Transcranial Magnetic Stimulation Combined With Nicotine Replacement Therapy for Smoking Cessation: A Randomized Controlled Trial

Highlights

• rTMS combined with nicotine increased the chances of abstinence in smokers

• 1 Hz-rTMS on right prefrontal cortex led most of the smokers to stay abstinent

• The stimulation-induced reduction in compulsivity may explain this result.

Abstract

Background

Further evidence suggests that repetitive Transcranial Magnetic Stimulation (rTMS) is an effective method to reduce tobacco craving among smokers.

Hypothesis

As relapse is common within a few days after smoking cessation, we hypothesized that combining the anti-craving effects of rTMS with Nicotine replacement therapy (NRT) to attenuate withdrawal symptoms could increase abstinence rates in smokers with severe nicotine dependence who quit smoking.

Methods

Thirty-seven smokers who failed to quit with the usual treatments were randomly assigned to two treatment groups to receive either active (n = 18) or sham (n = 19) 1-Hz rTMS of the right dorsolateral prefrontal cortex. The day after quitting smoking, each patient combined NRT (21-mg patch) with active or sham rTMS (10 sessions) for 2 weeks. Cessation support was then continued with NRT alone using lower-dose patches. Abstinence rates and self-report craving scales were used to assess the therapeutic results during the combined treatment and for up to 12 weeks after quitting.

Results

At the end of the combined treatment, there were significantly more abstinent participants in the active rTMS group (n = 16) than in the sham rTMS group (n = 9) (P = 0.027). The craving scales analysis revealed that active rTMS (P = 0.011) but not sham rTMS (P = 0.116) led to a significant decrease in the compulsive factor. However, no lasting rTMS effect was found.

Conclusions

1-Hz rTMS combined with NRT improved the success rate of abstinence in smokers during tobacco cessation. The stimulation-induced reduction in compulsivity may explain this result.

Introduction

Tobacco Use Disorder (TUD) is major health issue. It is a well-known risk factor for many diseases and the first cause of preventable death in the world today. There are 1.3 billion smokers worldwide, half of whom will die from diseases caused by smoking [1], [2]. Smoking causes 5 million deaths per year, and if current smoking patterns persist, 10 million smokers per year will be dying by 2025 [1].

Smoking cessation is difficult as only 3% of those quitting without treatment succeed at 6 months [3]. Even though pharmacological treatments or electronic cigarettes can increase quit rates, smoking remains a chronic addictive disease and carries a high rate of relapse [4], [5], [6]. A recent trial with 657 smokers showed low rates of cessation at 6 months with nicotine patches (21-mg patch, one daily), nicotine e-cigarettes or placebo e-cigarettes: verified abstinence was respectively 5.8%, 7.3% and 4.3% [7]. In this study, most participants relapsed within 50 days and the median time to relapse in the nicotine patch group was 14 days, indicating that relapse occurs especially during detoxification [7]. Thus, there is a need to find new therapeutic approaches to help smokers who wish to quit, especially during the first few days of abstinence as it is a critical period for relapse [8]. An ideal treatment would lead to reductions in both cigarette craving (strong subjective desire or irresistible urges with obsessive thoughts) and nicotine withdrawal symptoms (irritability, frustration or anger, anxiety, dysphoric or depressed mood, restlessness, difficulty concentrating, insomnia, decreased heart rate, and increased appetite) [1], [2], [3], [4], [5], [6], [7], [8], [9].

Over the last five years, a growing number of clinical and behavioral studies have indicated that repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive brain stimulation technique, is a promising way to treat Substance Use Disorders (SUD). Further evidence suggests that tobacco craving can be effectively reduced by modulating cortical excitability in the Dorso-Lateral Prefrontal Cortex (DLPFC) using rTMS [10], [11], [12], [13], [14], [15]. Brain stimulation seems to have direct effects on both general craving and cue-induced craving. These data have been consolidated by a recent meta-analysis of the effects of modulating activity in the DLPFC by non-invasive neurostimulation techniques including rTMS. The study provided evidence that stimulation can decrease craving levels in various addictive behaviors [16].

We hypothesized that combining rTMS, to inhibit neuronal firing in areas critically involved in processing craving for cigarettes, with NRT, to attenuate nicotine withdrawal symptoms, may help smokers to quit.

We chose to use the low frequency (LF) range of 1 Hz on the right DLPFC rather than High Frequency (HF) (5–20 Hz) as the stimulation parameter for several reasons:

• First, some studies had reported that abstinence-induced craving to smoke was predicted by increased cerebral blood flow in the right DLPFC, which reflects increased neuronal activity in this cortical region [17],

• Second, some studies had reported a decrease in cortical excitability in the target area after long-train LF rTMS [18], [19], [20], [21],

• Third, both LF right-sided DLPFC and HF left-sided DLPFC stimulation seem to have equivalent anti-craving effects [16].

Thus, in smokers with severe nicotine dependence who failed to quit with the usual treatments, we evaluated the clinical benefits of the combination of LF-rTMS with NRT in a randomized controlled study.