Varenicline (Champix): Mechanism of Action, Interactions, and Clinical Relevance

When nicotine binds to α4β2 nicotinic acetylcholine receptors (nAChRs) in the mesolimbic and mesocortical pathways, it induces a dopamine release, stimulating conditioned learning and reward-motivation behaviours. In addition, adaptation and sensitisation cause upregulation of these receptors resulting in the compulsive use of nicotine to maintain homeostasis. [Benowitz 2010]

The principle behind a partial agonist is that in the absence of nicotine during a quit attempt, the agonist activity of a partial agonist would replace nicotine and reduce craving and other withdrawal symptoms.

During a relapse, the antagonist activity would blunt nicotine reinforcement by competing with inhaled nicotine for the same α4β2 and α6β2 nAChR binding sites.

• Varenicline was developed after research on cytisine, a naturally occurring insecticide that binds to the α4β2 nicotinic acetylcholine receptor and was shown to have smoking cessation properties. [Coe et al. 2005]
• Cytisine is a nicotine analogue that is currently available as tablets in Eastern Europe, where it has been available as a smoking cessation aid since 1964. [Hajek et al. 2013]
• Varenicline is a partial agonist with high binding affinity and brain exposure, and as such, the binding results in a dopamine release that is 50% of that released by nicotine; however, due to its long half-life, varenicline also acts as an antagonist by occupying α4β2 and α6β2 receptors and effectively blocking nicotine stimulation. Furthermore, varenicline does not sensitise or upregulate the α4β2 receptor. [Rollema et al. 2007]
• The potent dual agonist-antagonist activity at α4β2 and α6β2 nAChRs is considered the key mechanism that underlies the clinical efficacy of varenicline.

Varenicline reaches maximum plasma drug concentrations typically within 3-4 hours, with steady-state conditions achieved after 4 days. [CHAMPIX® (varenicline) Tablets Prescribing Information]

• At the recommended dosing range, varenicline shows linear pharmacokinetics and is unaffected by food or time of day dosing.
• It is recommended that varenicline is administered for only 12 weeks, although an additional 12 weeks is possible for those who fail to stop smoking while relapse factors are addressed.

Varenicline has approximately 90% bioavailability and undergoes minimal metabolism, with 92% eliminated unchanged in the urine. The elimination half-life is about 24 hours; however, varenicline exposure has been shown to increase 1.5-fold and 2.1-fold in patients with moderate or severe renal impairment. [Faessel et al. 2010]

In vitro interaction studies have shown that varenicline does not inhibit cytochrome P450 enzymes. Furthermore, drug-drug interaction studies show that varenicline does not interact – or influence – commonly administered drugs such as digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, or metformin. [Faessel et al. 2010]

Smoking cessation therapies are more likely to succeed for patients motivated to stop smoking and provided with additional advice and support.

The patient should set a date to stop smoking. CHAMPIX dosing should start 1-2 weeks before this date.

The recommended dose of Varenicline (CHAMPIX) is 1 mg BD following a 1-week titration as follows:

Day 1-3: 0.5 mg OD

Day 4-7: 0.5 mg BD

Day 8 – end of treatment: 1 mg BD

Patients should be treated with CHAMPIX for 12 weeks.

For patients who have successfully stopped smoking at the end of 12 weeks, an additional 12 weeks of treatment with CHAMPIX at 1 mg twice daily is recommended to further increase the likelihood of long-term abstinence.

A retrial of varenicline is indicated for:

• Patients who have tried varenicline previously and failed to quit
• Patients who have succeeded in quitting, but subsequently relapsed.

Alternate dosing methods: 

Flexible approach:

• Patients can begin varenicline dosing and then quit smoking between days 8 and 35 of treatment.

Reduce to Quit:

• A gradual approach to quitting smoking with varenicline for patients who are not able or willing to quit abruptly.
• Patients should reduce smoking by 50% from baseline within the first four weeks with varenicline, by an additional 50% in the next four weeks on varenicline, and continue reducing to reach complete abstinence by 12 weeks.
• Patients should then continue taking varenicline for an additional 12 weeks for a total of 24 weeks of treatment

Low dose varenicline:

• Varenicline 0.5 mg BD
• Less nausea compared with the standard 1 mg BD dose.

High dose varenicline:

Varenicline dosing of up to 5 mg/day showed no additional benefit. [Hajek et al., 2015]

The most common adverse events associated with varenicline are nausea (mild or moderate), insomnia, abnormal dreams, headache, and fatigue/malaise.

Varenicline, like bupropion, also comes with a black box warning for possible neuropsychiatric severe side effects, including changes in behaviour such as hostility, agitation, depressed mood, and suicidal ideation.

However, a large FDA-sponsored retrospective cohort study showed no difference in the rates of psychiatric hospitalisation between those treated with either varenicline or nicotine replacement therapy. [Meyer et al. 2013] Despite these data, the FDA concluded that the evidence was insufficient to remove this black box warning.

• More recently, a meta-analysis of 39 randomised control trials showed no increase in the risk of neuropsychiatric adverse events, including suicide, suicide ideation, depression, or death, compared with a placebo. [Thomas et al. 2015]
• Furthermore, Pfizer has also performed one of the most extensive global clinical trials on smoking cessation drugs [EAGLES] and showed no significant increases in the incidence of serious neuropsychiatric adverse events. [Anthenelli et al. 2016]
• Similar results have been shown in patients with major depressive disorder and stable schizophrenia or schizoaffective disorder with no worsening of disease or significant neuropsychiatric adverse events. [Tonstad et al, 2020].
• The rate of serious neuropsychiatric AEs is higher in smokers with a psychiatric history attempting to quit than those without a psychiatric history. However, this is observed across all treatments, including placebo. Thus, quitting may be a risk factor rather than a specific medication.
• However, clinicians should continue to monitor all patients on varenicline for potential neuropsychiatric adverse events, especially among patients with a current or past psychiatric disorder.

Varenicline is considered the first-line treatment for smoking cessation based on evidence. Varenicline is more effective than placebo, bupropion and NRT in the general population and individuals with comorbid psychiatric conditions, comorbid CVD and COPD. [Tonstad et al, 2020].

A recent study published in October 2021 in JAMA investigated whether combining varenicline with a nicotine patch could improve cessation effectiveness. [Baker et al. 2021]

This study included 5,836 adults who smoked ≥5 cigarettes per day and were treated with either varenicline monotherapy or varenicline plus a nicotine patch for 12 weeks or 24 weeks.

• To determine the long-term abstinence rate, subjects were followed up to 52 weeks to assess cessation effectiveness.
• Combination therapy with varenicline and a nicotine patch was not significantly different (24.3% vs 24.8%; OR 0.99 [95% CI, 0.87 to 1.12]) when compared with those treated with varenicline monotherapy.

Interestingly, this is in contrast to a previous study in 2014, also published in JAMA, which showed that combining varenicline with nicotine replacement therapy was more effective than varenicline monotherapy based on higher abstinence rates at 6 months. [Koegelenberg et al 2014]

A recent meta-analysis showed:

• Varenicline, Bupropion, and NRT alone increased the odds of smoking abstinence better than the placebo.
• Combined interventions were superior to monotherapy
• Varenicline, combined with other interventions, had a better smoking cessation effect.[Guo et al., 2022].

Varenicline shows promise for post-smoking cessation nicotine use in individuals who continue to use nicotine replacement products for years.

Varenicline has also shown some potential for indications beyond smoking cessation, including for alcohol use disorder and other addictions, e.g. cocaine addiction. [Tonstad et al, 2020].

In many randomised trials and real-world observational studies, varenicline has been shown to improve the long-term cessation of smoking substantially.

Although substantial concerns have been raised about the neuropsychiatric safety of varenicline, several trials and meta-analyses have shown that varenicline is safe in adult smokers with and without psychiatric disorders.