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BMJ Clin Evid. 2007; 2007: 1206.
Published online 2007 May 1.
PMCID: PMC2943813

Essential tremor

Dr Joaquim Jos Ferreira, Neurologist# and Cristina Sampaio, Assistant Professor of Clinical Pharmacology and Therapeutics, Assistant Professor#

Abstract

Introduction

Essential tremor is one of the most common movement disorders throughout the world, with prevalence in the general population of 0.4% to 3.9%. Although most people with essential tremor are only mildly affected, those who seek medical care are disabled to some extent, and most are socially handicapped by the tremor.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug treatments in people with essential tremor of the hand? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: adding mirtazepine to other antitremor drugs; benzodiazepines; beta-blockers other than propranolol; botulinum A toxin-haemagglutinin complex; calcium channel blockers; carbonic anhydrase inhibitors; clonidine; flunarizine; gabapentin; isoniazid; Phenobarbital; primidone; propranolol; and topiramate.

Key Points

Essential tremor refers to a persistent bilateral oscillation of both hands and forearms, or an isolated tremor of the head, without abnormal posturing, and when there is no evidence that the tremor arises from another identifiable cause.

  • Essential tremor is one of the most common movement disorders throughout the world, with a prevalence of 0.4% to 3.9% in the general population.
  • Although most people with essential tremor are only mildly affected, those who seek medical care are disabled to some extent, and most are socially handicapped by the tremor.

Overall, we found few RCTs assessing the long-term effects of drug treatments for essential tremor of the hand.

Propranolol seems to effectively improve clinical scores, tremor amplitude, and self-evaluation of severity compared with placebo in people with hand tremor.

  • We didn't find sufficient evidence to judge the efficacy of other beta-blockers such as atenolol, metoprolol, nadolol, pindolol, and sotalol in treating essential tremor of the hand.

Barbiturates such a phenobarbital (phenobarbitone) and primidone may improve hand tremor in the short term, but are associated with depression, and with cognitive and behavioural adverse effects.

Benzodiazepines may improve hand tremor and function in the short term, but we were unable to draw reliable conclusions because of the weakness of the studies.

  • Benzodiazepines are also associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects.

We don't know whether carbonic anhydrase inhibitors, dihydropyridene calcium channel blockers, flunarizine, clonidine, isoniazid, or gabapentin are useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Botulinum A toxin-haemagglutinin complex and topiramate both appear to improve clinical rating scales for hand tremor in the short term, but are associated with frequent adverse effects.

  • Botulinum A toxin-haemagglutinin complex is associated with hand weakness which is dose dependent and transient.
  • The most common adverse effects of topiramate are appetite suppression, weight loss, and paraesthesia.

Adding mirtazapine to antitremor drugs such as propranolol does not seem to improve outcomes further in people with essential tremor of the hand, and leads to more frequent adverse effects, such as drowsiness, confusion, dry mouth, and weight gain.

About this condition

Definition

Tremor is a rhythmic, mechanical oscillation of at least one body region. The term essential tremor is used when there is either a persistent bilateral tremor of hands and forearms, or an isolated tremor of the head, without abnormal posturing, and when there is no evidence that the tremor arises from another identifiable cause. The diagnosis is not made if there are: abnormal neurological signs; known causes of enhanced physiological tremor; a history or signs of psychogenic tremor; sudden change in severity; primary orthostatic tremor; isolated voice tremor; isolated position-specific or task-specific tremors; and isolated tongue, chin, or leg tremor.

Incidence/ Prevalence

Essential tremor is one of the most common movement disorders throughout the world, with a prevalence of 0.4% to 3.9% in the general population.

Aetiology/ Risk factors

Essential tremor is sometimes inherited with an autosomal dominant pattern. About 40% of people with essential tremor have no family history of the condition. Alcohol ingestion provides symptomatic benefit in 50% to 70% of people.

Prognosis

Essential tremor is a persistent and progressive condition. It usually begins during early adulthood and the severity of the tremor slowly increases. Only a small proportion of people with essential tremor seek medical advice, but the proportion in different surveys varies from 0.5% to 11%. Most people with essential tremor are only mildly affected. However, most of the people who seek medical care are disabled to some extent, and most are socially handicapped by the tremor. A quarter of people receiving medical care for the tremor change jobs or retire because of essential tremor-induced disability.

Aims of intervention

To reduce tremor; to minimise disability and social embarrassment; to improve quality of life, with minimal adverse effects from treatment.

Outcomes

Tremor severity measured by clinical rating scales or patient self-evaluation. Clinical rating scales are often composite scores that grade tremor amplitude in each body segment in specific postures or tasks. Few scales have been formally validated. In the more recent trials, the Fahn–Tolosa–Marin clinical evaluation scale, which addresses the impairment and the disability domains of tremor, has become the preferred scale. Accelerometer recordings are reported in many trials but they are proxy outcomes that have been included in this review only when clinical outcomes were not available.

Methods

Clinical Evidence search and appraisal December 2006. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2006, Embase 1980 to December 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 4, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded. We excluded single-dose studies and RCTs lasting under 1 week. We included small RCTs because of the paucity of evidence in this population. Most of the RCTs we identified used a crossover design. This design is useful in situations like tremor, believed to be relative constant along months despite the existence of fluctuations, because it allows an intrasubject comparison, which increases the power of the analysis. However this analysis can be confounded by factors such as carryover of the effect seen before the crossover to the post-crossover period or because the effect is dependent on the moment of administration, meaning that effects of an intervention may differ in the period before and after crossover. Since most of the studies do not assess results before crossover and do not explicitly address these confounders or the impact of withdrawals from the trial, it is very difficult to interpret the data provided completely. We also use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Essential tremor.

Glossary

Accelerometer recording
Recording of the movements from a body segment to allow measurement of frequency, amplitude, or intensity of a tremor. Intensity of tremor is a measure of the overall magnitude of movement; it often refers to the product of the amplitude of tremor multiplied by its frequency.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr Joaquim Jos Ferreira, Instituto de Farmacologia e Teraputica Geral Lisbon School of Medicine University of Lisbon, Lisbon, Portugal.

Cristina Sampaio, Instituto de Farmacologia e Teraputica Geral Lisbon School of Medicine University of Lisbon, Lisbon, Portugal.

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2007; 2007: 1206.
Published online 2007 May 1.

Propranolol

Summary

Propranolol seems to effectively improve clinical scores, tremor amplitude, and self-evaluation of severity compared with placebo in people with hand tremor.

We found no clinically important results about the effects of propranolol compared with other beta-blockers.

Benefits and harms

Propranolol versus placebo:

We found no systematic review, but we found 11 small, brief RCTs, many of which had a crossover design.

Tremor severity

Propranolol compared with placebo Propranolol for up to 1 month may improve clinical scores, tremor amplitude, and self-evaluation of severity at up to 6 weeks compared with placebo (very low-quality evidence)

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
24 people with ET (23 completed), clinical diagnosis Clinical score (0–4) x segments 2 weeks
22/23 (96%) with propranolol 60 to 240 mg
5/23 (22%) with placebo

P <0.001
Effect size not calculated

RCT
11 people with ET (10 completed), clinical diagnosis Clinical score 6 weeks' treatment
with propranolol up titrated every 3 days to 120 mg/day
with placebo
Absolute results not reported

P <0.003
Effect size not calculatedpropranolol

RCT
Crossover design
Nine people with ET (7 completed), clinical diagnosis Clinical score
with propranolol 30 mg three times/day
with placebo
Absolute results not reported

P <0.01
Effect size not calculated

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Clinical score
with propranolol 120 and 240 mg/day
with placebo
Absolute results reported graphically

P <0.05 (propranolol 120 mg/day v placebo)
Effect size not calculatedpropranolol 120 mg/day

RCT
Crossover design
5-armed trial
23 people with ET (15 completed), clinical diagnosis Clinical score (0–5 each side, maximum 10)
with propranolol 80 mg three times/day
with propranolol LA 160 mg/day
with propranolol LA 240 mg/day
with propranolol LA 320 mg/day
with placebo
Absolute results reported graphically

P <0.05 (all doses of propranolol except 160 mg v placebo)
Effect size not calculatedpropranolol (80 mg 3 times/day or LA 240 mg/day or LA 320 mg/day)

RCT
Crossover design
5-armed trial
23 people with ET (15 completed), clinical diagnosis Self-rating (0–5)
with propranolol 80 mg three times/day
with propranolol LA 160 mg/day
with propranolol LA 240 mg/day
with propranolol LA 320 mg/day
with placebo
Absolute results reported graphically

P <0.05 (all doses of propranolol v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean clinical score (0–25)
6.6 with propranolol 60–160 mg
10.7 with placebo

P <0.01(propranolol v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
17 people with ET (12 completed), clinical diagnosis Clinical score (0–10): mean change from baseline
–2.58 with propranolol 1.7 ± 0.1 mg/kg
–1.08 with placebo

P <0.01 (propranolol v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Tremor Clinical Rating Scale score ( P1 + P2, 0–78)
with propranolol 40 mg three times/day
with placebo

Mean difference (propranolol v placebo): –4.95, P <0.01
Effect size not calculatedpropranolol
Accelerometry

RCT
Crossover design
24 people with ET (23 completed), clinical diagnosis Accelerometry (frequency) 2 weeks
with propranolol 60 to 240 mg
with placebo

Reported as unchanged

RCT
Crossover design
24 people with ET (23 completed), clinical diagnosis Accelerometry (amplitude) 2 weeks
with propranolol 60–240 mg
with placebo

P <0.001
Effect size not calculatedpropranolol

RCT
Crossover design
Nine people with ET (7 completed), clinical diagnosis Accelerometry
with propranolol 30 mg three times/day
with placebo

P <0.01
Effect size not calculatedpropranolol

RCT
Crossover design
16 people with ET (16 completed), clinical diagnosis Accelerometry (frequency)
with propranolol 120 and 240 mg/day
with placebo
Absolute results reported graphically

P <0.05
Effect size not calculatedpropranolol

RCT
Crossover design
16 people with ET (16 completed), clinical diagnosis Accelerometry (amplitude)
with propranolol 120 and 240 mg/day
with placebo
Absolute results reported graphically

P <0.01
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Accelerometry (amplitude)
with propranolol 120 mg/day
with placebo
Absolute results reported graphically

P reported as not significant (propranolol 120 mg/day v placebo)
Not significant

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Accelerometry (amplitude)
with propranolol 240 mg/day
with placebo
Absolute results reported graphically

P <0.02 (propranolol 240 mg/day v placebo)
Effect size not calculatedpropranolol 240 mg/day

RCT
Crossover design
5-armed trial
23 people with ET (15 completed), clinical diagnosis Accelerometry (magnitude)
with propranolol 80 mg three times/day
with propranolol LA 160 mg/day
with propranolol LA 240 mg/day
with propranolol LA 320 mg/day
with placebo
Absolute results reported graphically

P <0.02 (propranolol 240 mg/day v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
17 people with ET (12 completed), clinical diagnosis Accelerometry (frequency: mean change from baseline)
–0.20 with propranolol 1.7 ± 0.1 mg/kg
+0.11 with placebo

P value reported as not significant
Not significant

RCT
Crossover design
3-armed trial
17 people with ET (12 completed), clinical diagnosis Accelerometry (amplitude: mean change from baseline)
–87.60 with propranolol 1.7 ± 0.1 mg/kg
–66.90 with placebo

P <0.01
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Accelerometry (tremor magnitude)
with propranolol 40 mg three times/day
with placebo

P = 0. 05
Borderline significance
Not significant

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Tremor frequency
with propranolol 40 mg three times/day
with placebo

Reported as not significant
P value not reported
Not significant

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (frequency)
9.1 with propranolol (120 mg/day for 5 to 7 days)
9.4 with placebo for 5 to 7 days

Reported as not significant
P value not reported
Not significant

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (maximum amplitude)
71 with propranolol (120 mg/day for 5 to 7 days)
128 with placebo for 5 to 7 days

P <0.05 (propranolol v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (reduction in tremor intensity; % decrease from baseline)
42.9 with propranolol 80 mg/day
4.9 with placebo

P <0.001 (propranolol v placebo)
Effect size not calculatedpropranolol
Self-rating

RCT
Crossover design
24 people with ET (23 completed), clinical diagnosis Self-rating 2 weeks
with

RCT
11 people with ET (10 completed), clinical diagnosis Self-rating 6 weeks' treatment
5/5 (100%) with propranolol up titrated every three days to 120 mg/day
1/5 (20%) with placebo

P value not reported

RCT
Crossover design
Nine people with ET (7 completed), clinical diagnosis Number of people improved over two assessments
12 with propranolol 30 mg three times/day
2 with placebo

P <0.05
Effect size not calculated

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Self-rating (0–5)
with propranolol 120 and 240 mg/day
with placebo
Absolute results reported graphically

P <0.01 (propranolol 120 mg/day or 240 mg/day v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean subjective tremor score (0–10)
4.4 with propranolol 60–160 mg
6.2 with placebo

P = 0.1 (propranolol v placebo)
Not significant

RCT
Crossover design
3-armed trial
17 people with ET (12 completed), clinical diagnosis Self-rating (0–10): mean change from baseline
–4.50 with propranolol 1.7 ± 0.1 mg/kg
–2.04 with placebo

P <0.01(propranolol v placebo)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Self-rating: subjective Disability Scale (25–100)
with propranolol 40 mg three times/day
with placebo

Mean difference in Subjective Disability Scale score (propranolol v placebo) –4.48
P = 0.11
Not significant
Performance tests

RCT
11 people with ET (10 completed), clinical diagnosis Performance tests: pegboard test 6 weeks' treatment
+2.9 with propranolol up titrated every three days to 120 mg/day
–2.1 with placebo

P = 0.06
Not significant

RCT
Crossover design
3-armed trial
16 people with ET (16 completed), clinical diagnosis Performance tests
with propranolol 120 and 240 mg/day
with placebo
Absolute results reported graphically

P <0.01 (propranolol 120 mg v placebo)
Effect size not calculatedpropranolol 120 mg

RCT
Crossover design
5-armed trial
23 people with ET (15 completed), clinical diagnosis Performance test scores
with propranolol 80 mg three times/day
with propranolol LA 160 mg/day
with propranolol LA 240 mg/day
with propranolol LA 320 mg/day
with placebo
Absolute results reported graphically

P <0.01 (propranolol and propranolol LA 320 mg v placebo)
Effect size not calculatedpropranolol (80 mg/day three times/day or LA 320 mg/day)

RCT
Crossover design
3-armed trial
17 people with ET (12 completed), clinical diagnosis Performance tests: mean change from baseline in pegboard test (number of seconds to complete)
–8.58 with propranolol 1.7 ± 0.1 mg/kg
–6.17 with placebo

P value reported as not significant
Not significant

Adverse effects

No data from the following reference on this outcome.

Propranolol versus other beta-blockers:

See benefits and harms of beta-blockers other than propranolol.

Adverse effects

No data from the following reference on this outcome.

Propranolol versus clonidine:

We found one parallel RCTcomparing propranolol 250 mg daily versus clonidine 0.45 mg daily for 1 year. The trial was designed to test equivalence between drugs.

Tremor severity

Propranolol compared with clonidine Propranolol may be as effective as clonidine in improving tremor scores from baseline throughout follow-up for 1 year (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
186 people, 151 people evaluated Mean scores on the Fahn–Tolosa–Marin Clinical evaluation scale for tremor (maximum score 144) 3 months
22.6 with propranolol
24.4 with clonidine

RCT
186 people, 151 people evaluated Mean scores on the Fahn–Tolosa–Marin Clinical evaluation scale for tremor (maximum score 144) 1 year
19.4 with propranolol
29.3 with clonidine

P = 0.4
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
186 people, 151 people evaluated Withdrawal from study
with propranolol
with clonidine

RCT
186 people, 151 people evaluated Proportion of people who had hypotension
58% with propranolol
15% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculatedclonidine

RCT
186 people, 151 people evaluated Proportion of people who had depression
37% with propranolol
9% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculatedclonidine

RCT
186 people, 151 people evaluated Proportion of people who had body coldness
43% with propranolol
13% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculated clonidine

RCT
186 people, 151 people evaluated Proportion of people who had dry mouth
27% with propranolol
74% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculatedpropranolol

RCT
186 people, 151 people evaluated Proportion of people who had sleepiness
34% with propranolol
56% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculatedpropranolol

RCT
186 people, 151 people evaluated Proportion of people who had dizziness
28% with propranolol
50% with clonidine
Absolute numbers not reported

P <0.05
Effect size not calculatedpropranolol

Further information on studies

Both treatments significantly reduced tremor from baseline at 3 months and 1 year (at 3 months: P = 0.0004 for propranolol v baseline, P = 0.04 for clonidine v baseline; at 1 year: P = 0.001 for propranolol v baseline, P = 0.002 for clonidine v baseline).

It is worth noting that the population in the RCT was non-white people with mostly mild to moderate essential tremor at baseline.

Withdrawals (mainly because of fatigue and bradycardia) were uncommon (e.g., 1/10 [10%] people in this RCT).

Depression, diarrhoea, breathlessness, sedation, blurred vision, and sexual problems were each reported in less than 5% of people taking propranolol.

Comment

We found no placebo controlled RCTs addressing long-term outcomes. All trials were analysed as “on treatment” rather than by intention to treat, and this may have biased results. Accelerometry is a proxy outcome that was reported in several RCTs. All accelerometry results were in favour of propranolol, but there is an inconsistent relationship between accelerometry and clinical measures of effectiveness. People with congestive heart failure, second degree heart block, asthma, severe allergy, and insulin dependent diabetes were generally excluded from the RCTs. All but one of the studies were small. The possibility of publication bias has not been excluded. The RCT comparing propranolol versus clonidine for 1 year is the only source of double-blind data about long-term outcomes of propranolol. This is a well-designed trial, but the absence of the placebo arm is problematic, because propranolol has never been studied under double-blind conditions for more than 6 weeks.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Botulinum A toxin–haemagglutinin complex

Summary

Botulinum A toxin-haemagglutinin complex appears to improve clinical rating scales for hand tremor in the short term, but are associated with frequent adverse effects.

Hand weakness, which is dose-dependent and transient, is a frequent adverse effect.

We found no direct information about long-term outcomes from botulinum A toxin-haemagglutinin complex in people with essential tremor.

Benefits and harms

Botulinum versus placebo:

We found no systematic review. We found two parallel RCTs.

Tremor severity

Botulinum compared with placebo Botulinum A toxin–haemagglutinin complex may improve clinical rating scales at 4 to 12 weeks in people with essential hand tremor compared with placebo, but may not improve motor tasks or functional disability (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
25 people with essential hand tremor unresponsive to “optimal medical therapy” Clinical scores
with botulinum A toxin–haemagglutinin complex
with placebo

P <0.05
Effect size not calculatedbotulinum toxin

RCT
3-armed trial
133 people with essential tremor of the hand by the Tremor Investigation Group criteria Postural tremor on clinical rating scales 12 weeks
with single injections of low-dose botulinum A toxin–haemagglutinin complex (50 U)
with high-dose botulinum A toxin–haemagglutinin complex (100 U)
with placebo

P = 0.004 (low-dose botulinum toxin v placebo)
P = 0.0003 (high-dose botulinum toxin v placebo)
Effect size not calculatedbotulinum toxin
Accelerometry

RCT
25 people with essential hand tremor unresponsive to “optimal medical therapy” Accelerometer recordings
with botulinum A toxin–haemagglutinin complex
with placebo

Reported as not significant
P value not reported
Not significant
Self-rating/undefined improvement

RCT
25 people with essential hand tremor unresponsive to “optimal medical therapy” Proportion of people who responded to first injection
12/13 (92%) with botulinum A toxin–haemagglutinin complex
1/12 (8%) with placebo

P <0.001
Effect size not calculatedbotulinum A toxin–haemagglutinin complex

RCT
25 people with essential hand tremor unresponsive to “optimal medical therapy” Mild to moderate improvement 4 weeks
9/12 (75%) with botulinum A toxin–haemagglutinin complex
3/11 (27%) with placebo

P <0.04
Effect size not calculatedbotulinum toxin
Perfomance tests

RCT
25 people with essential hand tremor unresponsive to “optimal medical therapy” Functional tests
with botulinum A toxin–haemagglutinin complex
with placebo

Reported as not significant
P value not reported
Not significant

RCT
3-armed trial
133 people with essential tremor of the hand by the Tremor Investigation Group criteria Kinetic tremor, motor task performance, or functional disability 16 weeks
with single injections of low-dose botulinum A toxin–haemagglutinin complex (50 U)
with high-dose botulinum A toxin–haemagglutinin complex (100 U)
with placebo
Not significant

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The RCT stated that participants were unresponsive to “optimal medical therapy”, but did not state what this involved.

Comment

We found no RCTs addressing long-term outcomes. The main adverse effect of botulinum A toxin–haemagglutinin complex is dose dependent transient hand weakness.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Phenobarbital

Summary

Phenobarbital may improve hand tremor in the short term, but is associated with depression, and with cognitive and behavioural adverse effects.

Benefits and harms

Phenobarbital versus placebo:

We found three small, short-term, crossover RCTs.

Tremor severity

Phenobarbital compared with placebo The effect of phenobarbital (phenobarbitone) on tremor at 5 weeks is unclear compared with placebo (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
3-armed trial
17 people; 12/17 (70%) people completed the trial Clinical tremor scores 4 weeks
with phenobarbital (phenobarbitone; 1.25 mg/kg/day)
with placebo

No intention-to-treat analysis was performed
Not significant

RCT
Crossover design
3-armed trial
16 people Clinical score and self-evaluation of tremor 5 weeks
with phenobarbital
with placebo

Reported as not significant
CI not reported
Not significant
Acceleromtry

RCT
Crossover design
12 people Accelerometer recordings 5 weeks
with phenobarbital 120 mg daily
with placebo

P <0.01
Effect size not calculatedphenobarbital

RCT
Crossover design
12 people Proportion of people who responded (defined as decrease of 15% or more in tremor score measured by accelerometer)
11/11 (100%) with phenobarbital 120 mg daily
6/11 (55%) with placebo

Significance of the difference between groups not assessed
Self-rating

RCT
Crossover design
12 people Self-evaluation of tremor
with phenobarbital 120 mg daily
with placebo

No significant difference reported
Not significant

RCT
Crossover design
12 people Symptom rating scale 5 weeks
with phenobarbital 120 mg daily
with placebo

P <0.05
Effect size not calculatedphenobarbital
Performance tests

RCT
Crossover design
3-armed trial
17 people; 12/17 (70%) people completed the trial Functional test scores 4 weeks
with phenobarbital (phenobarbitone; 1.25 mg/kg/day)
with placebo

No intention-to-treat analysis performed
Not significant

RCT
Crossover design
12 people Handwriting tests
with phenobarbital 120 mg daily
with placebo

No significant difference reported
Not significant

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The RCTs were short term, small, and many randomised people did not complete the trials. The only RCT that addressed long-term outcomes of barbiturates was the trial that compared different doses of primidone. Equivalence trials are difficult to interpret in the absence of previous placebo controlled trials. Nevertheless, this was a well-designed trial, and the reported effect size is similar to the one seen in the RCT comparing propranolol versus clonidine. Both phenobarbital and primidone (metabolised to phenobarbital) are associated with depression and cognitive and behavioural effects (particularly in children, elderly people, and people with neuropsychiatric problems). See review on epilepsy.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Primidone

Summary

Primidone may improve hand tremor in the short term, but is associated with depression, and with cognitive and behavioural adverse effects.

Benefits and harms

Primidone versus placebo:

We found no systematic review. We found three small brief crossover RCTs.

Tremor severity

Primidone compared with placebo Primidone may improve tremor and functional ability over 4 to 10 weeks compared with placebo (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
3-armed trial
16 people Clinical score and self-evaluation of tremor 5 weeks
with primidone (up to 750 mg/day)
with placebo

P <0.05
Effect size not calculatedprimidone

RCT
Crossover design
22 people Clinical score (hand tremor) 10 weeks
with primidone (up to 750 mg/day)
with placebo

P <0.02
Effect size not calculatedprimidone
Self-rating

RCT
Crossover design
22 people Self-evaluation (hand tremor) 10 weeks
with primidone (up to 750 mg/day)
with placebo

P <0.01
Effect size not calculatedprimidone
Performance tests

RCT
Crossover design
4-armed trial
22 people Observer-rated score based on ability to write, feed, and function socially 4 weeks
5.2 with primidone (up to 750 mg/day, mean dose 402 mg)
7.8 with placebo

Significance of the difference between primidone and placebo not assessed

RCT
Crossover design
22 people Functional tests (hand tremor) 10 weeks
with primidone (up to 750 mg/day)
with placebo

P <0.01
Effect size not calculatedprimidone

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
22 people Adverse effects
with primidone (up to 750 mg/day)
with placebo

RCT
Crossover design
4-armed trial
22 people Adverse effects
with

Different doses of primidone:

We found one RCT that compared primidone 250 mg daily versus primidone 750 mg daily for 1 year.

Tremor severity

Different doses of primidone Different doses of primidone lead to similar improvements in tremor from baseline at 1 year (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
113 people, 87 completers Mean score on the Fahn–Tolosa–Marin clinical evaluation scale (maximum score 144) 1 year
19 with primidone 250 mg
26.3 with primidone 750 mg

P <0.06
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
113 people, 87 completers Adverse effects
with

Further information on studies

The trial was designed to test equivalence between doses.

Both doses significantly improved tremor from baseline (P <0.0001 for either dose v baseline).

Comment

The RCTs were short term, small, and many randomised people did not complete the trials. The only RCT that addressed long-term outcomes is the trial that compared different doses of primidone. Equivalence trials are difficult to interpret in the absence of previous placebo controlled trials. Nevertheless this was a well-designed trial and the reported effect size is similar to the one seen in the RCT comparing propranolol versus clonidine.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Topiramate

Summary

Topiramate appears to improve clinical rating scales for hand tremor in the short term, but is associated with frequent adverse effects. The most common adverse effects of topiramate are appetite suppression, weight loss, and paraesthesia.

Benefits and harms

Topiramate versus placebo:

We found three RCTs, one with parallel and two with crossover design.

Tremor severity

Topiramate compared with placebo Topiramate may improve observer-rated tremor score after 2 weeks, or after up to 24 weeks' treatment, compared with placebo (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Tremor score/improvement

RCT
223 people with moderate to severe essential tremor of the hands or forearms Mean reduction in tremor score 24 weeks
–10.8 with topiramate (400 mg/day or more; mean dose 292 mg/day)
–5.8 with placebo

P <0.001
Calculations adjusting for the use of other antitremor medication found that this did not impact the results
Effect size not calculatedtopiramate

RCT
Crossover design
24 people with tremor of hand, head, or voice Observer-rated tremor score improvement 6 weeks after crossover
0.88 with topiramate (400 mg/day or maximum tolerated dose; mean dose 333 mg/day)
0.15 with placebo

P = 0.015
Effect size not calculatedtopiramate

RCT
Crossover design
16 people with definitive or probable essential tremor involving the hand, head, or voice Proportion of people who improved 6 weeks
4/10 (40%) with topiramate (up titrated to 100 mg/day during 6 weeks)
0/10 (0%) with placebo

Reported as not significant
P value not reported
The RCT was underpowered to detect a clinically important difference between groups
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
223 people with moderate to severe essential tremor of the hands or forearms Proportion of people who withdrew because of adverse effects
32% with topiramate
10% with placebo

Significance not assessed

RCT
223 people with moderate to severe essential tremor of the hands or forearms Mean reduction in body weight
3.6 kg with topiramate
0.6 kg with placebo

P <0.001
Effect size not calculatedplacebo

RCT
Crossover design
24 people with tremor of hand, head, or voice Proportion of people who withdrew because of adverse effects
5/24 with topiramate
1/24 with placebo

No data from the following reference on this outcome.

Further information on studies

None.

Comment

We found no RCTs addressing long-term outcomes. For further information on general harms of topiramate see also review on epilepsy.

Substantive changes

Topiramate Two RCTs added; harms data enhanced. Recategorised from Likely to be beneficial to Trade-off between benefits and harms.

2007; 2007: 1206.
Published online 2007 May 1.

Benzodiazepines

Summary

Benzodiazepines may improve hand tremor and function in the short term, but we were unable to draw reliable conclusions because of the weakness of the studies.

Benzodiazepines are also associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects.

Benefits and harms

Alprazolam versus placebo:

We found no systematic review. We found two RCTs.

Tremor severity

Alprazolam compared with placebo Alprazolam may improve tremor and function at 2 to 4 weeks compared with placebo (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
24 people Clinical scores 2 weeks
with
Absolute results not reported

No direct comparison between groups, but assessed changes from baseline within each group

RCT
24 people Observer-rated global impression 2 weeks
with
with
Absolute results not reported

No direct comparison between groups, but assessed changes from baseline within each group
Self-rating

RCT
24 people Self-evaluation of tremor 2 weeks
with
Absolute results not reported

No direct comparison between groups, but assessed changes from baseline within each group
Performance tests

RCT
Crossover design
4-armed trial
22 people Observer-rated score based on ability to write, feed, and function socially 4 weeks
6.0 with alprazolam (up to 1.5 mg/day, mean dose 0.75 mg)
7.8 with placebo

P value not reported

RCT
24 people Functional tests 2 weeks
with
Absolute results not reported

No direct comparison between groups, but assessed changes from baseline within each group

Clonazepam versus placebo:

We found one RCT.

Tremor severity

clonazepam compared with placebo We don't know whether clonazepam is more effective (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Tremor outcomes

RCT
Crossover design
15 people Tremor outcomes
with clonazepam
with placebo
Absolute results reported graphically

Reported as not significant
Likely underpowered to detect a clinically important difference in outcomes
Not significant

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

We found no RCTs addressing long-term outcomes. Adverse effects with benzodiazepines, including dependency, sedation, and cognitive and behavioural effects, have been well described for other conditions (see review on panic disorder).

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Beta-blockers other than propranolol

Summary

We found no sufficient evidence to judge the efficacy of other beta-blockers such as atenolol, metoprolol, nadolol, pindolol, and sotalol in treating essential tremor of the hand.

Benefits and harms

Other beta-blockers (atenolol, metoprolol, nadolol, pindolol, and sotalol) versus placebo:

We found six small, brief crossover RCTs comparing different beta-blockers (atenolol, metoprolol, nadolol, pindolol, and sotalol) versus placebo.

Tremor severity

Other beta-blockers compared with placebo The effects of atenolol, metoprolol, nadolol, pindolol, or sotalol are unknown (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Clinical score
with metoprolol 150 and 300 mg/day
with placebo
Absolute results reported graphically

P value reported as not significant
Not significant

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean clinical score (0–25)
6.8 with sotalol 80 to 240 mg
8.1 with atenolol 50 to 100 mg
10.7 with placebo

P <0.01 (sotalol v placebo)
P <0.002 (atenolol v placebo)
Effect size not calculatedother beta-blockers (sotalol, or atenolol)

RCT
Crossover design
10 people with ET (10 completed), stratified for response to PRP: six responders, four non-responders, clinical diagnosis Clinical scores
with nadolol 120 to 240 mg/day
with placebo

Nadolol not directly compared with placebo; analysis of change in each group from baseline
Clinical scores improved in those that were responders to propranolol

RCT
Crossover design
4-armed trial
24 people with ET (24 completed), clinical diagnosis Clinical score: % improvement in objective clinical scores
4.5% with metoprolol 50 mg (17 people) or 100 mg (7 people)
0% with placebo (ascorbic acid 50 mg)

P value reported as not significant
Not significant

RCT
Crossover design
4-armed trial
24 people with ET (24 completed), clinical diagnosis Clinical score: % improvement in objective clinical scores
20% with sotalol 50 mg/day
0% with placebo (ascorbic acid 50 mg)

P <0.01 (sotalol v placebo)
Effect size not calculatedsotalol

RCT
Crossover design
4-armed trial
24 people with ET (24 completed), clinical diagnosis Clinical score: % improvement in objective clinical scores
16% with atenolol 50 mg/day
0% with placebo (ascorbic acid 50 mg)

P <0.01 (atenolol v placebo)
Effect size not calculatedatenolol
Accelerometry

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Accelerometry (amplitude)
with metoprolol 150 and 300 mg/day
with placebo
Absolute results reported graphically

P value reported as not significant
Not significant

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (frequency)
9.7 with pindolol 15 mg/day for 5 to 7 days
9.9 with placebo for 5 to 7 days

Reported as not significant
P value not reported
Not significant

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (maximum amplitude)
with
160 with pindolol 15 mg/day for 5 to 7 days
105 with placebo for 5 to 7 days

P <0.05 (pindolol v placebo)
Effect size not calculatedplacebo

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (reduction in tremor intensity; % decrease from baseline)
37.3 with atenolol 100 mg/day
4.9 with placebo

P <0.001 (pindolol v placebo)
Effect size not calculatedatenolol

RCT
Crossover design
10 people with ET (10 completed), stratified for response to PRP: 6 responders, 4 non-responders, clinical diagnosis Accelerometry (tremor frequency)
with nadolol 120–240 mg/day
with placebo

Nadolol not directly compared with placebo; analysis of change in each group from baseline
No significant change from baseline between nadolol at both doses and placebo in four people who had previously not responded to propranolol
Significant improvement from baseline in six people that were responders to propranolol
Self-rating

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Self-rating score (0–5)
with metoprolol 150 and 300 mg/day
with placebo
Absolute results reported graphically

P (metoprolol 150 or 300 mg/day v placebo) reported as not significant
Not significant

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean subjective tremor score (0–10)
4.2 with sotalol 80 to 240 mg
5.9 with atenolol 50 to 100 mg
6.2 with placebo

P <0.05 (sotalol v placebo)
P = 0.1 (atenolol v placebo)
Effect size not calculated

RCT
Crossover design
4-armed trial
24 people with ET (24 completed), clinical diagnosis Self-rating
with metoprolol 50 mg (17 people) or 100 mg (7 people)
with sotalol 50 mg/day
with atenolol 50 mg/day
with placebo (ascorbic acid 50 mg)
Absolute results reported graphically

P <0.01 (sotalol v placebo)
P <0.05 (atenolol or metoprolol v placebo)
Effect size not calculatedother beta-blockers (sotalol, atenolol, metoprolol)
Performance tests

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Performance tests
with metoprolol 150 and 300 mg/day
with placebo
Absolute results reported graphically

P value (metoprolol 150 or 300 mg/day v placebo) reported as not significant
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Adverse effects
with metoprolol 150 and 300 mg/day
with placebo

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Adverse effects
with

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Adverse effects
with

RCT
Crossover design
4-armed trial
24 people with ET (24 completed), clinical diagnosis Adverse effects
with

RCT
Crossover design
10 people with ET (10 completed), stratified for response to PRP: six responders, four non-responders, clinical diagnosis Adverse effects
with

No data from the following reference on this outcome.

Other beta-blockers versus propranolol:

We found no systematic review but found four small (16–24 people) and one large (175 people) crossover RCT.

Tremor severity

Compared with propranolol The effects of atenolol, metoprolol, nadolol, pindolol, or sotalol compared with propranolol are unknown (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Clinical score
with metoprolol 150 and 300 mg/day
with propranolol 120 and 240 mg/day
Absolute results reported graphically

P <0.05 (propranolol 120 mg v metoprolol 150 mg)
Effect size not calculatedpropranolol

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean clinical score (0–25)
6.8 with sotalol 80 to 240 mg
6.6 with propranolol 60 to 160 mg

P >0.1 (propranolol v sotalol)
Not significant

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean clinical score (0–25)
8.1 with atenolol 50 to 100 mg
6.6 with propranolol 60 to 160 mg

P <0.05 (propranolol v atenolol)
Effect size not calculatedpropranolol

RCT
Crossover design
23 people with essential tremor (20 completed), clinical diagnosis Proportion of people with clinical scores significantly improved from baseline
13/23 (56%) with metoprolol 50, 150, or 250 mg/day
10/20 (50%) with propranolol 120 and 240 mg/day

No direct comparison between propranolol and metoprolol
Accelerometry

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Accelerometry (tremor intensity; %decrease from baseline)
42.9 with propranolol 80 mg/day
37.3 with atenolol 100 mg/day

Reported as not significant
P value not reported
Not significant

RCT
Crossover design
23 people with essential tremor (20 completed), clinical diagnosis Accelerometry (tremor amplitude)
with metoprolol 50, 150, or 250 mg/day
with propranolol 120 and 240 mg/day

No direct comparison between propranolol and metoprolol
No significant improvement from baseline for propranolol or metoprolol; reported as not significant, no further data reported
For the subgroup of the clinical responders there was a difference for both treatments; P <0.05
Self-rating

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean subjective tremor score (0–10)
4.2 with sotalol 80 to 240 mg
4.4 with propranolol 60 to 160 mg

P = 0.1 (propranolol v sotalol)
Not significant

RCT
Crossover design
4-armed trial
Nine people with ET (9 completed), clinical diagnosis Mean subjective tremor score (0–10)
5.9 with atenolol 50 to 100 mg
4.4 with propranolol 60 to 160 mg

P <0.05 (propranolol v atenolol)
Effect size not calculatedpropranolol

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Proportion of people preferring each treatment
12/24 (50%) with propranolol 80 mg/day
1/24 (4%) with atenolol 100 mg/day

P value not reported

RCT
Crossover design
23 people with essential tremor (20 completed), clinical diagnosis Self-rating
with metoprolol 50, 150, or 250 mg/day
with propranolol 120 and 240 mg/day

No direct comparison between propranolol and metoprolol.

RCT
Crossover design
175 people with ET (145 completed), clinical diagnosis Self-reported disability scale score, dose-based comparison 8 to 14 weeks
9.78 with arotinolol 10 mg daily
10.12 with propranolol 40 mg daily
9.18 with arotinolol 20 mg daily
9.82 with propranolol 80 mg daily
8.90 with arotinolol 30 mg daily
9.38 with propranolol 80 mg daily

Reported as not significant
P values not reported
Not significant
Performance tests

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Performance tests
with metoprolol 150 and 300 mg/day
with propranolol 120 and 240 mg/day
Absolute results reported graphically

P <0.05 (propranolol 120 mg v metoprolol 150 mg)
P <0.05 (propranolol 240 mg v metoprolol 300 mg)
Effect size not calculatedpropranolol

RCT
Crossover design
175 people with ET (145 completed), clinical diagnosis; Motor task performance score 8 to 14 weeks
8.63 with arotinolol 10 mg daily
8.35 with propranolol 40 mg daily
7.93 with arotinolol 20 mg daily
9.82 with propranolol 80 mg daily
7.52 with arotinolol 30 mg daily
7.65 with propranolol 80 mg daily

Reported as not significant
P values not reported
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
5-armed trial
16 people with ET (16 completed), clinical diagnosis Adverse effects
with metopprolol 150 and 300 mg/day
with propranolol 120 and 240 mg/day

RCT
Crossover design
3-armed trial
24 people with ET (24 completed), clinical diagnosis Adverse effects
42.9 with propranolol 80 mg/day
37.3 with atenolol 100 mg/day

RCT
Crossover design
23 people with essential tremor (20 completed), clinical diagnosis Adverse effects
with metoprolol 50, 150, or 250 mg/day
with propranolol 120 and 240 mg/day

RCT
Crossover design
175 people with ET (145 completed), clinical diagnosis Proportion of people who had adverse effects during treatment
10/175 (6%) with arotinolol
13/175 (7%) with propranolol

P = 0.52
Not significant

No data from the following reference on this outcome.

Further information on studies

None.

Comment

People with congestive heart failure, second degree heart block, asthma, severe allergy, and insulin dependent diabetes were generally excluded from the RCTs. We found no RCTs addressing long-term outcomes.

Substantive changes

Beta-blockers other than propranolol One RCT added; evidence remains insufficient to assess effects of atenolol, metoprolol, nadolol, pindolol, and sotalol. Categorisation unchanged (Unknown effectiveness).

2007; 2007: 1206.
Published online 2007 May 1.

Calcium channel blockers (dihydropyridine)

Summary

We don't know whether dihydropyridene calcium channel blockers are useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Benefits and harms

Calcium channel blockers versus placebo:

We found no systematic review. We found one crossover RCT, which compared three interventions: nicardipine (1 mg/kg/day); propranolol 160 mg daily; and placebo, for 1 month.We found another crossover RCT, which did not directly compare nimodipine versus placebo, but compared changes from baseline within each group.

Tremor severity

Compared with placebo The dihydropyridine calcium channel blockers nicardipine and nimodipine may improve clinical scores compared with placebo (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
3-armed trial
14 people Symptom score 1 month
with nicardipine (1 mg/kg/day)
with placebo

CI not reported

RCT
Crossover design
15 people Clinical scores
with

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The possibility of publication bias has not been excluded. The evidence is too weak to assess the role of calcium channel blockers in essential hand tremor. We found no RCTs addressing long-term outcomes.

Nicardipine and nimodipine can provoke or aggravate heart failure. They are associated with dizziness, flushing, peripheral oedema, lethargy, headache, and fatigue. Adverse gastrointestinal effects (nausea/vomiting, loss of appetite, constipation, weight gain, thirst, indigestion, or altered taste) are reported by 1% to 3% of people. Abnormalities of laboratory tests (liver function tests) have been observed, usually within 1 to 8 weeks after starting treatment.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Carbonic anhydrase inhibitors

Summary

We don't know whether carbonic anhydrase inhibitors are useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Benefits and harms

Carbonic anhydrase inhibitors versus placebo:

We found one crossover RCT comparing methazolamide with placebo. We found another crossover RCT comparing four interventions: acetazolamide; alprazolam; primidone; and placebo.

Tremor severity

Carbonic anhydrase inhibitors compared with placebo The carbonic anhydrase inhibitors methazolamide or acetazolamide may improve clinical scores compared with placebo in people with essential tremor (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Tremor improvement

RCT
Crossover design
25 people, 18 people completed Proportion of people improved (assessed by clinical score, functional tasks, or self-evaluation)
7/18 (39%) with methazolamide (up to 300 mg/day)
4/18 (22%) with placebo

Reported as not significant
P value not reported.
Likely to have been underpowered to detect a clinically important difference between groups. The results were analysed on treatment rather than by intention to treat
Not significant

RCT
Crossover design
4-armed trial
22 people Observer-rated score based on ability to write, feed, and function socially 4 weeks
7.3 with acetazolamide (up to 750 mg/day, mean dose 562 mg)
7.8 with placebo

P = 0.81
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
4-armed trial
22 people Adverse effects
with

No data from the following reference on this outcome.

Further information on studies

None.

Comment

We found no RCTs addressing long-term outcomes.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Clonidine

Summary

We don't know whether clonidine is useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Benefits and harms

Clonidine versus placebo:

We found no systematic review. We found one crossover RCT comparing changes from baseline with clonidine (up to 0.6 mg/day) nad placebo.

Tremor severity

Clonidine compared with placebo Clonidine may not improve tremor amplitude compared with placebo (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Tremor amplitude

RCT
Crossover design
10 people Hand tremor amplitude
with clonidine (up to 0.6 mg/day)
with placebo
Absolute results reported graphically

Lacked power to detect a clinically important difference between groups

Adverse effects

No data from the following reference on this outcome.

Clonidine versus propranolol:

See benefits and harms of propranolol.

Further information on studies

None.

Comment

Clonidine has been associated in other studies with sedation, lethargy, drowsiness, constipation, dry mouth, headache, dizziness, fatigue, and weakness.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Flunarizine

Summary

We don't know whether flunarizine is useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Benefits and harms

Flunarizine versus placebo:

We found no systematic review. We found one crossover RCT.

Tremor severity

Compared with placebo Flunarizine may reduce the symptoms of essential hand tremor after 1 month's treatment compared with placebo (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
17 people Clinical scores and tremor amplitude 1 month of treatment
with flunarizine 10 mg daily
with placebo

P = 0.0006
Effect size not calculatedflunarizine

RCT
Crossover design
17 people Improvement
with

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The RCT was small and brief. The evidence is inconclusive. We found no RCTs addressing long-term outcomes. Observational studies suggest that flunarizine is associated with adverse neuropsychiatric effects, and with the development of parkinsonism and other movement disorders.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Gabapentin

Summary

We don't know whether gabapentin is useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

We found no direct information about long-term outcomes of gabapentin in people with essential tremor.

Benefits and harms

Gabapentin versus placebo:

We found no systematic review. We found three small crossover RCTs.

Tremor severity

Gabapentin compared with placebo The effects of gabapentin are unclear compared with placebo (very low-quality evidence)

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
3-armed trial
16 people Tremor Clinical Rating Scale score 2 weeks
with gabapentin (up to 1200 mg/day)
with placebo
Absolute results not reported

Mean difference gabapentin v placebo: –3.03
P <0.05
Effect size not calculatedgabapentin

RCT
3-armed trial
16 people Disability score 2 weeks
with gabapentin (up to 1200 mg/day)
with placebo
Absolute results not reported

Mean difference gabapentin v placebo: –6.04
P = 0.04,
Effect size not calculatedgabapentin

RCT
Crossover design
20 people Clinical scores 6 weeks
with gabapentin 1800 mg daily for 2 weeks
with placebo for 2 weeks

Reported as not significant
CI not reported
Not significant
Accelerometry

RCT
Crossover design
3-armed trial
25 people Accelerometry scores, spirographs, or investigator global impression scores 6 weeks
with gabapentin (1800 mg or 3600 mg daily)
with placebo

Reported as no significant difference
Not significant
Self-rating scores

RCT
3-armed trial
16 people Self-evaluation 2 weeks
with gabapentin (up to 1200 mg/day)
with placebo
Absolute results not reported

Mean difference gabapentin v placebo: –1.37
P = 0.006
Effect size not calculatedgabapentin

RCT
Crossover design
3-armed trial
25 people Participants' global assessments 6 weeks
with gabapentin (1800 mg or 3600 mg daily)
with placebo

P <0.05
Effect size not calculatedgabapentin

RCT
Crossover design
20 people |Self-evaluation 6 weeks
with gabapentin 1800 mg daily for 2 weeks
with placebo for 2 weeks

Reported as not significant
CI not reported
Not significant
Performance tests

RCT
Crossover design
3-armed trial
25 people Scores of activities of daily living 6 weeks
with gabapentin (1800 mg or 3600 mg daily)
with placebo

P <0.005
Effect size not calculatedgabapentin

RCT
Crossover design
3-armed trial
25 people Water pouring scores 6 weeks
with gabapentin (1800 mg or 3600 mg daily)
with placebo

P <0.05
Effect size not calculatedgabapentin

RCT
Crossover design
20 people Activities of daily living 6 weeks
with gabapentin 1800 mg daily for 2 weeks
with placebo for 2 weeks

Reported as not significant
CI not reported
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
People with essential tremor Adverse effects
gabapentin (up to 3600 mg daily v placebo) with

The RCTs reported fatigue, drowsiness, nausea, dizziness, and decreased libido in people taking gabapentin

Further information on studies

The RCT found no significant difference between high and low doses of gabapentin in the 20 people who completed the trial.

Comment

The results of the three RCTs differ. It is unclear whether the difference arose by chance or whether confounding variables, such as prior use of antitremor medications, baseline severity, or assessment rating scales, explain the difference. We found no RCTs addressing long-term outcomes. For further information about harms of gabapentin See review on epilepsy.

Substantive changes

No new evidence

2007; 2007: 1206.
Published online 2007 May 1.

Isoniazid

Summary

We don't know whether isoniazid is useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Benefits and harms

Isoniazid versus placebo:

We found no systematic review. We found one brief, crossover RCT.

Tremor severity

Isoniazid compared with placebo The effects of isoniazid compared with placebo are unknown in people with essential hand tremor (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Clinical scores

RCT
Crossover design
15 people, 11 with essential tremor Clinical scores
with isoniazid (up to 1200 mg/day)
with placebo
Absolute results not reported
Accelerometry

RCT
Crossover design
15 people, 11 with essential tremor Accelerometer recordings
with isoniazid (up to 1200 mg/day)
with placebo
Absolute results not reported

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
15 people, 11 with essential tremor Adverse effects
with

Further information on studies

None.

Comment

We found no RCTs addressing long-term outcomes. In other studies, isoniazid has been associated with hepatotoxicity and peripheral neuropathy.

Substantive changes

2007; 2007: 1206.
Published online 2007 May 1.

Mirtazapine

Summary

Adding mirtazapine to antitremor drugs such as propranolol does not seem to improve outcomes further in people with essential tremor of the hand, and leads to more frequent adverse effects, such as drowsiness, confusion, dry mouth, and weight gain.

Benefits and harms

Mirtazapine versus placebo:

We found no systematic review. We found one crossover RCT.

Tremor severity

Mirtazepine compared with placebo Mirtazepine may not improve tremor compared with placebo in people taking antitremor drugs such as propranolol (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Tremor score

RCT
Crossover design
17 people, 13 of whom were receiving other drug treatments, including propranolol and primidone Mean tremor (measured by questions 1–10 on the Fahn–Tolosa–Marin Tremor Rating Scale) 6 weeks
9.5 with mirtazapine (15 mg daily for 1 week, with weekly dose escalation to reach the target dose of 45 mg daily, maintained for 2 weeks)
9.5 with placebo for 3 weeks

Reported as not significant
P value not reported
Significance set at P <0.01
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
17 people, 13 of whom were receiving other drug treatments, including propranolol and primidone Advese effects
with
with
Absolute results not reported

Significance of the difference between groups not assessed

Further information on studies

None.

Comment

The RCT is small, but seems sufficient to show that a beneficial effect of mirtazapine is unlikely, and there are adverse reactions associated with taking the drug.

Substantive changes

No new evidence


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