Essential tremor

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


METHODS AND OUTCOMES
We conducted a systematic overview, aiming 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 January 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).


RESULTS
At this update, searching of electronic databases retrieved 56 studies. After deduplication and removal of conference abstracts, 31 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 18 studies and the further review of 13 full publications. Of the 13 full articles evaluated, two RCTs were added at this update. We performed a GRADE evaluation for 11 PICO combinations.


CONCLUSIONS
In this systematic overview, we categorised the efficacy for 13 interventions based on information about the effectiveness and safety of alprazolam, beta-blockers other than propranolol, botulinum A toxin-haemagglutinin complex, clonazepam, diazepam, gabapentin, levetiracetam, lorazepam, phenobarbital, primidone, propranolol, sodium oxybate, and topiramate.


INCIDENCE/ PREVALENCE
Essential tremor is one of the most common movement disorders in the world, with a prevalence of 0.4% to 3.9% in the general population. [2] 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. [3] 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. [4] Although most people with essential tremor are only mildly affected, it can be very disabling as the disease progresses and can cause physical and psychosocial impairment. Most of the people who seek medical care are disabled to some extent, and most are socially handicapped by the tremor. [3] One quarter of people receiving medical care for the tremor change jobs or retire because of essential tremor-induced disability. [5] [6] Essential tremor frequently causes embarrassment and limits patients socially.

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 more recent trials, the Fahn-Tolosa-Marin clinical evaluation scale, [7] which addresses the impairment and the disability domains of tremor, has become the preferred scale. The WHIGET and TETRAS scales have also been developed. Accelerometer recordings are reported in many trials, but they are proxy outcomes. Adverse effects.

METHODS
Search strategy BMJ Clinical Evidence search and appraisal date January 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to January 2014, Embase 1980 to January 2014, The Cochrane Database of Systematic Reviews 2013, issue 12 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, and at least single-blinded.
There was no minimum sample size and no maximum loss to follow-up. There was a minimum length of follow-up of 1 week. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. 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. While this design is useful in situations such as tremor (believed to be relatively constant despite the existence of fluctuations), because it allows an intrasubject comparison, thereby increasing the power of the analysis, it can be confounded by factors such as carry-over of the effect seen before the crossover to the post-crossover period. Also, because the effect is dependent on the moment of administration, this means 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. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Prespecified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robust-ness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following interventions from this overview: calcium channel blockers, carbonic anhydrase inhibitors, clonidine, flunarizine, isoniazid, mirtazapine; and we have added the following options: sodium oxybate and levetiracetam. We previously included benzodiazepines as an option, but at this update we have replaced this with the following more specific options: alprazolam, clonazepam, diazepam, and lorazepam. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 40 ). 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). • We were unable to draw reliable conclusions on the effects of alprazolam, as we only found two small RCTs that met our inclusion criteria. There was no direct comparison between intervention groups for clinical and self-rating scores in either study.

QUESTION
• The 2011 American Academy of Neurology guideline on essential tremor recommends that alprazolam is "probably effective" in reducing limb tremor, but that it should be used with caution because of its abuse potential.
• In general, benzodiazepines are associated with adverse effects such as dependency and sedation. Cognitive and behavioural effects are common in older adult patients.

Benefits and harms
Alprazolam versus placebo: We found two RCTs.

Tremor severity
Alprazolam compared with placebo We don't know whether alprazolam is more effective than placebo at improving tremor severity in people with essential tremor of the hand (very low-quality evidence). ----

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.

Clinical guide
The American Academy of Neurology 2011 guideline update on the treatment of essential tremor reported that alprazolam is "probably effective" in reducing limb tremor, based on the two RCTs we have included in this option. [8] [9] [10] However, the guideline also includes a statement that it should be used with caution because of its abuse potential. Alprazolam should not be used in the long-term treatment for essential tremor due to its short-acting nature and the tendency of dependence. However, alprazolam might be used on an 'as needed' basis (e.g., 30 minutes to 1 hour before a stressful situation that might worsen the tremor).  GRADE evaluation of interventions for Essential tremor, see table, p 40 . • We found insufficient evidence to judge the efficacy of beta-blockers other than propranolol (such as atenolol, metoprolol, nadolol, pindolol, and sotalol) in treating essential tremor (ET) of the hand, compared with placebo or with propranolol.

Benefits and harms
Beta-blockers other than propranolol versus placebo: We found six small, brief crossover RCTs comparing different beta-blockers (atenolol, metoprolol, nadolol, pindolol, and sotalol) with placebo. [ -

Tremor severity
Beta-blockers other than propranolol compared with placebo We don't know whether beta-blockers other than propranolol (trials included atenolol, metoprolol, nadolol, pindolol, and sotalol) are more effective than placebo at improving tremor scores in people with essential tremor of the hand, as we found insufficient evidence from small, brief RCTs (very low-quality evidence).  [11] RCT Crossover design with placebo had previously par-Absolute results reported graphically ticipated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover other beta-blockers (sotalol or atenolol) P <0.01 (sotalol v placebo) P <0.002 (atenolol v placebo)

Favours
Mean clinical score (0-25) 6.8 with sotalol 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design 8 [11] RCT Crossover design with placebo had previously par-Absolute results reported graphically ticipated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol  [13] RCT Crossover design 9.9 with placebo for 5-7 days 1 week washout between treatments, total duration of 6 weeks 3-armed trial Results after crossover The remaining arm evaluated propranolol (for 5-7 days) placebo P <0.05 (pindolol v placebo) Accelerometry (maximum amplitude) 24 people with ET (24 completed), clinical diagnosis [13] RCT Crossover design 160 with pindolol 105 with placebo for 5-7 days

3-armed trial
1 week washout between treatments, total duration of 6 weeks

Results after crossover
The remaining arm evaluated propranolol (for 5-7 days) atenolol P <0.001 (atenolol v placebo) Accelerometry (reduction in tremor intensity; % decrease from baseline) 24 people with ET (24 completed), clinical diagnosis [14] RCT Crossover design 37.3 with atenolol 4.9 with placebo 3-armed trial Results after crossover; 1 week crossover between drugs The remaining arm evaluated propranolol Nadolol not directly compared with placebo; analysis of change in each group from baseline

Accelerometry (tremor frequency)
with nadolol 10 people with ET (10 completed), stratified for response to propranolol: 6 respon- [15] RCT Crossover design No significant change from baseline between nadolol at both doses and placebo in four people with placebo Each treatment period was 4 weeks, with 1 week washout be-ders, 4 non-responders, clinical diagnosis who had previously not responded to propranolol tween treatments, total duration of 10 weeks Significant improvement from baseline in 6 people who were responders to propranolol  [11] RCT Crossover design with placebo had previously par-Absolute results reported graphically ticipated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design 4.2 with sotalol 6.2 with placebo

4-armed trial
Results assessed after crossover; no washout period between drugs The remaining arms evaluated propranolol and atenolol Not significant P = 0.1 (atenolol v placebo) Mean subjective tremor score (0-10) 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design 5.9 with atenolol 6.2 with placebo

4-armed trial
Results assessed after crossover; no washout period between drugs The remaining arms evaluated propranolol and sotalol other beta-blockers (sotalol, atenolol, metoprolol) P <0.01 (sotalol v placebo) P <0.05 (atenolol or metoprolol v placebo)

4-armed trial
with atenolol 50 mg/day with placebo (ascorbic acid 50 mg) Absolute results reported graphically  [11] RCT Crossover design with placebo had previously par-Absolute results reported graphically ticipated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol  15 of the participants in this RCT Propranolol and metoprolol were each given for two consecutive had previously par-treatment periods (each lasting ticipated in RCT [17] for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Similar proportions of people taking metoprolol or placebo had adverse effects, including breathlessness, palpitations, dizziness, tiredness, headache, and nausea Adverse effects 24 people with ET (24 completed), clinical diagnosis [14] RCT Crossover design with atenolol with placebo Similar proportions of people taking atenolol or placebo had 3-armed trial adverse effects, including breathlessness, palpitations, dizziness, tiredness, headache, and nausea The remaining arm evaluated propranolol Adverse effects 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design with sotalol with atenolol with placebo 4-armed trial The RCT suggested that no one taking sotalol or atenolol had adverse effects The remaining arm evaluated propranolol Adverse effects 24 people with ET (24 completed), clinical diagnosis [16] RCT Crossover design with metoprolol with sotalol with atenolol 4-armed trial with placebo The RCT suggested that no one taking metoprolol, sotalol, or atenolol had adverse effects Adverse effects 10 people with ET (10 completed), [15] RCT with nadolol stratified for response to propra-Crossover design with placebo The RCT suggested that no one taking nadolol had adverse effects nolol: 6 responders, 4 non-responders, clinical diagnosis -No data from the following reference on this outcome. [13] --

Tremor severity
Beta-blockers other than propranolol compared with propranolol We don't know how beta-blockers other than propranolol (trials included atenolol, metoprolol, sotalol, arotinolol) and propranolol compare at improving tremor in people with essential tremor of the hand. We found insufficient evidence to draw reliable conclusions (very lowquality evidence).  [11] RCT Crossover design with propranolol 120 and 240 mg/day had previously participated in RCT [17] Absolute results reported graphically Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol

Favours
The RCT included placebo as a comparator Results before crossover Not significant P >0.1 (propranolol v sotalol) Mean clinical score (0-25) 6.8 with sotalol 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design

with propranolol
Results assessed after crossover; no washout period between drugs 4-armed trial The remaining arms evaluated placebo and atenolol propranolol P <0.05 (propranolol v atenolol) Mean clinical score (0-25) 8.1 with atenolol 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design 6.6 with propranolol Results assessed after crossover; no washout period between drugs 4-armed trial The remaining arms evaluated placebo and sotalol

No direct comparison between propranolol and metoprolol
Proportion of people with clinical scores significantly improved from baseline 23 people with essential tremor (20 completed), clinical diagnosis [18] RCT

with atenolol
Results after crossover; 1 week crossover between drugs

3-armed trial
The remaining arm evaluated placebo No direct comparison between propranolol and metoprolol Accelerometry (tremor amplitude) 23 people with essential tremor (20 completed), clinical diagnosis [18] RCT

Crossover design
No significant improvement from baseline for propranolol or metoprolol; reported as not significant, no further data reported with metoprolol 50, 150, or 250 mg/day with propranolol 120 and 240 mg/day For the subgroup of the clinical responders there was a difference for both treatments; P <0.05 Each treatment period was 6 weeks, escalating doses every 2 weeks, with 1 week washout between treatments, total duration of 14 weeks

4-armed trial
Results assessed after crossover; no washout period between drugs The remaining arms evaluated placebo and atenolol propranolol P <0.05 (propranolol v atenolol) Mean subjective tremor score (0-10) 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design

4-armed trial
Results assessed after crossover; no washout period between drugs The remaining arms evaluated placebo and sotalol P value not reported Proportion of people preferring each treatment 24 people with ET (24 completed), clinical diagnosis [14] RCT Crossover design 12/24 (50%) with propranolol 1/24 (4%) with atenolol

3-armed trial
Results after crossover; 1 week crossover between drugs The remaining arm evaluated placebo No direct comparison between propranolol and metoprolol Self-rating with metoprolol 50, 150, or 250 mg/day 23 people with essential tremor (20 completed), clinical diagnosis [18] RCT Crossover design with propranolol 120 and 240 mg/day  [11] RCT Crossover design P <0.05 (propranolol 240 mg v metoprolol 300 mg) with propranolol 120 and 240 mg/day had previously participated in RCT [17] Absolute results reported graphically Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol  [11] RCT Crossover design with metoprolol 150 and 300 mg/day with propranolol 120 and 240 mg/day 15 of the participants in this RCT had previously participated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol The RCT included placebo as a comparator Similar proportions of people taking metoprolol or propranolol had adverse effects, including tiredness, headache, and breathlessness Adverse effects 24 people with ET (24 completed), clinical diagnosis [14] RCT Crossover design 42.9 with propranolol

with atenolol
The third RCT found that similar proportions of people taking 3-armed trial atenolol or propranolol had adverse effects, including tiredness, dizziness, and nausea The remaining arm evaluated placebo Adverse effects 23 people with essential tremor (20 [18] RCT The most frequently reported adverse effects (occurring in >1% of people) were gastrointestinal discomfort (dyspepsia, diarrhoea, and gastric upset), bradycardia, headache, dizziness, sleep disturbance, and skin rash -No data from the following reference on this outcome. [13] ----

Comment:
People with congestive heart failure, second-degree heart block, asthma, severe allergy, and insulindependent diabetes were generally excluded from the RCTs. We found no RCTs addressing longterm outcomes.

Clinical guide
There is no sufficient evidence that beta-blockers other than propranolol are superior to or even equally effective as propranolol. So far, propranolol remains the beta-blocker with the most evidence to treat essential tremor and is recommended in clinical guidelines as a preferred beta-blocker for clinicians to treat essential tremor. • For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• Botulinum A toxin-haemagglutinin complex appears to improve clinical rating scales for tremor in the short term (up to 12 weeks) in people with essential tremor of the hand, but is 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 of the hand.

Benefits and harms Botulinum A toxin-haemagglutinin complex versus placebo:
We found no systematic reviews. We found two parallel RCTs.

Tremor severity
Botulinum A toxin-haemagglutinin complex compared with placebo Botulinum A toxin-haemagglutinin complex may be more effective than placebo at improving clinical scores and self-rating scores at up to 12 weeks in people with essential tremor of the hand, but we don't know about accelerometry scores, motor tests, or functional scores (very low-quality evidence).  25 people with essential hand tremor unresponsive to "optimal medical therapy" [20] RCT with placebo 25 people with essential hand tremor unresponsive to "optimal medical therapy" [20] RCT with placebo

Favours
Botulinum toxin 50 U was injected in forearm muscles, and was repeated, if necessary, after 1 month (100 U).

Not significant
Reported as not significant P value not reported Functional tests (write a sentence, Archimedes' spirals, a straight line, a sine wave between lines, pour water into a cup) 25 people with essential hand tremor unresponsive to "optimal medical therapy" [20] RCT with botulinum A toxin-haemagglutinin complex with placebo Botulinum toxin 50 U was injected in forearm muscles, and was repeated, if necessary, after 1 month (100 U). ---Further information on studies [20] 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 toxinhaemagglutinin complex is dose-dependent transient hand weakness.The effectiveness of botulinum A toxin-haemagglutinin complex could be highly dependent on the site of injections and the dose used.

Clinical guide
Botulinum A toxin-haemagglutinin complex may be used in the patients with essential tremor of the hand who have large-amplitude and disabling tremor that is refractory to first-line therapy, such as propranolol and primidone. [22] However, in the two RCTs we found, the decreased tremor severity did not seem to be translated into functional improvement measured by performance testing. [20] [21] Therefore, botulinum A toxin-haemagglutinin complex might be more helpful for improving performance of simple tasks rather than complex tasks that require a high level of hand dexterity. Unlike other pharmacological therapy for essential tremor, botulinum A toxin-haemagglutinin complex acts mostly on the peripheral nervous system and does not have side effects affecting emotional state or cognition.
• In general, benzodiazepines are associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects, although clonazepam is a longer-acting benzodiazepine and may have fewer side effects than shorter-acting agents.

Benefits and harms
Clonazepam versus placebo: We found one RCT. [23] -

Tremor severity
Clonazepam compared with placebo We don't know whether clonazepam is more effective than placebo at improving tremor severity in people with essential tremor of the hand (very low-quality evidence).  [23] RCT

Crossover design
Results after crossover -Adverse effects --No data from the following reference on this outcome. [23] ----

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. • We found no RCTs on the effects of diazepam in people with essential tremor of the hand.
• In general, benzodiazepines are associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects.

OPTION
• For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• We don't know whether gabapentin is useful in treating essential tremor of the hand, as studies were small and the results were inconsistent.
• We found no direct information about long-term outcomes of gabapentin in people with essential tremor.

Essential tremor Neurological disorders
Benefits and harms

Tremor severity
Gabapentin compared with placebo Gabapentin may be more effective than placebo at improving some outcomes at up to 6 weeks in people with essential tremor of the hand, but studies were small and short term and results were inconsistent between trials (very low-quality evidence)  [24] RCT Crossover design P = 0.04 with placebo

3-armed trial
Absolute results not reported Results before crossover The remaining arm evaluated propranolol (up to 120 mg/day)

Not significant
Reported as not significant Clinical scores , 6 weeks with gabapentin 1800 mg daily for 2 weeks 20 people [25] RCT Crossover design with placebo for 2 weeks Results after crossover

Not significant
Reported as not significant Accelerometry scores, spirographs, or investigator global impression scores , 6 weeks 25 people [26] RCT Crossover design with gabapentin (1800 mg or 3600 mg daily)

3-armed trial
with placebo Results before crossover

Self-rating scores
gabapentin Mean difference gabapentin v placebo: -1.37

3-armed trial
Absolute results not reported Results before crossover The remaining arm evaluated propranolol (up to 120 mg/day)  [26] RCT with gabapentin (1800 mg or 3600 mg daily) Crossover design with placebo

3-armed trial
Results before crossover Not significant Reported as not significant Self-evaluation , 6 weeks with gabapentin 1800 mg daily for 2 weeks 20 people [25] RCT Crossover design with placebo for 2 weeks Results after crossover

Performance tests
gabapentin P <0.005 Scores of activities of daily living , 6 weeks 25 people [26] RCT with gabapentin (1800 mg or 3600 mg daily) Crossover design with placebo

3-armed trial
Results before crossover gabapentin P <0.05 Water pouring scores , 6 weeks with gabapentin (1800 mg or 3600 mg daily) 25 people [26] RCT Crossover design with placebo

3-armed trial
Results before crossover

Not significant
Reported as not significant Activities of daily living , 6 weeks 20 people [25] RCT with gabapentin 1800 mg daily for 2 weeks Crossover design with placebo for 2 weeks Results after crossover -Adverse effects -

Adverse effects
with gabapentin (up to 3600 mg daily v placebo) People with essential tremor [24] [25] [26] RCT and decreased libido in people taking gabapentin Crossover design ---Further information on studies [26] The RCT found no significant difference between high and low doses of gabapentin in the 20 people who completed the trial.

Essential tremor Neurological disorders
-

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.

. . . New
• For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• We don't know whether levetiracetam is more effective than placebo at reducing symptoms in people with essential tremor.
• Evidence came from two very small RCTs, both of which were terminated early.

Levetiracetam versus placebo:
We found two small double-blinded RCTs, both of which were terminated early (see Further information on studies).

Tremor severity
Levetiracetam compared with placebo Levetiracetam may be no more effective than placebo at improving measures of tremor in people aged 35-83 years who have had long-standing essential tremor. However, evidence was very weak (very low-quality evidence).

Ref (type)
Tremor score Not significant P = 0.113 The study was terminated early (see Further information on studies)  [28] RCT Crossover design reduction in tremor severity of 30%

UTRA Tremor Functional Rating scales) reduction from baseline
The study was terminated early (see Further information on studies) - The study was terminated early (see Further information on studies)

Global evaluation by examiner (negative numbers = more tremor, positive numbers = improvement)
-2 with levetiracetam 12 people aged 67-81 years, with essential tremor, median duration 42 years [28] RCT Crossover design +9 with placebo Results based on 10 people The study was terminated early (see Further information on studies)

with placebo
Results based on 10 people Accelerometry Not significant P = 0.25 The study was terminated early (see Further information on studies)

Crossover design with placebo
The most common adverse effects reported were increased tremor (5 with levetiracetam v 4 with placebo), drowsiness (4 v 0), depressed mood (3 v 0), and impaired balance or hearing (3 v 2; P value for comparisons of adverse effects not reported) Adverse effects 12 people aged 67-81 years, with [28] RCT with levetiracetam essential tremor, median duration 42 years Crossover design with placebo The most common adverse effects reported were worse tremor (7 with levetiracetam v 2 with placebo), fatigue (5 v 1), drowsiness (4 v 2), and impaired bal-

Ref (type)
ance (2 v 0; P value for comparisons of adverse effects not reported) ---Further information on studies [27] The method of randomisation and allocation concealment was not described. Ten people took 1 or 2 additional drugs for tremor during the study (including propranolol, primidone, clonazepam, gabapentin, mirtazapine, and atenolol; further details not reported). Each drug period consisted of a 5-week titration phase, followed by a 4week maintenance phase on the maximum tolerated dose, with a 3-week washout phase. It was planned to enrol 45 people, but enrolment was stopped when a blinded interim analysis of the first 15 people "revealed no possibility of efficacy". Three people dropped out during the levetiracetam phase due to: increased tremor, disequilibrium, drowsiness, and leg cramps; no improvement, mild depression, and fatigue; and increased tremor and anxiety. However, they were included in the analysis (last value carried forward). [28] During the study, one concurrent anti-tremor medication was taken by seven people, two medications by two people, and four medications by one person. Each drug arm consisted of a 4-week titration phase, 2 weeks of stable dose (a target dose or lower maximal tolerated dose), and 4-week washout period. The study was discontinued at an interim analysis when the levetiracetim arm had a mean drop in the primary endpoint of about 3% compared with placebo of 11%. Three people withdrew during treatment with levetiracetam, compared with two people with placebo (P value not reported).

Comment:
One RCT noted that at interim analysis, levetiracetam failed to demonstrate the 30% fall in tremor scores that was required; hence, it was unlikely to exert efficacy comparable to that of propranolol or primidone. [28] It noted that whether levetiracetam had a lower degree of anti-tremor potency was not assessed in the study. • We found no RCTs on the effects of lorazepam.
• In general, benzodiazepines are associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects.
• For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• We don't know whether phenobarbital is more effective than placebo at improving tremor in people with essential tremor of the hand. It improved some outcome measures but not others, and evidence was weak and inconsistent from three RCTs with small numbers.
• Phenobarbital is associated with depression, and with cognitive and behavioural adverse effects.

Essential tremor Neurological disorders
Benefits and harms

Tremor severity
Phenobarbital compared with placebo We don't know whether phenobarbital (phenobarbitone) is more effective than placebo at improving symptoms at up to 5 weeks in people with essential tremor of the hand (very low-quality evidence).  [29] RCT Crossover design with phenobarbital (phenobarbitone) with placebo

3-armed trial
Results after crossover Each treatment period was 4 weeks, total duration of 12 weeks The remaining arm evaluated propranolol No intention-to-treat analysis was performed Not significant Reported as not significant Clinical score and self-evaluation of tremor , 5 weeks 16 people [30] RCT with phenobarbital Crossover design with placebo

3-armed trial
Results before crossover The remaining arm evaluated primidone Accelerometry phenobarbital P <0.01 Accelerometer recordings , 5 weeks 12 people [31] RCT with phenobarbital Crossover design with placebo Significance of the difference between groups not assessed Proportion of people who responded (defined as decrease of 15% or more in tremor score measured by accelerometer) 12 people [31] RCT Crossover design 11/11 (100%) with phenobarbital 6/11 (55%) with placebo Results after crossover

Not significant
No significant difference reported Self-evaluation of tremor with phenobarbital 12 people [31] RCT with placebo Crossover design phenobarbital P <0.05 Symptom rating scale , 5 weeks 12 people [31] RCT with phenobarbital Crossover design with placebo  [31] RCT with placebo Crossover design -Adverse effects --No data from the following reference on this outcome. [29] [30] [31] ----

Comment:
The RCTs were short term and small, and many randomised people did not complete the trials. Both phenobarbital and primidone (metabolised to phenobarbital) are associated with depression and cognitive and behavioural effects (particularly in children, older adults, and people with neuropsychiatric problems) and should be used with caution. • For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• Primidone may improve hand tremor in the short term (up to 10 weeks), but is associated with depression, and with cognitive and behavioural adverse effects.

Tremor severity
Primidone compared with placebo Primidone may be more effective than placebo at improving clinical scores, selfrating scores, and functional tests at 4-10 weeks in people with essential tremor of the hand (very low-quality evidence).

Results after crossover
No intention-to-treat analysis was performed Self-rating primidone P <0.01 Self-evaluation (hand tremor) , 10 weeks

Results after crossover
No intention-to-treat analysis was performed

Performance tests
Significance of the difference between primidone and placebo not assessed Observer-rated score based on ability to write, feed, and function socially , 4 weeks 22 people [8] RCT Crossover design 5.2 with primidone 7.8 with placebo

4-armed trial
Results before crossover; 4 weeks' treatment, with a 2-week washout between treatments Scale: 0 = normal, 11 = unable to keep pencil on paper, needs help to feed, and no social activity  [8] with primidone RCT with placebo Crossover design 8/24 (33%) people receiving primidone discontinued treatment 4-armed trial because of adverse effects, including nausea, ataxia, dizziness, or confusion The remaining arms evaluated alprazolam and acetazolamide ----

Comment:
The RCTs were short term and small, and many randomised people did not complete the trials. Both primidone and propranolol improve tremor by a magnitude of effect of about 50%. However, about 30% to 50% of essential tremor patients will not derive benefit from either. [33] Clinical guide Both primidone (metabolised to phenobarbital) and phenobarbital are associated with depression and cognitive and behavioural effects (particularly in children, older adults, and people with neuropsychiatric problems). Although primidone can be difficult to titrate in the early stages, it can be very helpful to people with essential tremor. Slow titration from a very low dose of primidone could help with initial side effects of dizziness and cognitive impairment. • For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• We found several small RCTs, mostly of a crossover design, that only reported on results in the short term.
• Propranolol seems to effectively improve tremor severity (clinical scores, tremor amplitude, performance test scores, and self-evaluation of severity) compared with placebo in people with essential tremor (ET) of the hand.
• We found insufficient evidence about the effects of propranolol compared with other beta-blockers.
• Propranolol may be associated with adverse effects, including hypotension and depression. The potential benefits and adverse effects need to be discussed with the patient before treatment.

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 may be more effective than placebo at improving tremor severity (clinical scores, tremor amplitude, performance test scores, and self-evaluation of severity) at up to 6 weeks in people with ET of the hand (very low-quality evidence).  [11] RCT Crossover design with placebo Absolute results reported graphically 15 of the participants in this RCT had previously participated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover Unclear; no report of a significant difference (propranolol 120 mg/day v placebo) Clinical score with propranolol 120 mg/day with placebo 16 people with ET (16 completed), clinical diagnosis 15 of the participants in this RCT [11] RCT

Crossover design
Absolute results reported graphically had previously participated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol 6.6 with propranolol 9 people with ET (9 completed), clinical diagnosis [12] RCT Crossover design

3-armed trial
Results after crossover Each treatment period was 2 weeks, with 1 week washout between treatments, total duration of 10 weeks The remaining arm evaluated gabapentin Accelerometry Reported as unchanged Accelerometry (frequency) , 2 weeks 24 people with ET (23 completed), clinical diagnosis [34] RCT Crossover design with propranolol with placebo propranolol P <0.001 Accelerometry (amplitude) , 2 weeks 24 people with ET (23 completed), clinical diagnosis [34] RCT Crossover design with propranolol with placebo propranolol P <0.01 Accelerometry with propranolol 9 people with ET (7 completed), clinical diagnosis [36] RCT Crossover design with placebo Each treatment period was 1 week, total duration of 5 weeks (1st week, no treatment given)  [11] RCT

Crossover design
Absolute results reported graphically had previously participated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover propranolol 240 mg/day P <0.02 (propranolol 240 mg/day v placebo)

Accelerometry (amplitude)
with propranolol 240 mg/day 16 people with ET (16 completed), clinical diagnosis [11] RCT Crossover design with placebo Absolute results reported graphically 15 of the participants in this RCT had previously participated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover propranolol (all included dosing regi-P <0.02 (all propranolol dosing regimens combined v placebo)

3-armed trial
Results after crossover Each treatment period was 2 weeks, with 1 week washout between treatments, total duration of 10 weeks  [24] RCT Crossover design with placebo

3-armed trial
Results after crossover Each treatment period was 2 weeks, with 1 week washout between treatments, total duration of 10 weeks The remaining arm evaluated gabapentin Not significant Reported as not significant P value not reported Accelerometry (frequency) 9.1 with propranolol for 5 to 7 days 24 people with ET (24 completed), clinical diagnosis [13] RCT Crossover design 9.4 with placebo for 5 to 7 days

3-armed trial
1 week washout between treatments, total duration of 6 weeks

Results after crossover
The remaining arm evaluated pindolol for 5-7 days propranolol P <0.05 (propranolol v placebo) Accelerometry (maximum amplitude) 24 people with ET (24 completed), clinical diagnosis [13] RCT Crossover design 71 with propranolol for 5 to 7 days 128 with placebo for 5 to 7 days 3-armed trial 1 week washout between treatments, total duration of 6 weeks

Results after crossover
The remaining arm evaluated pindolol for 5-7 days 24 people with ET (24 completed), clinical diagnosis [14] RCT Crossover design 42.9 with propranolol 3-armed trial 4.9 with placebo Results after crossover; 1 week crossover between drugs The remaining arm evaluated atenolol Self-rating Self-rating 24 people with ET (23 completed), clinical diagnosis [34] RCT Crossover design with propranolol with placebo 83% improved with propranolol, 75% of whom felt improvement was clinically important No self-rating reported for placebo Results after crossover P value not reported Self-rating , 6 weeks' treatment 11 people with ET (10 completed), clinical diagnosis [35] RCT 5/5 (100%) with propranolol 1/5 (20%) with placebo propranolol P <0.05 Number of people improved >2 assessments 9 people with ET (7 completed), clinical diagnosis [36] RCT Crossover design 12 with propranolol 2 with placebo Each treatment period was 1 week, total duration of 5 weeks (1st week, no treatment given) Results after crossover Self-rating calculation compares assessments rather than participants, losing the benefits of randomisation propranolol P <0.01 (propranolol 120 mg/day or 240 mg/day v placebo)

Self-rating (0-5)
with propranolol 120 and 240 mg/day 16 people with ET (16 completed), clinical diagnosis 15 of the participants in this RCT [11] RCT Crossover design with placebo had previously par-Absolute results reported graphically ticipated in RCT [17] Propranolol and metoprolol were each given for two consecutive treatment periods (each lasting for 2 weeks) during which two dosage regimens were used: 120 and 240 mg daily for propranolol and 150 and 300 mg daily for metoprolol Results before crossover propranolol P <0.05 (all doses of propranolol v placebo)

4-armed trial
Results assessed after crossover; no washout period between drugs The remaining arms evaluated sotalol and atenolol propranolol P <0.01 (propranolol v placebo) Self-rating (0-10): mean change from baseline 17 people with ET (12 completed), clinical diagnosis [29] RCT Crossover design  [24] RCT Crossover design P = 0.11 with placebo

3-armed trial
Results after crossover Each treatment period was 2 weeks, with 1 week washout between treatments, total duration of 10 weeks  [11] RCT Crossover design with propranolol 120 and 240 mg/day had previously participated in RCT [17] with placebo Absolute results reported graphically --

Propranolol versus other beta-blockers:
See Beta-blockers other than propranolol, p 6 .

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. Accelerometry (amplitude) results were mostly in favour of propranolol. Propranolol did not change tremor frequency but rather dampened the tremor amplitude and provided clinical benefits (including improvements in activities of daily living). Patients are more likely to be disabled from the tremor amplitude (unable to hold on to things and dropping things, etc) rather than tremor frequency. Some small RCTs did not find statistical significant benefits for propranolol. However, overall, there was a trend towards clinical benefits with propranolol compared with placebo in these studies, which might have been underpowered to detect statistical significance. In addition, a moderate proportion of patients did not respond to propranolol, highlighting that ET is a heterogeneous disorder. Both primidone and propranolol improve tremor by a magnitude of effect of about 50%. About 30% to 50% of people with ET will not get benefit from either, however. [33] People with congestive heart failure, second-degree heart block, asthma, severe allergy, and insulin-dependent diabetes were generally excluded from the RCTs. All of the studies were small. The possibility of publication bias has not been excluded.

Clinical guide
There is a risk of depression in patients taking propranolol. Propranolol should be used with caution in patients with certain respiratory problems, such as asthma and chronic obstructive pulmonary disease. In addition, beta-blockers can worsen severe congestive heart failure and mask the catecholamine responses to hypoglycaemia in diabetic patients. • We found no RCTs on the effects of sodium oxybate in people with essential tremor of the hand.

Benefits and harms
Sodium oxybate versus placebo: We found no RCTs. • For GRADE evaluation of interventions for Essential tremor, see table, p 40 .
• Topiramate appears to improve clinical rating scales for hand tremor in the short term in people with essential tremor of the hand, but is associated with frequent adverse effects.

Benefits and harms
Topiramate versus placebo: We found three RCTs, one with parallel [38] and two with crossover [39] [40] design. -

Tremor severity
Topiramate compared with placebo Topiramate may be more effective than placebo at improving observer-rated tremor scores between 6 and 24 weeks in people with essential tremor of the hand (low-quality evidence).

Effect size
Results and statistical analysis Outcome, Interventions Population

Ref (type)
placebo P <0.001 Mean reduction in body weight 3.6 kg with topiramate 223 people with moderate to severe essential tremor of the hands or forearms [38] RCT 0.6 kg with placebo About half of participants also took one other antitremor drug; dose had to remain stable throughout the trial Proportion of people who withdrew because of adverse effects 24 people with tremor of hand, head, or voice [39] RCT Crossover design 5/24 (21%) with topiramate 1/24 (4%) with placebo The most common adverse effects with topiramate were appetite suppression, weight loss, and paraesthesia -No data from the following reference on this outcome. [40] ----

Comment:
We found no RCTs addressing long-term outcomes.

Clinical guide
Topiramate is useful in the treatment of tremor but hampered by side effects. It cannot be used in patients who are prone to urinary stones and who are allergic to sulfa. However, in a sub-analysis of a larger study, [41] significant improvements were noted with topiramate use in doses of 100 mg/day, which means that patients might not need to titrate up to large doses. It does not carry the side effects of depression and orthostatic hypotension. The clinical evidence for topiramate to treat essential tremor is less robust than that for propranolol and primidone, and it might be used as a second-line therapy. In addition, topiramate also has different side effect profiles from propranolol and primidone. Topiramate also has migraine prophylaxis effects and could be beneficial for patients with essential tremor and comorbid migraine. In certain patients, appetite suppression and weight loss might be seen as beneficial effects of topiramate. Topiramate should be used with caution in patients with a history of angle closure glaucoma and calcium phosphate nephrolithiasis.

GLOSSARY Accelerometry
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.
Very low-quality evidence Any estimate of effect is very uncertain.

SUBSTANTIVE CHANGES
Alprazolam New option. Two RCTs added that were included in a previous version of this overview. [8] [9] Categorised as 'unknown effectiveness'.
Clonazepam New option. One RCT added that was included in a previous version of this overview. [23] Categorised as 'unknown effectiveness'.  [8] [9] for no statistical analysis between groups (baseline analysis) Quality points deducted for sparse data, poor followup, incomplete reporting of results, and weak methods Very low 0 0 0 -3 4 Beta-blockers other than propranolol versus placebo Tremor severity 6 (107) [11] [12] [13] [14] [15] [16] Quality points deducted for incomplete reporting of results and weak methods (no washout period, low Very low 0 -1 0 -2 4 Beta-blockers other than propranolol versus propranolol Tremor severity 5 (247) [11] [12] [14] [18] [19] follow up); directness point deducted for no statistical analysis between groups in some RCTs Quality points deducted for sparse data and incomplete reporting of results; directness point deducted Very low 0 -1 0 -2 4 Botulinum A toxinhaemagglutinin complex versus placebo Tremor severity 2 (158) [20] [21] for unclear population (people in 1 RCT were unresponsive to medical therapy, but this was not defined) Quality points deducted for sparse data, incomplete reporting of results, and poor follow-up Very low 0 0 0 -3 4 Clonazepam versus placebo Tremor severity 1 (6) [23] Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for conflicting results (possible confounding variables) Very low 0 -1 0 -2 4 Gabapentin versus placebo Tremor severity 3 (unclear, less than 61) [24] [25] [26] Quality points deducted for weak methods and sparse data; directness points deducted for early termination of trials and use of concomitant medication Very low 0 -2 0 -2 4 Levetiracetam versus placebo Tremor severity 2 (25) [27] [28] Quality points deducted for sparse data, incomplete reporting of results, and weak methods (no intentionto-treat analysis, and high withdrawals) Very low 0 0 0 -3 4 Phenobarbital versus placebo Tremor severity 3 (45) [29] [30] [31] Quality points deducted for sparse data, incomplete reporting of results, and weak methods (no intentionto-treat analysis, and high withdrawals) Very low 0 0 0 -3 4 Primidone versus placebo Tremor severity 3 (60) [30] [32] [8] Quality points deducted for sparse data, incomplete reporting of results, and weak methods ('on treatment' Very low 0 0 0 -3 4 Propranolol versus placebo Tremor severity 11 (less than 189) [ [14] and no intention-to-treat analysis, short term [ [38] [39] [40] poor follow-up, composite outcome score); directness point deducted for use of co-interventions  We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasirandomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.