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Article Author:
Dharminder Singh
Article Editor:
Abdolreza Saadabadi
5/26/2020 12:54:59 PM
For CME on this topic:
Varenicline CME
PubMed Link:


Smoking is a leading cause of morbidity and mortality in the human population and poses as one of the most modifiable risk factors towards preventing human disease. More than 400,000 individuals die prematurely each year in the United States from cigarette use. This statistic represents almost one of every five deaths in the United States. The major diseases caused by cigarette smoking include premature atherosclerosis, coronary artery disease, cerebrovascular disease, aortic aneurysms, chronic airway obstruction, malignancies, and sudden infant death syndrome. It is a preventable risk factor that can be modified through counseling and pharmacotherapy to decrease the burden of disease caused by smoking impacting the human population.

Nicotine is the principal constituent of tobacco responsible for its addictive behavior.[1] A comprehensive approach to education, including cessation advice, pharmacologic assistance, and counseling, can increase smoking cessation success by almost threefold. Various first-line agents have been used to aid in smoking cessation, including nicotine and bupropion. However, they have minimal long-term efficacy.[2] One of the newest agents introduced to the market is varenicline.

The first trials of varenicline began in 2006. Varenicline acts as a partial nicotine receptor agonist similar to cytisine. Varenicline is used as a smoking cessation aid to help people stop smoking in conjunction with education and counseling. Varenicline is the first drug of choice for smoking cessation because it has demonstrated a significant effect in preventing both short-term and long-term relapse.  Varenicline has been shown superior to bupropion and has equal efficacy to nicotine replacement therapy.[3] Varenicline, due to its partial agonist properties, has also been shown to have a lower risk of withdrawal symptoms compared to other drugs.

Mechanism of Action

Nicotine works through the dopamine receptor to cause drug reinforcement. The components of the midbrain that play a pivotal role in drug reinforcement, motility, and associative motor learning include the ventral tegmental area and substantial migration pars compacta.[4] An increase in the release of dopamine from ventral tegmental area neurons onto their targets in the nucleus accumbens contributes to addiction. Nicotine acts on dopaminergic receptors in the ventral tegmental area, causing a burst firing of dopamine neurons leading to drug reinforcement.

Varenicline works by blocking the effects of nicotine on the brain.[5] It is a partial agonist and blocks alpha-4-beta-2 nicotinic acetylcholine receptor subtypes. Through partial agonism, varenicline inhibits dopaminergic activation produced by smoking and decreases the craving and withdrawal syndrome that occurs with cessation attempts. It prevents nicotine stimulation of the mesolimbic dopamine system associated with nicotine addiction.


Varenicline is prescribed only to patients 18 years or older. Varenicline is taken as a tablet and comes in an oral formulation. Varenicline can be taken 0.5 mg orally once daily on days 1 to 3 and increased to 0.5 mg twice daily on days 4 through 7 and 1 mg twice daily after day 8 for 11 weeks. Therapy should be started one week before the target quit date. The medication should be taken with a full glass of water after eating to decrease gastric upset. In patients with renal impairment (CrCL less than 30), a maximum dose of 0.5 mg twice daily is recommended.[5] In end-stage renal disease (ESRD) patients on hemodialysis, a maximum dose of 0.5 mg once daily is recommended. Treatment duration can be up to 6 months and even longer in certain patients. Further trials are needed to determine efficacy and outcomes in those using varenicline beyond 12 months.

Adverse Effects

The most common adverse effects experienced with varenicline are nausea, insomnia, abnormal vivid dreams, and headaches. The adverse effect of nausea can be mitigated by starting at lower doses and up-titrating the dose as tolerated. Patients also complain of disturbed sleep, sleepwalking, agitation, drowsiness, and constipation.[5] Varenicline has also been implicated in specific skin syndromes such as Stevens-Johnson syndrome, erythema multiforme,  and photosensitivity. Renal function also must be monitored as varenicline can cause renal failure and kidney stones. Varenicline may also increase the risk of pancreatitis, and patients taking varenicline should be monitored for abdominal symptoms of pancreatitis.[6]


There is an FDA-mandated warning for severe psychiatric symptoms, including suicidal ideation, as there are reports of such adverse outcomes with varenicline. Patients taking varenicline should have closer therapeutic supervision to monitor for these behavioral symptoms.[6] It is not a contraindication to use varenicline in patients with underlying psychiatric illnesses; however, symptoms should have monitoring for further deterioration. Patients exhibiting worsening of psychiatric behaviors or suicidal ideation should promptly stop varenicline therapy. Serious hypersensitivity reactions or skin reactions to varenicline may occur, and patients exhibiting Stevens-Johnson syndrome or erythema multiforme should be advised not to take varenicline. Take caution and monitor closely if the patient has a history of renal impairment, psychiatric disorder, or seizure disorder.


Varenicline excretion is via the renal route, and thus it is crucial to monitor renal function. Before initiating a patient on varenicline, the clinician should obtain a baseline creatinine.[7] Patients on varenicline require close monitoring for signs or symptoms of depression, agitation, behavior changes, skin reactions, or suicidal ideation. Smoking in pregnancy is widespread and poses a significant public health issue.  Varenicline and other newer pharmacologic agents have not been studied well and generally are not used to promote cessation during pregnancy. Because varenicline is a relatively new drug on the market, there are not many studies that have shown strong evidence for either major positive or negative outcomes associated with gestational use of varenicline. Currently, controlled studies have shown no evidence of increased risk of spontaneous abortion, major congenital malformation, or intrauterine death.  Due to limited efficacy and pregnancy safety date, varenicline is not a routine recommendation as a smoking cessation aid for pregnant women. Further studies are necessary for this topic. If a patient has been exposed to varenicline inadvertently during the first trimester, the recommendation is to perform a detailed fetal anomaly scan.[8]


There are currently no antidotes to varenicline. If serious adverse effects, including psychiatric conditions or skin hypersensitivity reaction, occur, discontinue varenicline immediately.[8] Varenicline therapy may stop abruptly with no side effects, and there is no need for taper. Evaluation of prolonged exposure to varenicline in adults has not revealed any alteration of hematological, biochemical, and anatomicopathological parameters.

Enhancing Healthcare Team Outcomes

Therapy with varenicline requires an interprofessional approach.

Smoking remains a significant public health problem, and despite decades of research, there is no definitive solution to help people quit this social habit. There are many drugs on the market touted to help people quit smoking, but none works consistently, and relapse rates are high. Because smokers can present with various medical disorders, the onus is on healthcare workers to educate them on the dangers of smoking. Varenicline is a relatively new drug on the market, and data indicate that it can help people quit smoking in the short term; however, the patient also has to be provided with psychosocial support at the same time.[9][10]


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[8] Zaccarelli-Magalhães J,Moreira N,Sandini TM,de Abreu GR,Sánchez-Sarmiento AM,Ricci EL,Fukushima AR,de Souza Spinosa H, Evaluation of Prolonged Exposure to Varenicline in Adult Rats: Haematological, Biochemical and Anatomopathological Studies. Basic     [PubMed PMID: 28944993]
[9] Klemperer EM,Hughes JR,Naud S, Study characteristics influence the efficacy of substance abuse treatments: A meta-analysis of medications for smoking cessation. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2018 Oct 20     [PubMed PMID: 30380134]
[10] Goulden R,Nguyen QD,Azoulay L, Risk of Bias in Study of Varenicline and Cardiovascular Outcomes. American journal of respiratory and critical care medicine. 2018 Sep 1     [PubMed PMID: 29708402]