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Repetitive Transcranial Magnetic Stimulation in Patients With Opioid Use Disorders

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ClinicalTrials.gov Identifier: NCT03229642
Recruitment Status : Recruiting
First Posted : July 25, 2017
Last Update Posted : March 29, 2018
Sponsor:
Collaborator:
Ministry of Science and Technology, Taiwan
Information provided by (Responsible Party):
Tzu-Yun Wang, National Cheng-Kung University Hospital

Brief Summary:

Opioid use disorder (OUD) is prevalent and causes substantial health and social burdens. Although evidence have showed the effectiveness of opioid agonist maintenance therapy in OUD, high drop-out rate and the requirement of continuing use of opioid agonists are the major problems. Therefore, to develop novel treatment for OUD is important.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method of brain stimulation used to treat a variety of neuropsychiatric disorders. Recent studies showed that there may be potential therapeutic effects in rTMS for addictive disorder, including reducing craving and substance use severity. The underlying mechanisms of rTMS in treating addictions may involve increased dopamine function in corticomesolimbic brain circuits and modulation of neural activity in brain circuits that relevant to addiction. However, the treatment results of rTMS in OUD were lacked, and the analysis in functional brain imaging study, neuropsychological tests and other potential biomarkers under rTMS treatment were limited, too.

Thus, the investigators will conduct the add-on double-blinded, sham-controlled study rTMS treatment in 40-60 patients with OUD under methadone maintenance therapy. Patients will be allocated to active and sham rTMS in a 1 : 1 ratio, and participants will receive rTMS on the left dorsolateral prefrontal cortex (DLPFC) (15 Hz frequency, 4 seconds per train, inter-train interval of 26 seconds, 40 trains per session, total 11 sessions in 4 weeks). The treatment response, urine drug tests, craving scales and side effects to evaluate the therapeutic effects of rTMS will be examined. Neuropsychological assessments, functional magnetic resonance imaging (fMRI) and tests for potential biomarkers of immune parameters will also be measured during 12-weeks follow up. The study results will provide the important data in whether rTMS add-on methadone maintenance therapy is able to 1) reduce heroin use; 2) reduce craving for heroin; 3) be an effective treatment for OUD, and 4) be associated with improvement in fMRI, biological markers and psychological tests.


Condition or disease Intervention/treatment Phase
Transcranial Magnetic Stimulation Heroin Dependence Device: Active rTMS Device: Sham rTMS Not Applicable

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Opioid Use Disorders: Analysis of Clinical Outcomes, Functional Magnetic Resonance Imaging, Biomarkers, and Neuropsychological Tests
Actual Study Start Date : August 1, 2017
Estimated Primary Completion Date : August 2018
Estimated Study Completion Date : August 2018

Arm Intervention/treatment
Experimental: Active rTMS treatment
The rTMS parameters were as follows: 15Hz frequency, pulse intensity 100% of the rMT, 60 pulses per train, inter train pause of 26 sec, 40 stimulation trains, and 2400 total pulses for a total duration of 20 min. The patients received one rTMS session per day during the first five days of treatment, and then twice a week for the following three weeks, for a total of 11 rTMS sessions.
Device: Active rTMS
The stimulator device was a Magstim super rapid magnetic stimulator (Magstim Company, Ltd., Wales, United Kingdom) with 4 booster modules equipped with a 70-mm air-cooled figure-eight-shaped coil. We performed rTMS on the left dorsolateral prefrontal cortex (DLPFC).The TMS parameters were as follows: 15Hz frequency, pulse intensity 100% of the rMT, 60 pulses per train, inter train pause of 26 sec, 40 stimulation trains, and 2400 total pulses for a total duration of 20 min. The patients received one rTMS session per day during the first five days of treatment, and then twice a week for the following three weeks, for a total of 11 rTMS sessions. The sham group was administered rTMS with the same parameters, but using a figure-of-eight sham coil.

Sham Comparator: Sham rTMS treatment
The rTMS parameters were as follows: 15Hz frequency, pulse intensity 100% of the rMT, 60 pulses per train, inter train pause of 26 sec, 40 stimulation trains, and 2400 total pulses for a total duration of 20 min, with a figure-of-eight sham coil. The patients received one rTMS session per day during the first five days of treatment, and then twice a week for the following three weeks, for a total of 11 rTMS sessions.
Device: Sham rTMS
The stimulator device was a Magstim super rapid magnetic stimulator (Magstim Company, Ltd., Wales, United Kingdom) with 4 booster modules equipped with a 70-mm air-cooled figure-eight-shaped coil. We performed rTMS on the left dorsolateral prefrontal cortex (DLPFC).The TMS parameters were as follows: 15Hz frequency, pulse intensity 100% of the rMT, 60 pulses per train, inter train pause of 26 sec, 40 stimulation trains, and 2400 total pulses for a total duration of 20 min. The patients received one rTMS session per day during the first five days of treatment, and then twice a week for the following three weeks, for a total of 11 rTMS sessions. The sham group was administered rTMS with the same parameters, but using a figure-of-eight sham coil.




Primary Outcome Measures :
  1. The treatment retention rate [ Time Frame: 12 weeks ]
    To compare the treatment retention rate between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  2. The treatment attendance rate [ Time Frame: 12 weeks ]
    To compare the treatment attendance rate between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  3. Urinary assessment [ Time Frame: 12 weeks ]
    Urinary morphine examinations will be measured at every visit. The rate of positive urinary morphine tests will be compared between active and sham rTMS groups in 12 weeks of follow up.


Secondary Outcome Measures :
  1. fMRI [ Time Frame: 5 weeks ]
    The fMRI scan will be done at initial screen and at week 5 (after rTMS treatment) with resting-state fMRI and task activation fMRI with an IGT.

  2. Immunological markers [ Time Frame: 12 weeks ]

    Twenty milliliters of blood will be drawn from each participant. Plasma will be isolated from the whole blood after it has been centrifuged at 3000 g for 15 min at 4℃, and the will be immediately stored at -80℃. Cytokine and BDNF levels will be quantified using an antibody pair assay system (Flexia; BioSource Intl., Camarillo, CA). Sample processing and data analysis will be done according to the manufacturer's instructions.

    The immunological parameters that we intend to analyze will include TNF-α, CRP, TGF-β1, IL-8, Il-10 and BDNF. The immunological markers will be measured from baseline to endpoint (week 12) in each patient group.


  3. Wechsler Memory Scale - third edition(WMS-III) [ Time Frame: 12 weeks ]
    WMS-III will be tested at initial screen and at the end of study (week 12) and compared between the active and sham rTMS groups.

  4. Wisconsin Card Sorting Test(WCST) [ Time Frame: 12 weeks ]
    WCST will be tested at initial screen and at the end of study (week 12) and compared between the active and sham rTMS groups.

  5. Continuous performance tests(CPT) [ Time Frame: 12 weeks ]
    CPT will be tested at initial screen and at the end of study (week 12) and compared between the active and sham rTMS groups.

  6. Side effect checklist [ Time Frame: 12 weeks ]
    To compare the side effect profiles using side effect checklist between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  7. Assessment of craving [ Time Frame: 12 weeks ]
    To compare the severity of craving between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  8. 17-item Hamilton Depression Rating Scale (HDRS) [ Time Frame: 12 weeks ]
    To compare the mood symptoms between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  9. World Health Organization's Quality of Life Assessment-Brief of Taiwan (WHOQOL-BREF TW) [ Time Frame: 12 weeks ]
    To compare the life quality (using WHOQOL-BREF TW) between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  10. Family APGAR index [ Time Frame: 12 weeks ]
    To compare the level of family support (using family APGAR index) between the active and sham rTMS groups from baseline to endpoint (12 weeks).

  11. The Opiate Treatment Index (OTI) [ Time Frame: 12 weeks ]
    To compare the OTI tween the active and sham rTMS groups from baseline to endpoint (12 weeks).

  12. Clinical Global Impressions (CGI) [ Time Frame: 12 weeks ]
    To compare the CGI tween the active and sham rTMS groups from baseline to endpoint (12 weeks).

  13. Barratt Impulsiveness Scale(BIS) [ Time Frame: 12 weeks ]
    To compare the BIS tween the active and sham rTMS groups from baseline to endpoint (12 weeks).



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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent by patient or legal representative.
  2. Male or female patient aged ≧20 and ≦65 years.
  3. A diagnosis of OUD according to DSM criteria made by a specialist in psychiatry.
  4. Patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.

Exclusion Criteria:

  1. Women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study.
  2. Females who are pregnant or lactation.
  3. Other major Axis-I DSM-IV diagnosis other than opioid use disorder or amphetamine use disorder, except for tobacco use disorder.
  4. Current evidence of an uncontrolled and/or clinically significant medical condition, e.g.,cardiac, hepatic and renal failure that would compromise patient safety or preclude study participation.
  5. History of seizure or epilepsy.
  6. History of neurological diseases or traumatic brain injury.
  7. Suicidal attempts or risks during screen or study period.
  8. Presence of devices, e.g. pace-makers, cochlear prosthesis, neuro-stimulators, magnetic cochlear prosthesis, intraocular metallic fragments.
  9. Patient has received electroconvulsive therapy (ECT) within 4 weeks prior to the first intervention of the double-blinded treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03229642


Locations
Taiwan
National Cheng Kung University Hospital Recruiting
Tainan, Taiwan
Contact: Tzu-Yun Wang    +886-6-235-3535 ext 4200    tzuyun0105@hotmail.com   
Principal Investigator: Tzu-Yun Wang         
Sponsors and Collaborators
National Cheng-Kung University Hospital
Ministry of Science and Technology, Taiwan

Responsible Party: Tzu-Yun Wang, Doctor, National Cheng-Kung University Hospital
ClinicalTrials.gov Identifier: NCT03229642     History of Changes
Other Study ID Numbers: B-BR-105-094
First Posted: July 25, 2017    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Tzu-Yun Wang, National Cheng-Kung University Hospital:
repetitive transcranial magnetic stimulation
opioid use disorder
craving
functional magnetic resonance imaging
neuropsychological tests

Additional relevant MeSH terms:
Heroin Dependence
Opioid-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents