 12.1±7.2 years)
with “classical” ET were enrolled15 with the following inclusion criteria:
Diagnosis of ET assessed by movement disorders specialists (NK, FN) had to be
unambiguous based on the clinical diagnostic criteria15.
Tremor had to be severe enough to produce disability.
Patients had to sign a written informed consent according with the approval of the
Regional Ethical Board of University of Pécs (3677 and 3892/2010).
The exclusion criteria were established in accordance to the guidelines of Elble et al16.:
Presence of any medical conditions capable of producing tremor (e.g.
hyperthyroidism, drug withdrawal, neuropathy, etc.).
Except for cogwheel phenomenon, the presence of any abnormal neurological
signs (e.g. dystonia, myoclonus, ataxia, parkinsonism, cerebellar or pyramidal
Atypical tremor appearance for ET (e.g. isolated vocal-cord tremor, orthostatic
tremor, task-specific tremor, etc.)
Presence or suspicion of psychogenic tremor
Usage of medication capable of producing tremor (e.g. sympathomimetics,
Concomitant administration of any drugs potentially capable of improving ET (e.g.
antiepileptics, beta-receptor blockers).
Previous neurosurgical treatment (e.g. deep brain stimulation or thalamotomy).
Presence of serious concomitant disorders capable of interfering with the study
(e.g. heart failure, tumorous disorders, etc.)
Presence of any contraindication for pramipexole treatment (e.g. impulsive control
disorder, known hypersensitivity to any components of the tablets, etc.).
During the enrollment, we emphasized the importance of establishing the diagnosis of
essential tremor. Therefore, each patient was examined by movement disorders specialists to
exclude any other etiologies or the coincidence of ET and PD. Out of the enrolled patients, 20
have never received any pharmacological treatment for ET. In the cases of remaining 9 patients,
either propranolol (n=4, up to 120mg/die) or primidone monotherapy (n=7 up to 750mg/die) or
their combination (n=3) was applied without satisfactory outcome. Before enrolling them to the
study, 4 weeks of wash-out period was required. Seventeen patients had positive response to
alcohol intake; whereas, only 10 patients had a positive family history for ET.
The dose of pramipexole was slowly titrated up 2.1 mg daily maximum whereas all the
other medication remained unchanged. The dosage of pramipexole is given in pramipexole-base
throughout this manuscript in accordance with the European labeling (0.7mg pramipexole-base
equals with 1mg pramipexole-salt).
Each patient underwent 5 visits: Baseline condition was recorded before initiation of
pramipexole treatment. Assuming the possibility of dose-dependent efficacy, two different
dosages were evaluated (1.05mg and 2.1mg/die, Visit 2 and 3, respectively). To examine
whether pramipexole treatment has sustained tremor control capability, the effects of 2.1mg
dosage were evaluated twice 4 weeks apart (Visit 3 and 4). Subsequently, we also compared
the effectiveness of immediate-release (IR) and extended-release (ER) formulations (Visit 4 and
5). Refer to Table 1 for detailed information about each visit.
Besides physical examination and structured interview about possible pramipexole side-
effects, each visit included the video-taped assessment of Fahn-Tolosa-Marin Tremor Rating
Scale (FTMTRS)17 and Activities of Daily Living Scale (Schwab and England Scale, ADL)18. After
completing the study, a rater blinded to the actual treatment reassessed the FTMTRS based on
the video recordings; each subscore and total score of FTMTRS data had been analyzed
separately17 and utilized for further calculations.
The standardized EuroQol instrument for detecting health-related outcome including 5
questions on different health domains (mobility, self-care, usual activities, pain/discomfort and
anxiety/depression) and a visual analogue scale about the quality of health (EQ-5D and EQ-
VAS, respectively) were also obtained at each visit19. Based on the responses, we computed a
single value for EQ-5D based on the Hungarian population norms20. This EQ-5D value had the
range of -0.590 to 1.000 meaning the worst and the best possible health-related state19.
At control visits (Visit 2-4), Clinical Global Impression of Improvement Scale (CGI-I) was
also obtained and the size of improvement on FTMTRS compared to baseline was calculated in
percentage. (Table 1)
Treatment responsiveness was defined as a score <3 points on CGI-I representing either
“very much improvement” or “much improvement”. Taken from established utilities from a broad
range of chronic conditions, a minimally important improvement in EQ-5D was defined as an
absolute increase of 0.07420.
Repeated measures ANOVA and paired t-tests were applied by using PASW Software
(SPSS Inc, version 18, Chicago, IL). The level of statistical significance was set at 0.05.
Twenty-four patients completed the study (82.6% of enrolled patients). Causes for
discontinuation were the well-known pramipexole side-effects: intolerable nausea (n=3), daytime
sleepiness interfering with work (n=1), and anxiety (n=1).
Twenty-one patients had a score <3 on CGI-I at the end of the study, they were
considered as treatment responders (72.4% of patients intended-to-treat and 87.5% of patients
completed the study).
All the major outcome values (FTMTRS sub- and total scores, EQ-5D, EQ-VAS and
ADL) demonstrated significant improvement. (Table 2). The total score of FTMTRS was
improved by 52.0% by the end of study (43.7 vs. 20.8 points). The increase in EQ-5D was 0.22,
which largely exceeded the size of minimal clinically important difference (0.074)20.
Simultaneously the EQ-VAS and the ADL scores also improved from 65.3 and 72.1 to 89.6 and
90.3, respectively. Neither positive family history nor alcohol-responsiveness was associated
with better responsiveness to pramipexole; however, the sample size was too small to establish
Between Visit 2 and 3, there were significant changes in both EQ-5D and FTMTRS
scores (part A and total score of FTMTRS). Therefore, pramipexole seemed to improve ET in a
dose dependent manner: The dose of 2.1mg IR pramipexole achieved better tremor control and
health-related quality of life than that of 1.05mg. However, the comparison of IR and ER
pramipexole formulation at the daily dose of 2.1 mg revealed no difference suggesting equal
After the completion of the study 15 patients wanted to remain on pramipexole treatment
(51.7% of enrolled patients): Eleven of them requested the ER formulation, whereas, the
remaining 4 preferred the IR form of pramipexole.
To our knowledge, this study is the first pilot trial about the efficacy of pramipexole in the
treatment of ET. Based on our results, pramipexole was highly effective in both controlling the
tremor and improving the health-related quality of life. About 72% of the patients intended to
treat reported either “very much improvement” or “much improvement” on CGI-I; they were
considered as the treatment responders. The severity of tremor measured by FTMTRS
decreased from 43.7 points to 20.8 points representing an approximately 52% improvement. The
size of minimally important difference for FTMTRS has not been determined yet; therefore, we
also applied that of EQ-5D to evaluate clinical outcome. Because EQ-5D is proven to be a
sensitive and validated tool for detecting health-related quality of life in various movement
disorders21-23 and the size of improvement in EQ-5D exceeded the level of the clinically
important minimal change (0.22 vs.0.074,respectively) several times, we consider the outcome
of our pilot study as highly effective.
The tremor control of pramipexole at 2.1mg daily dosage was superior to that of at
1.05mg dose (48.6% vs. 22.8%, Visit 4 vs. Visit 2, p<0.01). This dose-dependent efficacy is well-
known in PD where the higher dosage is associated with better symptomatic effect on motor
symptoms including tremor.
The ER formulation of pramipexole has been recently introduced into Hungary with the
convenience of taking a single tablet each day. Based on the comparative studies in PD, the ER
formulation demonstrated non-inferiority to IR formulation. Similarly, we also performed a direct
comparison (visit 4 and 5) in ET. Based on the achieved tremor control and improvement in
health-related quality of life, both IR and ER formulations were equally efficacious (48.6% vs.
52.0%, Visit 4 vs. Visit5, p>0.05). It is further confirmed by the fact, that majority of patients
requesting to continue pramipexole medication after completing the study preferred the ER
formulation (11 out of 15 patients, 73%).
The possible pathomechanism of pramipexole in the treatment of ET needs to be
clarified by further studies. Although recent postmortem studies have found limited Lewy body
pathology in some ET patients24, 25 and the existence of a relationship between ET and PS is
also presumed by controversial observations26, 27, these data are still insufficient to declare any
dopaminergic deficiency in the background of ET. Therefore, other mechanisms besides
stimulating certain dopamine receptors may also explain the efficaciousness of pramipexole.
The authors are also aware of the major limitation of the present pilot study: the lack of
control. Because there was no published a priori evidence about the possible efficacy of
pramipexole, we were able to obtain ethical approval for only an open-label study. Based on the
promising results of this pilot study; however, further randomized and controlled studies can be
We would like to thank Katalin Takács, our Parkinson nurse, for helping manage the patients
enrolled into study. NN and JJ were supported by the government-based Bolyai Scholarship of
Hungarian Academy of Sciences.
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1. Research project: A. Conception.
2. Statistical Analysis: A. Design.
MH 1BC. 2C. 3B1
FN 1C. 2C. 3B
EP 1C. 2C. 3B
JJ 1A. 2C. 3B
IK 1C. 2C. 3B
SK 1C. 2C. 3B
NK 1. 2. 3 All statistical analyses had been carried by NK.
B. Review and Critique
C. Review and Critique;
A. Writing of the first draft.
MH reported no financial disclosure.
FN received <1000 EUR consultation fees from Hungarian subsidiaries of Novartis and
GlaxoSmithKline. Regarding this pilot study the author did not receive any corporate funding.
EP received <1000 EUR consultation fees from Hungarian subsidiaries of Novartis.
GlaxoSmithKline and Pfizer.
JJ received <1000 EUR consultation fees from Hungarian subsidiaries of UCB and Eisai.
Regarding this pilot study the author did not receive any corporate funding. JJ is supported by
the government-based Bolyai Scholarship of Hungarian Academy of Sciences.
IK received <1000 EUR consultation fees from Hungarian subsidiaries of Boehringer Ingelheim
and GlaxoSmithKline. Regarding this pilot study the author did not receive any corporate
SK received <1000 EUR consultation fees Bayer Schering Pharma AG. Boehringer Ingelheim.
Novartis AG. Richter Gedeon Rt. Hungary. Teva Pharmaceutical Industries Ltd. Regarding this
pilot study the author did not receive any corporate funding.
NK received <1000 EUR consultation fees from Hungarian subsidiaries of Medtronic. Boehringer
Ingelheim. Novartis. GlaxoSmithKline. UCB. Regarding this pilot study the author did not receive
any corporate funding. NK is supported by the government-based Bolyai Scholarship of
Hungarian Academy of Sciences.
Table 1. Detailed summary about the timing of visits and the applied formulation and
dosage of pramipexole.
Pramipexole dosage Applied tests
1 0 IR Baseline, 0 mg ADL, EQ-5D, EQ-VAS, FTMTRS, PE, SI, video
2 5-6 IR 1.05 mg (0.35 mg t.i.d) ADL, CGI-I, EQ-5D, EQ-VAS, FTMTRS, PE, SI, video
3 8-9 IR 2.1 mg (0.7 mg t.i.d) ADL, CGI-I, EQ-5D, EQ-VAS, FTMTRS, PE, SI, video
4 12-13 IR 2.1 mg (0.7 mg t.i.d) ADL, CGI-I, EQ-5D, EQ-VAS, FTMTRS, PE, SI, video
5 16-17 ER Once-daily 2.1 mg ADL, CGI-I, EQ-5D, EQ-VAS, FTMTRS, PE, SI, video
Timing is given in weeks after pramipexole initiation. Dosage of pramipexole is given in
pramipexole-base in accordance with the European labeling (1mg pramipexole-salt = 0.7mg
Abbreviations: ADL =Activities of Daily Living (Schwab and England Scale), CGI-I =
Clinical Global Impression of Improvement Scale; EQ-5D = The EuroQol instrument for
detecting health outcome; EQ-VAS = visual analogue scale included in EQ-5D; ER= extended
release formulation; FTMTRS = Fahn-Tolosa-Marin Tremor Rating Scale; IR= immediate release
formulation, PE = Physical examination; SI = structured interview also including any side-effects
associated with pramipexole treatment (e.g. any domains about impulsive control disorder,
extensive daytime sleepiness) and any improvement in ET
Table 2. The results of obtained tests and the statistical analyses. Download full-text
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
FTM-A 18.50 ± 9.12 13.00 ± 6.85 8.48 ± 5.75 8.00 ± 4.17 6.60 ± 3.69 p<0.01 p<0.05 NS NS
FTM-B 16.50 ± 9.39 14.08 ± 9.92 12.00 ± 10.02 10.60 ± 8.45 10.10 ± 8.670 p<0.05 NS NS NS
FTM-C 8.71 ± 5.38 6.38 ± 4.73 5.14 ± 4.84 4.52 ± 4.08 4.05 ± 3.41 p<0.05 NS NS NS
FTM total score 43.71 ± 21.80 33.46 ± 20.04 25.62 ± 19.36 23.12 ± 15.72 20.75 ± 14.01 p<0.01 NS NS NS
NA 23.69 ± 35.32 53.50 ± 27.84 53.59 ± 23.48 65.23 ± 17.55 p<0.01 p<0.01 NS NS
NA 15.80 ± 23.31 28.29 ± 22.65 38.32 ± 27.23 33.80 ± 25.21 p<0.01 NS NS NS
NA 25.47 ± 24.96 47.65 ± 28.34 54.21 ± 26.96 59.45 ± 21.54 p<0.01 p<0.01 NS NS
Improvement in total
score of FTM
NA 22.83 ± 20.63 41.62 ± 20.15 48.60 ± 18.84 51.98 ± 12.79 p<0.01 p<0.01 NS NS
EQ-5D 0.69 ± 0.30 0.71 ± 0.26 0.90 ± 0.17 0.88 ± 0.15 0.91 ± 0.08 p<0.01 p<0.01 NS NS
EQ_VAS 65.38 ± 13.75 77.92 ± 10.93 83.19 ± 10.14 89.20 ± 6.40 89.55 ± 5.61 p<0.01 NS NS NS
ADL 72.08 ± 13.51 80.83 ± 10.39 84.05 ± 10.20 90.60 ± 5.46 90.25 ± 4.13 p<0.01 NS NS NS
Abbreviations: ADL =Activities of Daily Living (Schwab and England Scale). EQ-5D = The EuroQol instrument for detecting health outcome; EQ-
VAS = visual analogue scale included in EQ-5D; ER= extended release formulation; FTMTRS = Fahn-Tolosa-Marin Tremor Rating Scale; IR=
immediate release formulation. NA= not applicable; NS = non-significant; PE = Physical examination; SI = structured interview also including any
side-effects associated with pramipexole treatment (e.g. any domains about impulsive control disorder. extensive daytime sleepiness) and any
improvement in ET