Accepted Manuscript

Clonidine adhesive patch for the treatment of tic disorders: a systematic review and
meta-analysis

Shuai Wang, Yan-zhao Wei, Jianhong Yang, Yuming Zhou, Yi Zheng

PII: S1090-3798(17)30182-4
DOI: 10.1016/j.ejpn.2017.03.003
Reference: YEJPN 2195

To appear in: European Journal of Paediatric Neurology

Received Date: 18 October 2016
Revised Date: 4 February 2017
Accepted Date: 11 March 2017

Please cite this article as: Wang S, Wei Y-z, Yang J, Zhou Y, Zheng Y, Clonidine adhesive patch for
the treatment of tic disorders: a systematic review and meta-analysis, European Journal of Paediatric
Neurology (2017), doi: 10.1016/j.ejpn.2017.03.003.

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ACCEPTED MANUSCRIPT

Clonidine adhesive patch for the treatment of tic disorders:
a systematic review and meta-analysis

Shuai Wang, Yan-zhao Wei, Jianhong Yang, Yuming Zhou, Yi Zheng*

PT
1.Beijing Anding Hospital, Capital Medical University 2. Beijing Institute for Brain Disorders,
Beijing, 100001, China
* Corresponding author. E-mail address: yizheng@ccmu.edu.cn

RI
SC
Objective: The aim of this study was to evaluate the efficacy and safety

of clonidine adhesive patch for tic disorders(TDs).

U
Methods: Medline, Embase, Cochrane central register of controlled trials
AN
and Chinese databases of CBM, CNKI were searched from inception to
M

08.2016 for randomized controlled studies(RCTs), open-label control

studies of clonidine adhesive patch versus other medications or/and
D

placebo for TDs. The cochrane Handbook for Systematic Reviews of
TE

Interventions was used to guide our study.
EP

Results:Five studies involving 1069 participants were included in this

study. Among these studies, one study(N = 437 patients) used placebo as
C

a control and four studies(N = 632 patients) used positive drug controls.
AC

The results of meta-analysis suggested that clonidine adhesive patch may

be as effective as haloperidol or tiapride for TDs. Adverse events (AEs)

were reported in all studies, and the most common AEs of clonidine

adhesive patch were rash(8.9%), lightheadedness(8.0%), dry

mouth(4.0%). The AEs of clonidine adhesive patch were slight.

RI Tiapride. the side effects may limit their D clinical application9. Clonidine is a 2-adrenoceptor agonist that can decrease the functional activity of the noradrenergic system. so it is necessary to develop new pharmacotherapy TE for TDs. and results from further trials are urgently needed to extend the evidence base. repetitive and stereotyped U phonic production and/or motor movements1-3. ACCEPTED MANUSCRIPT Conclusion: These data provide moderate quality evidence that clonidine adhesive patch might be an effective and safe treatment option for TDs. Previous studies have suggested that oral and transdermal clonidine EP was an effective treatment for TDs in children and adolescents with a C safer and better-tolerated profile10-12. Tics are often associated AN with a diminished quality of life and functional impairment4. sudden. SC characterized by fast. despite their efficacy. PT Keywords: Clonidine adhesive patch. Meta-analysis Tic disorders(TDs) are common in children and adolescents. and the clonidine adhesive patch is an adhesive patch that releases clonidine at a relatively invariable rate for one week without “valley or peak” . Haloperidol. Currently. Tic disorders. non-rhythmic. Six RCTs of oral and the AC transdermal Clonidine provided a moderate degree of evidence quality that it was superior to placebo13. TDs have been managed with antipsychotics such as tiapride and M haloperidol6-8.5.

DSM-V1. Inclusion and exclusion criteria EP According to the PICOS principles.uk/prospero/). changed only at weekly intervals. placebo or/and .ac. and (3) the Chinese Classification and Diagnostic Criteria of Mental Disorders (CCMD)20. RI The primary aim of the systematic reviews and meta-analysis was to evaluate the efficacy of clonidine adhesive patch for TDs. easy disposal and a rapid onset of action).15. Intervention (I): clonidine adhesive patch.17.18. The D registration number is CRD42016048163 at the Preferred Reporting TE Items for Systematic Reviews and Meta-Analyses(PRISMA)16. DSM-IV. it might be an ideal medication for TDs. Participants (P): patients with TDs according AC to these diagnostic criteria (1) the International Classification of Diseases-10 (ICD-10)3 (2)the Diagnostic and Statistical Manual of Mental Disorders-III (DSM-III). there is no a systematic review and meta-analysis of the PT clonidine adhesive patch for TDs. Because of its ease of use (self-administered patch. However.york. the following selection criteria were C used to conduct our study. ACCEPTED MANUSCRIPT plasma concentration changes14. and particular SC attention was also paid to the safety and tolerability of clonidine adhesive U patch.crd. AN Methods The protocol used for reviewing clonidine adhesive patch for TDs has M been published online(http://www.

reviews and non-original U research (reviews and meta-analyses) were excluded. treatment period. C Selection of studies and data extraction AC Two reviewers (Wang and Wei) independently screened every record. outcome measures indicators and diagnostic criteria. Data were independently extracted by each reviewer and summarized into simple standard forms. Study design (S): RI RCTs and open-label control studies reporting the efficacy and safety of SC clonidine adhesive patch for TDs. and the adverse PT events(AEs) was assessed by the scales including the Treatment Emergent Symptom Scale (TESS) or other scales19. Case series. AN Search strategy A search of the medical literature using Embase.2016. CNKI was conducted from inception to 08. Outcomes (O): efficacy and safety. the M Cochrane central register of controlled trials and Chinese databases of D CBM. ACCEPTED MANUSCRIPT other treatments. interventions. The terms TE clonidine adhesive patch or transdermal clondine patch or transcutaneous clondine patch and tic disorder[mesh] or tics or tourette syndrome were EP combined for searching relevant studies. Any disagreement . Medline. The data extraction form included the following contents: characteristics of participants. The outcomes of the efficacy were assessed based on the following standard tools: Yale Global Tic Severity Scale(YGTSS). Comparison (C): clonidine adhesive patch versus other medicatons and/or placebo.

Then I2<50%. a fixed AC effect model was employed. For continuous outcomes. AN Statistical methods The RevMan 5. Quality assessment Two reviewers(Wang and Wei) independently assessed the methodological quality of identified studies. standardized mean difference D (SMDs)±95% confidence intervals(CIs)(if different scales were used) or TE mean difference (MDs)±95% confidence intervals(CIs) (if the same scale for each trial was available) were evaluated. selective outcome and other biases. incomplete outcome data. and for dichotomous data. Results Results of the literature search A total of 32 potentially articles in the initial database search were . The I2 C method was used to assess statistical heterogeneity. ACCEPTED MANUSCRIPT was resolved by consensus. blinding. otherwise. The methodological criteria was performed SC according to the Cochrane Handbook for Systematic Reviews of U Interventions20. a random effects model was used21. EP OR and 95%CI wereestimated according to outcome measure. using the risk of bias tool PT under the domains of six aspects containing sequence generation. the RI allocation concealment.3 software was employed to conduct the M meta-analysis.

one study used placebo. Among these studies. because two studies lacked the available data.3%(848/1069). only EP two study provided the details for the methods of blinding(Figure 2). and three studies used the CCMD. all studies were conducted in China. two U studies used tiapride and three studies used haloperidol as a control(Table AN 1). ACCEPTED MANUSCRIPT ascertained. three studies were included in the meta-analysis.10). Participants were aged between 5 and 18 years. two studies used the DSM-IV. (Figure 1) Characteristics of included studies PT 1069 participants were included in our study. The allocation concealment methods were unclear risk in three studies. M Assessment of risk of bias D Three studies only mentioned randomized allocation without the TE description of an adequate method of random sequence generation.12 to 10.36). The proportion of male RI participants was 79. P=0. I2=3%.61 (95% CI: 9.03(95% CI: 3. C Treatment efficacy AC The results for continuous outcomes illustrated that clonidine adhesive patch outperformed haloperidol in the total YGTSS with a WMD of 9. For diagnostic criteria.(Figure 3) .64 to 10. Eventually. and five studies met the selection criteria for the systematic review. and was also superior to tiapride with a WMD of 7. The sample size ranged SC from 92 to 437 cases.42).

Nausea(9. PT however. one study comparing clonidine adhesive patch and tiapride RI showed there was no differece in reducing tic occurring(OR = 2.(Figure 3) SC Du et al (2008) studied the clinical efficacy and safety of clonidine U adhesive patch compared with placebo in a multicenter.28.4%).9%). AN double-blind trial of 437 children and adolescents who suffered from TDs.59].0%). meta-analysis of two studies which used tic symptom control ≧30% as outcome measure showed that there was significant difference between clonidine adhesive patch and haloperidol in reduction of tics(OR = 2. mild dorwsiness and fatigue(3.13.6%). randomized. The most common AC AEs of haloperidol were somnolence(7. Discussion . I2 = 0%).29]. clonidine adhesive patch was more effective in M reducing tic occurring. 4. lightheadedness(8.5%) and anxiety(8.3%). Adverse events(AEs) EP The most common AEs with clonidine adhesive patch were C rash(8.90. 95%CI [1. P = 0.76. we found that clonidine adhesive D patch monotherapy may also superior to haloperidol or tiapride TE monotherapy in reduction of tics. The most frequent clinically AEs for tiapride were somnolence(11. Compared with placebo.44%)and Nausea/vomiting(2. 10. 95%CI [0.0%). The AEs are summarized in Table 2. In our study. dry mouth(4.74. ACCEPTED MANUSCRIPT For dichotomous data.9%).

D YGTSS is a semi-structured clinical interview which is designed to TE assess tic severity. are observed in approximately 6 20% of children worldwide25. sudden. TDs can affect sleep quality. tardive dyskinesia andweight gain. YGTSS is widely used to assess tic severity in clinical trials. C In our study. so it is important to SC develop effective treatmeat for TDs. chronic tic and Tourette s syndrome PT by duration and severity36-38. Previous studies have suggested that U clonidine adhesive patch is a potential effective and safe medication for AN TDs. To our knowledge. we included five studies which used the YGTSS scale as the AC outcome measurement. nonrhythmic vocalisation or motor movement. The scale is consisted of three summary scores including vocal tic score (0–25). The spectrum of TDs ranges from mild to severe. however the use of antipsychotics is limited by their severe AEs such as extrapyramidal reactions. this is the first systematic review and meta-analysis to evaluate the efficacy and safety of clonidine adhesive M patch for TDs. which are characterised by repetitive. TDs are classified into transient tic. and the results suggested that clonidine adhesive patch may be as effective as haloperidol or tiapride for TDs. ACCEPTED MANUSCRIPT TDs. In severe cases. motor tic score (0–25). academic RI achievement and emotional status (including depression or anxiety). and impairment EP scale (0–50). they may cause social withdrawal29. The . Antipsychotic medications were effective in reducing tics.

For clonidine adhesive patch. were D not observed in current studies. it is TE still possible that unpublished studies have not been identified. The results of our systematic review and meta-analysis are EP encouraging. and the limited evidence supports that clonidine adhesive C patch may be an effective and relatively safe medication for TDs. and compared with antipsychotics. ACCEPTED MANUSCRIPT a-2-adrenoceptor agonists guanfacine and clonidine were known to be effective for tics30. their tolerability is better. (2)All SC studies were conducted in China with a relatively small sample (63 437 U cases). (4)Although the search was thorough. clonidine adhesive patch appears to be a promising therapy for children with TDs. and further well-conducted RCTs are required to confirm this conclusion. AC In conclusion. and it does not run through the digestive tract. PT which may improve its potency and cause less AEs. the efficacy of clonidine adhesive patch needs to be AN tested in other ethnicities. with a lack of placebo control. Conflict of interest We declare that we do not have any commercial or associative interest . The long-term M evaluation of outcomes such as low blood pressure and weight gain.31. (3)The short and variable time course of treatment in the identified studies may limit our study. RI There are several limitations of our study: (1) Most of these studies used positive drugs as controls. it is easy to use because it is changed once a week. Therefore.

Zheng and Wang AN have been involved in drafting the manuscript and looking for the most suitable M references. Competing interests The authors declare that they have no competing interests. Yang and Zhou have given substantial U contribution to analysis and interpretation of data. C AC . Zheng has given substantial contributions SC to conception and design. PT Authors' contributions RI Wang and Wei have been involved in revising the manuscript for important intellectual outcome. D Acknowledgment TE This study was financially and ethically supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special EP Funding Support(grand ID: ZYLX 201403). ACCEPTED MANUSCRIPT that represents a conflict of interest in connection with the work submitted. All authors read and approved the final manuscrip.

Jimenez-Shahed and L. Separable noradrenergic and AC dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette syndrome. J. Swerdlow NR. Gillberg C. 7.. C 6. 39:548-55. Brown. Jankovic. Moll GH. J Am Acad Child Adolesc D Psychiatry 2000. TE 5. Wicker M. AN 1993. The ICD-10 Classification of Mental and U Behavioral Disorders Diagnostic Criteria for Research. ACCEPTED MANUSCRIPT References: 1. 186:246-54. Biol Psychiatry 2008. VA:American Psychiatric Publishing Inc. Early administration of tiapride to young rats without long-lasting changes in the development of the dopaminergic . PT 2. double-blind placebo-controlled study of topiramate in the treatment of EP Tourette Syndrome. 5th ed. WorId Health Organization.W. Tochen L. 64: 219 25. American Psychiatric Association. Bongivanni MJ. Kadesjo B. SC 3. Bock N. J Neurol Neurosurg Psychiatry 2010. Geneva: WHO. J. Arlington. 4. Tourette s disorder: epidemiology and M comorbidity in primary school children. A randomised. Diagnostic and statisticalmanual of mental disorders: DSM-5. 81: 70 3. Mathews CA. Grados MA. Latent class analysis of gilles de la RI tourette syndrome using comorbidities: clinical and genetic implications. 2013. Psychopharmacology 2006.

et al.2006. Clonidine treatment of Gilles de TE la Tourette s syndrome. Drugs Today 2014. ACCEPTED MANUSCRIPT system. Can J C Psychiatry 2012. Randomizeddouble-blind multicentre placebo controlled clinical trial SC ofthe clonidine adhesive patch for the treatment of ticdisorders. AC 14. 20(1):80-4. 253(1):1 15. Zhang X. Eur J Paediatr Neurol. Beck B.42(9):807-13. Egolf A. Li Hua-fang. Hardin MA.Jiao F. Doja A. Tic disorders: from pathophysiology to treatment. Clinical observation on treatment of Tourette syndrome in Chinese childr M en by clonidine adhesive patch. RI 10. Arch Gen Psychiatry 1991. Bioequivalence and adhesion evaluation of transdermal clonidine following a change in excipient .J Neurol. Cong S. Canadian guidelinesfor the EP evidence-based treatment of tic disorders:pharmacotherapy. et al. 37:163-7. et al.Ehrlich J. A lvano A . 8. AN 11.15(4):261-5. D 12. 9. 57:133-43. Coffey BJ. 2016. 13.Battaglia G. Pringsheim T.Li AY. 48(4): 324 8. Pharmacopsychiatry 2004. 50(2):159-79. Thiedmann R et al. Zhang X et al.Rampello L. Chin J Integr Med2009.Du Ya-song.Leckman MT. et al. 15. Clinical observation on treatment ofTourette syndrome by integrative medicine. Riddle J. Vance Alasdair. Gorman D. Aust N Z U J Psychiatry 2008. Current pharmacotherapeutic approachesfor the PT treatment of Tourette syndrome. Lu H.

Available from www. Higgins JPT. Liberati A. Riddle MA. Measuring AC inconsistency in meta-analyses. 151: 264 9. et al. 1988. 327: 557 60.org. Green S. Kang H. Thompson SG. Liu meina. Int J Clin Pharmacol Ther. et al. SC 18. Towbin KE. 19. Ort SI. Zhang hongyu. 2016.0. 54(10):816-24. The Cochrane Collaboration. et al. 2003.1. PT 17. J Am Acad D Child Adolesc Psychiatry 1989. Deeks JJ. ACCEPTED MANUSCRIPT supplier. New York. 6:5 AN 9. TE 20. Zhang YF. et al. Hardin MT. Journal of Pediatric Pharmacy 2006. NY: John Wiley& Sons. C 21. Higgins JP. Moher D. Altman DG. Lin yue. Cochrane Handbook for Systematic Reviews of Interventions Version 5.Leckman JF. In: Tourette s Syndrome and Tic Disorders. Leckman JF. Yan WW. Clinical assessment of tic RI disorderseverity. A review of diagnostic and statistical manual of mental U disorder-III. 16. The Yale Global TicSeverity M Scale: initial testing of a clinician-rating scale of ticseverity. Jiao FY. editors.cochrane-handbook. BMJ. Foreign Medical Sciences (Section of Psychiatry) 1981. 28:566-73. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. clinical trial ofthe clonidine adhesive patch for the treatment of ticdisorders. Tetzlaff J. EP 2011. Ann Intern Med 2009. Efficacy of clonidine transdermal . 55 78. 12(6): 8-16. 23. 22.

. Tourette syndrome in children: an RI updated review. Cath DC. Plessen KJ. Tourette syndrome. Kurlan R. Eur EP Child Adolesc Psychiatry 2011. Rothenberger A. lu J. ACCEPTED MANUSCRIPT patch for treatment of Tourette's syndrome in children. 2009. 20(4):155 71.Zhongguo Dang Dai Er Ke Za Zhi. Cognitive-behavioral therapy for childhood repetitive AN behavior disorders: tic disorders and trichotillomania. 26. Roessner V. The management of tics. M 28. et al.Neurol Clin 2015.11(7):537-9.Ganos Christos. U 27. China National Knowledge Infrastructure(CNKI). 51(5):255 64. 20(2):319 28. Shprecher D. Termine C. SC 24(1):15 24. Hedderly T. Comparative Study in Treatment of Tic Disorders by Clonidine and Tiapride. Lee KM. Eur ChildAdolesc Psychiatry 2011. Part I: assessment. D 724:375 83 TE 29. Child Adolesc Psychiatr Clin N Am 2011. et al. et al. Europeanclinical AC guidelines for Tourette syndrome and other ticdisorders. Pediatr Neonatol 2010. Mov Disord 2009. Part II: pharmacological treatment. Chiu TF. 24. 33:115-36. C 30. Cavanna AE. Flessner CA. Martino Davide. 31. European clinical guidelines for Tourette syndrome and other tic disorders. PT 25. Du JC. Ludolph AG. Tics and Tourette syndrome. Adv Exp Med Biol 2012. 20:173-96.

ACCEPTED MANUSCRIPT Figure 1. DSM-IV diagnostic and statistical manual of mental disorder-IV. Flow chart of literature screening and the selection process PT Figure 2. Table 2 The reported AEs of included studies . CCMD Chinese classification and diagnostic criteria of mental disorders. ICD-10 international code of diseases.tics scores after EP treatment) /tics scores before treatment C DSM-IV-TR diagnostic and statistical manual of mental disorder-IV-Text AC Revision. Quality assessment of included studies RI Figure 3. Meta-analysis of symptom improvement assessed by YGTSS (a) compare clonidine adhesive patch with haloperidol for continuous SC outcomes (b) compare clonidine adhesive patch with tiapride for U continuous outcomes (c)compare clonidine adhesive patch with AN haloperidol for dichotomous data (d)compare clonidine adhesive patch with tiapride for dichotomous data M Table 1 General characteristics of included studies D Total Yale Global Tic Severity Scale Score(YGTSS) = Motor Tic Severity TE score(0-25) + Vocal Tic Severity(0-25) + Impairment score (0 50) Decreased YGTSS score= (tics scores before treatment.

ACCEPTED MANUSCRIPT Abbreviations: PT TDs tic disorders RI RCTs randomized controlled studies YGTSS Yale Global Tic Severity Scale SC ICD-10 the International Classification of Diseases-10 U DSM-IV the Diagnostic and Statistical Manual of Mental AN Disorders-IV CCMD the Chinese Classification and Diagnostic Criteria of M Mental Disorders D TESS Treatment Emergent Symptom Scale TE C EP AC .

ACCEPTED MANUSCRIPT PT RI U SC AN M D TE EP C AC .

84 AN [23] syndorme were given 1. C AC .3±1.25mg/film.44±0. 4 YGTSS scale CCMD-3 2016 Tourette 1. 4 YGTSS scale CCMD-2-R U 2009 Tourette 1.0 mg/film TE Lu 6-17 year 160(124) Comparable 20-40 kg were given Tiapride:50mg/d.0 mg/film.84 [10] syndorme were given 1.86 SC >10 years were given (Haloperidol) 2.34 PT >60 kg were given 2mg/d.5 mg/f.63±3. dose.40-60 kg gradually increasing T*:16. maximum dose: C: (58. dose.66 D >60 kg were given 2.5-6mg/d 12 YGTSS scale DSM-IV RI 2006 Tic 1.15±3.0 mg/film M Du 6-18 year 437( 366) Comparable 20-40 kg were given placebo 4 YGTSS scale CCMD-3 2008 Tic 1.38)% EP >60 kg were given 400mg/d.38)% [24] disorder were given 1.63±2.4mg/d.40-60 kg gradually increasing T*:(55.9 mg/f 100mg/d-200mg/d C :16.45±8. maximum dose: C : 36.75 (Tiapride) Kang 5-17 year 119(86 Comparable 20-40 kg were given Haloperidol:1-1. maximum dose: C: 22.0 mg/film.06±7.4mg/d.40-60 kg T*:9.5 mg/f.5 mg/f. C: 11. 2.69±3.5 mg/f. ACCEPTED MANUSCRIPT Table 1 General characteristics of included studies Study Characteristics of Participants Interventions Treatment Outcome Diagnostic Age Sample Comparability Treatment Group Control Group Period Measures Criteria Indication (Male) of Baseline (weeks) Indicators Jiao 5-12 year 261(187) Comparable 20-40 kg were given Haloperidol:1-1.6-10 were Tiapride: T*: 10.40-60 kg gradually increasing T*: 26.43 [11] disorder were given 1.28±2. 12 decreased rate DSM-IV 2015 Tic 1.0 mg/film.5mg/film C:18.54 [22] disorder given 1.05±2.73 >60 kg were given 2mg/d. 2.87±0.0 mg/film. dose.0 mg/film Zhang 5-16 year 92(85) Comparable <6 years were given Haloperidol:1.

- Skin Rash 9/101(8.44%) mild dorwsiness and fatigue SC 3/84 (3.3%) somnolence 4/54(7. - Digestive system . ACCEPTED MANUSCRIPT Table 2 The reported AEs of included studies Clonidine adhesive patch Haloperidol Tiapride Neuromuscular system and Dizziness 2/90(2.0%) 4/170(2.6%) - Cardiovascular system abnormal ECG2/321(0.0%) mild dorwsiness and fatigue dry mouth 5/84 (6. 4/116(3. Nausea 1/38(2.5%) PT Endocrine system . - RI Others Dry mouth 4/101(4.4%) somnolence 10/84 (11.9%) .4%) lightheadedness4/84(4.2%) mild cervital muscle tension anxiety 7/84 (8. weight gain 1/38(2.6%) U AN M D TE C EP AC .8%) insomnia 1/321(0.0%) .6%) Nausea/vomiting 8/84(9.6%) .9%) Somnolence1/321( 0.3%) .3%) mental symptom Lightheadedness 2/25(8.

ACCEPTED MANUSCRIPT Identification Records identified through Additional records identified database searching through other sources PT (n = 32 ) (n = 0 ) RI Records after duplicates removed (n =20 ) SC Screening U Records screened Records excluded based AN (n = 20 ) on title and abstract(n=12) (n = ) M Full-text articles excluded Full-text articles assessed (n = 3) for eligibility Other coparisons(n=1) (n =8) Data repeatedly published Eligibility D (n=2) TE Studies included in Full-text articles excluded qualitative synthesis (n= 2 ) (n = 5 ) Not avaliable data(n=2) C EP Studies included in Included quantitative synthesis AC (meta-analysis) (n = 3 ) From: Moher D. Preferred Reporting Items for Systematic Reviews and Meta- Analyses: The PRISMA Statement. . PLoS Med 6(7): e1000097. doi:10. Altman DG. visit www. The PRISMA Group (2009).org. Tetzlaff J. Liberati A.prisma-statement.pmed1000097 For more information.1371/journal.

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2. and further well-conducted RCTs are required to SC confirm this conclusion. lightheadedness(8. The AEs of clonidine adhesive PT patch were slight. ACCEPTED MANUSCRIPT 1. The results of our study suggested that clonidine adhesive patch may be as effective as haloperidol or tiapride for tic disorders. The clonidine adhesive patch appears to be a promising therapy for children with TDs. dry mouth(4.9%).0%). U AN M D TE C EP AC . The most common AEs of clonidine adhesive patch were rash(8. RI 3.0%).