Pharmacological Approaches to Tobacco Cessation

Editor’s note: This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine. The article in its entirety, including a complete list of references, can be found here.

By Humberto K. Choi, MD, Jorge Ataucuri-Vargas, MD, Charlie Lin, MD, and Amanda Singrey, PharmD

Tobacco use continues to be a major public health problem and a major risk factor for deaths from heart disease and several types of cancer such as lung, head and neck, and colorectal cancers. The prevalence of smoking has declined over the last six decades, to an all-time low of 13.7% in adults in 2018. However, nicotine dependence is still considered a common and significant clinical problem.

A number of effective therapies exist, yet treating patients for tobacco cessation remains a challenge, not only for patients, but also for clinicians, who may not be aware of effective therapies available and may fail to offer treatment. Therefore, it is important for clinicians to familiarize themselves with treatment options they can offer to every smoker.

In this article, we review pharmacological interventions to treat nicotine dependence associated with tobacco use. A previous article addressed behavioral interventions.

First-line therapeutics

Nicotine replacement therapy (NRT)

NRT delivers nicotine in place of smoking or tobacco use to reduce the urge to smoke, as well as associated withdrawal symptoms.

Clinical guidelines recommend NRT as a first-line treatment for tobacco cessation. All commercially available forms (gum, transdermal patch, nasal spray, inhaler and lozenges) are effective in helping smokers increase their chance of quitting successfully. Each product has about the same efficacy, increasing quit rates by 50% to 70% compared with placebo. However, NRT is most effective when the nicotine patch is used in conjunction with a more rapidly absorbed form of NRT (e.g., gum).

In the United States, nicotine replacement products are available over the counter or by prescription. The initial dosing of most products is based on the number of cigarettes smoked daily or on the time to the first cigarette after waking.

Nicotine patches deliver nicotine in a sustained manner throughout the day. More rapidly absorbed forms of NRT such as gum, lozenges, inhalers and spray relieve withdrawal symptoms more quickly than patches. None of the available nicotine delivery systems reproduces the rapid and high levels of arterial nicotine achieved when cigarette smoke is inhaled. This partially explains why nicotine replacement does not completely eliminate the symptoms of withdrawal. A rapid-release of nicotine gum has been formulated and may achieve faster withdrawal relief.

In general, NRT is recommended for two to three months after smoking cessation. However, it may be used through the period when patients are at high risk for relapse. Some smokers may need to use nicotine replacement products indefinitely.

Side effects of nicotine replacement products include nausea, vomiting, abdominal pain, diarrhea, headache, and local irritation depending on the delivery method. Long-term use is not associated with any serious harmful effects, and the risk of dependence on nicotine replacement products is small.

Bupropion

Bupropion is an antidepressant. Its mechanism of action in the treatment of nicotine dependence is not well understood. The main hypothesized effect is the attenuation of withdrawal symptoms (e.g., irritability, anxiety) by mimicking nicotinic effects on dopamine and noradrenaline receptors.

Sustained-release bupropion is an effective aid to help smokers quit with or without depression. It is effective as monotherapy and comparable to the nicotine patch in efficacy. However, the combination of bupropion with NRT is more effective than bupropion or NRT alone.

Bupropion is typically started one to two weeks before a patient’s planned quit date, at a dose of 150 mg daily. After three days, the dose should be increased to 150 mg twice daily for seven to 12 weeks. After this period, bupropion can be continued for up to 12 months, as long as abstinence is attained (maintenance dosage 300 mg/day).

Common side effects are insomnia (decreased if medication given at least 8 hours before bedtime), headache, dizziness, diaphoresis, weight loss, xerostomia, nausea and vomiting, and pharyngitis. There is no increase in the incidence of neuropsychiatric adverse events with bupropion compared with placebo in psychiatric and nonpsychiatric cohorts.

Bupropion is contraindicated in patients with seizure disorder and high-risk conditions such as brain arteriovenous malformation, severe head injury, severe stroke and central nervous tumor or infection.

Varenicline

Varenicline is a partial agonist on two nicotinic acetylcholine receptors. These receptors mediate the release of dopamine, the main neurotransmitter underlying nicotine addiction. The partial agonist action decreases the intensity of withdrawal symptoms. It also reduces nicotine binding to nicotinic acetylcholine receptors that generates rewarding effects, thus reducing the perceived pleasure generated by nicotine consumption. This explains why patients on this medication reduce their cigarette consumption even before their quit date.

Although it is recommended to start varenicline dosing at least one to two weeks before the target quit date, other approaches are acceptable.

Dosing titration starts with 0.5 mg orally once daily for three days, with up-titration every three days to 1 mg orally twice daily until the end of treatment. In patients who develop adverse effects, lower doses of varenicline (e.g., 0.5 mg twice daily) can be used. If well tolerated, varenicline may be used up to six months for continued abstinence.

Varenicline is effective in helping smokers achieve tobacco abstinence. It is superior to placebo, bupropion and NRT. Clinical guidelines recommend varenicline as first-line treatment in conjunction with behavioral therapy for a minimum of 12 weeks. It may be used in combination with NRT to achieve higher rates of abstinence.

Contraindications are a history of severe hypersensitivity reactions and skin reactions to varenicline. Common side effects of varenicline use are nausea, insomnia, abnormal dreams, headache, nasopharyngitis and xerostomia.

Postmarketing reports of neuropsychiatric adverse effects have prompted drug label warnings in many countries. Observational studies, randomized clinical trials and meta-analyses have not confirmed these concerns, leading the FDA to remove the boxed warning in 2015 for both varenicline and bupropion

Second-line therapeutics

Nortriptyline and clonidine are second-line pharmacotherapies. Nortriptyline is a tricyclic antidepressant that has a beneficial effect in smoking cessation.

Clonidine is a selective alpha-adrenergic receptor agonist used to treat hypertension. It is effective for smoking cessation when compared with placebo, but side effects such as dry mouth and sedation limit its use.

It is not clear whether one second-line therapy is more effective than the other. Second-line therapies can be considered when first-line treatments fail or are contraindicated.