Pharmacology Update 

Pharmacologic Approaches to Smoking Cessation

Abby M. Bailey, PharmD; Tracy Macaulay, PharmD, BCPS (AQ Cardiology)


Cigarette smokers experience greater rates of morbidity and mortality. Despite the known health risks, use of tobacco products remains high throughout the United States (approximately 19.3% of adults). Tobacco use is associated with higher rates of cardiovascular illness, cardiovascular risk factors (ie, hypertension and atherosclerosis), chronic obstructive pulmonary disease, emphysema, and various types of cancer. Pharmacologic smoking cessation therapies have been used to facilitate abstinence from smoking. This article provides clinicians with instructions for the use of pharmacologic agents for smoking cessation, including considerations for special populations.


Cigarette smokers experience greater rates of morbidity and mortality. Despite the known health risks, use of tobacco products remains high throughout the United States (approximately 19.3% of adults). Tobacco use is associated with higher rates of cardiovascular illness, cardiovascular risk factors (ie, hypertension and atherosclerosis), chronic obstructive pulmonary disease, emphysema, and various types of cancer. Pharmacologic smoking cessation therapies have been used to facilitate abstinence from smoking. This article provides clinicians with instructions for the use of pharmacologic agents for smoking cessation, including considerations for special populations.

Drs Bailey and Macaulay are from UK HealthCare, Department of Pharmacy Services, University of Kentucky, Lexington, Kentucky.

Drs Bailey and Macaulay have no relevant financial relationships to disclose.

Correspondence should be addressed to: Tracy Macaulay, PharmD, BCPS (AQ Cardiology), UK HealthCare, Department of Pharmacy Services, University of Kentucky, 800 Rose St H-112B, Lexington, KY 40536-0293 (temaca2@email.uky.edu).

It is well established that tobacco use is associated with higher rates of cardiovascular illness, cardiovascular risk factors (eg, hypertension and atherosclerosis), chronic obstructive pulmonary disease, emphysema, and various types of cancer.1 Ultimately, cigarette smokers experience greater rates of morbidity and mortality compared with non-smokers of similar age. Despite known health risks, use of tobacco products remains high throughout the United States. Approximately 19.3% of adults report smoking tobacco at an average rate of 16.8 cigarettes per day (range, 15–18 cigarettes per day).2 Because of the great frequency of tobacco use and these patients’ increased use of health care resources, clinicians will inevitably encounter smokers in their practice. This article provides clinicians with tools to helppatients successfully stop tobacco use, including considerations for special populations.

Considerations for Orthopedic Patients

Patients who smoke prior to surgical procedures are at an increased risk of postoperative morbidity and mortality.3 Many complications are caused by the fact that nicotine directly stimulates the adrenal glands and the medulla to maintain a higher sympathetic tone, resulting in higher systolic and diastolic blood pressure, increased heart rate, and increased systemic vascular resistance. Cigarette smoke also increases the percentage of carbon monoxide circulating in the blood, creating carboxyhemoglobin and resulting in less oxygen available for the tissues.4 Both of these contribute to the fact that overall cardiac function is compromised in patients who smoke during the preoperative period. In a large survey performed by Schwilk et al,5 these differences contributed to smokers having a 1.8-times greater risk of respiratory complications (eg, reintubation, laryngospasm, and aspiration) during anesthesia. When smoking and obesity are combined, the risk is 6.3 times higher.5

Other important implications of smoking include interactions with anesthesia and wound healing. Drug interactions between smoking and medications used for general anesthesia and postoperative pain control have been well documented in the literature.4 In terms of pain control, smokers have been found to have a decreased tolerance for pain, indicating a need for larger doses of narcotic medications during the postoperative period.6 Because nicotine also stimulates the acetylcholine receptors, patients who smoke may require larger and more frequent dosing of neuromuscular blockers during procedures.4 Tobacco use complicates perioperative wound healing because it is also known to induce vasoconstriction, reduce collagen production, promote platelet aggregation, create a state of tissue hypoxia, and promote bacterial growth.7

Smoking Cessation Therapies

Smoking is a complex addiction that includes not only chemical dependence, but also behavioral characteristics that make abstinence a multifactorial process. Pharmacologic approaches to smoking cessation are just a portion of the tactics available to patients and clinicians to improve abstinence rates. Medical advice alone can produce a 1-year abstinence rate of 5% to 10%; however, <50% of medical professionals provide cessation advice to their patients because it is often goes unrewarded.8

However, this brief counseling may motivate patients to move toward thinking about quitting or give them the stimulus to finally quit smoking. Self-help groups, including small-group sessions and telephone sessions, have been shown to be better than no intervention at all,9 but large, randomized trials establishing their role in promoting long-term abstinence are lacking. Nontraditional methods, including nicotine vaccines and acupuncture therapy, have been used in cessation efforts, although their use in large-scale trials or in clinical practice is limited.10 Overall, cessation rates are best when cognitive therapy (individual or group counseling) is used in combination with pharmacologic intervention; this combination has shown to have improved outcomes vs using either method alone.11,12

Nicotine Replacement Therapy

Nicotine replacement products have been shown to double the success rate of quitting compared with placebo (eg, cold turkey) approaches.1 Nicotine replacement therapy should help reduce the withdrawal effects, making abstinence easier in those trying to quit. Most nicotine replacement therapy products are available over the counter, with other options, such as nicotine nasal spray or inhalers, available by prescription only.

An important concept when prescribing nicotine replacement therapy is that dosing should be based on the number of cigarettes smoked per day.13 Another crucial concept is that patients are advised not to continue smoking once initiating nicotine replacement therapy. This is different from non-nicotine cessation therapies in that patients can continue to smoke during the titration phase of therapy (generally 1 week).

One of the most commonly used types of nicotine replacement therapy is the transdermal patch, which allows slow and steady release of nicotine. Once-daily patches are available in 7-, 14-, and 21-mg doses. When patches are prescribed as approximately 1 mg per cigarette smoked (ie, a 21-mg patch is used for someone who smokes 1 pack of cigarettes per day), systemic levels of cotine, nicotine’s main metabolite, are similar. Nicotine patches have the advantage of ease of administration and few adverse events (eg, nausea, or sleep disturbances). However, the slow delivery system limits their use in acute cravings, so it may be appropriate to pair this therapy with a short-acting nicotine replacement therapy, such as nicotine gum.13

Nicotine gum and lozenges are available without a prescription in 2- or 4-mg dosages. These short-acting formulations are rapidly absorbed through the buccal mucosa, reaching peak concentrations in approximately 15 to 30 minutes. Recommended starting doses depend on the amount of tobacco used or the degree of addiction; those who smoke more than 25 cigarettes per day or those who smoke their first cigarette <30 minutes after waking should use the 4-mg lozenges. To activate the gum, it must be chewed until a tingling sensation occurs, and then the gum should be placed in the buccal area until the sensation stops. However, the lozenge will dissolve completely in the buccal region.

Major adverse events associated with the use of the chewing gum include nausea, burping, and jaw fatigue. Acidic liquids should be avoided directly before or after use because acidic pH decreases absorption of nicotine. A nicotine lozenge will dissolve entirely; however, the gum will deliver approximately 25% less nicotine because some will remain in the gum after chewing. Gum disposal is also complicated because small children and animals can access the reserves of nicotine gum and, if ingested, can experience nicotine toxicity. The lozenge may be the better choice for patients with dentures, dental implants, or fillings or those who prefer not to chew gum.13

The nicotine inhaler comprises a vaporized nicotine cartridge that is inhaled and absorbed via the buccal mucosa. Each cartridge contains 10 mg of nicotine, with a recommended dose of approximately 6 cartridges per day. Several noted adverse events have been shown to compromise compliance and reduce efficacy. These include a burning sensation, irritation, coughing, sneezing, and indigestion. The nicotine inhaler thought to provide smokers with the hand-to-mouth ritual they are used to with smoking cigarettes; however, this does not address the behavioral aspect of smoking as that behavior is enforced.13

The nicotine nasal spray provides the fastest delivery of nicotine (4–15 minutes). The multi-dose pump delivers 0.5 mg of nicotine per actuation (1 dose=2 actuations). The usual recommended dose is 1 to 2 actuations (0.5–1 mg) per hour (a minimum of 8 doses per day and a maximum of 40 doses per day) for 8 weeks. Although effective, the spray is available by prescription only and is often not tolerated well. Its adverse events including nasal burning, itching, and irritation. For these reasons, it typically has the lowest adherence rate compared with other nicotine replacement therapy formulations.13

As previously stated, data support the use of higher doses of nicotine replacement therapy in heavy smokers. Dale et al14 evaluated the level of nicotine replacement, toxicity, and withdrawal symptoms in participants receiving an 11-, 22-, or 44-mg patch per day. They found that patients who smoked an average of 40 cigarettes per day who were treated with a 22-mg patch vs a 44-mg patch achieved cotine (nicotine metabolite) level replacements of 41% and 99%, respectively. Their study concluded that withdrawal symptom relief was related to the dose of nicotine replacement. Importantly, higher doses were found to be safe and well tolerated.14

Overall, this suggests the current maximum recommended patch containing a dose of 21 mg per day for those who smoke >10 cigarettes per day may be inadequate. Full dosing recommendations are available in Tables 1 and 2; however, dosing and tapering should be individualized to the patient whenever possible.

Nicotine Replacement Therapy

Table 1: Nicotine Replacement Therapy

Additional Pharmacologic Methods for Smoking Cessation

Table 2: Additional Pharmacologic Methods for Smoking Cessation

Non-nicotine Smoking Cessation Therapies

Sustained-release bupropion (Wellbutrin [GlaxoS-mithKline, London, United Kingdom] and Zyban [Glaxo-SmithKline]) has been shown to attenuate withdrawal symptoms and reduce the rewarding effects related to smoking. This is achieved through antagonizing the nicotine receptor sites and inhibiting the reuptake of dopamine and norepinephrine.15 Initiation of bupropion should begin approximately 1 week prior to the quit date for the drug to reach steady state conditions (Tables 1, 2). The recommended treatment duration ranges from 7 to 12 weeks, which can extend to up to 12 months to prevent relapse.

The recommended dosing for Zyban is 150 mg orally twice daily.16 However, Wellbutrin has been studied for use in psychiatric disorders in doses up to 450 mg daily.16 These doses have not been evaluated for smoking cessation and should not be considered when initiating therapy.13 Bupropion can also lower the seizure threshold and its use should be evaluated in patients with an increased risk of seizures, including trauma patients, patients with structural lesions or known seizure disorders, or patients taking medications known to reduce the seizure threshold (eg, haloperidol and local anesthetics such as lidocaine, meperidine, theophylline, and baclofen). Because this product is available by prescription only, its availability can be limited to some patients.

Varenicline is a partial agonist of the nicotinic acetylcholine receptor, which is linked to the addictive properties of nicotine. Its mechanism of action results in attenuation of the rewarding responses of nicotine use. Varenicline should be titrated up over a period of 1 week, with a recommended duration of treatment of 12 weeks (Tables 1, 2).

Varenicline has been associated with gastrointestinal side effects in approximately 8% to 40% of patients, including flatulence, nausea, and vomiting. Recently, the Food and Drug Administration (FDA) issued a black box warning regarding an increased risk of suicidal ideation, aggressive and erratic behavior, and depression noted with its use. Other neuropyschiatric side effects have also been noted, such as vivid dreams.13,17

Comparative Efficacy

Among all smoking cessation therapies (used as monotherapy), varenicline has been shown to be most effective followed by nicotine nasal spray and gum. When assessing combination therapies (varenicline not included) and 6-month abstinence rates, the combination of a nicotine patch and nicotine gum was found to be most efficacious in comparison with a nicotine lozenge, nicotine patch, sustained-release bupropion, nicotine patch plus nicotine lozenge, or bupropion plus nicotine lozenge.18

Treatment Emphasizing Special Populations


Smoking is a direct irritant to the respiratory tract. It creates hyperviscous mucus and impairs cilia function, leading to decreased mucus clearance from airways. Warner et al19 evaluated the postoperative respiratory complications in patients who stopped smoking at least 8 weeks preoperatively and those who stopped <8 weeks preoperatively. It was determined that patients who stopped smoking earlier had a 14.5% complication rate vs 57% in those who stopped <8 weeks preoperatively.

Other studies have demonstrated similar results, indicating that in terms of surgical morbidity, smoking cessation is beneficial when done at least 8 weeks preoperatively.20 No one particular therapy has been shown to be more beneficial in surgical patients. However, it is the job of the clinician to provide counseling, follow-up, and support in terms of nicotine replacement therapy preoperatively to be successful.

In patients already using pharmacologic cessation therapies on admission, therapy dose need not be interrupted during their hospital course unless clinically appropriate (eg, intubation resulting in an inability to crush the sustained-release bupropion tablet or hemodynamic instability perhaps warranting the avoidance of vasoactive nicotine replacement products). In fact, interruption would likely induce withdrawal symptoms and make continued abstinence difficult. However, special consideration should be taken for patients who use the transdermal patch because it is formulated with a foil backing that can become hot during imaging procedures, such as magnetic resonance imaging, causing burns.7 Patients should remove the patch prior to imaging and replace it afterward.


Children and adolescents are most susceptible to tobacco addiction in the second decade of life. Most dependent smokers state that they began smoking before the age of 18 years, with 20% of those stating that they began using tobacco-containing products by age 13 years.21 It is thought that addiction begins early in new smokers and is often evident after only a few cigarettes.22 Although most direct adverse health effects from smoking are not seen until mid-life, those who start smoking during adolescence often smoke more cigarettes per day, are less likely to quit, and are more likely to relapse if they do try to quit.23

When offering smoking cessation to pediatric and adolescent patients, clinicians may prefer to spare children from the use of pharmacologic cessation therapies, given that little literature is available about this patient population. However, behavioral treatments, including counseling and classroom education, show poor long-term success rates (<50%) in pediatric and adolescent smokers.22 Many attribute low success rates in adolescents to untreated chemical withdrawal symptoms and suggest combining pharmacologic and behavioral techniques for maximum success.22 Combination therapy is further supported by low success rates of nicotine replacement monotherapy in adolescents.21 Dosing for this population is similar to that for adults and is based on the amount of cigarettes smoked per day and the extent of their withdrawal symptoms.24

Nicotine replacement therapy use in an adolescent population has been shown to be safe and tolerable. However, short-term quit rates are at best 30%, with long-term abstinence rates even lower.21 Many trials lack randomization, blinding, or placebo controls, which makes long-term abstinence tracking difficult.21 Nicotine replacement therapy products that are traditionally available without a prescription state that they are not for sale to those younger than 18 years. This limits accessibility for pediatric or adolescent patients.25

The safety and tolerability of varenicline has been studied in adolescent patients aged 12 to 20 years.26 The Food and Drug Administration advised the manufacturer to study the drug for efficacy in this patient population. However, since that time, the drug was labeled with a black box warning for neuropsychiatric symptoms, halting many further studies of the drug in this population.27 Overall, bupropion is well tolerated among adolescents, with a similar side effect profile as seen in adults. Benefits to using this therapy have been seen in the management of adolescent smoking cessation, with 6-month abstinence rates as high as 15% to 20%.26,28

Sex Differences

Important differences are found when examining the effect of sex on tobacco-related health outcomes, smoking rates, and cessation treatment efficacy. Likely due to the increased prevalence of tobacco use in women, rates of death related to lung cancer continue to increase in women compared with declining rates in men over the past several decades.29

Sex differences have been noted in the age at which smokers become addicted to nicotine and the degree of nicotine dependence. Several studies have described that men not only begin smoking at a younger age, but also have a higher level of addiction.30 However, lower success rates have been found with using nicotine replacement therapy in women vs men. This may be related to more severe withdrawal symptoms, lower compliance rates with nicotine replacement therapy, and more sensitivity to non-nicotine related aspects of smoking (eg, smells, sights, and sensations of smoking) in women.29 Trials evaluating bupropion and varenicline as monotherapy have demonstrated similar smoking cessation rates in women and men. However, long-term abstinence rates were better in men unless other adjuvant therapies were used for women.31

Depression and Schizophrenia

Smoking rates among patients with psychiatric disorders is much higher than in the general population, and long-term abstinence after cessation is rarer. Among these patients, it is also debated whether quitting smoking will exacerbate an already present psychiatric disorder and which treatments are appropriate. Given the psychiatric warnings with varenicline, this medication should be avoided for this patient population. Experts often recommend a multipronged approach with cognitive interventions, nicotine replacement therapy, and bupropion.32,33

Addiction and Polysubstance Abuse

Many providers are under the impression that treatment for smoking cessation initiated at the same time as treatment for other substance abuse would interfere with success rates. However, several meta-analyses have demonstrated that treatment for tobacco addiction did not interfere with nontobacco addiction outcomes.34 Compared with other patient populations, opioid abusers tend to be highly resistant to nicotine replacement therapies and can have overall low success rates with nicotine replacement monotherapy.35

The Bottom Line

  • Because clinicians are likely to encounter patients who smoke, understanding the different approaches to smoking cessation and the effect of smoking on surgical procedures is essential.
  • Patients should be encouraged to quit smoking 8 weeks prior to their surgical procedures to optimize outcomes.
  • Pharmacologic smoking cessation therapies can double the success rates when compared with placebo (or cold turkey) attempts, and therapies can ameliorate the withdrawal symptoms that make quitting difficult for most long-term smokers.
  • Beacuse morbidity and mortality increase in surgical patients who smoke, special attention should be paid to their pre- and postoperative respiratory and cardiovascular function indicated by their oxygenation status and cardiovascular indices (eg, heart rate, blood pressure, signs of vasoconstriction, and increased vascular resistance).


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Nicotine Replacement Therapy

Patch Gum Lozenge Inhaler
Method of obtainment Over the counter Over the counter Over the counter Prescription
Adult dosing >10 cigarettes per d: 21 mg per d for 4–6 wk 14 mg per d for 2 wk 7 mg per d for 2 wk <10 cigarettes per d: 14 mg per d for 6 wk 7 mg per d for 2 wk >25 cigarettes per d: 4 mg <25 cigarettes per d: 2 mg Wk 1–6:1 piece every 1–2 h Wk 7–9: 1 piece every 2–4 h Wk 10–12: 1 piece every 4–8 h Maximum: 24 pieces per d 1st cigarette <30 min after waking: 4 mg 1st cigarette >30 min after waking: 2 mg Wk 1–6: 1 lozenge every 1–2 h Wk 7–9: 1 lozenge every 2–4 h Wk 10–12: 1 lozenge every 4–8 h Maximum: 20 lozenges per d 10-mg cartridge delivers 4 mg of nicotine per spray Usual: 6–16 cartridges per d Initially: 1 cartridge every 1–2 h
Duration of use 8–10 wk Up to 12 wk Up to 12 wk 3–6 mo

Can wear patch for 16 hrs per d if sleep disturbances occur at night Place between cheek and gum when peppery or tingling sensation appears (approx15–30 chews); repeat chew/place steps until most of the nicotine is gone (ie, taste or tingle does not return; generally 30 min) and place in different areas of mouth Allow to dissolve slowly (20–30 min) Patient should inhale into back of throat or puff in short breaths; do not inhale into the lungs (like a cigarette) but puff as if lighting a pipe; open cartridge retains potency for 24 h; no food or beverages 5 min before or during use
Adverse events Local skin reactions (erythema, pruritus, burning); headache; sleep disturbances (insomnia or abnormal dreams) Jaw fatigue; hiccups; dyspepsia; throat/mouth irritation Nausea; hiccups; flatulence; heartburn; headache; insomnia Mouth and throat irritation; unpleasant taste; cough; rhinitis dyspepsia; hiccups; headache
Advantages Taken once per d; easy to use; provides consistent nicotine levels Gum may satisfy oral craving; can titrate to withdrawal symptoms Gum may satisfy oral craving; can titrate to withdrawal symptoms Mimics the hand-to-mouth ritual of smoking
Disadvantages Does not relieve acute withdrawal episodes; allergic dermatologic reactions can limit its use Chewing gum is difficult for some with dentures or fillings; gum must be chewed correctly to avoid adverse events Significant gastrointestinal side effects can limit its use Should not be used in patients with severe reactive airway disease; nasal and throat irritation

Additional Pharmacologic Methods for Smoking Cessation

Nasal Spray Bupropion Varenicline
Method of obtainment Prescription Prescription Prescription
Adult Dosing 0.5 mg nicotine in 50 mcL of solution Usual: 1–2 doses per h (8–40 doses per d) 1 dose = 2 sprays (1 in each nostril) Each spray delivers 0.5 mg of nicotine Maximum: 5 doses per h or 40 doses per d For best results, initially use at least 8 doses per d 150 mg sustained-release tablet Initial: 150 mg 3 times per d, then increase to 150 mg twice daily Max: 300 mg per d Patients should begin therapy 1–2 wk prior to quit date Days 1–3: 0.5 mg once daily Days 4–7: 0.5 mg twice daily Wk 2–12: 1 mg twice daily Patients should begin therapy 1 wk prior to quit date
Duration of use 3–6 mo Up to 6 mo 12 wks (up to 24 wks in selected patients)

Patients should not sniff, swallow, or inhale through the nose as the spray is being administered Can be used safely with nicotine replacement therapy Should not be used with nicotine replacement therapy
Adverse Events Mouth/throat irritation (burning/peppery sensation); rhinitis; sneezing; coughing; headache Insomnia; dry mouth; rash; constipation; seizure (1/1000) Constipation; flatulence; nausea/vomiting; abnormal dreams; insomnia; headache
Advantages Easily titratable Can be used in patients who use nicotine replacement therapy; easy to use, oral formulation; may be beneficial in patients with coexisting psychiatric problems Easy-to-use oral formulation; reduces cravings; can be more economical when compared to nicotine replacement therapies (depending on insurance coverage)
Disadvantages Should not be used in patients with severe reactive airway disease; nasal/throat irritation Can lower the seizure threshold; cannot be used in patients with anorexia or bulemia nervosa Can cause vivid dreams disturbing sleep; has been associated with worsening preexisting psychiatric illnesses; can cause significant gastrointestinal toxicity


Drs Bailey and Macaulay are from UK HealthCare, Department of Pharmacy Services, University of Kentucky, Lexington, Kentucky.

Drs Bailey and Macaulay have no relevant financial relationships to disclose.

Correspondence should be addressed to: Tracy Macaulay, PharmD, BCPS (AQ Cardiology), UK HealthCare, Department of Pharmacy Services, University of Kentucky, 800 Rose St H-112B, Lexington, KY 40536-0293 (temaca2@email.uky.edu).


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