Digital Therapeutics for Nicotine Dependence

According to a WHO 2023 report, tobacco use kills 8.7 million people worldwide each year.¹ Asia has a large population of smokers, including in China, India and Indonesia.² While efforts to stop smoking are being implemented at a global level, 2018 data show that smoking rates in men have plateaued in Japan, South Korea, Singapore and Taiwan, but have steadily increased in China and India.³ In addition, African-Americans and Asians living in Asia have higher death rates than people of European descent, indicating that tobacco smoking is a significant public health problem in Asian countries and that comprehensive efforts to quit smoking are expected.⁴ Many studies have already evaluated the effectiveness of digital interventions for smoking cessation in Asian countries, along with the widespread use of digital devices.⁵

Digital therapeutics (DTx) for nicotine dependence often include the use of smartphones or digital devices to support smoking cessation through disease education and behaviour modification.⁶ While smartphone use varies from country to country, in terms of number of users, China is first, India is second and Indonesia is among the top 10 countries in the world.⁷

In smoking cessation treatments, both physical dependence (addiction) and psychological dependence (emotional/physiological connections) must be treated as pathological conditions.⁸ For physical dependence, pharmacotherapy and nicotine replacement therapies, such as gums and patches, are commonly used to deal with nicotine withdrawal symptoms. In contrast, according to WHO guidelines for smoking cessation, cognitive behavioural therapies (CBT) are recommended for addressing cravings to smoke.⁸ These include strategies such as delaying smoking cigarettes as long as possible, deep breathing, drinking water and engaging in alternative activities to distract from cravings.⁸

Regarding psychological dependence, one approach is acceptance and commitment therapy (ACT), which provides individuals with skills to manage cravings and resist the urge to smoke.⁹ In these psychological interventions, smartphones and digital devices are expected to provide treatment tailored to meet the specific needs of users.¹⁰ There are examples of ACT being incorporated into smartphone apps for smoking cessation.¹¹ The methods and terminology of interventions vary depending on the DTx programme, leading to differences in their effectiveness. It has been suggested that even similar intervention methods may have different treatment outcomes depending on the guidelines followed or the app user’s background.¹² Although the efficacy of DTx has been established in various fields, its clinical application is still in the process of optimisation.¹⁰

In this review, we examine clinical studies of DTx for nicotine dependence conducted worldwide, summarise the current findings and provide suggestions for future research and application.

Definition of Digital Therapeutics

DTx is defined as the therapeutic option that provides treatment for diseases or disorders through software apps delivered on digital devices.⁶ DTx generally requires certification in regulatory affairs.⁶ Table 1 summarises DTx clinical research evidence in the US, Germany and Japan as of May 2024.

Digital Therapeutics in the US, Germany and Japan

Digital Therapeutics in the US

iCanQuit

iCanQuit is a smartphone app based on ACT that teaches skills to cope with the urge to smoke, motivates individuals who want to quit smoking and prevents relapse.¹¹ Developed by the Cancer Institute of New South Wales, iCanQuit is provided to many people free of charge. The app consists of eight levels of intervention content and is approved by the Food and Drug Administration.

QuitGuide

QuitGuide is an app developed by smokefree.gov, which is a smoking cessation resource created by the Tobacco Control Research Branch at the National Cancer Institute in collaboration with tobacco control professionals and smoking cessation experts.¹² It contains four sections, similar to iCanQuit, in terms of intention formation, including setting up a specific and actionable plan for quitting smoking, setting up quitting dates and education on dealing with smoking triggers or resumption. The main difference is that iCanQuit has an acceptance attitude, whereas QuitGuide provides avoidance education.

iCanQuit and QuitGuide were evaluated in a stratified, double-blind, individually randomised clinical trial (RCT) involving 2,415 adult smokers (69% white) from 50 US states. Patients were stratified by daily smoking frequency (≤20 versus ≥21 cigarettes per day), education level (high school or lower versus some college or higher education), race/ethnicity (minority versus non-Hispanic white) and depression screening results, and then assigned to groups using iCanQuit and QuitGuide. The 30-day continuous smoking rate at 12 months for the primary endpoint was 28.2% [293 of 1,040] in iCanQuit versus 21.1% [225 of 1,067] in QuitGuide (OR 1.49; 95% CI [1.22–1.83]; p<0.001).¹²

Pivot

Pivot is a 12-month digital smoking cessation programme based on the US clinical practice guidelines for tobacco cessation.¹³ Pivot includes the Pivot Breath Sensor and Pivot app.

The Pivot app features interactive educational activities, practice quits ranging from 1 to 24 hours, educational games, carbon monoxide (CO) breath sample values and trends viewing, access to a moderated web-based community discussion forum, nicotine replacement therapy ordering and CBT-based counselling with a live human coach.¹³ In a remote pilot RCT, self-reported continuous abstinence using the Pivot app at 52 weeks was 20% (19 of 94 participants) and biochemically confirmed abstinence was 31% (29 of 94).¹³

Digital Therapeutics in Germany

NichtraucherHelden (Non-smoking Hero)

The Non-smoking Hero app is a 3-month smoking cessation programme that includes CBT coaching through coaching videos, supplementary exercises, podcasts, a quit date setting feature and a digital diary function.^14,15 A multicentre, prospective, randomised, open-label study was conducted with 661 participants assigned to the intervention or control group between November 2021 and March 2023. The primary outcome, self-reported 7-day smoking cessation after 6 months was significantly higher in the intervention group compared to the control group.¹⁴ Based on the results, the app has been permanently recorded by the Federal Institute for Drugs and Medical Devices in Germany and is priced at €211.¹⁵

Smoke Free

The Smoke Free smartphone app is a 3-month smoking cessation programme. It includes daily missions to quit smoking, a coach chatbot, virtual pet games, self-help tools, progress indicators and a diary function.¹⁶ A prospective, double-blind, multicentre, randomised controlled intervention using the app with 1,442 participants will be implemented with a 6-month observation period. The app is preliminarily recorded from 29 January 2023 to 28 January 2025 and is priced at €389.¹⁶

Digital Therapeutics in Japan

CureApp SC

CureApp SC provides a therapeutic system to quit smoking in addition to a 12-week standard outpatient smoking cessation programme.⁶ It supports psychological dependence during the period between outpatient visits when a physician is unable to provide support. The DTx system consists of a smartphone app, a Bluetooth-paired mobile exhaled CO checker device and web-based management software for physicians.⁶ In a multicentre RCT, 584 patients were assigned to either the intervention group using the DTx system in addition to a standard smoking cessation programme or the control group using a sham app in addition to a standard smoking cessation programme.¹⁷ The primary outcome, the biochemically validated rate of continuous abstinence from weeks 9 to 24, was significantly higher in the DTx intervention group than in the control group (63.9% versus 50.5%). This DTx add-on effect continued for at least 52 weeks. Based on these results, CureApp SC received its first approval as a DTx app in Japan and was reimbursed by the Ministry of Health, Labour and Welfare in Japan in 2020. The coverage is for patients who have been diagnosed with nicotine dependence by the Tobacco Dependence Screening test, a Brinkman index >200 (for ages ≥35 years) and the desire to quit smoking. It can be used when prescribed by a physician and has an insurance reimbursement cost of ¥24,000.

Ascure

Ascure incorporates a physician’s prescription and smoking cessation outpatient services. Features include all professional guidance provided remotely, follow-up conducted over 24 weeks using a smartphone app and nicotine replacement therapy (an over-the-counter medical patch) delivered to the patient’s home.¹⁸

In a retrospective study using Ascure, continuous abstinence rates during weeks 9–12 and weeks 21–24 were 48.6% and 47.5%, respectively.¹⁸ In a retrospective study focusing on differences in smoking products, such as the use of heated tobacco products (HTPs) or cigarettes, the primary endpoint of continuous abstinence rates during weeks 21–24 were 64.8% for HTP users and 52.6% for cigarette users, indicating that this programme might be a useful smoking cessation option for both groups of users.¹⁹

Clinical Studies Using Digital Therapeutics for Nicotine Dependence

Participants

Significant differences arise from epidemiological factors and patient backgrounds associated with nicotine dependence.^12,20 Epidemiological factors include age, sex, race, region of residence and income.²¹ In the US, where there is considerable racial diversity, clinical studies focused on whether treatment efficacy varies by race. For example, in evaluating the efficacy of iCanQuit, analysed participants were stratified into subgroups, including black men, Native Americans/Alaska Natives, those with low income and those residing in rural areas.^21–24 All primary outcomes were self-reported complete-case 30-day point prevalence abstinence (PPA; i.e. no smoking at all in the past 30 days) at the 12-month follow-up.¹² The results showed that self-reported complete-case 30-day PPA at 12 months ranged from 27% to 30% across all subgroups.^10–13 In addition, studies have been conducted on smoking cessation treatment for various participants as described below.

Reduction of smoking during pregnancy is important because smoking poses significant risks to maternal and infant health.⁸ However, smoking cessation in pregnancy has had limited effectiveness, which has been attributed to patient inability to change generational patterns and environmental factors that increase the risk of smoking.²⁵ On average, self-help interventions nearly doubled the odds of quitting compared with standard care.²⁶

SKIP-IT is a narrative and picture-based smoking cessation intervention based on self-help interventions. A pilot trial showed that it was well accepted and that study retention rates were good.²⁵ However, a feasibility challenge of the study was difficult in follow-up contact because for pregnant women who smoke, smoking cessation interventions may be perceived as moral condemnation. Digital storytelling interventions could help pregnant women to quit smoking, but further research is required to identify alternative methods for studies in these patients.²⁵

For sexual and gender minorities (SGM) assigned to a 90-day Facebook smoking cessation intervention (treatment group) or referred to smokefree.gov (control group), participants reported their smoking status and other health risk behaviours at baseline, 3, 6 and 12 months.²⁷ SGM and non-SGM young adult smokers did not differ in smoking cessation rates, perceptions of, or engagement in a digital intervention; 7-day PPA from smoking was 20.0% for SGMs and 21.6% for non-SGMs at 12 months, (OR 0.95; 95% CI [0.59–1.52]; p=0.83). Health risk behaviour patterns were similar; however, the disparity in physical activity between SGM and non-SGM smokers increased over time. The authors suggested that tailored interventions for SGM young adult smokers could increase focus on SGM experiences that can underlie multiple health risk behaviours, such as discrimination and the normativity of smoking.

For people living with HIV, a two-arm RCT offered eight weekly video-call counselling sessions for smoking cessation, nicotine patches or gum for 8 weeks and a storytelling narrative film; the only difference between the two arms was the content of the film (participants in the treatment arm viewed a smoking cessation film in which six women living with HIV talked about their experience with quitting smoking).²⁰ As the outcome, the 7-day PPA rate by self-report and cotinine test at 3-month follow-up was 43.5% and 23.1% for the treatment arm and control arm, respectively, with no significant difference. However, 3-month prolonged abstinence rates (43.5% versus 15.4%) did show a significant difference (OR 4.23, 95% CI [1.10–16.27]).

Smartphone apps are reported to be effective in treating mental health challenges, particularly anxiety and depression.²⁸ The clinical benefits of such tools, which eliminate some of the barriers involved in receiving traditional face-to-face care (i.e. inconvenient transportation or busy work environments), have been suggested to address health disparities by expanding their use to populations that have difficulty accessing treatment, such as patients with serious mental illness.²⁸ In addition, background conditions of patients may differ depending on the device used, including HTPs or e-cigarettes.^19,29 Assessment of the effectiveness of DTx on existing treatment engagement barriers or patient background differences in each population by setting the optimal target as the participants is an important step to better understand the effectiveness mechanisms of DTx, improve results and optimise its development.

Variety of Intervention Tools as Digital Therapeutics

Interventions for smoking cessation can be effectively delivered through digital platforms. Among the most recently studied tools are smartphone apps, with their efficacy rigorously evaluated, mainly in the US.¹²

Apps and Programmes

Apps for treating nicotine dependence provide texts, images and videos using smartphones or mobile devices, with many of them incorporating essential components of CBT/ACT/USCPG into their programmes.¹² For example, iCanQuit is based on ACT and QuitGuide and Pivot follow USCPG.

In addition to educational content on smoking cessation, programmes often create a quit plan and allow the recording of smoking status. Smoking status may be self-reported, or an objective measurement may be used with an attached testing device. Examples of objective indicators include the Pivot or CureApp SC breath sensor, which measures CO concentration in the exhaled breath.^13,17

Other content also varies widely and characterises each programme. For example, some apps include community access, peer support, human professional counselling, chatbot functionality and educational or virtual pet games.^13,16 In addition, many are used in combination with nicotine replacement therapies and are expected to have a synergistic effect that complements existing therapies.

Although duration of intervention and compliance rates vary across products, these interventions are more effective with frequent or long-term application.³⁰

Text Messages, Movies and Videos

Digital storytelling interventions are based on CBT.²¹ Content should be optimised according to the individual. Digital storytelling may be used in combination with nicotine replacement therapy.

SKIP-IT, a narrative storytelling intervention designed to be delivered via automated text messages, includes the following three key elements:

1. A fictional story of a young pregnant woman, Megan, who tries to stop smoking by overcoming a series of commonplace barriers.
2. Images depicting increasing foetal size and describing its stage of development.
3. A help function to receive a supportive smoking cessation message.

Development of the intervention used the Medical Research Council framework for development of complex healthcare interventions, which combines psychological theories of behaviour change, humanities literature on narrative and storytelling and inductively derived theories. The intervention targets participants’ perceptions of risk, social norms, consequences and self-efficacy, which have been proven to predict smoking behaviour during pregnancy. The intervention incorporates behaviour change techniques aimed at changing these predictors and behaviours.

In one study of DVD-based interventions, participants viewed 60-minute smoking cessation DVDs.³¹ These DVDs represent a substantial enhancement of the written Pathways to Freedom guide (e.g. focus on theoretical models of behaviour change and pharmacological therapies; testimonials from African-American smokers, former smokers and cancer survivors; recent Food and Drug Administration legislation; and new research findings). Topics include deep structure (e.g. African-American smoking statistics, physiological findings, smoking norms, pharmacotherapy concerns, religion/spirituality, family/collectivism, unique stressors, comorbid addiction, environmental influences, targeted marketing, menthol cigarettes, weight concerns, working against the tobacco industry) and surface structure (e.g. race-matched experts, images/graphics of African-Americans). The smoking cessation and relapse prevention content was based on a CBT protocol with demonstrated efficacy among black smokers.

Facebook

Some interventions use Facebook to connect specific target populations with smoking cessation interventions, including content that supports participants through group functions within Facebook. Targeted interventions, such as Alaska Natives and SGM, are being evaluated. In some cases, the Quitline call service is used.³²

CAN Quit (Connecting Alaska Native People to Quit Smoking) is a culturally tailored social media-delivered intervention (via a secret Facebook group) to promote evidence-based smoking treatment uptake and cessation among Alaska Native people who smoke. The need for CAN Quit arose from a long-term collaboration between the Alaska Native Tribal Health Consortium and the Mayo Clinic. Content included digital stories and photos with text provided by the Centers for Disease Control Tips from Former Smokers and the Alaska Native Tribal Health Consortium. Like Tips from Former Smokers, taglines to all content included a call to action for tobacco treatment by providing the State of Alaska toll-free Quitline number, URLs of regional tribal tobacco cessation programme websites and the URL of the smokefree.gov quit smoking resources website.³²

As a 1-month follow-up, among the 10 participants, six reported at least one quit attempt and two ceased smoking (both called Quitline).³² Feedback on the Facebook group revealed an overall social media usability score of 4.1 (SD 0.58; range 3.1–5.0; 1 = strongly disagree, 5 = strongly agree).

Controls

In RCTs for evaluating efficacy of DTx apps, various control groups have been established. For the US ACT-based app iCanQuit, a National Cancer Institute-supplied QuitGuide based on the smokefree.gov website was set as the control.¹¹ The RCT results showed a 4–12% higher success rate of smoking cessation for ACT, depending on the target population. Another control option is to set up a sham control app. Although there is no universal definition of a sham app, it has been described in prior studies as a comparator designed to mimic the DTx (e.g. with a similar design, components and duration of treatment) but with the DTx active principle or component removed or reduced in intensity.³³

In a clinical study of CureApp SC, only the following basic functions were provided in control apps: showing the user guide; entering participants’ profiles and setting a target quit date; displaying the schedule and summary of each visit; showing the date of the next appointment; technical support contact form; and displaying an app version, privacy policy and administrative information.¹⁷ This will make it easier to set up single-blind studies and help verify the effectiveness of only the smoking cessation treatment portion of the app.

Moreover, regular face-to-face treatment without digital tools could also be used as a control.³⁴ In some cases, digital therapy is an add-on to regular treatment or a complement to regular face-to-face care. Therefore, clarifying the difference between the DTx and the control groups is necessary to determine its effect.

Outcomes

The outcome of smoking cessation is often referred to as PPA; however, its duration and timing can vary widely, with measurement periods ranging from 9 to 52 weeks.³³ Given the extended nature of smoking cessation treatment and the potential for relapse, evaluating both the impact of intervention and long-term success rates is crucial. The two main outcome measures are self-reported and biochemically confirmed smoking cessation. The self-reported outcome measure tends to underestimate smoking status, whereas biochemical confirmation is more reliable in its assessment.³⁵ The RCT study using Pivot and CureApp SC assessed biochemically confirmed abstinence validated by exhaled CO level.^13,17 The RCT study using the Non-smoking Hero and Smoke Free apps assessed biochemically confirmed abstinence validated by cotinine saliva test in the secondary endpoint.^15,16

It is important to confirm the efficacy of the intended intervention. For example, for apps, adherence can be analysed using indicators such as the number of app opens, number of interactions with the programme and weeks active with the app.³⁶

Conclusion

DTx is being developed and has undergone clinical studies in many countries worldwide. Nicotine dependence is one of the conditions for which DTx is expected to be highly effective, due to the disease mechanism requiring behavioural change. As DTx is a new treatment method, evidence was generated and the current results were reviewed based on RCT studies from various countries. To safely and reliably use DTx for treatment, it is also necessary to understand the regulatory frameworks that guide its use. With ongoing regulatory revisions in various countries, healthcare professionals should prioritise staying current with information from regulatory authorities and clinical guidelines.

As suggestions for future research and application of DTx, first, it is necessary to integrate current results, analyse treatment targets and their efficacy and maximise efficacy by taking advantage of the customisable nature of DTx to bring it closer to personalised medicine. Second, it is necessary to clarify the benefits of using DTx in terms of medical economics. Now that both conventional and DTx treatment options are available, cost-effectiveness analysis is an essential factor in determining in which cases medical practitioners and patients should choose DTx.³⁷ As it is a new treatment method, there are some barriers to the widespread use of DTx; however, we look forward to the promotion of DTx and the accumulation of treatment evidence in various countries.