Insula deep rTMS and varenicline for smoking cessation: A randomized control trial study protocol

Christine Ibrahim, Saima Malik, Mera S Barr, Daniel M Blumberger, Zafiris J Daskalakis, Bernard Le Foll, Christine Ibrahim, Saima Malik, Mera S Barr, Daniel M Blumberger, Zafiris J Daskalakis, Bernard Le Foll

Abstract

Background: Current approved therapies for smoking cessation have modest long-term effects for abstinence. The insular cortex has been identified by preclinical and clinical studies as a critical target for addiction treatment. Insula functions can be modulated non-invasively using brain stimulation. It is unknown if deep repetitive transcranial magnetic stimulation (rTMS) of the insula can improve smoking cessation of smokers trying to quit using varenicline. Methods: This will be a randomized, double-blind, sham-controlled clinical trial with 50 nicotine dependent smokers looking to quit. They will be randomly assigned to receive either active (10 Hz) or sham insula deep rTMS. Deep rTMS will be administered for 4 weeks (5 days/week). All participants will receive open label varenicline for 12 weeks. The primary outcome measure will be the 7-day point prevalence abstinence at the end of 12 weeks. The secondary outcomes will be Fagerström Test of Nicotine Dependence, Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire of Smoking Urges, expired carbon monoxide measurements, cigarettes smoked per day, point prevalence abstinence at end of 4 weeks, prolonged and continuous abstinence at 6 months. The measures will be collected throughout the 3-month treatment period as well as at the 6-month follow up. Discussion: This trial will test for the first time the impact of deep insula rTMS on smoking cessation in smokers treated with varenicline. This trial will use an H-coil specific to the insula, while previous studies have targeted both the insula and prefrontal cortex. This trial will inform on the utility to combine insula deep rTMS with varenicline to improve smoking abstinence rates. Clinical Trial Registration: Trial registered at https://ichgcp.net/clinical-trials-registry/NCT04083144 (Identifier: NCT04083144).

Keywords: RCT; deep repetitive transcranial magnetic stimulation (dTMS); insula; protocol; randomized controlled trial; smoking cesation; varenicline.

Conflict of interest statement

MB has received research support from the Brain and Behavior Research Foundation (Formerly NARSAD) and is a full-time employee at Otsuka Canada Pharmaceutical Inc. DB receives research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health, United States (NIH), Brain Canada Foundation and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. He has participated in an advisory board for Welcony Inc. ZD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc. and Magventure Inc. He is also on the scientific advisory board for Brainsway Inc. and Gazebo Health Inc. His work has been supported by the National Institutes of Mental Health (NIMH), the Canadian Institutes of Health Research (CIHR), Brain Canada and the Temerty Family, Grant and Kreutzcamp Family Foundations. BF has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects. BF has obtained funding from Indivior for a clinical trial sponsored by Indivior. BF has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. He was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. BF has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), Alkermes and Universal Ibogaine. Lastly, BF has received in kind donations of nabiximols from GW Pharmaceuticals for past studies funded by CIHR and NIH. BF has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and has been consultant for Shinogi. He is supported by CAMH, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Ibrahim, Malik, Barr, Blumberger, Daskalakis and Le Foll.

Figures

FIGURE 1
FIGURE 1
Overview of trial design and outcome measures. Bold indicates our abstinence measures which also includes plasma cotinine measurements. rTMS, repetitive transcranial magnetic stimulation; FTND, Fagerström Test of Nicotine Dependence; CO, Carbon monoxide; TLFB, Timeline Followback; MNWS, Minnesota Nicotine Withdrawal Scale; T-QSU, Tiffany Questionnaire of Smoking Urges; PPA, Point prevalence abstinence; PA, Prolonged abstinence; CA, Continuous abstinence.
FIGURE 2
FIGURE 2
Timeline of Abstinence measures. Abstinence measures are collected at various points during the trial (Week 4, 12, and 26). Measures of various abstinence durations are collected (represented by the red bolded lines). All abstinence measures are collected with self-report and verified with plasma cotinine.

References

    1. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders. Virginia, United States: American Psychiatric Association.
    1. Anthenelli R. M., Benowitz N. L., West R., St Aubin L., McRae T., Lawrence D., et al. (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): A double-blind, randomised, placebo-controlled clinical trial. Lancet 387 (10037), 2507–2520. 10.1016/s0140-6736(16)30272-0
    1. Barker A. T., Jalinous R., Freeston I. L. (1985). Non-invasive magnetic stimulation of human motor cortex. Lancet 325 (8437), 1106–1107. 10.1016/S0140-6736(85)92413-4
    1. Biener L., Abrams D. B. (1991). The contemplation ladder: Validation of a measure of readiness to consider smoking cessation. Health Psychol. 10 (5), 360–365. 10.1037//0278-6133.10.5.360
    1. Brody A. L., Mandelkern M. A., London E. D., Childress A. R., Lee G. S., Bota R. G., et al. (2002). Brain metabolic changes during cigarette craving. Arch. Gen. Psychiatry 59 (12), 1162–1172. 10.1001/archpsyc.59.12.1162
    1. Cahill K., Lindson-Hawley N., Thomas K. H., Fanshawe T. R., Lancaster T. (2016). Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst. Rev. 2016 (5), Cd006103. 10.1002/14651858.CD006103.pub7
    1. Craig A. D. (2009). How do you feel — Now? The anterior insula and human awareness. Nat. Rev. Neurosci. 10 (1), 59–70. 10.1038/nrn2555
    1. Croghan I. T., Trautman J. A., Winhusen T., Ebbert J. O., Kropp F. B., Schroeder D. R., et al. (2012). Tobacco dependence counseling in a randomized multisite clinical trial. Contemp. Clin. Trials 33 (4), 576–582. 10.1016/j.cct.2012.02.014
    1. Dinur-Klein L., Dannon P., Hadar A., Rosenberg O., Roth Y., Kotler M., et al. (2014). Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: A prospective, randomized controlled trial. Biol. Psychiatry 76 (9), 742–749. 10.1016/j.biopsych.2014.05.020
    1. Folstein M. F., Folstein S. E., McHugh P. R. (1975). Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12 (3), 189–198. 10.1016/0022-3956(75)90026-6
    1. Forget B., Pushparaj A., Le Foll B. (2010). Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. Biol. Psychiatry 68 (3), 265–271. 10.1016/j.biopsych.2010.01.029
    1. Hajek P., Stead L. F., West R., Jarvis M., Hartmann-Boyce J., Lancaster T. (2013). Relapse prevention interventions for smoking cessation. Cochrane Database Syst. Rev. 8, Cd003999. 10.1002/14651858.CD003999.pub4
    1. Hajek P., Tønnesen P., Arteaga C., Russ C., Tonstad S. (2009). Varenicline in prevention of relapse to smoking: Effect of quit pattern on response to extended treatment. Addiction 104 (9), 1597–1602. 10.1111/j.1360-0443.2009.02646.x
    1. Heatherton T. F., Kozlowski L. T., Frecker R. C., Fagerström K. O. (1991). The Fagerström test for nicotine dependence: A revision of the Fagerström tolerance questionnaire. Br. J. Addict. 86 (9), 1119–1127. 10.1111/j.1360-0443.1991.tb01879.x
    1. Hughes J. R., Hatsukami D. (1986). Signs and symptoms of tobacco withdrawal. Arch. Gen. Psychiatry 43 (3), 289–294. 10.1001/archpsyc.1986.01800030107013
    1. Ibrahim C., Rubin-Kahana D. S., Pushparaj A., Musiol M., Blumberger D. M., Daskalakis Z. J., et al. (2019). The insula: A brain stimulation target for the treatment of addiction. Front. Pharmacol. 10 (720). 10.3389/fphar.2019.00720
    1. Jasinska A. J., Stein E. A., Kaiser J., Naumer M. J., Yalachkov Y. (2014). Factors modulating neural reactivity to drug cues in addiction: A survey of human neuroimaging studies. Neurosci. Biobehav. Rev. 38, 1–16. 10.1016/j.neubiorev.2013.10.013
    1. Le Foll B., Piper M. E., Fowler C. D., Tonstad S., Bierut L., Lu L., et al. (2022). Tobacco and nicotine use. Nat. Rev. Dis. Prim. 8 (1), 19. 10.1038/s41572-022-00346-w
    1. Le Strat Y., Rehm J., Le Foll B. (2011). How generalisable to community samples are clinical trial results for treatment of nicotine dependence: A comparison of common eligibility criteria with respondents of a large representative general population survey. Tob. Control 20 (5), 338–343. 10.1136/tc.2010.038703
    1. Leeman R. F., McKee S. A., Toll B. A., Krishnan-Sarin S., Cooney J. L., Makuch R. W., et al. (2008). Risk factors for treatment failure in smokers: Relationship to alcohol use and to lifetime history of an alcohol use disorder. Nicotine Tob. Res. 10 (12), 1793–1809. 10.1080/14622200802443742
    1. Lefaucheur J.-P., André-Obadia N., Antal A., Ayache S. S., Baeken C., Benninger D. H., et al. (2014). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin. Neurophysiol. 125 (11), 2150–2206. 10.1016/j.clinph.2014.05.021
    1. Levine J., Schooler N. R. (1986). Saftee: A technique for the systematic assessment of side effects in clinical trials. Psychopharmacol. Bull. 22 (2), 343–381.
    1. Malik S., Jacobs M., Cho S. S., Boileau I., Blumberger D., Heilig M., et al. (2018). Deep TMS of the insula using the H-coil modulates dopamine release: A crossover [(11)C] PHNO-pet pilot trial in healthy humans. Brain Imaging Behav. 12 (5), 1306–1317. 10.1007/s11682-017-9800-1
    1. Molenberghs G., Verbeke G. (2005). Models for discrete longitudinal data. New York, NY: Spinger.
    1. Naqvi N. H., Bechara A. (2010). The insula and drug addiction: An interoceptive view of pleasure, urges, and decision-making. New York, NY: Springer-Verlag.
    1. Naqvi N. H., Rudrauf D., Damasio H., Bechara A. (2007). Damage to the insula disrupts addiction to cigarette smoking. Science 315, 531–534. 10.1126/science.1135926
    1. Perini I., Kämpe R., Arlestig T., Karlsson H., Löfberg A., Pietrzak M., et al. (2020). Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: A randomized controlled trial. Neuropsychopharmacology 45 (5), 842–850. 10.1038/s41386-019-0565-7
    1. Posner K., Brown G. K., Stanley B., Brent D. A., Yershova K. V., Oquendo M. A., et al. (2011). The columbia-suicide severity rating scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am. J. Psychiatry 168 (12), 1266–1277. 10.1176/appi.ajp.2011.10111704
    1. Pushparaj A., Hamani C., Yu W., Shin D. S., Kang B., Nobrega J. N., et al. (2013). Electrical stimulation of the insular region attenuates nicotine-taking and nicotine-seeking behaviors. neuropsychopharmacology 38, 690–698. 10.1038/npp.2012.235
    1. Pushparaj A., Le Foll B. (2015). Involvement of the caudal granular insular cortex in alcohol self-administration in rats. Behav. Brain Res. 293, 203–207. 10.1016/j.bbr.2015.07.044
    1. Robinson S. M., Sobell L. C., Sobell M. B., Leo G. I. (2014). Reliability of the Timeline Followback for cocaine, cannabis, and cigarette use. Psychol. Addict. Behav. 28 (1), 154–162. 10.1037/a0030992
    1. Tiffany S. T., Drobes D. J. (1991). The development and initial validation of a questionnaire on smoking urges. Br. J. Addict. 86 (11), 1467–1476. 10.1111/j.1360-0443.1991.tb01732.x
    1. World Health Organization (2021). Tobacco. Available: .
    1. Zangen A., George M. (2020). 3-Weeks of prefrontal and insular deep TMS combined with cue-induced craving significantly increases smoking abstinence: Results from an international, multi-site, randomized, sham controlled trial. Biol. Psychiatry 87 (9), S129. 10.1016/j.biopsych.2020.02.348
    1. Zangen A., Moshe H., Martinez D., Barnea-Ygael N., Vapnik T., Bystritsky A., et al. (2021). Repetitive transcranial magnetic stimulation for smoking cessation: A pivotal multicenter double-blind randomized controlled trial. World Psychiatry. 20 (3), 397–404. 10.1002/wps.20905
    1. Zangen A., Roth Y., Voller B., Hallett M. (2005). Transcranial magnetic stimulation of deep brain regions: Evidence for efficacy of the H-coil. Clin. Neurophysiol. 116 (4), 775–779. 10.1016/j.clinph.2004.11.008
    1. Zawertailo L., Ivanova A., Ng G., Le Foll B., Selby P. (2020). Safety and efficacy of varenicline for smoking cessation in alcohol-dependent smokers in concurrent treatment for alcohol use disorder: A pilot, randomized placebo-controlled trial. J. Clin. Psychopharmacol. 40 (2), 130–136. 10.1097/JCP.0000000000001172

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit