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Non-antiepileptic drugs for trigeminal neuralgia

  1. Jingjing Zhang1,
  2. Mi Yang1,
  3. Muke Zhou1,
  4. Li He1,*,
  5. Ning Chen1,
  6. Joanna M Zakrzewska2

Editorial Group: Cochrane Neuromuscular Group

Published Online: 3 DEC 2013

Assessed as up-to-date: 20 MAY 2013

DOI: 10.1002/14651858.CD004029.pub4


How to Cite

Zhang J, Yang M, Zhou M, He L, Chen N, Zakrzewska JM. Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD004029. DOI: 10.1002/14651858.CD004029.pub4.

Author Information

  1. 1

    West China Hospital, Sichuan University, Department of Neurology, Chengdu, Sichuan, China

  2. 2

    Eastman Dental Institute, Oral Medicine, London, UK

*Li He, Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Xiang 37#, Chengdu, Sichuan, 610041, China. heli2003new@126.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 3 DEC 2013

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Characteristics of included studies [ordered by study ID]
Kondziolka 1994

MethodsDouble-blind, randomised, parallel-group study
Single application of drugs with 30 days of follow-up. Baseline time of observation unclear


Participants47 participants (25 treatment group and 22 placebo)

Not reported whether participants had idiopathic TN
Mean age 59 years in proparacaine group, 63 in control group
70% female. Duration of illness from 0.2 to 25 years. Baseline pain scores unreported
Diagnosis clear. Inclusion criteria described. Only 12 participants (5 active, 7 placebo) were not taking any systemic medications for their TN
Exclusion criteria were: surgery intended within 3 days, atypical TN, hyperthyroidism, pregnancy or with a known allergic reaction to any local anaesthetic agent


InterventionsTreatment group: 2 drops of 0.5% proparacaine hydrochloride were instilled onto the ipsilateral cornea once

Control group: 2 drops of buffered saline were instilled onto the ipsilateral cornea once


OutcomesFrequency of pain: participants kept a log of frequency of pain attacks and were telephoned at 3, 10 and 30 days. The change in severity of pain was assessed in comparison with the previous conversation

Severity of pain using both a rating scale and descriptive indices:

  • verbal pain rating (participant rating of the severity of their current pain from 0 to 10 based on their experience with TN, with 10 being the worst pain and 0 being no pain)
  • a descriptive scale (unchanged, moderately better, markedly better or worse) to grade outcome


Endpoint criteria included clinical response (defined as improved, worsened or unchanged pain in comparison to pain level before instillation) and the need for an increase in oral medication or for surgical intervention during the observation period


NotesFunding and conflicts of interest: not reported in the paper


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to a group using a coin toss

Allocation concealment (selection bias)Low riskParticipants could not foresee assignments

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInstilled by individual blinded to agent; participants could not distinguish the agents

Blinding of outcome assessment (detection bias)
All outcomes
Low riskInstilled by individual blinded to agent; participants could not distinguish the agents

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts. No missing outcome data

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported

Other biasUnclear riskThe report does not state whether participants had idiopathic TN

Lechin 1989

MethodsRandomised, double-blind (methods not described), cross-over study
Trial duration 8 weeks with unclear follow-up. Baseline time of observation 4 weeks


Participants68 participants with idiopathic TN joined initially; 59 were randomly distributed into 2 groups; 48 participants completed

Diagnosis of TN clear
Mean age 59.3 years, 50% females. Duration of illness 8 to 17 years. Baseline pain scores unclear. Placebo responders, patients with severe physical illness, a history of psychotic episodes, drug or alcohol addiction or mental retardation, and pregnant and nursing women were excluded


Interventions4 weeks placebo, 8 weeks carbamazepine or pimozide. 4 weeks of abrupt withdrawal by placebo substitution, and 8 weeks of cross-over treatment

Pimozide: 4 mg/day from days 1 to 4, 6 mg/day from days 5 to 9, 8 mg/day from days 10 to 14, 12 mg/day from day 14 to the end

Carbamazepine: 300 mg/day from days 1 to 4, 600 mg/day from days 5 to 9, 900 mg/day from days 10 to 14, 1200 mg/day from day 14 to the end


OutcomesMean % changes in total TN scores from baseline at visits 5 to 12 and 17 to 24 (i.e. in each treatment phase). TN symptom score (1 to 100) was based on weekly interviews with 2 physicians. The score was the mean of the 2 assessments

Adverse events


NotesFunding: grant from the Foundation of the Institute of Experimental Medicine. Conflicts of interest: not reported in the paper
All participants continued taking pimozide after the controlled trial; none of the participants showed tolerance to pimozide


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of sequence generation was not described

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "All medications were administered in identical dark capsules under double-blind conditions"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStated to be "double-blind"; insufficient information to permit judgement of high or low risk of bias

Incomplete outcome data (attrition bias)
All outcomes
Low risk11 dropouts. No ITT analysis. Details of missing data and reasons were reported in each group

Selective reporting (reporting bias)High riskThis trial reported data primarily in graphs. The first period data for reduction in TN score were reported in the text after 6 weeks of treatment, which the trial authors describe as the point of "maximal improvement" for both pimozide and carbamazepine

Other biasUnclear riskNo baseline characteristics; carry-over effect might exist

Lindström 1987

MethodsRandomised, double-blind (methods not described), cross-over study


Participants12 participants. Age 41 to 78 years

All participants had idiopathic TN
58% females. Duration of illness 5 to 19 years
All participants were on carbamazepine but none experienced complete relief. 8 were able to be without medication to record the pain before the trial. Baseline scores of pain 4.0 to 10. Only participants whose condition was active, with several pain attacks over a long period of time, were selected. Cardiovascular disease, liver and renal insufficiency were exclusion criteria


InterventionsTocainide and carbamazepine were given for 2 weeks each. No details provided of how cross-over was done and it is impossible to look at each arm separately
Tocainide 20 mg/kg divided into 3 daily doses
Carbamazepine was used at the maximum tolerated dose


Outcomes0 to 10-point scale summarising frequency and severity (duration and intensity) of attacks. Mean score values before treatment and for the last 10 days of each 2-week period with carbamazepine and tocainide

A telephone interview twice weekly "to supplement the evaluation procedure and to obtain information concerning the patients' activity pattern, pain precipitation factors and possible side effects"


NotesFunders: Folksam Research Foundation and the Vivian L Smith Foundation for Restorative Neurology

Conflicts of interest: not reported in the paper


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of sequence generation was not described

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated to be "double-blind"; insufficient information to permit judgement of high or low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStated to be "double-blind"; insufficient information to permit judgement of high or low risk of bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts. No missing outcome data

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported

Other biasHigh riskNo complete baseline characteristics; possibility of carry-over effect

Vilming 1986

MethodsRandomised, double-blind, parallel-group study (methods not described)
3-week trial but baseline time of observation unclear


Participants12 participants (6 tizanidine group and 6 carbamazepine)

Whether participants had idiopathic TN was not reported
Mean age 60 years. Proportion of females was unclear
Duration of illness and baseline frequency of pain not reported
No diagnostic criteria for TN. Typical TN participants were included
No exclusion criteria


InterventionsThe medication was gradually increased during the first 12 days, and participants received optimal medication for the following 9 days: 18 mg tizanidine or 900 mg carbamazepine daily in 3 divided doses


OutcomesFrequency, duration, severity of attacks

Pain relief

"Inability to participate in daily activities"

VAS pain recorded daily

Spontaneously reported side effects recorded 4 times during test period

Overall efficacy (no efficacy, slight, moderate, good, very good) assessed by investigator and the participant at the end of the study


NotesFunding and conflicts of interest not provided in report

3 participants taking tizanidine discontinued taking the optimal dose, 1 because of the unrelated disease, 2 due to intolerable pain. Side effects not specifically reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of sequence generation was not described

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated to be "double-blind"; insufficient information to permit judgement of high or low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStated to be "double-blind"; insufficient information to permit judgement of high or low risk of bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskDetails of missing data and reasons were reported in each group. Results for 11 of the 12 participants reported. ITT analysis was not used to analyse the results

Selective reporting (reporting bias)High riskSide effects not specifically reported and the VAS results were not reported in a suitable format for interpretation

Other biasUnclear riskThe study report did not describe baseline characteristics or whether participants had idiopathic or symptomatic TN

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Carasso 1979Single-blind only

Fromm 1984No washout period. The first phase of this cross-over study was too short (only 7 days)

Fromm 1987No washout period. The first phase of this cross-over study was too short (only 7 days)

Fromm 1993No washout period. The first phase of this cross-over study was too short (only 4 days)

Gazerani 2009The participants enrolled did not fulfil the protocol criteria

Gilron 2000Cross-over, double-blind, randomised trial. 19 participants with facial neuralgia and 3 TN participants. 1 TN participant dropped out, which means only 2 TN participants were treated. We do not know how the 2 TN participants were allocated, and details of their characteristics were unavailable

Jiang 2007Repeated report

Jiang 2008The participants enrolled did not fulfil the protocol criteria

Kanai 2006aThe participants enrolled did not fulfil the protocol criteria and the study was not of a single non-antiepileptic drug

Kanai 2006bNot a randomised study

Kanai 2006cThe participants enrolled did not fulfil the protocol criteria

Laurinda 2008The participants enrolled did not fulfil the protocol criteria

Liu 1999Participants were divided into groups by age, course and clinical situation. Allocation was not randomised

Luo 1995Retrospective, not prospective study

Parekh 1989The trial lasted only 10 days. No baseline; not enough time to wash out the previous drug, such as carbamazepine; no details of how drugs were escalated; no side effects reported

Shao 1999The study was not of a single non-antiepileptic drug

Shao 2011Not a RCT

Silver 2007The study was not of a single non-antiepileptic drug

Stajcic 1990RCT; 5 weekly peripheral streptomycin/lidocaine versus lidocaine alone injections in TN patients. However, the dropouts were more than 20% of all patients (35%, 6/17)

Wang 2007Not double-blind

Xu 1998Not a RCT

Yan 2011Not a RCT

Zhao 2011Not a RCT

 
Characteristics of ongoing studies [ordered by study ID]
NCT00004431

Trial name or titleRandomized study of L-baclofen in patients with refractory trigeminal neuralgia

MethodsA randomised, double-blind, placebo-controlled, parallel study

ParticipantsAges eligible for study: 18 years to 80 years, both genders

Disease characteristics: idiopathic TN, i.e. paroxysmal attacks of facial or frontal pain lasting a few seconds to less than 2 minutes. Pain has at least 4 of the following characteristics: distribution along one or more divisions of the trigeminal nerve; sudden, intense, sharp, superficial, stabbing or burning quality; pain intensity severe; precipitation from trigger areas or by certain daily activities such as eating, talking, washing the face or cleaning the teeth; between paroxysms entirely asymptomatic; no neurological deficit; attacks are stereotyped in the individual patient; exclusion of other causes of facial pain by history, physical examination and special investigations when necessary; must be uncontrolled or refractory as defined by occurrence of at least 2 paroxysms of pain per day despite conventional treatment with maximally tolerated doses of carbamazepine

Prior or concurrent therapy: no concurrent medication for TN other than carbamazepine, phenytoin and Neurontin (gabapentin)

Concurrent medication for other conditions allowed, on stable dose(s)

InterventionsDrug: L-baclofen

OutcomesNone known

Starting dateJune 1998

Contact informationPittsburgh, Pennsylvania, United States, 15261. Contact: Michael J Soso 412-648-1239

Notes-

NCT01540630

Trial name or titleA Phase IIa withdrawal study of CNV1014802 in patients with trigeminal neuralgia

MethodsA phase IIa placebo-controlled, double-blind, randomised withdrawal study

ParticipantsAges eligible for study: 18 years to 70 years, both genders
Inclusion criteria:
• Male or female aged between 18 and 70 years, with a diagnosis of TN; IHS criteria to be used
• Female patients must be of non-child bearing potential or agree to use an approved form of contraception
• Male patients must agree to use an approved form of contraception
• Body weight > 50 kg for men and > 45 kg for women
• BMI ≤ 34.9
• Capable of giving written informed consent. Informed consent must be obtained prior to the commencement of any study-related procedures
• QTcB either/or QTcF < 450 ms in 2 of 3 ECGs conducted at screening
• AST and ALT < 2 upper limit of normal; alkaline phosphatase and bilirubin < 1.5 upper limit of normal
• Approved concomitant medications must have been stable for at least 3 weeks prior to day 0

InterventionsDrug: CNV1014802
Control: placebo

OutcomesPrimary outcome measures:

  • The number of failures on CNV1014802 versus number of failures on placebo during the double-blind treatment period (time frame: 4 weeks)


Criteria for treatment failure:

  • 50% increase in the frequency of paroxysms compared to the final 7 days of the open-label period
  • 50% increase in the severity of pain experienced in the paroxysms compared to the final 7 days of the open-label period
  • A Patient Global Improvement of Change [sic] rating of much worse/very much worse
  • Discontinuation due to "lack of efficacy"
  • Discontinuation due to an adverse reaction related to study medication or poor tolerability


Secondary outcome measures:

  • Secondary pain endpoints (time frame 4 weeks)
  • Number and severity of paroxysms of pain in the 21-day open-label period, both evoked and spontaneous

Starting dateMarch 2012

Contact informationContact: Kevin Gunn, MD, kevin.gunn@convergencepharma.com

Notes-

 
Comparison 1. Tizanidine versus carbamazepine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number improved (reported by participant on global efficacy scale)111Risk Ratio (M-H, Fixed, 95% CI)0.3 [0.05, 1.89]

 
Comparison 2. Proparacaine hydrochloride 0.5% versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number improved (reported by participant on verbal pain rating scale)147Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.37, 2.99]

 
Comparison 3. Pimozide versus carbamazepine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Improvement (reduction in total TN score)148Mean Difference (IV, Fixed, 95% CI)28.70 [20.88, 36.52]

 
Summary of findings for the main comparison. Tizanidine versus carbamazepine for trigeminal neuralgia

Tizanidine versus carbamazepine for trigeminal neuralgia

Patient or population: patients with trigeminal neuralgia
Settings: unclear, Norway
Intervention: tizanidine versus carbamazepine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

CarbamazepineTizanidine

Immediate improvement in pain relief

Number of participants improved (good/very good efficacy) on a self assessed categorical 'overall efficacy score' (0 = no efficacy to 4 = very good)
Follow-up: 21 days (end of treatment)
667 per 1000200 per 1000
(33 to 1000)
RR 0.3
(0.05 to 1.89)
11
(1 study)
⊕⊕⊝⊝
low1,2
-

50% pain reduction 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (21 days) duration

Quality of life assessment 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (21 days) duration

Adverse effects (not reported)See commentSee commentNot estimable11

(1 study)
See commentAdverse event data collected but no details provided. "Tizanidine was generally better tolerated than carbamazepine, and few side effects were noted"2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

 1Quality of the evidence downgraded for imprecision. This trial had relatively few patients and thus the measure of effect has wide CIs.
2Further downgrading for risk of bias and potential indirectness. Three participants taking tizanidine discontinued taking the optimal dose: two because of lack of efficacy, one due to unrelated disease. Other potential risks of bias were from unclear randomisation, allocation concealment and blinding procedures. Investigators used a non-validated outcome scale.
 
Summary of findings 2. Tocainide versus carbamazepine for trigeminal neuralgia

Tocainide versus carbamazepine for trigeminal neuralgia

Patient or population: patients with trigeminal neuralgia
Settings: unclear, Sweden
Intervention: tocainide versus carbamazepine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

CarbamazepineTocainide

Pain relief (frequency and intensity) from the baseline
0 to 10-point scale
Follow-up: mean 2 weeks
See commentSee commentNot estimable24
(1 study)
See commentA carry-over effect may exist and the report does not provide data from the first phase, so we are unable to analyse data for this outcome1,2

50% pain reduction 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (2 weeks) duration

Quality of life assessment 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (2 weeks) duration

Adverse effectsSee commentSee commentNot estimable24
(1 study)
See comment3 participants reported adverse effects of tocainide3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

 1Four participants in this trial could not tolerate being off the drug and so they had no baseline score.
2This is a cross-over study and it may have carry-over effects.
3Tocainide produced nausea, distal paraesthesias and skin rash in three participants, but the report provides no information about adverse effects of carbamazepine.
 
Summary of findings 3. Proparacaine hydrochloride 0.5% eye drops versus placebo for trigeminal neuralgia

Proparacaine hydrochloride 0.5% eye drops versus placebo for trigeminal neuralgia

Patient or population: patients with trigeminal neuralgia
Settings: inpatients, the United States
Intervention: proparacaine hydrochloride 0.5% versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboProparacaine hydrochloride 0.5%

Immediate improvement in pain relief

Number of participants improved (≥ 2 level decrease in pain on 10-point verbal rating scale, or pain gone or rare)

Follow-up: 30 days
227 per 1000241 per 1000
(84 to 680)
RR 1.06
(0.37 to 2.99)
47
(1 study)
⊕⊕⊝⊝
low1,2
-

50% pain reduction 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (30 days) duration

Quality of life assessment 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable-See commentOnly trial of this intervention was of short (30 days) duration

Adverse effects (not reported)See commentSee commentNot estimable47
(1 study)
See comment-

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

 1Two participants in the control group required medication.
2This trial had relatively few patients and thus the RR has wide CIs.
 
Summary of findings 4. Pimozide versus carbamazepine for trigeminal neuralgia

Pimozide versus carbamazepine for trigeminal neuralgia

Patient or population: patients with trigeminal neuralgia
Settings: outpatients, Venezuela
Intervention: pimozide versus carbamazepine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

CarbamazepinePimozide

Pain relief (TN score)

Follow-up: 8 weeks (outcome measured at 6 weeks)
The mean improvement in pain at 6 weeks in the carbamazepine group was
49.7%
The mean improvement in TN score at 6 weeks in the pimozide group was
28.7% greater (20.88% to 36.52% greater)
Not estimable96
(1 study)
⊕⊕⊝⊝
low1,2
No definition is given for 'improvement' in this paper and we have not therefore presented the number of participants improved

50% pain reduction 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable96
(1 study)
See commentCross-over study, each phase 8 weeks

Quality of life assessment 12 weeks after the start of treatment

Not measured
See commentSee commentNot estimable96
(1 study)
See commentCross-over study, each phase 8 weeks

Adverse effects
The number of participants with adverse effects
Follow-up: 24 weeks
See commentSee commentNot estimable96
(1 study)
See commentStudy report does not provide the number of participants with adverse events for carbamazepine

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

 1This is a cross-over study and it may have carry-over effects. Results are from first period only. Risk of selective reporting bias present: first period TN score available at six weeks, when improvement greatest, but not at end of treatment (eight weeks) (other than in graphical format). Second period TN scores available in graphical format only. Insufficient information to assess selection bias and fully analyse blinding.
2No baseline characteristics provided.